Clinical trial NCT03075904
Conditions: Pemphigus Pemphigus Vulgaris Pemphigus Foliaceus
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2017-07-18; Completion date: 2019-01-16
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This was a multicenter, open-label safety study to determine the dose regimen of SYNT001 (ALXN1830) administered intravenously in participants with pemphigus (vulgaris or foliaceus).

Detailed description:
This study planned to evaluate 2 cohorts: up to 8 participants to receive 5 weekly intravenous (IV) doses of ALXN1830 at 10 milligram/kilogram (mg/kg) (Cohort 1) and up to 12 participants to receive 3 x 30 mg/kg weekly doses of ALXN1830 IV (loading) followed by 5 x 10 mg/kg doses of ALXN1830 IV every other week or 10 weekly doses of ALXN1830 IV (maintenance) (Cohort 2).

This study was terminated after the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy were characterized in participants with pemphigus at a single dose level (10 mg/kg) in Cohort 1, before any participants were enrolled in Cohort 2.

The study consisted of 3 periods: Screening, Treatment, and Follow-Up.

Arms: arm 1: Participants received 5 doses of ALXN1830 10 mg/kg administered weekly. arm 2: Participants were to receive 3 doses of ALXN1830 30 mg/kg administered weekly (loading) followed by 5 doses of ALXN1830 10 mg/kg administered every other week or 10 weekly doses of ALXN1830 IV (maintenance).
Interventions: intervention 1: ALXN1830
Intervention descriptions: intervention 1: Administered via IV infusion.

Protocol documents:
Prot_001.pdf: 
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, 
and Activity Study of SYNT001 in Subjects with Chronic 
Pemphigus (Vulgaris or Foliaceus) 
Unique Protocol ID:
NCT Number:
Date of Protocol:  
SYNT001-103
NCT03075904
18 September 2018 


Clinical Study Report 
 
SYNT001-103 
16.1 Study Information 
 
 
Page 1 of 1 
 
 
Alexion Confidential 
 
1. 
PROTOCOL AND AMENDMENTS 
 
• SYNT001-103 Protocol Version 1, 18 January 2017 
• SYNT001-103 Protocol Amendment 1.1, 21 March 2017 
• SYNT001-103 Protocol Amendment 1.1 SOC, 21 March 2017 
• SYNT001-103 Protocol Amendment 2.0, 12 April 2017 
• SYNT001-103 Protocol Amendment 2.0 SOC, 12 April 2017 
• SYNT001-103 Administrative Letter 1.0, 10 May 2017 
• SYNT001-103 Administrative Letter 2.0, 11 August 2017 
• SYNT001-103 Administrative Letter 3.0, 21 September 2017 
• SYNT001-103 Protocol Amendment 3.0, 10 October 2017 
• SYNT001-103 Protocol Amendment 3.0 SOC, 10 October 2017 
• SYNT001-103 Administrative Letter 4.0, 02 March 2018 
• SYNT001-103 Protocol Amendment 4.0, 08 June 2018 
• SYNT001-103 Protocol Amendment 4.0 SOC, 08 June 2018 
• SYNT001-103 Protocol Amendment 5.0, 18 September 2018 
• SYNT001-103 Protocol Amendment 5.0 SOC, 18 September 2018 


Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Syntimmune, Inc. and 
any unauthorized use or disclosure of such information without the prior written authorization of 
Syntimmune is expressly prohibited. 
Syntimmune, Inc. 
CLINICAL STUDY PROTOCOL 
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and Activity 
Study of SYNT001 in Subjects with Chronic Pemphigus (Vulgaris or 
Foliaceus)  
Protocol Number: 
SYNT001-103 
 
IND Number: 
132727 
 
Study Drug: 
SYNT001 
 
Sponsor: 
Syntimmune, Inc. 
 
257 Park Avenue South 
 
15th Floor 
 
New York, NY 10010 
 
Medical Monitor: 
 
43 Thorndike Street, Cambridge, MA 01240 
 
Phone:
 extension
 
Mobile:
 
 
  
 
Original Protocol: 
18 January 2017 
 
 
 
 
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SPONSOR SIGNATURE 
 
 
I have read and approve this protocol.  My signature, in conjunction with the signature of the 
Investigator, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Conference on Harmonisation Guideline for Good Clinical Practice (GCP), 
the Code of Federal Regulations (CFR), and the ethical principles that have their origins in the 
Declaration of Helsinki. 
 
 
Date of Signature 
(DD Mm YYYY) 
 
25/01/2017
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PROCEDURES IN CASE OF EMERGENCY 
 
Serious Adverse Events  
Any death, serious adverse event (SAE)* occurring in a subject while receiving study drug or 
within 7 days of receiving study drug, even though the event may not appear to be study drug 
related, must be promptly reported (within 24 hours) by telephone or electronic communication to 
the sponsor (or designee).   
 
Emergency Contact Information  
 
 
 
 
SAE CRITERIA 
* A serious adverse event (SAE) is any untoward medical occurrence that at any dose results in any of the following outcomes, regardless of 
relationship to study drug (see Section 11.3.1, Serious Adverse Events for additional information): 
• 
Death 
• 
Life-threatening adverse drug event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability/ incapacity 
• 
A congenital anomaly/birth defect 
• 
An important medical event that may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above. 
 
For SAE reporting: 
For any other questions or to  
contact the Medical Monitor: 
Medpace Clinical Safety  
Medpace SAE hotline:  
Telephone: 
dial  or 
 dial  
Facsimile: 
 or 
 
 
Mobile phone
 
Office phone: 
ext.
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 INVESTIGATOR SIGNATURE 
 
I have read and approve this protocol.  My signature, in conjunction with the signature of the 
sponsor, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Conference on Harmonization Guideline for Good Clinical Practice (GCP), 
the Code of Federal Regulations (CFR), and the ethical principles that have their origins in the 
Declaration of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations.  
 
 
Investigator Signature 
 
 
Date of Signature 
(DD Mm YYYY) 
Name of Investigator (please print) 
 
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1 
SYNOPSIS 
Study title 
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and Activity Study of 
SYNT001 in Subjects with Chronic Pemphigus (Vulgaris or Foliaceus) 
Protocol number 
SYNT001-103 
Number of study 
centers 
Approximately 10 (US) 
Clinical phase  
Phase 1b 
Study background 
SYNT001, a humanized, affinity-matured IgG4-kappa monoclonal antibody 
(mAb), blocks IgG and IgG immune complex (IC) interactions with the neonatal 
Fc receptor (FcRn) and thereby the major functions of FcRn in protecting IgG 
and IgG immune complexes from degradation and their role in downstream 
signaling events. Specific and high affinity blockade of FcRn with SYNT001 has 
been shown to increase the catabolism of IgG and IgG IC in healthy volunteers. 
This predicts that SYNT001 will also accelerate degradation of endogenous 
circulating IgG autoantibodies and IgG-antigen IC specifically involved in the 
pathogenesis of autoimmunity.  Blocking FcRn interactions with IgG containing 
immune complexes further predicts that SYNT001 will have consequences for 
innate and adaptive cellular immunity.  In the first instance, blocking multimeric 
IgG IC interactions with FcRn within antigen presenting cells will result in 
inhibition of IC-stimulated inflammatory cytokine production and release by 
these cells.  In addition, as FcRn determines the intracellular itinerary of IgG 
immune complexes within and among compartments important in cellular 
immunity, it is further anticipated that SYNT001 will block antigen processing 
and presentation of antigens contained within IC that otherwise lead to CD8+ and 
CD4+ T cell activation. Thus, SYNT001 will specifically target immune 
functions associated with IgG and IC that are involved in many autoimmune 
conditions and dismantle their ability to cause disease. 
SYNT001 targets mechanisms contributing to pathology in a variety of IgG-
mediated autoimmune disorders, including warm antibody autoimmune 
hemolytic anemia (WAIHA), pemphigus, and chronic inflammatory 
demyelinating polyneuropathy (CIDP).     
While current treatments for certain autoimmune disorders including chronic 
steroids, immunosuppressants, intravenous immunoglobulin (IVIG), 
plasmapheresis, and anti-CD20 monoclonal antibodies (mAbs), such as 
rituximab, can be effective, they are frequently associated with significant 
adverse effects, and delayed or non-durable responses.  
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin 
and mucous membranes. Autoantibodies are thought to play an important 
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pathogenic role in the mucosal and cutaneous manifestations in patients with 
pemphigus. Administration of SYNT001, leading to a significant decrease in 
total IgG, and thereby a corresponding decrease in the level of the pathogenic 
autoantibodies as well as the ICs to which they are associated, should lead to a 
decrease in the mucosal and cutaneous manifestations in subjects with 
pemphigus. Moreover, the ability of SYNT001 to reduce circulating immune 
complexes (CICs) and the associated innate and adaptive immune responses may 
allow for further sustained disease modification. 
Study rationale 
This study is being conducted to further evaluate the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of 
intravenous (IV) SYNT001 as well as its effects on pemphigus disease activity 
markers. 
Study objectives 
Primary objective 
• 
To evaluate the safety and tolerability of 5 once-weekly IV infusions of 
SYNT001 at different dose levels in subjects with chronic pemphigus 
(vulgaris or foliaceus) 
Secondary objectives 
• 
To determine the PK of SYNT001 following 5 once-weekly 1-hour IV 
infusions at different dose levels 
• 
To assess the effect of 5 once-weekly doses of SYNT001 at different dose 
levels on the following PD biomarkers: 
o Immunoglobulins: IgG, IgG subtypes (IgG1-4), IgA, IgM 
o Albumin 
• 
To assess the effect of 5 once-weekly doses of SYNT001 at different dose 
levels on the following disease activity markers: 
o Serum anti-desmoglein (Dsg) (1 and 3) antibody levels 
o Pemphigus Disease Area Index (PDAI) 
• 
To assess immunogenicity (anti-SYNT001 antibodies) 
Exploratory objectives 
• 
To assess the effect of 5 once-weekly doses of SYNT001 at different dose 
levels on the following biomarkers, including: 
o Serum anti-epithelial cell antibody (AECA) levels by indirect 
immunofluorescence 
o Circulating immune complexes (CIC) 
o Complement component 3 (C3) 
o Exploratory biomarkers (FCGR2A (single nucleotide polymorphism-
SNP), RNAseq, urine IgG) 
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o Immune phenotyping by flow cytometry for CD3+CD4+ T, 
CD3+CD8+ T, monocytes, NK cells and B cells 
o SYNT001 levels in skin biopsies (optional) 
• 
To characterize corticosteroid use during the study 
Study design 
Phase 1b, multicenter, open-label, safety, tolerability, and activity study 
Methodology 
Two cohorts of 8 eligible subjects each will receive 5 once-weekly 60-minute 
infusions of SYNT001 in planned doses of 10 mg/kg or 30 mg/kg. Based on 
review of safety, PD, and clinical outcomes of these 2 cohorts, a third cohort of 
up to 8 subjects may be treated at another dose, with a maximum dose of 45 
mg/kg, but may also be lower than 10 mg/kg or between 10 and 30 mg/kg, 
inclusive.  
Cohort 
No. of subjects 
Dose 
1 
8 
SYNT001 10 mg/kg 
2 
8 
SYNT001 30 mg/kg 
Cohorts will be dosed sequentially beginning with Cohort 1.  The first 2 subjects 
will be dosed at least 24 hours apart.  A review of the 24-hour safety data for the 
first subject will be performed to ensure that there are no overt safety concerns 
before dosing the second subject.  A review of the 7-day safety data for the first 
2 subjects will be performed prior to dosing the remaining 6 subjects in the 
cohort.  This evaluation will include a review of AE/SAE reports, vital sign 
assessments, physical examinations, ECGs, and clinical laboratory testing.  The 
seriousness, severity, and relatedness of AEs/SAEs will also be considered in the 
safety evaluation.  Safety data will be reviewed on a continuous basis throughout 
the study.  All safety data and any available and relevant PD data through Day 
42 (2 weeks after the last subject’s last dose in Cohort 1) will be reviewed by a 
dose escalation committee before Cohort 2 is initiated.  Escalation to Cohort 2 
will proceed if there are no concerning safety signals and the review of available 
and relevant PD data supports advancing to a higher dose. The dose for Cohort 2 
will be finalized after review of the safety and PD data, but will not exceed 30 
mg/kg.  Cohort 2 and Cohort 3, if added, will be dosed per the same schedule as 
Cohort 1. 
On days where study drug is administered, vital sign and pulse oximetry 
measurements will be collected immediately prior to the infusion; 15, 30, and 45 
minutes after the start of the infusion; at completion of the infusion; and 
30 minutes, 1 hour and 2 hours following completion of the infusion.  
On Days 0 and 28, PK blood samples will be collected prior to infusion start and 
then over the subsequent 48 hours.  Subjects will remain at the clinic through the 
6-hour PK sample collection and will return to the clinic for the 24- and 48-hour 
collections.  Additional samples will be collected on Days 5 and 33. 
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On Day 0 photographs will be taken of active lesions.  Follow-up photographs 
will be taken of the same areas on Days 33 and 56.  If a subject begins a steroid 
taper, additional photographs will be taken at the clinic visit during which the 
decision to begin the taper is made. 
Subsequent visits will occur on Days 1, 2, 5, 7, 12, 14, 19, 21, 28, 29, 30, 33, and 
42 for safety assessments, study drug dosing, sample collections, and other study 
procedures. 
Subjects also will return to the clinic on Day 56 (28 days after receiving their last 
dose of study drug) for an End-of-Study/Follow-Up visit. 
See Table 1 for a schedule of all study events.  To assess safety and tolerability, 
subjects will undergo physical examinations (PEs; including weight), vital sign 
measurements, clinical (safety) laboratory tests, adverse event (AE) assessments, 
concomitant medication assessments, and electrocardiograms (ECG). 
 
Number of subjects 
Approximately 16; two cohorts of 8 subjects each.  An additional cohort of up to 
8 subjects may be enrolled.  Subjects who withdraw for any reason other than an 
AE and who do not receive study drug or have only received one dose of study 
drug may be replaced, up to one subject per cohort.   The maximum number of 
subjects who may be enrolled in this study is 27 (24 + up to 3 replacements, as 
necessary).  Within each dosing cohort, no more than 3 subjects with pemphigus 
foliaceus may be enrolled. 
Diagnosis and main 
entry criteria 
Inclusion criteria: 
Subjects must meet the following criteria to be included: 
1. Willing and able to read, understand and sign an informed consent form;  
2. Male or female ≥ 18 years of age at the time of screening;  
3. Documented diagnosis of pemphigus vulgaris or foliaceus based on all 3 of 
the following criteria: 
a. Documented clinical history consistent with pemphigus vulgaris or 
foliaceus (clinical presentation defined as mucosal and/ or skin 
lesions); 
b. Presence of Anti-Dsg 1 or 3 antibodies above the upper limit of 
normal;  
c. History of at least one positive tissue-based test (e.g., biopsy, direct 
immunofluorescence [DIF]) 
4. Active disease: Lesions lasting > 2 weeks, and 3 active lesions in skin or 
mucosa or 2 active lesions with at least one being a skin lesion > 1 cm 
diameter: 
a. If treated with rituximab or other anti-CD20 antibodies, last dose 
> 12 months prior to screening; 
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b. If being treated with other immunosuppressants (i.e., azathioprine, 
mycophenolate mofetil or cyclosporine), must be on stable dose 
(< 10% change in dose) for 6 weeks prior to screening; 
c. If being treated with corticosteroids, must be ≤ 1mg/kg/day and 
stable (< 10% change in dose) for 2 weeks prior to screening; 
d. Allowed topical therapies for pemphigus lesions upon entering the 
study include petroleum jelly or Aquaphor® for the skin or 
chlorhexidine for the mouth 
5. Body mass index (BMI) 18.5 – 35.0 kg/m2; 
6. Has a negative urine pregnancy test (for women of childbearing potential) 
documented prior to the first dose of study drug;     
7. Females of childbearing potential must agree to be abstinent or else use any 
two of the following medically acceptable forms of contraception (<1% per 
year failure rate) from the Screening Period through 60 days after the final 
study dose: oral contraceptive, condom with or without spermicidal jelly, 
diaphragm or cervical cap with spermicidal jelly, or intra-uterine device 
(IUD). A female whose male partner has had a vasectomy must agree to use 
one additional form of medically acceptable contraception.  
8. Females of non-childbearing potential, defined as surgically sterile (status 
post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or 
post-menopausal for at least 12 months do not require contraception during 
the study. 
9. Males with female partners of childbearing potential, including males who 
are surgically sterile (post vasectomy), must agree to be abstinent or else use 
a medically acceptable form of contraception from the screening period 
through 60 days after the final study dose. 
 
Exclusion criteria: 
Subjects meeting any of the following criteria are to be excluded:  
1. Subject unable or unwilling to comply with the protocol; 
2. Active non-hematologic malignancy or history of non-hematologic 
malignancy in the 3 years prior to screening (exclusive of non-melanoma 
skin cancer and cervical cancer in situ); 
3. Positive for HIV or hepatitis C antibody;  
4. Positive for hepatitis B surface antigen; 
5. Active infection or history of recurrent infections; 
6. IVIG use within 60 days of screening; 
7. Received any cytotoxic (other than azathioprine) or mAb therapy in the 3 
months prior to screening; 
8. Any exposure to an investigational drug or device within the 30 days prior to 
screening 
9. Plasmapheresis or immunoadsorption within 60 days of screening 
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10. Cellular therapy at any time prior to screening 
11. Use of any immunosuppressive drugs apart from corticosteroids, 
azathioprine, mycophenolate mofetil, or cyclosporine within 3 months of 
screening 
12. Serum total IgG < 600 mg/dL; 
13. Subject has any current medical condition that, in the opinion of the 
Investigator, may compromise their safety or compliance, preclude 
successful conduct of the study, or interfere with interpretation of the results 
(e.g., a significant pre-existing illness or other major comorbidity that the 
Investigator considers may confound the interpretation of the study results); 
14. Any vaccination within 2 weeks of screening 
 
Study drug, dosage, 
and administration 
 SYNT001 
 
Doses: 10 mg/kg and 30 mg/kg. A third cohort of up to 8 subjects may be treated 
at another dose, with a maximum dose of 45 mg/kg, but may also be lower than 
10 mg/kg or between 10 and 30 mg/kg, inclusive. 
SYNT001 is provided as a liquid at a nominal concentration of 50 mg/mL. 
SYNT001 is diluted in Dextrose 5% in Water (D5W) to prepare the solution for 
infusion. 
Route of administration: IV in 250 mL over 1 hour 
Control, dose, and 
route of 
administration 
 Not applicable 
Duration of subject 
participation and 
duration of study 
Up to 70 days (10 weeks): Screening of up to 2 weeks (14 days); dosing period 
of 4 weeks (28 days); and 4 weeks (28 days) of follow-up 
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Prohibited 
Concomitant 
treatments 
All treatments a subject receives within 14 days prior to enrollment through the 
end of the study (Day 56) will be documented.  Concomitant medication and 
treatment for co-existing conditions, including those for pemphigus, are 
permitted if not excluded below.  Topical antibiotics are permitted to treat active 
infections that occur on study.  Topical or systemic treatments for oral 
candidiasis are permitted.  Topical lidocaine for transient pain relief is acceptable 
as needed.  Significant increases in anti-pemphigus medications may result in 
subjects being discontinued from the study.  Concomitant treatment that is 
medically indicated for any AEs the subject experiences during the study are 
permitted. 
Use of the following medications will not be permitted during the study unless 
otherwise specified: 
• 
Rituximab or other anti-CD20 antibody 
• 
Monoclonal antibodies other than study drug 
• 
Any immunosuppressive drugs apart from corticosteroids, azathioprine, 
mycophenolate mofetil, or cyclosporine 
• 
Topical steroids 
• 
Any dietary herbal supplements 
• 
Any investigational drug or device 
• 
Any vaccinations 
If over a period of at least two weeks on study drug, a subject on corticosteroids 
shows the absence of new lesions and significant healing of lesions that existed 
at study baseline, a slow corticosteroid taper may be started as per the following 
suggested schedule  
• 
If on > 30 mg of prednisone per day, decrease by 10 mg every two 
weeks until a dose of 30 mg per day then decrease by 5 mg every two 
weeks 
• 
If on < 30 mg of prednisone per day, decrease by 5 mg every two weeks 
 
Safety assessments 
Safety assessments include AEs, serious adverse events (SAEs), PEs, vital sign 
measurements, clinical safety laboratory evaluations, ECGs, and reasons for 
treatment discontinuations due to toxicity. Safety assessments will be performed 
at specified time points and prior to discharge from the clinic.  Vital sign 
measurements, including blood pressure, pulse rate, respiratory rate, and 
temperature will be monitored throughout the study.  Pulse oximetry will be 
monitored during the study drug infusion and for 2 hours following the end of 
the infusion. 
The National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE; Version 4.03) will be used for grading clinical and 
laboratory AEs.    
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The AE reporting period for a subject enrolled in the study begins when the 
subject provides informed consent and is continued for 28 days after the last 
dose of study drug. All AEs that occur in the enrolled subjects during the AE 
reporting period must be recorded, regardless of the relationship of the AE to 
study drug. Any known untoward event that occurs beyond the AE reporting 
period that the Investigator assesses as related to study drug should also be 
recorded. 
Dose-escalation rules 
Dose-limiting toxicity (DLT) will be defined generally as clinically significant, 
severe (Grade 3) AEs occurring in ≥ 2 subjects that are determined to be 
clinically significant and considered related to study drug. 
If 2 or more subjects at any time in any cohort (8 total subjects per cohort) have 
Grade 3 AEs that are determined to be clinically significant and considered to be 
related to study drug, dosing will be halted within that cohort and no further 
dose-escalation will occur. If the dose-escalation stopping rule is met in Cohort 1 
(10 mg/kg) all safety data and all available pharmacodynamics data will be 
reviewed and a cohort may be added at a dose at least 50% lower than the 10 
mg/kg dose.  If the stopping rule is not met after Cohort 1 (10 mg/kg), dose-
escalation may proceed up to a maximum of 30 mg/kg.  If the dose-escalation 
stopping rule is met in Cohort 2, all safety data and all available 
pharmacodynamics data will be reviewed and a cohort may be added at a dose at 
least 30% lower than the Cohort 2 dose. If the stopping rule is not met after 
Cohort 2, dose-escalation may proceed up to a maximum of 45 mg/kg; however, 
this cohort may also receive a dose equal to or less than 30 mg/kg based on 
evaluation of all safety and pharmacodynamic data.   
Study stopping rule 
If any subject experiences a life-threatening AE (Grade 4) that is considered to 
be related to study drug, any further dosing in all enrolled subjects will be 
suspended until the DEC has evaluated the event and determined the next 
appropriate course of action.  At any time during the study, the study may be 
discontinued if the DEC determines that further drug exposure would pose an 
undue risk to subjects. 
 
Individual stopping 
rule 
 
Dosing for any individual subject will be discontinued (i.e., further treatment 
with the study drug will not be given) if the subject experiences any study drug-
related SAE or any study drug-related non-SAE adverse event that, in the 
judgement of the Investigator and Medical Monitor, suggest that it could be 
unsafe to administer further study drug to that subject.  Additionally, a subject 
may be discontinued from further treatment with study drug, at the discretion of 
the Investigator with consultation with the Medical Monitor, if they require a 
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significant increase in dose(s) of anti-pemphigus medication(s) for the 
management of pemphigus. 
Pharmacokinetics 
The PK of SYNT001 will be evaluated following the first and last (fifth) doses 
of SYNT001.   
Starting on Days 0 and 28, serum samples will be collected just prior to the start 
of study drug infusion (pre-dose), at 5 minutes and 2, 4, 6, 24, and 48 hours after 
the end-of-study drug infusion.  Additional samples will be collected on Days 5 
and 33. 
Study drug concentration will be used to calculate the following PK parameters: 
t1/2, Cmax, Tmax, AUC0-24, and AUC0-∞. 
Pharmacodynamics/ 
Activity 
PD samples will be collected for analysis of IgG (serial assessment of IgG levels 
to identify Cmin, Tmin); IgG1-4 subtype levels; IgA levels; IgM levels; albumin 
levels; anti-Dsg (1 and 3) antibody levels; serum AECA by direct 
immunofluorescence; CIC; C3; exploratory biomarkers (FCGR2A SNP, 
RNAseq, urine IgG, CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B 
cells).  
Immunogenicity 
Up to 4 samples will be collected for immunogenicity analyses.  Samples will be 
collected on Days 0 (pre-dose), 14, 28, and 56. 
Skin biopsy 
Optional skin biopsy samples will be collected on Day 0 pre-dose and on Days 1, 
2, 14, 33 and 56 to analyze SYNT001 levels.   
Photography 
Photographs of active lesions will be taken at Day 0.  Follow-up photographs of 
the same areas will be taken on Days 33 and 56.  Subjects who begin a steroid 
taper will have additional photographs taken at the clinic visit during which the 
decision to begin the taper is made. 
Statistical methods 
Sample size consideration 
Formal sample size calculations were not performed.  The number of subjects 
was chosen based on feasibility and was considered sufficient to meet the study 
objectives. 
 
Data presentations/Descriptive statistics 
Three populations will be employed in the analysis of study data. 
• 
The intent-to-treat (ITT) population will consist of all subjects who have 
received at least one dose of study drug.  All safety analyses will be 
performed on the ITT population. 
• 
The PK population will consist of all subjects who receive at least one 
dose of study drug and have sufficient post-dose blood samples to obtain 
PK parameters. 
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• 
The PD population will consist of all subjects who receive at least one 
dose of study drug and have post-dose PD data available. 
 
Primary safety analyses will be performed on the ITT population. Demographics, 
subject disposition, and screening and baseline characteristics will be 
summarized for the PK and ITT populations, where appropriate. 
 
Criteria for evaluation 
Objective 
Endpoint 
Primary  
Safety and tolerability of 5 once-
weekly IV infusions of SYNT001 to 
subjects with pemphigus vulgaris or 
foliaceus 
AEs and clinical (safety) 
laboratory tests 
Secondary  
PK of SYNT001 following a 1-hour IV 
infusion 
PK parameters: t1/2, Cmax, Tmax, 
AUC0-24, and AUC0-∞. 
Effect of 5 once-weekly IV doses of 
SYNT001 on: 
• Total IgG (IgG1-4), IgA, IgM, and 
albumin 
• Serum anti-Dsg (1 and 3) antibodies 
Changes in levels of IgG, IgG 
subtypes (IgG1-4), IgA, IgM, 
albumin, serum anti-Dsg (1 and 
3) antibodies 
Assess immunogenicity  
Anti-SYNT001 antibodies 
Disease Activity 
PDAI Scores 
Exploratory  
Effect of 5 once-weekly IV doses of 
SYNT001 on biomarkers including: 
• CIC 
• C3 
• Serum anti-epithelial cell antibody 
(AECA) levels 
• Exploratory biomarkers (FCGR2A 
SNP, RNAseq, urine IgG) 
• Immune phenotyping by flow 
cytometry 
Changes in CIC; C3; AECA 
levels by indirect 
immunofluorescence; FCGR2A 
SNP; RNAseq; urine IgG, 
CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B 
cells; urine IgG levels; changes 
in blood transcriptome 
Concomitant Treatment 
Corticosteroid use during the 
study 
SYNT001 levels in skin biopsies  
Measures of SYNT001 levels in 
skin biopsies 
Treatment-emergent AEs (TEAEs) will be summarized using the Medical 
Dictionary for Regulatory Activities (MedDRA®; Version 19 or higher) System 
Organ Class (SOC) and preferred term, classified from verbatim terms.  The 
incidence and percentage of subjects with at least 1 occurrence of a preferred 
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term will be included, using the most severe grade.  The number of events per 
preferred term will also be summarized.  Causality (relationship to study 
treatment) will be summarized separately. 
TEAEs, SAEs, and AEs leading to withdrawal, or treatment discontinuation will 
be listed by subject, and cohort using SOC and preferred terms. Duration of AEs 
will be determined and included in listings, along with action taken, and 
outcome.   
Laboratory results will be summarized by time point and cohort.  The incidence 
of laboratory abnormalities will be summarized.  The worst on-study grade after 
the first dose of study drug will be summarized.  Results for variables that are 
not coded will be presented in the listings as below, within, and above the 
normal limits of the central laboratory.  Vital sign measurements will be 
summarized by cohort at each scheduled time point using descriptive statistics.    
Study drug concentrations will be used to calculate the following PK parameters:  
t1/2, Cmax, Tmax, and area under the curve (AUC).  PK parameters will be 
determined using non-compartmental method(s).   Descriptive statistics of PK 
parameters for SYNT001 will include mean, standard deviation (SD), coefficient 
of variation (CV), median, minimum, and maximum. Tmax will be reported as 
median and range. All descriptive statistics will be performed on untransformed 
PK parameters and after log10 transformation of PK parameters. 
PD results will be summarized by cohort.  Descriptive statistics of PD 
parameters for SYNT001 will include mean, SD, CV, median, minimum, and 
maximum. 
Immunogenicity results will be summarized by cohort.  Descriptive statistics will 
include mean, SD, CV, median, minimum, and maximum. 
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Table 1: 
Study Assessments  
Timepoint (Study Day) 
Screen 
-14 to -1 
0 
1 
(±1 
hr) 
2 
(± 2 
hr) 
5p 
(±4 
hr) 
7  
(±4 
hr) 
12p  
(±6 
hr) 
14  
(±6 
hr) 
19p  
(±6 
hr) 
21 
(±6 
hr) 
28 
(±6 
hr) 
29 
(±1 
hr) 
30 
(±2 
hr) 
33 
(±4 
hr) 
42 
(±3 
day) 
Follow-Up 
56  
(±5 days) or 
ET Visit 
Extended 
Follow-
upq 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationa 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
Vital Signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pulse Oximetryc 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
Clinical Safety Labsd 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECGf 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Tetanus & VZV antibodiesg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
PDAI Score 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
 
PK Samplingh 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
Immunogenicityi  
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Study Drug Administrationj 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
Immunoglobulins (IgG, IgA, IgM) 
and IgG subtypes (IgG 1-4)k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CIC 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
Anti-Dsg (1 & 3) antibody titer 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
C3 and AECAl 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
FCGR2Am 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNAseqm 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Urine IgGm 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Immune phenotypingn 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Optional Skin Biopsy 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Photographyo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Adverse Events 
To be collected from the date that the ICF is signed until 28 days after last dose of study drug.  
Concomitant Medications 
To be collected from within 14 days prior to Day 0 through 28 days after last dose of study drug. 
ECG = electrocardiogram; ET= Early Termination; HIV = human immunodeficiency virus; ICF = informed consent form; PD = pharmacodynamic; PK = pharmacokinetic; VZV = 
varicella-zoster virus 
 
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a: Complete PE, including weight, to be performed.  Height and BMI will be additional assessments conducted at screening. 
b: Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and oral temperature) to be obtained after 5 minutes of seated rest.  Any abnormal measurements are to 
be repeated after 5 minutes of rest.  On Days 0, 7, 14, 21, and 28 vital sign measurements will be collected immediately prior to the infusion; 15, 30, and 45 minutes after the start 
of the infusion; at completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion.   
c: Pulse oximetry: On Days 0, 7, 14, 21, and 28, pulse oximetry to be measured immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at completion 
of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion. 
d: Clinical safety labs: hematology, clinical chemistry, and urinalysis (see Section 6.7 for a complete list).  Full clinical safety lab draws will be collected at Screening and on Days 
0, 7, 14, 21, 28, 33, 42 and 56. 
e: Pregnancy test:  To be performed at time of screening and prior to first dose of SYNT001 on Day 0 and on Day 56 (urine or serum test is acceptable, however, positive urine tests 
must be confirmed with serum testing.) 
f: Digital 12-lead ECG to be obtained after 5 minutes of rest in the supine position and in triplicate at least 1-2 minutes apart (see Section 6.6 for additional information).  On Days 0 
and 28 to be obtained 5 minutes after the completion of infusion. Day 12 ECG will be collected only if the visit is conducted at the study site.  
g: Serology:  Testing at Day 56 will not be done for any subject whose baseline titer is below the level of detection. If the Day 56 results are greater than 30% below the baseline 
value, or if the subject falls below the level of detection, the subject will be re-tested at 1 month after the Follow-Up visit (approximately 2 months after the subject’s last dose); if 
still below the baseline value (or level of detection), the subject will be re-tested after another month (3 months after last dose). Any subject whose baseline value for tetanus or 
VZV was above the detectable level at baseline, and is not within 30% of the baseline value or is below the detectable level on Day 56 and upon 2 retests (2 and 3 months 
following last dose of SYNT001), will be referred to their primary care physician for further management. See Section 6.7.3 for additional information. 
h: PK:  Starting on Days 0 and 28, serum samples will be collected just prior to the start of study drug infusion (pre-dose), and at 5 minutes and 2, 4, 6, 24, and 48 hours after the 
end-of-study drug infusion.  Additional samples will be collected on Days 5 and 33.  See Section 6.7.4 for additional information.  
i: Immunogenicity:  Blood samples will be collected pre-dose when collected on dosing days.  See Section 6.7.6 for additional information. 
j: Prior to study drug infusion, SYNT001 drug product is to be diluted in Dextrose 5% in Water (D5W) to a total volume of 250 mL and administered intravenously over 1 hour 
using a 0.2-micron, inline filter.  See Section 9 for additional information. 
k: Immunoglobulins (IgG, IgA, IgM) and IgG subtypes (IgG 1-4): Collected for measurements of IgG, IgG subtypes (IgG1-4), IgA, and IgM at every visit. On Days 0, 7, 14, 21, 
and 28, samples are collected prior to infusion of study drug. See Section 6.7.5 for additional information   
l: Exploratory PD samples (C3 and AECA): collected pre-dose when collected on dosing days. See Section 6.7.5  for complete information. 
m: Samples to be collected and stored; pending review of clinical and pharmacodynamics assessments 
n: Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B cells 
o: Photographs of active lesions taken prior to first dose on Day 0.  Follow-up photographs will be taken at Days 33 and 56.  Subjects who begin a steroid taper will have additional 
photographs taken at the clinic visit during which the decision to begin the taper is made. 
p: Visit Days 5, 12 and 19 may be conducted via at-home nursing in lieu of a subject visit to the study site. 
q: Extended follow-up visits will occur only if additional testing for anti-tetanus and/ or anti-VZV titers are required.  These visits will occur as needed at approximately 2 months 
post last dose and 3 months post last dose. 
 
 
 
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Table 2: 
Timing Window Allowances for PK/PD Sampling, ECG, and Vital Sign Measurements 
Pharmacokinetic and Pharmacodynamic Sampling 
 
Timepoint 
Tolerance Window 
0 hour 
−240 min to 0 hour 
5 minutes post end-of-infusion 
± 5 minutes 
2, 4, & 6 hours post end-of-infusion 
± 15 minutes 
24 hours post end-of-infusion 
± 60 minutes 
48 hours post end-of-infusion  
± 120 minutes 
ECG 
 
Timepoint 
Tolerance Window 
5 minutes post end-of-infusion 
± 10 minutes 
Vital Signsa 
 
Timepoint 
Tolerance Window 
0 hour 
−240 min to 0 hour 
15, 30, and 45 minutes after start of infusion 
± 5 minutes 
60 minutes after start of infusion 
± 10 minutes 
30, 60 and 120 minutes post end-of-infusion 
± 10 minutes 
a:  Vital signs to include blood pressure, pulse rate, respiratory rate, oral temperature, and pulse oximetry.
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TABLE OF CONTENTS 
PROCEDURES IN CASE OF EMERGENCY ...................................................................3 
INVESTIGATOR SIGNATURE.........................................................................................4 
1 
SYNOPSIS ..................................................................................................................5 
LIST OF ABBREVIATIONS ............................................................................................24 
2 
BACKGROUND AND RATIONALE .....................................................................26 
2.1 
Study Rationale ................................................................................................27 
2.2 
Selection of Doses in this Study ......................................................................27 
2.3 
Compliance Statement .....................................................................................28 
3 
STUDY OBJECTIVES .............................................................................................29 
3.1 
Primary Objective ............................................................................................29 
3.2 
Secondary Objectives.......................................................................................29 
3.3 
Exploratory Objectives ....................................................................................29 
4 
STUDY DESIGN......................................................................................................30 
4.1 
Study Sites .......................................................................................................30 
4.2 
Study Endpoints ...............................................................................................30 
4.3 
Overview of Study Design ...............................................................................31 
4.4 
Randomization and Blinding ...........................................................................33 
5 
STUDY POPULATION ...........................................................................................34 
5.1 
Target Population .............................................................................................34 
5.2 
Inclusion Criteria .............................................................................................34 
5.3 
Exclusion Criteria ............................................................................................35 
6 
STUDY PROCEDURES ..........................................................................................37 
6.1 
Informed Consent.............................................................................................37 
6.2 
Demographics and Medical History ................................................................37 
6.3 
Physical Examination.......................................................................................37 
6.4 
Pemphigus Disease Area Index (PDAI) Scoring .............................................37 
6.5 
Vital Sign Measurements .................................................................................37 
6.6 
12-Lead Electrocardiogram (ECG) ..................................................................38 
6.7 
Clinical Laboratory Measurements ..................................................................39 
6.7.1 
Pregnancy Testing ................................................................................40 
6.7.2 
Virology ...............................................................................................40 
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6.7.3 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing40 
6.7.4 
Pharmacokinetics (PK) Sampling ........................................................41 
6.7.5 
Pharmacodynamic Sampling ...............................................................41 
6.7.6 
Immunogenicity Testing ......................................................................42 
6.8 
Study Drug Administration ..............................................................................43 
6.9 
Prior and Concomitant Medications ................................................................43 
6.10 
Adverse Event Assessments ............................................................................43 
6.11 
Photographs......................................................................................................44 
6.12 
Skin Biopsy ......................................................................................................44 
7 
STUDY ASSESSMENTS ........................................................................................45 
7.1 
Screening Period: Day -14 to Day -1 ...............................................................45 
7.2 
Enrollment and First Treatment: Day 0 ...........................................................45 
7.3 
Follow-up: Day 1 .............................................................................................47 
7.4 
Follow-up: Day 2 .............................................................................................47 
7.5 
Follow-up: Day 5 .............................................................................................48 
7.6 
Treatment Day 7 (Dose 2) ................................................................................48 
7.7 
Dose 2 Follow-up Day 12 ................................................................................49 
7.8 
Treatment Day 14 (Dose 3) ..............................................................................49 
7.9 
Dose 3 Follow-up Day 19 ................................................................................51 
7.10 
Treatment Day 21 (Dose 4) ..............................................................................51 
7.11 
Treatment Day 28 (Dose 5) ..............................................................................52 
7.12 
Follow-up Day 29 ............................................................................................53 
7.13 
Follow-up Day 30 ............................................................................................54 
7.14 
Follow-up Day 33 ............................................................................................54 
7.15 
Follow-up Day 42 ............................................................................................55 
7.16 
Follow-up Day 56 (End-of-Study) or Early Termination Visit .......................55 
7.17 
Extended Follow-up Visits ..............................................................................56 
8 
REMOVING SUBJECTS FROM STUDY ..............................................................57 
8.1 
Subject Withdrawal ..........................................................................................57 
8.2 
Study Discontinuation ......................................................................................58 
8.3 
Replacements ...................................................................................................58 
8.4 
Stopping Rule...................................................................................................58 
8.4.1 
Dose-Escalation Stopping Rule ...........................................................58 
8.4.2 
Study Stopping Rule ............................................................................59 
8.4.3 
Individual Stopping Rule .....................................................................59 
9 
STUDY DRUG .........................................................................................................60 
9.1 
SYNT001 .........................................................................................................60 
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9.2 
Cohort Dosing ..................................................................................................60 
9.3 
Timing of Dosing .............................................................................................60 
9.4 
Identity of Investigational Products .................................................................60 
9.5 
Investigational Product Retention at Study Site ..............................................61 
9.6 
Warnings and Precautions................................................................................61 
9.6.1 
Infusion Reaction .................................................................................61 
9.6.2 
Potential Immune Effects .....................................................................66 
10 
CONCOMITANT MEDICATION AND TREATMENT ........................................67 
11 
SAFETY ...................................................................................................................69 
11.1 
Safety Parameters.............................................................................................69 
11.2 
Adverse Event Definition ................................................................................69 
11.3 
Evaluating Adverse Events ..............................................................................70 
11.3.1 
Serious Adverse Events .......................................................................70 
11.3.2 
Overdose ..............................................................................................71 
11.3.3 
Non-Serious Adverse Events ...............................................................71 
11.3.4 
Protocol-Related Adverse Events ........................................................71 
11.3.5 
Assessment of Causality ......................................................................71 
11.3.6 
Recording Adverse Events ...................................................................72 
11.3.7 
Planned Hospitalization .......................................................................72 
11.3.8 
Reporting Pregnancies .........................................................................73 
11.3.9 
Serious Adverse Event Reporting ........................................................73 
11.3.9.1 Governing Regulatory Requirements ..................................................73 
11.3.9.2 Time Frame for Reporting ...................................................................74 
11.3.9.3 Information to be Provided by the Investigator ...................................75 
11.3.10 Regulatory Reporting ...........................................................................76 
11.3.11 Follow-up Information on a Serious Adverse Event (SAE) ................77 
11.4 
Other Safety Considerations ............................................................................77 
11.4.1 
Laboratory Data ...................................................................................77 
11.4.2 
Medication Errors ................................................................................77 
11.4.3 
Follow-Up of Adverse Events .............................................................77 
11.5 
Safety Monitoring for Dose Escalation............................................................78 
12 
STATISTICAL CONSIDERATIONS......................................................................79 
12.1 
General Design.................................................................................................79 
12.2 
Sample Size Justification .................................................................................79 
12.3 
Statistical Considerations .................................................................................79 
12.3.1 
Study Populations ................................................................................79 
12.3.2 
Subject Accountability, Demographics, and Baseline Characteristics 80 
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12.3.3 
Concomitant Medications ....................................................................80 
12.4 
Planned PK Analysis........................................................................................80 
12.5 
Safety Data .......................................................................................................81 
12.6 
Pharmacodynamic/Activity Data .....................................................................81 
12.7 
Immunogenicity Data.......................................................................................81 
12.8 
Interim Analysis ...............................................................................................82 
13 
DATA QUALITY ASSURANCE ............................................................................83 
14 
STUDY ADMINISTRATION..................................................................................84 
14.1 
Study Administrative Structure........................................................................84 
14.2 
Ethical Conduct of the Study ...........................................................................84 
14.3 
Informed Consent (ICF) ...................................................................................84 
14.4 
Institutional Review Board ..............................................................................85 
14.5 
Dose Escalation Committee .............................................................................85 
14.6 
Future Use of Subject Samples ........................................................................86 
15 
CONDITIONS FOR MODIFYING THE PROTOCOL...........................................87 
16 
CONDITIONS FOR TERMINATING THE STUDY .............................................88 
17 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING .......................89 
17.1 
Investigator’s Files and Retention of Documents ............................................89 
17.2 
Source Documents and Background Data .......................................................89 
17.3 
Audits and Inspections .....................................................................................90 
17.4 
Electronic Case Report Forms .........................................................................91 
18 
MONITORING THE STUDY ..................................................................................92 
19 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS ...93 
20 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS............94 
21 
REFERENCES .........................................................................................................95 
 
 
 
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LIST OF TABLES 
Table 1: 
Study Assessments .................................................................................... 16 
Table 2: 
Timing Window Allowances for PK/PD Sampling, ECG, and Vital Sign 
Measurements ........................................................................................... 18 
Table 3: 
Clinical Laboratory Panels ........................................................................ 39 
Table 4:  
Pharmacodynamic/ Activity Assessments ................................................ 42 
Table 5: 
Grading and Management of Allergic or Infusion-Related Reactions ..... 65 
Table 6 :  
Study Administrative Structure................................................................. 84 
 
LIST OF FIGURES 
Figure 1:  Management of Mild (Grade 1) to Moderate (Grade 2) Infusion Reactions .... 63 
Figure 2:  Management of Severe (Grade 3 or higher) Infusion Reactions ...................... 64 
 
 
LIST OF APPENDICES 
Appendix A: NCI CTCAE, Version 4.03 ......................................................................... 96 
Appendix B: Pemphigus Disease Area Index ................................................................... 97 
 
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LIST OF ABBREVIATIONS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AECA 
Anti-epithelial cell antibody 
ALT 
Alanine aminotransferase 
ANA 
Antinuclear antibody 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC0-24 
Area under the plasma concentration-time curve from pre-dose (time 0) to 24 hours post-dose 
AUC0-∞ 
Area under the plasma concentration-time curve from pre-dose (time 0) to infinity 
BLQ 
Below the limit of quantification  
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CAR-T 
Chimeric antigen receptor and T-cell 
CFR 
Code of Federal Regulations 
C3 
Complement component 3 
CBC 
Complete blood count 
CIC 
Circulating immune complexes 
CIDP 
Chronic inflammatory demyelinating polyneuropathy 
Cmax 
Maximum plasma concentration determined directly from the concentration-time profile 
CRO 
Contract research organization 
CV 
Coefficient of variation 
CVID 
Common variable immune deficiency 
DEC 
Dose escalation committee 
D5W 
Dextrose 5% in Water 
DIF 
Direct immunofluorescence 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ESR 
Erythrocyte sedimentation rate 
FcGR2a 
Fc Gamma R2a receptor 
FcRn 
Neonatal Fc receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
IC 
Immune complex 
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ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgG1-4 
Immunoglobulin G1-G4 
IgM 
Immunoglobulin M 
IL-12 
Interleukin 12 
IND 
Investigational new drug 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IUD 
Intrauterine devices 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHL 
Non-Hodgkin lymphoma 
PD 
Pharmacodynamics 
PE 
Physical examination 
PK 
Pharmacokinetic 
RBC 
RNAseq 
Red blood cells 
RNA sequencing 
QTcF 
Corrected QT interval using Fridericia's formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SD 
Standard deviation 
SNP 
Single nucleotide polymorphism 
SOC 
System Organ Class 
SOP 
Standard operating procedures 
SYNT001 
A humanized, affinity matured IgG4-kappa monoclonal antibody 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Observed time to reach peak plasma concentration 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
UNS 
Unscheduled 
VZV 
Varicella-zoster virus 
WAIHA 
Warm antibody autoimmune hemolytic anemia 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
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2 
BACKGROUND AND RATIONALE 
SYNT001, a humanized, affinity-matured IgG4-kappa monoclonal antibody (mAb), blocks IgG 
and IgG immune complex (IC) interactions with the neonatal Fc receptor (FcRn) and thereby the 
major functions of FcRn in protecting IgG and IgG ICs from degradation and their role in 
downstream signaling events. Specific and high affinity blockade of FcRn with SYNT001 has 
been shown to increase the catabolism of IgG and IgG IC in healthy volunteers. This predicts 
that SYNT001 will also accelerate degradation of endogenous circulating IgG autoantibodies and 
IgG-antigen IC specifically involved in the pathogenesis of autoimmunity.  Blocking FcRn 
interactions with IgG-containing ICs further predicts that SYNT001 will have consequences for 
innate and adaptive cellular immunity.  In the first instance, blocking multimeric IgG IC 
interactions with FcRn within antigen-presenting cells will result in inhibition of IC-stimulated 
inflammatory cytokine production and release by these cells.  In addition, as FcRn determines 
the intracellular itinerary of IgG ICs within and among compartments important in cellular 
immunity, it is anticipated that SYNT001 will block antigen processing and presentation of 
antigens contained within IC that otherwise lead to CD8+ and CD4+ T cell activation. Thus, 
SYNT001 will specifically target immune functions associated with IgG that are involved in 
certain autoimmune conditions and dismantle their ability to cause disease. 
SYNT001 targets key mechanisms contributing to pathology in a variety of IgG-mediated 
autoimmune disorders, including warm antibody autoimmune hemolytic anemia (WAIHA), 
pemphigus, and chronic inflammatory demyelinating polyneuropathy (CIDP).   
While current treatments for certain autoimmune disorders, including high-dose steroids, 
immunosuppressants, intravenous immunoglobulin (IVIG), plasmapheresis, and anti-CD20 
monoclonal antibodies (mAbs), such as rituximab, can be effective, they are associated with 
significant adverse effects, as well as delayed or non-durable responses.  
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous 
membranes. Autoantibodies have been shown to play an important pathogenic role in the 
mucosal and cutaneous manifestations in patients with pemphigus. Administration of SYNT001, 
which significantly decreases total IgG, including a corresponding decrease in the level of the 
pathogenic autoantibodies and the ICs to which they are associated, may lead to a decrease in the 
mucosal and cutaneous manifestations in patients with pemphigus. Moreover, the ability of 
SYNT001 to reduce circulating immune complexes (CICs) and the associated innate and 
adaptive immune responses may allow for further sustained disease modification. 
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2.1 
Study Rationale 
This study is being conducted to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD) and immunogenicity of intravenous (IV) SYNT001 as well as its 
effects on pemphigus disease activity markers. 
2.2 
Selection of Doses in this Study  
The planned dose levels of SYNT001 for this Phase 1b safety and proof-of-concept study of 10 
mg/kg and 30 mg/kg were selected from careful review of the safety, tolerability, and PD effect 
on total IgG levels after single and repeat dosing of SYNT001 in non-human primates (NHPs), 
as well as the safety, tolerability, and PD effect on total IgG levels after single ascending doses 
of SYNT001 in healthy volunteers. In addition, further consideration was given to the desired 
level of FcRn blockade to achieve suppression of IgG to a range that has been previously 
correlated with disease remission. Further, we considered the potential effects of inhibiting FcRn 
function as they relate to immune complex associated innate and adaptive immunity in choosing 
these dose levels based upon exploratory studies of a single ascending dose of SYNT001 in 
healthy volunteers. From the NHP studies, single doses of SYNT001 produced a dose-dependent 
decrease in total IgG and a further decrease was seen with repeated weekly doses up to a 
maximum 70% reduction at 100 mg/kg. This magnitude of total IgG reduction is approaching the 
expected maximal effect of 100% inhibition of FcRn function based on murine studies also 
performed by Syntimmune and others [Roopenian 2003, Nixon 2015]. In the recently completed 
Phase 1a trial with SYNT001 in healthy volunteers a single dose caused a maximum average 
50% drop in total IgG with IV dosing at 30 mg/kg. Based on the NHP studies further reductions 
are expected following multiple dosing. A comparable decrease in pathogenic autoantibodies is 
also anticipated. 
In the NHP studies, relevant adverse effects, mild-to-moderate infusion reactions, were observed 
only after the third weekly IV administration, concurrent with the development of anti-SYNT001 
antibodies. In the recently completed Phase 1a healthy male volunteer study, the doses of 
SYNT001 up to and including 30 mg/kg have been well tolerated. There were no dose limiting 
toxicities, serious adverse events, or any other safety concerns identified.  No AEs were observed 
in the 1 and 3 mg/kg dose cohorts. A single Grade 2 AE was observed; a headache in the 10 
mg/kg cohort, treated with acetaminophen. Other subjects had mild (Grade 1) AEs at 10 mg/kg. 
In Cohort 4 (30 mg/kg), 5 subjects received SYNT001. All five subjects experienced AEs; all 
were mild (Grade 1), transient and resolved spontaneously without intervention. Therefore, it is 
anticipated that the doses selected for this study should be well tolerated and have clinically 
relevant PD effects in patients with chronic pemphigus (vulgaris or foliaceus). For a summary of 
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findings from the single dose, clinical study in healthy subjects and further details on the 
nonclinical findings, please refer to the SYNT001 Investigator’s Brochure.  
2.3 
Compliance Statement 
This study will be conducted in compliance with Good Clinical Practice (GCP), including the 
International Conference on Harmonisation (ICH) Guidelines and FDA regulations, consistent 
with the principles outlined in the Declaration of Helsinki.  In addition, the Investigator agrees to 
adhere to all applicable local laws and regulatory requirements relevant to the use of new 
therapeutic agents. 
The study will be conducted in compliance with the protocol.  The appropriate Institutional 
Review Boards (IRBs) must approve the protocol, any amendments, and the subject informed 
consent form (ICF) prior to implementation.  
Freely given written informed consent must be obtained from every subject prior to participation 
in this clinical trial.  As part of this procedure, the Investigator must explain orally and in writing 
the nature, duration, and purpose of the study, and the action of the drug in such a manner that 
the study subject is aware of the potential risks, inconveniences, or AEs that may occur.  The 
study subject should be informed that he/she is free to withdraw from the study at any time.  
He/she will receive all information that is required by federal regulations and ICH guidelines.  
The Investigator or designee will provide the Sponsor with a copy of the IRB-approved informed 
consent form prior to the start of the study. The rights, safety, and well-being of participating 
subjects are the most important considerations and should prevail over interests of science and 
society. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s).  This trial will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct or 
fraud (e.g., loss of medical licensure, debarment). 
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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of 5 once-weekly IV 
infusions of SYNT001 at different dose levels in subjects with chronic pemphigus (vulgaris or 
foliaceus). 
3.2 
Secondary Objectives 
The secondary objectives of this study are as follow: 
• To determine the PK of SYNT001 following 5 once-weekly 1-hour IV infusions at 
different dose levels 
• To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the 
following PD biomarkers: 
o Immunoglobulins: IgG, IgG subtypes (IgG1-4), IgA, IgM  
o Albumin 
• To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the 
following disease activity markers: 
o Serum anti-desmoglein (Dsg) (1 and 3) antibody levels 
o Pemphigus Disease Area Index (PDAI) 
• To assess immunogenicity (anti-SYNT001 antibodies) 
3.3 
Exploratory Objectives 
The exploratory objectives of this study are as follow: 
• To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the 
following biomarkers, including: 
o Serum anti-epithelial cell antibody (AECA) levels by indirect immunofluorescence  
o Circulating immune complexes (CIC) 
o Complement component 3 (C3) 
o Exploratory biomarkers (FCGR2A single nucleotide polymorphism-SNP, RNAseq, 
urine IgG) 
o Immune phenotyping by flow cytometry for CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B cells 
o SYNT001 levels in skin biopsies (optional) 
• To characterize corticosteroid use during the study 
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4 
STUDY DESIGN 
4.1 
Study Sites 
This study will be conducted at approximately 10 sites in the United States (US). 
4.2 
Study Endpoints 
Primary Outcome Measures:  Assessment of safety data (adverse events [AEs], serious 
adverse events [SAEs], vital sign measurements, ECGs and clinical laboratory tests) will be the 
primary safety measure.   
Secondary Outcome Measures 
Pharmacokinetics: 
• Half-life (t1/2), maximum plasma concentration determined directly from the 
concentration-time profile (Cmax), observed time to reach peak plasma concentration 
(Tmax), area under the plasma concentration-time curve from pre-dose (time 0) to 
24 hours post-dose (AUC0-24), and area under the plasma concentration-time curve 
from pre-dose (time 0) to infinity (AUC0-∞) 
PD Biomarkers: 
• Ig Assessments: Serial assessments of total IgG and IgG subtypes (IgG1-4)  
o Serial assessments of total IgG and IgG subtypes (IgG1-4) 
o IgA levels 
o IgM levels 
• Albumin levels 
 
Disease activity markers: 
• Serum anti-desmoglein (Dsg) (1 and 3) antibody levels 
• Pemphigus Disease Area Index (PDAI) scores 
Immunogenicity: 
• Anti-SYNT001 antibodies 
Exploratory Outcome Measures 
Biomarkers, including: 
• CIC 
• C3 
• Serum AECA levels  
• Exploratory biomarkers (FCGR2A SNP, RNAseq, urine IgG) 
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• Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, 
CD3+CD8+ T, monocytes, NK cells and B cells 
• SYNT001 levels in skin biopsies (optional) 
 
Concomitant Treatments 
• Corticosteroid use 
 
Further details on the statistical and analytical plan for these endpoints are available in 
Section 12, Statistical Considerations.           
4.3 
Overview of Study Design 
This will be a multicenter, open-label study to assess the safety, tolerability, activity, PK, PD, 
and immunogenicity of 5 once-weekly IV infusions of SYNT001 to subjects with chronic 
pemphigus (vulgaris or foliaceus). 
Planned doses of SYNT001 to be studied are 10 mg/kg and up to 30 mg/kg.  Two cohorts of 8 
eligible subjects each will receive 5 once-weekly 60-minute infusions of SYNT001 10 mg/kg or 
up to 30 mg/kg. Based on review of safety, PD, and clinical outcomes of the first cohort, the dose 
for the second cohort may be adjusted, but with a maximum dose of 30 mg/kg.  Based on review 
of safety, PD and clinical outcomes from these 2 cohorts, a third cohort of up to 8 subjects may 
be treated at another dose, with a maximum dose of 45 mg/kg, but may also be lower than 10 
mg/kg or between 10 and 30 mg/kg, inclusive. 
Cohort 
No. of 
Subjects 
Dose 
1 
8 
SYNT001 10 mg/kg 
2 
8 
SYNT001 30 mg/kg 
Cohorts will be dosed sequentially beginning with Cohort 1.  The first 2 subjects will be dosed at 
least 24 hours apart.  A review of the 24-hour safety data for the first subject will be performed 
to ensure that there are no overt safety concerns before dosing the second subject.  A review of 
the 7-day safety data for the first 2 subjects will be performed prior to dosing the remaining 6 
subjects in the cohort.  This evaluation will include a review of AE/SAE reports, vital sign 
assessments, physical examinations, ECGs and clinical laboratory testing.  The seriousness, 
severity, and relatedness of AEs/SAEs will also be considered in the safety evaluation.  Safety 
data will be reviewed on a continuous basis throughout the study.  All data through Day 42 
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(2 weeks after the last subject’s last dose in Cohort 1) will be reviewed before Cohort 2 is 
initiated.  Cohort 2 and Cohort 3, if added, will be dosed per the same schedule.  
Safety evaluations will be conducted by a dose escalation committee (DEC). The DEC will 
consist of the Medical Monitor, an Independent Clinical Expert and a Syntimmune Medical 
Officer. To assist in the safety assessments, the DEC may request that Investigators, other 
experts, or members within their organizations review the data and participate in the 
discussions.  Dosing and dose escalation will proceed if the DEC has determined that it would be 
safe and appropriate to do so.  In addition, over the course of the study, the DEC will review any 
drug-related SAEs to determine if modifications to the study or other measures are necessary to 
ensure the safety of the subjects.   
On days where study drug is administered, vital sign and pulse oximetry measurements will be 
collected immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; 
at completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the 
infusion.  
On Days 0 and 28, PK blood samples will be collected prior to infusion start and then over the 
subsequent 48 hours.  Subjects will remain at the clinic through the 6-hour PK sample collection 
and will return to the clinic for the 24- and 48-hour collections.  Additional samples will be 
collected on Days 5 and 33.   
On Day 0 photographs will be taken of active lesions.  Follow-up photographs will be taken of 
the same areas on Days 33 and 56.  If a subject begins a steroid taper, additional photographs 
will be taken at the clinic visit during which the decision to begin the taper is made. 
Subsequent visits will occur on Days 1, 2, 5, 7, 12, 14, 19, 21, 28, 29, 30, 33, and 42 for safety 
assessments, study drug dosing, sample collections, and other study procedures. 
Subjects also will return to the clinic on Day 56 (28 days after receiving their last dose of study 
drug) for an End-of-Study/Follow-Up visit. 
See Table 1 for a schedule of all study events.  To assess safety and tolerability, subjects will 
undergo physical examinations (PEs; including weight), vital sign measurements, clinical 
(safety) laboratory tests, AE assessments, concomitant medication assessments, and 
electrocardiograms (ECG). 
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Note:  No vaccinations may be given from within 2 weeks of screening until 2 months following 
the last dose of study drug. 
4.4 
Randomization and Blinding 
This is an open-label study. 
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5 
STUDY POPULATION 
5.1 
Target Population 
This study will be conducted in approximately 16 male and female subjects (2 cohorts of 8 
subjects each) with a confirmed diagnosis of pemphigus (vulgaris or foliaceus); however, a third 
cohort of up to 8 subjects may be added.  Subjects will be enrolled only once in the study and 
will not be included in subsequent dosing cohorts. Subjects who withdraw for any reason other 
than an AE and who do not receive study drug or have only received one dose of study drug may 
be replaced, up to one subject per cohort. Subjects who do not receive all doses of study drug 
will continue to be followed through 28 days after their last dose.  The maximum number of 
subjects who may be enrolled in this study is 27 (24 + up to 3 replacements, as necessary).  
Within each dosing cohort, no more than 3 subjects may be enrolled with pemphigus foliaceus. 
5.2 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for the study: 
1. Willing and able to read, understand and sign an informed consent form;  
2. Male or female ≥ 18 years of age;  
3. Documented diagnosis of pemphigus vulgaris or foliaceus based on all 3 of the following 
criteria: 
a. Documented clinical history consistent with pemphigus vulgaris or foliaceus 
(clinical presentation defined as mucosal and/ or skin lesions); 
b.  Presence of Anti-Dsg 1 or 3 antibodies above the upper limit of normal; 
c. History of at least one positive tissue based test (biopsy, DIF) 
4. Active disease: Lesions lasting > 2 weeks, and 3 active lesions in skin or mucosa or 2 
active lesions with at least one being a skin lesion > 1 cm diameter: 
a. If treated with rituximab or other anti-CD20 antibodies, last dose > 12 months 
prior to screening; 
b. If being treated with other immunosuppressants (i.e., azathioprine, mycophenolate 
mofetil or cyclosporine), must be on stable dose (< 10% change in dose) for 
6 weeks prior to screening; 
c. If being treated with corticosteroids, must be ≤ 1mg/kg/day and stable (< 10% 
change in dose) for 2 weeks prior to screening; 
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d. Allowed topical therapies for pemphigus lesions upon entering the study include 
petroleum jelly or Aquaphor® for the skin or chlorhexidine for the mouth  
5. Body mass index (BMI) 18.5 – 35.0 kg/m2; 
6. Has a negative urine pregnancy test (for women of childbearing potential) documented 
prior to the first dose of study drug;     
7. Females of childbearing potential must agree to be abstinent or else use any two of the 
following medically acceptable forms of contraception (<1% per year failure rate) from 
the Screening Period through 60 days after the final study dose: oral contraceptive, 
condom with or without spermicidal jelly, diaphragm or cervical cap with spermicidal 
jelly, or intra-uterine device (IUD). A female whose male partner has had a vasectomy 
must agree to use one additional form of medically acceptable contraception.  
8. Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for 
at least 12 months do not require contraception during the study. 
9. Males with female partners of childbearing potential, including males who are surgically 
sterile (post vasectomy), must agree to be abstinent or else use a medically acceptable 
form of contraception from the screening period through 60 days after the final study 
dose.  
5.3 
Exclusion Criteria    
A subject who meets any of the following criteria is ineligible for the study: 
 
1. Unable or unwilling to comply with the protocol; 
2. Active non-hematologic malignancy or history of non-hematologic malignancy in the 
3 years prior to screening (exclusive of non-melanoma skin cancer and cervical cancer in 
situ); 
3. Positive for HIV or hepatitis C antibody;  
4. Positive for hepatitis B surface antigen; 
5. Active infection or history of recurrent infections; 
6. IVIG treatment within 60 days of screening; 
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7. Received any cytotoxic (other than azathioprine) or mAb therapy in the 3 months prior to 
screening; 
8. Any exposure to an investigational drug or device within 30 days prior to screening; 
9. Plasmapheresis or immunoadsorption within 60 days of screening 
10. Cellular therapy at any time prior to screening 
11. Use of any immunosuppressive drugs apart from corticosteroids, azathioprine, 
mycophenolate mofetil, or cyclosporine within 3 months of screening; 
12. Serum total IgG < 600 mg/dL; 
13. Subject has any current medical condition that, in the opinion of the Investigator, may 
compromise their safety or compliance, preclude successful conduct of the study, or 
interfere with interpretation of the results (e.g., a significant pre-existing illness or other 
major comorbidity that the Investigator considers may confound the interpretation of the 
study results); 
14. Any vaccination within 2 weeks of screening 
 
 
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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All subjects must take part in the informed consent process.  Adequate time must be allowed for 
the subject to ask questions and make a voluntary decision.  No protocol-specific procedures, 
including screening procedures, are to be performed until the subject has signed and dated an 
IRB-approved ICF.  Subjects may withdraw consent at any time. Participation in the study may 
be terminated at any time without the subject’s consent as determined by the Investigator.  
6.2 
Demographics and Medical History 
Demographics (age, gender, race and ethnicity) and medical history will be obtained from the 
subject and recorded on the source document and eCRF.  Medical history will capture the 
subject’s current medical history (current disease processes), past medical status (past disease 
processes), history of surgery and concomitant treatments.  
6.3 
Physical Examination 
A complete physical examination will be performed as outlined in Table 1.  The complete PE 
will include measurements of weight (in kg) and height (in cm; height to be measured only at 
screening visit) and a review of the following body systems: 
• General appearance 
• Head, eyes, ears, nose, and throat 
• Neck 
• Respiratory 
• Cardiovascular 
• Abdomen 
• Neurologic 
• Extremities 
• Dermatologic 
• Lymphatic 
Any abnormal and clinically significant findings from the PE must be recorded in the appropriate 
eCRF.  Findings at screening and Day 0 (pre-dose) will be recorded as medical history. 
6.4 
Pemphigus Disease Area Index (PDAI) Scoring 
Pemphigus severity and disease activity will be measured using the PDAI.  See Appendix B. 
6.5 
Vital Sign Measurements 
Vital sign measurements will be collected after the subject has been sitting for 5 minutes.  Vital 
sign assessments will include measurements of sitting blood pressure (mm Hg), heart rate (beats 
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per minute), respiration rate (breaths per minute), oral temperature (Celsius).  Abnormal results 
are to be repeated after 5 minutes of rest.  Pulse oximetry (%) also is to be measured.  See 
Table 2 for timing window allowances with respect to measurement collection. 
On Days 0, 7, 14, 21, and 28, vital sign measurements are to be obtained immediately prior to the 
infusion; 15, 30, and 45 minutes after the start of the infusion; at completion of the infusion; and 
30 minutes, 1 hour and 2 hours following completion of the infusion.  Details on the 
management of mild to moderate and severe infusion reactions can be found in Figure 1 and 
Figure 2.  Abnormalities in vital sign measurements will be graded in severity per the NCI 
CTCAE scale Version 4.03. 
Subjects should be seated quietly for at least 5 minutes in a chair with their backs supported, 
their feet flat on floor (legs uncrossed), and their arms bared on a hard surface, with the arm 
slightly abducted and bent, with palm up and the midpoint of upper arm at heart level.  Correct 
cuff and bladder size should be utilized and the same cuff and arm should be used per subject 
throughout study.     
6.6 
12-Lead Electrocardiogram (ECG)   
Digital 12-lead ECG measurements will be obtained at screening, on Days 0 and 28 at 5 minutes 
after the completion of the infusion and at the Day 56 (Follow-Up) Visit.  Subjects who conduct 
their Day 12 visit at the investigative site, as opposed to an at-home nurse visit, will have an 
additional ECG performed.  ECGs are to be performed with the subject in a supine position 
having rested in this position for at least 5 minutes before each reading. ECGs are to be 
performed in triplicate, each 1 to 2 minutes apart.  See Table 2 for timing window allowances 
with respect to performing ECG. 
The following ECG parameters will be collected: PR interval, RR interval, QRS interval, and QT 
interval.  The ECG findings will be evaluated by a qualified physician for the presence of 
abnormalities (qualitative assessment).  The physician will assess each ECG as normal, 
abnormal/not clinically significant, or abnormal/clinically significant.   
Normal QTcF is ≤ 450 msec.  
Abnormalities in the ECG that appear following therapy or that result in clinical signs and 
symptoms are considered clinically significant for the purposes of this study and will be recorded 
on the AE eCRF.   
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6.7 
Clinical Laboratory Measurements   
Collection time for all safety, PD, and exploratory labs are outlined in Table 1. 
Laboratory testing (hematology, urinalysis, serum chemistry, virology, serology, pregnancy tests, 
PD samples, PK samples, and anti-drug antibody samples) will be performed using established 
methods by a central laboratory. Safety laboratory panels are defined as listed in Table 3. Blood 
and urine samples for hematology, serum chemistry, and urinalysis will be prepared using 
standard procedures.  Results will be provided to the Investigator.  Aliquots from the PK, 
biomarker and anti-drug antibody samples may be retained as back-up for additional testing as 
necessary. Subjects will be in a seated or supine position during blood collection. Full clinical 
safety lab draws will be collected at Screening and on Days 0, 7, 14, 21, 28, 33, 42 and 56.  The 
total blood draw for each subject who completes the study at Day 56, will be approximately 308 
mL.  Please refer to the Laboratory Manual for more information.    
Table 3: 
Clinical Laboratory Panels 
Hematology 
Serum Chemistry 
Urinalysis 
• 
CBC with differential 
• 
Erythrocyte Sedimentation Rate 
(ESR) 
 
• 
Albumin 
• 
Alkaline phosphatase 
• 
ALT 
• 
AST 
• 
BUN 
• 
Calcium 
• 
Carbon dioxide 
• 
Chloride 
• 
Creatinine 
• 
Glucose 
• 
LDH 
• 
Phosphorus 
• 
Potassium 
• 
Sodium 
• 
Total and direct bilirubin 
• 
Total protein 
• 
Uric acid 
• 
C-Reactive Protein 
 
• 
Appearance 
• 
Color 
• 
pH 
• 
Specific gravity 
• 
Ketones 
• 
Protein 
• 
Glucose 
• 
Nitrite 
• 
Urobilinogen 
• 
Blood/hemoglobin 
• 
Leukocyte esterase 
• 
Bilirubin 
• 
Microscopic examination of 
sediment: only if the results of 
the urinalysis dipstick evaluation 
are positive for 
blood/hemoglobin 
Virology 
 
 
• 
Hepatitis C 
• 
Hepatitis B 
 
 
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• 
HIV 
• 
VZV 
• 
Tetanus 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; BUN = blood urea 
nitrogen; HIV = human immunodeficiency virus; LDH = lactate dehydrogenase; VZV = varicella-zoster virus 
 
Abnormalities in clinical laboratory tests that are considered clinically significant are to be 
recorded on the AE electronic case report form (eCRF) page.   Laboratory results will be graded 
using the NCI CTCAE, Version 4.03. If laboratory values constitute part of an event that meets 
criteria defining it as serious, the event (and associated laboratory values) must be reported as an 
SAE (see Section 11.3.1). 
6.7.1 
Pregnancy Testing 
Pregnancy testing will be performed for women of childbearing potential at screening and prior 
to first dose of SYNT001 on Day 0 and Day 56 (urine or serum test is acceptable however, 
positive urine tests must be confirmed with serum testing.) 
6.7.2 
Virology 
Testing for HCV antibody, hepatitis B surface antigen, and HIV antibody will be performed at 
screening. 
6.7.3 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing 
Samples for serum tetanus antibody and varicella-zoster virus antibody testing are to be collected 
at baseline (pre-dose, Day 0) and on Day 56 (Follow-Up visit).  Testing at Day 56 will not be 
done for any subject whose baseline titer is below the level of detection. Specifically, if the 
baseline VZV titer is above the detectable level, but tetanus is not, only the VZV antibody titer 
will be tested on Day 56. If the Day 56 results are below the baseline value, defined as greater 
than 30% below the baseline value, or if the subject falls below the level of detection, the subject 
will be re-tested at 1 month after the Follow-Up visit (approximately 2 months after the subject’s 
last dose); if still below the baseline value (or level of detection), the subject will be re-tested 
after another month (3 months after last dose). Any subject whose baseline value for tetanus or 
VZV was above the detectable level at baseline, and is not within 30% of the baseline value or is 
below the detectable level on Day 56 and upon 2 retests (2 and 3 months following last dose of 
SYNT001), will be referred to their primary care physician for further management.  
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6.7.4 
Pharmacokinetics (PK) Sampling 
Starting on Days 0 and 28, serum samples will be collected just prior to the start of study drug 
infusion (pre-dose), at 5 minutes and 2, 4, 6, 24, and 48 hours after the end-of-study drug 
infusion.  Additional samples will be collected on Days 5 and 33.  The actual time and date of 
each blood draw is to be recorded.   
Study drug concentration will be used to calculate the following PK parameters: t1/2, Cmax, Tmax, 
AUC0-24, and AUC0-∞.   
Detailed instructions for sample collection and preparation will be provided in a separate 
laboratory manual 
6.7.5 
Pharmacodynamic Sampling 
PD samples will be collected for analyses throughout the study. On Days 0, 7, 14, 21, and 28, 
samples should be collected prior to infusion of study drug.  Measurements for albumin PD 
biomarkers will be derived from the clinical safety laboratory results.  Samples for each type of 
PD will be collected according to the schedule shown in Table 4. 
 
 
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Table 4: Pharmacodynamic/ Activity Assessments 
Parameter 
Collection Timepoints 
• 
IgG, IgG subtypes (IgG1-4), IgA, IgM  
Screening, and Days 0, 1, 2, 5, 7, 12, 14, 19, 
21, 28, 29, 30, 33, 42, and 56 
• 
Circulating immune complexes (CIC) 
Days 0, 5, 7, 12, 14, 19, 21, 28, 33, 42, and 
56 
• 
Albumin 
Screening, and Days 0, 7, 14,21, 28, 33, 42, 
and 56 
• 
Anti-Dsg (1 and 3) antibody titer 
Screening, Days 0, 7, 14, 33, and 56 
• 
Complement component 3 (C3) 
• 
Anti-epithelial cell antibody (AECA) levels by 
indirect immunofluorescence 
 
Days 0, 14, 33, and 56 
• 
Exploratory biomarker (RNAseq, Urine IgG) 
 
Days 0, 14, 33, and 56 
• 
Immune phenotyping by flow cytometry for 
measurement of CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B cells 
Days 0 and 28 
• 
Exploratory biomarker (FCGR2A SNP) 
Day 0 
 
See Table 2 for timing window allowances with respect to measurement collection. 
Detailed instructions for sample collection (including collection tubes) and preparation will be 
provided in a separate laboratory manual. 
6.7.6 
Immunogenicity Testing 
Up to 4 serum samples will be collected for immunogenicity analyses.  Samples will be collected 
on Days 0 (pre-dose), 14, 28, and 56. 
SYNT001 is being developed for the acute and chronic therapy of autoimmune disorders. 
Although SYNT001 is a humanized IgG4 monoclonal antibody, exposure to SYNT001 in 
clinical trials could result in the development of anti-drug antibodies (ADAs), with potential 
consequences ranging from neutralization or lessening of drug efficacy to safety consequences 
such as allergic reactions.  Testing will first detect binding ADAs, then, for all confirmed 
positive samples, there will be testing for neutralizing effects.  
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Detailed instructions for sample collection and preparation will be provided in a separate 
laboratory manual. 
6.8 
Study Drug Administration 
Two cohorts of 8 eligible subjects each will receive 5 once-weekly 60-minute IV infusions of 
SYNT001 10 mg/kg or up to 30 mg/kg. SYNT001 will be given as a 250-mL IV infusion over 1 
hour using a 0.2-micron, inline filter. Based on review of safety data, as well as available and 
relevant PD results, and clinical outcomes of Cohort 1, a decision about proceeding with Cohort 
2 will be made.  Based on review of all safety data, available PD results, and clinical outcomes 
of these 2 cohorts, a third cohort of 8 subjects may be treated at another dose, with a maximum 
dose of 45 mg/kg, but may also be lower than 10 mg/kg or between 10 and 30 mg/kg, inclusive.   
Cohort No. 
Study Drug 
Dose Level 
(mg/kg/dose) 
1 
SYNT001 
10 mg/kg 
2 
SYNT001 
30 mg/kg 
See Section 9.1 for dosing schedule.   
6.9 
Prior and Concomitant Medications 
All medications a subject receives within 14 days prior to enrollment through the end of the 
study (Day 56) will be documented on the source document and eCRF.   
Note:  No vaccinations may be given from within 2 weeks of screening until 2 months following 
the last dose of study drug. 
6.10 
Adverse Event Assessments 
Information regarding the occurrence of AEs will be collected from the time the subject signs the 
informed consent form throughout their participation in the study, including a period of 28 days 
after study drug dosing.  Findings at screening and Day 0 (pre-dose) will be recorded as medical 
history.   Any known untoward event that occurs beyond the AE reporting period that the 
Investigator assesses as related to study drug also should be reported as an AE. 
Clinical AEs will be graded using the NCI CTCAE, Version 4.03 (Appendix A).   
Note:   AEs resulting in a subject’s permanent discontinuation from the study, regardless of 
seriousness or relationship to study drug, MUST be promptly reported to the sponsor.  
Additionally, subjects must be followed until return to normal and/or resolution of the AE. 
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See Section 11 for more information. 
6.11 
Photographs 
On Day 0 photographs will be taken of active lesions.  Follow-up photographs will be taken of 
the same areas on Days 33 and 56.  Subjects who begin a steroid taper will have additional 
photographs taken at the clinic visit during which the decision to begin the taper is made.  A 
separate manual describing the procedures for taking photographs will be provided. 
6.12 
Skin Biopsy 
Optional skin biopsy samples will be collected on Day 0 pre-dose and on Days 1, 2, 14, 33 and 
56 to analyze SYNT001 levels. 
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7 
STUDY ASSESSMENTS 
7.1 
Screening Period: Day -14 to Day -1 
Informed consent must be obtained before any study-specific samples are taken or study-specific 
tests or evaluations are conducted.  The following assessments at the screening visit are to occur 
within 14 days before dosing.  Study eligibility will be based on satisfying all the study inclusion 
and exclusion criteria.   
At the screening visit, information will be collected and subjects will have clinical evaluations as 
follows: 
• Informed consent (Section 6.1) 
• Medical history and demographic data (Section 6.2) 
• Review inclusion and exclusion criteria (Section 5.2, Section 5.3) 
• Complete PE, including height and weight (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• 12-Lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position) 
(Section 6.6) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Pregnancy test (Section 6.7) 
• Hepatitis and HIV screen (Section 6.7) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• Anti-Dsg (1 and 3) antibody titer 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.2 
Enrollment and First Treatment: Day 0  
Study Day 0 is defined as the date the subject is administered their first dose of study drug. On 
Day 0, subjects will be asked to come to the clinic and the following procedures will be 
performed prior to the first dose of study drug: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
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• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Pregnancy test (Section 6.7) 
• Serum tetanus antibody and VZV antibody (Section 6.7) 
• PDAI Score (Section 6.4) 
• PK baseline sample collection (collected just prior to the start of the study drug infusion) 
(Section 6.7) 
• Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
(Section 6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• Anti-Dsg (1 and 3) antibody titer 
• CIC  
• C3 
• AECA 
• FCGR2A SNP 
• RNAseq 
• Urine IgG 
• Immune phenotyping 
• Optional skin biopsy (Section 6.12) 
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
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temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• PK sample collection at 5 minutes and 2, 4, 6 hours after the end-of-study drug infusion; 
record collection date and time for each PK sample (Section 6.7) 
• 12-Lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion (Section 6.6) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.3 
Follow-up: Day 1  
On Day 1 (24 hours ± 1 hour from end-of-infusion time on Day 0), the subject will return to the 
clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• PK sampling (record collection date and time) (Section 6.7) 
• Optional skin biopsy (Section 6.12) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.4 
Follow-up: Day 2 
On Day 2 (48 hours ± 2 hours from end-of-infusion time on Day 0), the subject will return to the 
clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• PK sampling (record collection date and time) (Section 6.7) 
• Optional skin biopsy (Section 6.12) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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7.5 
Follow-up: Day 5  
On Day 5 (120 hours ± 4 hours from end-of-infusion time on Day 0), subjects may return to the 
clinic or be visited by at-home nurse, and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PK sampling (record collection date and time) (Section 6.7) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.6 
Treatment Day 7 (Dose 2)  
On Day 7 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
• PDAI Score (Section 6.4) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
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and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.7 
Dose 2 Follow-up Day 12 
On Day 12 (± 6 hours) the subject may will return to the clinic, or be visited by at-home nurse, 
and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• If visit performed at the study site: 12-Lead ECG to be obtained in triplicate (Section 6.6) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.8 
Treatment Day 14 (Dose 3) 
On Day 14 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
• PDAI Score (Section 6.4) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
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• Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
(Section 6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• Anti-Dsg (1 and 3) antibody titer 
• CIC 
• C3 
• AECA 
• RNAseq 
• Urine IgG  
• Optional skin biopsy (Section 6.12) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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7.9 
Dose 3 Follow-up Day 19 
On Day 19 (± 6 hours) the subject may return to the clinic, or be visited by an at-home nurse, and 
the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.10 
Treatment Day 21 (Dose 4) 
On Day 21, (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
• PDAI Score (Section 6.4) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
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• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.11 
Treatment Day 28 (Dose 5) 
On Day 28 (± 1 Day), subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PDAI Score (Section 6.4) 
• PK sampling (collected just prior to the start of the study drug infusion; record collection 
date and time for each PK sample) (Section 6.7) 
• Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
(Section 6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Immune phenotyping 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
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and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• PK sample collection at 5 minutes and 2, 4, 6 hours after the end-of-study drug infusion; 
record collection date and time for each PK sample (Section 6.7) 
• 12-Lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion (Section 6.6) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.12 
Follow-up Day 29  
On Day 29 (24 hours ± 1 hour from end-of-infusion time on Day 28), the subject will return to 
the clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• PK sampling (record collection date and time) (Section 6.7) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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7.13 
Follow-up Day 30 
On Day 30 (48 hours ± 2 hours from end-of-infusion time on Day 28), the subject will return to 
the clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• PK sampling (record collection date and time) (Section 6.7) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.14 
Follow-up Day 33  
On Day 33 (120 hours ± 4 hours from end-of-infusion time on Day 28), subjects will return to 
the clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PDAI Score (Section 6.4) 
• PK sampling (record collection date and time) (Section 6.7) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• C3 
• AECA 
• RNAseq 
• Urine IgG  
• Optional skin biopsy (Section 6.12) 
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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7.15 
Follow-up Day 42  
On Day 42 (± 3 days), subjects will return to the clinic and the following procedures are to be 
performed: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.16 
Follow-up Day 56 (End-of-Study) or Early Termination Visit 
On Day 56 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Pregnancy test (Section 6.7) 
• 12-Lead ECG (to be obtained in triplicate after 5 minutes of rest in the sitting position) 
(Section 6.5) 
• Serum tetanus antibody and VZV antibody; Testing at Day 56 will not be done for any 
subject whose baseline titer is below the level of detection. See Section 6.7.3 for 
additional information.   
• Immunogenicity sample collection (Section 6.7) 
• PDAI Score (Section 6.4) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• C3 
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• AECA 
• RNAseq 
• Urine IgG  
• Optional skin biopsy (Section 6.12) 
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.17 
Extended Follow-up Visits 
Extended follow-up visits will occur only if additional testing for anti-tetanus and/ or anti-VZV 
titers are required.  These visits will occur as needed at approximately 2 months post last dose 
and 3 months post last dose.  See Section 6.7.3. 
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8 
REMOVING SUBJECTS FROM STUDY 
Every reasonable effort will be made to keep the subject in the study; however, if a subject is 
withdrawn from the study, every effort will be made by the Investigator to complete and report 
the reasons for withdrawal as thoroughly as possible.  The reason(s) for termination must be 
clearly documented on the appropriate page of the eCRF.  Once a subject discontinues from the 
study for any reason, every effort will be made to collect all clinical and laboratory data as 
scheduled for the Early Termination Visit (See Table 1).  A termination eCRF must be 
completed for all enrolled subjects. 
8.1 
Subject Withdrawal  
A subject’s participation in the study may be prematurely discontinued for any of the following 
reasons:  
1. The subject wishes to withdraw from the study. 
2. Request by a regulatory agency (e.g., Institutional Review Board). 
3. Subject experiences a significant or intolerable AE.   
4. The subject experiences a significant adverse change in vital signs, PE findings, or a 
clinical laboratory parameter. 
5. The subject has a need for a concomitant medication that is not permitted by the study 
protocol. 
6. The subject experiences generalized impairment or mental incompetence that would result 
in the subject being unable to understand his or her participation in the study. 
7. If, in the Investigator’s medical judgment, further participation would be injurious to the 
health and well-being of the subject, or is not in the best interest of the subject.  
8. Administrative reasons, such as subject non-compliance or a major protocol violation. 
Subjects who are withdrawn from this study due to an AE determined to be related to study drug 
are to be followed until there is either: 
• Resolution or stabilization of the AE determined to be related 
• The subject is lost to follow-up 
• The event is otherwise explained 
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If there is a persistent AE contributing to discontinuation that is determined to be related to 
SYNT001, subjects must be followed with appropriate medical management until resolution or 
stabilization. 
A reasonable effort should be made to contact any subject lost to follow-up during the study to 
complete assessments and retrieve any outstanding data.  If the subjects are unreachable by 
telephone after three (3) attempts, the minimum of a registered letter should be sent requesting 
that contact be made with the Investigator to report survival information.   
8.2 
Study Discontinuation 
Syntimmune Inc. has the right to terminate or to stop the study at any time.  Reasons for study 
discontinuation may include, but are not limited to the following:  
• The incidence or severity of AEs in this or other related studies indicates a potential health 
hazard to subjects  
• Subject enrollment is unsatisfactory 
• Drug supply issues 
• Excessive subject self-withdrawal 
• Significant protocol violations (e.g., violation of eligibility criteria, dosing errors, missing 
data for study endpoint analysis) 
8.3 
Replacements 
Enrolled subjects withdrawn for a reason other than an AE will be replaced if they have not been 
dosed or have only received one dose of study drug at the time of discontinuation, up to one 
subject per cohort. Subjects who do not receive all doses of study drug will continue to be 
followed through 28 days after their last dose.   
8.4 
Stopping Rule 
8.4.1 
Dose-Escalation Stopping Rule 
Dose-limiting toxicity (DLT) will be defined generally as clinically significant, severe (Grade 3) 
AEs occurring in ≥2 subjects that are determined to be clinically significant and considered 
related to study drug. 
If 2 or more subjects at any time in any cohort (8 total subjects per cohort) have Grade 3 AEs 
that are determined to be clinically significant and considered to be related to study drug, dosing 
will be halted within that cohort and no further dose-escalation will occur. If the dose-escalation 
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stopping rule is met in Cohort 1 (10 mg/kg) all safety data and all available pharmacodynamics 
will be reviewed and a cohort may be added at a dose at least 50% lower than the 10 mg/kg dose.  
If the stopping rule is not met after Cohort 1, dose-escalation may proceed up to a maximum of 
30 mg/kg.  If the dose-escalation stopping rule is met in Cohort 2, all safety data and all available 
pharmacodynamics will be reviewed and a cohort may be added at a dose a minimum of 30% 
lower than the Cohort 2 dose. If the stopping rule is not met after Cohort 2, dose-escalation may 
proceed up to a maximum of 45 mg/kg; however, this cohort may also receive a dose equal to or 
less than 30 mg/kg based on evaluation of all safety and pharmacodynamic data.   
8.4.2 
Study Stopping Rule 
If any subject experiences a life-threatening AE (Grade 4) that is considered to be related to 
study drug, further dosing in all enrolled subjects will be suspended until the DEC has evaluated 
the event and determined the appropriate course of action.  At any time during the study, the 
study may be discontinued if the DEC determines that further drug exposure would pose an 
undue risk to subjects. 
8.4.3 
Individual Stopping Rule 
Dosing for any individual subject will be discontinued (i.e., no further study drug will be given 
to that subject) if the subject experiences any study drug-related SAE or any study drug-related 
non-SAE adverse event that, in the judgement of the Investigator and Medical Monitor suggest 
that it could be unsafe to administer further study drug to that subject.  Additionally, a subject 
may be discontinued from further treatment with study drug, at the discretion of the Investigator 
with consultation with the Medical Monitor, if they require a significant increase in dose(s) of 
anti-pemphigus medication(s) for the management of pemphigus. 
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9 
STUDY DRUG 
For detailed information regarding SYNT001 preparation and administration, refer to the 
Pharmacy Manual. 
9.1 
SYNT001  
SYNT001 is provided in vials containing 5 mL SYNT001 (extractable volume) at a nominal 
concentration of 50 mg/mL.  The product is supplied as a liquid at pH 6.5 ± 0.5. SYNT001 is 
diluted in Dextrose 5% in Water (D5W) to prepare the solution for infusion.  SYNT001 will be 
infused via IV in 250 mL over 1 hour using a 0.2-micron, inline filter.   
Two cohorts of 8 eligible subjects each will receive 5 once-weekly 60-minute infusions of 
SYNT001 in planned doses of 10 mg/kg or 30 mg/kg. Based on review of safety, PD, and 
clinical outcomes of these two cohorts, a third cohort of up to 8 subjects may be treated at 
another dose, with a maximum dose of 45 mg/kg, but may also be lower than 10 mg/kg or 
between 10 and 30 mg/kg, inclusive.  
The specification for host cell DNA in SYNT001 is < 2 pg/mg, the limit of quantitation of the 
assay.  To comply with regulatory guidelines, which specify a maximum level of 10 ng host cell 
DNA per dose, dosing is limited to 5000 mg of SYNT001. Therefore, at the highest dose 
possible in this study (45 mg/kg), maximum subject weight will be limited to 111 kg.  
9.2 
Cohort Dosing 
Cohorts will be dosed sequentially beginning with Cohort 1.  The first 2 subjects will be dosed at 
least 24 hours apart.  A review of the 24-hour safety data for the first subject will be performed 
to ensure that there are no overt safety concerns before dosing the second subject.  A review of 
the 7-day safety data for the first 2 subjects will be performed prior to dosing the remaining 6 
subjects in the cohort.  Cohort 2, and Cohort 3 if added, will be dosed per the same schedule 
9.3 
Timing of Dosing  
On Days 0, 7, 14, 21, and 28, subjects will receive a 60-minute IV infusion of SYNT001 in the 
morning.  The date and time the dose is administered will be recorded.   
9.4 
Identity of Investigational Products 
All supplies of SYNT001 will be supplied by Syntimmune and must be stored refrigerated (2ºC 
to 8ºC/36ºF to 46ºF) in the carton and protected from light, in a securely locked area, accessible 
to authorized persons only, until needed for dose preparation.  Qualified site personnel will 
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inventory the investigational product received and will maintain records of disposition of the 
drug, including dates, quantity and use. 
9.5 
Investigational Product Retention at Study Site 
The Investigator (or designee) is responsible for maintaining accurate accountability records of 
the investigational product throughout the clinical study. All study drug received at the site must 
be inventoried and accounted for in an accountability log provided by the Sponsor. All 
dispensing and accountability records will be available for Sponsor review. Study drug 
accountability will be verified during on-site monitoring visits. 
Upon the completion or termination of the study, and upon written authorization from the 
Sponsor, or its representative, all unused and/or partially used study drug should be returned or 
destroyed at the investigational site, as specified by Sponsor.  It is the Investigator’s 
responsibility to ensure that the Sponsor, or its representative, has provided written authorization 
that procedures for proper disposal of the study drug have been established, and that appropriate 
records of the disposal are documented and maintained.  No unused study drug may be disposed 
until fully accounted for by the Sponsor monitor (or designee) 
9.6 
Warnings and Precautions  
Note: Subjects must not receive any vaccinations from within 2 weeks of screening until 
2 months after the last dose of study drug. 
9.6.1 
Infusion Reaction 
SYNT001 will be given as an IV infusion over 1 hour. As with all mAbs administered by IV 
infusion, infusion reactions are possible.  In nonclinical testing of SYNT001 in NHPs, clinical 
observations were limited to infusion reactions due to the immunogenicity of SYNT001 in 
NHPs. These reactions included transient emesis/vomitus which typically occurred within 1 hour 
of dosing at all dose groups, but only after the third weekly infusion following the development 
of ADAs. Transient histamine-type responses were noted 30 minutes post-dose in some animals 
in all dose groups, but only following the third weekly infusion as above.  These reactions were 
consistent with a histamine reaction (decreased activity, periocular swelling, erythema, facial 
flushing, eyelids partially/completely closed, and/or generalized weakness).  With the exception 
of vomitus/emesis and red skin discoloration associated with injection or blood draw sites, these 
observations spontaneously resolved within 1-hour post-dose. Subsequent pretreatment with 
intramuscular diphenhydramine prevented further histamine-type reactions.  All doses of 
SYNT001 were administered by bolus infusion over approximately 5 minutes in the NHP 
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studies.  However, all of the observed infusion reactions (including vomitus/emesis and 
histamine-type reactions) associated with ADAs are not at all predictive of what may occur in 
humans [Bugelski 2004, Ponce 2009] and furthermore, are not considered relevant to predicting 
responses in humans [ICH S6(R1) 2011].   
Typically, infusion reactions to monoclonal antibodies observed in human studies develop within 
30 minutes to 2 hours after the initiation of drug infusion, although symptoms may be delayed 
for up to 24 hours. Most are mild in severity, although severe and even fatal reactions can occur.  
Guidelines for Grading and Management of Allergic or Infusion-Related Reactions 
Allergic and/or infusion-related reactions include hypersensitivity reactions and cytokine release 
syndromes. These reactions are experienced by patients during or within hours of the infusion of 
monoclonal antibody therapy. Symptoms can include flushing, alterations in heart rate and blood 
pressure, dyspnea, bronchospasm, back pain, fever, urticaria, edema, nausea, and all types of 
rashes. Anaphylaxis is recognized as a severe, life-threatening, generalized, or systemic reaction. 
This is a medical emergency characterized by rapidly developing life-threatening airway and/or 
breathing and/or circulation problems usually associated with skin or mucosal changes.  
Management of Grade 1 infusion reactions include decreasing the rate of infusion by 50% and 
observing.  Symptoms may also be treated as needed with medications such as diphenhydramine, 
hydrocortisone or acetaminophen. 
Management of Grade 2 and higher infusion reactions should include stopping the infusion of 
study drug.  See Figure 1 and Figure 2 for details on the management of Grades 1-2 and Grade 3 
or higher infusion reactions. The severity of and management of allergic or infusion-related 
reactions will be graded and managed using NCI CTCAE Version 4.03 (see Table 5).   
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Figure 1:  Management of Mild (Grade 1) to Moderate (Grade 2) Infusion Reactions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stop  
Infusion 
Assess airway, breathing, circulation, and consciousness, and recline subject 
 
Start high flow oxygen 
Insert large bore IV and start IV fluids 
Initiate vital sign assessments at least every 15 minutes 
Any problem with airway, breathing 
circulation, or consciousness? 
NO: 
Initiate medical 
review 
YES:   
Initiate treatment per the 
Severe Infusion Reaction 
Flow Chart 
Monitor for symptom resolution 
If symptoms persist, proceed with medications as needed.  For example: 
diphenhydramine 25-50 mg IV and/ or hydrocortisone 200 mg IV 
Note:  If desaturation, 
hypotension, or urticaria 
present, refer to Severe 
Infusion Reaction Flow 
Chart. 
Subject presents with any of 
the below: 
• 
Altered vision 
• 
Impending feeling 
of doom 
• 
Pain:  Back, 
abdomen, chest 
• 
Flushing 
• 
Wheezing without 
desaturation 
• 
Pyrexia 
• 
Peripheral edema 
• 
GI symptoms 
 
If ongoing symptoms, consider ongoing 
observation or hospital admission 
If symptoms and signs resolve completely either spontaneously or after administration of diphenhydramine 
with or without hydrocortisone, consider rechallenge:   
Wait at least 20 minutes following medication administration before commencing rechallenge at an infusion 
rate of 50% or less of the initial infusion rate or 
Consider pre-medicating the subject with the same medication(s) 20-30 minutes in advance of subsequent 
administrations of SYNT001 and starting infusion at 50% of the planned infusion rate for the first 30 minutes, 
then returning to the intended infusion rate in the absence of any infusion reaction 
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Figure 2:  Management of Severe (Grade 3 or higher) Infusion Reactions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject presents with any of the below: 
• 
Urticaria 
• 
Airway threatened by angioedema 
• 
Angioedema: Lip, mouth, facial swelling 
• 
Respiratory compromise - wheezing, dyspnea, stridor or hypoxia 
(O2 saturation < 90%) 
• 
BP < 90 mmHg SBP or >30% decrease from patient baseline 
Stop  
Infusion 
Consider (under medial direction): 
 
Epinephrine 1:1000 
• 
0.3 mg (0.3 mL) IM into lateral thigh 
Transfer to Emergency Room/ICU 
Observe until all symptoms resolved. 
Start basic life support: 
• 
High oxygen flow 
• 
On bed, head down, legs up 
• 
Large bore IV cannula, 1 L normal saline STAT 
• 
Initiate vital signs at least every 15 minutes 
Airway Threatened: 
Nebulized epinephrine 1:1000, 3–5 mL (3–5 mg) 
Bronchospasm: 
Nebulized salbutamol 5 mg 
(Wheeze or Hypoxia) 
Consider: Intubation / nebulized epinephrine 
 
Hypotension: 
Place on cardiac monitor 
(Systolic BP <100 mmHg) 
Further epinephrine 1:1000, 0.3 mg IM and  
 
IV normal saline bolus 20 mL/kg STAT as needed 
 
Have vasopressin on hand 
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Table 5: 
Grading and Management of Allergic or Infusion-Related Reactions  
Adverse 
Event 
Grade 
1 
2 
3 
4 
5 
Infusion-
Related 
Reaction 
Mild transient 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤ 24 hours 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated for 
clinical sequelae 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Allergic 
Reaction 
Transient 
flushing or 
rash, drug 
fever 
< 38.0°C. 
Intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤ 24 hours 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated for 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Anaphylaxis 
- 
- 
Symptomatic 
bronchospasm, with or 
without urticarial; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Cytokine 
release 
syndrome 
Mild 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤ 24 hours 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated for 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Life-
threatening 
consequences; 
pressor or 
ventilator 
support 
indicated 
Death 
Abstracted from NCI CTCAE Version 4.03. 
 
 
 
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9.6.2 
Potential Immune Effects 
An antibody blocking FcRn is anticipated to have several effects.  These include acceleration of 
catabolism of IgG, but not other immunoglobulin isotypes such as IgA and IgM, leading to dose-
dependent decreases in circulating IgG levels by up to an estimated 50% from the baseline levels 
after a single dose and further decreases after multiple doses up to a 70% to 80% reduction. 
Based on studies in humans, it is expected that with a single dose, the nadir of this effect will 
occur approximately 5 days after dosing.  The time course of recovery of IgG following dosing 
in the Phase 1a study suggests that a return to within normal limits occurs within 4 weeks after a 
single dose and within 4 weeks after multiple doses as shown in NHPs. 
Given the normal adult range of IgG of 700 to 1600 mg/dL (in some references), with a mean of 
1150 mg/dL, a 50% decrease in the mean would be to 575 mg/dL and a 50% decrease from the 
low end of the normal range of 700 mg/dL would be to 350 mg/dL. An 80% decrease from 
baseline after multiple doses would result in IgG levels of 230 mg/dL and 140 mg/dL, 
respectively.  While these levels are in the range found in patients with primary humoral 
immunodeficiency [Ameratunga 2013], the levels will be transient. Study subjects will be 
monitored clinically for any infection. Further, commercial IVIG can be given to reverse the low 
IgG levels in case of a bacterial infection occurring while their IgG levels are decreased. 
An antibody blocking FcRn is expected to also down modulate innate and adaptive immunity 
and the catabolism of IgG-containing immune complexes (IC). Specifically, it is expected that 
anti-FcRn will promote the clearance of IgG-containing ICs and the effects of these IC on 
stimulating innate immune cell production of inflammatory cytokines (e.g., IL-12, interferon-γ, 
and tumor necrosis factor [TNF]) and inhibit the processing and presentation of antigens 
contained within IC and thus the antigen-specific activation of CD4+ and CD8+ T-cells. 
Therefore, subjects with pre-existing conditions that are dependent upon IgG antibodies, such as 
chronic infections (e.g., HIV, HBV or HCV), will be excluded from this study, as will subjects 
with active infection in general. 
SYNT001 administration could decrease the level of protective antibodies from prior 
vaccinations. Protective antibody levels for tetanus and varicella-zoster virus (chickenpox) are to 
be tested in accordance with Section 6.7.3.  
 
 
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10 
CONCOMITANT MEDICATION AND TREATMENT 
All treatments a subject receives within 14 days prior to enrollment through the end of the study 
(Day 56) will be documented.  Concomitant medication and treatment for co-existing conditions, 
including those for pemphigus, are permitted if not excluded below.  Topical antibiotics are 
permitted to treat active infections that occur on study.  Topical or systemic treatments for oral 
candidiasis are permitted.  Topical lidocaine for transient pain relief is acceptable as needed. 
Significant increases in anti-pemphigus medications may result in subjects being discontinued 
from the study.  Concomitant treatment that is medically indicated for any AEs the subject 
experiences during the study are permitted    
Use of the following treatments will not be permitted during the study unless otherwise 
specified: 
• Rituximab or other anti-CD20 antibody 
• Monoclonal antibodies other than study drug 
• Any immunosuppressive drugs apart from corticosteroids, azathioprine, mycophenolate 
mofetil, or cyclosporine. 
• Topical steroids 
• Any dietary herbal supplements 
• Any investigational drug or device 
• Any vaccinations 
If over a period of at least two weeks on study drug, a subject on corticosteroids shows the 
absence of new lesions and significant healing of lesions that existed at study baseline, a slow 
corticosteroid taper may be started as per the following suggested schedule  
• If on > 30 mg of prednisone per day, decrease by 10 mg every two weeks until a dose of 
30 mg per day then decrease by 5 mg every two weeks 
• If on < 30 mg of prednisone per day, decrease by 5 mg every two weeks 
In cases in which concomitant medications are used, details to be recorded include the following: 
medication name, start date and time, stop date and time, dose, route, frequency, and reason for 
use.  The concomitant medication names are to be coded using the World Health Organization 
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(WHO) Drug Dictionary (WHO-DD March 2013, Type B2 or later) and classified by anatomical 
therapeutic chemical (ATC) categories. 
 
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11 
SAFETY 
11.1 
Safety Parameters 
Clinical and laboratory AEs will be graded using the NCI CTCAE; Version 4.03 (See 
Appendix A).  
 Subjects will be monitored throughout the treatment and follow-up period for occurrence of AEs 
(acute, delayed, and/or cumulative), as well as for changes in clinical status, vital sign 
measurements, and laboratory data (including PD).  Safety parameters to be measured/assessed 
include PEs, vital sign measurements, hematology, serum chemistries, urinalysis, and ECG. 
11.2 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical trial subject associated with 
the use of a drug, whether considered drug related.  An AE can be an unfavorable and 
unintended sign (e.g., an abnormal laboratory value finding), a symptom, or a disease temporally 
associated with the use of a drug, without judgment as to causality.  An AE can arise from use of 
the drug (e.g., use in combination with another drug) and from any route of administration, 
formulation or dose, including an overdose.  An AE also includes, but is not limited to, any 
clinically significant worsening of a pre-existing condition.  Examples include: 
• Any sign, symptom, physical finding, or laboratory result that has worsened in nature, 
severity or frequency compared to baseline; 
• Reactions from an investigational drug, including those occurring because of an 
overdose, abuse of the study drug, withdrawal phenomena, sensitivity or toxicity; 
• Concurrent illness that was not present or worsens in nature, severity, or frequency 
compared to baseline;  
• Injury or accident; and/or 
• Exacerbation of a pre-existing condition. 
For data collection, all untoward events that occur after informed consent through 28 days after 
study drug dosing are to be recorded on eCRFs by the investigational site. 
While pregnancy alone is not considered as an AE or SAE, any pregnancy complication(s) 
should be recorded as an AE(s) or SAE(s) (if applicable).  Elective abortions without 
complications should not be regarded as AEs, unless they were therapeutic abortions (see 
below).  Hospitalization for normal delivery of a healthy newborn should not be considered an 
SAE.  If a female subject becomes pregnant during the conduct of the study, the Investigator 
must notify the Sponsor according to the procedures provided in Section 11.3.8). 
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11.3 
Evaluating Adverse Events 
The Investigator will determine the seriousness, intensity, and causality of an AE associated with 
the use of the study drug (i.e., events where there is a reasonable possibility that the event may 
have been caused by the study drug) based on the definitions that follow. 
11.3.1 
Serious Adverse Events 
(Notify Medpace Safety within 24 hours; document on eCRF) 
The SAE definition and reporting requirements are in accordance with Title 21 Part Code of 
Federal Regulations (CFR) 312.32 and the Guidance for Industry and Investigators Safety 
Reporting Requirements for Investigational New Drug (INDs) and Bioavailability 
/Bioequivalence Studies. 
SAE:  An AE is considered "serious" if, in the view of either the Investigator or sponsor, it 
results in any of the following outcomes: 
• Death:  This includes any death that occurs while the subject is “on study” as well as any 
death that occurs within 28 days after study drug administration.  
Note: Death is an outcome of an AE, and not an AE.  The event(s) that caused death 
(e.g., illness, accident) is the SAE.  Death due to any other cause(s) must also 
be reported as an outcome of the reportable SAE. 
• Life-threatening adverse drug event:  An AE or suspected adverse reaction is 
considered “life threatening” if, in the view of either the Investigator or sponsor, its 
occurrence places the patient or subject at immediate risk of death. It does not include an 
AE or suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death.   
• Inpatient hospitalization or prolongation of existing hospitalization: 
In the absence of an AE, the Investigator should not report hospitalization or prolongation 
of hospitalization.  This is the case in the following situations: 
o Hospitalization or prolongation of hospitalization is needed for a procedure 
required by the protocol 
o Hospitalization or prolongation of hospitalization is part of routine procedure 
followed by study center 
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o Hospitalization for survey visits or annual physicals 
o Hospitalization for observation with release within 24 hours 
In addition, a hospitalization planned before the start of the study for a pre-existing 
condition, which has not worsened, does not count as an SAE.  
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions    
• Congenital anomaly/birth defect 
• Important medical event:  An event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, it may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.   
11.3.2 
Overdose 
An overdose is defined as a significant variation from the recommended/scheduled dosage for a 
product. The dosing for this study will be conducted in a controlled clinical setting and an 
overdose is not anticipated. However, in the event of an accident, for this study, an overdose of 
SYNT001 is considered a dose that is two-fold higher than the intended dose for the subject. 
11.3.3 
Non-Serious Adverse Events  
(Document on eCRF) 
All other AEs, not fulfilling the previous definitions, are classified as non-serious. 
11.3.4 
Protocol-Related Adverse Events 
AEs that are not test drug related may nevertheless be considered by the Investigator or the 
Medical Monitor to be related to the conduct of the clinical study.  That is, the event may be 
related to the fact that a subject is participating in the study.  For example, a protocol-related AE 
may be an event that occurs during a screening period or that is related to a procedure required 
by the protocol. 
11.3.5 
Assessment of Causality 
A medically qualified Investigator must assess the relationship of any AE (including SAEs) to 
the use of the investigational product, as related or not related, based on clinical judgment and 
using all available information, and may include consideration of the following factors: 
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• Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic 
factors. 
• The temporal association between drug exposure and onset of the AE. 
• Whether the manifestations of the AE are consistent with known actions or toxicity of the 
investigational product. 
• The AE resolved or improved with decreasing the dose or stopping use of the 
investigational product (dechallenge).  Judgment should be used if multiple products are 
discontinued at the same time. 
The causal relationship between the study medication and the AE will be assessed using one of 
the following categories: 
Not Related:  Factors consistent with an assessment of Not Related include: 
• Temporal relationship is lacking (e.g., the event did not occur within a reasonable 
time frame following administration of the study medication); or 
• Other causative factors more likely explain the event (e.g., a pre-existing 
condition, other concomitant treatments). 
Related:  Factors consistent with an assessment of Related include: 
• There is a positive temporal relationship (e.g., the event occurred within a 
reasonable time frame following administration of study medication); or 
The AE is more likely explained by the investigational product than by another cause (i.e., the 
AE shows a pattern consistent with previous knowledge of the investigational product or the 
class of the investigational product) 
11.3.6 
Recording Adverse Events 
All AEs (including SAEs) are to be accurately recorded on the Adverse Event page of the 
subject’s eCRF.  The severity of each AE will be graded using the NCI CTCAE, Version 4.03.  
The date of onset as well as the end date of the event also should be recorded or the event should 
be entered as “ongoing”.  In addition, the method used to treat the AE and the outcome of the AE 
also will be noted.  The Investigator will assess the relationship of the event to study drug.       
11.3.7 
Planned Hospitalization 
A hospitalization planned by the subject prior to the first dose of study medication is considered 
a therapeutic intervention and not the result of a new SAE and should be recorded as medical 
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history.  If the planned hospitalization or procedure is executed as planned, the record in the 
subject’s medical history is considered complete.  However, if the event/condition worsens 
during the trial, it must be reported as an AE. 
11.3.8 
Reporting Pregnancies 
If a female subject or the female partner of a male subject becomes pregnant during the course of 
the study, the Investigator must report the pregnancy to the Medpace Safety using the 
Pregnancy Reporting Form within 24 hours of becoming aware of the event.  The Investigator 
must obtain consent to collect pregnancy information (including the status of the newborn, if 
applicable). 
If some of the information required for completion of the Pregnancy Reporting Form is 
unavailable at the time of the initial report, follow-up reports will be completed and submitted 
within 24 hours of becoming aware of the new information.  Any pregnancy will be followed 
through delivery for the observation of any SAEs.  Any SAE that occurs during pregnancy must 
be recorded on the SAE report form in the EDC system (e.g., maternal serious complications, 
therapeutic or spontaneous abortion, ectopic pregnancy, stillbirth, neonatal death, congenital 
abnormality, birth defect) and reported within 24 hours in accordance with the procedure for 
reporting SAEs (See Section 11.3.9).   
11.3.9 
Serious Adverse Event Reporting 
11.3.9.1 
Governing Regulatory Requirements 
Compliance with this request for prompt reporting is essential in that the sponsor is responsible 
for informing the US Food and Drug Administration (FDA) and other regulatory authorities as 
well as all other participating Investigators of the event.  
Under FDA ruling (US Code of Federal Regulations, Title 21 CFR Part 312.32) and the ICH 
Guidelines for Clinical Safety Data Management Definitions and Standards for Expedited 
Reporting, the sponsor is required to submit written documentation, in the form of a safety 
report, detailing: 
• Any event associated with the use of the drug, that is both serious and unexpected, or  
• Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.  
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Written submission must be made by the sponsor to the FDA and the IRBs as soon as possible 
and in no event later than 15 calendar days after the sponsor’s initial notification of the event.  
The sponsor shall also inform all Investigators. 
11.3.9.2 
Time Frame for Reporting 
Any death, SAE, pregnancy, or unexpected (and severe) AE experienced by the subject after 
informed consent or within 28 days of receiving study drug, regardless of relationship to study 
drug, or any death that occurs more than 28 days after receiving study drug, and is believed to be 
study drug related, must be promptly reported (within 24 hours of the Investigator becoming 
aware of the event) by telephone or electronic transmission to the sponsor (or designee). 
 
 
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Contact information for SAE reporting: 
 
 
 
Medpace Clinical Safety  
Medpace SAE hotline:  
Telephone: 
 dial or 
 dial
Facsimile: 
or 
 
e-mail
 
Additionally, the Investigator will be able to contact the Medical Monitor: 
Medical Safety Contact 
Phone (US): 
 extension
Mobile phone:
Email:
 
11.3.9.3 
Information to be Provided by the Investigator 
SAEs must be recorded on the SAE form in the EDC system.  This requirement includes all 
SAEs that occur after informed consent and through 28 days after study drug dosing, and in 
addition, any SAE that are assessed as related to study treatment by the Investigator, even if the 
SAE occurs more than 28 days after study drug dosing. 
The minimum information required for SAE reporting includes identity of Investigator, site 
number, subject number, an event description, SAE term(s), onset date, the reason why the event 
is serious (i.e., the seriousness criteria) and the Investigator’s assessment of the relationship of 
the event to study treatment.  Additional SAE information including medications or other 
therapeutic measures used to treat the event, action taken with the study treatment due to the 
event, and the outcome/resolution of the event will be recorded.  Paper forms for reporting SAEs 
will be provided to the study sites as back-up in case the EDC system is not accessible. 
In all cases, the Investigator should continue to monitor the clinical situation and report all 
material facts relating to the progression or outcome of the SAE.  Furthermore, the Investigator 
may be required to provide supplementary information as requested by Syntimmune or designee. 
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When reporting an SAE, the following additional points should be noted: 
• When the diagnosis of an SAE is known or suspected, the Investigator should report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms.  Signs 
and symptoms may then be described in the event description.  For example, dyspnea 
should not be used as an SAE term if the diagnosis, which caused the dyspnea, is known 
to be malignant pleural effusion.   
• Death should not be reported as an SAE, but as an outcome of a specific SAE, unless the 
event preceding the death is unknown.  In the exceptional case where the events leading 
to death are unknown, then death may be used as an event term.  If an autopsy was 
performed, the autopsy report should be provided.  
• While most hospitalizations necessitate reporting of an SAE, some hospitalizations do not 
require SAE reporting, as follows:  
• Elective or previously scheduled surgery, e.g., a previously scheduled ventral 
hernia repair 
• Procedures for pre-existing conditions that have not worsened after initiation of 
treatment 
• Pre-specified study hospitalizations for observation 
• Events that result in hospital stays of less than 24 hours and that do not require 
admission, e.g., an emergency room visit for hematuria that results in a diagnosis 
of cystitis and discharge to home on oral antibiotics 
• SAEs must, however, be reported for any surgical or procedural complication resulting in 
prolongation of the hospitalization. 
11.3.10 
Regulatory Reporting 
Syntimmune (or designee) will process and evaluate all SAEs as soon as the reports are received.  
For each SAE received, Syntimmune will decide as to whether the criteria for expedited 
reporting have been met. 
Syntimmune (or designee) will submit SAEs that meet the criteria for expedited reporting to the 
regulatory authorities in accordance with local regulations governing safety reporting.  Reporting 
of SAEs by the Investigator to his or her IRB will be done in accordance with the standard 
operating procedures and policies of the IRB.  Adequate documentation must be maintained 
showing that the IRB was properly notified. 
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11.3.11 
Follow-up Information on a Serious Adverse Event (SAE) 
Appropriate diagnostic tests should be performed and therapeutic measures, if indicated, should 
be instituted.  Appropriate consultation and follow-up evaluations should be carried out until the 
event has returned to baseline or is otherwise explained by the Investigator.   
If all required information on the SAE form is not available at the time of the initial report, 
follow-up information will be completed in the EDC system. 
11.4 
Other Safety Considerations 
11.4.1 
Laboratory Data 
All laboratory data obtained during the study should be reviewed.  Any abnormal value that leads 
to a change in subject management (e.g., requirement for additional medication or monitoring) or 
is of clinical significance by the Investigator should be reported as an AE and/or SAE as 
appropriate, unless this value is consistent with values obtained before entry into the study.   
11.4.2 
Medication Errors 
Any medication error that results in an AE, even if it does not meet the definition of serious, 
requires reporting within 24 hours to the safety Medical Monitor. 
11.4.3 
Follow-Up of Adverse Events 
Any SAE or AE assessed as related that led to treatment discontinuation (including clinically 
significant abnormal laboratory values that meet these criteria) and ongoing 28 days after study 
drug dosing must be followed until either resolution of the event or determination by the 
Investigator that the event has become stable or irreversible.  This follow-up guidance also 
applies to related SAE that occur more than 28 days after study drug dosing.  The status of all 
other continuing AEs will be documented as of 28 days after study drug dosing.  The 
Investigator will follow all subjects who experience AEs until there is a return to the subject’s 
baseline condition, or until a clinically satisfactory resolution has been achieved.  The 
appropriate follow-up visits must be scheduled and the specific tests repeated or performed as 
necessary. 
Where a diagnosis is possible, it is preferable to report this diagnosis rather than a series of terms 
(signs/symptoms) relating to the diagnosis. 
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11.5 
Safety Monitoring for Dose Escalation 
Following dosing in each cohort, all safety/tolerability data (e.g., PEs, vital signs [including 
pulse oximetry], clinical safety laboratory tests, ECGs and AE/SAE assessments) as well as any 
available and relevant PD data collected through Day 42 will be reviewed by the DEC.  A 
decision to escalate to the next cohort will be made.  The recommendation may be to continue to 
the next scheduled dose level, discontinue the study or to modify dosing to a dose less than the 
current dose or higher than the current dose but lower than the next planned dose.   
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12 
STATISTICAL CONSIDERATIONS  
All descriptive and inferential statistical analyses will be performed using the most recently 
released and available Statistical Analysis System (SAS) software, unless otherwise noted.  
Missing data will not be imputed unless otherwise stated.  All clinical data captured will be 
provided in data listings. A Statistical Analysis Plan (SAP) and a Pharmacokinetic Analysis Plan 
(PAP) will be finalized prior to database lock. 
12.1 
General Design  
All data for enrolled subjects will be presented in data listings by subject number.    
Continuous data will be described using descriptive statistics: number of observations (n), mean, 
standard deviation (SD), median, minimum, and maximum.  Frequencies and percentages will be 
used for summarizing discrete (categorical) data.  When categorical data are presented, the 
percent will be suppressed when the count is zero to draw attention to the non-zero counts.  The 
denominator for all percentages, unless otherwise specified, will be the number of subjects in the 
specified analysis population. 
12.2 
Sample Size Justification  
Formal sample size calculations were not performed. The number of subjects was chosen based 
on feasibility and was considered sufficient to meet the study objectives. 
12.3 
Statistical Considerations  
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP). The SAP may modify the plans outlined in 
the protocol; any deviations from the previously described statistical plan will be described and 
justified in an SAP amendment. Additional statistical analyses other than those described in this 
section may be performed if deemed appropriate and will be described in the SAP. Methods of 
handling of missing data for different endpoints will be further specified in the SAP. In general, 
where individual data points are missing because of insufficient samples, dropouts, or other 
reasons, the data will be analyzed based on reduced denominators unless specified otherwise in 
the SAP.  
Results will be summarized by cohorts.  
12.3.1 
Study Populations  
Three populations will be employed in the analysis of study data: 
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• The intent-to-treat (ITT) population will consist of all subjects who have received at least 
one dose of study drug.  All safety analyses will be performed on the ITT population. 
• The PK population will consist of all subjects who receive at least one dose of study drug 
and have sufficient post-dose blood samples to obtain PK parameters. 
• The PD population will consist of all subjects who receive at least one dose of study drug 
and have post-dose PD data available.  
Primary safety analyses will be performed on the ITT population.  Demographics, subject 
disposition, and screening and baseline characteristics will be summarized for the ITT, PK, and 
PD populations, where appropriate. 
12.3.2 
Subject Accountability, Demographics, and Baseline Characteristics  
Subject disposition, demographic information and baseline characteristics will be presented.  
Any discrepancy between treatment to be given and treatment received will be accounted for in 
these displays.  
12.3.3 
Concomitant Medications  
Concomitant medications will be coded using WHO Drug Dictionary (WHO-DD March 2013, 
Type B2 or later) and the data will be summarized and presented in tables and listings.  
12.4 
Planned PK Analysis 
Study drug concentrations will be used to calculate the following PK parameters: t1/2, Cmax, Tmax, 
and AUC0-24 and AUC0-∞.  PK parameters will be determined using noncompartmental 
method(s).  Descriptive statistics of PK parameters for SYNT001 will include mean, SD, 
coefficient of variation (CV), median, minimum, and maximum. Tmax will be reported as median 
and range. All descriptive statistics will be performed on untransformed PK parameters and after 
log10 transformation of PK parameters. 
For calculation of mean concentrations and generation of mean concentration-time profiles, all 
below the limit of quantification (BLQ) values will be set to zero except when an individual 
BLQ falls between 2 quantifiable values, in which case it will be omitted. 
If there are values above the BLQ, but too sparse to allow full analysis, descriptive statistics will 
be performed on available values. 
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12.5 
Safety Data  
Safety observations and measurements include AEs, safety laboratory tests, vital sign 
measurements, PEs, and ECGs.  
Treatment-emergent AEs will be summarized using the Medical Dictionary for Regulatory 
Activities (MedDRA®; Version 19 or higher) System Organ Class (SOC) and preferred term, 
classified from verbatim terms.  The incidence and percentage of subjects with at least 1 
occurrence of a preferred term will be included, using the most severe grade.  The number of 
events per preferred term will also be summarized.  Causality (relationship to study treatment) 
will be summarized separately.   
AEs, SAEs, and AEs leading to withdrawal, dose modification, or treatment discontinuation will 
be listed by subject, cohort, and overall per SOC and preferred terms. Duration of AEs will be 
determined and included in listings, along with action taken and outcome.   
Laboratory results will be summarized by cohort.  Incidence of laboratory abnormalities will be 
summarized.  The worst on-study grade after the first dose of study drug will be summarized.  
Results for variables that are not coded will be presented in the listings as below, within, and 
above the normal limits of the local laboratory. 
Vital sign measurements and change from baseline will be summarized at each scheduled time 
point by cohort using descriptive statistics.      
Arithmetic mean of parameters from triplicate ECG will be calculated first for each participant at 
each planned time point. Then summary statistics of ECG test parameters (mean of triplicate) 
and change from baseline to each post-dose time point will be calculated. Shift tables for ECG 
test result category change (normal, abnormal, clinically abnormal) from pre-dose to each post-
dose time point showing number and percentage of subjects with movement between categories 
will be presented by treatment group. Frequency and percentage of subjects experiencing 
potential QTc prolongation (QTcF > 450) will be summarized at each time point by cohort. 
12.6 
Pharmacodynamic/Activity Data  
PD results will be summarized by cohort. 
12.7 
Immunogenicity Data  
Immunogenicity results will be summarized by cohort. 
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12.8 
Interim Analysis 
No interim analysis is planned.  Safety results will be examined for making dose-escalation 
decisions; no statistical analyses are planned for aiding these dose-escalation decisions. 
 
 
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13 
DATA QUALITY ASSURANCE 
All data will be entered in a validated electronic data capture system using single data entry. 
Standard procedures (including following data review guidelines, manual clinical review based 
on subject profiles, computerized validation to produce queries, and maintenance of an audit file 
which includes all database modifications) will be followed to ensure accurate data. Clinical 
personnel will review all data listings for outliers, data inconsistencies, and spelling errors. 
During the study, a study site monitor will make site visits to review protocol compliance, 
compare electronic case report forms (eCRFs) against individual subject medical records, assess 
drug accountability, and ensure that the study is being conducted using pertinent regulatory 
requirements.  eCRF entries will be verified with source documentation. The review of medical 
records will be performed in a manner to ensure that subject confidentiality is maintained.  
Checking the eCRFs for completeness, clarity and cross checking with source documents is 
required to monitor the progress of the study. Direct access to source data is also required for 
inspections and audits, and will be carried out giving due consideration to data protection and 
medical confidentiality. Each Investigator will have assured Syntimmune of full access to 
complete source data for study participants and associated necessary support at all times. 
In addition to routine monitoring procedures, audits of clinical research activities in accordance 
with standard operating procedures (SOPs) may be performed to evaluate compliance with the 
principles of GCP.  A regulatory authority may also wish to conduct an inspection (during the 
study or even after its completion).  If a regulatory authority requests an inspection, the 
Investigator must immediately inform Syntimmune that this request has been made. Study 
conduct may be assessed during the study by a Clinical Quality Assurance representative(s) to 
ensure that the study is conducted in compliance with the protocol.  This designee, as well as the 
site monitor, will be permitted to inspect the study documents (study protocol, eCRFs, 
investigational product accountability, original study-relevant medical records).  All subject data 
will be treated confidentially.  During the clinical study, access will be available to Syntimmune 
or their designee (e.g., contract research organization [CRO]) to view the eCRFs after 
completion of the individual sections of the study. Furthermore, the study protocol, each step of 
the data-recording procedure and the handling of the data as well as the study report may be 
subject to independent review by a Quality Assurance representative.  Clinical site and study 
audits will be conducted as necessary to assure the validity of the study data. 
 
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14 
STUDY ADMINISTRATION 
14.1 
Study Administrative Structure 
The study administration structure is provided in Table 6. 
Table 6 :  
Study Administrative Structure 
Sponsor Contact: 
Phone:
Email:
Sponsor Medical Director: 
 
Phone:
Email: 
Medical Monitor: 
Medpace 
43 Thorndike Street 
Cambridge, MA 01240 
Phone:
ext.
Email:
Study Monitoring: 
Medpace 
5375 Medpace Way 
Cincinnati, OH 45227 
Phone (Main):
Email: 
 
14.2 
Ethical Conduct of the Study 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
ICH E6 Tripartite Guideline (January 1997), and in general, be conducted in a manner consistent 
with the principles described in the Declaration of Helsinki. The Investigator will ensure that the 
conduct of the study complies with the basic principles of GCP as outlined in the current version 
of 21 CFR, subpart D, Part 312, “Responsibilities of Sponsors and Investigators”, Part 50, 
“Protection of Human Subjects”, and Part 56, “Institutional Review Boards”. 
14.3 
Informed Consent (ICF) 
A properly executed, written informed consent document, in compliance with 21 CFR, Part 50 
and the ICH guidelines, will be obtained from each subject before the subject is entered into the 
study and before any study screening procedure is performed that involves risk.  Attention will 
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be directed to the basic elements required for incorporation into the informed consent under US 
Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a]) and (21 CFR 
50.25[b]), as necessary. 
Sample ICFs will be supplied to each site. Syntimmune or its designee must review any proposed 
deviations from the sample ICF. The final IRB-approved document must be provided to 
Syntimmune for regulatory purposes. 
It is the responsibility of the Investigator, or a person designated by the Investigator, to obtain 
written informed consent from each subject (or the subject’s legally authorized representative) 
participating in this study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study. In the case where the subject is unable to read, an impartial 
witness should be present during the entire informed consent discussion. After the subject has 
orally consented to participation in the trial, the witness’ signature on the form will attest that the 
information in the consent form was accurately explained and understood. A copy of the ICF 
must be provided to the subject or to the subject’s legally authorized representative. If applicable, 
it will be provided in a certified translation of the local language. 
The eCRF for this study contains a section for documenting informed subject consent, and this 
must be completed appropriately. Signed ICFs must remain in each subject’s study file and must 
be available for verification by site monitors at any time. If new safety information results in 
significant changes in the risk/benefit assessment, the consent form should be reviewed and 
updated as necessary. All subjects (including those already being treated) should be informed of 
the new information, should be given a copy of the revised form, and should give their consent to 
continue in the study. 
14.4 
Institutional Review Board 
This study is being conducted under US IND 128152. This protocol (and any modifications) and 
appropriate consent procedures must be reviewed and approved by an IRB. This board must 
operate in accordance with the current federal or local regulations. The Investigator will send a 
letter or certificate of IRB approval to Syntimmune (or designee) before subject enrollment and 
whenever subsequent modifications to the protocol are made. 
14.5 
Dose Escalation Committee 
The DEC will be responsible for confirming the safety of the investigative product prior to 
dose escalation, as well as the dose level for each successive cohort.  In addition, over the course 
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of the study, the DEC will review any drug-related SAEs to determine if modifications to the 
study or other measures are necessary to ensure the safety of the subjects.  The DEC will consist 
of the Medical Monitor, an Independent Clinical Expert and a Syntimmune Medical Officer.  To 
assist in the safety assessments, the DEC may request that Investigators, other experts, or 
members within their organizations review the data and participate in the discussions. 
14.6 
Future Use of Subject Samples 
Not all the tissue and blood components obtained during this study may be required for the tests 
that are part of the clinical trial. Available samples may be used for additional research. This 
research will help to understand disease subtypes, drug response and AE, and possibly identify 
new drug targets or biomarkers that predict subject response to treatment. The use of the samples 
for internal research will be done using the guidelines defined by the FDA guidance for In Vitro 
Diagnostic Device Studies Using Leftover Human Specimens that are Not Individual Identifiable 
(issued 25 April 2006) and the European Medicines Agency (EMA) Reflection Paper on 
Pharmacogenetic Samples, Testing and Data Handling (Doc. Ref. 
EMEA/CHMP/PGxWP/201914/2006; 15 November 2007).  If a subject requests destruction of 
their tissue and blood samples and the samples have not yet been de-identified, Syntimmune will 
destroy the samples as described in this FDA guidance. Syntimmune will notify the Investigator 
in writing that the samples have been destroyed. 
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15 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between a 
Syntimmune representative and the Investigator. Protocol modifications will be prepared, 
reviewed, and approved by Syntimmune representatives. 
All protocol modifications must be submitted to the IRB for information and approval in 
accordance with local requirements, and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects, or when the change involves only logistical or administrative 
aspects of the trial (e.g., change in site monitor, change of telephone number). 
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16 
CONDITIONS FOR TERMINATING THE STUDY 
Syntimmune has the right to terminate the study at any time. In terminating the study, 
Syntimmune and the Investigator will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 
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17 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
17.1 
Investigator’s Files and Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into 2 separate categories as follows: (1) Investigator’s study file and (2) subject 
clinical source documents. 
The Investigator’s study file will contain the protocol and protocol amendments, eCRFs, query 
forms, IRB and governmental approval with correspondence, sample informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
Subject clinical source documents (usually predefined by the project to record key efficacy and 
safety parameters independent of the eCRFs) may include subject hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, 
electroencephalogram, X-ray, pathology and special assessment reports, signed ICFs, consultant 
letters, and subject screening and enrollment logs. The Investigator must keep these 2 categories 
of documents on file for at least 2 years following the marketing application approval date for the 
study treatment and for the indication being investigated or for 2 years after the development 
program is discontinued and the FDA notified. After that period, the documents may be 
destroyed subject to local regulations with prior written permission from Syntimmune. If the 
Investigator wants to assign the study records to another party or move them to another location, 
Syntimmune must be notified in advance. 
If the Investigator cannot guarantee the archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and Syntimmune to 
store these in a sealed container outside of the study site so that they can be returned sealed to the 
Investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside of the study site. 
17.2 
Source Documents and Background Data 
Investigators must maintain adequate and accurate source documents on which the eCRFs for 
each subject are based. They are separate and distinct from the eCRFs. 
These records include detailed notes on the following: 
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• Medical history 
• Date and time of informed consent with Health Insurance Portability and Accountability 
Act (HIPAA) authorization either contained in the ICF or presented to the subject 
candidate as a standalone document 
• Description of the complete consenting process 
• The basic identifying information that linked the subject’s medical record with the 
eCRFs 
• The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject 
• The medical condition of the subject during their involvement in the study 
• All AEs 
• The subject’s exposure to the study medication 
• The subject’s exposure to any concomitant therapy 
• All relevant observations and data on the condition of the subject throughout the trial 
• Justification for all entries in the subject’s eCRF 
A subject log of all potentially eligible subjects considered, but not consented, for obvious 
deviations from the entry criteria, will be kept at each site. The log will contain subjects’ initials, 
diagnosis, eligibility, or, if not eligible, reason for not consenting.  All consented subjects will be 
logged, regardless of whether they ultimately enroll.  
Upon request, the Investigator will supply Syntimmune with any required background data from 
the study documentation or clinic records. This is particularly important when eCRFs are 
illegible or when errors in data transcription are suspected. In case of special problems or 
governmental queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected. 
17.3 
Audits and Inspections 
The Investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from Syntimmune (or designee), or to health 
authority inspectors after appropriate notification. The verification of the eCRF data must be by 
direct inspection of source documents. 
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17.4 
Electronic Case Report Forms 
Clinical trial data for this study will be captured on eCRF designed for computer processing and 
analysis.  This computerized system will be validated and compliant with 21 CFR Part 11. 
Corrections to data will be made using 21 CFR Part 11, Electronic Records; Electronic 
Signatures. If corrections are made after review and sign-off by the Investigator, he/she must be 
aware of the changes and provide written acknowledgement. There will also be an electronic 
audit trail. Corrections on paper CRFs must be initialed and dated by the person making the 
change. The Investigator agrees to provide all information requested on the eCRF in an accurate 
manner using instructions provided.  The Investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported to Syntimmune in the eCRF and in all required 
reports. 
An eCRF is required to be submitted for every subject who receives any amount of study drug.  
This includes submission of retrievable data on subjects who withdraw before completion of the 
study.  Prior to submission, eCRFs must be reviewed for completeness and accuracy, and signed 
and dated where either indicated, by the Principal Investigator or authorized delegate from the 
study staff.  If a subject stops treatment or terminates from the study, the dates and reasons must 
be noted on the eCRF. 
 
 
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18 
MONITORING THE STUDY 
It is understood that the responsible Syntimmune site monitor (or designee) will contact and visit 
the Investigator regularly and will be allowed on request to inspect the various records of the trial 
(eCRFs and other pertinent data) if subject confidentiality is maintained in accordance with local 
requirements. 
It will be the site monitor’s responsibility to inspect the eCRFs at regular intervals throughout the 
study, to verify the adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The site monitor should have access to laboratory test reports 
and other subject records needed to verify the entries on the eCRF. The Investigator (or 
designee) must agree to cooperate with the site monitor to ensure that any problems detected 
during these monitoring visits are resolved. 
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19 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS 
The Investigator must ensure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On eCRFs or other documents submitted to 
Syntimmune, subjects should be identified by an identification code and not by their names. The 
Investigator should keep a subject enrollment log showing codes, names, and addresses. The 
Investigator should maintain documents not for submission to Syntimmune (e.g., subjects’ 
written consent forms) in strict confidence. 
Authorized regulatory officials and Syntimmune personnel (or their representatives) will be 
allowed full access to inspect and copy the records.  All study drugs, subject bodily fluids and 
tissue, and/or other materials collected shall be used solely in accordance with this protocol, 
unless otherwise agreed to in writing by Syntimmune. 
The Principal Investigator also agrees that all information received from Syntimmune, including 
but not limited to the IB, this protocol, eCRFs, the INDs, and any other study information remain 
the sole and exclusive property of Syntimmune during the conduct of the study and thereafter.  
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from the 
sponsor. The Principal Investigator further agrees to take all reasonable precautions to prevent 
the disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain. 
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20 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. The Investigator 
agrees that any manuscript or abstract they author may be published only after receiving written 
permission from Syntimmune. 
If Syntimmune coordinates a publication or presentation of study results from all study sites, the 
participation of Investigator or other representatives of study site as a named author shall be 
determined in accordance with Syntimmune policy and generally accepted standards for 
authorship. 
 
 
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21 
REFERENCES 
Ameratunga R, Woon ST, Gillis D, Koopmans W, Steele R. New diagnostic criteria for common 
variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or 
subcutaneous immunoglobulin. Clin. Exp. Immunol. 2013;174: 203-211. 
Bugelski PJ and Treacy G. (2004) Predictive power of preclinical studies in animals for the 
immunogenicity of recombinant therapeutic proteins in humans. Curr Opin Mol Ther.  
2004;6:10−16. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) (2011). S6(R1) Preclinical Safety Evaluation of 
Biotechnology-Derived Pharmaceuticals. Accessed 03 June 2016. 
http://www.ich.org/products/guidelines/safety/safety-single/article/preclinical-safety-evaluation-
of-biotechnology-derived-pharmaceuticals.html     
Nixon AE, Chen J, Sexton DJ, Muruganandam A, Bitonti AJ, Dumont J, Viswanathan M, Martik 
D, Wassaf D, Mezo A, Wood CR, Biedenkapp JC, TenHoor C. (2015). Fully human monoclonal 
antibody inhibitors of the neonatal Fc receptor reduce circulating IgG in non-human 
primates. Front. Immun. 6:176 
Ponce R, Abad L, Amaravadi, L, et al. Immunogenicity of biologically-derived therapeutics: 
assessment and interpretation of nonclinical safety studies. Regul Toxicol Pharmacol. 
2009;54,164–182.   
Roopenian, D.C., Christianson, G.J., Sproule, T.J., Brown, A.C., Akilesh, S., Jung, N., Petkova, 
S., Avanessian, L., Choi, E.Y., Shaffer, D.J., Eden, P.A., Anderson, C. L. The MHC class I-like 
IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled 
drugs. 2003. J. Immun. 170 3528-3533 
 
 
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Appendix A: NCI CTCAE, Version 4.03 
 
 
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1. CTCAE 4.03
 
 
Common Terminology Criteria for
Adverse Events (CTCAE)
Version 4.0
Published: May 28, 2009 (v4.03: June 14, 2010)
U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Cancer Institute
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C o m m o n T er mi n ol o g y Crit eri a f or A d v ers e E v e nts v 4. 0 ( C T C A E)  
P u blis h D at e: M a y 2 8, 2 0 0 9  
Q uic k R ef er e nc e  
T h e  
N CI  C o m m o n  T er mi n ol o g y  Crit eri a f or  
A d v ers e E v e nts is a d escri ptiv e t er mi n ol o g y w hic h 
c a n b e utiliz e d f or A d v ers e E v e nt ( A E) r e p orti n g.    
A gr a di n g (s ev erity) sc al e is pr o vi d e d f or e ac h A E 
t er m. 
C o m p o n e nts a n d Or g a niz ati o n 
S O C  
S yst e m  Or g a n Cl ass, t h e  hi g h est l ev el of t h e 
M e d D R A hi er arc hy, is i d e ntifi e d b y a n at o mic al or 
p h ysi ol o gic al s yst e m, eti ol o g y, or p ur p os e ( e. g., 
S O C I n v esti g ati o ns f or l a b or at or y t est r es ults). 
C T C A E t er ms ar e gr o u p e d b y  M e d D R A Pri m ar y 
S O Cs.  
Wit hi n e ac h S O C,  A Es ar e list e d a n d 
ac c o m p a ni e d b y d escri pti o ns of s ev erit y ( Gr a d e). 
C T C A E T er ms  
A n A d v ers e E v e nt ( A E) is a n y u nf a v or a bl e a n d 
u ni nt e n d e d  si g n  (i ncl u di n g  a n    a b n or m al 
l a b or at or y   fi n di n g),   sy m pt o m,   or   dis e as e 
t e m p or ally ass oci at e d wit h t h e us e of a m e dic al 
tr e at m e nt or pr oc e d ur e t h at m a y or m a y n ot b e 
c o nsi d er e d r el at e d t o t h e m e dic al tr e at m e nt or 
pr oc e d ur e. A n A E is a t er m t h at is a u ni q u e 
r e pr es e nt ati o n  of  a s p ecific  ev e nt  us e d f or  
m e dic al d oc u m e nt ati o n a n d sci e ntific a n alys es. 
E ac h C T C A E v 4. 0 t er m is a M e d D R A LL T (L o w est 
L ev el T er m).  
D efi niti o ns  
A bri ef d efi niti o n is pr ovi d e d 
m e a ni n g of e ac h A E t er m.  
Gr a d es  
N ot all  Gr a d es ar e a p pr o pri at e f or all  A Es. 
T h er ef or e, s o m e A Es ar e list e d wit h f e w er t h a n 
fiv e o pti o ns f or Gr a d e s el ecti o n. 
Gr a d e 5  
Gr a d e 5 ( D e at h) is n ot a p pr o pri at e f or s o m e A Es 
a n d t h er ef or e is n ot a n  o pti o n.  
Acti viti es of D ail y Li vi n g  ( A DL) 
*I nstr u m e nt al  A DL r ef er t o  pr e p ari n g  
m e als, 
s h o p pi n g f or gr oc eri es  or cl ot h es,  usi n g t h e 
t el e p h o n e, m a n a gi n g m o n ey, etc. 
* * S elf c ar e A DL r ef er t o b at hi n g, dr essi n g a n d 
u n dr essi n g, f e e di n g s elf, usi n g t h e t oil et, t aki n g 
m e dic ati o ns, a n d n ot b e dri d d e n.  
t o cl arify t h e 
Gr a d e r ef ers t o t h e s ev erit y of t h e A E. T h e C T C A E 
dis pl a ys Gr a d es 1 t hr o u g h 5 wit h u ni q u e cli nic al 
d escri pti o ns of s ev erit y f or e ac h A E b as e d o n t his 
g e n er al g ui d eli n e:  
Gr a d e 1  
Mil d;   
asy m pt o m atic   
or   
mil d 
s y m pt o ms;  cli nic al  or  di a g n ostic 
o bs er v ati o ns o nly; i nt er v e nti o n n ot 
i n dic at e d. 
Gr a d e 2   M o d er at e;   
mi ni m al,   
l oc al  or  
n o ni n v asiv e i nt er v e nti o n i n dic at e d;  
li miti n g 
i nstr u m e nt al A DL *. 
a g e -a p pr o pri at e  
Gr a d e 3   S ev er e or m e dic ally si g nific a nt b ut  
n ot i m m e di at ely lif e -t hr e at e ni n g; 
h os pit aliz ati o n or pr ol o n g ati o n of 
h os pit aliz ati o n i n dic at e d; dis a bli n g; 
li miti n g s elf c ar e A DL * *. 
Gr a d e 4   Lif e-t hr e at e ni n g  
c o ns e q u e nc es; 
ur g e nt i nt er v e nti o n i n dic at e d.  
D e at h r el at e d t o A E.  
Gr a d e 5  
A S e mi -c ol o n i n dic at es ‘ or’ wit hi n t h e d escri pti o n 
of t h e  gr a d e.  
A si n gl e d as h ( -) i n dic at es a gr a d e is n ot a v ail a bl e. 
† C T C A E v 4. 0 i nc or p or at es c ert ai n el e m e nts of t h e M e d D R A t er mi n ol o g y. F or f urt h er d et ails o n M e d D R A r ef er t o t h e M e d D R A M S S O W e b sit e ( htt p:// w w w. m e d dr a mss o.c o m).  
Pa ge 9 9 of 9 7 9  
Ale xi o n C o nfi de ntial  
 
 


C O N T E N T S 
P a g e 
Bl o o d a n d l y m p h atic s yst e m dis or d ers  
3  
C ar di ac dis or d ers  
4  
C o n g e nit al, f a mili al a n d g e n etic dis or d ers  
7  
E ar a n d l a b yri nt h dis or d ers  
8  
E n d ocri n e dis or d ers  
9  
E y e dis or d ers  
1 0  
G astr oi nt esti n al dis or d ers  
1 2  
G e n er al dis or d ers a n d a d mi nistr ati o n sit e c o n diti o ns  
2 2  
H e p at o bili ar y dis or d ers  
2 4  
I m m u n e s yst e m dis or d ers 
2 6  
I nf ecti o ns a n d i nf est ati o ns 
2 7  
I nj ur y, p ois o ni n g a n d pr oc e d ur al c o m plic ati o ns 
3 4  
I nv esti g ati o ns 
4 1  
M et a b olis m a n d n utriti o n dis or d ers  
4 4  
M usc ul os k el et al a n d c o n n ectiv e tiss u e dis or d ers  
4 6  
N e o pl as ms b e ni g n, m ali g n a nt a n d u ns p ecifi e d (i ncl cysts a n d p oly ps)  
5 0  
N er v o us s yst e m dis or d ers  
5 1  
Pr e g n a ncy, p u er p eri u m a n d p eri n at al c o n diti o ns  
5 6  
Ps yc hi atric dis or d ers  
5 7  
R e n al a n d uri n ary dis or d ers  
5 9  
R e pr o d uctiv e syst e m a n d br e ast dis or d ers  
6 1  
R es pir at or y, t h or acic a n d m e di asti n al dis or d ers  
6 5  
S ki n a n d s u bc ut a n e o us tiss u e dis or d ers  
7 1  
S oci al circ u mst a nc es  
7 5  
S ur gic al a n d m e dic al pr oc e d ur es  
7 6  
V asc ul ar dis or d ers  
7 7  


CTCAE 4.03 - June 14, 2010 : Blood and lymphatic system disorders 
3
2. Blood and lymphatic system disorders
Blood and lymphatic system disorders
Grade
Adverse Event
1
2
3
4
5
Anemia
Hemoglobin (Hgb) <LLN - 10.0
g/dL; <LLN - 6.2 mmol/L; <LLN -
100 g/L
Hgb <10.0 - 8.0 g/dL; <6.2 - 4.9
mmol/L;  <100 - 80g/L
Hgb <8.0 g/dL; <4.9 mmol/L;
<80 g/L; transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an reduction in the amount of hemoglobin in 100 ml of blood. Signs and symptoms of anemia may include pallor of the skin and mucous
membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.
Bone marrow hypocellular
Mildly hypocellular or <=25%
reduction from normal cellularity
for age
Moderately hypocellular or >25 -
<50% reduction from normal
cellularity for age
Severely hypocellular or >50 -
<=75% reduction cellularity from
normal for age
Aplastic persistent for longer
than 2 weeks
Death
Definition: A disorder characterized by the inability of the bone marrow to produce hematopoietic elements.
Disseminated intravascular
coagulation
 -
Laboratory findings with no
bleeding
Laboratory findings and
bleeding
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by systemic pathological activation of blood clotting mechanisms which results in clot formation throughout the body. There is an increase in the
risk of hemorrhage as the body is depleted of platelets and coagulation factors.
Febrile neutropenia
 -
 -
ANC <1000/mm3 with a single
temperature of >38.3 degrees C
(101 degrees F) or a sustained
temperature of >=38 degrees C
(100.4 degrees F) for more than
one hour.
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an ANC <1000/mm3 and a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >=38 degrees C (100.4
degrees F) for more than one hour.
Hemolysis
Laboratory evidence of
hemolysis only (e.g., direct
antiglobulin test; DAT; Coombs';
schistocytes; decreased
haptoglobin)
Evidence of hemolysis and >=2
gm decrease in hemoglobin.
Transfusion or medical
intervention indicated (e.g.,
steroids)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate widespread erythrocyte cell membrane destruction.
Hemolytic uremic syndrome
Evidence of RBC destruction
(schistocytosis) without clinical
consequences
 -
Laboratory findings with clinical
consequences (e.g., renal
insufficiency, petechiae)
Life-threatening consequences,
(e.g., CNS hemorrhage or
thrombosis/embolism or renal
failure)
Death
Definition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, hemolytic anemia, and severe thrombocytopenia.
Leukocytosis
 -
 -
>100,000/mm3
Clinical manifestations of
leucostasis; urgent intervention
indicated
Death
Definition: A disorder characterized by laboratory test results that indicate an increased number of white blood cells in the blood.
Lymph node pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in a lymph node.
Spleen disorder
Incidental findings (e.g., Howell-
Jolly bodies); mild degree of
thrombocytosis and
leukocytosis
Prophylactic antibiotics
indicated
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder of the spleen.
Thrombotic thrombocytopenic
purpura
Evidence of RBC destruction
(schistocytosis) without clinical
consequences
 -
Laboratory findings with clinical
consequences (e.g., renal
insufficiency, petechiae)
Life-threatening consequences,
(e.g., CNS hemorrhage or
thrombosis/embolism or renal
failure)
Death
Definition: A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic purpura, fever, renal abnormalities and neurological abnormalities such
as seizures, hemiplegia, and visual disturbances. It is an acute or subacute condition.
Blood and lymphatic system
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
4
3. Cardiac disorders
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Acute coronary syndrome
 -
Symptomatic, progressive
angina; cardiac enzymes
normal; hemodynamically stable
Symptomatic, unstable angina
and/or acute myocardial
infarction, cardiac enzymes
abnormal, hemodynamically
stable
Symptomatic, unstable angina
and/or acute myocardial
infarction, cardiac enzymes
abnormal, hemodynamically
unstable
Death
Definition: A disorder characterized by signs and symptoms related to acute ischemia of the myocardium secondary to coronary artery disease. The clinical presentation covers a
spectrum of heart diseases from unstable angina to myocardial infarction.
Aortic valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in aortic valve function or structure.
Asystole
Periods of asystole; non-urgent
medical management indicated
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without cardiac electrical activity. Typically, this is accompanied by cessation of the pumping function of the heart.
Atrial fibrillation
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker), or ablation
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without discernible P waves and an irregular ventricular response due to multiple reentry circuits. The rhythm disturbance
originates above the ventricles.
Atrial flutter
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker), or ablation
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with organized rhythmic atrial contractions with a rate of 200-300 beats per minute. The rhythm disturbance originates in the
atria.
Atrioventricular block complete
 -
Non-urgent intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with complete failure of atrial electrical impulse conduction through the AV node to the ventricles.
Atrioventricular block first
degree
Asymptomatic, intervention not
indicated
Non-urgent intervention
indicated
 -
 -
 -
Definition: A disorder characterized by a dysrhythmia with a delay in the time required for the conduction of an electrical impulse through the atrioventricular (AV) node beyond 0.2
seconds; prolongation of the PR interval greater than 200 milliseconds.
Cardiac arrest
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by cessation of the pumping function of the heart.
Chest pain - cardiac
Mild pain
Moderate pain; limiting
instrumental ADL
Pain at rest; limiting self care
ADL
 -
 -
Definition: A disorder characterized by substernal discomfort due to insufficient myocardial oxygenation.
Conduction disorder
Mild symptoms; intervention not
indicated
Moderate symptoms
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by pathological irregularities in the cardiac conduction system.
Constrictive pericarditis
 -
 -
Symptomatic heart failure or
other cardiac symptoms,
responsive to intervention
Refractory heart failure or other
poorly controlled cardiac
symptoms
Death
Definition: A disorder characterized by a thickened and fibrotic pericardial sac; these fibrotic changes impede normal myocardial function by restricting myocardial muscle action.
Heart failure
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe with symptoms at rest or
with minimal activity or exertion;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., continuous IV therapy or
mechanical hemodynamic
support)
Death
Definition: A disorder characterized by the inability of the heart to pump blood at an adequate volume to meet tissue metabolic requirements, or, the ability to do so only at an elevation
in the filling pressure.
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CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
5
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Left ventricular systolic
dysfunction
 -
 -
Symptomatic due to drop in
ejection fraction responsive to
intervention
Refractory or poorly controlled
heart failure due to drop in
ejection fraction; intervention
such as ventricular assist
device, intravenous vasopressor
support, or heart transplant
indicated
Death
Definition: A disorder characterized by failure of the left ventricle to produce adequate output despite an increase in distending pressure and in end-diastolic volume. Clinical
manifestations mayinclude dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema.
Mitral valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in mitral valve function or structure.
Mobitz (type) II atrioventricular
block
Asymptomatic, intervention not
indicated
Symptomatic; medical
intervention indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with relatively constant PR interval prior to the block of an atrial impulse. This is the result of intermittent failure of atrial electrical
impulse conduction through the atrioventricular (AV) node to the ventricles.
Mobitz type I
Asymptomatic, intervention not
indicated
Symptomatic; medical
intervention indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a progressively lengthening PR interval prior to the blocking of an atrial impulse. This is the result of intermittent failure of
atrial electrical impulse conduction through the atrioventricular (AV) node to the ventricles.
Myocardial infarction
 -
Asymptomatic and cardiac
enzymes minimally abnormal
and no evidence of ischemic
ECG changes
Severe symptoms; cardiac
enzymes abnormal;
hemodynamically stable; ECG
changes consistent with
infarction
Life-threatening consequences;
hemodynamically unstable
Death
Definition: A disorder characterized by gross necrosis of the myocardium; this is due to an interruption of blood supply to the area.
Myocarditis
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe with symptoms at rest or
with minimal activity or exertion;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., continuous IV therapy or
mechanical hemodynamic
support)
Death
Definition: A disorder characterized by inflammation of the muscle tissue of the heart.
Palpitations
Mild symptoms; intervention not
indicated
Intervention indicated
 -
 -
 -
Definition: A disorder characterized by an unpleasant sensation of irregular and/or forceful beating of the heart.
Paroxysmal atrial tachycardia
Asymptomatic, intervention not
indicated
Symptomatic; medical
management indicated
IV medication indicated
Life-threatening consequences;
incompletely controlled
medically; cardioversion
indicated
Death
Definition: A disorder characterized by a dysrhythmia with abrupt onset and sudden termination of atrial contractions with a rate of 150-250 beats per minute. The rhythm disturbance
originates in the atria.
Pericardial effusion
 -
Asymptomatic effusion size
small to moderate
Effusion with physiologic
consequences
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by fluid collection within the pericardial sac, usually due to inflammation.
Pericardial tamponade
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in intrapericardial pressure due to the collection of blood or fluid in the pericardium.
Pericarditis
Asymptomatic, ECG or physical
findings (e.g., rub) consistent
with pericarditis
Symptomatic pericarditis (e.g.,
chest pain)
Pericarditis with physiologic
consequences (e.g., pericardial
constriction)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by irritation to the layers of the pericardium (the protective sac around the heart).
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CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
6
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Pulmonary valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in pulmonary valve function or structure.
Restrictive cardiomyopathy
 -
 -
Symptomatic heart failure or
other cardiac symptoms,
responsive to intervention
Refractory heart failure or other
poorly controlled cardiac
symptoms
Death
Definition: A disorder characterized by an inability of the ventricles to fill with blood because the myocardium (heart muscle) stiffens and loses its flexibility.
Right ventricular dysfunction
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe symptoms, associated
with hypoxemia, right heart
failure; oxygen indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., ventricular assist device);
heart transplant indicated
Death
Definition: A disorder characterized by impairment of right ventricular function associated with low ejection fraction and a decrease in motility of the right ventricular wall.
Sick sinus syndrome
Asymptomatic, intervention not
indicated
Non-urgent intervention
indicated
Severe, medically significant;
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with alternating periods of bradycardia and atrial tachycardia accompanied by syncope, fatigue and dizziness.
Sinus bradycardia
Asymptomatic, intervention not
indicated
Symptomatic, medical
intervention indicated
Severe, medically significant,
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate less than 60 beats per minute that originates in the sinus node.
Sinus tachycardia
Asymptomatic, intervention not
indicated
Symptomatic; non-urgent
medical intervention indicated
Urgent medical intervention
indicated
 -
 -
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates in the sinus node.
Supraventricular tachycardia
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates above the ventricles.
Tricuspid valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis;
symptoms controlled with
medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in tricuspid valve function or structure.
Ventricular arrhythmia
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia that originates in the ventricles.
Ventricular fibrillation
 -
 -
 -
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without discernible QRS complexes due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the
ventricles.
Ventricular tachycardia
 -
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates distal to the bundle of His.
Wolff-Parkinson-White
syndrome
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically or
controlled with procedure
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the presence of an accessory conductive pathway between the atria and the ventricles that causes premature ventricular activation.
Cardiac disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Congenital, familial and genetic disorders 
7
4. Congenital, familial and genetic disorders
Congenital, familial and genetic disorders
Grade
Adverse Event
1
2
3
4
5
Congenital, familial and genetic
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Ear and labyrinth disorders 
8
5. Ear and labyrinth disorders
Ear and labyrinth disorders
Grade
Adverse Event
1
2
3
4
5
Ear pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the ear.
External ear inflammation
External otitis with erythema or
dry desquamation
External otitis with moist
desquamation, edema,
enhanced cerumen or
discharge; tympanic membrane
perforation; tympanostomy
External otitis with mastoiditis;
stenosis or osteomyelitis;
necrosis of soft tissue or bone
Urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation, swelling and redness to the outer ear and ear canal.
External ear pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the external ear region.
Hearing impaired
Adults enrolled on a Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift of 15 - 25 dB averaged at 2
contiguous test frequencies in at
least one ear.
Adults not enrolled in Monitoring
Program: subjective change in
hearing in the absence of
documented hearing loss.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift >20 dB at 8 kHz in at least
one ear.
Adults enrolled in Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz  audiogram):  Threshold
shift of >25 dB averaged at 2
contiguous test frequencies in at
least one ear.
Adults not enrolled in Monitoring
Program: hearing loss but
hearing aid or intervention not
indicated; limiting instrumental
ADL.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift >20 dB at 4 kHz and above
in at least one ear.
Adults enrolled in Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift of >25 dB averaged at 3
contiguous test frequencies in at
least one ear; therapeutic
intervention indicated.
Adults not enrolled in Monitoring
Program:  hearing loss with
hearing aid or intervention
indicated; limiting self care ADL.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): hearing loss
sufficient to indicate therapeutic
intervention, including hearing
aids; threshold shift >20 dB at 3
kHz and above in at least one
ear; additional speech-language
related services indicated.
Adults: Decrease in hearing to
profound bilateral loss (absolute
threshold >80 dB HL  at 2 kHz
and above); non-servicable
hearing.
Pediatric: Audiologic indication
for cochlear implant and
additional speech-language
related services indicated.
 -
Definition: A disorder characterized by partial or complete loss of the ability to detect or understand sounds resulting from damage to ear structures.
Middle ear inflammation
Serous otitis
Serous otitis, medical
intervention indicated
Mastoiditis; necrosis of canal
soft tissue or bone
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation (physiologic response to irritation), swelling and redness to the middle ear.
Tinnitus
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by noise in the ears, such as ringing, buzzing, roaring or clicking.
Vertigo
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective
vertigo).
Vestibular disorder
 -
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by dizziness, imbalance, nausea, and vision problems.
Ear and labyrinth disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Endocrine disorders 
9
6. Endocrine disorders
Endocrine disorders
Grade
Adverse Event
1
2
3
4
5
Adrenal insufficiency
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms;
hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder that occurs when the adrenal cortex does not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. It may be due to a disorder
of the adrenal cortex as in Addison's disease or primary adrenal insufficiency.
Cushingoid
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms, medical
intervention or hospitalization
indicated
 -
 -
Definition: A disorder characterized by signs and symptoms that resemble Cushing's disease or syndrome: buffalo hump obesity, striations, adiposity, hypertension, diabetes, and
osteoporosis, usually due to exogenous corticosteroids.
Delayed puberty
 -
No breast development by age
13 yrs for females; testes
volume of <3 cc or no Tanner
Stage 2 development by age
14.5 yrs for males
No breast development by age
14 yrs for females; no increase
in testes volume or no Tanner
Stage 2 by age 16 yrs for
males; hormone replacement
indicated
 -
 -
Definition: A disorder characterized by unusually late sexual maturity.
Growth accelerated
 -
>= +2 SD (standard deviation)
above mid parental height or
target height
 -
 -
 -
Definition: A disorder characterized by greater growth than expected for age.
Hyperparathyroidism
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by an increase in production of parathyroid hormone by the parathyroid glands. This results in hypercalcemia (abnormally high levels of calcium in
the blood).
Hyperthyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thyroid
suppression therapy indicated;
limiting instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by excessive levels of thyroid hormone in the body. Common causes include an overactive thyroid gland or thyroid hormone overdose.
Hypoparathyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; medical
intervention or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a decrease in production of parathyroid hormone by the parathyroid glands.
Hypothyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thyroid
replacement indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a decrease in production of thyroid hormone by the thyroid gland.
Precocious puberty
Physical signs of puberty with
no biochemical markers for
females <8 years and males <9
years
Physical signs and biochemical
markers of puberty for females
<8 years and males <9 years
 -
 -
 -
Definition: A disorder characterized by unusually early development of secondary sexual features; the onset of sexual maturation begins usually before age 8 for girls and before age
9 for boys.
Virilization
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by inappropriate masculinization occurring in a female or prepubertal male.
Endocrine disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Eye disorders 
10
7. Eye disorders
Eye disorders
Grade
Adverse Event
1
2
3
4
5
Blurred vision
Intervention not indicated
Symptomatic; limiting
instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by visual perception of unclear or fuzzy images.
Cataract
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; moderate
decrease in visual acuity
(20/40 or better)
Symptomatic with marked
decrease in visual acuity
(worse than 20/40 but better
than 20/200); operative
intervention indicated (e.g.,
cataract surgery)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by partial or complete opacity of the crystalline lens of one or both eyes. This results in a decrease in visual acuity and eventual blindness if
untreated.
Conjunctivitis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; topical
intervention indicated (e.g.,
antibiotics); limiting
instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by inflammation, swelling and redness to the conjunctiva of the eye.
Corneal ulcer
 -
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Limiting self care ADL;
declining vision (worse than
20/40 but better than 20/200)
Perforation or blindness
(20/200 or worse) in the
affected eye
 -
Definition: A disorder characterized by an area of epithelial tissue loss on the surface of the cornea. It is associated with inflammatory cells in the cornea and anterior chamber.
Dry eye
Asymptomatic; clinical or
diagnostic observations only;
mild symptoms relieved by
lubricants
Symptomatic; multiple
agents indicated; limiting
instrumental ADL
Decrease in visual acuity
(<20/40); limiting self care
ADL
 -
 -
Definition: A disorder characterized by dryness of the cornea and conjunctiva.
Extraocular muscle paresis
Asymptomatic; clinical or
diagnostic observations only
Symptomatic; limiting
instrumental ADL
Limiting self care ADL;
disabling
 -
 -
Definition: A disorder characterized by incomplete paralysis of an extraocular muscle.
Eye pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the eye.
Eyelid function disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; nonoperative
intervention indicated;
limiting instrumental ADL
Limiting self care ADL;
operative intervention
indicated
 -
 -
Definition: A disorder characterized by impaired eyelid function.
Flashing lights
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by a sudden or brief burst of light.
Floaters
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by an individual seeing spots before their eyes. The spots are shadows of opaque cell fragments in the vitreous humor or lens.
Glaucoma
Elevated intraocular
pressure (EIOP) with single
topical agent for intervention;
no visual field deficit
EIOP causing early visual
field deficits; multiple topical
or oral agents indicated;
limiting instrumental ADL
EIOP causing marked visual
field deficits (e.g., involving
both superior and inferior
visual fields); operative
intervention indicated;
limiting self care ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by an increase in pressure in the eyeball due to obstruction of the aqueous humor outflow.
Keratitis
 -
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Decline in vision (worse than
20/40 but better than
20/200); limiting self care
ADL
Perforation or blindness
(20/200 or worse) in the
affected eye
 -
Definition: A disorder characterized by inflammation to the cornea of the eye.
Night blindness
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by an inability to see clearly in dim light.
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CTCAE 4.03 - June 14, 2010 : Eye disorders 
11
Eye disorders
Grade
Adverse Event
1
2
3
4
5
Optic nerve disorder
Asymptomatic; clinical or
diagnostic observations only
Limiting vision of the affected
eye (20/40 or better)
Limiting vision in the affected
eye (worse than 20/40 but
better than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by involvement of the optic nerve (second cranial nerve).
Papilledema
Asymptomatic; no visual field
defects
Symptomatic decline in
vision; visual field defect
present sparing the central
20 degrees
Marked visual field defect
(worse than 20/40 but better
than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by swelling around the optic disc.
Photophobia
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by fear and avoidance of light.
Retinal detachment
Asymptomatic
Exudative and visual acuity
20/40 or better
Rhegmatogenous or
exudative detachment;
operative intervention
indicated; decline in vision
(worse than 20/40 but better
than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by the separation of the inner retina layers from the underlying pigment epithelium.
Retinal tear
 -
Laser therapy or
pneumopexy indicated
Vitroretinal surgical repair
indicated
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by a small laceration of the retina, this occurs when the vitreous separates from the retina. Symptoms include flashes and floaters.
Retinal vascular disorder
 -
Topical medication indicated
Intravitreal medication;
operative intervention
indicated
 -
 -
Definition: A disorder characterized by pathological retinal blood vessels that adversely affects vision.
Retinopathy
Asymptomatic; clinical or
diagnostic observations only
Symptomatic with moderate
decrease in visual acuity
(20/40 or better); limiting
instrumental ADL
Symptomatic with marked
decrease in visual acuity
(worse than 20/40);
disabling; limiting self care
ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder involving the retina.
Scleral disorder
Asymptomatic; clinical or
diagnostic observations only
Symptomatic, limiting
instrumental ADL; moderate
decrease in visual acuity
(20/40 or better)
Symptomatic, limiting self
care ADL; marked decrease
in visual acuity (worse than
20/40)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by involvement of the sclera of the eye.
Uveitis
Asymptomatic; clinical or
diagnostic observations only
Anterior uveitis; medical
intervention indicated
Posterior or pan-uveitis
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by inflammation to the uvea of the eye.
Vitreous hemorrhage
Asymptomatic or mild
symptoms; clinical or
diagnostic observations only
Symptomatic; limiting
instrumental ADL
Limiting self care ADL;
vitrectomy indicated
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by blood extravasation into the vitreous humor.
Watering eyes
Intervention not indicated
Intervention indicated
Operative intervention
indicated
 -
 -
Definition: A disorder of excessive tearing in the eyes; it can be caused by overproduction of tears or impaired drainage of the tear duct.
Eye disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or
diagnostic observations only;
intervention not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental
ADL
Severe or medically
significant but not
immediately sight-
threatening; hospitalization
or prolongation of existing
hospitalization indicated;
disabling;  limiting self care
ADL
Sight-threatening
consequences; urgent
intervention indicated;
blindness (20/200 or worse)
in the affected eye
 -
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
12
8. Gastrointestinal disorders
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Abdominal distension
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe discomfort; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling of the abdomen.
Abdominal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the abdominal region.
Anal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the opening in the anal canal to the perianal skin.
Anal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the anal region.
Anal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the anus.
Anal necrosis
 -
 -
TPN or hospitalization indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the anal region.
Anal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the anal region.
Anal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Symptomatic and severely
altered GI function; non-
emergent operative intervention
indicated; TPN or hospitalization
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the anal canal.
Anal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the anal canal.
Ascites
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; invasive
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by accumulation of serous or hemorrhagic fluid in the peritoneal cavity.
Bloating
No change in bowel function or
oral intake
Symptomatic, decreased oral
intake; change in bowel function
 -
 -
 -
Definition: A disorder characterized by subject-reported feeling of uncomfortable fullness of the abdomen.
Cecal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the cecum.
Cheilitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; intervention indicated
 -
 -
Definition: A disorder characterized by inflammation of the lip.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
13
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Colitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Abdominal pain; mucus or blood
in stool
Severe abdominal pain; change
in bowel habits; medical
intervention indicated;
peritoneal signs
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the colon.
Colonic fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
bowel rest, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the large intestine and another organ or anatomic site.
Colonic hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the colon.
Colonic obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Hospitalization indicated;
elective operative intervention
indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the colon.
Colonic perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the colonic wall.
Colonic stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the colon.
Colonic ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the colon.
Constipation
Occasional or intermittent
symptoms; occasional use of
stool softeners, laxatives,
dietary modification, or enema
Persistent symptoms with
regular use of laxatives or
enemas; limiting instrumental
ADL
Obstipation with manual
evacuation indicated; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by irregular and infrequent or difficult evacuation of the bowels.
Dental caries
One or more dental caries, not
involving the root
Dental caries involving the root
Dental caries resulting in pulpitis
or periapical abscess or
resulting in tooth loss
 -
 -
Definition: A disorder characterized by the decay of a tooth, in which it becomes softened, discolored and/or porous.
Diarrhea
Increase of <4 stools per day
over baseline; mild increase in
ostomy output compared to
baseline
Increase of 4 - 6 stools per day
over baseline; moderate
increase in ostomy output
compared to baseline
Increase of >=7 stools per day
over baseline; incontinence;
hospitalization indicated; severe
increase in ostomy output
compared to baseline; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by frequent and watery bowel movements.
Dry mouth
Symptomatic (e.g., dry or thick
saliva) without significant dietary
alteration; unstimulated saliva
flow >0.2 ml/min
Moderate symptoms; oral intake
alterations (e.g., copious water,
other lubricants, diet limited to
purees and/or soft, moist foods);
unstimulated saliva 0.1 to 0.2
ml/min
Inability to adequately aliment
orally; tube feeding or TPN
indicated; unstimulated saliva
<0.1 ml/min
 -
 -
Definition: A disorder characterized by reduced salivary flow in the oral cavity.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
14
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Duodenal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the duodenum and another organ or anatomic site.
Duodenal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the duodenum.
Duodenal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Hospitalization or elective
operative intervention indicated;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of stomach contents through the duodenum.
Duodenal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the duodenal wall.
Duodenal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the duodenum.
Duodenal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the duodenal wall.
Dyspepsia
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; surgical
intervention indicated
 -
 -
Definition: A disorder characterized by an uncomfortable, often painful feeling in the stomach, resulting from impaired digestion. Symptoms include burning stomach, bloating,
heartburn, nausea and vomiting.
Dysphagia
Symptomatic, able to eat
regular diet
Symptomatic and altered
eating/swallowing
Severely altered
eating/swallowing; tube feeding
or TPN or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by difficulty in swallowing.
Enterocolitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Abdominal pain; mucus or blood
in stool
Severe or persistent abdominal
pain; fever; ileus; peritoneal
signs
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the small and large intestines.
Enterovesical fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; noninvasive
intervention indicated
Severe, medically significant;
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the urinary bladder and the intestine.
Esophageal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the esophagus and another organ or anatomic site.
Esophageal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the esophagus.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
15
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Esophageal necrosis
 -
 -
Inability to aliment adequately
by GI tract; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the esophageal wall.
Esophageal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents in the esophagus.
Esophageal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the esophageal region.
Esophageal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the wall of the esophagus.
Esophageal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the esophagus.
Esophageal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the esophageal wall.
Esophageal varices
hemorrhage
 -
Self-limited; intervention not
indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from esophageal varices.
Esophagitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered
eating/swallowing;  oral
supplements indicated
Severely altered
eating/swallowing; tube feeding,
TPN or hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the esophageal wall.
Fecal incontinence
Occasional use of pads required Daily use of pads required
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by inability to control the escape of stool from the rectum.
Flatulence
Mild symptoms; intervention not
indicated
Moderate; persistent;
psychosocial sequelae
 -
 -
 -
Definition: A disorder characterized by a state of excessive gas in the alimentary canal.
Gastric fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
bowel rest; tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the stomach and another organ or anatomic site.
Gastric hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the gastric wall.
Gastric necrosis
 -
 -
Inability to aliment adequately
by GI tract; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the gastric wall.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
16
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Gastric perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the stomach wall.
Gastric stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the stomach.
Gastric ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; medical intervention
indicated; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the stomach.
Gastritis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; medical intervention
indicated
Severely altered eating or
gastric function; TPN or
hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the stomach.
Gastroesophageal reflux
disease
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; surgical
intervention indicated
 -
 -
Definition: A disorder characterized by reflux of the gastric and/or duodenal contents into the distal esophagus. It is chronic in nature and usually caused by incompetence of the lower
esophageal sphincter, and may result in injury to the esophageal mucosal. Symptoms include heartburn and acid indigestion.
Gastrointestinal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between any part of the gastrointestinal system and another organ or anatomic site.
Gastrointestinal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gastrointestinal region.
Gastroparesis
Mild nausea, early satiety and
bloating, able to maintain caloric
intake on regular diet
Moderate symptoms; able to
maintain nutrition with dietary
and lifestyle modifications; may
need pharmacologic
intervention
Weight loss; refractory to
medical intervention; unable to
maintain nutrition orally
 -
 -
Definition: A disorder characterized by an incomplete paralysis of the muscles of the stomach wall resulting in delayed emptying of the gastric contents into the small intestine.
Gingival pain
Mild pain
Moderate pain interfering with
oral intake
Severe pain; inability to aliment
orally
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gingival region.
Hemorrhoidal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the hemorrhoids.
Hemorrhoids
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; banding or
medical intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by the presence of dilated veins in the rectum and surrounding area.
Ileal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the ileum and another organ or anatomic site.
Ileal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the ileal wall.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
17
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Ileal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the ileum.
Ileal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the ileal wall.
Ileal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the ileum.
Ileal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the ileum.
Ileus
 -
Symptomatic; altered GI
function; bowel rest indicated
Severely altered GI function;
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by failure of the ileum to transport intestinal contents.
Intra-abdominal hemorrhage
 -
Medical intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding in the abdominal cavity.
Jejunal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the jejunum and another organ or anatomic site.
Jejunal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the jejunal wall.
Jejunal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the jejunum.
Jejunal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the jejunal wall.
Jejunal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the jejunum.
Jejunal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the jejunum.
Lip pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort of the lip.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
18
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Lower gastrointestinal
hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the lower gastrointestinal tract (small intestine, large intestine, and anus).
Malabsorption
 -
Altered diet; oral intervention
indicated
Inability to aliment adequately;
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inadequate absorption of nutrients in the small intestine. Symptoms include abdominal marked discomfort, bloating and diarrhea.
Mucositis oral
Asymptomatic or mild
symptoms; intervention not
indicated
Moderate pain; not interfering
with oral intake; modified diet
indicated
Severe pain; interfering with oral
intake
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the oral mucosal.
Nausea
Loss of appetite without
alteration in eating habits
Oral intake decreased without
significant weight loss,
dehydration or malnutrition
Inadequate oral caloric or fluid
intake; tube feeding, TPN, or
hospitalization indicated
 -
 -
Definition: A disorder characterized by a queasy sensation and/or the urge to vomit.
Obstruction gastric
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents in the stomach.
Oral cavity fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the oral cavity and another organ or anatomic site.
Oral dysesthesia
Mild discomfort; not interfering
with oral intake
Moderate pain; interfering with
oral intake
Disabling pain; tube feeding or
TPN indicated
 -
 -
Definition: A disorder characterized by a burning or tingling sensation on the lips, tongue or entire mouth.
Oral hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the mouth.
Oral pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the mouth, tongue or lips.
Pancreatic duct stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the pancreatic duct.
Pancreatic fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the pancreas and another organ or anatomic site.
Pancreatic hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the pancreas.
Pancreatic necrosis
 -
 -
Tube feeding or TPN indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the pancreas.
Pancreatitis
 -
Enzyme elevation or radiologic
findings only
Severe pain; vomiting; medical
intervention indicated (e.g.,
analgesia, nutritional support)
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
19
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by inflammation of the pancreas.
Periodontal disease
Gingival recession or gingivitis;
limited bleeding on probing; mild
local bone loss
Moderate gingival recession or
gingivitis; multiple sites of
bleeding on probing; moderate
bone loss
Spontaneous bleeding; severe
bone loss with or without tooth
loss; osteonecrosis of maxilla or
mandible
 -
 -
Definition: A disorder in the gingival tissue around the teeth.
Peritoneal necrosis
 -
 -
Tube feeding or TPN  indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the peritoneum.
Proctitis
Rectal discomfort, intervention
not indicated
Symptoms (e.g., rectal
discomfort, passing blood or
mucus); medical intervention
indicated; limiting instrumental
ADL
Severe symptoms; fecal
urgency or stool incontinence;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the rectum.
Rectal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the rectum and another organ or anatomic site.
Rectal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the rectal wall and discharged from the anus.
Rectal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the rectum.
Rectal necrosis
 -
 -
Tube feeding or TPN indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the rectal wall.
Rectal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the rectum.
Rectal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the rectal region.
Rectal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the rectal wall.
Rectal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the rectum.
Rectal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function (e.g. altered dietary
habits, vomiting, diarrhea)
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the rectum.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
20
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Retroperitoneal hemorrhage
 -
Self-limited; intervention
indicated
Transfusion, medical, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the retroperitoneal area.
Salivary duct inflammation
Slightly thickened saliva; slightly
altered taste (e.g., metallic)
Thick, ropy, sticky saliva;
markedly altered taste;
alteration in diet indicated;
secretion-induced symptoms;
limiting instrumental ADL
Acute salivary gland necrosis;
severe secretion-induced
symptoms (e.g., thick saliva/oral
secretions or gagging);  tube
feeding or TPN indicated;
limiting self care ADL; disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the salivary duct.
Salivary gland fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; tube feeding indicated
Severely altered GI function;
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between a salivary gland and another organ or anatomic site.
Small intestinal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe pain; interfering with oral
intake; tube feeding, TPN or
hospitalization indicated; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the small intestine.
Small intestinal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents.
Small intestinal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the small intestine wall.
Small intestinal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Symptomatic and severely
altered GI function; tube
feeding, TPN or hospitalization
indicated; non-emergent
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the small intestine.
Small intestine ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the small intestine.
Stomach pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the stomach.
Tooth development disorder
Asymptomatic; hypoplasia of
tooth or enamel
Impairment correctable with oral
surgery
Maldevelopment with
impairment not surgically
correctable; disabling
 -
 -
Definition: A disorder characterized by a pathological process of the teeth occurring during tooth development.
Tooth discoloration
Surface stains
 -
 -
 -
 -
Definition: A disorder characterized by a change in tooth hue or tint.
Toothache
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the tooth.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
21
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Typhlitis
 -
 -
Symptomatic (e.g., abdominal
pain, fever, change in bowel
habits with ileus); peritoneal
signs
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the cecum.
Upper gastrointestinal
hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the upper gastrointestinal tract (oral cavity, pharynx, esophagus, and stomach).
Vomiting
1 - 2 episodes (separated by 5
minutes) in 24 hrs
3 - 5 episodes (separated by 5
minutes) in 24 hrs
>=6 episodes (separated by 5
minutes) in 24 hrs; tube feeding,
TPN or hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
Gastrointestinal disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : General disorders and administration site conditions 
22
9. General disorders and administration site conditions
General disorders and administration site conditions
Grade
Adverse Event
1
2
3
4
5
Chills
Mild sensation of cold;
shivering; chattering of teeth
Moderate tremor of the entire
body; narcotics indicated
Severe or prolonged, not
responsive to narcotics
 -
 -
Definition: A disorder characterized by a sensation of cold that often marks a physiologic response to sweating after a fever.
Death neonatal
 -
 -
 -
 -
Death
Definition: A disorder characterized by cessation of life occurring during the first 28 days of life.
Death NOS
 -
 -
 -
 -
Death
Definition: A cessation of life that cannot be attributed to a CTCAE term associated with Grade 5.
Edema face
Localized facial edema
Moderate localized facial
edema; limiting instrumental
ADL
Severe swelling; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in facial tissues.
Edema limbs
5 - 10% inter-limb discrepancy
in volume or circumference at
point of greatest visible
difference; swelling or
obscuration of anatomic
architecture on close inspection
>10 - 30% inter-limb
discrepancy in volume or
circumference at point of
greatest visible difference;
readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour; limiting
instrumental ADL
>30% inter-limb discrepancy in
volume; gross deviation from
normal anatomic contour;
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the upper or lower extremities.
Edema trunk
Swelling or obscuration of
anatomic architecture on close
inspection
Readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour; limiting
instrumental ADL
Gross deviation from normal
anatomic contour; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the trunk area.
Facial pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the face.
Fatigue
Fatigue relieved by rest
Fatigue not relieved by rest;
limiting instrumental ADL
Fatigue not relieved by rest,
limiting self care ADL
 -
 -
Definition: A disorder characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities.
Fever
38.0 - 39.0 degrees C  (100.4 -
102.2 degrees F)
>39.0 - 40.0 degrees C (102.3 -
104.0 degrees F)
>40.0 degrees C (>104.0
degrees F) for <=24 hrs
>40.0 degrees C (>104.0
degrees F) for >24 hrs
Death
Definition: A disorder characterized by elevation of the body's temperature above the upper limit of normal.
Flu like symptoms
Mild flu-like symptoms present
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a group of symptoms similar to those observed in patients with the flu. It includes fever, chills, body aches, malaise, loss of appetite and dry
cough.
Gait disturbance
Mild change in gait (e.g., wide-
based, limping or hobbling)
Moderate change in gait (e.g.,
wide-based, limping or
hobbling); assistive device
indicated; limiting instrumental
ADL
Disabling; limiting self care ADL
 -
 -
Definition: A disorder characterized by walking difficulties.
Hypothermia
 -
35 - >32 degrees C;  95 - >89.6
degrees F
32 - >28 degrees C;  89.6 -
>82.4 degrees F
<=28 degrees C; 82.4 degrees
F; life-threatening
consequences (e.g., coma,
hypotension, pulmonary edema,
acidemia, ventricular fibrillation)
Death
Definition: A disorder characterized by an abnormally low body temperature. Treatment is required when the body temperature is 35C (95F) or below.
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CTCAE 4.03 - June 14, 2010 : General disorders and administration site conditions 
23
General disorders and administration site conditions
Grade
Adverse Event
1
2
3
4
5
Infusion related reaction
Mild transient reaction; infusion
interruption not indicated;
intervention not indicated
Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.,
antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic
medications indicated for <=24
hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by adverse reaction to the infusion of pharmacological or biological substances.
Infusion site extravasation
 -
Erythema with associated
symptoms (e.g., edema, pain,
induration, phlebitis)
Ulceration or necrosis; severe
tissue damage; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by leakage of a pharmacologic or a biologic substance from the infusion site into the surrounding tissue. Signs and symptoms include induration,
erythema, swelling, burning sensation and marked discomfort at the infusion site.
Injection site reaction
Tenderness with or without
associated symptoms (e.g.,
warmth, erythema, itching)
Pain; lipodystrophy; edema;
phlebitis
Ulceration or necrosis; severe
tissue damage; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an intense adverse reaction (usually immunologic) developing at the site of an injection.
Irritability
Mild; easily consolable
Moderate; limiting instrumental
ADL; increased attention
indicated
Severe abnormal or excessive
response; limiting self care ADL;
inconsolable
 -
 -
Definition: A disorder characterized by an abnormal responsiveness to stimuli or physiological arousal; may be in response to pain, fright, a drug, an emotional situation or a medical
condition.
Localized edema
Localized to dependent areas,
no disability or functional
impairment
Moderate localized edema and
intervention indicated; limiting
instrumental ADL
Severe localized edema and
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation at a specific anatomic site.
Malaise
Uneasiness or lack of well being Uneasiness or lack of well
being; limiting instrumental ADL
 -
 -
 -
Definition: A disorder characterized by a feeling of general discomfort or uneasiness, an out-of-sorts feeling.
Multi-organ failure
 -
 -
Shock with azotemia and acid-
base disturbances; significant
coagulation abnormalities
Life-threatening consequences
(e.g., vasopressor dependent
and oliguric or anuric or
ischemic colitis or lactic
acidosis)
Death
Definition: A disorder characterized by progressive deterioration of the lungs, liver, kidney and clotting mechanisms.
Neck edema
Asymptomatic localized neck
edema
Moderate neck edema; slight
obliteration of anatomic
landmarks; limiting instrumental
ADL
Generalized neck edema (e.g.,
difficulty in turning neck);
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to an accumulation of excessive fluid in the neck.
Non-cardiac chest pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by discomfort in the chest unrelated to a heart disorder.
Pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by the sensation of marked discomfort, distress or agony.
Sudden death NOS
 -
 -
 -
 -
Death
Definition: An unexpected cessation of life that cannot be attributed to a CTCAE term associated with Grade 5.
General disorders and
administration site conditions -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Hepatobiliary disorders 
24
10. Hepatobiliary disorders
Hepatobiliary disorders
Grade
Adverse Event
1
2
3
4
5
Bile duct stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; IV fluids indicated <24
hrs
Severely altered GI function;
radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the bile duct.
Biliary fistula
 -
Symptomatic and intervention
not indicated
Severely altered GI function;
TPN indicated; endoscopic
intervention indicated; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the bile ducts and another organ or anatomic site.
Cholecystitis
 -
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation involving the gallbladder. It may be associated with the presence of gallstones.
Gallbladder fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Symptomatic or severely altered
GI function; TPN indicated;
radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the gallbladder and another organ or anatomic site.
Gallbladder necrosis
 -
 -
 -
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the gallbladder.
Gallbladder obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; IV fluids indicated  <24
hrs
Symptomatic and severely
altered GI function; tube
feeding, TPN or hospitalization
indicated; non-emergent
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents of the gallbladder.
Gallbladder pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gallbladder region.
Gallbladder perforation
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the gallbladder wall.
Hepatic failure
 -
 -
Asterixis; mild encephalopathy;
limiting self care ADL
Moderate to severe
encephalopathy; coma; life-
threatening consequences
Death
Definition: A disorder characterized by the inability of the liver to metabolize chemicals in the body. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic
dehydrogenase, and alkaline phosphatase.
Hepatic hemorrhage
Mild; intervention not indicated
Symptomatic; medical
intervention indicated
Transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the liver.
Hepatic necrosis
 -
 -
 -
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the hepatic parenchyma.
Hepatic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the liver region.
Perforation bile duct
 -
 -
Radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the wall of the extrahepatic or intrahepatic bile duct.
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CTCAE 4.03 - June 14, 2010 : Hepatobiliary disorders 
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Hepatobiliary disorders
Grade
Adverse Event
1
2
3
4
5
Portal hypertension
 -
Decreased portal vein flow
Reversal/retrograde portal vein
flow; associated with varices
and/or ascites
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in blood pressure in the portal venous system.
Portal vein thrombosis
 -
Intervention not indicated
Medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the formation of a thrombus (blood clot) in the portal vein.
Hepatobiliary disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Immune system disorders 
26
11. Immune system disorders
Immune system disorders
Grade
Adverse Event
1
2
3
4
5
Allergic reaction
Transient flushing or rash, drug
fever <38 degrees C (<100.4
degrees F); intervention not
indicated
Intervention or infusion
interruption indicated; responds
promptly to symptomatic
treatment (e.g., antihistamines,
NSAIDS, narcotics);
prophylactic medications
indicated for <=24 hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae (e.g., renal
impairment, pulmonary
infiltrates)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
 -
 -
Symptomatic bronchospasm,
with or without urticaria;
parenteral intervention
indicated; allergy-related
edema/angioedema;
hypotension
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivity
immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death.
Autoimmune disorder
Asymptomatic; serologic or
other evidence of autoimmune
reaction, with normal organ
function;  intervention not
indicated
Evidence of autoimmune
reaction involving a non-
essential organ or function (e.g.,
hypothyroidism)
Autoimmune reactions involving
major organ (e.g., colitis,
anemia, myocarditis, kidney)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder resulting from loss of function or tissue destruction of an organ or multiple organs, arising from humoral or cellular immune responses of the individual to his own
tissue constituents.
Cytokine release syndrome
Mild reaction; infusion
interruption not indicated;
intervention not indicated
Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.,
antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic
medications indicated for <=24
hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae (e.g., renal
impairment, pulmonary
infiltrates)
Life-threatening consequences;
pressor or ventilatory support
indicated
Death
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused by the release of cytokines from the cells.
Serum sickness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate arthralgia; fever, rash,
urticaria, antihistamines
indicated
Severe arthralgia or arthritis;
extensive rash; steroids or IV
fluids indicated
Life-threatening consequences;
pressor or ventilatory support
indicated
Death
Definition: A disorder characterized by a delayed-type hypersensitivity reaction to foreign proteins derived from an animal serum. It occurs approximately six to twenty-one days
following the administration of the foreign antigen. Symptoms include fever, arthralgias, myalgias, skin eruptions, lymphadenopathy, chest marked discomfort and dyspnea.
Immune system disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
27
12. Infections and infestations
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Abdominal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the abdominal cavity.
Anorectal infection
Localized; local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the anal area and the rectum.
Appendicitis
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent.
Appendicitis perforated
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent with gangrenous changes resulting in the rupture of the
appendiceal wall. The appendiceal wall rupture causes the release of inflammatory and bacterial contents from the appendiceal lumen into the abdominal cavity.
Arteritis infective
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving an artery.
Biliary tract infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the biliary tract.
Bladder infection
 -
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bladder.
Bone infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bones.
Breast infection
 -
Local infection with moderate
symptoms; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral)
Severe infection; axillary
adenitis;  IV antibacterial,
antifungal, or antiviral
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the breast.
Bronchial infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bronchi.
Catheter related infection
 -
Localized; local intervention
indicated; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process that arises secondary to catheter use.
Cecal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
28
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the cecum.
Cervicitis infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the uterine cervix.
Conjunctivitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the conjunctiva. Clinical manifestations include pink or red color in the eyes.
Corneal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the cornea.
Cranial nerve infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a cranial nerve.
Device related infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the use of a medical device.
Duodenal infection
 -
Moderate symptoms; medical
intervention indicated (e.g., oral
antibiotics)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the duodenum.
Encephalitis infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
severe changes in mental
status; self-limited seizure
activity; focal neurologic
abnormalities
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the brain tissue.
Encephalomyelitis infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the brain and spinal cord tissues.
Endocarditis infective
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the endocardial layer of the heart.
Endophthalmitis
 -
Local intervention indicated
Systemic intervention or
hospitalization indicated
Blindness (20/200 or worse)
 -
Definition: A disorder characterized by an infectious process involving the internal structures of the eye.
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
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Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Enterocolitis infectious
 -
Passage of >3 unformed stools
per 24 hrs or duration of illness
>48 hrs; moderate abdominal
pain
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated;
profuse watery diarrhea with
signs of hypovolemia;  bloody
diarrhea; fever; severe
abdominal pain; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the small and large intestines.
Esophageal infection
 -
Local intervention indicated
(e.g., oral antibiotic, antifungal,
antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the esophagus.
Eye infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated;
enucleation
Death
Definition: A disorder characterized by an infectious process involving the eye.
Gallbladder infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the gallbladder.
Gum infection
Local therapy indicated (swish
and swallow)
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the gums.
Hepatic infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the liver.
Hepatitis viral
Asymptomatic, treatment not
indicated
 -
Symptomatic liver dysfunction;
fibrosis by biopsy; compensated
cirrhosis; reactivation of chronic
hepatitis
Decompensated liver function
(e.g., ascites, coagulopathy,
encephalopathy, coma)
Death
Definition: A disorder characterized by a viral pathologic process involving the liver parenchyma.
Infective myositis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the skeletal muscles.
Joint infection
 -
Localized; local intervention
indicated; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral); needle
aspiration indicated (single or
multiple)
Arthroscopic intervention
indicated (e.g., drainage) or
arthrotomy (e.g., open surgical
drainage)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a joint.
Kidney infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the kidney.
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
30
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Laryngitis
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammatory process involving the larynx.
Lip infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by an infectious process involving the lips.
Lung infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the lungs.
Lymph gland infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the lymph nodes.
Mediastinal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the mediastinum.
Meningitis
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated; focal
neurologic deficit
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation of the meninges of the brain and/or spinal cord.
Mucosal infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a mucosal surface.
Nail infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by an infectious process involving the nail.
Otitis externa
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the outer ear and ear canal. Contributory factors include excessive water exposure (swimmer's ear infection)
and cuts in the ear canal. Symptoms include fullness, itching, swelling and marked discomfort in the ear and ear drainage.
Otitis media
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the middle ear.
Ovarian infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the ovary.
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
31
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Pancreas infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pancreas.
Papulopustular rash
Papules and/or pustules
covering <10% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness
Papules and/or pustules
covering 10-30% BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness; associated with
psychosocial impact; limiting
instrumental ADL
Papules and/or pustules
covering >30% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness; limiting self-care
ADL; associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering  any % BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness and are associated
with extensive superinfection
with IV antibiotics indicated; life-
threatening consequences
Death
Definition: A disorder characterized by an eruption consisting of papules (a small, raised pimple) and pustules (a small pus filled blister), typically appearing in face, scalp, and upper
chest and back Unlike acne, this rash does not present with whiteheads or blackheads, and can be symptomatic, with itchy or tender lesions.
Paronychia
Nail fold edema or erythema;
disruption of the cuticle
Localized intervention indicated;
oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral);
nail fold edema or erythema
with pain; associated with
discharge or nail plate
separation; limiting instrumental
ADL
Surgical intervention or IV
antibiotics indicated; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an infectious process involving the soft tissues around the nail.
Pelvic infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pelvic cavity.
Penile infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the penis.
Periorbital infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the orbit of the eye.
Peripheral nerve infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the peripheral nerves.
Peritoneal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the peritoneum.
Pharyngitis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the throat.
Phlebitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
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Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the vein. Clinical manifestations include erythema, marked discomfort, swelling, and induration along the course
of the infected vein.
Pleural infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pleura.
Prostate infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the prostate gland.
Rash pustular
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by a circumscribed and elevated skin lesion filled with pus.
Rhinitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
 -
 -
 -
Definition: A disorder characterized by an infectious process involving the nasal mucosal.
Salivary gland infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the salivary gland.
Scrotal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the scrotum.
Sepsis
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the presence of pathogenic microorganisms in the blood stream that cause a rapidly progressing systemic reaction that may lead to shock.
Sinusitis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the mucous membranes of the paranasal sinuses.
Skin infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the skin.
Small intestine infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the small intestine.
Soft tissue infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving soft tissues.
Splenic infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
33
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the spleen.
Stoma site infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a stoma (surgically created opening on the surface of the body).
Tooth infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a tooth.
Tracheitis
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the trachea.
Upper respiratory infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the upper respiratory tract (nose, paranasal sinuses, pharynx, larynx, or trachea).
Urethral infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the urethra.
Urinary tract infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the urinary tract, most commonly the bladder and the urethra.
Uterine infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the endometrium. It may extend to the myometrium and parametrial tissues.
Vaginal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the vagina.
Vulval infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the vulva.
Wound infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the wound.
Infections and infestations -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
34
13. Injury, poisoning and procedural complications
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Ankle fracture
Mild; non-surgical intervention
indicated
Limiting instrumental ADL;
operative intervention indicated
Limiting self care ADL; elective
surgery indicated
 -
 -
Definition: A finding of damage to the ankle joint characterized by a break in the continuity of the ankle bone. Symptoms include marked discomfort, swelling and difficulty moving the
affected leg and foot.
Aortic injury
 -
 -
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to the aorta.
Arterial injury
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic (e.g.,
claudication); repair or revision
not indicated
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to an artery.
Biliary anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of bile due to breakdown of a biliary anastomosis (surgical connection of two separate anatomic structures).
Bladder anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of urine due to breakdown of a bladder anastomosis (surgical connection of two separate anatomic structures).
Bruising
Localized or in a dependent
area
Generalized
 -
 -
 -
Definition: A finding of injury of the soft tissues or bone characterized by leakage of blood into surrounding tissues.
Burn
Minimal symptoms; intervention
not indicated
Medical intervention; minimal
debridement indicated
Moderate to major debridement
or reconstruction indicated
Life-threatening consequences
Death
Definition: A finding of impaired integrity to the anatomic site of an adverse thermal reaction. Burns can be caused by exposure to chemicals, direct heat, electricity, flames and
radiation. The extent of damage depends on the length and intensity of exposure and time until provision of treatment.
Dermatitis radiation
Faint erythema or dry
desquamation
Moderate to brisk erythema;
patchy moist desquamation,
mostly confined to skin folds
and creases; moderate edema
Moist desquamation in areas
other than skin folds and
creases; bleeding induced by
minor trauma or abrasion
Life-threatening consequences;
skin necrosis or ulceration of full
thickness dermis; spontaneous
bleeding from involved site; skin
graft indicated
Death
Definition: A finding of cutaneous inflammatory reaction occurring as a result of exposure to biologically effective levels of ionizing radiation.
Esophageal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an esophageal anastomosis (surgical connection of two separate anatomic structures).
Fall
Minor with no resultant injuries;
intervention not indicated
Symptomatic; noninvasive
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding of sudden movement downward, usually resulting in injury.
Fallopian tube anastomotic leak
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a fallopian tube anastomosis (surgical connection of two separate anatomic structures).
Fallopian tube perforation
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated (e.g., organ resection)
Death
Definition: A finding of rupture of the fallopian tube wall.
Fracture
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic but non-displaced;
immobilization indicated
Severe symptoms; displaced or
open wound with bone
exposure; disabling; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of traumatic injury to the bone in which the continuity of the bone is broken.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
35
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Gastric anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a gastric anastomosis (surgical connection of two separate anatomic structures).
Gastrointestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a gastrointestinal anastomosis (surgical connection of two separate anatomic structures).
Gastrointestinal stoma necrosis
 -
Superficial necrosis;
intervention not indicated
Severe symptoms;
hospitalization or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of a necrotic process occurring in the gastrointestinal tract stoma.
Hip fracture
 -
Hairline fracture; mild pain;
limiting instrumental ADL; non-
surgical intervention indicated
Severe pain; hospitalization or
intervention indicated for pain
control (e.g., traction); operative
intervention indicated
Life-threatening consequences;
symptoms associated with
neurovascular compromise
 -
Definition: A finding of traumatic injury to the hip in which the continuity of either the femoral head, femoral neck, intertrochanteric or subtrochanteric regions is broken.
Injury to carotid artery
 -
 -
Severe symptoms; limiting self
care ADL (e.g., transient
cerebral ischemia); repair or
revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the carotid artery.
Injury to inferior vena cava
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the inferior vena cava.
Injury to jugular vein
 -
 -
Symptomatic limiting self care
ADL; disabling; repair or
revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the jugular vein.
Injury to superior vena cava
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic; repair or revision
not indicated
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to the superior vena cava.
Intestinal stoma leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of contents from an intestinal stoma (surgically created opening on the surface of the body).
Intestinal stoma obstruction
 -
Self-limited; intervention not
indicated
Severe symptoms; IV fluids,
tube feeding, or TPN indicated
>=24 hrs; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of blockage of the normal flow of the contents of the intestinal stoma.
Intestinal stoma site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of blood leakage from the intestinal stoma.
Intraoperative arterial injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to an artery during a surgical procedure.
Intraoperative breast injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
36
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of damage to the breast parenchyma during a surgical procedure.
Intraoperative cardiac injury
 -
 -
Primary repair of injured
organ/structure indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the heart during a surgical procedure.
Intraoperative ear injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection of injured
organ/structure indicated;
disabling (e.g., impaired
hearing; impaired balance)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the ear during a surgical procedure.
Intraoperative endocrine injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the endocrine gland during a surgical procedure.
Intraoperative gastrointestinal
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the gastrointestinal system during a surgical procedure.
Intraoperative head and neck
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the head and neck during a surgical procedure.
Intraoperative hemorrhage
 -
 -
Postoperative radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of uncontrolled bleeding during a surgical procedure.
Intraoperative hepatobiliary
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the hepatic parenchyma and/or biliary tract during a surgical procedure.
Intraoperative musculoskeletal
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the musculoskeletal system during a surgical procedure.
Intraoperative neurological
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the nervous system during a surgical procedure.
Intraoperative ocular injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the eye during a surgical procedure.
Intraoperative renal injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the kidney during a surgical procedure.
Intraoperative reproductive tract
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
37
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of damage to the reproductive organs during a surgical procedure.
Intraoperative respiratory injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the respiratory system during a surgical procedure.
Intraoperative skin injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the skin during a surgical procedure.
Intraoperative splenic injury
 -
Primary repair of injured
organ/structure indicated
Resection or reconstruction of
injured organ/structure
indicated; disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the spleen during a surgical procedure.
Intraoperative urinary injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the urinary system during a surgical procedure.
Intraoperative venous injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to a vein during a surgical procedure.
Kidney anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of urine due to breakdown of a kidney anastomosis (surgical connection of two separate anatomic structures).
Large intestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the large intestine.
Pancreatic anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a pancreatic anastomosis (surgical connection of two separate anatomic structures).
Pharyngeal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a pharyngeal anastomosis (surgical connection of two separate anatomic structures).
Postoperative hemorrhage
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; radiologic,
endoscopic, or operative
intervention indicated
Transfusion indicated of >=2
units (10 cc/kg for pediatrics)
pRBCs beyond protocol
specification; urgent radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding occurring after a surgical procedure.
Postoperative thoracic
procedure complication
 -
Extubated within 24 - 72 hrs
postoperatively
Extubated >72 hrs
postoperatively, but before
tracheostomy indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A finding of a previously undocumented problem that occurs after a thoracic procedure.
Prolapse of intestinal stoma
Asymptomatic; reducible
Recurrent after manual
reduction; local irritation or stool
leakage; difficulty to fit
appliance; limiting instrumental
ADL
Severe symptoms; elective
operative intervention indicated;
limiting self care ADL
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
38
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of protrusion of the intestinal stoma (surgically created opening on the surface of the body) above the abdominal surface.
Prolapse of urostomy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Local care or maintenance;
minor revision indicated
Dysfunctional stoma; elective
operative intervention or major
stomal revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of displacement of the urostomy.
Radiation recall reaction
(dermatologic)
Faint erythema or dry
desquamation
Moderate to brisk erythema;
patchy moist desquamation,
mostly confined to skin folds
and creases; moderate edema
Moist desquamation in areas
other than skin folds and
creases; bleeding induced by
minor trauma or abrasion
Life-threatening consequences;
skin necrosis or ulceration of full
thickness dermis; spontaneous
bleeding from involved site; skin
graft indicated
Death
Definition: A finding of acute skin inflammatory reaction caused by drugs, especially chemotherapeutic agents, for weeks or months following radiotherapy. The inflammatory reaction
is confined to the previously irradiated skin and the symptoms disappear after the removal of the pharmaceutical agent.
Rectal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a rectal anastomosis (surgical connection of two separate anatomic structures).
Seroma
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; simple aspiration
indicated
Symptomatic, elective radiologic
or operative intervention
indicated
 -
 -
Definition: A finding of tumor-like collection of serum in the tissues.
Small intestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the small bowel.
Spermatic cord anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a spermatic cord anastomosis (surgical connection of two separate anatomic structures).
Spinal fracture
Mild back pain; nonprescription
analgesics indicated
Moderate back pain;
prescription analgesics
indicated; limiting instrumental
ADL
Severe back pain;
hospitalization or intervention
indicated for pain control (e.g.,
vertebroplasty); limiting self care
ADL; disability
Life-threatening consequences;
symptoms associated with
neurovascular compromise
Death
Definition: A finding of traumatic injury to the spine in which the continuity of a vertebral bone is broken.
Stenosis of gastrointestinal
stoma
 -
Symptomatic; IV fluids indicated
<24 hrs; manual dilation at
bedside
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of narrowing of the gastrointestinal stoma (surgically created opening on the surface of the body).
Stomal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the jejunal mucosal surface close to the anastomosis site following a
gastroenterostomy procedure.
Tracheal hemorrhage
Minimal bleeding identified on
clinical or diagnostic exam;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding from the trachea.
Tracheal obstruction
Partial asymptomatic
obstruction on examination
(e.g., visual, radiologic or
endoscopic)
Symptomatic (e.g., noisy airway
breathing), no respiratory
distress; medical intervention
indicated (e.g., steroids); limiting
instrumental ADL
Stridor; radiologic or endoscopic
intervention indicated (e.g.,
stent, laser); limiting self care
ADL
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A finding of blockage of the lumen of the trachea.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
39
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Tracheostomy site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of blood leakage from the tracheostomy site.
Ureteric anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a ureteral anastomosis (surgical connection of two separate anatomic structures).
Urethral anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a urethral anastomosis (surgical connection of two separate anatomic structures).
Urostomy leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of contents from a urostomy.
Urostomy obstruction
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; dilation or
endoscopic repair or stent
placement indicated
Altered organ function (e.g.,
sepsis or hydronephrosis, or
renal dysfunction); elective
operative intervention indicated
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A finding of blockage of the urostomy.
Urostomy site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding from the urostomy site.
Urostomy stenosis
 -
Symptomatic but no
hydronephrosis, no sepsis or no
renal dysfunction; dilation or
endoscopic repair or stent
placement indicated
Symptomatic (e.g.,
hydronephrosis, or renal
dysfunction); elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of narrowing of the opening of a urostomy.
Uterine anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a uterine anastomosis (surgical connection of two separate anatomic structures).
Uterine perforation
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the uterine wall.
Vaginal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a vaginal anastomosis (surgical connection of two separate anatomic structures).
Vas deferens anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a vas deferens anastomosis (surgical connection of two separate anatomic structures).
Vascular access complication
 -
Device dislodgement, blockage,
leak, or malposition; device
replacement indicated
Deep vein or cardiac
thrombosis; intervention
indicated (e.g., anticoagulation,
lysis, filter, invasive procedure)
Embolic event including
pulmonary embolism or life-
threatening thrombus
Death
Definition: A finding of a previously undocumented problem related to the vascular access site.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
40
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Venous injury
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic (e.g.,
claudication); repair or revision
not indicated
Severe symptoms; limiting self
care ADL; repair or revision
indicated; disabling
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to a vein.
Wound complication
Incisional separation of <=25%
of wound, no deeper than
superficial fascia
Incisional separation >25% of
wound; local care indicated
Hernia without evidence of
strangulation; fascial
disruption/dehiscence; primary
wound closure or revision by
operative intervention indicated
Hernia with evidence of
strangulation; major
reconstruction flap, grafting,
resection, or amputation
indicated
Death
Definition: A finding of development of a new problem at the site of an existing wound.
Wound dehiscence
Incisional separation of <=25%
of wound, no deeper than
superficial fascia
Incisional separation >25% of
wound with local care;
asymptomatic hernia or
symptomatic hernia without
evidence of strangulation
Fascial disruption or dehiscence
without evisceration; primary
wound closure or revision by
operative intervention indicated
Life-threatening consequences;
symptomatic hernia with
evidence of strangulation;
fascial disruption with
evisceration; major
reconstruction flap, grafting,
resection, or amputation
indicated
Death
Definition: A finding of separation of the approximated margins of a surgical wound.
Wrist fracture
Mild; non-surgical intervention
indicated
Limiting instrumental ADL;
operative intervention indicated
Limiting self care ADL; elective
surgery indicated
 -
 -
Definition: A finding of traumatic injury to the wrist joint in which the continuity of a wrist bone is broken.
Injury, poisoning and procedural
complications - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Investigations 
41
14. Investigations
Investigations
Grade
Adverse Event
1
2
3
4
5
Activated partial thromboplastin
time prolonged
>ULN - 1.5 x ULN
>1.5 - 2.5 x ULN
>2.5 x ULN; hemorrhage
 -
 -
Definition: An abnormal laboratory test result in which the partial thromboplastin time is found to be greater than the control value. As a possible indicator of coagulopathy, a prolonged
partial thromboplastin time (PTT) may occur in a variety of diseases and disorders, both primary and related to treatment.
Alanine aminotransferase
increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT or SGPT) in the blood specimen.
Alkaline phosphatase increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of alkaline phosphatase in a blood specimen.
Aspartate aminotransferase
increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of aspartate aminotransferase (AST or SGOT) in a blood specimen.
Blood antidiuretic hormone
abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of antidiuretic hormone in the blood specimen.
Blood bilirubin increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an abnormally high level of bilirubin in the blood. Excess bilirubin is associated with jaundice.
Blood corticotrophin decreased
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of corticotrophin in a blood specimen.
Blood gonadotrophin abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of gonadotrophin hormone in a blood specimen.
Blood prolactin abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
 -
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of prolactin hormone in a blood specimen.
Carbon monoxide diffusing
capacity decreased
3 - 5 units below LLN; for follow-
up, a decrease of 3 - 5 units
(ml/min/mm Hg) below the
baseline value
6 - 8 units below LLN; for follow-
up, an asymptomatic decrease
of >5 - 8 units (ml/min/mm Hg)
below the baseline value
Asymptomatic decrease  of >8
units drop;  >5 units drop along
with the presence of pulmonary
symptoms (e.g. , >Grade 2
hypoxia or >Grade 2 or higher
dyspnea)
 -
 -
Definition: A finding based on lung function test results that indicate  a decrease in the lung capacity to absorb carbon monoxide.
Cardiac troponin I increased
Levels above the upper limit of
normal and below the level of
myocardial infarction as defined
by the manufacturer
 -
Levels consistent with
myocardial infarction as defined
by the manufacturer
 -
 -
Definition: A laboratory test result which indicates increased levels of cardiac troponin I in a biological specimen.
Cardiac troponin T increased
Levels above the upper limit of
normal and below the level of
myocardial infarction as defined
by the manufacturer
 -
Levels consistent with
myocardial infarction as defined
by the manufacturer
 -
 -
Definition: A laboratory test result which indicates increased levels of cardiac troponin T in a biological specimen.
CD4 lymphocytes decreased
<LLN - 500/mm3;  <LLN - 0.5 x
10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x
10e9 /L
<200 - 50/mm3; <0.2 x 0.05 -
10e9 /L
<50/mm3; <0.05 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of CD4 lymphocytes in a blood specimen.
Cholesterol high
>ULN - 300 mg/dL; >ULN - 7.75
mmol/L
>300 - 400 mg/dL; >7.75 - 10.34
mmol/L
>400 - 500 mg/dL; >10.34 -
12.92 mmol/L
>500 mg/dL; >12.92 mmol/L
 -
Definition: A finding based on laboratory test results that indicate higher than normal levels of cholesterol in a blood specimen.
CPK increased
>ULN - 2.5 x ULN
>2.5 x ULN - 5 x ULN
>5 x ULN - 10 x ULN
>10 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in levels of creatine phosphokinase in a blood specimen.
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CTCAE 4.03 - June 14, 2010 : Investigations 
42
Investigations
Grade
Adverse Event
1
2
3
4
5
Creatinine increased
>1 - 1.5 x baseline; >ULN - 1.5
x ULN
>1.5 - 3.0 x baseline; >1.5 - 3.0
x ULN
>3.0 baseline; >3.0 - 6.0 x ULN
>6.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate increased levels of creatinine in a biological specimen.
Ejection fraction decreased
 -
Resting ejection fraction (EF) 50
- 40%; 10 - 19% drop from
baseline
Resting ejection fraction (EF) 39
- 20%; >20% drop from baseline
Resting ejection fraction (EF)
<20%
 -
Definition: The percentage computed when the amount of blood ejected during a ventricular contraction of the heart is compared to the amount that was present prior to the
contraction.
Electrocardiogram QT corrected
interval prolonged
QTc 450 - 480 ms
QTc 481 - 500 ms
QTc >= 501 ms on at least two
separate ECGs
QTc >= 501 or >60 ms change
from baseline and Torsade de
pointes or polymorphic
ventricular tachycardia or
signs/symptoms of serious
arrhythmia
 -
Definition: A finding of a cardiac dysrhythmia characterized by an abnormally long corrected QT interval.
Fibrinogen decreased
<1.0 - 0.75 x LLN  or <25%
decrease from baseline
<0.75 - 0.5 x LLN or 25 - <50%
decrease from baseline
<0.5 - 0.25 x LLN or 50 - <75%
decrease from baseline
<0.25 x LLN  or 75% decrease
from baseline or absolute value
<50 mg/dL
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of fibrinogen in a blood specimen.
Forced expiratory volume
decreased
FEV1% (percentages of
observed FEV1 and FVC
related to their respective
predicted values)  99 - 70%
predicted
FEV1 60 - 69%
50 - 59%
<= 49%
 -
Definition: A finding based on test results that indicate a relative decrease in the fraction of the forced vital capacity that is exhaled in a specific number of seconds.
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate higher than normal levels of the enzyme gamma-glutamyltransferase in the blood specimen. GGT (gamma-
glutamyltransferase ) catalyzes the transfer of a gamma glutamyl group from a gamma glutamyl peptide to another peptide, amino acids or water.
Growth hormone abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
 -
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of growth hormone in a biological specimen.
Haptoglobin decreased
<LLN
 -
 -
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of haptoglobin in a blood specimen.
Hemoglobin increased
Increase in >0 - 2 gm/dL above
ULN or above baseline if
baseline is above ULN
Increase in >2 - 4 gm/dL above
ULN or above baseline if
baseline is above ULN
Increase in >4 gm/dL above
ULN or above baseline if
baseline is above ULN
 -
 -
Definition: A finding based on laboratory test results that indicate increased levels of hemoglobin in a biological specimen.
INR increased
>1 - 1.5 x ULN; >1 - 1.5 times
above baseline if on
anticoagulation
>1.5 - 2.5 x ULN; >1.5 - 2.5
times above baseline if on
anticoagulation
>2.5 x ULN; >2.5 times above
baseline if on anticoagulation
 -
 -
Definition: A finding based on laboratory test results that indicate an increase in the ratio of the patient's prothrombin time to a control sample in the blood.
Lipase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of lipase in a biological specimen.
Lymphocyte count decreased
 <LLN - 800/mm3; <LLN - 0.8 x
10e9 /L
<800 - 500/mm3; <0.8 - 0.5 x
10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x
10e9 /L
<200/mm3; <0.2 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of lymphocytes in a blood specimen.
Lymphocyte count increased
 -
>4000/mm3 - 20,000/mm3
>20,000/mm3
 -
 -
Definition: A finding based on laboratory test results that indicate an abnormal increase in the number of lymphocytes in the blood, effusions or bone marrow.
Neutrophil count decreased
<LLN - 1500/mm3; <LLN - 1.5 x
10e9 /L
<1500 - 1000/mm3; <1.5 - 1.0 x
10e9 /L
<1000 - 500/mm3; <1.0 - 0.5 x
10e9 /L
<500/mm3; <0.5 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of neutrophils in a blood specimen.
Pancreatic enzymes decreased
<LLN and asymptomatic
Increase in stool frequency,
bulk, or odor; steatorrhea
Sequelae of absorption
deficiency
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of pancreatic enzymes in a biological specimen.
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CTCAE 4.03 - June 14, 2010 : Investigations 
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Investigations
Grade
Adverse Event
1
2
3
4
5
Platelet count decreased
<LLN - 75,000/mm3; <LLN -
75.0 x 10e9 /L
<75,000 - 50,000/mm3; <75.0 -
50.0 x 10e9 /L
<50,000 - 25,000/mm3; <50.0 -
25.0 x 10e9 /L
<25,000/mm3; <25.0 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.
Serum amylase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the levels of amylase in a serum specimen.
Urine output decreased
 -
 -
Oliguria (<80 ml in 8 hr)
Anuria (<240 ml in 24 hr)
 -
Definition: A finding based on test results that indicate urine production is less relative to previous output.
Vital capacity abnormal
90 - 75% of predicted value
<75 - 50% of predicted value;
limiting instrumental ADL
<50% of predicted value;
limiting self care ADL
 -
 -
Definition: A finding based on pulmonary function test results that indicate an abnormal vital capacity (amount of exhaled after a maximum inhalation) when compared to the predicted
value.
Weight gain
5 - <10% from baseline
10 - <20% from baseline
>=20% from baseline
 -
 -
Definition: A finding characterized by an increase in overall body weight; for pediatrics, greater than the baseline growth curve.
Weight loss
5 to <10% from baseline;
intervention not indicated
10 - <20% from baseline;
nutritional support indicated
>=20% from baseline; tube
feeding or TPN indicated
 -
 -
Definition: A finding characterized by a decrease in overall body weight; for pediatrics, less than the baseline growth curve.
White blood cell decreased
<LLN - 3000/mm3; <LLN - 3.0 x
10e9 /L
<3000 - 2000/mm3; <3.0 - 2.0 x
10e9 /L
<2000 - 1000/mm3; <2.0 - 1.0 x
10e9 /L
<1000/mm3; <1.0 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate an decrease in number of white blood cells in a blood specimen.
Investigations - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Metabolism and nutrition disorders 
44
15. Metabolism and nutrition disorders
Metabolism and nutrition disorders
Grade
Adverse Event
1
2
3
4
5
Acidosis
pH <normal, but >=7.3
 -
pH <7.3
Life-threatening consequences
Death
Definition: A disorder characterized by abnormally high acidity (high hydrogen-ion concentration) of the blood and other body tissues.
Alcohol intolerance
 -
Present
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in sensitivity to the adverse effects of alcohol, which can include nasal congestion, skin flushes, heart dysrhythmias, nausea,
vomiting, indigestion and headaches.
Alkalosis
pH >normal, but <=7.5
 -
pH >7.5
Life-threatening consequences
Death
Definition: A disorder characterized by abnormally high alkalinity (low hydrogen-ion concentration) of the blood and other body tissues.
Anorexia
Loss of appetite without
alteration in eating habits
Oral intake altered without
significant weight loss or
malnutrition; oral nutritional
supplements indicated
Associated with significant
weight loss or malnutrition (e.g.,
inadequate oral caloric and/or
fluid intake); tube feeding or
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a loss of appetite.
Dehydration
Increased oral fluids indicated;
dry mucous membranes;
diminished skin turgor
IV fluids indicated <24 hrs
IV fluids or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Glucose intolerance
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; dietary
modification or oral agent
indicated
Severe symptoms; insulin
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inability to properly metabolize glucose.
Hypercalcemia
Corrected serum calcium of
>ULN - 11.5 mg/dL; >ULN - 2.9
mmol/L;  Ionized calcium  >ULN
- 1.5 mmol/L
Corrected serum calcium of
>11.5 - 12.5 mg/dL; >2.9 - 3.1
mmol/L;  Ionized calcium >1.5 -
1.6 mmol/L; symptomatic
Corrected serum calcium of
>12.5 - 13.5 mg/dL; >3.1 - 3.4
mmol/L;  Ionized calcium  >1.6 -
1.8 mmol/L; hospitalization
indicated
Corrected serum calcium of
>13.5 mg/dL; >3.4 mmol/L;
Ionized calcium  >1.8 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of calcium (corrected for albumin) in blood.
Hyperglycemia
Fasting glucose value >ULN -
160 mg/dL; Fasting glucose
value >ULN - 8.9 mmol/L
Fasting glucose value >160 -
250 mg/dL; Fasting glucose
value >8.9 - 13.9 mmol/L
>250 - 500 mg/dL; >13.9 - 27.8
mmol/L; hospitalization
indicated
>500 mg/dL; >27.8 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of blood sugar. It is usually an indication of diabetes mellitus or glucose
intolerance.
Hyperkalemia
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L
>6.0 - 7.0 mmol/L;
hospitalization indicated
>7.0 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of potassium in the blood; associated with kidney failure or sometimes with
the use of diuretic drugs.
Hypermagnesemia
>ULN - 3.0 mg/dL; >ULN - 1.23
mmol/L
 -
>3.0 - 8.0 mg/dL; >1.23 - 3.30
mmol/L
>8.0 mg/dL; >3.30 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of magnesium in the  blood.
Hypernatremia
>ULN - 150 mmol/L
>150 - 155 mmol/L
>155 - 160 mmol/L;
hospitalization indicated
>160 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of sodium in the  blood.
Hypertriglyceridemia
150 mg/dL - 300 mg/dL; 1.71
mmol/L - 3.42 mmol/L
>300 mg/dL - 500 mg/dL;  >3.42
mmol/L - 5.7 mmol/L
>500 mg/dL - 1000 mg/dL;  >5.7
mmol/L - 11.4 mmol/L
>1000 mg/dL; >11.4 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of triglyceride concentration in the blood.
Hyperuricemia
>ULN - 10 mg/dL (0.59 mmol/L)
without physiologic
consequences
 -
>ULN - 10 mg/dL (0.59 mmol/L)
with physiologic consequences
>10 mg/dL; >0.59 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of uric acid.
Hypoalbuminemia
<LLN - 3 g/dL; <LLN - 30 g/L
<3 - 2 g/dL; <30 - 20 g/L
<2 g/dL; <20 g/L
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of albumin in the blood.
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CTCAE 4.03 - June 14, 2010 : Metabolism and nutrition disorders 
45
Metabolism and nutrition disorders
Grade
Adverse Event
1
2
3
4
5
Hypocalcemia
Corrected serum calcium of
<LLN - 8.0 mg/dL; <LLN - 2.0
mmol/L; Ionized calcium  <LLN -
1.0 mmol/L
Corrected serum calcium of
<8.0 - 7.0 mg/dL; <2.0 - 1.75
mmol/L; Ionized calcium  <1.0 -
0.9 mmol/L; symptomatic
Corrected serum calcium of
<7.0 - 6.0 mg/dL; <1.75 - 1.5
mmol/L;  Ionized calcium  <0.9 -
0.8 mmol/L; hospitalization
indicated
Corrected serum calcium of
<6.0 mg/dL; <1.5 mmol/L;
Ionized calcium  <0.8 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of calcium (corrected for albumin) in the  blood.
Hypoglycemia
<LLN - 55 mg/dL; <LLN - 3.0
mmol/L
<55 - 40 mg/dL; <3.0 - 2.2
mmol/L
<40 - 30 mg/dL; <2.2 - 1.7
mmol/L
<30 mg/dL; <1.7 mmol/L; life-
threatening consequences;
seizures
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of glucose in the blood.
Hypokalemia
<LLN - 3.0 mmol/L
<LLN - 3.0 mmol/L;
symptomatic; intervention
indicated
<3.0 - 2.5 mmol/L;
hospitalization indicated
<2.5 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of potassium in the  blood.
Hypomagnesemia
<LLN - 1.2 mg/dL; <LLN - 0.5
mmol/L
<1.2 - 0.9 mg/dL; <0.5 - 0.4
mmol/L
<0.9 - 0.7 mg/dL; <0.4 - 0.3
mmol/L
<0.7 mg/dL; <0.3 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of magnesium in the  blood.
Hyponatremia
<LLN - 130 mmol/L
 -
<130 - 120 mmol/L
<120 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of sodium in the blood.
Hypophosphatemia
<LLN - 2.5 mg/dL; <LLN - 0.8
mmol/L
<2.5 - 2.0 mg/dL; <0.8 - 0.6
mmol/L
<2.0 - 1.0 mg/dL; <0.6 - 0.3
mmol/L
<1.0 mg/dL; <0.3 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of phosphates in the  blood.
Iron overload
 -
Moderate symptoms;
intervention not indicated
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by accumulation of iron in the tissues.
Obesity
 -
BMI 25 - 29.9 kg/m2
BMI 30 - 39.9 kg/m2
BMI >=40 kg/m2
 -
Definition: A disorder characterized by having a high amount of body fat.
Tumor lysis syndrome
 -
 -
Present
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by metabolic abnormalities that result from a spontaneous or therapy-related cytolysis of tumor cells.
Metabolism and nutrition
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
46
16. Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Abdominal soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g. tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the abdominal wall.
Arthralgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in a joint.
Arthritis
Mild pain with inflammation,
erythema, or joint swelling
Moderate pain associated with
signs of inflammation,
erythema, or joint swelling;
limiting instrumental ADL
Severe pain associated with
signs of inflammation,
erythema, or joint swelling;
irreversible joint damage;
disabling; limiting self care ADL
 -
 -
Definition: A disorder characterized by inflammation involving a joint.
Avascular necrosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by necrotic changes in the bone tissue due to interruption of blood supply. Most often affecting the epiphysis of the long bones, the necrotic
changes result in the collapse and the destruction of the bone structure.
Back pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the back region.
Bone pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the bones.
Buttock pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the buttocks.
Chest wall pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the chest wall region.
Exostosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by non-neoplastic overgrowth of bone.
Fibrosis deep connective tissue
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration; unable to
slide or pinch skin; limiting joint
or orifice movement (e.g.
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by fibrotic degeneration of the deep connective tissues.
Flank pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation on the lateral side of the body in the region below the ribs and above the hip.
Generalized muscle weakness
Symptomatic; weakness
perceived by patient but not
evident on physical exam
Symptomatic; weakness evident
on physical exam; weakness
limiting instrumental ADL
Weakness limiting self care
ADL; disabling
 -
 -
Definition: A disorder characterized by a reduction in the strength of muscles in multiple anatomic sites.
Growth suppression
Reduction in growth velocity by
10 - 29% ideally measured over
the period of a year
Reduction in growth velocity by
30 - 49% ideally measured over
the period of a year or 0 - 49%
reduction in growth from the
baseline growth curve
Reduction in growth velocity of
>=50% ideally measured over
the period of a year
 -
 -
Definition: A disorder characterized by of stature that is smaller than normal as expected for age.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
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Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Head soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the head.
Joint effusion
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated; disabling
 -
 -
Definition: A disorder characterized by excessive fluid in a joint, usually as a result of joint inflammation.
Joint range of motion decreased <=25% loss of ROM (range of
motion); decreased ROM
limiting athletic activity
>25 - 50% decrease in ROM;
limiting instrumental ADL
>50% decrease in ROM; limiting
self care ADL; disabling
 -
 -
Definition: A disorder characterized by a decrease in joint flexibility of any joint.
Joint range of motion decreased
cervical spine
Mild restriction of rotation or
flexion between 60 - 70 degrees
Rotation <60 degrees to right or
left; <60 degrees of flexion
Ankylosed/fused over multiple
segments with no C-spine
rotation
 -
 -
Definition: A disorder characterized by a decrease in flexibility of a cervical spine joint.
Joint range of motion decreased
lumbar spine
Stiffness; difficulty bending to
the floor to pick up a very light
object but able to do athletic
activity
Pain with range of motion
(ROM) in lumbar spine; requires
a reaching aid to pick up a very
light object from the floor
<50% lumbar spine flexion;
associated with symptoms of
ankylosis or fused over multiple
segments with no L-spine
flexion (e.g., unable to reach to
floor to pick up a very light
object)
 -
 -
Definition: A disorder characterized by a decrease in flexibility of a lumbar spine joint.
Kyphosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate accentuation; limiting
instrumental ADL
Severe accentuation; operative
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an abnormal increase in the curvature of the thoracic portion of the spine.
Lordosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate accentuation; limiting
instrumental ADL
Severe accentuation; operative
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an abnormal increase in the curvature of the lumbar portion of the spine.
Muscle weakness left-sided
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the muscles on the left side of the body.
Muscle weakness lower limb
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the lower limb muscles.
Muscle weakness right-sided
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the muscles on the right side of the body.
Muscle weakness trunk
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the trunk muscles.
Muscle weakness upper limb
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the upper limb muscles.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
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Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Musculoskeletal deformity
Cosmetically and functionally
insignificant hypoplasia
Deformity, hypoplasia, or
asymmetry able to be
remediated by prosthesis (e.g.,
shoe insert) or covered by
clothing
Significant deformity,
hypoplasia, or asymmetry,
unable to be remediated by
prosthesis or covered by
clothing; disabling
 -
 -
Definition: A disorder characterized by of a malformation of the musculoskeletal system.
Myalgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation originating from a muscle or group of muscles.
Myositis
Mild pain
Moderate pain associated with
weakness; pain limiting
instrumental ADL
Pain associated with severe
weakness; limiting self care
ADL
 -
 -
Definition: A disorder characterized by inflammation involving the skeletal muscles.
Neck pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the neck area.
Neck soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the neck.
Osteonecrosis of jaw
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the bone of the mandible.
Osteoporosis
Radiologic evidence of
osteoporosis or Bone Mineral
Density (BMD) t-score -1 to -2.5
(osteopenia); no loss of height
or intervention indicated
BMD t-score <-2.5; loss of
height <2 cm; anti-osteoporotic
therapy indicated; limiting
instrumental ADL
Loss of height >=2 cm;
hospitalization indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by reduced bone mass, with a decrease in cortical thickness and in the number and size of the trabeculae of cancellous bone (but normal chemical
composition), resulting in increased fracture incidence.
Pain in extremity
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the upper or lower extremities.
Pelvic soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the pelvis.
Scoliosis
<20 degrees; clinically
undetectable
>20 - 45 degrees; visible by
forward flexion; limiting
instrumental ADL
>45 degrees; scapular
prominence in forward flexion;
operative intervention indicated;
limiting self care ADL; disabling
 -
 -
Definition: A disorder characterized by a malformed, lateral curvature of the spine.
Soft tissue necrosis lower limb
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the lower extremity.
Soft tissue necrosis upper limb
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the upper extremity.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
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Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Superficial soft tissue fibrosis
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration; unable to
slide or pinch skin; limiting joint
or orifice movement (e.g.,
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by fibrotic degeneration of the superficial soft tissues.
Trismus
Decreased ROM (range of
motion) without impaired eating
Decreased ROM requiring small
bites, soft foods or purees
Decreased ROM with inability to
adequately aliment or hydrate
orally
 -
 -
Definition: A disorder characterized by lack of ability to open the mouth fully due to a decrease in the range of motion of the muscles of mastication.
Unequal limb length
Mild length discrepancy <2 cm
Moderate length discrepancy 2 -
5 cm; shoe lift indicated; limiting
instrumental ADL
Severe length discrepancy >5
cm; limiting self care ADL;
disabling; operative intervention
indicated
 -
 -
Definition: A disorder characterized by of a discrepancy between the lengths of the lower or upper extremities.
Musculoskeletal and connective
tissue disorder -  Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
50
17. Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Grade
Adverse Event
1
2
3
4
5
Leukemia secondary to
oncology chemotherapy
 -
 -
 -
Present
Death
Definition: A disorder characterized by leukemia arising as a result of the mutagenic effect of chemotherapy agents.
Myelodysplastic syndrome
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by insufficiently healthy hematapoietic cell production by the bone marrow.
Treatment related secondary
malignancy
 -
 -
Non life-threatening secondary
malignancy
Acute life-threatening secondary
malignancy; blast crisis in
leukemia
Death
Definition: A disorder characterized by development of a malignancy most probably as a result of treatment for a previously existing malignancy.
Tumor pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort from a neoplasm that may be pressing on a nerve, blocking blood vessels, inflamed or fractured from metastasis.
Neoplasms benign, malignant
and unspecified (incl cysts and
polyps) - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
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18. Nervous system disorders
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Abducens nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the abducens nerve (sixth cranial nerve).
Accessory nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the accessory nerve (eleventh cranial nerve).
Acoustic nerve disorder NOS
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the acoustic nerve (eighth cranial nerve).
Akathisia
Mild restlessness or increased
motor activity
Moderate restlessness or
increased motor activity; limiting
instrumental ADL
Severe restlessness or
increased motor activity; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an uncomfortable feeling of inner restlessness and inability to stay still; this is a side effect of some psychotropic drugs.
Amnesia
Mild; transient memory loss
Moderate; short term memory
loss; limiting instrumental ADL
Severe; long term memory loss;
limiting self care ADL
 -
 -
Definition: A disorder characterized by systematic and extensive loss of memory.
Aphonia
 -
 -
Voicelessness; unable to speak
 -
 -
Definition: A disorder characterized by the inability to speak. It may result from injuries to the vocal cords or may be functional (psychogenic).
Arachnoiditis
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the arachnoid membrane and adjacent subarachnoid space.
Ataxia
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; mechanical
assistance indicated
 -
 -
Definition: A disorder characterized by lack of coordination of muscle movements resulting in the impairment or inability to perform voluntary activities.
Brachial plexopathy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by regional paresthesia of the brachial plexus, marked discomfort and muscle weakness, and limited movement in the arm or hand.
Central nervous system
necrosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms;
corticosteroids indicated
Severe symptoms; medical
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the brain and/or spinal cord.
Cerebrospinal fluid leakage
Post-craniotomy: asymptomatic;
Post-lumbar puncture: transient
headache; postural care
indicated
Post-craniotomy: moderate
symptoms; medical intervention
indicated; Post-lumbar
puncture: persistent moderate
symptoms; blood patch
indicated
Severe symptoms; medical
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by loss of cerebrospinal fluid into the surrounding tissues.
Cognitive disturbance
Mild cognitive disability; not
interfering with work/school/life
performance; specialized
educational services/devices
not indicated
Moderate cognitive disability;
interfering with work/school/life
performance but capable of
independent living; specialized
resources on part time basis
indicated
Severe cognitive disability;
significant impairment of
work/school/life performance
 -
 -
Definition: A disorder characterized by a conspicuous change in cognitive function.
Concentration impairment
Mild inattention or decreased
level of concentration
Moderate impairment in
attention or decreased level of
concentration; limiting
instrumental ADL
Severe impairment in attention
or decreased level of
concentration; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a deterioration in the ability to concentrate.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
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Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Depressed level of
consciousness
Decreased level of alertness
Sedation; slow response to
stimuli; limiting instrumental
ADL
Difficult to arouse
Life-threatening consequences
Death
Definition: A disorder characterized by a decrease in ability to perceive and respond.
Dizziness
Mild unsteadiness or sensation
of movement
Moderate unsteadiness or
sensation of movement; limiting
instrumental ADL
Severe unsteadiness or
sensation of movement; limiting
self care ADL
 -
 -
Definition: A disorder characterized by a disturbing sensation of lightheadedness, unsteadiness, giddiness, spinning or rocking.
Dysarthria
Mild slurred speech
Moderate impairment of
articulation or slurred speech
Severe impairment of
articulation or slurred speech
 -
 -
Definition: A disorder characterized by slow and slurred speech resulting from an inability to coordinate the muscles used in speech.
Dysesthesia
Mild sensory alteration
Moderate sensory alteration;
limiting instrumental ADL
Severe sensory alteration;
limiting self care ADL
 -
 -
Definition: A disorder characterized by distortion of sensory perception, resulting in an abnormal and unpleasant sensation.
Dysgeusia
Altered taste but no change in
diet
Altered taste with change in diet
(e.g., oral supplements);
noxious or unpleasant taste;
loss of taste
 -
 -
 -
Definition: A disorder characterized by abnormal sensual experience with the taste of foodstuffs; it can be related to a decrease in the sense of smell.
Dysphasia
Awareness of receptive or
expressive characteristics; not
impairing ability to communicate
Moderate receptive or
expressive characteristics;
impairing ability to communicate
spontaneously
Severe receptive or expressive
characteristics; impairing ability
to read, write or communicate
intelligibly
 -
 -
Definition: A disorder characterized by impairment of verbal communication skills, often resulting from brain damage.
Edema cerebral
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the brain.
Encephalopathy
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a pathologic process involving the brain.
Extrapyramidal disorder
Mild involuntary movements
Moderate involuntary
movements; limiting
instrumental ADL
Severe involuntary movements
or torticollis; limiting self care
ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormal, repetitive, involuntary muscle movements, frenzied speech and extreme restlessness.
Facial muscle weakness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a reduction in the strength of the facial muscles.
Facial nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the facial nerve (seventh cranial nerve).
Glossopharyngeal nerve
disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the glossopharyngeal nerve (ninth cranial nerve).
Headache
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in various parts of the head, not confined to the area of distribution of any nerve.
Hydrocephalus
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms;
intervention not indicated
Severe symptoms or
neurological deficit; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal increase of cerebrospinal fluid in the ventricles of the brain.
Hypersomnia
Mild increased need for sleep
Moderate increased need for
sleep
Severe increased need for
sleep
 -
 -
Definition: A disorder characterized by characterized by excessive sleepiness during the daytime.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
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Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Hypoglossal nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the hypoglossal nerve (twelfth cranial nerve).
Intracranial hemorrhage
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Ventriculostomy, ICP
monitoring, intraventricular
thrombolysis, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the cranium.
Ischemia cerebrovascular
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms
 -
 -
 -
Definition: A disorder characterized by a decrease or absence of blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurological
damage.
IVth nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the trochlear nerve (fourth cranial nerve).
Lethargy
Mild symptoms; reduced
alertness and awareness
Moderate symptoms; limiting
instrumental ADL
 -
 -
 -
Definition: A disorder characterized by a decrease in consciousness characterized by mental and physical inertness.
Leukoencephalopathy
Asymptomatic; small focal
T2/FLAIR hyperintensities;
involving periventricular white
matter or <1/3 of susceptible
areas of cerebrum +/- mild
increase in subarachnoid space
(SAS) and/or mild
ventriculomegaly
Moderate symptoms; focal
T2/FLAIR hyperintensities,
involving periventricular white
matter extending into centrum
semiovale or involving 1/3 to 2/3
of susceptible areas of
cerebrum +/- moderate increase
in SAS and/or moderate
ventriculomegaly
Severe symptoms; extensive
T2/FLAIR hyperintensities,
involving periventricular white
matter involving 2/3 or more of
susceptible areas of cerebrum
+/- moderate to severe increase
in SAS and/or moderate to
severe ventriculomegaly
Life-threatening consequences;
extensive T2/FLAIR
hyperintensities, involving
periventricular white matter
involving most of susceptible
areas of cerebrum +/- moderate
to severe increase in SAS
and/or moderate to severe
ventriculomegaly
Death
Definition: A disorder characterized by diffuse reactive astrocytosis with multiple areas of necrotic foci without inflammation.
Memory impairment
Mild memory impairment
Moderate memory impairment;
limiting instrumental ADL
Severe memory impairment;
limiting self care ADL
 -
 -
Definition: A disorder characterized by a deterioration in memory function.
Meningismus
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by neck stiffness, headache, and photophobia resulting from irritation of the cerebral meninges.
Movements involuntary
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by uncontrolled and purposeless movements.
Myelitis
Asymptomatic; mild signs (e.g.,
Babinski's reflex or Lhermitte's
sign)
Moderate weakness or sensory
loss; limiting instrumental ADL
Severe weakness or sensory
loss; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving the spinal cord. Symptoms include weakness, paresthesia, sensory loss, marked discomfort and incontinence.
Neuralgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by intense painful sensation along a nerve or group of nerves.
Nystagmus
 -
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involuntary movements of the eyeballs.
Oculomotor nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the oculomotor nerve (third cranial nerve).
Olfactory nerve disorder
 -
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the olfactory nerve (first cranial nerve).
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
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Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Paresthesia
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by functional disturbances of sensory neurons resulting in abnormal cutaneous sensations of tingling, numbness, pressure, cold, and warmth that
are experienced in the absence of a stimulus.
Peripheral motor neuropathy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; assistive device
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation or degeneration of the peripheral motor nerves.
Peripheral sensory neuropathy
Asymptomatic; loss of deep
tendon reflexes or paresthesia
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation or degeneration of the peripheral sensory nerves.
Phantom pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort related to a limb or an organ that is removed from or is not physically part of the body.
Presyncope
 -
Present (e.g., near fainting)
 -
 -
 -
Definition: A disorder characterized by an episode of lightheadedness and dizziness which may precede an episode of syncope.
Pyramidal tract syndrome
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by dysfunction of the corticospinal (pyramidal) tracts of the spinal cord. Symptoms include  an increase in the muscle tone in the lower extremities,
hyperreflexia, positive Babinski and a decrease in fine motor coordination.
Radiculitis
Mild symptoms
Moderate symptoms; limiting
instrumental ADL; medical
intervention indicated
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving a nerve root. Patients experience marked discomfort radiating along a nerve path because of spinal pressure on the
connecting nerve root.
Recurrent laryngeal nerve palsy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms
Severe symptoms; medical
intervention indicated (e.g.,
thyroplasty, vocal cord injection)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by paralysis of the recurrent laryngeal nerve.
Reversible posterior
leukoencephalopathy syndrome
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; abnormal
imaging studies; limiting
instrumental ADL
Severe symptoms; very
abnormal imaging studies;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by headaches, mental status changes, visual disturbances, and seizures associated with imaging findings of posterior leukoencephalopathy. It has
been observed in association with hypertensive encephalopathy, eclampsia, and immunosuppressive and cytotoxic drug treatment. It is an acute or subacute reversible condition.
Seizure
Brief partial seizure; no loss of
consciousness
Brief generalized seizure
Multiple seizures despite
medical intervention
Life-threatening; prolonged
repetitive seizures
Death
Definition: A disorder characterized by a sudden, involuntary skeletal muscular contractions of cerebral or brain stem origin.
Sinus pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort in the face, between the eyes, or upper teeth originating from the sinuses.
Somnolence
Mild but more than usual
drowsiness or sleepiness
Moderate sedation; limiting
instrumental ADL
Obtundation or stupor
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by characterized by excessive sleepiness and drowsiness.
Spasticity
Mild or slight increase in muscle
tone
Moderate increase in muscle
tone and increase in resistance
through range of motion
Severe increase in muscle tone
and increase in resistance
through range of motion
Life-threatening; unable to move
active or passive range of
motion
Death
Definition: A disorder characterized by increased involuntary muscle tone that affects the regions interfering with voluntary movement. It results in gait, movement, and speech
disturbances.
Stroke
Asymptomatic or mild
neurologic deficit; radiographic
findings only
Moderate neurologic deficit
Severe neurologic deficit
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a sudden loss of sensory function due to an intracranial vascular event.
Syncope
 -
 -
Fainting; orthostatic collapse
 -
 -
Definition: A disorder characterized by spontaneous loss of consciousness caused by insufficient blood supply to the brain.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
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Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Transient ischemic attacks
Mild neurologic deficit with or
without imaging confirmation
Moderate neurologic deficit with
or without imaging confirmation
 -
 -
 -
Definition: A disorder characterized by a brief attack (less than 24 hours) of cerebral dysfunction of vascular origin, with no persistent neurological deficit.
Tremor
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by the uncontrolled shaking movement of the whole body or individual parts.
Trigeminal nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the trigeminal nerve (fifth cranial nerve).
Vagus nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the vagus nerve (tenth cranial nerve).
Vasovagal reaction
 -
 -
Present
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a sudden drop of the blood pressure, bradycardia, and peripheral vasodilation that may lead to loss of consciousness. It results from an
increase in the stimulation of the vagus nerve.
Nervous system disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Pregnancy, puerperium and perinatal conditions 
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19. Pregnancy, puerperium and perinatal conditions
Pregnancy, puerperium and perinatal conditions
Grade
Adverse Event
1
2
3
4
5
Fetal death
 -
 -
 -
 -
Fetal loss at
any
gestational
age
Definition: A disorder characterized by death in utero; failure of the product of conception to show evidence of respiration, heartbeat, or definite movement of a voluntary muscle after
expulsion from the uterus, without possibility of resuscitation.
Fetal growth retardation
 -
<10% percentile of weight for
gestational age
<5% percentile of weight for
gestational age
<1% percentile of weight for
gestational age
 -
Definition: A disorder characterized by inhibition of fetal growth resulting in the inability of the fetus to achieve its potential weight.
Premature delivery
Delivery of a liveborn infant at
>34 to 37 weeks gestation
Delivery of a liveborn infant at
>28 to 34 weeks gestation
Delivery of a liveborn infant at
24 to 28 weeks gestation
Delivery of a liveborn infant at
24 weeks of gestation or less
 -
Definition: A disorder characterized by delivery of a viable infant before the normal end of gestation. Typically, viability is achievable between the twentieth and thirty-seventh week of
gestation.
Unintended pregnancy
 -
 -
Unintended pregnancy
 -
 -
Definition: A disorder characterized by an unexpected pregnancy at the time of conception.
Pregnancy, puerperium and
perinatal conditions - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate, local or noninvasive
intervention indicated; limiting
instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Psychiatric disorders 
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20. Psychiatric disorders
Psychiatric disorders
Grade
Adverse Event
1
2
3
4
5
Agitation
Mild mood alteration
Moderate mood alteration
Severe agitation; hospitalization
not indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a state of restlessness associated with unpleasant feelings of irritability and tension.
Anorgasmia
Inability to achieve orgasm not
adversely affecting relationship
Inability to achieve orgasm
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by an inability to achieve orgasm.
Anxiety
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization not
indicated
Life-threatening; hospitalization
indicated
Death
Definition: A disorder characterized by apprehension of danger and dread accompanied by restlessness, tension, tachycardia, and dyspnea unattached to a clearly identifiable
stimulus.
Confusion
Mild disorientation
Moderate disorientation; limiting
instrumental ADL
Severe disorientation; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a lack of clear and orderly thought and behavior.
Delayed orgasm
Delay in achieving orgasm not
adversely affecting relationship
Delay in achieving orgasm
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by sexual dysfunction characterized by a delay in climax.
Delirium
Mild acute confusional state
Moderate and acute confusional
state; limiting instrumental ADL
Severe and acute confusional
state; limiting self care ADL;
hospitalization indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by the acute and sudden development of confusion, illusions, movement changes, inattentiveness, agitation, and hallucinations. Usually, it is a
reversible condition.
Delusions
 -
Moderate delusional symptoms
Severe delusional symptoms;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by false personal beliefs held contrary to reality, despite contradictory evidence and common sense.
Depression
Mild depressive symptoms
Moderate depressive
symptoms; limiting instrumental
ADL
Severe depressive symptoms;
limiting self care ADL;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by melancholic feelings of grief or unhappiness.
Euphoria
Mild mood elevation
Moderate mood elevation
Severe mood elevation (e.g.,
hypomania)
 -
 -
Definition: A disorder characterized by an exaggerated feeling of well-being which is disproportionate to events and stimuli.
Hallucinations
Mild hallucinations (e.g.,
perceptual distortions)
Moderate hallucinations
Severe hallucinations;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by a false sensory perception in the absence of an external stimulus.
Insomnia
Mild difficulty falling asleep,
staying asleep or waking up
early
Moderate difficulty falling
asleep, staying asleep or
waking up early
Severe difficulty in falling
asleep, staying asleep or
waking up early
 -
 -
Definition: A disorder characterized by difficulty in falling asleep and/or remaining asleep.
Libido decreased
Decrease in sexual interest not
adversely affecting relationship
Decrease in sexual interest
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by a decrease in sexual desire.
Libido increased
Mild increase in sexual interest
not adversely affecting
relationship
Moderate increase in sexual
interest adversely affecting
relationship
Severe increase in sexual
interest leading to dangerous
behavior
 -
 -
Definition: A disorder characterized by an increase in sexual desire.
Mania
Mild manic symptoms (e.g.,
elevated mood, rapid thoughts,
rapid speech, decreased need
for sleep)
Moderate manic symptoms
(e.g., relationship and work
difficulties; poor hygiene)
Severe manic symptoms (e.g.,
hypomania; major sexual or
financial indiscretions);
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behavior and elevation of mood.
Personality change
Mild personality change
Moderate personality change
Severe personality change;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
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CTCAE 4.03 - June 14, 2010 : Psychiatric disorders 
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Psychiatric disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by a conspicuous change in a person's behavior and thinking.
Psychosis
Mild psychotic symptoms
Moderate psychotic symptoms
(e.g., disorganized speech;
impaired reality testing)
Severe psychotic symptoms
(e.g., paranoid; extreme
disorganization); hospitalization
not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by personality change, impaired functioning, and loss of touch with reality. It may be a manifestation of schizophrenia, bipolar disorder or brain
tumor.
Restlessness
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an inability to rest, relax or be still.
Suicidal ideation
Increased thoughts of death but
no wish to kill oneself
Suicidal ideation with no specific
plan or intent
Specific plan to commit suicide
without serious intent to die
which may not require
hospitalization
Specific plan to commit suicide
with serious intent to die which
requires hospitalization
 -
Definition: A disorder characterized by thoughts of taking one's own life.
Suicide attempt
 -
 -
Suicide attempt or gesture
without intent to die which may
not require hospitalization
Suicide attempt with intent to
die which requires
hospitalization
Death
Definition: A disorder characterized by self-inflicted harm in an attempt to end one's own life.
Psychiatric disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; disabling;  limiting
self care ADL
Life-threatening consequences;
hospitalization or urgent
intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Renal and urinary disorders 
59
21. Renal and urinary disorders
Renal and urinary disorders
Grade
Adverse Event
1
2
3
4
5
Acute kidney injury
Creatinine level increase of >0.3
mg/dL; creatinine 1.5 - 2.0 x
above baseline
Creatinine 2 - 3 x above
baseline
Creatinine >3 x baseline or >4.0
mg/dL; hospitalization indicated
Life-threatening consequences;
dialysis indicated
Death
Definition: A disorder characterized by the acute loss of renal function and is traditionally classified as pre-renal (low blood flow into kidney), renal (kidney damage) and post-renal
causes (ureteral or bladder outflow obstruction).
Bladder perforation
 -
Extraperitoneal perforation,
indwelling catheter indicated
Intraperitoneal perforation;
elective radiologic, endoscopic
or operative intervention
indicated
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A disorder characterized by a rupture in the bladder wall.
Bladder spasm
Intervention not indicated
Antispasmodics indicated
Hospitalization indicated
 -
 -
Definition: A disorder characterized by a sudden and involuntary contraction of the bladder wall.
Chronic kidney disease
eGFR (estimated Glomerular
Filtration Rate) or CrCl
(creatinine clearance) <LLN - 60
ml/min/1.73 m2 or proteinuria
2+ present; urine
protein/creatinine >0.5
eGFR or CrCl 59 - 30
ml/min/1.73 m2
eGFR or CrCl 29 - 15
ml/min/1.73 m2
eGFR or CrCl <15 ml/min/1.73
m2; dialysis or renal transplant
indicated
Death
Definition: A disorder characterized by gradual and usually permanent loss of kidney function resulting in renal failure.
Cystitis noninfective
Microscopic hematuria; minimal
increase in frequency, urgency,
dysuria, or nocturia; new onset
of incontinence
Moderate hematuria; moderate
increase in frequency, urgency,
dysuria, nocturia or
incontinence; urinary catheter
placement or bladder irrigation
indicated; limiting instrumental
ADL
Gross hematuria; transfusion, IV
medications or hospitalization
indicated; elective endoscopic,
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by inflammation of the bladder which is not caused by an infection of the urinary tract.
Hematuria
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; urinary catheter
or bladder irrigation indicated;
limiting instrumental ADL
Gross hematuria; transfusion, IV
medications or hospitalization
indicated; elective endoscopic,
radiologic or operative
intervention indicated; limiting
self care ADL
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate blood in the urine.
Hemoglobinuria
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by laboratory test results that indicate the presence of free hemoglobin in the urine.
Proteinuria
1+ proteinuria; urinary protein
<1.0 g/24 hrs
Adults: 2+ proteinuria; urinary
protein 1.0 - 3.4 g/24 hrs;
Pediatric: urine P/C
(Protein/Creatinine) ratio 0.5 -
1.9
Adults: urinary protein >=3.5
g/24 hrs;
Pediatric: urine P/C >1.9
 -
 -
Definition: A disorder characterized by laboratory test results that indicate the presence of excessive protein in the urine. It is predominantly albumin, but also globulin.
Renal calculi
Asymptomatic or mild
symptoms; occasional use of
nonprescription analgesics
indicated
Symptomatic; oral antiemetics
indicated; around the clock
nonprescription analgesics or
any oral narcotic analgesics
indicated
Hospitalization indicated; IV
intervention (e.g., analgesics,
antiemetics); elective
endoscopic or radiologic
intervention indicated
Life-threatening consequences;
urgent radiologic, endoscopic or
operative intervention indicated
Death
Definition: A disorder characterized by the formation of crystals in the pelvis of the kidney.
Renal colic
Mild pain not interfering with
activity; nonprescription
medication indicated
Moderate pain; limiting
instrumental ADL; prescription
medication indicated
Hospitalization indicated;
limiting self care ADL
 -
 -
Definition: A disorder characterized by paroxysmal and severe flank marked discomfort radiating to the inguinal area. Often, the cause is the passage of kidney stones.
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CTCAE 4.03 - June 14, 2010 : Renal and urinary disorders 
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Renal and urinary disorders
Grade
Adverse Event
1
2
3
4
5
Renal hemorrhage
Mild symptoms; intervention not
indicated
Analgesics and hematocrit
monitoring indicated
Transfusion, radiation, or
hospitalization indicated;
elective radiologic, endoscopic
or operative intervention
indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by bleeding from the kidney.
Urinary fistula
 -
Noninvasive intervention
indicated; urinary or suprapubic
catheter placement indicated
Limiting self care ADL; elective
radiologic, endoscopic or
operative intervention indicated;
permanent urinary diversion
indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between any part of the urinary system and another organ or anatomic site.
Urinary frequency
Present
Limiting instrumental ADL;
medical management indicated
 -
 -
 -
Definition: A disorder characterized by urination at short intervals.
Urinary incontinence
Occasional (e.g., with coughing,
sneezing, etc.), pads not
indicated
Spontaneous; pads indicated;
limiting instrumental ADL
Intervention indicated (e.g.,
clamp, collagen injections);
operative intervention indicated;
limiting self care ADL
 -
 -
Definition: A disorder characterized by inability to control the flow of urine from the bladder.
Urinary retention
Urinary, suprapubic or
intermittent catheter placement
not indicated; able to void with
some residual
Placement of urinary,
suprapubic or intermittent
catheter placement indicated;
medication indicated
Elective operative or radiologic
intervention indicated;
substantial loss of affected
kidney function or mass
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A disorder characterized by accumulation of urine within the bladder because of the inability to urinate.
Urinary tract obstruction
Asymptomatic; clinical or
diagnostic observations only
Symptomatic but no
hydronephrosis, sepsis or renal
dysfunction; urethral dilation,
urinary or suprapubic catheter
indicated
Symptomatic and altered organ
function (e.g., hydronephrosis,
or renal dysfunction); elective
radiologic, endoscopic or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the normal flow of contents of the urinary tract.
Urinary tract pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the urinary tract.
Urinary urgency
Present
Limiting instrumental ADL;
medical management indicated
 -
 -
 -
Definition: A disorder characterized by a sudden compelling urge to urinate.
Urine discoloration
Present
 -
 -
 -
 -
Definition: A disorder characterized by a change in the color of the urine.
Renal and urinary disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate, local or noninvasive
intervention indicated; limiting
instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
61
22. Reproductive system and breast disorders
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Azoospermia
 -
 -
Absence of sperm in ejaculate
 -
 -
Definition: A disorder characterized by laboratory test results that indicate complete absence of spermatozoa in the semen.
Breast atrophy
Minimal asymmetry; minimal
atrophy
Moderate asymmetry; moderate
atrophy
Asymmetry >1/3 of breast
volume; severe atrophy
 -
 -
Definition: A disorder characterized by underdevelopment of the breast.
Breast pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the breast region.
Dysmenorrhea
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by abnormally painful abdominal cramps during menses.
Dyspareunia
Mild discomfort or pain
associated with vaginal
penetration; discomfort relieved
with use of vaginal lubricants or
estrogen
Moderate discomfort or pain
associated with vaginal
penetration; discomfort or pain
partially relieved with use of
vaginal lubricants or estrogen
Severe discomfort or pain
associated with vaginal
penetration; discomfort or pain
unrelieved by vaginal lubricants
or estrogen
 -
 -
Definition: A disorder characterized by painful or difficult coitus.
Ejaculation disorder
Diminished ejaculation
Anejaculation or retrograde
ejaculation
 -
 -
 -
Definition: A disorder characterized by problems related to ejaculation. This category includes premature, delayed, retrograde and painful ejaculation.
Erectile dysfunction
Decrease in erectile function
(frequency or rigidity of
erections) but intervention not
indicated (e.g., medication or
use of mechanical device,
penile pump)
Decrease in erectile function
(frequency/rigidity of erections),
erectile intervention indicated,
(e.g., medication or mechanical
devices such as penile pump)
Decrease in erectile function
(frequency/rigidity of erections)
but erectile intervention not
helpful (e.g., medication or
mechanical devices such as
penile pump); placement of a
permanent penile prosthesis
indicated (not previously
present)
 -
 -
Definition: A disorder characterized by the persistent or recurrent inability to achieve or to maintain an erection during sexual activity.
Fallopian tube obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the normal flow of the contents in the fallopian tube.
Fallopian tube stenosis
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated (e.g., organ resection)
Death
Definition: A disorder characterized by a narrowing of the fallopian tube lumen.
Female genital tract fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between a female reproductive system organ and another organ or anatomic site.
Feminization acquired
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by the development of secondary female sex characteristics in males due to extrinsic factors.
Genital edema
Mild swelling or obscuration of
anatomic architecture on close
inspection
Readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour
Lymphorrhea; gross deviation
from normal anatomic contour;
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the genitals.
Gynecomastia
Asymptomatic breast
enlargement
Symptomatic (e.g., pain or
psychosocial impact)
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by excessive development of the breasts in males.
Hematosalpinx
Minimal bleeding identified on
imaging study or laparoscopy;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
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Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by the presence of blood in a fallopian tube.
Irregular menstruation
Intermittent menses with
skipped menses for no more
than 1 to 3 months
Intermittent menses with
skipped menses for more than 4
to 6 months
Persistent amenorrhea for more
than 6 months
 -
 -
Definition: A disorder characterized by irregular cycle or duration of menses.
Lactation disorder
Mild changes in lactation, not
significantly affecting production
or expression of breast milk
Changes in lactation,
significantly affecting breast
production or expression of
breast milk
 -
 -
 -
Definition: A disorder characterized by disturbances of milk secretion. It is not necessarily related to pregnancy that is observed in females and can be observed in males.
Menorrhagia
Mild; iron supplements indicated Moderate symptoms; medical
intervention indicated (e.g.,
hormones)
Severe; transfusion indicated;
surgical intervention indicated
(e.g., hysterectomy)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormally heavy vaginal bleeding during menses.
Nipple deformity
Asymptomatic; asymmetry with
slight retraction and/or
thickening of the nipple areolar
complex
Symptomatic; asymmetry of
nipple areolar complex with
moderate retraction and/or
thickening of the nipple areolar
complex
 -
 -
 -
Definition: A disorder characterized by a malformation of the nipple.
Oligospermia
Sperm concentration >48
million/mL or motility >68%
Sperm concentration 13 - 48
million/mL or motility 32 - 68%
Sperm concentration <13
million/mL or motility <32%
 -
 -
Definition: A disorder characterized by a decrease in the number of spermatozoa in the semen.
Ovarian hemorrhage
Minimal bleeding identified on
imaging study or laproscopy;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic  intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the ovary.
Ovarian rupture
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by tearing or disruption of the ovarian tissue.
Ovulation pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in one side of the abdomen between menstrual cycles, around the time of the discharge of the ovum from the
ovarian follicle.
Pelvic floor muscle weakness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic, not interfering
with bladder, bowel, or vaginal
function; limiting instrumental
ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a reduction in the strength of the muscles of the pelvic floor.
Pelvic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pelvis.
Penile pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the penis.
Perineal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the area between the genital organs and the anus.
Premature menopause
 -
 -
Present
 -
 -
Definition: A disorder characterized by ovarian failure before the age of 40. Symptoms include hot flashes, night sweats, mood swings and a decrease in sex drive.
Prostatic hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by bleeding from the prostate gland.
Prostatic obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by compression of the urethra secondary to enlargement of the prostate gland. This results in voiding difficulties (straining to void, slow urine
stream, and incomplete emptying of the bladder).
Prostatic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the prostate gland.
Scrotal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the scrotal area.
Spermatic cord hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the spermatic cord.
Spermatic cord obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the normal flow of the contents of the spermatic cord.
Testicular disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic but not interfering
with urination or sexual
activities; intervention not
indicated; limiting instrumental
ADL
Severe symptoms; interfering
with urination or sexual function;
limiting self care ADL;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the testis.
Testicular hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the testis.
Testicular pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the testis.
Uterine fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the uterus and another organ or anatomic site.
Uterine hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the uterus.
Uterine obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the uterine outlet.
Uterine pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the uterus.
Vaginal discharge
Mild vaginal discharge (greater
than baseline for patient)
Moderate to heavy vaginal
discharge; use of perineal pad
or tampon indicated
 -
 -
 -
Definition: A disorder characterized by vaginal secretions. Mucus produced by the cervical glands is discharged from the vagina naturally, especially during the childbearing years.
Vaginal dryness
Mild vaginal dryness not
interfering with sexual function
Moderate vaginal dryness
interfering with sexual function
or causing frequent discomfort
Severe vaginal dryness
resulting in dyspareunia or
severe discomfort
 -
 -
Definition: A disorder characterized by an uncomfortable feeling of itching and burning in the vagina.
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Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Vaginal fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the vagina and another organ or anatomic site.
Vaginal hemorrhage
Minimal bleeding identified on
clinical exam or imaging study;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the vagina.
Vaginal inflammation
Mild discomfort or pain, edema,
or redness
Moderate discomfort or pain,
edema, or redness; limiting
instrumental ADL
Severe discomfort or pain,
edema, or redness; limiting self
care ADL; small areas of
mucosal ulceration
Widespread areas of mucosal
ulceration; life-threatening
consequences; urgent
intervention indicated
Death
Definition: A disorder characterized by inflammation involving the vagina. Symptoms may include redness, edema, marked discomfort and an increase in vaginal discharge.
Vaginal obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of vaginal canal.
Vaginal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the vagina.
Vaginal perforation
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the vaginal wall.
Vaginal stricture
Asymptomatic; mild vaginal
shortening or narrowing
Vaginal narrowing and/or
shortening not interfering with
physical examination
Vaginal narrowing and/or
shortening interfering with the
use of tampons, sexual activity
or physical examination
 -
Death
Definition: A disorder characterized by a narrowing of the vaginal canal.
Vaginismus
Mild discomfort or pain
associated with vaginal
spasm/tightening; no impact
upon sexual function or physical
examination
Moderate discomfort or pain
associated with vaginal
spasm/tightening; disruption in
sexual function and physical
examination
Severe discomfort or pain
associated with vaginal
spasm/tightening; unable to
tolerate vaginal penetration or
physical examination
 -
 -
Definition: A disorder characterized by involuntary spasms of the pelvic floor muscles, resulting in pathologic tightness of the vaginal wall during penetration such as during sexual
intercourse.
Reproductive system and breast
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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65
23. Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Adult respiratory distress
syndrome
 -
 -
Present with radiologic findings;
intubation not indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by progressive and life-threatening pulmonary distress in the absence of an underlying pulmonary condition, usually following major trauma or
surgery.
Allergic rhinitis
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by an inflammation of the nasal mucous membranes caused by an IgE-mediated response to external allergens. The inflammation may also
involve the mucous membranes of the sinuses, eyes, middle ear, and pharynx. Symptoms include sneezing, nasal congestion, rhinorrhea and itching.
Apnea
 -
 -
Present; medical intervention
indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by cessation of breathing.
Aspiration
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Altered eating habits; coughing
or choking episodes after eating
or swallowing; medical
intervention indicated (e.g.,
suction or oxygen)
Dyspnea and pneumonia
symptoms (e.g., aspiration
pneumonia); hospitalization
indicated; unable to aliment
orally
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by inhalation of solids or liquids into the lungs.
Atelectasis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., dyspnea,
cough); medical intervention
indicated (e.g., chest
physiotherapy, suctioning);
bronchoscopic suctioning
Oxygen indicated;
hospitalization or elective
operative intervention indicated
(e.g., stent, laser)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by the collapse of part or the entire lung.
Bronchial fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
with thoracoplasty, chronic open
drainage or multiple
thoracotomies indicated
Death
Definition: A disorder characterized by an abnormal communication between the bronchus and another organ or anatomic site.
Bronchial obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., mild
wheezing); endoscopic
evaluation indicated;
radiographic evidence of
atelectasis/lobar collapse;
medical management indicated
(e.g., steroids, bronchodilators)
Shortness of breath with stridor;
endoscopic intervention
indicated (e.g., laser, stent
placement)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by blockage of a bronchus passage, most often by bronchial secretions and exudates.
Bronchial stricture
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., rhonchi or
wheezing) but without
respiratory distress; medical
intervention indicated (e.g.,
steroids, bronchodilators)
Shortness of breath with stridor;
endoscopic intervention
indicated (e.g., laser, stent
placement)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the bronchial tube.
Bronchopleural fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
with thoracoplasty, chronic open
drainage or multiple
thoracotomies indicated
Death
Definition: A disorder characterized by an abnormal communication between a bronchus and the pleural cavity.
Bronchopulmonary hemorrhage
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the bronchial wall and/or lung parenchyma.
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Bronchospasm
Mild symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Limiting self care ADL; oxygen
saturation decreased
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by a sudden contraction of the smooth muscles of the bronchial wall.
Chylothorax
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thoracentesis or
tube drainage indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by milky pleural effusion (abnormal collection of fluid) resulting from accumulation of lymph fluid in the pleural cavity.
Cough
Mild symptoms; nonprescription
intervention indicated
Moderate symptoms, medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by sudden, often repetitive, spasmodic contraction of the thoracic cavity, resulting in violent release of air from the lungs and usually accompanied
by a distinctive sound.
Dyspnea
Shortness of breath with
moderate exertion
Shortness of breath with
minimal exertion; limiting
instrumental ADL
Shortness of breath at rest;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an uncomfortable sensation of difficulty breathing.
Epistaxis
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated (e.g.,
nasal packing, cauterization;
topical vasoconstrictors)
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the nose.
Hiccups
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; interfering
with sleep; limiting self care
ADL
 -
 -
Definition: A disorder characterized by repeated gulp sounds that result from an involuntary opening and closing of the glottis. This is attributed to a spasm of the diaphragm.
Hoarseness
Mild or intermittent voice
change; fully understandable;
self-resolves
Moderate or persistent voice
changes; may require
occasional repetition but
understandable on telephone;
medical evaluation indicated
Severe voice changes including
predominantly whispered
speech
 -
 -
Definition: A disorder characterized by harsh and raspy voice arising from or spreading to the larynx.
Hypoxia
 -
Decreased oxygen saturation
with exercise (e.g., pulse
oximeter <88%); intermittent
supplemental oxygen
Decreased oxygen saturation at
rest (e.g., pulse oximeter <88%
or PaO2 <=55 mm Hg)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a decrease in the level of oxygen in the body.
Laryngeal edema
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated (e.g.,
dexamethasone, epinephrine,
antihistamines)
Stridor; respiratory distress;
hospitalization indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the larynx.
Laryngeal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
indicated (e.g., thoracoplasty,
chronic open drainage or
multiple thoracotomies)
Death
Definition: A disorder characterized by an abnormal communication between the larynx and another organ or anatomic site.
Laryngeal hemorrhage
Mild cough or trace hemoptysis;
laryngoscopic findings
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by bleeding from the larynx.
Laryngeal inflammation
Mild sore throat; raspy voice
Moderate sore throat;
analgesics indicated
Severe throat pain; endoscopic
intervention indicated
 -
 -
Definition: A disorder characterized by an inflammation involving the larynx.
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Laryngeal mucositis
Endoscopic findings only; mild
discomfort with normal intake
Moderate discomfort; altered
oral intake
Severe pain; severely altered
eating/swallowing; medical
intervention indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the larynx.
Laryngeal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids); limiting instrumental
ADL
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the laryngeal airway.
Laryngeal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids)
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a narrowing of the laryngeal airway.
Laryngopharyngeal dysesthesia
Mild symptoms; no anxiety;
intervention not indicated
Moderate symptoms; mild
anxiety, but no dyspnea; short
duration of observation and or
anxiolytic indicated; limiting
instrumental ADL
Severe symptoms; dyspnea and
swallowing difficulty; limiting self
care ADL
Life-threatening consequences
Death
Definition: A disorder characterized by an uncomfortable persistent sensation in the area of the laryngopharynx.
Laryngospasm
 -
Transient episode; intervention
not indicated
Recurrent episodes;
noninvasive intervention
indicated (e.g., breathing
technique, pressure point
massage)
Persistent or severe episodes
associated with syncope; urgent
intervention indicated (e.g.,
fiberoptic laryngoscopy,
intubation, botox injection)
Death
Definition: A disorder characterized by paroxysmal spasmodic muscular contraction of the vocal cords.
Mediastinal hemorrhage
Radiologic evidence only;
minimal symptoms; intervention
not indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
(e.g., hemostasis of bleeding
site)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the mediastinum.
Nasal congestion
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Associated with bloody nasal
discharge or epistaxis
 -
 -
Definition: A disorder characterized by obstruction of the nasal passage due to mucosal edema.
Pharyngeal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the pharynx and another organ or anatomic site.
Pharyngeal hemorrhage
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the pharynx.
Pharyngeal mucositis
Endoscopic findings only;
minimal symptoms with normal
oral intake; mild pain but
analgesics not indicated
Moderate pain and analgesics
indicated; altered oral intake;
limiting instrumental ADL
Severe pain; unable to
adequately aliment or hydrate
orally; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the pharynx.
Pharyngeal necrosis
 -
 -
Inability to aliment adequately
by GI tract; tube feeding or TPN
indicated; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by a necrotic process occurring in the pharynx.
Pharyngeal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids); limiting instrumental
ADL
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a narrowing of the pharyngeal airway.
Pharyngolaryngeal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pharyngolaryngeal region.
Pleural effusion
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; intervention
indicated (e.g., diuretics or
limited therapeutic
thoracentesis)
Symptomatic with respiratory
distress and hypoxia; surgical
intervention including chest tube
or pleurodesis indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by an increase in amounts of fluid within the pleural cavity. Symptoms include shortness of breath, cough and marked chest discomfort.
Pleural hemorrhage
Asymptomatic; mild hemorrhage
confirmed by thoracentesis
Symptomatic or associated with
pneumothorax; chest tube
drainage indicated
>1000 ml of blood evacuated;
persistent bleeding (150-200
ml/hr for 2 - 4 hr); persistent
transfusion indicated; elective
operative intervention indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the pleural cavity.
Pleuritic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pleura.
Pneumonitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; oxygen indicated
Life-threatening respiratory
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma.
Pneumothorax
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; intervention
indicated (e.g., tube placement
without sclerosis)
Sclerosis and/or operative
intervention indicated;
hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormal presence of air in the pleural cavity resulting in the collapse of the lung.
Postnasal drip
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by excessive mucous secretion in the back of the nasal cavity or throat, causing sore throat and/or coughing.
Productive cough
Occasional/minimal production
of sputum with cough
Moderate sputum production;
limiting instrumental ADL
Persistent or copious production
of sputum; limiting self care ADL
 -
 -
Definition: A disorder characterized by expectorated secretions upon coughing.
Pulmonary edema
Radiologic findings only;
minimal dyspnea on exertion
Moderate dyspnea on exertion;
medical intervention indicated;
limiting instrumental ADL
Severe dyspnea or dyspnea at
rest; oxygen indicated; limiting
self care ADL
Life-threatening respiratory
compromise; urgent intervention
or intubation with ventilatory
support indicated
Death
Definition: A disorder characterized by accumulation of fluid in the lung tissues that causes a disturbance of the gas exchange that may lead to respiratory failure.
Pulmonary fibrosis
Mild hypoxemia; radiologic
pulmonary fibrosis <25% of lung
volume
Moderate hypoxemia; evidence
of pulmonary hypertension;
radiographic pulmonary fibrosis
25 - 50%
Severe hypoxemia; evidence of
right-sided heart failure;
radiographic pulmonary fibrosis
>50 - 75%
Life-threatening consequences
(e.g., hemodynamic/pulmonary
complications); intubation with
ventilatory support indicated;
radiographic pulmonary fibrosis
>75% with severe
honeycombing
Death
Definition: A disorder characterized by the replacement of the lung tissue by connective tissue, leading to progressive dyspnea, respiratory failure or right heart failure.
Pulmonary fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Limiting self care ADL;
endoscopic stenting or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an abnormal communication between the lung and another organ or anatomic site.
Pulmonary hypertension
Minimal dyspnea; findings on
physical exam or other
evaluation
Moderate dyspnea, cough;
requiring evaluation by cardiac
catheterization and medical
intervention
Severe symptoms, associated
with hypoxemia, right heart
failure; oxygen indicated
Life-threatening airway
consequences; urgent
intervention indicated (e.g.,
tracheotomy or intubation)
Death
Definition: A disorder characterized by an increase in pressure within the pulmonary circulation due to lung or heart disorder.
Respiratory failure
 -
 -
 -
Life-threatening consequences;
urgent intervention, intubation,
or ventilatory support indicated
Death
Definition: A disorder characterized by impaired gas exchange by the respiratory system resulting in hypoxemia and a decrease in oxygenation of the tissues that may be associated
with an increase in arterial levels of carbon dioxide.
Retinoic acid syndrome
Fluid retention; <3 kg of weight
gain; intervention with fluid
restriction and/or diuretics
indicated
Moderate signs or symptoms;
steroids indicated
Severe symptoms;
hospitalization indicated
Life-threatening consequences;
ventilatory support indicated
Death
Definition: A disorder characterized by weight gain, dyspnea, pleural and pericardial effusions, leukocytosis and/or renal failure originally described in patients treated with all-trans
retinoic acid.
Sinus disorder
Asymptomatic mucosal crusting;
blood-tinged secretions
Symptomatic stenosis or
edema/narrowing interfering
with airflow; limiting instrumental
ADL
Stenosis with significant nasal
obstruction; limiting self care
ADL
Necrosis of soft tissue or bone;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by involvement of the paranasal sinuses.
Sleep apnea
Snoring and nocturnal sleep
arousal without apneic periods
Moderate apnea and oxygen
desaturation; excessive daytime
sleepiness; medical evaluation
indicated; limiting instrumental
ADL
Oxygen desaturation;
associated with hypertension;
medical intervention indicated;
limiting self care ADL
Cardiovascular or
neuropsychiatric symptoms;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by cessation of breathing for short periods during sleep.
Sneezing
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by the involuntary expulsion of air from the nose.
Sore throat
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL; limiting ability to swallow
 -
 -
Definition: A disorder characterized by of marked discomfort in the throat
Stridor
 -
 -
Respiratory distress limiting self
care ADL; medical intervention
indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a high pitched breathing sound due to laryngeal or upper airway obstruction.
Tracheal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
indicated (e.g., thoracoplasty,
chronic open drainage or
multiple thoracotomies)
Death
Definition: A disorder characterized by an abnormal communication between the trachea and another organ or anatomic site.
Tracheal mucositis
Endoscopic findings only;
minimal hemoptysis, pain, or
respiratory symptoms
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe pain; hemorrhage or
respiratory symptoms; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the trachea.
Tracheal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids)
Stridor or respiratory distress
limiting self care ADL;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a narrowing of the trachea.
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Voice alteration
Mild or intermittent change from
normal voice
Moderate or persistent change
from normal voice; still
understandable
Severe voice changes including
predominantly whispered
speech; may require frequent
repetition or face-to-face contact
for understandability; may
require assistive technology
 -
 -
Definition: A disorder characterized by a change in the sound and/or speed of the voice.
Wheezing
Detectable airway noise with
minimal symptoms
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe respiratory symptoms
limiting self care ADL; oxygen
therapy or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a high-pitched, whistling sound during breathing. It results from the narrowing or obstruction of the respiratory airways.
Respiratory, thoracic and
mediastinal disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
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24. Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Alopecia
Hair loss of <50% of normal for
that individual that is not
obvious from a distance but only
on close inspection; a different
hair style may be required to
cover the hair loss but it does
not require a wig or hair piece to
camouflage
Hair loss of >=50% normal for
that individual that is readily
apparent to others; a wig or hair
piece is necessary if the patient
desires to completely
camouflage the hair loss;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by a decrease in density of hair compared to normal for a given individual at a given age and body location.
Body odor
Mild odor; physician intervention
not indicated; self care
interventions
Pronounced odor; psychosocial
impact; patient seeks medical
intervention
 -
 -
 -
Definition: A disorder characterized by an abnormal body smell resulting from the growth of bacteria on the body.
Bullous dermatitis
Asymptomatic; blisters covering
<10% BSA
Blisters covering 10 - 30% BSA;
painful blisters; limiting
instrumental ADL
Blisters covering >30% BSA;
limiting self care ADL
Blisters covering >30% BSA;
associated with fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by inflammation of the skin characterized by the presence of bullae which are filled with fluid.
Dry skin
Covering <10% BSA and no
associated erythema or pruritus
Covering 10 - 30% BSA and
associated with erythema or
pruritus; limiting instrumental
ADL
Covering >30% BSA and
associated with pruritus; limiting
self care ADL
 -
 -
Definition: A disorder characterized by flaky and dull skin; the pores are generally fine, the texture is a papery thin texture.
Erythema multiforme
Target lesions covering <10%
BSA and not associated with
skin tenderness
Target lesions covering 10 -
30% BSA and associated with
skin tenderness
Target lesions covering >30%
BSA and associated with oral or
genital erosions
Target lesions covering >30%
BSA; associated with fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by target lesions (a pink-red ring around a pale center).
Erythroderma
 -
Erythema covering >90% BSA
without associated symptoms;
limiting instrumental ADL
Erythema covering >90% BSA
with associated symptoms (e.g.,
pruritus or tenderness); limiting
self care ADL
Erythema covering >90% BSA
with associated fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by generalized inflammatory erythema and exfoliation. The inflammatory process involves > 90% of the body surface area.
Fat atrophy
Covering <10% BSA and
asymptomatic
Covering 10 - 30% BSA and
associated with erythema or
tenderness; limiting instrumental
ADL
Covering >30% BSA;
associated with erythema or
tenderness; limiting self-care
ADL
 -
 -
Definition: A disorder characterized by shrinking of adipose tissue.
Hirsutism
In women, increase in length,
thickness or density of hair in a
male distribution that the patient
is able to camouflage by
periodic shaving, bleaching, or
removal of hair
In women, increase in length,
thickness or density of hair in a
male distribution that requires
daily shaving or consistent
destructive means of hair
removal to camouflage;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by the presence of excess hair growth in women in anatomic sites where growth is considered to be a secondary male characteristic and under
androgen control (beard, moustache, chest, abdomen)
Hyperhidrosis
Limited to one site (palms,
soles, or axillae); self care
interventions
Involving >1 site; patient seeks
medical intervention; associated
with psychosocial impact
Generalized involving sites
other than palms, soles, or
axillae; associated with
electrolyte/hemodynamic
imbalance
 -
 -
Definition: A disorder characterized by excessive perspiration.
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
72
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Hypertrichosis
Increase in length, thickness or
density of hair that the patient is
either able to camouflage by
periodic shaving or removal of
hairs or is not concerned
enough about the overgrowth to
use any form of hair removal
Increase in length, thickness or
density of hair at least on the
usual exposed areas of the
body [face (not limited to
beard/moustache area)
plus/minus arms] that requires
frequent  shaving or use of
destructive means of hair
removal to camouflage;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by hair density or length beyond the accepted limits of normal in a particular body region, for a particular age or race.
Hypohidrosis
 -
Symptomatic; limiting
instrumental ADL
Increase in body temperature;
limiting self care ADL
Heat stroke
Death
Definition: A disorder characterized by reduced sweating.
Lipohypertrophy
Asymptomatic and covering
<10% BSA
Covering 10 - 30% BSA and
associated tenderness; limiting
instrumental ADL
Covering >30% BSA and
associated tenderness and
narcotics or NSAIDs indicated;
lipohypertrophy; limiting self
care ADL
 -
 -
Definition: A disorder characterized by hypertrophy of the subcutaneous adipose tissue at the site of multiple subcutaneous injections of insulin.
Nail discoloration
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by a change in the color of the nail plate.
Nail loss
Asymptomatic separation of the
nail bed from the nail plate or
nail loss
Symptomatic separation of the
nail bed from the nail plate or
nail loss; limiting instrumental
ADL
 -
 -
 -
Definition: A disorder characterized by loss of all or a portion of the nail.
Nail ridging
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by vertical or horizontal ridges on the nails.
Pain of skin
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the skin.
Palmar-plantar
erythrodysesthesia syndrome
Minimal skin changes or
dermatitis (e.g., erythema,
edema, or hyperkeratosis)
without pain
Skin changes (e.g., peeling,
blisters, bleeding, edema, or
hyperkeratosis) with pain;
limiting instrumental ADL
Severe skin changes (e.g.,
peeling, blisters, bleeding,
edema, or hyperkeratosis) with
pain; limiting self care ADL
 -
 -
Definition: A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet.
Periorbital edema
Soft or non-pitting
Indurated or pitting edema;
topical intervention indicated
Edema associated with visual
disturbance; increased
intraocular pressure, glaucoma
or retinal hemorrhage; optic
neuritis; diuretics indicated;
operative intervention indicated
 -
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid around the orbits of the face.
Photosensitivity
Painless erythema and
erythema covering <10% BSA
Tender erythema covering 10 -
30% BSA
Erythema covering >30% BSA
and erythema with blistering;
photosensitivity; oral
corticosteroid therapy indicated;
pain control indicated (e.g.,
narcotics or NSAIDs)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in sensitivity of the skin to light.
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
73
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Pruritus
Mild or localized; topical
intervention indicated
Intense or widespread;
intermittent; skin changes from
scratching (e.g., edema,
papulation, excoriations,
lichenification, oozing/crusts);
oral intervention indicated;
limiting instrumental ADL
Intense or widespread;
constant; limiting self care ADL
or sleep; oral corticosteroid or
immunosuppressive therapy
indicated
 -
 -
Definition: A disorder characterized by an intense itching sensation.
Purpura
Combined area of lesions
covering <10% BSA
Combined area of lesions
covering 10 - 30% BSA;
bleeding with trauma
Combined area of lesions
covering >30% BSA;
spontaneous bleeding
 -
 -
Definition: A disorder characterized by hemorrhagic areas of the skin and mucous membrane. Newer lesions appear reddish in color. Older lesions are usually a darker purple color
and eventually become a brownish-yellow color.
Rash acneiform
Papules and/or pustules
covering <10% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness
Papules and/or pustules
covering 10 - 30% BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness; associated with
psychosocial impact; limiting
instrumental ADL
Papules and/or pustules
covering >30% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness; limiting self care
ADL; associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering any % BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness and are associated
with extensive superinfection
with IV antibiotics indicated; life-
threatening consequences
Death
Definition: A disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest and back.
Rash maculo-papular
Macules/papules covering
<10% BSA with or without
symptoms (e.g., pruritus,
burning, tightness)
Macules/papules covering 10 -
30% BSA with or without
symptoms (e.g., pruritus,
burning, tightness); limiting
instrumental ADL
Macules/papules covering
>30% BSA with or without
associated symptoms; limiting
self care ADL
 -
 -
Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbillform rash, it is one of the most common cutaneous adverse
events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus.
Scalp pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the skin covering the top and the back of the head.
Skin atrophy
Covering <10% BSA;
associated with telangiectasias
or changes in skin color
Covering 10 - 30% BSA;
associated with striae or
adnexal structure loss
Covering >30% BSA;
associated with ulceration
 -
 -
Definition: A disorder characterized by the degeneration and thinning of the epidermis and dermis.
Skin hyperpigmentation
Hyperpigmentation covering
<10% BSA; no psychosocial
impact
Hyperpigmentation covering
>10% BSA; associated
psychosocial impact
 -
 -
 -
Definition: A disorder characterized by darkening of the skin due to excessive melanin deposition.
Skin hypopigmentation
Hypopigmentation or
depigmentation covering <10%
BSA; no psychosocial impact
Hypopigmentation or
depigmentation covering >10%
BSA; associated psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by loss of skin pigment.
Skin induration
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration, unable to
slide or pinch skin; limiting joint
movement or orifice (e.g.,
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by an area of hardness in the skin.
Skin ulceration
Combined area of ulcers <1 cm;
nonblanchable erythema of
intact skin with associated
warmth or edema
Combined area of ulcers 1 - 2
cm; partial thickness skin loss
involving skin or subcutaneous
fat
Combined area of ulcers >2 cm;
full-thickness skin loss involving
damage to or necrosis of
subcutaneous tissue that may
extend down to fascia
Any size ulcer with extensive
destruction, tissue necrosis, or
damage to muscle, bone, or
supporting structures with or
without full thickness skin loss
Death
Definition: A disorder characterized by circumscribed, inflammatory and necrotic erosive lesion on the skin.
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
74
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Stevens-Johnson syndrome
 -
 -
Skin sloughing covering <10%
BSA with associated signs (e.g.,
erythema, purpura, epidermal
detachment and mucous
membrane detachment)
Skin sloughing covering 10 -
30% BSA with associated signs
(e.g., erythema, purpura,
epidermal detachment and
mucous membrane
detachment)
Death
Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the
mucous membranes.
Telangiectasia
Telangiectasias covering <10%
BSA
Telangiectasias covering >10%
BSA; associated with
psychosocial impact
 -
 -
 -
Definition: A disorder characterized by local dilatation of small vessels resulting in red discoloration of the skin or mucous membranes.
Toxic epidermal necrolysis
 -
 -
 -
Skin sloughing covering >=30%
BSA with associated symptoms
(e.g., erythema, purpura, or
epidermal detachment)
Death
Definition: A disorder characterized by greater than 30% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the
mucous membranes.
Urticaria
Urticarial lesions covering <10%
BSA; topical intervention
indicated
Urticarial lesions covering 10 -
30% BSA; oral intervention
indicated
Urticarial lesions covering >30%
BSA; IV intervention indicated
 -
 -
Definition: A disorder characterized by an itchy skin eruption characterized by wheals with pale interiors and well-defined red margins.
Skin and subcutaneous tissue
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Social circumstances 
75
25. Social circumstances
Social circumstances
Grade
Adverse Event
1
2
3
4
5
Menopause
Menopause occurring at age 46
- 53 years of age
Menopause occurring at age 40
- 45 years of age
Menopause occurring before
age 40 years of age
 -
 -
Definition: A disorder characterized by the permanent cessation of menses, usually defined by 12 consecutive months of amenorrhea in a woman over 45 years of age.
Social circumstances - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Surgical and medical procedures 
76
26. Surgical and medical procedures
Surgical and medical procedures
Grade
Adverse Event
1
2
3
4
5
Surgical and medical
procedures - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Vascular disorders 
77
27. Vascular disorders
Vascular disorders
Grade
Adverse Event
1
2
3
4
5
Capillary leak syndrome
 -
Symptomatic; medical
intervention indicated
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by leakage of intravascular fluids into the extravascular space. This syndrome is observed in patients who demonstrate a state of generalized
leaky capillaries following shock syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. It can lead to generalized edema and multiple organ
failure.
Flushing
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Symptomatic, associated with
hypotension and/or tachycardia;
limiting self care ADL
 -
 -
Definition: A disorder characterized by episodic reddening of the face.
Hematoma
Mild symptoms; intervention not
indicated
Minimally invasive evacuation or
aspiration indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel.
Hot flashes
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an uncomfortable and temporary sensation of intense body warmth, flushing, sometimes accompanied by sweating upon cooling.
Hypertension
Prehypertension (systolic BP
120 - 139 mm Hg or diastolic
BP  80 - 89 mm Hg)
Stage 1 hypertension (systolic
BP 140 - 159 mm Hg or
diastolic BP 90 - 99 mm Hg);
medical intervention indicated;
recurrent or persistent (>=24
hrs); symptomatic increase by
>20 mm Hg (diastolic) or to
>140/90 mm Hg if previously
WNL; monotherapy indicated
Pediatric: recurrent or persistent
(>=24 hrs) BP >ULN;
monotherapy indicated
Stage 2 hypertension (systolic
BP >=160 mm Hg or diastolic
BP >=100 mm Hg); medical
intervention indicated; more
than one drug or more intensive
therapy than previously used
indicated
Pediatric: Same as adult
Life-threatening consequences
(e.g., malignant hypertension,
transient or permanent
neurologic deficit, hypertensive
crisis); urgent intervention
indicated
Pediatric: Same as adult
Death
Definition: A disorder characterized by a pathological increase in blood pressure; a repeatedly elevation in the blood pressure exceeding 140 over 90 mm Hg.
Hypotension
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention or
hospitalization indicated
Life-threatening and urgent
intervention indicated
Death
Definition: A disorder characterized by a blood pressure that is below the normal expected for an individual in a given environment.
Lymph leakage
 -
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the loss of lymph fluid into the surrounding tissue or body cavity.
Lymphedema
Trace thickening or faint
discoloration
Marked discoloration; leathery
skin texture; papillary formation;
limiting instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by excessive fluid collection in tissues that causes swelling.
Lymphocele
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by a cystic lesion containing lymph.
Peripheral ischemia
 -
Brief (<24 hrs) episode of
ischemia managed non-
surgically and without
permanent deficit
Recurring or prolonged (>=24
hrs) and/or invasive intervention
indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by impaired circulation to an extremity.
Phlebitis
 -
Present
 -
 -
 -
Definition: A disorder characterized by inflammation of the wall of a vein.
Superficial thrombophlebitis
 -
Present
 -
 -
 -
Definition: A disorder characterized by a blood clot and inflammation involving a superficial vein of the extremities.
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CTCAE 4.03 - June 14, 2010 : Vascular disorders 
78
Vascular disorders
Grade
Adverse Event
1
2
3
4
5
Superior vena cava syndrome
Asymptomatic; incidental finding
of SVC thrombosis
Symptomatic; medical
intervention indicated (e.g.,
anticoagulation, radiation or
chemotherapy)
Severe symptoms; multi-
modality intervention indicated
(e.g., anticoagulation,
chemotherapy, radiation,
stenting)
Life-threatening consequences;
urgent multi-modality
intervention indicated (e.g.,
lysis, thrombectomy, surgery)
Death
Definition: A disorder characterized by obstruction of the blood flow in the superior vena cava. Signs and symptoms include swelling and cyanosis of the face, neck, and upper arms,
cough, orthopnea and headache.
Thromboembolic event
Venous thrombosis (e.g.,
superficial thrombosis)
Venous thrombosis (e.g.,
uncomplicated deep vein
thrombosis), medical
intervention indicated
Thrombosis (e.g.,
uncomplicated pulmonary
embolism [venous], non-embolic
cardiac mural [arterial]
thrombus), medical intervention
indicated
Life-threatening (e.g.,
pulmonary embolism,
cerebrovascular event, arterial
insufficiency); hemodynamic or
neurologic instability; urgent
intervention indicated
Death
Definition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via the blood stream.
Vasculitis
Asymptomatic, intervention not
indicated
Moderate symptoms, medical
intervention indicated
Severe symptoms, medical
intervention indicated (e.g.,
steroids)
Life-threatening; evidence of
peripheral or visceral ischemia;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving the wall of a vessel.
Visceral arterial ischemia
 -
Brief (<24 hrs) episode of
ischemia managed medically
and without permanent deficit
Prolonged (>=24 hrs) or
recurring symptoms and/or
invasive intervention indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a decrease in blood supply due to narrowing or blockage of a visceral (mesenteric) artery.
Vascular disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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28. Publication Information
NIH Publication No. 09-5410
Revised June 2010
Reprinted June 2010
J[TUTE 
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SYNT001 
Pemphigus 
Protocol SYNT001-103 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 97 of 97 
Confidential and Proprietary 
Final 18 January 2017 
 
Appendix B: Pemphigus Disease Area Index 
 
- 
Skin 
- 
Activity 
- 
Damage 
Anatomical 
Location 
Erosion / Blisters or new erythema 
 
Post-inflammatory hyperpigmentation or 
erythema from resolving lesion 
 
0 
1 
 
2 
 
3 
5 
10 
absent 
1-3 lesions up to one > 2 cm in any diameter, none 
> 6 cm 
2-3 lesions, at least two > 2 cm diameter, none > 6 
cm 
> 3 lesions, none > 6 cm diameter 
> 3 lesions, and/or at least one > 6 cm 
> 3 lesions, and/or at least one lesion > 16 cm 
diameter or entire area 
Number 
lesions if    3  
0   absent 
1   present 
Ears 
Nose 
Rest of the face 
Neck 
Chest 
Abdomen 
Back, buttocks 
Arms 
Hands 
Legs 
Feet 
Genitals 
Total skin 
/120 
/12 
- 
Scalp 
Scalp 
Erosion/Blisters or new erythema 
Number 
lesions if    3  
Post-inflammatory hyperpigmentation or 
erythema from resolving lesion 
 
0   absent 
1 in one quadrant 
2 two quadrants 
3 three quadrants 
4 affects whole skull 
10 at least one lesion > 6 cm 
 
 
0   absent 
1   present 
Total Scalp (0-10) 
/10 
/1 
Mucous membrane 
Anatomical 
location 
Erosion/Blisters 
 
 
 
0   absent 
1 1 lesion 
2 2-3 lesions 
5    > 3 lesions or 2 lesions > 2 cm 
10   entire area 
Number 
lesions 
if    3 
Eyes 
Nose 
Buccal mucosa 
Hard palate 
Soft palate 
Upper gingiva 
Lower gingiva 
Tongue 
Floor of mouth 
Labial bucosa 
Posterior pharynx 
Anogenital 
Total Mucosa 
/120 
 
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Confidentiality Statement
The information contained herein is confidential and the proprietary property of Syntimmune, Inc. and 
any unauthorized use or disclosure of such information without the prior written authorization of 
Syntimmune is expressly prohibited.
Syntimmune, Inc.
CLINICAL STUDY PROTOCOL
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and Activity 
Study of SYNT001 in Subjects with Chronic Pemphigus (Vulgaris or 
Foliaceus)
Protocol Number:
SYNT001-103
IND Number:
132727
Study Drug:
SYNT001
Sponsor:
Syntimmune, Inc.
257 Park Avenue South
15th Floor
New York, NY 10010
Medical Monitor:
43 Thorndike Street, Cambridge, MA 01240
Phone:
 extension
Mobile:
Original Protocol:
18 January 2017
Amendment 1.1:
21 March 2017
Alexion Confidential
Page 179 of 979
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SYNT001
Pemphigus
Protocol SYNT001-103
Syntimmune, Inc.
Page 2 of 97
Confidential and Proprietary
Amendment 1.1 Final  21 March
2017
SPONSOR SIGNATURE
I have read and approve this protocol.  My signature, in conjunction with the signature of the 
Investigator, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Conference on Harmonisation Guideline for Good Clinical Practice (GCP), 
the Code of Federal Regulations (CFR), and the ethical principles that have their origins in the 
Declaration of Helsinki.
Date of Signature
(DD Mm YYYY)
March 21, 2017
Alexion Confidential
Page 180 of 979
PPD


SYNT001
Pemphigus
Protocol SYNT001-103
Syntimmune, Inc.
Page 3 of 97
Confidential and Proprietary
Amendment 1.1 Final  21 March
2017
PROCEDURES IN CASE OF EMERGENCY
Serious Adverse Events 
Any death, serious adverse event (SAE)* occurring in a subject while receiving study drug or 
within 7 days of receiving study drug, even though the event may not appear to be study drug 
related, must be promptly reported (within 24 hours) by telephone or electronic communication to 
the sponsor (or designee).  
Emergency Contact Information 
SAE CRITERIA
* A serious adverse event (SAE) is any untoward medical occurrence that at any dose results in any of the following outcomes, regardless of 
relationship to study drug (see Section 11.3.1, Serious Adverse Events for additional information):
•
Death
•
Life-threatening adverse drug event
•
Inpatient hospitalization or prolongation of existing hospitalization
•
A persistent or significant disability/ incapacity
•
A congenital anomaly/birth defect
•
An important medical event that may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above.
For SAE reporting:
For any other questions or to 
contact the Medical Monitor:
Medpace Clinical Safety 
Medpace SAE hotline: 
Telephone: 
dial or 
dial 
Facsimile: 
 or 
e-mail:
Mobile phone: 
Office phone: 
ext.
Alexion Confidential
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P
D
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P
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PPD
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SYNT001
Pemphigus
Protocol SYNT001-103
Syntimmune, Inc.
Page 4 of 97
Confidential and Proprietary
Amendment 1.1 Final  21 March
2017
INVESTIGATOR SIGNATURE
I have read and approve this protocol.  My signature, in conjunction with the signature of the 
sponsor, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Conference on Harmonization Guideline for Good Clinical Practice (GCP), 
the Code of Federal Regulations (CFR), and the ethical principles that have their origins in the 
Declaration of Helsinki.
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations. 
Investigator Signature
Date of Signature
(DD Mm YYYY)
Name of Investigator (please print)
Alexion Confidential
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SYNT001
Pemphigus
Protocol SYNT001-103
Syntimmune, Inc.
Page 5 of 97
Confidential and Proprietary
Amendment 1.1 Final  21 March
2017
1
SYNOPSIS
Study title
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and Activity Study of 
SYNT001 in Subjects with Chronic Pemphigus (Vulgaris or Foliaceus)
Protocol number
SYNT001-103
Number of study 
centers
Approximately 10 (US)
Clinical phase 
Phase 1b
Study background
SYNT001, a humanized, affinity-matured IgG4-kappa monoclonal antibody
(mAb), blocks IgG and IgG immune complex (IC) interactions with the neonatal 
Fc receptor (FcRn) and thereby the major functions of FcRn in protecting IgG 
and IgG immune complexes from degradation and their role in downstream 
signaling events. Specific and high affinity blockade of FcRn with SYNT001 has 
been shown to increase the catabolism of IgG and IgG IC in healthy volunteers. 
This predicts that SYNT001 will also accelerate degradation of endogenous 
circulating IgG autoantibodies and IgG-antigen IC specifically involved in the 
pathogenesis of autoimmunity.  Blocking FcRn interactions with IgG containing 
immune complexes further predicts that SYNT001 will have consequences for 
innate and adaptive cellular immunity. In the first instance, blocking multimeric 
IgG IC interactions with FcRn within antigen presenting cells will result in 
inhibition of IC-stimulated inflammatory cytokine production and release by 
these cells. In addition, as FcRn determines the intracellular itinerary of IgG 
immune complexes within and among compartments important in cellular 
immunity, it is further anticipated that SYNT001 will block antigen processing 
and presentation of antigens contained within IC that otherwise lead to CD8+ and 
CD4+ T cell activation. Thus, SYNT001 will specifically target immune 
functions associated with IgG and IC that are involved in many autoimmune 
conditions and dismantle their ability to cause disease.
SYNT001 targets mechanisms contributing to pathology in a variety of IgG-
mediated autoimmune disorders, including warm antibody autoimmune 
hemolytic anemia (WAIHA), pemphigus, and chronic inflammatory 
demyelinating polyneuropathy (CIDP).  
While current treatments for certain autoimmune disorders including chronic
steroids, immunosuppressants, intravenous immunoglobulin (IVIG), 
plasmapheresis, and anti-CD20 monoclonal antibodies (mAbs), such as 
rituximab, can be effective, they are frequently associated with significant 
adverse effects, and delayed or non-durable responses.
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin
and mucous membranes. Autoantibodies are thought to play an important 
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pathogenic role in the mucosal and cutaneous manifestations in patients with 
pemphigus. Administration of SYNT001, leading to a significant decrease in 
total IgG, and thereby a corresponding decrease in the level of the pathogenic 
autoantibodies as well as the ICs to which they are associated, should lead to a 
decrease in the mucosal and cutaneous manifestations in subjects with 
pemphigus. Moreover, the ability of SYNT001 to reduce circulating immune 
complexes (CICs) and the associated innate and adaptive immune responses may 
allow for further sustained disease modification.
Study rationale
This study is being conducted to further evaluate the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of 
intravenous (IV) SYNT001 as well as its effects on pemphigus disease activity 
markers.
Study objectives
Primary objective
•
To evaluate the safety and tolerability of 5 once-weekly IV infusions of 
SYNT001 at different dose levels in subjects with chronic pemphigus 
(vulgaris or foliaceus)
Secondary objectives
•
To determine the PK of SYNT001 following 5 once-weekly 1-hour IV 
infusions at different dose levels
•
To assess the effect of 5 once-weekly doses of SYNT001 at different dose 
levels on the following PD biomarkers:
o
Immunoglobulins: IgG, IgG subtypes (IgG1-4), IgA, IgM
o
Albumin
•
To assess the effect of 5 once-weekly doses of SYNT001 at different dose 
levels on the following disease activity markers:
o
Serum anti-desmoglein (Dsg) (1 and 3) antibody levels
o
Pemphigus Disease Area Index (PDAI)
•
To assess immunogenicity (anti-SYNT001 antibodies)
Exploratory objectives
•
To assess the effect of 5 once-weekly doses of SYNT001 at different dose 
levels on the following biomarkers, including:
o
Serum anti-epithelial cell antibody (AECA) levels by indirect 
immunofluorescence
o
Circulating immune complexes (CIC)
o
Complement component 3 (C3)
o
Exploratory biomarkers (FCGR2A (single nucleotide polymorphism-
SNP), RNAseq, urine IgG)
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o
Immune phenotyping by flow cytometry for CD3+CD4+ T, 
CD3+CD8+ T, monocytes, NK cells and B cells
o
SYNT001 levels in skin biopsies (optional)
•
To characterize corticosteroid use during the study
Study design
Phase 1b, multicenter, open-label, safety, tolerability, and activity study
Methodology
Two cohorts of 8 eligible subjects each will receive 5 once-weekly 60-minute 
infusions of SYNT001 in planned doses of 10 mg/kg or 30 mg/kg. Based on 
review of safety, PD, and clinical outcomes of these 2 cohorts, a third cohort of 
up to 8 subjects may be treated at another dose, with a maximum dose of 45 
mg/kg, but may also be lower than 10 mg/kg or between 10 and 30 mg/kg,
inclusive.
Cohort
No. of subjects
Dose
1
8
SYNT001 10 mg/kg
2
8
SYNT001 30 mg/kg
Cohorts will be dosed sequentially beginning with Cohort 1. The first 2 subjects 
will be dosed at least 24 hours apart. A review of the 24-hour safety data for the 
first subject will be performed to ensure that there are no overt safety concerns 
before dosing the second subject. A review of the 7-day safety data for the first 
2 subjects will be performed prior to dosing the remaining 6 subjects in the 
cohort. This evaluation will include a review of AE/SAE reports, vital sign 
assessments, physical examinations, ECGs, and clinical laboratory testing.  The 
seriousness, severity, and relatedness of AEs/SAEs will also be considered in the 
safety evaluation. Safety data will be reviewed on a continuous basis throughout 
the study. All safety data and any available and relevant PD data through Day 
42 (2 weeks after the last subject’s last dose in Cohort 1) will be reviewed by a 
dose escalation committee before Cohort 2 is initiated. Escalation to Cohort 2
will proceed if there are no concerning safety signals and the review of available 
and relevant PD data supports advancing to a higher dose. The dose for Cohort 2 
will be finalized after review of the safety and PD data, but will not exceed 30 
mg/kg. Cohort 2 and Cohort 3, if added, will be dosed per the same schedule as
Cohort 1.
On days where study drug is administered, vital sign and pulse oximetry 
measurements will be collected immediately prior to the infusion; 15, 30, and 45 
minutes after the start of the infusion; at completion of the infusion; and 
30 minutes, 1 hour and 2 hours following completion of the infusion. 
On Days 0 and 28, PK blood samples will be collected prior to infusion start and 
then over the subsequent 48 hours.  Subjects will remain at the clinic through the 
6-hour PK sample collection and will return to the clinic for the 24- and 48-hour 
collections. Additional samples will be collected on Days 5 and 33.
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On Day 0 photographs will be taken of active lesions.  Follow-up photographs 
will be taken of the same areas on Days 33 and 56. If a subject begins a steroid 
taper, additional photographs will be taken at the clinic visit during which the 
decision to begin the taper is made.
Subsequent visits will occur on Days 1, 2, 5, 7, 12, 14, 19, 21, 28, 29, 30, 33, and 
42 for safety assessments, study drug dosing, sample collections, and other study 
procedures.
Subjects also will return to the clinic on Day 56 (28 days after receiving their last 
dose of study drug) for an End-of-Study/Follow-Up visit.
See Table 1 for a schedule of all study events.  To assess safety and tolerability, 
subjects will undergo physical examinations (PEs; including weight), vital sign 
measurements, clinical (safety) laboratory tests, adverse event (AE) assessments, 
concomitant medication assessments, and electrocardiograms (ECG).
Number of subjects
Approximately 16; two cohorts of 8 subjects each.  An additional cohort of up to 
8 subjects may be enrolled. Subjects who withdraw for any reason other than an 
AE and who do not receive study drug or have only received one dose of study 
drug may be replaced, up to one subject per cohort. The maximum number of 
subjects who may be enrolled in this study is 27 (24 + up to 3 replacements, as 
necessary). Within each dosing cohort, no more than 3 subjects with pemphigus 
foliaceus may be enrolled.
Diagnosis and main 
entry criteria
Inclusion criteria:
Subjects must meet the following criteria to be included:
1.
Willing and able to read, understand and sign an informed consent form;
2.
Male or female ≥ 18 years of age at the time of screening;
3.
Documented diagnosis of pemphigus vulgaris or foliaceus based on all 3 of 
the following criteria:
a.
Documented clinical history consistent with pemphigus vulgaris or 
foliaceus (clinical presentation defined as mucosal and/ or skin 
lesions);
b.
Presence of Anti-Dsg 1 or 3 antibodies above the upper limit of 
normal;
c.
History of at least one positive tissue-based test (e.g., biopsy, direct 
immunofluorescence [DIF])
4.
Active disease: Lesions lasting > 2 weeks, and 3 active lesions in skin or 
mucosa or 2 active lesions with at least one being a skin lesion > 1 cm 
diameter:
a.
If treated with rituximab or other anti-CD20 antibodies, last dose 
> 12 months prior to screening;
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b.
If being treated with other immunosuppressants (i.e., azathioprine, 
mycophenolate mofetil or cyclosporine), must be on stable dose 
(< 10% change in dose) for 6 weeks prior to screening;
c.
If being treated with corticosteroids, must be ≤1mg/kg/day and 
stable (< 10% change in dose) for 2 weeks prior to screening;
d.
Allowed topical therapies for pemphigus lesions upon entering the 
study include petroleum jelly or Aquaphor® for the skin or 
chlorhexidine for the mouth
5.
Body mass index (BMI) 18.5 – 35.0 kg/m2;
6.
Has a negative urine pregnancy test (for women of childbearing potential) 
documented prior to the first dose of study drug;    
7.
Females of childbearing potential must agree to be abstinent or else use any 
two of the following medically acceptable forms of contraception (<1% per 
year failure rate) from the Screening Period through 60 days after the final 
study dose: oral contraceptive, condom with or without spermicidal jelly, 
diaphragm or cervical cap with spermicidal jelly, or intra-uterine device 
(IUD). A female whose male partner has had a vasectomy must agree to use 
one additional form of medically acceptable contraception. 
8.
Females of non-childbearing potential, defined as surgically sterile (status 
post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or 
post-menopausal for at least 12 months do not require contraception during 
the study.
9.
Males with female partners of childbearing potential, including males who 
are surgically sterile (post vasectomy), must agree to be abstinent or else use 
a medically acceptable form of contraception from the screening period 
through 60 days after the final study dose.
Exclusion criteria:
Subjects meeting any of the following criteria are to be excluded: 
1.
Subject unable or unwilling to comply with the protocol;
2.
Active non-hematologic malignancy or history of non-hematologic 
malignancy in the 3 years prior to screening (exclusive of non-melanoma 
skin cancer and cervical cancer in situ);
3.
Positive for HIV or hepatitis C antibody; 
4.
Positive for hepatitis B surface antigen;
5.
Active infection or history of recurrent infections;
6.
IVIG use within 60 days of screening;
7.
Received any cytotoxic (other than azathioprine) or mAb therapy in the 3 
months prior to screening;
8.
Any exposure to an investigational drug or device within the 30 days prior to 
screening
9.
Plasmapheresis or immunoadsorption within 60 days of screening
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10. Cellular therapy at any time prior to screening
11. Use of any immunosuppressive drugs apart from corticosteroids, 
azathioprine, mycophenolate mofetil, or cyclosporine within 3 months of 
screening
12. Serum total IgG < 600 mg/dL;
13. Subject has any current medical condition that, in the opinion of the 
Investigator, may compromise their safety or compliance, preclude 
successful conduct of the study, or interfere with interpretation of the results 
(e.g., a significant pre-existing illness or other major comorbidity that the 
Investigator considers may confound the interpretation of the study results);
14. Any vaccination within 2 weeks of screening
Study drug, dosage, 
and administration
SYNT001
Doses: 10 mg/kg and 30 mg/kg. A third cohort of up to 8 subjects may be treated 
at another dose, with a maximum dose of 45 mg/kg, but may also be lower than 
10 mg/kg or between 10 and 30 mg/kg, inclusive.
SYNT001 is provided as a liquid at a nominal concentration of 50 mg/mL.
SYNT001 is diluted in Dextrose 5% in Water (D5W) to prepare the solution for 
infusion.
Route of administration: IV in 250 mL over 1 hour
Control, dose, and 
route of 
administration
Not applicable
Duration of subject 
participation and 
duration of study
Up to 70 days (10 weeks): Screening of up to 2 weeks (14 days); dosing period 
of 4 weeks (28 days); and 4 weeks (28 days) of follow-up
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Prohibited 
Concomitant 
treatments
All treatments a subject receives within 14 days prior to enrollment through the 
end of the study (Day 56) will be documented. Concomitant medication and 
treatment for co-existing conditions, including those for pemphigus, are 
permitted if not excluded below.  Topical antibiotics are permitted to treat active 
infections that occur on study.  Topical or systemic treatments for oral 
candidiasis are permitted.  Topical lidocaine for transient pain relief is acceptable 
as needed.  Significant increases in anti-pemphigus medications may result in 
subjects being discontinued from the study. Concomitant treatment that is 
medically indicated for any AEs the subject experiences during the study are 
permitted.
Use of the following medications will not be permitted during the study unless 
otherwise specified:
•
Rituximab or other anti-CD20 antibody
•
Monoclonal antibodies other than study drug
•
Any immunosuppressive drugs apart from corticosteroids, azathioprine, 
mycophenolate mofetil, or cyclosporine
•
Topical steroids
•
Any dietary herbal supplements
•
Any investigational drug or device
•
Any vaccinations
If over a period of at least two weeks on study drug, a subject on corticosteroids 
shows the absence of new lesions and significant healing of lesions that existed 
at study baseline, a slow corticosteroid taper may be started as per the following 
suggested schedule 
•
If on > 30 mg of prednisone per day, decrease by 10 mg every two 
weeks until a dose of 30 mg per day then decrease by 5 mg every two 
weeks
•
If on < 30 mg of prednisone per day, decrease by 5 mg every two weeks
Safety assessments
Safety assessments include AEs, serious adverse events (SAEs), PEs, vital sign 
measurements, clinical safety laboratory evaluations, ECGs, and reasons for 
treatment discontinuations due to toxicity. Safety assessments will be performed 
at specified time points and prior to discharge from the clinic.  Vital sign 
measurements, including blood pressure, pulse rate, respiratory rate, and 
temperature will be monitored throughout the study.  Pulse oximetry will be 
monitored during the study drug infusion and for 2 hours following the end of 
the infusion.
The National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE; Version 4.03) will be used for grading clinical and 
laboratory AEs.   
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The AE reporting period for a subject enrolled in the study begins when the 
subject provides informed consent and is continued for 28 days after the last 
dose of study drug. All AEs that occur in the enrolled subjects during the AE 
reporting period must be recorded, regardless of the relationship of the AE to
study drug. Any known untoward event that occurs beyond the AE reporting 
period that the Investigator assesses as related to study drug should also be 
recorded.
Dose-escalation rules
Dose-limiting toxicity (DLT) will be defined generally as clinically significant, 
severe (Grade 3) AEs occurring in ≥2 subjects that are determined to be 
clinically significant and considered related to study drug.
If 2 or more subjects at any time in any cohort (8 total subjects per cohort) have 
Grade 3 AEs that are determined to be clinically significant and considered to be 
related to study drug, dosing will be halted within that cohort and no further 
dose-escalation will occur. If the dose-escalation stopping rule is met in Cohort 1 
(10 mg/kg) all safety data and all available pharmacodynamics data will be 
reviewed and a cohort may be added at a dose at least 50% lower than the 10 
mg/kg dose.  If the stopping rule is not met after Cohort 1 (10 mg/kg), dose-
escalation may proceed up to a maximum of 30 mg/kg.  If the dose-escalation 
stopping rule is met in Cohort 2, all safety data and all available 
pharmacodynamics data will be reviewed and a cohort may be added at a dose at 
least 30% lower than the Cohort 2 dose. If the stopping rule is not met after 
Cohort 2, dose-escalation may proceed up to a maximum of 45 mg/kg; however, 
this cohort may also receive a dose equal to or less than 30 mg/kg based on 
evaluation of all safety and pharmacodynamic data.
Study stopping rule
If any subject experiences a life-threatening AE (Grade 4) that is considered to 
be related to study drug, any further dosing in all enrolled subjects will be 
suspended until the DEC has evaluated the event and determined the next 
appropriate course of action.  At any time during the study, the study may be 
discontinued if the DEC determines that further drug exposure would pose an 
undue risk to subjects.
Individual stopping 
rule
Dosing for any individual subject will be discontinued (i.e., further treatment 
with the study drug will not be given) if the subject experiences any study drug-
related SAE or any study drug-related non-SAE adverse event that, in the 
judgement of the Investigator and Medical Monitor, suggest that it could be 
unsafe to administer further study drug to that subject.  Additionally, a subject 
may be discontinued from further treatment with study drug, at the discretion of 
the Investigator with consultation with the Medical Monitor, if they require a 
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significant increase in dose(s) of anti-pemphigus medication(s) for the 
management of pemphigus.
Pharmacokinetics
The PK of SYNT001 will be evaluated following the first and last (fifth) doses 
of SYNT001.  
Starting on Days 0 and 28, serum samples will be collected just prior to the start 
of study drug infusion (pre-dose), at 5 minutes and 2, 4, 6, 24, and 48 hours after 
the end-of-study drug infusion. Additional samples will be collected on Days 5 
and 33.
Study drug concentration will be used to calculate the following PK parameters: 
t1/2, Cmax, Tmax, AUC0-24, and AUC0-∞.
Pharmacodynamics/
Activity
PD samples will be collected for analysis of IgG (serial assessment of IgG levels 
to identify Cmin, Tmin); IgG1-4 subtype levels; IgA levels; IgM levels; albumin 
levels; anti-Dsg (1 and 3) antibody levels; serum AECA by direct 
immunofluorescence; CIC; C3; exploratory biomarkers (FCGR2A SNP,
RNAseq, urine IgG, CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B 
cells).
Immunogenicity
Up to 4 samples will be collected for immunogenicity analyses.  Samples will be 
collected on Days 0 (pre-dose), 14, 28, and 56.
Skin biopsy
Optional skin biopsy samples will be collected on Day 0 pre-dose and on Days 1, 
2, 14, 33 and 56 to analyze SYNT001 levels.
Photography
Photographs of active lesions will be taken at Day 0.  Follow-up photographs of 
the same areas will be taken on Days 33 and 56.  Subjects who begin a steroid 
taper will have additional photographs taken at the clinic visit during which the 
decision to begin the taper is made.
Statistical methods
Sample size consideration
Formal sample size calculations were not performed.  The number of subjects 
was chosen based on feasibility and was considered sufficient to meet the study 
objectives.
Data presentations/Descriptive statistics
Three populations will be employed in the analysis of study data.
•
The intent-to-treat (ITT) population will consist of all subjects who have 
received at least one dose of study drug.  All safety analyses will be 
performed on the ITT population.
•
The PK population will consist of all subjects who receive at least one 
dose of study drug and have sufficient post-dose blood samples to obtain 
PK parameters.
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•
The PD population will consist of all subjects who receive at least one 
dose of study drug and have post-dose PD data available.
Primary safety analyses will be performed on the ITT population. Demographics, 
subject disposition, and screening and baseline characteristics will be 
summarized for the PK and ITT populations, where appropriate.
Criteria for evaluation
Objective
Endpoint
Primary 
Safety and tolerability of 5 once-
weekly IV infusions of SYNT001 to 
subjects with pemphigus vulgaris or 
foliaceus
AEs and clinical (safety) 
laboratory tests
Secondary 
PK of SYNT001 following a 1-hour IV 
infusion
PK parameters: t1/2, Cmax, Tmax,
AUC0-24, and AUC0-∞.
Effect of 5 once-weekly IV doses of 
SYNT001 on:
• Total IgG (IgG1-4), IgA, IgM, and 
albumin
• Serum anti-Dsg (1 and 3) antibodies
Changes in levels of IgG, IgG 
subtypes (IgG1-4), IgA, IgM, 
albumin, serum anti-Dsg (1 and 
3) antibodies
Assess immunogenicity 
Anti-SYNT001 antibodies
Disease Activity
PDAI Scores
Exploratory 
Effect of 5 once-weekly IV doses of 
SYNT001 on biomarkers including:
• CIC
• C3
• Serum anti-epithelial cell antibody 
(AECA) levels
• Exploratory biomarkers (FCGR2A
SNP, RNAseq, urine IgG)
• Immune phenotyping by flow 
cytometry
Changes in CIC; C3; AECA 
levels by indirect 
immunofluorescence; FCGR2A
SNP; RNAseq; urine IgG,
CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B 
cells; urine IgG levels; changes 
in blood transcriptome
Concomitant Treatment
Corticosteroid use during the 
study
SYNT001 levels in skin biopsies 
Measures of SYNT001 levels in 
skin biopsies
Treatment-emergent AEs (TEAEs) will be summarized using the Medical 
Dictionary for Regulatory Activities (MedDRA®; Version 19 or higher) System 
Organ Class (SOC) and preferred term, classified from verbatim terms.  The 
incidence and percentage of subjects with at least 1 occurrence of a preferred 
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term will be included, using the most severe grade.  The number of events per 
preferred term will also be summarized.  Causality (relationship to study 
treatment) will be summarized separately.
TEAEs, SAEs, and AEs leading to withdrawal, or treatment discontinuation will 
be listed by subject, and cohort using SOC and preferred terms. Duration of AEs 
will be determined and included in listings, along with action taken, and 
outcome.  
Laboratory results will be summarized by time point and cohort. The incidence
of laboratory abnormalities will be summarized.  The worst on-study grade after 
the first dose of study drug will be summarized.  Results for variables that are 
not coded will be presented in the listings as below, within, and above the 
normal limits of the central laboratory.  Vital sign measurements will be 
summarized by cohort at each scheduled time point using descriptive statistics.   
Study drug concentrations will be used to calculate the following PK parameters:  
t1/2, Cmax, Tmax, and area under the curve (AUC).  PK parameters will be 
determined using non-compartmental method(s).   Descriptive statistics of PK 
parameters for SYNT001 will include mean, standard deviation (SD), coefficient
of variation (CV), median, minimum, and maximum. Tmax will be reported as 
median and range. All descriptive statistics will be performed on untransformed 
PK parameters and after log10 transformation of PK parameters.
PD results will be summarized by cohort.  Descriptive statistics of PD 
parameters for SYNT001 will include mean, SD, CV, median, minimum, and 
maximum.
Immunogenicity results will be summarized by cohort.  Descriptive statistics will 
include mean, SD, CV, median, minimum, and maximum.
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Table 1:
Study Assessments 
Timepoint (Study Day)
Screen
-14 to -1
0
1
(±1 
hr)
2
(± 2 
hr)
5p
(±4 
hr)
7
(±4 
hr)
12p
(±6 
hr) 
14
(±6 
hr)
19p
(±6 
hr) 
21
(±6 
hr)
28
(±6
hr)
29
(±1 
hr)
30
(±2 
hr)
33
(±4
hr)
42
(±3 
day)
Follow-Up
56
(±5 days) or 
ET Visit
Extended 
Follow-
upq
Informed Consent
X
 
 
Demographics/Medical History
X
 
 
Inclusion/Exclusion
X
 
 
Physical Examinationa
X
X
X
 
X
 
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X 
X
X 
X
X
X
X
X
X
X
Pulse Oximetryc
X
X
 
X
 
X
X
Clinical Safety Labsd
X
X
X
 
X
 
X
X
X
X
X
Pregnancy teste
X
X
 
 
X
Hepatitis & HIV Screen
X
 
 
12-Lead ECGf
X
X
X 
 
X
X
Tetanus & VZV antibodiesg
X
 
 
X
X
PDAI Score
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
 
PK Samplingh
X
X
X
X
 
 
X
X
X
X
Immunogenicityi
X
 
X
 
X
X
Study Drug Administrationj
X
X
 
X
 
X
X
Immunoglobulins (IgG, IgA, IgM) 
and IgG subtypes (IgG 1-4)k
X
X
X
X
X
X
X 
X
X 
X
X
X
X
X
X
X
CIC
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
Anti-Dsg (1 & 3) antibody titer
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
C3 and AECAl
X
 
X
 
X
X
FCGR2Am
X
 
 
RNAseqm
X
 
X
 
X
X
Urine IgGm
X
 
X
 
X
X
Immune phenotypingn
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Optional Skin Biopsy
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Photographyo
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Adverse Events
To be collected from the date that the ICF is signed until 28 days after last dose of study drug.
Concomitant Medications
To be collected from within 14 days prior to Day 0 through 28 days after last dose of study drug.
ECG = electrocardiogram; ET= Early Termination; HIV = human immunodeficiency virus; ICF = informed consent form; PD = pharmacodynamic; PK = pharmacokinetic; VZV = 
varicella-zoster virus
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a: Complete PE, including weight, to be performed.  Height and BMI will be additional assessments conducted at screening.
b: Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and oral temperature) to be obtained after 5 minutes of seated rest.  Any abnormal measurements are to 
be repeated after 5 minutes of rest.  On Days 0, 7, 14, 21, and 28 vital sign measurements will be collected immediately prior to the infusion; 15, 30, and 45 minutes after the start 
of the infusion; at completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion.  
c: Pulse oximetry: On Days 0, 7, 14, 21, and 28, pulse oximetry to be measured immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at completion 
of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion.
d: Clinical safety labs: hematology, clinical chemistry, and urinalysis (see Section 6.7 for a complete list). Full clinical safety lab draws will be collected at Screening and on Days 
0, 7, 14, 21, 28, 33, 42 and 56.
e: Pregnancy test:  To be performed at time of screening and prior to first dose of SYNT001 on Day 0 and on Day 56 (urine or serum test is acceptable, however, positive urine tests 
must be confirmed with serum testing.)
f:
Digital 12-lead ECG to be obtained after 5 minutes of rest in the supine position and in triplicate at least 1-2 minutes apart (see Section 6.6 for additional information). On Days 0 
and 28 to be obtained 5 minutes after the completion of infusion. Day 12 ECG will be collected only if the visit is conducted at the study site.
g: Serology: Testing at Day 56 will not be done for any subject whose baseline titer is below the level of detection. If the Day 56 results are greater than 30% below the baseline 
value, or if the subject falls below the level of detection, the subject will be re-tested at 1 month after the Follow-Up visit (approximately 2 months after the subject’s last dose); if 
still below the baseline value (or level of detection), the subject will be re-tested after another month (3 months after last dose). Any subject whose baseline value for tetanus or 
VZV was above the detectable level at baseline, and is not within 30% of the baseline value or is below the detectable level on Day 56 and upon 2 retests (2 and 3 months 
following last dose of SYNT001), will be referred to their primary care physician for further management. See Section 6.7.3 for additional information.
h: PK: Starting on Days 0 and 28, serum samples will be collected just prior to the start of study drug infusion (pre-dose), and at 5 minutes and 2, 4, 6, 24, and 48 hours after the 
end-of-study drug infusion. Additional samples will be collected on Days 5 and 33. See Section 6.7.4 for additional information. 
i:
Immunogenicity: Blood samples will be collected pre-dose when collected on dosing days.  See Section 6.7.6 for additional information.
j:
Prior to study drug infusion, SYNT001 drug product is to be diluted in Dextrose 5% in Water (D5W) to a total volume of 250 mL and administered intravenously over 1 hour 
using a 0.2-micron, inline filter.  See Section 9 for additional information.
k: Immunoglobulins (IgG, IgA, IgM) and IgG subtypes (IgG 1-4): Collected for measurements of IgG, IgG subtypes (IgG1-4), IgA, and IgM at every visit. On Days 0, 7, 14, 21,
and 28, samples are collected prior to infusion of study drug. See Section 6.7.5 for additional information
l:
Exploratory PD samples (C3 and AECA): collected pre-dose when collected on dosing days. See Section 6.7.5 for complete information.
m: Samples to be collected and stored; pending review of clinical and pharmacodynamics assessments
n: Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B cells
o: Photographs of active lesions taken prior to first dose on Day 0.  Follow-up photographs will be taken at Days 33 and 56.  Subjects who begin a steroid taper will have additional 
photographs taken at the clinic visit during which the decision to begin the taper is made.
p: Visit Days 5, 12 and 19 may be conducted via at-home nursing in lieu of a subject visit to the study site.
q: Extended follow-up visits will occur only if additional testing for anti-tetanus and/ or anti-VZV titers are required.  These visits will occur as needed at approximately 2 months 
post last dose and 3 months post last dose.
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Table 2:
Timing Window Allowances for PK/PD Sampling, ECG, and Vital Sign Measurements
Pharmacokinetic and Pharmacodynamic Sampling
Timepoint
Tolerance Window
0 hour
−240 min to 0 hour
5 minutes post end-of-infusion
± 5 minutes
2, 4, & 6 hours post end-of-infusion
± 15 minutes
24 hours post end-of-infusion
± 60 minutes
48 hours post end-of-infusion 
± 120 minutes
ECG
Timepoint
Tolerance Window
5 minutes post end-of-infusion
± 10 minutes
Vital Signsa
Timepoint
Tolerance Window
0 hour
−240 min to 0 hour
15, 30, and 45 minutes after start of infusion
± 5 minutes
60 minutes after start of infusion
± 10 minutes
30, 60 and 120 minutes post end-of-infusion
± 10 minutes
a:  Vital signs to include blood pressure, pulse rate, respiratory rate, oral temperature, and pulse oximetry.
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TABLE OF CONTENTS
PROCEDURES IN CASE OF EMERGENCY...................................................................3 
INVESTIGATOR SIGNATURE.........................................................................................4 
1 
SYNOPSIS..................................................................................................................5 
LIST OF ABBREVIATIONS............................................................................................24 
2 
BACKGROUND AND RATIONALE.....................................................................26 
2.1 
Study Rationale................................................................................................27 
2.2 
Selection of Doses in this Study ......................................................................27 
2.3 
Compliance Statement .....................................................................................28 
3 
STUDY OBJECTIVES.............................................................................................29 
3.1 
Primary Objective............................................................................................29 
3.2 
Secondary Objectives.......................................................................................29 
3.3 
Exploratory Objectives ....................................................................................29 
4 
STUDY DESIGN......................................................................................................30 
4.1 
Study Sites .......................................................................................................30 
4.2 
Study Endpoints...............................................................................................30 
4.3 
Overview of Study Design...............................................................................31 
4.4 
Randomization and Blinding ...........................................................................33 
5 
STUDY POPULATION...........................................................................................34 
5.1 
Target Population.............................................................................................34 
5.2 
Inclusion Criteria .............................................................................................34 
5.3 
Exclusion Criteria ............................................................................................35 
6 
STUDY PROCEDURES ..........................................................................................37 
6.1 
Informed Consent.............................................................................................37 
6.2 
Demographics and Medical History ................................................................37 
6.3 
Physical Examination.......................................................................................37 
6.4 
Pemphigus Disease Area Index (PDAI) Scoring.............................................37 
6.5 
Vital Sign Measurements.................................................................................37 
6.6 
12-Lead Electrocardiogram (ECG)..................................................................38 
6.7 
Clinical Laboratory Measurements..................................................................39 
6.7.1 
Pregnancy Testing................................................................................40 
6.7.2 
Virology...............................................................................................40 
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6.7.3 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing40 
6.7.4 
Pharmacokinetics (PK) Sampling........................................................41 
6.7.5 
Pharmacodynamic Sampling ...............................................................41 
6.7.6 
Immunogenicity Testing......................................................................42 
6.8 
Study Drug Administration..............................................................................43 
6.9 
Prior and Concomitant Medications ................................................................43 
6.10 
Adverse Event Assessments ............................................................................43 
6.11 
Photographs......................................................................................................44 
6.12 
Skin Biopsy......................................................................................................44 
7 
STUDY ASSESSMENTS ........................................................................................45 
7.1 
Screening Period: Day -14 to Day -1...............................................................45 
7.2 
Enrollment and First Treatment: Day 0 ...........................................................45 
7.3 
Follow-up: Day 1.............................................................................................47 
7.4 
Follow-up: Day 2.............................................................................................47 
7.5 
Follow-up: Day 5.............................................................................................48 
7.6 
Treatment Day 7 (Dose 2)................................................................................48 
7.7 
Dose 2 Follow-up Day 12................................................................................49 
7.8 
Treatment Day 14 (Dose 3)..............................................................................49 
7.9 
Dose 3 Follow-up Day 19................................................................................51 
7.10 
Treatment Day 21 (Dose 4)..............................................................................51 
7.11 
Treatment Day 28 (Dose 5)..............................................................................52 
7.12 
Follow-up Day 29 ............................................................................................53 
7.13 
Follow-up Day 30 ............................................................................................54 
7.14 
Follow-up Day 33 ............................................................................................54 
7.15 
Follow-up Day 42 ............................................................................................55 
7.16 
Follow-up Day 56 (End-of-Study) or Early Termination Visit .......................55 
7.17 
Extended Follow-up Visits ..............................................................................56 
8 
REMOVING SUBJECTS FROM STUDY ..............................................................57 
8.1 
Subject Withdrawal..........................................................................................57 
8.2 
Study Discontinuation......................................................................................58 
8.3 
Replacements ...................................................................................................58 
8.4 
Stopping Rule...................................................................................................58 
8.4.1 
Dose-Escalation Stopping Rule ...........................................................58 
8.4.2 
Study Stopping Rule ............................................................................59 
8.4.3 
Individual Stopping Rule.....................................................................59 
9 
STUDY DRUG.........................................................................................................60 
9.1 
SYNT001.........................................................................................................60 
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9.2 
Cohort Dosing..................................................................................................60 
9.3 
Timing of Dosing.............................................................................................60 
9.4 
Identity of Investigational Products.................................................................60 
9.5 
Investigational Product Retention at Study Site ..............................................61 
9.6 
Warnings and Precautions................................................................................61 
9.6.1 
Infusion Reaction.................................................................................61 
9.6.2 
Potential Immune Effects.....................................................................66 
10 
CONCOMITANT MEDICATION AND TREATMENT........................................67 
11 
SAFETY ...................................................................................................................69 
11.1 
Safety Parameters.............................................................................................69 
11.2 
Adverse Event Definition ................................................................................69 
11.3 
Evaluating Adverse Events..............................................................................70 
11.3.1 
Serious Adverse Events .......................................................................70 
11.3.2 
Overdose ..............................................................................................71 
11.3.3 
Non-Serious Adverse Events...............................................................71 
11.3.4 
Protocol-Related Adverse Events ........................................................71 
11.3.5 
Assessment of Causality ......................................................................71 
11.3.6 
Recording Adverse Events...................................................................72 
11.3.7 
Planned Hospitalization .......................................................................72 
11.3.8 
Reporting Pregnancies .........................................................................73 
11.3.9 
Serious Adverse Event Reporting........................................................73 
11.3.9.1 Governing Regulatory Requirements ..................................................73 
11.3.9.2 Time Frame for Reporting ...................................................................74 
11.3.9.3 Information to be Provided by the Investigator...................................75 
11.3.10 Regulatory Reporting...........................................................................76 
11.3.11 Follow-up Information on a Serious Adverse Event (SAE)................77 
11.4 
Other Safety Considerations ............................................................................77 
11.4.1 
Laboratory Data ...................................................................................77 
11.4.2 
Medication Errors ................................................................................77 
11.4.3 
Follow-Up of Adverse Events .............................................................77 
11.5 
Safety Monitoring for Dose Escalation............................................................78 
12 
STATISTICAL CONSIDERATIONS......................................................................79 
12.1 
General Design.................................................................................................79 
12.2 
Sample Size Justification.................................................................................79 
12.3 
Statistical Considerations.................................................................................79 
12.3.1 
Study Populations ................................................................................79 
12.3.2 
Subject Accountability, Demographics, and Baseline Characteristics 80 
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12.3.3 
Concomitant Medications....................................................................80 
12.4 
Planned PK Analysis........................................................................................80 
12.5 
Safety Data.......................................................................................................81 
12.6 
Pharmacodynamic/Activity Data.....................................................................81 
12.7 
Immunogenicity Data.......................................................................................81 
12.8 
Interim Analysis...............................................................................................82 
13 
DATA QUALITY ASSURANCE............................................................................83 
14 
STUDY ADMINISTRATION..................................................................................84 
14.1 
Study Administrative Structure........................................................................84 
14.2 
Ethical Conduct of the Study...........................................................................84 
14.3 
Informed Consent (ICF)...................................................................................84 
14.4 
Institutional Review Board ..............................................................................85 
14.5 
Dose Escalation Committee.............................................................................85 
14.6 
Future Use of Subject Samples........................................................................86 
15 
CONDITIONS FOR MODIFYING THE PROTOCOL...........................................87 
16 
CONDITIONS FOR TERMINATING THE STUDY .............................................88 
17 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING .......................89 
17.1 
Investigator’s Files and Retention of Documents............................................89 
17.2 
Source Documents and Background Data .......................................................89 
17.3 
Audits and Inspections.....................................................................................90 
17.4 
Electronic Case Report Forms .........................................................................91 
18 
MONITORING THE STUDY..................................................................................92 
19 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS...93 
20 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS............94 
21 
REFERENCES .........................................................................................................95 
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LIST OF TABLES
Table 1: 
Study Assessments.................................................................................... 16 
Table 2: 
Timing Window Allowances for PK/PD Sampling, ECG, and Vital Sign 
Measurements ........................................................................................... 18 
Table 3: 
Clinical Laboratory Panels........................................................................ 39 
Table 4: 
Pharmacodynamic/ Activity Assessments ................................................ 42 
Table 5: 
Grading and Management of Allergic or Infusion-Related Reactions ..... 65 
Table 6 :  
Study Administrative Structure................................................................. 84 
LIST OF FIGURES
Figure 1:  Management of Mild (Grade 1) to Moderate (Grade 2) Infusion Reactions.... 63 
Figure 2:  Management of Severe (Grade 3 or higher) Infusion Reactions...................... 64 
LIST OF APPENDICES
Appendix A: NCI CTCAE, Version 4.03......................................................................... 96 
Appendix B: Pemphigus Disease Area Index................................................................... 97 
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LIST OF ABBREVIATIONS
ADA
Anti-drug antibodies
AE
Adverse event
AECA
Anti-epithelial cell antibody
ALT
Alanine aminotransferase
ANA
Antinuclear antibody
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic chemical
AUC0-24
Area under the plasma concentration-time curve from pre-dose (time 0) to 24 hours post-dose
AUC0-∞
Area under the plasma concentration-time curve from pre-dose (time 0) to infinity
BLQ
Below the limit of quantification 
BMI
Body mass index
BUN
Blood urea nitrogen
CAR-T
Chimeric antigen receptor and T-cell
CFR
Code of Federal Regulations
C3
Complement component 3
CBC
Complete blood count
CIC
Circulating immune complexes
CIDP
Chronic inflammatory demyelinating polyneuropathy
Cmax
Maximum plasma concentration determined directly from the concentration-time profile
CRO
Contract research organization
CV
Coefficient of variation
CVID
Common variable immune deficiency
DEC
Dose escalation committee
D5W
Dextrose 5% in Water
DIF
Direct immunofluorescence
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
ESR
Erythrocyte sedimentation rate
FcGR2a
Fc Gamma R2a receptor
FcRn
Neonatal Fc receptor
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
IC
Immune complex
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ICF
Informed consent form
ICH
International Conference on Harmonization
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgG1-4
Immunoglobulin G1-G4
IgM
Immunoglobulin M
IL-12
Interleukin 12
IND
Investigational new drug
IRB
Institutional review board
ITT
Intent-to-treat
IUD
Intrauterine devices
IV
Intravenous
IVIG
Intravenous immunoglobulin
MedDRA
Medical Dictionary for Regulatory Activities
NHL
Non-Hodgkin lymphoma
PD
Pharmacodynamics
PE
Physical examination
PK
Pharmacokinetic
RBC
RNAseq
Red blood cells
RNA sequencing
QTcF
Corrected QT interval using Fridericia's formula
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical Analysis System
SD
Standard deviation
SNP
Single nucleotide polymorphism
SOC
System Organ Class
SOP
Standard operating procedures
SYNT001
A humanized, affinity matured IgG4-kappa monoclonal antibody
t1/2
Half-life
TEAE
Treatment-emergent adverse event
Tmax
Observed time to reach peak plasma concentration
TNF
Tumor necrosis factor
ULN
Upper limit of normal
UNS
Unscheduled
VZV
Varicella-zoster virus
WAIHA
Warm antibody autoimmune hemolytic anemia
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
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2
BACKGROUND AND RATIONALE
SYNT001, a humanized, affinity-matured IgG4-kappa monoclonal antibody (mAb), blocks IgG 
and IgG immune complex (IC) interactions with the neonatal Fc receptor (FcRn) and thereby the 
major functions of FcRn in protecting IgG and IgG ICs from degradation and their role in 
downstream signaling events. Specific and high affinity blockade of FcRn with SYNT001 has 
been shown to increase the catabolism of IgG and IgG IC in healthy volunteers. This predicts 
that SYNT001 will also accelerate degradation of endogenous circulating IgG autoantibodies and 
IgG-antigen IC specifically involved in the pathogenesis of autoimmunity.  Blocking FcRn 
interactions with IgG-containing ICs further predicts that SYNT001 will have consequences for 
innate and adaptive cellular immunity. In the first instance, blocking multimeric IgG IC 
interactions with FcRn within antigen-presenting cells will result in inhibition of IC-stimulated 
inflammatory cytokine production and release by these cells. In addition, as FcRn determines 
the intracellular itinerary of IgG ICs within and among compartments important in cellular 
immunity, it is anticipated that SYNT001 will block antigen processing and presentation of 
antigens contained within IC that otherwise lead to CD8+ and CD4+ T cell activation. Thus, 
SYNT001 will specifically target immune functions associated with IgG that are involved in 
certain autoimmune conditions and dismantle their ability to cause disease.
SYNT001 targets key mechanisms contributing to pathology in a variety of IgG-mediated 
autoimmune disorders, including warm antibody autoimmune hemolytic anemia (WAIHA), 
pemphigus, and chronic inflammatory demyelinating polyneuropathy (CIDP).  
While current treatments for certain autoimmune disorders, including high-dose steroids, 
immunosuppressants, intravenous immunoglobulin (IVIG), plasmapheresis, and anti-CD20 
monoclonal antibodies (mAbs), such as rituximab, can be effective, they are associated with 
significant adverse effects, as well as delayed or non-durable responses. 
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous 
membranes. Autoantibodies have been shown to play an important pathogenic role in the 
mucosal and cutaneous manifestations in patients with pemphigus. Administration of SYNT001, 
which significantly decreases total IgG, including a corresponding decrease in the level of the 
pathogenic autoantibodies and the ICs to which they are associated, may lead to a decrease in the 
mucosal and cutaneous manifestations in patients with pemphigus. Moreover, the ability of 
SYNT001 to reduce circulating immune complexes (CICs) and the associated innate and 
adaptive immune responses may allow for further sustained disease modification.
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2.1
Study Rationale
This study is being conducted to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD) and immunogenicity of intravenous (IV) SYNT001 as well as its 
effects on pemphigus disease activity markers.
2.2
Selection of Doses in this Study 
The planned dose levels of SYNT001 for this Phase 1b safety and proof-of-concept study of 10 
mg/kg and 30 mg/kg were selected from careful review of the safety, tolerability, and PD effect 
on total IgG levels after single and repeat dosing of SYNT001 in non-human primates (NHPs), 
as well as the safety, tolerability, and PD effect on total IgG levels after single ascending doses 
of SYNT001 in healthy volunteers. In addition, further consideration was given to the desired 
level of FcRn blockade to achieve suppression of IgG to a range that has been previously 
correlated with disease remission. Further, we considered the potential effects of inhibiting FcRn 
function as they relate to immune complex associated innate and adaptive immunity in choosing 
these dose levels based upon exploratory studies of a single ascending dose of SYNT001 in 
healthy volunteers. From the NHP studies, single doses of SYNT001 produced a dose-dependent 
decrease in total IgG and a further decrease was seen with repeated weekly doses up to a 
maximum 70% reduction at 100 mg/kg. This magnitude of total IgG reduction is approaching the 
expected maximal effect of 100% inhibition of FcRn function based on murine studies also 
performed by Syntimmune and others [Roopenian 2003, Nixon 2015]. In the recently completed 
Phase 1a trial with SYNT001 in healthy volunteers a single dose caused a maximum average 
50% drop in total IgG with IV dosing at 30 mg/kg. Based on the NHP studies further reductions 
are expected following multiple dosing. A comparable decrease in pathogenic autoantibodies is 
also anticipated.
In the NHP studies, relevant adverse effects, mild-to-moderate infusion reactions, were observed 
only after the third weekly IV administration, concurrent with the development of anti-SYNT001 
antibodies. In the recently completed Phase 1a healthy male volunteer study, the doses of 
SYNT001 up to and including 30 mg/kg have been well tolerated. There were no dose limiting 
toxicities, serious adverse events, or any other safety concerns identified.  No AEs were observed 
in the 1 and 3 mg/kg dose cohorts. A single Grade 2 AE was observed; a headache in the 10 
mg/kg cohort, treated with acetaminophen. Other subjects had mild (Grade 1) AEs at 10 mg/kg. 
In Cohort 4 (30 mg/kg), 5 subjects received SYNT001. All five subjects experienced AEs; all 
were mild (Grade 1), transient and resolved spontaneously without intervention. Therefore, it is 
anticipated that the doses selected for this study should be well tolerated and have clinically 
relevant PD effects in patients with chronic pemphigus (vulgaris or foliaceus). For a summary of 
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findings from the single dose, clinical study in healthy subjects and further details on the 
nonclinical findings, please refer to the SYNT001 Investigator’s Brochure. 
2.3
Compliance Statement
This study will be conducted in compliance with Good Clinical Practice (GCP), including the 
International Conference on Harmonisation (ICH) Guidelines and FDA regulations, consistent 
with the principles outlined in the Declaration of Helsinki. In addition, the Investigator agrees to 
adhere to all applicable local laws and regulatory requirements relevant to the use of new 
therapeutic agents.
The study will be conducted in compliance with the protocol. The appropriate Institutional 
Review Boards (IRBs) must approve the protocol, any amendments, and the subject informed 
consent form (ICF) prior to implementation. 
Freely given written informed consent must be obtained from every subject prior to participation 
in this clinical trial. As part of this procedure, the Investigator must explain orally and in writing 
the nature, duration, and purpose of the study, and the action of the drug in such a manner that 
the study subject is aware of the potential risks, inconveniences, or AEs that may occur.  The
study subject should be informed that he/she is free to withdraw from the study at any time.  
He/she will receive all information that is required by federal regulations and ICH guidelines.  
The Investigator or designee will provide the Sponsor with a copy of the IRB-approved informed 
consent form prior to the start of the study. The rights, safety, and well-being of participating 
subjects are the most important considerations and should prevail over interests of science and 
society.
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct or 
fraud (e.g., loss of medical licensure, debarment).
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3
STUDY OBJECTIVES
3.1
Primary Objective
The primary objective of this study is to evaluate the safety and tolerability of 5 once-weekly IV 
infusions of SYNT001 at different dose levels in subjects with chronic pemphigus (vulgaris or 
foliaceus).
3.2
Secondary Objectives
The secondary objectives of this study are as follow:
•
To determine the PK of SYNT001 following 5 once-weekly 1-hour IV infusions at 
different dose levels
•
To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the 
following PD biomarkers:
o
Immunoglobulins: IgG, IgG subtypes (IgG1-4), IgA, IgM
o
Albumin
•
To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the 
following disease activity markers:
o
Serum anti-desmoglein (Dsg) (1 and 3) antibody levels
o
Pemphigus Disease Area Index (PDAI)
•
To assess immunogenicity (anti-SYNT001 antibodies)
3.3
Exploratory Objectives
The exploratory objectives of this study are as follow:
•
To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the 
following biomarkers, including:
o
Serum anti-epithelial cell antibody (AECA) levels by indirect immunofluorescence
o
Circulating immune complexes (CIC)
o
Complement component 3 (C3)
o
Exploratory biomarkers (FCGR2A single nucleotide polymorphism-SNP, RNAseq, 
urine IgG)
o
Immune phenotyping by flow cytometry for CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B cells
o
SYNT001 levels in skin biopsies (optional)
•
To characterize corticosteroid use during the study
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4
STUDY DESIGN
4.1
Study Sites
This study will be conducted at approximately 10 sites in the United States (US).
4.2
Study Endpoints
Primary Outcome Measures: Assessment of safety data (adverse events [AEs], serious 
adverse events [SAEs], vital sign measurements, ECGs and clinical laboratory tests) will be the 
primary safety measure.  
Secondary Outcome Measures
Pharmacokinetics:
•
Half-life (t1/2), maximum plasma concentration determined directly from the 
concentration-time profile (Cmax), observed time to reach peak plasma concentration 
(Tmax), area under the plasma concentration-time curve from pre-dose (time 0) to 
24 hours post-dose (AUC0-24), and area under the plasma concentration-time curve 
from pre-dose (time 0) to infinity (AUC0-∞)
PD Biomarkers:
•
Ig Assessments: Serial assessments of total IgG and IgG subtypes (IgG1-4)
o
Serial assessments of total IgG and IgG subtypes (IgG1-4)
o
IgA levels
o
IgM levels
•
Albumin levels
Disease activity markers:
•
Serum anti-desmoglein (Dsg) (1 and 3) antibody levels
•
Pemphigus Disease Area Index (PDAI) scores
Immunogenicity:
•
Anti-SYNT001 antibodies
Exploratory Outcome Measures
Biomarkers, including:
•
CIC
•
C3
•
Serum AECA levels
•
Exploratory biomarkers (FCGR2A SNP, RNAseq, urine IgG)
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•
Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, 
CD3+CD8+ T, monocytes, NK cells and B cells
•
SYNT001 levels in skin biopsies (optional)
Concomitant Treatments
•
Corticosteroid use
Further details on the statistical and analytical plan for these endpoints are available in 
Section 12, Statistical Considerations.
4.3
Overview of Study Design
This will be a multicenter, open-label study to assess the safety, tolerability, activity, PK, PD, 
and immunogenicity of 5 once-weekly IV infusions of SYNT001 to subjects with chronic 
pemphigus (vulgaris or foliaceus).
Planned doses of SYNT001 to be studied are 10 mg/kg and up to 30 mg/kg.  Two cohorts of 8 
eligible subjects each will receive 5 once-weekly 60-minute infusions of SYNT001 10 mg/kg or 
up to 30 mg/kg. Based on review of safety, PD, and clinical outcomes of the first cohort, the dose 
for the second cohort may be adjusted, but with a maximum dose of 30 mg/kg.  Based on review 
of safety, PD and clinical outcomes from these 2 cohorts, a third cohort of up to 8 subjects may 
be treated at another dose, with a maximum dose of 45 mg/kg, but may also be lower than 10 
mg/kg or between 10 and 30 mg/kg, inclusive.
Cohort
No. of 
Subjects
Dose
1
8
SYNT001 10 mg/kg
2
8
SYNT001 30 mg/kg
Cohorts will be dosed sequentially beginning with Cohort 1. The first 2 subjects will be dosed at 
least 24 hours apart. A review of the 24-hour safety data for the first subject will be performed 
to ensure that there are no overt safety concerns before dosing the second subject. A review of 
the 7-day safety data for the first 2 subjects will be performed prior to dosing the remaining 6 
subjects in the cohort. This evaluation will include a review of AE/SAE reports, vital sign 
assessments, physical examinations, ECGs and clinical laboratory testing.  The seriousness, 
severity, and relatedness of AEs/SAEs will also be considered in the safety evaluation. Safety 
data will be reviewed on a continuous basis throughout the study. All data through Day 42
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(2 weeks after the last subject’s last dose in Cohort 1) will be reviewed before Cohort 2 is 
initiated. Cohort 2 and Cohort 3, if added, will be dosed per the same schedule.
Safety evaluations will be conducted by a dose escalation committee (DEC). The DEC will 
consist of the Medical Monitor, an Independent Clinical Expert and a Syntimmune Medical 
Officer. To assist in the safety assessments, the DEC may request that Investigators, other 
experts, or members within their organizations review the data and participate in the 
discussions.  Dosing and dose escalation will proceed if the DEC has determined that it would be 
safe and appropriate to do so. In addition, over the course of the study, the DEC will review any 
drug-related SAEs to determine if modifications to the study or other measures are necessary to 
ensure the safety of the subjects.
On days where study drug is administered, vital sign and pulse oximetry measurements will be 
collected immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; 
at completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the 
infusion. 
On Days 0 and 28, PK blood samples will be collected prior to infusion start and then over the 
subsequent 48 hours.  Subjects will remain at the clinic through the 6-hour PK sample collection 
and will return to the clinic for the 24- and 48-hour collections. Additional samples will be 
collected on Days 5 and 33.
On Day 0 photographs will be taken of active lesions.  Follow-up photographs will be taken of 
the same areas on Days 33 and 56. If a subject begins a steroid taper, additional photographs 
will be taken at the clinic visit during which the decision to begin the taper is made.
Subsequent visits will occur on Days 1, 2, 5, 7, 12, 14, 19, 21, 28, 29, 30, 33, and 42 for safety 
assessments, study drug dosing, sample collections, and other study procedures.
Subjects also will return to the clinic on Day 56 (28 days after receiving their last dose of study 
drug) for an End-of-Study/Follow-Up visit.
See Table 1 for a schedule of all study events.  To assess safety and tolerability, subjects will 
undergo physical examinations (PEs; including weight), vital sign measurements, clinical 
(safety) laboratory tests, AE assessments, concomitant medication assessments, and 
electrocardiograms (ECG).
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Note:  No vaccinations may be given from within 2 weeks of screening until 2 months following 
the last dose of study drug.
4.4
Randomization and Blinding
This is an open-label study.
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5
STUDY POPULATION
5.1
Target Population
This study will be conducted in approximately 16 male and female subjects (2 cohorts of 8 
subjects each) with a confirmed diagnosis of pemphigus (vulgaris or foliaceus); however, a third 
cohort of up to 8 subjects may be added. Subjects will be enrolled only once in the study and 
will not be included in subsequent dosing cohorts. Subjects who withdraw for any reason other 
than an AE and who do not receive study drug or have only received one dose of study drug may 
be replaced, up to one subject per cohort. Subjects who do not receive all doses of study drug 
will continue to be followed through 28 days after their last dose. The maximum number of 
subjects who may be enrolled in this study is 27 (24 + up to 3 replacements, as necessary).
Within each dosing cohort, no more than 3 subjects may be enrolled with pemphigus foliaceus.
5.2
Inclusion Criteria
A subject must meet the following criteria to be eligible for the study:
1. Willing and able to read, understand and sign an informed consent form;
2. Male or female ≥ 18 years of age; 
3. Documented diagnosis of pemphigus vulgaris or foliaceus based on all 3 of the following
criteria:
a.
Documented clinical history consistent with pemphigus vulgaris or foliaceus 
(clinical presentation defined as mucosal and/ or skin lesions);
b.
Presence of Anti-Dsg 1 or 3 antibodies above the upper limit of normal;
c.
History of at least one positive tissue based test (biopsy, DIF)
4. Active disease: Lesions lasting > 2 weeks, and 3 active lesions in skin or mucosa or 2 
active lesions with at least one being a skin lesion > 1 cm diameter:
a.
If treated with rituximab or other anti-CD20 antibodies, last dose > 12 months 
prior to screening;
b. If being treated with other immunosuppressants (i.e., azathioprine, mycophenolate 
mofetil or cyclosporine), must be on stable dose (< 10% change in dose) for 
6 weeks prior to screening;
c.
If being treated with corticosteroids, must be ≤1mg/kg/day and stable (< 10% 
change in dose) for 2 weeks prior to screening;
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d. Allowed topical therapies for pemphigus lesions upon entering the study include
petroleum jelly or Aquaphor® for the skin or chlorhexidine for the mouth 
5. Body mass index (BMI) 18.5 – 35.0 kg/m2;
6. Has a negative urine pregnancy test (for women of childbearing potential) documented 
prior to the first dose of study drug;    
7. Females of childbearing potential must agree to be abstinent or else use any two of the 
following medically acceptable forms of contraception (<1% per year failure rate) from 
the Screening Period through 60 days after the final study dose: oral contraceptive, 
condom with or without spermicidal jelly, diaphragm or cervical cap with spermicidal 
jelly, or intra-uterine device (IUD). A female whose male partner has had a vasectomy 
must agree to use one additional form of medically acceptable contraception. 
8. Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for 
at least 12 months do not require contraception during the study.
9. Males with female partners of childbearing potential, including males who are surgically 
sterile (post vasectomy), must agree to be abstinent or else use a medically acceptable 
form of contraception from the screening period through 60 days after the final study
dose.
5.3
Exclusion Criteria
A subject who meets any of the following criteria is ineligible for the study:
1. Unable or unwilling to comply with the protocol;
2. Active non-hematologic malignancy or history of non-hematologic malignancy in the 
3 years prior to screening (exclusive of non-melanoma skin cancer and cervical cancer in 
situ);
3. Positive for HIV or hepatitis C antibody; 
4. Positive for hepatitis B surface antigen;
5. Active infection or history of recurrent infections;
6. IVIG treatment within 60 days of screening;
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7. Received any cytotoxic (other than azathioprine) or mAb therapy in the 3 months prior to 
screening;
8. Any exposure to an investigational drug or device within 30 days prior to screening;
9. Plasmapheresis or immunoadsorption within 60 days of screening
10. Cellular therapy at any time prior to screening
11. Use of any immunosuppressive drugs apart from corticosteroids, azathioprine, 
mycophenolate mofetil, or cyclosporine within 3 months of screening;
12. Serum total IgG < 600 mg/dL;
13. Subject has any current medical condition that, in the opinion of the Investigator, may 
compromise their safety or compliance, preclude successful conduct of the study, or 
interfere with interpretation of the results (e.g., a significant pre-existing illness or other 
major comorbidity that the Investigator considers may confound the interpretation of the 
study results);
14. Any vaccination within 2 weeks of screening
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6
STUDY PROCEDURES
6.1
Informed Consent
All subjects must take part in the informed consent process.  Adequate time must be allowed for 
the subject to ask questions and make a voluntary decision.  No protocol-specific procedures, 
including screening procedures, are to be performed until the subject has signed and dated an 
IRB-approved ICF. Subjects may withdraw consent at any time. Participation in the study may 
be terminated at any time without the subject’s consent as determined by the Investigator.
6.2
Demographics and Medical History
Demographics (age, gender, race and ethnicity) and medical history will be obtained from the 
subject and recorded on the source document and eCRF.  Medical history will capture the 
subject’s current medical history (current disease processes), past medical status (past disease 
processes), history of surgery and concomitant treatments.
6.3
Physical Examination
A complete physical examination will be performed as outlined in Table 1. The complete PE 
will include measurements of weight (in kg) and height (in cm; height to be measured only at 
screening visit) and a review of the following body systems:
•
General appearance
•
Head, eyes, ears, nose, and throat
•
Neck
•
Respiratory
•
Cardiovascular
•
Abdomen
•
Neurologic
•
Extremities
•
Dermatologic
•
Lymphatic
Any abnormal and clinically significant findings from the PE must be recorded in the appropriate 
eCRF.  Findings at screening and Day 0 (pre-dose) will be recorded as medical history.
6.4
Pemphigus Disease Area Index (PDAI) Scoring
Pemphigus severity and disease activity will be measured using the PDAI. See Appendix B.
6.5
Vital Sign Measurements
Vital sign measurements will be collected after the subject has been sitting for 5 minutes.  Vital 
sign assessments will include measurements of sitting blood pressure (mm Hg), heart rate (beats 
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per minute), respiration rate (breaths per minute), oral temperature (Celsius).  Abnormal results 
are to be repeated after 5 minutes of rest.  Pulse oximetry (%) also is to be measured.  See 
Table 2 for timing window allowances with respect to measurement collection.
On Days 0, 7, 14, 21, and 28, vital sign measurements are to be obtained immediately prior to the 
infusion; 15, 30, and 45 minutes after the start of the infusion; at completion of the infusion; and 
30 minutes, 1 hour and 2 hours following completion of the infusion. Details on the 
management of mild to moderate and severe infusion reactions can be found in Figure 1 and 
Figure 2.  Abnormalities in vital sign measurements will be graded in severity per the NCI 
CTCAE scale Version 4.03.
Subjects should be seated quietly for at least 5 minutes in a chair with their backs supported, 
their feet flat on floor (legs uncrossed), and their arms bared on a hard surface, with the arm 
slightly abducted and bent, with palm up and the midpoint of upper arm at heart level.  Correct 
cuff and bladder size should be utilized and the same cuff and arm should be used per subject 
throughout study.
6.6
12-Lead Electrocardiogram (ECG)  
Digital 12-lead ECG measurements will be obtained at screening, on Days 0 and 28 at 5 minutes 
after the completion of the infusion and at the Day 56 (Follow-Up) Visit. Subjects who conduct 
their Day 12 visit at the investigative site, as opposed to an at-home nurse visit, will have an 
additional ECG performed.  ECGs are to be performed with the subject in a supine position 
having rested in this position for at least 5 minutes before each reading. ECGs are to be 
performed in triplicate, each 1 to 2 minutes apart.  See Table 2 for timing window allowances 
with respect to performing ECG.
The following ECG parameters will be collected: PR interval, RR interval, QRS interval, and QT 
interval.  The ECG findings will be evaluated by a qualified physician for the presence of 
abnormalities (qualitative assessment).  The physician will assess each ECG as normal, 
abnormal/not clinically significant, or abnormal/clinically significant.  
Normal QTcF is ≤450 msec.
Abnormalities in the ECG that appear following therapy or that result in clinical signs and 
symptoms are considered clinically significant for the purposes of this study and will be recorded 
on the AE eCRF.  
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6.7
Clinical Laboratory Measurements 
Collection time for all safety, PD, and exploratory labs are outlined in Table 1.
Laboratory testing (hematology, urinalysis, serum chemistry, virology, serology, pregnancy tests, 
PD samples, PK samples, and anti-drug antibody samples) will be performed using established 
methods by a central laboratory. Safety laboratory panels are defined as listed in Table 3. Blood 
and urine samples for hematology, serum chemistry, and urinalysis will be prepared using 
standard procedures. Results will be provided to the Investigator. Aliquots from the PK, 
biomarker and anti-drug antibody samples may be retained as back-up for additional testing as
necessary. Subjects will be in a seated or supine position during blood collection. Full clinical 
safety lab draws will be collected at Screening and on Days 0, 7, 14, 21, 28, 33, 42 and 56.  The 
total blood draw for each subject who completes the study at Day 56, will be approximately 311
mL. Please refer to the Laboratory Manual for more information.
Table 3:
Clinical Laboratory Panels
Hematology
Serum Chemistry
Urinalysis
•
CBC with differential
•
Erythrocyte Sedimentation Rate 
(ESR)
•
Albumin
•
Alkaline phosphatase
•
ALT
•
AST
•
BUN
•
Calcium
•
Carbon dioxide
•
Chloride
•
Creatinine
•
Glucose
•
LDH
•
Phosphorus
•
Potassium
•
Sodium
•
Total and direct bilirubin
•
Total protein
•
Uric acid
•
C-Reactive Protein
•
Appearance
•
Color
•
pH
•
Specific gravity
•
Ketones
•
Protein
•
Glucose
•
Nitrite
•
Urobilinogen
•
Blood/hemoglobin
•
Leukocyte esterase
•
Bilirubin
•
Microscopic examination of 
sediment: only if the results of 
the urinalysis dipstick evaluation 
are positive for 
blood/hemoglobin
Virology
•
Hepatitis C
•
Hepatitis B
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•
HIV
•
VZV
•
Tetanus
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; BUN = blood urea 
nitrogen; HIV = human immunodeficiency virus; LDH = lactate dehydrogenase; VZV = varicella-zoster virus
Abnormalities in clinical laboratory tests that are considered clinically significant are to be
recorded on the AE electronic case report form (eCRF) page.   Laboratory results will be graded 
using the NCI CTCAE, Version 4.03. If laboratory values constitute part of an event that meets 
criteria defining it as serious, the event (and associated laboratory values) must be reported as an 
SAE (see Section 11.3.1).
6.7.1
Pregnancy Testing
Pregnancy testing will be performed for women of childbearing potential at screening and prior 
to first dose of SYNT001 on Day 0 and Day 56 (urine or serum test is acceptable however, 
positive urine tests must be confirmed with serum testing.)
6.7.2
Virology
Testing for HCV antibody, hepatitis B surface antigen, and HIV antibody will be performed at 
screening.
6.7.3
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing
Samples for serum tetanus antibody and varicella-zoster virus antibody testing are to be collected 
at baseline (pre-dose, Day 0) and on Day 56 (Follow-Up visit). Testing at Day 56 will not be 
done for any subject whose baseline titer is below the level of detection. Specifically, if the 
baseline VZV titer is above the detectable level, but tetanus is not, only the VZV antibody titer 
will be tested on Day 56. If the Day 56 results are below the baseline value, defined as greater 
than 30% below the baseline value, or if the subject falls below the level of detection, the subject 
will be re-tested at 1 month after the Follow-Up visit (approximately 2 months after the subject’s 
last dose); if still below the baseline value (or level of detection), the subject will be re-tested 
after another month (3 months after last dose). Any subject whose baseline value for tetanus or 
VZV was above the detectable level at baseline, and is not within 30% of the baseline value or is
below the detectable level on Day 56 and upon 2 retests (2 and 3 months following last dose of 
SYNT001), will be referred to their primary care physician for further management.
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6.7.4
Pharmacokinetics (PK) Sampling
Starting on Days 0 and 28, serum samples will be collected just prior to the start of study drug 
infusion (pre-dose), at 5 minutes and 2, 4, 6, 24, and 48 hours after the end-of-study drug 
infusion. Additional samples will be collected on Days 5 and 33.  The actual time and date of 
each blood draw is to be recorded.  
Study drug concentration will be used to calculate the following PK parameters: t1/2, Cmax, Tmax,
AUC0-24, and AUC0-∞.
Detailed instructions for sample collection and preparation will be provided in a separate 
laboratory manual
6.7.5
Pharmacodynamic Sampling
PD samples will be collected for analyses throughout the study. On Days 0, 7, 14, 21, and 28,
samples should be collected prior to infusion of study drug. Measurements for albumin PD 
biomarkers will be derived from the clinical safety laboratory results.  Samples for each type of 
PD will be collected according to the schedule shown in Table 4.
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Table 4: Pharmacodynamic/ Activity Assessments
Parameter
Collection Timepoints
•
IgG, IgG subtypes (IgG1-4), IgA, IgM 
Screening, and Days 0, 1, 2, 5, 7, 12, 14, 19, 
21, 28, 29, 30, 33, 42, and 56
•
Circulating immune complexes (CIC)
Days 0, 5, 7, 12, 14, 19, 21, 28, 33, 42, and 
56
•
Albumin
Screening, and Days 0, 7, 14,21, 28, 33, 42, 
and 56
•
Anti-Dsg (1 and 3) antibody titer
Screening, Days 0, 7, 14, 33, and 56
•
Complement component 3 (C3)
•
Anti-epithelial cell antibody (AECA) levels by 
indirect immunofluorescence
Days 0, 14, 33, and 56
•
Exploratory biomarker (RNAseq, Urine IgG)
Days 0, 14, 33, and 56
•
Immune phenotyping by flow cytometry for 
measurement of CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B cells
Days 0 and 28
•
Exploratory biomarker (FCGR2A SNP)
Day 0
See Table 2 for timing window allowances with respect to measurement collection.
Detailed instructions for sample collection (including collection tubes) and preparation will be 
provided in a separate laboratory manual.
6.7.6
Immunogenicity Testing
Up to 4 serum samples will be collected for immunogenicity analyses.  Samples will be collected 
on Days 0 (pre-dose), 14, 28, and 56.
SYNT001 is being developed for the acute and chronic therapy of autoimmune disorders. 
Although SYNT001 is a humanized IgG4 monoclonal antibody, exposure to SYNT001 in 
clinical trials could result in the development of anti-drug antibodies (ADAs), with potential 
consequences ranging from neutralization or lessening of drug efficacy to safety consequences 
such as allergic reactions.  Testing will first detect binding ADAs, then, for all confirmed 
positive samples, there will be testing for neutralizing effects. 
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Detailed instructions for sample collection and preparation will be provided in a separate 
laboratory manual.
6.8
Study Drug Administration
Two cohorts of 8 eligible subjects each will receive 5 once-weekly 60-minute IV infusions of 
SYNT001 10 mg/kg or up to 30 mg/kg. SYNT001 will be given as a 250-mL IV infusion over 1 
hour using a 0.2-micron, inline filter. Based on review of safety data, as well as available and 
relevant PD results, and clinical outcomes of Cohort 1, a decision about proceeding with Cohort 
2 will be made.  Based on review of all safety data, available PD results, and clinical outcomes 
of these 2 cohorts, a third cohort of 8 subjects may be treated at another dose, with a maximum 
dose of 45 mg/kg, but may also be lower than 10 mg/kg or between 10 and 30 mg/kg, inclusive.
Cohort No.
Study Drug
Dose Level 
(mg/kg/dose)
1
SYNT001
10 mg/kg
2
SYNT001
30 mg/kg
See Section 9.1 for dosing schedule.  
6.9
Prior and Concomitant Medications
All medications a subject receives within 14 days prior to enrollment through the end of the 
study (Day 56) will be documented on the source document and eCRF.
Note:  No vaccinations may be given from within 2 weeks of screening until 2 months following 
the last dose of study drug.
6.10
Adverse Event Assessments
Information regarding the occurrence of AEs will be collected from the time the subject signs the 
informed consent form throughout their participation in the study, including a period of 28 days 
after study drug dosing.  Findings at screening and Day 0 (pre-dose) will be recorded as medical 
history.   Any known untoward event that occurs beyond the AE reporting period that the 
Investigator assesses as related to study drug also should be reported as an AE.
Clinical AEs will be graded using the NCI CTCAE, Version 4.03 (Appendix A).
Note: AEs resulting in a subject’s permanent discontinuation from the study, regardless of 
seriousness or relationship to study drug, MUST be promptly reported to the sponsor.
Additionally, subjects must be followed until return to normal and/or resolution of the AE.
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See Section 11 for more information.
6.11
Photographs
On Day 0 photographs will be taken of active lesions.  Follow-up photographs will be taken of 
the same areas on Days 33 and 56. Subjects who begin a steroid taper will have additional 
photographs taken at the clinic visit during which the decision to begin the taper is made. A
separate manual describing the procedures for taking photographs will be provided.
6.12
Skin Biopsy
Optional skin biopsy samples will be collected on Day 0 pre-dose and on Days 1, 2, 14, 33 and 
56 to analyze SYNT001 levels.
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7
STUDY ASSESSMENTS
7.1
Screening Period: Day -14 to Day -1
Informed consent must be obtained before any study-specific samples are taken or study-specific 
tests or evaluations are conducted. The following assessments at the screening visit are to occur 
within 14 days before dosing. Study eligibility will be based on satisfying all the study inclusion
and exclusion criteria. 
At the screening visit, information will be collected and subjects will have clinical evaluations as 
follows:
•
Informed consent (Section 6.1)
•
Medical history and demographic data (Section 6.2)
•
Review inclusion and exclusion criteria (Section 5.2, Section 5.3)
•
Complete PE, including height and weight (Section 6.3)
•
Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate,
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest
(Section 6.5)
•
12-Lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position)
(Section 6.6)
•
Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7)
•
Pregnancy test (Section 6.7)
•
Hepatitis and HIV screen (Section 6.7)
•
PD sample collection (Section 6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
Anti-Dsg (1 and 3) antibody titer
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
7.2
Enrollment and First Treatment: Day 0
Study Day 0 is defined as the date the subject is administered their first dose of study drug. On 
Day 0, subjects will be asked to come to the clinic and the following procedures will be 
performed prior to the first dose of study drug:
•
Complete physical exam (Section 6.3)
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5)
•
Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5)
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•
Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7)
•
Pregnancy test (Section 6.7)
•
Serum tetanus antibody and VZV antibody (Section 6.7)
•
PDAI Score (Section 6.4)
•
PK baseline sample collection (collected just prior to the start of the study drug infusion)
(Section 6.7)
•
Immunogenicity sample collection (collected just prior to the start of study drug infusion)
(Section 6.7)
•
PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
Anti-Dsg (1 and 3) antibody titer
•
CIC
•
C3
•
AECA
•
FCGR2A SNP
•
RNAseq
•
Urine IgG
•
Immune phenotyping
•
Optional skin biopsy (Section 6.12)
•
Photography (Section 6.11)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
After the preceding procedures and assessments are completed:
•
Study drug administration (record date and time of dose of study drug) (Section 9)
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion
and at completion of the infusion (Section 6.5)
•
Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion
and at completion of the infusion (Section 6.5)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
After administration of study drug, the following post treatment procedures and 
assessments will be performed:
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
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temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion;
abnormal results to be repeated after 5 minutes of rest (Section 6.5)
•
Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion
(Section 6.5)
•
PK sample collection at 5 minutes and 2, 4, 6 hours after the end-of-study drug infusion;
record collection date and time for each PK sample (Section 6.7)
•
12-Lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion (Section 6.6)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
7.3
Follow-up: Day 1
On Day 1 (24 hours ± 1 hour from end-of-infusion time on Day 0), the subject will return to the 
clinic and the following procedures are to be performed:
•
Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest
(Section 6.5)
•
PD sample collection (Section 6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
PK sampling (record collection date and time) (Section 6.7)
•
Optional skin biopsy (Section 6.12)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
7.4
Follow-up: Day 2
On Day 2 (48 hours ± 2 hours from end-of-infusion time on Day 0), the subject will return to the 
clinic and the following procedures are to be performed:
•
Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest
(Section 6.5)
•
PD sample collection (Section 6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
PK sampling (record collection date and time) (Section 6.7)
•
Optional skin biopsy (Section 6.12)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
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7.5
Follow-up: Day 5
On Day 5 (120 hours ± 4 hours from end-of-infusion time on Day 0), subjects may return to the 
clinic or be visited by at-home nurse, and the following procedures are to be performed:
•
Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest
(Section 6.5)
•
PK sampling (record collection date and time) (Section 6.7)
•
PD sample collection (Section 6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
CIC
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
7.6
Treatment Day 7 (Dose 2)
On Day 7 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion:
•
Complete physical exam (Section 6.3)
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5)
•
Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5)
•
PDAI Score (Section 6.4)
•
Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7)
•
PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
CIC
•
Anti-Dsg (1 and 3) antibody titer
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
After the preceding procedures and assessments are completed:
•
Study drug administration (record date and time of dose of study drug) (Section 9)
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion
and at completion of the infusion (Section 6.5)
•
Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion
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and at completion of the infusion (Section 6.5)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
After administration of study drug, the following post treatment procedures and 
assessments will be performed:
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion;
abnormal results to be repeated after 5 minutes of rest (Section 6.5)
•
Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion
(Section 6.5)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
7.7
Dose 2 Follow-up Day 12
On Day 12 (± 6 hours) the subject may will return to the clinic, or be visited by at-home nurse, 
and the following procedures are to be performed:
•
Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5)
•
PD sample collection (Section 6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
CIC
•
If visit performed at the study site: 12-Lead ECG to be obtained in triplicate (Section 6.6)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
7.8
Treatment Day 14 (Dose 3)
On Day 14 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion:
•
Complete physical exam (Section 6.3)
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5)
•
Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5)
•
PDAI Score (Section 6.4)
•
Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7)
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•
Immunogenicity sample collection (collected just prior to the start of study drug infusion)
(Section 6.7)
•
PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
Anti-Dsg (1 and 3) antibody titer
•
CIC
•
C3
•
AECA
•
RNAseq
•
Urine IgG
•
Optional skin biopsy (Section 6.12)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
After the preceding procedures and assessments are completed:
•
Study drug administration (record date and time of dose of study drug) (Section 9)
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion
and at completion of the infusion (Section 6.5)
•
Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion
and at completion of the infusion (Section 6.5)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
After administration of study drug, the following post treatment procedures and 
assessments will be performed:
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion;
abnormal results to be repeated after 5 minutes of rest (Section 6.5)
•
Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion
(Section 6.5)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
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7.9
Dose 3 Follow-up Day 19
On Day 19 (± 6 hours) the subject may return to the clinic, or be visited by an at-home nurse, and 
the following procedures are to be performed:
•
Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5)
•
PD sample collection (Section 6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
CIC
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
7.10
Treatment Day 21 (Dose 4)
On Day 21, (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion:
•
Complete physical exam (Section 6.3)
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5)
•
Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5)
•
PDAI Score (Section 6.4)
•
Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7)
•
PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
CIC
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
After the preceding procedures and assessments are completed:
•
Study drug administration (record date and time of dose of study drug) (Section 9)
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion
and at completion of the infusion (Section 6.5)
•
Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion
and at completion of the infusion (Section 6.5)
•
Concomitant medication assessment (Section 6.9)
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•
AE assessment (Section 6.10)
After administration of study drug, the following post treatment procedures and 
assessments will be performed:
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion;
abnormal results to be repeated after 5 minutes of rest (Section 6.5)
•
Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion
(Section 6.5)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
7.11
Treatment Day 28 (Dose 5)
On Day 28 (± 1 Day), subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion:
•
Complete physical exam (Section 6.3)
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5)
•
Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5)
•
Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7)
•
PDAI Score (Section 6.4)
•
PK sampling (collected just prior to the start of the study drug infusion; record collection 
date and time for each PK sample) (Section 6.7)
•
Immunogenicity sample collection (collected just prior to the start of study drug infusion)
(Section 6.7)
•
PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
CIC
•
Immune phenotyping
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
After the preceding procedures and assessments are completed:
•
Study drug administration (record date and time of dose of study drug) (Section 9)
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion
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and at completion of the infusion (Section 6.5)
•
Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion
and at completion of the infusion (Section 6.5)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
After administration of study drug, the following post treatment procedures and 
assessments will be performed:
•
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion;
abnormal results to be repeated after 5 minutes of rest (Section 6.5)
•
Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion
(Section 6.5)
•
PK sample collection at 5 minutes and 2, 4, 6 hours after the end-of-study drug infusion;
record collection date and time for each PK sample (Section 6.7)
•
12-Lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion (Section 6.6)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
7.12
Follow-up Day 29
On Day 29 (24 hours ± 1 hour from end-of-infusion time on Day 28), the subject will return to 
the clinic and the following procedures are to be performed:
•
Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest
(Section 6.5)
•
PD sample collection (Section 6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
PK sampling (record collection date and time) (Section 6.7)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
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7.13
Follow-up Day 30
On Day 30 (48 hours ± 2 hours from end-of-infusion time on Day 28), the subject will return to 
the clinic and the following procedures are to be performed:
•
Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest
(Section 6.5)
•
PD sample collection (Section 6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
PK sampling (record collection date and time) (Section 6.7)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
7.14
Follow-up Day 33
On Day 33 (120 hours ± 4 hours from end-of-infusion time on Day 28), subjects will return to 
the clinic and the following procedures are to be performed:
•
Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest
(Section 6.5)
•
Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7)
•
PDAI Score (Section 6.4)
•
PK sampling (record collection date and time) (Section 6.7)
•
PD sample collection (Section 6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
CIC
•
Anti-Dsg (1 and 3) antibody titer
•
C3
•
AECA
•
RNAseq
•
Urine IgG
•
Optional skin biopsy (Section 6.12)
•
Photography (Section 6.11)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
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7.15
Follow-up Day 42
On Day 42 (± 3 days), subjects will return to the clinic and the following procedures are to be 
performed:
•
Complete physical exam (Section 6.3)
•
Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest
(Section 6.5)
•
Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7)
•
PD sample collection (Section 6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
CIC
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
7.16
Follow-up Day 56 (End-of-Study) or Early Termination Visit
On Day 56 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed:
•
Complete physical exam (Section 6.3)
•
Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest
(Section 6.5)
•
Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7)
•
Pregnancy test (Section 6.7)
•
12-Lead ECG (to be obtained in triplicate after 5 minutes of rest in the sitting position)
(Section 6.5)
•
Serum tetanus antibody and VZV antibody; Testing at Day 56 will not be done for any 
subject whose baseline titer is below the level of detection. See Section 6.7.3 for 
additional information.  
•
Immunogenicity sample collection (Section 6.7)
•
PDAI Score (Section 6.4)
•
PD sample collection (Section 6.7)
•
IgG, IgG subtypes (IgG1-4), IgA, IgM
•
CIC
•
Anti-Dsg (1 and 3) antibody titer
•
C3
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•
AECA
•
RNAseq
•
Urine IgG 
•
Optional skin biopsy (Section 6.12)
•
Photography (Section 6.11)
•
Concomitant medication assessment (Section 6.9)
•
AE assessment (Section 6.10)
7.17
Extended Follow-up Visits
Extended follow-up visits will occur only if additional testing for anti-tetanus and/ or anti-VZV 
titers are required.  These visits will occur as needed at approximately 2 months post last dose 
and 3 months post last dose.  See Section 6.7.3.
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8
REMOVING SUBJECTS FROM STUDY
Every reasonable effort will be made to keep the subject in the study; however, if a subject is 
withdrawn from the study, every effort will be made by the Investigator to complete and report 
the reasons for withdrawal as thoroughly as possible.  The reason(s) for termination must be 
clearly documented on the appropriate page of the eCRF.  Once a subject discontinues from the 
study for any reason, every effort will be made to collect all clinical and laboratory data as 
scheduled for the Early Termination Visit (See Table 1). A termination eCRF must be 
completed for all enrolled subjects.
8.1
Subject Withdrawal 
A subject’s participation in the study may be prematurely discontinued for any of the following 
reasons: 
1. The subject wishes to withdraw from the study.
2. Request by a regulatory agency (e.g., Institutional Review Board).
3. Subject experiences a significant or intolerable AE.
4. The subject experiences a significant adverse change in vital signs, PE findings, or a
clinical laboratory parameter.
5. The subject has a need for a concomitant medication that is not permitted by the study 
protocol.
6. The subject experiences generalized impairment or mental incompetence that would result 
in the subject being unable to understand his or her participation in the study.
7. If, in the Investigator’s medical judgment, further participation would be injurious to the 
health and well-being of the subject, or is not in the best interest of the subject.
8. Administrative reasons, such as subject non-compliance or a major protocol violation.
Subjects who are withdrawn from this study due to an AE determined to be related to study drug 
are to be followed until there is either:
•
Resolution or stabilization of the AE determined to be related
•
The subject is lost to follow-up
•
The event is otherwise explained
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If there is a persistent AE contributing to discontinuation that is determined to be related to 
SYNT001, subjects must be followed with appropriate medical management until resolution or 
stabilization.
A reasonable effort should be made to contact any subject lost to follow-up during the study to
complete assessments and retrieve any outstanding data.  If the subjects are unreachable by 
telephone after three (3) attempts, the minimum of a registered letter should be sent requesting 
that contact be made with the Investigator to report survival information.
8.2
Study Discontinuation
Syntimmune Inc. has the right to terminate or to stop the study at any time.  Reasons for study 
discontinuation may include, but are not limited to the following: 
•
The incidence or severity of AEs in this or other related studies indicates a potential health 
hazard to subjects 
•
Subject enrollment is unsatisfactory
•
Drug supply issues
•
Excessive subject self-withdrawal
•
Significant protocol violations (e.g., violation of eligibility criteria, dosing errors, missing 
data for study endpoint analysis)
8.3
Replacements
Enrolled subjects withdrawn for a reason other than an AE will be replaced if they have not been 
dosed or have only received one dose of study drug at the time of discontinuation, up to one 
subject per cohort. Subjects who do not receive all doses of study drug will continue to be 
followed through 28 days after their last dose.  
8.4
Stopping Rule
8.4.1
Dose-Escalation Stopping Rule
Dose-limiting toxicity (DLT) will be defined generally as clinically significant, severe (Grade 3) 
AEs occurring in ≥2 subjects that are determined to be clinically significant and considered 
related to study drug.
If 2 or more subjects at any time in any cohort (8 total subjects per cohort) have Grade 3 AEs 
that are determined to be clinically significant and considered to be related to study drug, dosing 
will be halted within that cohort and no further dose-escalation will occur. If the dose-escalation 
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stopping rule is met in Cohort 1 (10 mg/kg) all safety data and all available pharmacodynamics 
will be reviewed and a cohort may be added at a dose at least 50% lower than the 10 mg/kg dose.  
If the stopping rule is not met after Cohort 1, dose-escalation may proceed up to a maximum of 
30 mg/kg.  If the dose-escalation stopping rule is met in Cohort 2, all safety data and all available 
pharmacodynamics will be reviewed and a cohort may be added at a dose a minimum of 30% 
lower than the Cohort 2 dose. If the stopping rule is not met after Cohort 2, dose-escalation may 
proceed up to a maximum of 45 mg/kg; however, this cohort may also receive a dose equal to or 
less than 30 mg/kg based on evaluation of all safety and pharmacodynamic data.
8.4.2
Study Stopping Rule
If any subject experiences a life-threatening AE (Grade 4) that is considered to be related to 
study drug, further dosing in all enrolled subjects will be suspended until the DEC has evaluated 
the event and determined the appropriate course of action.  At any time during the study, the 
study may be discontinued if the DEC determines that further drug exposure would pose an 
undue risk to subjects.
8.4.3
Individual Stopping Rule
Dosing for any individual subject will be discontinued (i.e., no further study drug will be given
to that subject) if the subject experiences any study drug-related SAE or any study drug-related 
non-SAE adverse event that, in the judgement of the Investigator and Medical Monitor suggest 
that it could be unsafe to administer further study drug to that subject.  Additionally, a subject 
may be discontinued from further treatment with study drug, at the discretion of the Investigator 
with consultation with the Medical Monitor, if they require a significant increase in dose(s) of 
anti-pemphigus medication(s) for the management of pemphigus.
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9
STUDY DRUG
For detailed information regarding SYNT001 preparation and administration, refer to the 
Pharmacy Manual.
9.1
SYNT001
SYNT001 is provided in vials containing 5 mL SYNT001 (extractable volume) at a nominal 
concentration of 50 mg/mL. The product is supplied as a liquid at pH 6.5 ± 0.5. SYNT001 is 
diluted in Dextrose 5% in Water (D5W) to prepare the solution for infusion.  SYNT001 will be 
infused via IV in 250 mL over 1 hour using a 0.2-micron, inline filter.  
Two cohorts of 8 eligible subjects each will receive 5 once-weekly 60-minute infusions of 
SYNT001 in planned doses of 10 mg/kg or 30 mg/kg. Based on review of safety, PD, and 
clinical outcomes of these two cohorts, a third cohort of up to 8 subjects may be treated at 
another dose, with a maximum dose of 45 mg/kg, but may also be lower than 10 mg/kg or 
between 10 and 30 mg/kg, inclusive.
The specification for host cell DNA in SYNT001 is < 2 pg/mg, the limit of quantitation of the 
assay.  To comply with regulatory guidelines, which specify a maximum level of 10 ng host cell 
DNA per dose, dosing is limited to 5000 mg of SYNT001. Therefore, at the highest dose 
possible in this study (45 mg/kg), maximum subject weight will be limited to 111 kg.
9.2
Cohort Dosing
Cohorts will be dosed sequentially beginning with Cohort 1. The first 2 subjects will be dosed at 
least 24 hours apart. A review of the 24-hour safety data for the first subject will be performed 
to ensure that there are no overt safety concerns before dosing the second subject. A review of 
the 7-day safety data for the first 2 subjects will be performed prior to dosing the remaining 6 
subjects in the cohort. Cohort 2, and Cohort 3 if added, will be dosed per the same schedule
9.3
Timing of Dosing 
On Days 0, 7, 14, 21, and 28, subjects will receive a 60-minute IV infusion of SYNT001 in the 
morning. The date and time the dose is administered will be recorded.  
9.4
Identity of Investigational Products
All supplies of SYNT001 will be supplied by Syntimmune and must be stored refrigerated (2ºC 
to 8ºC/36ºF to 46ºF) in the carton and protected from light, in a securely locked area, accessible 
to authorized persons only, until needed for dose preparation.  Qualified site personnel will 
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inventory the investigational product received and will maintain records of disposition of the 
drug, including dates, quantity and use.
9.5
Investigational Product Retention at Study Site
The Investigator (or designee) is responsible for maintaining accurate accountability records of 
the investigational product throughout the clinical study. All study drug received at the site must 
be inventoried and accounted for in an accountability log provided by the Sponsor. All 
dispensing and accountability records will be available for Sponsor review. Study drug 
accountability will be verified during on-site monitoring visits.
Upon the completion or termination of the study, and upon written authorization from the 
Sponsor, or its representative, all unused and/or partially used study drug should be returned or 
destroyed at the investigational site, as specified by Sponsor.  It is the Investigator’s 
responsibility to ensure that the Sponsor, or its representative, has provided written authorization 
that procedures for proper disposal of the study drug have been established, and that appropriate 
records of the disposal are documented and maintained.  No unused study drug may be disposed 
until fully accounted for by the Sponsor monitor (or designee)
9.6
Warnings and Precautions
Note: Subjects must not receive any vaccinations from within 2 weeks of screening until 
2 months after the last dose of study drug.
9.6.1
Infusion Reaction
SYNT001 will be given as an IV infusion over 1 hour. As with all mAbs administered by IV
infusion, infusion reactions are possible. In nonclinical testing of SYNT001 in NHPs, clinical 
observations were limited to infusion reactions due to the immunogenicity of SYNT001 in 
NHPs. These reactions included transient emesis/vomitus which typically occurred within 1 hour 
of dosing at all dose groups, but only after the third weekly infusion following the development 
of ADAs. Transient histamine-type responses were noted 30 minutes post-dose in some animals 
in all dose groups, but only following the third weekly infusion as above. These reactions were 
consistent with a histamine reaction (decreased activity, periocular swelling, erythema, facial 
flushing, eyelids partially/completely closed, and/or generalized weakness). With the exception 
of vomitus/emesis and red skin discoloration associated with injection or blood draw sites, these 
observations spontaneously resolved within 1-hour post-dose. Subsequent pretreatment with 
intramuscular diphenhydramine prevented further histamine-type reactions. All doses of 
SYNT001 were administered by bolus infusion over approximately 5 minutes in the NHP 
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studies. However, all of the observed infusion reactions (including vomitus/emesis and 
histamine-type reactions) associated with ADAs are not at all predictive of what may occur in
humans [Bugelski 2004, Ponce 2009] and furthermore, are not considered relevant to predicting 
responses in humans [ICH S6(R1) 2011].  
Typically, infusion reactions to monoclonal antibodies observed in human studies develop within 
30 minutes to 2 hours after the initiation of drug infusion, although symptoms may be delayed 
for up to 24 hours. Most are mild in severity, although severe and even fatal reactions can occur. 
Guidelines for Grading and Management of Allergic or Infusion-Related Reactions
Allergic and/or infusion-related reactions include hypersensitivity reactions and cytokine release 
syndromes. These reactions are experienced by patients during or within hours of the infusion of 
monoclonal antibody therapy. Symptoms can include flushing, alterations in heart rate and blood 
pressure, dyspnea, bronchospasm, back pain, fever, urticaria, edema, nausea, and all types of 
rashes. Anaphylaxis is recognized as a severe, life-threatening, generalized, or systemic reaction. 
This is a medical emergency characterized by rapidly developing life-threatening airway and/or 
breathing and/or circulation problems usually associated with skin or mucosal changes. 
Management of Grade 1 infusion reactions include decreasing the rate of infusion by 50% and 
observing.  Symptoms may also be treated as needed with medications such as diphenhydramine, 
hydrocortisone or acetaminophen.
Management of Grade 2 and higher infusion reactions should include stopping the infusion of 
study drug. See Figure 1 and Figure 2 for details on the management of Grades 1-2 and Grade 3 
or higher infusion reactions. The severity of and management of allergic or infusion-related 
reactions will be graded and managed using NCI CTCAE Version 4.03 (see Table 6). 
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Figure 1: Management of Mild (Grade 1) to Moderate (Grade 2) Infusion Reactions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stop 
Infusion
Assess airway, breathing, circulation, and consciousness, and recline subject
Start high flow oxygen
Insert large bore IV and start IV fluids
Initiate vital sign assessments at least every 15 minutes
Any problem with airway, breathing 
circulation, or consciousness?
NO:
Initiate medical 
review
YES:
Initiate treatment per the 
Severe Infusion Reaction 
Flow Chart
Monitor for symptom resolution
If symptoms persist, proceed with medications as needed.  For example:
diphenhydramine 25-50 mg IV and/ or hydrocortisone 200 mg IV
Note:  If desaturation, 
hypotension, or urticaria 
present, refer to Severe
Infusion Reaction Flow 
Chart.
Subject presents with any of 
the below:
•
Altered vision
•
Impending feeling 
of doom
•
Pain:  Back, 
abdomen, chest
•
Flushing
•
Wheezing without 
desaturation
•
Pyrexia
•
Peripheral edema
•
GI symptoms
If ongoing symptoms, consider ongoing 
observation or hospital admission
If symptoms and signs resolve completely either spontaneously or after administration of diphenhydramine 
with or without hydrocortisone, consider rechallenge:
Wait at least 20 minutes following medication administration before commencing rechallenge at an infusion 
rate of 50% or less of the initial infusion rate or
Consider pre-medicating the subject with the same medication(s) 20-30 minutes in advance of subsequent 
administrations of SYNT001 and starting infusion at 50% of the planned infusion rate for the first 30 minutes, 
then returning to the intended infusion rate in the absence of any infusion reaction
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Figure 2: Management of Severe (Grade 3 or higher) Infusion Reactions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject presents with any of the below:
•
Urticaria
•
Airway threatened by angioedema
•
Angioedema: Lip, mouth, facial swelling
•
Respiratory compromise - wheezing, dyspnea, stridor or hypoxia 
(O2 saturation < 90%)
•
BP < 90 mmHg SBP or >30% decrease from patient baseline
Stop 
Infusion
Consider (under medial direction):
Epinephrine 1:1000
•
0.3 mg (0.3 mL) IM into lateral thigh
Transfer to Emergency Room/ICU
Observe until all symptoms resolved.
Start basic life support:
•
High oxygen flow
•
On bed, head down, legs up
•
Large bore IV cannula, 1 L normal saline STAT
•
Initiate vital signs at least every 15 minutes
Airway Threatened:
Nebulized epinephrine 1:1000, 3–5 mL (3–5 mg)
Bronchospasm:
Nebulized salbutamol 5 mg
(Wheeze or Hypoxia)
Consider: Intubation / nebulized epinephrine
Hypotension:
Place on cardiac monitor
(Systolic BP <100 mmHg)
Further epinephrine 1:1000, 0.3 mg IM and
IV normal saline bolus 20 mL/kg STAT as needed
Have vasopressin on hand
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Table 5:
Grading and Management of Allergic or Infusion-Related Reactions
Adverse 
Event
Grade
1
2
3
4
5
Infusion-
Related 
Reaction
Mild transient 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤24 hours
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated for 
clinical sequelae
Life-
threatening 
consequences; 
urgent 
intervention 
required
Death
Allergic 
Reaction
Transient 
flushing or 
rash, drug 
fever 
< 38.0°C. 
Intervention 
not indicated
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤24 hours
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated for 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Life-
threatening 
consequences; 
urgent 
intervention 
required
Death
Anaphylaxis
-
-
Symptomatic 
bronchospasm, with or 
without urticarial;
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension
Life-
threatening 
consequences; 
urgent 
intervention 
required
Death
Cytokine 
release 
syndrome
Mild 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤24 hours
Prolonged (e.g., not rapidly 
responsive to symptomatic
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated for 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Life-
threatening 
consequences; 
pressor or 
ventilator 
support 
indicated
Death
Abstracted from NCI CTCAE Version 4.03.
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9.6.2
Potential Immune Effects
An antibody blocking FcRn is anticipated to have several effects.  These include acceleration of 
catabolism of IgG, but not other immunoglobulin isotypes such as IgA and IgM, leading to dose-
dependent decreases in circulating IgG levels by up to an estimated 50% from the baseline levels 
after a single dose and further decreases after multiple doses up to a 70% to 80% reduction. 
Based on studies in humans, it is expected that with a single dose, the nadir of this effect will 
occur approximately 5 days after dosing.  The time course of recovery of IgG following dosing 
in the Phase 1a study suggests that a return to within normal limits occurs within 4 weeks after a 
single dose and within 4 weeks after multiple doses as shown in NHPs.
Given the normal adult range of IgG of 700 to 1600 mg/dL (in some references), with a mean of 
1150 mg/dL, a 50% decrease in the mean would be to 575 mg/dL and a 50% decrease from the 
low end of the normal range of 700 mg/dL would be to 350 mg/dL. An 80% decrease from 
baseline after multiple doses would result in IgG levels of 230 mg/dL and 140 mg/dL, 
respectively.  While these levels are in the range found in patients with primary humoral 
immunodeficiency [Ameratunga 2013], the levels will be transient. Study subjects will be 
monitored clinically for any infection. Further, commercial IVIG can be given to reverse the low 
IgG levels in case of a bacterial infection occurring while their IgG levels are decreased.
An antibody blocking FcRn is expected to also down modulate innate and adaptive immunity
and the catabolism of IgG-containing immune complexes (IC). Specifically, it is expected that 
anti-FcRn will promote the clearance of IgG-containing ICs and the effects of these IC on
stimulating innate immune cell production of inflammatory cytokines (e.g., IL-12, interferon-γ, 
and tumor necrosis factor [TNF]) and inhibit the processing and presentation of antigens 
contained within IC and thus the antigen-specific activation of CD4+ and CD8+ T-cells. 
Therefore, subjects with pre-existing conditions that are dependent upon IgG antibodies, such as 
chronic infections (e.g., HIV, HBV or HCV), will be excluded from this study, as will subjects 
with active infection in general.
SYNT001 administration could decrease the level of protective antibodies from prior 
vaccinations. Protective antibody levels for tetanus and varicella-zoster virus (chickenpox) are to 
be tested in accordance with Section 6.7.3.
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10
CONCOMITANT MEDICATION AND TREATMENT
All treatments a subject receives within 14 days prior to enrollment through the end of the study 
(Day 56) will be documented.  Concomitant medication and treatment for co-existing conditions, 
including those for pemphigus, are permitted if not excluded below.  Topical antibiotics are 
permitted to treat active infections that occur on study.  Topical or systemic treatments for oral 
candidiasis are permitted.  Topical lidocaine for transient pain relief is acceptable as needed.
Significant increases in anti-pemphigus medications may result in subjects being discontinued 
from the study.  Concomitant treatment that is medically indicated for any AEs the subject 
experiences during the study are permitted
Use of the following treatments will not be permitted during the study unless otherwise 
specified:
•
Rituximab or other anti-CD20 antibody
•
Monoclonal antibodies other than study drug
•
Any immunosuppressive drugs apart from corticosteroids, azathioprine, mycophenolate 
mofetil, or cyclosporine.
•
Topical steroids
•
Any dietary herbal supplements
•
Any investigational drug or device
•
Any vaccinations
If over a period of at least two weeks on study drug, a subject on corticosteroids shows the 
absence of new lesions and significant healing of lesions that existed at study baseline, a slow 
corticosteroid taper may be started as per the following suggested schedule 
•
If on > 30 mg of prednisone per day, decrease by 10 mg every two weeks until a dose of 
30 mg per day then decrease by 5 mg every two weeks
•
If on < 30 mg of prednisone per day, decrease by 5 mg every two weeks
In cases in which concomitant medications are used, details to be recorded include the following: 
medication name, start date and time, stop date and time, dose, route, frequency, and reason for 
use.  The concomitant medication names are to be coded using the World Health Organization 
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(WHO) Drug Dictionary (WHO-DD March 2013, Type B2 or later) and classified by anatomical 
therapeutic chemical (ATC) categories.
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11
SAFETY
11.1
Safety Parameters
Clinical and laboratory AEs will be graded using the NCI CTCAE; Version 4.03 (See 
Appendix A).
Subjects will be monitored throughout the treatment and follow-up period for occurrence of AEs
(acute, delayed, and/or cumulative), as well as for changes in clinical status, vital sign 
measurements, and laboratory data (including PD).  Safety parameters to be measured/assessed 
include PEs, vital sign measurements, hematology, serum chemistries, urinalysis, and ECG.
11.2
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a clinical trial subject associated with 
the use of a drug, whether considered drug related.  An AE can be an unfavorable and 
unintended sign (e.g., an abnormal laboratory value finding), a symptom, or a disease temporally 
associated with the use of a drug, without judgment as to causality.  An AE can arise from use of 
the drug (e.g., use in combination with another drug) and from any route of administration, 
formulation or dose, including an overdose.  An AE also includes, but is not limited to, any 
clinically significant worsening of a pre-existing condition.  Examples include:
•
Any sign, symptom, physical finding, or laboratory result that has worsened in nature, 
severity or frequency compared to baseline;
•
Reactions from an investigational drug, including those occurring because of an 
overdose, abuse of the study drug, withdrawal phenomena, sensitivity or toxicity;
•
Concurrent illness that was not present or worsens in nature, severity, or frequency 
compared to baseline;
•
Injury or accident; and/or
•
Exacerbation of a pre-existing condition.
For data collection, all untoward events that occur after informed consent through 28 days after 
study drug dosing are to be recorded on eCRFs by the investigational site.
While pregnancy alone is not considered as an AE or SAE, any pregnancy complication(s) 
should be recorded as an AE(s) or SAE(s) (if applicable). Elective abortions without 
complications should not be regarded as AEs, unless they were therapeutic abortions (see 
below). Hospitalization for normal delivery of a healthy newborn should not be considered an 
SAE.  If a female subject becomes pregnant during the conduct of the study, the Investigator 
must notify the Sponsor according to the procedures provided in Section 11.3.8).
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11.3
Evaluating Adverse Events
The Investigator will determine the seriousness, intensity, and causality of an AE associated with 
the use of the study drug (i.e., events where there is a reasonable possibility that the event may 
have been caused by the study drug) based on the definitions that follow.
11.3.1
Serious Adverse Events
(Notify Medpace Safety within 24 hours; document on eCRF)
The SAE definition and reporting requirements are in accordance with Title 21 Part Code of 
Federal Regulations (CFR) 312.32 and the Guidance for Industry and Investigators Safety 
Reporting Requirements for Investigational New Drug (INDs) and Bioavailability 
/Bioequivalence Studies.
SAE:  An AE is considered "serious" if, in the view of either the Investigator or sponsor, it 
results in any of the following outcomes:
•
Death: This includes any death that occurs while the subject is “on study” as well as any 
death that occurs within 28 days after study drug administration. 
Note: Death is an outcome of an AE, and not an AE.  The event(s) that caused death 
(e.g., illness, accident) is the SAE.  Death due to any other cause(s) must also 
be reported as an outcome of the reportable SAE.
•
Life-threatening adverse drug event: An AE or suspected adverse reaction is 
considered “life threatening” if, in the view of either the Investigator or sponsor, its 
occurrence places the patient or subject at immediate risk of death. It does not include an
AE or suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death. 
•
Inpatient hospitalization or prolongation of existing hospitalization:
In the absence of an AE, the Investigator should not report hospitalization or prolongation 
of hospitalization.  This is the case in the following situations:
o
Hospitalization or prolongation of hospitalization is needed for a procedure 
required by the protocol
o
Hospitalization or prolongation of hospitalization is part of routine procedure 
followed by study center
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o
Hospitalization for survey visits or annual physicals
o
Hospitalization for observation with release within 24 hours
In addition, a hospitalization planned before the start of the study for a pre-existing 
condition, which has not worsened, does not count as an SAE.
•
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
•
Congenital anomaly/birth defect
•
Important medical event: An event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, it may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.  
11.3.2
Overdose
An overdose is defined as a significant variation from the recommended/scheduled dosage for a 
product. The dosing for this study will be conducted in a controlled clinical setting and an 
overdose is not anticipated. However, in the event of an accident, for this study, an overdose of 
SYNT001 is considered a dose that is two-fold higher than the intended dose for the subject.
11.3.3
Non-Serious Adverse Events 
(Document on eCRF)
All other AEs, not fulfilling the previous definitions, are classified as non-serious.
11.3.4
Protocol-Related Adverse Events
AEs that are not test drug related may nevertheless be considered by the Investigator or the 
Medical Monitor to be related to the conduct of the clinical study.  That is, the event may be 
related to the fact that a subject is participating in the study.  For example, a protocol-related AE
may be an event that occurs during a screening period or that is related to a procedure required 
by the protocol.
11.3.5
Assessment of Causality
A medically qualified Investigator must assess the relationship of any AE (including SAEs) to 
the use of the investigational product, as related or not related, based on clinical judgment and 
using all available information, and may include consideration of the following factors:
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•
Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic 
factors.
•
The temporal association between drug exposure and onset of the AE.
•
Whether the manifestations of the AE are consistent with known actions or toxicity of the 
investigational product.
•
The AE resolved or improved with decreasing the dose or stopping use of the 
investigational product (dechallenge).  Judgment should be used if multiple products are 
discontinued at the same time.
The causal relationship between the study medication and the AE will be assessed using one of 
the following categories:
Not Related: Factors consistent with an assessment of Not Related include:
•
Temporal relationship is lacking (e.g., the event did not occur within a reasonable 
time frame following administration of the study medication); or
•
Other causative factors more likely explain the event (e.g., a pre-existing 
condition, other concomitant treatments).
Related: Factors consistent with an assessment of Related include:
•
There is a positive temporal relationship (e.g., the event occurred within a 
reasonable time frame following administration of study medication); or
The AE is more likely explained by the investigational product than by another cause (i.e., the 
AE shows a pattern consistent with previous knowledge of the investigational product or the 
class of the investigational product)
11.3.6
Recording Adverse Events
All AEs (including SAEs) are to be accurately recorded on the Adverse Event page of the 
subject’s eCRF.  The severity of each AE will be graded using the NCI CTCAE, Version 4.03.
The date of onset as well as the end date of the event also should be recorded or the event should 
be entered as “ongoing”.  In addition, the method used to treat the AE and the outcome of the AE 
also will be noted.  The Investigator will assess the relationship of the event to study drug.   
11.3.7
Planned Hospitalization
A hospitalization planned by the subject prior to the first dose of study medication is considered 
a therapeutic intervention and not the result of a new SAE and should be recorded as medical 
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history.  If the planned hospitalization or procedure is executed as planned, the record in the 
subject’s medical history is considered complete.  However, if the event/condition worsens 
during the trial, it must be reported as an AE.
11.3.8
Reporting Pregnancies
If a female subject or the female partner of a male subject becomes pregnant during the course of 
the study, the Investigator must report the pregnancy to the Medpace Safety using the 
Pregnancy Reporting Form within 24 hours of becoming aware of the event. The Investigator 
must obtain consent to collect pregnancy information (including the status of the newborn, if 
applicable).
If some of the information required for completion of the Pregnancy Reporting Form is 
unavailable at the time of the initial report, follow-up reports will be completed and submitted 
within 24 hours of becoming aware of the new information.  Any pregnancy will be followed 
through delivery for the observation of any SAEs. Any SAE that occurs during pregnancy must 
be recorded on the SAE report form in the EDC system (e.g., maternal serious complications, 
therapeutic or spontaneous abortion, ectopic pregnancy, stillbirth, neonatal death, congenital 
abnormality, birth defect) and reported within 24 hours in accordance with the procedure for 
reporting SAEs (See Section 11.3.9).
11.3.9
Serious Adverse Event Reporting
11.3.9.1
Governing Regulatory Requirements
Compliance with this request for prompt reporting is essential in that the sponsor is responsible 
for informing the US Food and Drug Administration (FDA) and other regulatory authorities as 
well as all other participating Investigators of the event. 
Under FDA ruling (US Code of Federal Regulations, Title 21 CFR Part 312.32) and the ICH 
Guidelines for Clinical Safety Data Management Definitions and Standards for Expedited 
Reporting, the sponsor is required to submit written documentation, in the form of a safety 
report, detailing:
•
Any event associated with the use of the drug, that is both serious and unexpected, or 
•
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.
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Written submission must be made by the sponsor to the FDA and the IRBs as soon as possible 
and in no event later than 15 calendar days after the sponsor’s initial notification of the event.  
The sponsor shall also inform all Investigators.
11.3.9.2
Time Frame for Reporting
Any death, SAE, pregnancy, or unexpected (and severe) AE experienced by the subject after 
informed consent or within 28 days of receiving study drug, regardless of relationship to study 
drug, or any death that occurs more than 28 days after receiving study drug, and is believed to be 
study drug related, must be promptly reported (within 24 hours of the Investigator becoming 
aware of the event) by telephone or electronic transmission to the sponsor (or designee).
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Contact information for SAE reporting:
Medpace Clinical Safety 
Medpace SAE hotline: 
Telephone: 
 dial or 
dial 
Facsimile: 
 or 
e-mail:
Additionally, the Investigator will be able to contact the Medical Monitor:
Medical Safety Contact
 
Phone (US): 
 extension 
Mobile phone: 
Email: 
11.3.9.3
Information to be Provided by the Investigator
SAEs must be recorded on the SAE form in the EDC system. This requirement includes all 
SAEs that occur after informed consent and through 28 days after study drug dosing, and in 
addition, any SAE that are assessed as related to study treatment by the Investigator, even if the 
SAE occurs more than 28 days after study drug dosing.
The minimum information required for SAE reporting includes identity of Investigator, site 
number, subject number, an event description, SAE term(s), onset date, the reason why the event 
is serious (i.e., the seriousness criteria) and the Investigator’s assessment of the relationship of 
the event to study treatment. Additional SAE information including medications or other 
therapeutic measures used to treat the event, action taken with the study treatment due to the 
event, and the outcome/resolution of the event will be recorded.  Paper forms for reporting SAEs
will be provided to the study sites as back-up in case the EDC system is not accessible.
In all cases, the Investigator should continue to monitor the clinical situation and report all 
material facts relating to the progression or outcome of the SAE. Furthermore, the Investigator 
may be required to provide supplementary information as requested by Syntimmune or designee.
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When reporting an SAE, the following additional points should be noted:
•
When the diagnosis of an SAE is known or suspected, the Investigator should report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms. Signs 
and symptoms may then be described in the event description. For example, dyspnea 
should not be used as an SAE term if the diagnosis, which caused the dyspnea, is known 
to be malignant pleural effusion.
•
Death should not be reported as an SAE, but as an outcome of a specific SAE, unless the 
event preceding the death is unknown. In the exceptional case where the events leading 
to death are unknown, then death may be used as an event term. If an autopsy was 
performed, the autopsy report should be provided. 
•
While most hospitalizations necessitate reporting of an SAE, some hospitalizations do not 
require SAE reporting, as follows: 
•
Elective or previously scheduled surgery, e.g., a previously scheduled ventral 
hernia repair
•
Procedures for pre-existing conditions that have not worsened after initiation of 
treatment
•
Pre-specified study hospitalizations for observation
•
Events that result in hospital stays of less than 24 hours and that do not require 
admission, e.g., an emergency room visit for hematuria that results in a diagnosis 
of cystitis and discharge to home on oral antibiotics
•
SAEs must, however, be reported for any surgical or procedural complication resulting in 
prolongation of the hospitalization.
11.3.10
Regulatory Reporting
Syntimmune (or designee) will process and evaluate all SAEs as soon as the reports are received.
For each SAE received, Syntimmune will decide as to whether the criteria for expedited 
reporting have been met.
Syntimmune (or designee) will submit SAEs that meet the criteria for expedited reporting to the 
regulatory authorities in accordance with local regulations governing safety reporting. Reporting 
of SAEs by the Investigator to his or her IRB will be done in accordance with the standard 
operating procedures and policies of the IRB. Adequate documentation must be maintained 
showing that the IRB was properly notified.
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11.3.11
Follow-up Information on a Serious Adverse Event (SAE)
Appropriate diagnostic tests should be performed and therapeutic measures, if indicated, should 
be instituted.  Appropriate consultation and follow-up evaluations should be carried out until the 
event has returned to baseline or is otherwise explained by the Investigator.  
If all required information on the SAE form is not available at the time of the initial report, 
follow-up information will be completed in the EDC system.
11.4
Other Safety Considerations
11.4.1
Laboratory Data
All laboratory data obtained during the study should be reviewed.  Any abnormal value that leads 
to a change in subject management (e.g., requirement for additional medication or monitoring) or 
is of clinical significance by the Investigator should be reported as an AE and/or SAE as 
appropriate, unless this value is consistent with values obtained before entry into the study.
11.4.2
Medication Errors
Any medication error that results in an AE, even if it does not meet the definition of serious, 
requires reporting within 24 hours to the safety Medical Monitor.
11.4.3
Follow-Up of Adverse Events
Any SAE or AE assessed as related that led to treatment discontinuation (including clinically 
significant abnormal laboratory values that meet these criteria) and ongoing 28 days after study 
drug dosing must be followed until either resolution of the event or determination by the 
Investigator that the event has become stable or irreversible. This follow-up guidance also 
applies to related SAE that occur more than 28 days after study drug dosing. The status of all 
other continuing AEs will be documented as of 28 days after study drug dosing. The 
Investigator will follow all subjects who experience AEs until there is a return to the subject’s 
baseline condition, or until a clinically satisfactory resolution has been achieved.  The 
appropriate follow-up visits must be scheduled and the specific tests repeated or performed as 
necessary.
Where a diagnosis is possible, it is preferable to report this diagnosis rather than a series of terms 
(signs/symptoms) relating to the diagnosis.
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11.5
Safety Monitoring for Dose Escalation
Following dosing in each cohort, all safety/tolerability data (e.g., PEs, vital signs [including 
pulse oximetry], clinical safety laboratory tests, ECGs and AE/SAE assessments) as well as any 
available and relevant PD data collected through Day 42 will be reviewed by the DEC.  A 
decision to escalate to the next cohort will be made.  The recommendation may be to continue to 
the next scheduled dose level, discontinue the study or to modify dosing to a dose less than the 
current dose or higher than the current dose but lower than the next planned dose.  
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12
STATISTICAL CONSIDERATIONS
All descriptive and inferential statistical analyses will be performed using the most recently 
released and available Statistical Analysis System (SAS) software, unless otherwise noted.
Missing data will not be imputed unless otherwise stated. All clinical data captured will be 
provided in data listings. A Statistical Analysis Plan (SAP) and a Pharmacokinetic Analysis Plan 
(PAP) will be finalized prior to database lock.
12.1
General Design 
All data for enrolled subjects will be presented in data listings by subject number.   
Continuous data will be described using descriptive statistics: number of observations (n), mean, 
standard deviation (SD), median, minimum, and maximum.  Frequencies and percentages will be 
used for summarizing discrete (categorical) data.  When categorical data are presented, the 
percent will be suppressed when the count is zero to draw attention to the non-zero counts.  The 
denominator for all percentages, unless otherwise specified, will be the number of subjects in the 
specified analysis population.
12.2
Sample Size Justification 
Formal sample size calculations were not performed. The number of subjects was chosen based 
on feasibility and was considered sufficient to meet the study objectives.
12.3
Statistical Considerations 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP). The SAP may modify the plans outlined in 
the protocol; any deviations from the previously described statistical plan will be described and 
justified in an SAP amendment. Additional statistical analyses other than those described in this 
section may be performed if deemed appropriate and will be described in the SAP. Methods of 
handling of missing data for different endpoints will be further specified in the SAP. In general, 
where individual data points are missing because of insufficient samples, dropouts, or other 
reasons, the data will be analyzed based on reduced denominators unless specified otherwise in 
the SAP. 
Results will be summarized by cohorts. 
12.3.1
Study Populations 
Three populations will be employed in the analysis of study data:
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•
The intent-to-treat (ITT) population will consist of all subjects who have received at least 
one dose of study drug.  All safety analyses will be performed on the ITT population.
•
The PK population will consist of all subjects who receive at least one dose of study drug 
and have sufficient post-dose blood samples to obtain PK parameters.
•
The PD population will consist of all subjects who receive at least one dose of study drug 
and have post-dose PD data available.
Primary safety analyses will be performed on the ITT population.  Demographics, subject 
disposition, and screening and baseline characteristics will be summarized for the ITT, PK, and 
PD populations, where appropriate.
12.3.2
Subject Accountability, Demographics, and Baseline Characteristics 
Subject disposition, demographic information and baseline characteristics will be presented.
Any discrepancy between treatment to be given and treatment received will be accounted for in 
these displays. 
12.3.3
Concomitant Medications 
Concomitant medications will be coded using WHO Drug Dictionary (WHO-DD March 2013, 
Type B2 or later) and the data will be summarized and presented in tables and listings. 
12.4
Planned PK Analysis
Study drug concentrations will be used to calculate the following PK parameters: t1/2, Cmax, Tmax,
and AUC0-24 and AUC0-∞.  PK parameters will be determined using noncompartmental 
method(s).  Descriptive statistics of PK parameters for SYNT001 will include mean, SD, 
coefficient of variation (CV), median, minimum, and maximum. Tmax will be reported as median
and range. All descriptive statistics will be performed on untransformed PK parameters and after 
log10 transformation of PK parameters.
For calculation of mean concentrations and generation of mean concentration-time profiles, all 
below the limit of quantification (BLQ) values will be set to zero except when an individual 
BLQ falls between 2 quantifiable values, in which case it will be omitted.
If there are values above the BLQ, but too sparse to allow full analysis, descriptive statistics will 
be performed on available values.
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12.5
Safety Data 
Safety observations and measurements include AEs, safety laboratory tests, vital sign
measurements, PEs, and ECGs.
Treatment-emergent AEs will be summarized using the Medical Dictionary for Regulatory 
Activities (MedDRA®; Version 19 or higher) System Organ Class (SOC) and preferred term, 
classified from verbatim terms.  The incidence and percentage of subjects with at least 1 
occurrence of a preferred term will be included, using the most severe grade. The number of 
events per preferred term will also be summarized.  Causality (relationship to study treatment) 
will be summarized separately.
AEs, SAEs, and AEs leading to withdrawal, dose modification, or treatment discontinuation will 
be listed by subject, cohort, and overall per SOC and preferred terms. Duration of AEs will be 
determined and included in listings, along with action taken and outcome.  
Laboratory results will be summarized by cohort.  Incidence of laboratory abnormalities will be 
summarized.  The worst on-study grade after the first dose of study drug will be summarized.  
Results for variables that are not coded will be presented in the listings as below, within, and 
above the normal limits of the local laboratory.
Vital sign measurements and change from baseline will be summarized at each scheduled time 
point by cohort using descriptive statistics.  
Arithmetic mean of parameters from triplicate ECG will be calculated first for each participant at 
each planned time point. Then summary statistics of ECG test parameters (mean of triplicate) 
and change from baseline to each post-dose time point will be calculated. Shift tables for ECG 
test result category change (normal, abnormal, clinically abnormal) from pre-dose to each post-
dose time point showing number and percentage of subjects with movement between categories 
will be presented by treatment group. Frequency and percentage of subjects experiencing 
potential QTc prolongation (QTcF > 450) will be summarized at each time point by cohort.
12.6
Pharmacodynamic/Activity Data 
PD results will be summarized by cohort.
12.7
Immunogenicity Data 
Immunogenicity results will be summarized by cohort.
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12.8
Interim Analysis
No interim analysis is planned.  Safety results will be examined for making dose-escalation
decisions; no statistical analyses are planned for aiding these dose-escalation decisions.
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13
DATA QUALITY ASSURANCE
All data will be entered in a validated electronic data capture system using single data entry. 
Standard procedures (including following data review guidelines, manual clinical review based 
on subject profiles, computerized validation to produce queries, and maintenance of an audit file 
which includes all database modifications) will be followed to ensure accurate data. Clinical 
personnel will review all data listings for outliers, data inconsistencies, and spelling errors.
During the study, a study site monitor will make site visits to review protocol compliance, 
compare electronic case report forms (eCRFs) against individual subject medical records, assess 
drug accountability, and ensure that the study is being conducted using pertinent regulatory 
requirements. eCRF entries will be verified with source documentation. The review of medical 
records will be performed in a manner to ensure that subject confidentiality is maintained.  
Checking the eCRFs for completeness, clarity and cross checking with source documents is 
required to monitor the progress of the study. Direct access to source data is also required for 
inspections and audits, and will be carried out giving due consideration to data protection and 
medical confidentiality. Each Investigator will have assured Syntimmune of full access to 
complete source data for study participants and associated necessary support at all times.
In addition to routine monitoring procedures, audits of clinical research activities in accordance 
with standard operating procedures (SOPs) may be performed to evaluate compliance with the 
principles of GCP.  A regulatory authority may also wish to conduct an inspection (during the 
study or even after its completion).  If a regulatory authority requests an inspection, the 
Investigator must immediately inform Syntimmune that this request has been made. Study 
conduct may be assessed during the study by a Clinical Quality Assurance representative(s) to 
ensure that the study is conducted in compliance with the protocol.  This designee, as well as the 
site monitor, will be permitted to inspect the study documents (study protocol, eCRFs, 
investigational product accountability, original study-relevant medical records).  All subject data 
will be treated confidentially.  During the clinical study, access will be available to Syntimmune 
or their designee (e.g., contract research organization [CRO]) to view the eCRFs after 
completion of the individual sections of the study. Furthermore, the study protocol, each step of 
the data-recording procedure and the handling of the data as well as the study report may be 
subject to independent review by a Quality Assurance representative.  Clinical site and study 
audits will be conducted as necessary to assure the validity of the study data.
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STUDY ADMINISTRATION
14.1
Study Administrative Structure
The study administration structure is provided in Table 6.
Table 6 :
Study Administrative Structure
Sponsor Contact:
Phone: 
Email: 
Sponsor Medical Director:
Phone: 
Email: 
Medical Monitor:
Medpace
43 Thorndike Street
Cambridge, MA 01240
Phone: 
Email: 
Study Monitoring:
Medpace
5375 Medpace Way
Cincinnati, OH 45227
Phone (Main): 
Email: 
14.2
Ethical Conduct of the Study
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
ICH E6 Tripartite Guideline (January 1997), and in general, be conducted in a manner consistent 
with the principles described in the Declaration of Helsinki. The Investigator will ensure that the 
conduct of the study complies with the basic principles of GCP as outlined in the current version 
of 21 CFR, subpart D, Part 312, “Responsibilities of Sponsors and Investigators”, Part 50,
“Protection of Human Subjects”, and Part 56, “Institutional Review Boards”.
14.3
Informed Consent (ICF)
A properly executed, written informed consent document, in compliance with 21 CFR, Part 50 
and the ICH guidelines, will be obtained from each subject before the subject is entered into the 
study and before any study screening procedure is performed that involves risk.  Attention will 
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be directed to the basic elements required for incorporation into the informed consent under US 
Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a]) and (21 CFR 
50.25[b]), as necessary.
Sample ICFs will be supplied to each site. Syntimmune or its designee must review any proposed 
deviations from the sample ICF. The final IRB-approved document must be provided to 
Syntimmune for regulatory purposes.
It is the responsibility of the Investigator, or a person designated by the Investigator, to obtain 
written informed consent from each subject (or the subject’s legally authorized representative) 
participating in this study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study. In the case where the subject is unable to read, an impartial 
witness should be present during the entire informed consent discussion. After the subject has 
orally consented to participation in the trial, the witness’ signature on the form will attest that the 
information in the consent form was accurately explained and understood. A copy of the ICF 
must be provided to the subject or to the subject’s legally authorized representative. If applicable, 
it will be provided in a certified translation of the local language.
The eCRF for this study contains a section for documenting informed subject consent, and this 
must be completed appropriately. Signed ICFs must remain in each subject’s study file and must 
be available for verification by site monitors at any time. If new safety information results in 
significant changes in the risk/benefit assessment, the consent form should be reviewed and 
updated as necessary. All subjects (including those already being treated) should be informed of 
the new information, should be given a copy of the revised form, and should give their consent to 
continue in the study.
14.4
Institutional Review Board
This study is being conducted under US IND 128152. This protocol (and any modifications) and 
appropriate consent procedures must be reviewed and approved by an IRB. This board must 
operate in accordance with the current federal or local regulations. The Investigator will send a 
letter or certificate of IRB approval to Syntimmune (or designee) before subject enrollment and 
whenever subsequent modifications to the protocol are made.
14.5
Dose Escalation Committee
The DEC will be responsible for confirming the safety of the investigative product prior to
dose escalation, as well as the dose level for each successive cohort.  In addition, over the course 
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of the study, the DEC will review any drug-related SAEs to determine if modifications to the 
study or other measures are necessary to ensure the safety of the subjects.  The DEC will consist 
of the Medical Monitor, an Independent Clinical Expert and a Syntimmune Medical Officer.  To 
assist in the safety assessments, the DEC may request that Investigators, other experts, or
members within their organizations review the data and participate in the discussions.
14.6
Future Use of Subject Samples
Not all the tissue and blood components obtained during this study may be required for the tests 
that are part of the clinical trial. Available samples may be used for additional research. This 
research will help to understand disease subtypes, drug response and AE, and possibly identify 
new drug targets or biomarkers that predict subject response to treatment. The use of the samples 
for internal research will be done using the guidelines defined by the FDA guidance for In Vitro 
Diagnostic Device Studies Using Leftover Human Specimens that are Not Individual Identifiable 
(issued 25 April 2006) and the European Medicines Agency (EMA) Reflection Paper on 
Pharmacogenetic Samples, Testing and Data Handling (Doc. Ref. 
EMEA/CHMP/PGxWP/201914/2006; 15 November 2007). If a subject requests destruction of 
their tissue and blood samples and the samples have not yet been de-identified, Syntimmune will 
destroy the samples as described in this FDA guidance. Syntimmune will notify the Investigator 
in writing that the samples have been destroyed.
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CONDITIONS FOR MODIFYING THE PROTOCOL
Protocol modifications to ongoing studies must be made only after consultation between a 
Syntimmune representative and the Investigator. Protocol modifications will be prepared, 
reviewed, and approved by Syntimmune representatives.
All protocol modifications must be submitted to the IRB for information and approval in 
accordance with local requirements, and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects, or when the change involves only logistical or administrative 
aspects of the trial (e.g., change in site monitor, change of telephone number).
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CONDITIONS FOR TERMINATING THE STUDY
Syntimmune has the right to terminate the study at any time. In terminating the study, 
Syntimmune and the Investigator will ensure that adequate consideration is given to the 
protection of the subjects’ interests.
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STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING
17.1
Investigator’s Files and Retention of Documents
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into 2 separate categories as follows: (1) Investigator’s study file and (2) subject 
clinical source documents.
The Investigator’s study file will contain the protocol and protocol amendments, eCRFs, query 
forms, IRB and governmental approval with correspondence, sample informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence.
Subject clinical source documents (usually predefined by the project to record key efficacy and 
safety parameters independent of the eCRFs) may include subject hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, 
electroencephalogram, X-ray, pathology and special assessment reports, signed ICFs, consultant 
letters, and subject screening and enrollment logs. The Investigator must keep these 2 categories 
of documents on file for at least 2 years following the marketing application approval date for the 
study treatment and for the indication being investigated or for 2 years after the development 
program is discontinued and the FDA notified. After that period, the documents may be 
destroyed subject to local regulations with prior written permission from Syntimmune. If the 
Investigator wants to assign the study records to another party or move them to another location, 
Syntimmune must be notified in advance.
If the Investigator cannot guarantee the archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and Syntimmune to 
store these in a sealed container outside of the study site so that they can be returned sealed to the 
Investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside of the study site.
17.2
Source Documents and Background Data
Investigators must maintain adequate and accurate source documents on which the eCRFs for 
each subject are based. They are separate and distinct from the eCRFs.
These records include detailed notes on the following:
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•
Medical history
•
Date and time of informed consent with Health Insurance Portability and Accountability 
Act (HIPAA) authorization either contained in the ICF or presented to the subject 
candidate as a standalone document
•
Description of the complete consenting process
•
The basic identifying information that linked the subject’s medical record with the 
eCRFs
•
The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject
•
The medical condition of the subject during their involvement in the study
•
All AEs
•
The subject’s exposure to the study medication
•
The subject’s exposure to any concomitant therapy
•
All relevant observations and data on the condition of the subject throughout the trial
•
Justification for all entries in the subject’s eCRF
A subject log of all potentially eligible subjects considered, but not consented, for obvious 
deviations from the entry criteria, will be kept at each site. The log will contain subjects’ initials, 
diagnosis, eligibility, or, if not eligible, reason for not consenting.  All consented subjects will be 
logged, regardless of whether they ultimately enroll. 
Upon request, the Investigator will supply Syntimmune with any required background data from 
the study documentation or clinic records. This is particularly important when eCRFs are 
illegible or when errors in data transcription are suspected. In case of special problems or 
governmental queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected.
17.3
Audits and Inspections
The Investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from Syntimmune (or designee), or to health 
authority inspectors after appropriate notification. The verification of the eCRF data must be by 
direct inspection of source documents.
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17.4
Electronic Case Report Forms
Clinical trial data for this study will be captured on eCRF designed for computer processing and 
analysis.  This computerized system will be validated and compliant with 21 CFR Part 11. 
Corrections to data will be made using 21 CFR Part 11, Electronic Records; Electronic 
Signatures. If corrections are made after review and sign-off by the Investigator, he/she must be 
aware of the changes and provide written acknowledgement. There will also be an electronic 
audit trail. Corrections on paper CRFs must be initialed and dated by the person making the 
change. The Investigator agrees to provide all information requested on the eCRF in an accurate 
manner using instructions provided.  The Investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported to Syntimmune in the eCRF and in all required 
reports.
An eCRF is required to be submitted for every subject who receives any amount of study drug.  
This includes submission of retrievable data on subjects who withdraw before completion of the 
study.  Prior to submission, eCRFs must be reviewed for completeness and accuracy, and signed 
and dated where either indicated, by the Principal Investigator or authorized delegate from the 
study staff.  If a subject stops treatment or terminates from the study, the dates and reasons must 
be noted on the eCRF.
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MONITORING THE STUDY
It is understood that the responsible Syntimmune site monitor (or designee) will contact and visit 
the Investigator regularly and will be allowed on request to inspect the various records of the trial 
(eCRFs and other pertinent data) if subject confidentiality is maintained in accordance with local 
requirements.
It will be the site monitor’s responsibility to inspect the eCRFs at regular intervals throughout the 
study, to verify the adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The site monitor should have access to laboratory test reports 
and other subject records needed to verify the entries on the eCRF. The Investigator (or 
designee) must agree to cooperate with the site monitor to ensure that any problems detected 
during these monitoring visits are resolved.
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CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS
The Investigator must ensure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On eCRFs or other documents submitted to 
Syntimmune, subjects should be identified by an identification code and not by their names. The 
Investigator should keep a subject enrollment log showing codes, names, and addresses. The 
Investigator should maintain documents not for submission to Syntimmune (e.g., subjects’ 
written consent forms) in strict confidence.
Authorized regulatory officials and Syntimmune personnel (or their representatives) will be 
allowed full access to inspect and copy the records.  All study drugs, subject bodily fluids and 
tissue, and/or other materials collected shall be used solely in accordance with this protocol, 
unless otherwise agreed to in writing by Syntimmune.
The Principal Investigator also agrees that all information received from Syntimmune, including 
but not limited to the IB, this protocol, eCRFs, the INDs, and any other study information remain 
the sole and exclusive property of Syntimmune during the conduct of the study and thereafter.  
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from the 
sponsor. The Principal Investigator further agrees to take all reasonable precautions to prevent 
the disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
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PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS
The results of this study may be published or presented at scientific meetings. The Investigator 
agrees that any manuscript or abstract they author may be published only after receiving written 
permission from Syntimmune.
If Syntimmune coordinates a publication or presentation of study results from all study sites, the 
participation of Investigator or other representatives of study site as a named author shall be 
determined in accordance with Syntimmune policy and generally accepted standards for 
authorship.
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REFERENCES
Ameratunga R, Woon ST, Gillis D, Koopmans W, Steele R. New diagnostic criteria for common 
variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or 
subcutaneous immunoglobulin. Clin. Exp. Immunol. 2013;174: 203-211.
Bugelski PJ and Treacy G. (2004) Predictive power of preclinical studies in animals for the 
immunogenicity of recombinant therapeutic proteins in humans. Curr Opin Mol Ther.
2004;6:10−16.
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) (2011). S6(R1) Preclinical Safety Evaluation of 
Biotechnology-Derived Pharmaceuticals. Accessed 03 June 2016. 
http://www.ich.org/products/guidelines/safety/safety-single/article/preclinical-safety-evaluation-
of-biotechnology-derived-pharmaceuticals.html    
Nixon AE, Chen J, Sexton DJ, Muruganandam A, Bitonti AJ, Dumont J, Viswanathan M, Martik
D, Wassaf D, Mezo A, Wood CR, Biedenkapp JC, TenHoor C. (2015). Fully human monoclonal
antibody inhibitors of the neonatal Fc receptor reduce circulating IgG in non-human
primates. Front. Immun. 6:176
Ponce R, Abad L, Amaravadi, L, et al. Immunogenicity of biologically-derived therapeutics: 
assessment and interpretation of nonclinical safety studies. Regul Toxicol Pharmacol.
2009;54,164–182.
Roopenian, D.C., Christianson, G.J., Sproule, T.J., Brown, A.C., Akilesh, S., Jung, N., Petkova,
S., Avanessian, L., Choi, E.Y., Shaffer, D.J., Eden, P.A., Anderson, C. L. The MHC class I-like
IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled
drugs. 2003. J. Immun. 170 3528-3533
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Appendix A: NCI CTCAE, Version 4.03
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Appendix B: Pemphigus Disease Area Index (PDAI)
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Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Syntimmune, Inc. and 
any unauthorized use or disclosure of such information without the prior written authorization of 
Syntimmune is expressly prohibited. 
Syntimmune, Inc. 
SUMMARY OF CHANGES TO CLINICAL STUDY PROTOCOL 
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and Activity 
Study of SYNT001 in Subjects with Chronic Pemphigus (Vulgaris or 
Foliaceus) 
Protocol Number: 
SYNT001-103 
 
IND Number: 
132727 
 
Study Drug: 
SYNT001 
 
Sponsor: 
Syntimmune, Inc. 
 
257 Park Avenue South 
 
15th Floor 
 
New York, NY 10010 
 
Medical Monitor: 
 
 
43 Thorndike Street, Cambridge, MA 01240 
 
Phone: 
 extension 
 
 
Mobile: 
 
 
  
 
Original Protocol: 
28 January 2017 
Amendment 1.1 
21 March 2017
 
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SUMMARY 
The SYNT001-103 protocol has been amended with administrative changes as follows:   
 
• Removal of Anti-desmoglein (1&3) antibody testing on Day 28 from the Study 
Assessments table.   
• Total blood draw for subjects completing the study at Day 56 updated to approximately 
311 mL in Section 6.7 
• Corrected format and reference for the Pemphigus Disease area Index (PDAI) in 
Appendix B  
 
 
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SPECIFIC CHANGES 
Text deletions are shown using strike through font; additions in italic font. 
SECTION 1, STUDY SYNOPSIS 
Table 1, Study Assessments 
Anti-Dsg (1&3) antibody titer: ‘X’ removed from Day 28 box.  Incorrectly included in the 
Study Assessments Table. 
SECTION 6 STUDY PROCEDURES 
Section 6.7, Clinical Laboratory Measurements 
Laboratory testing (hematology, urinalysis, serum chemistry, virology, serology, pregnancy tests, 
PD samples, PK samples, and anti-drug antibody samples) will be performed using established 
methods by a central laboratory. Safety laboratory panels are defined as listed in Table 3. Blood 
and urine samples for hematology, serum chemistry, and urinalysis will be prepared using 
standard procedures.  Results will be provided to the Investigator.   Aliquots from the PK, 
biomarker and anti-drug antibody samples may be retained as back-up for additional testing as 
necessary. Subjects will be in a seated or supine position during blood collection. Full clinical 
safety lab draws will be collected at Screening and on Days 0, 7, 14, 21, 28, 33, 42 and 56.  The 
total blood draw for each subject who completes the study at Day 56, will be approximately 308 
311 mL.  Please refer to the Laboratory Manual for more information 
APPENDIX B:  
Pemphigus Disease Area Index (PDAI) 
Replaced PDAI form with an updated version as provided by University of Pennsylvania 
 
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Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Syntimmune, Inc. and 
any unauthorized use or disclosure of such information without the prior written authorization of 
Syntimmune is expressly prohibited. 
Syntimmune, Inc. 
CLINICAL STUDY PROTOCOL 
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and Activity 
Study of SYNT001 in Subjects with Chronic Pemphigus (Vulgaris or 
Foliaceus)  
Protocol Number: 
SYNT001-103 
 
IND Number: 
132727 
 
Study Drug: 
SYNT001 
 
Sponsor: 
Syntimmune, Inc. 
 
257 Park Avenue South 
 
15th Floor 
 
New York, NY 10010 
 
Medical Monitor: 
 
 
43 Thorndike Street, Cambridge, MA 01240 
 
Phone: 
 extension 
 
 
Mobile: 
 
 
 
  
 
Original Protocol: 
18 January 2017 
Amendment 1.1: 
21 March 2017  
Amendment 2.0 
12 April 2017  
 
 
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SPONSOR SIGNATURE 
Protocol SYNTOO I-I 03 
I have read and approve this protocol. My signature, in conjunction with the signature of the 
Investigator, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Conference on Harmonisation Guideline for Good Clinical Practice (GCP), 
the Code of Federal Regulations (CFR), and the ethical principles that have their origins in the 
Declaration of Helsinki. 
Syntimmune, Inc. 
Page 2 of 100 
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Date of Signature 
(DD Mm YYYY) 
Amendment 2.0 Final 12 April 
2017 
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PROCEDURES IN CASE OF EMERGENCY 
 
Serious Adverse Events  
Any death, serious adverse event (SAE)* occurring in a subject while receiving study drug or 
within 7 days of receiving study drug, even though the event may not appear to be study drug 
related, must be promptly reported (within 24 hours) by telephone or electronic communication to 
the sponsor (or designee).   
 
Emergency Contact Information  
 
 
 
 
SAE CRITERIA 
* A serious adverse event (SAE) is any untoward medical occurrence that at any dose results in any of the following outcomes, regardless of 
relationship to study drug (see Section 11.3.1, Serious Adverse Events for additional information): 
• 
Death 
• 
Life-threatening adverse drug event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability/ incapacity 
• 
A congenital anomaly/birth defect 
• 
An important medical event that may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above. 
 
For SAE reporting: 
For any other questions or to  
contact the Medical Monitor: 
Medpace Clinical Safety  
Medpace SAE hotline:  
Telephone: 
 dial  or 
 dial   
Facsimile: 
 or 
  
 
 
 
 
Mobile phone: 
 
Office phone: 
 ext. 
 
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2017 
 
 INVESTIGATOR SIGNATURE 
 
I have read and approve this protocol.  My signature, in conjunction with the signature of the 
sponsor, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Conference on Harmonization Guideline for Good Clinical Practice (GCP), 
the Code of Federal Regulations (CFR), and the ethical principles that have their origins in the 
Declaration of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations.  
 
 
Investigator Signature 
 
 
Date of Signature 
(DD Mm YYYY) 
Name of Investigator (please print) 
 
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1 
SYNOPSIS 
Study title 
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and Activity Study of 
SYNT001 in Subjects with Chronic Pemphigus (Vulgaris or Foliaceus) 
Protocol number 
SYNT001-103 
Number of study 
centers 
Approximately 10 (US) 
Clinical phase  
Phase 1b 
Study background 
SYNT001, a humanized, affinity-matured IgG4-kappa monoclonal antibody 
(mAb), blocks IgG and IgG immune complex (IC) interactions with the neonatal 
Fc receptor (FcRn) and thereby the major functions of FcRn in protecting IgG 
and IgG immune complexes from degradation and their role in downstream 
signaling events. Specific and high affinity blockade of FcRn with SYNT001 has 
been shown to increase the catabolism of IgG and IgG IC in healthy volunteers. 
This predicts that SYNT001 will also accelerate degradation of endogenous 
circulating IgG autoantibodies and IgG-antigen IC specifically involved in the 
pathogenesis of autoimmunity.  Blocking FcRn interactions with IgG containing 
immune complexes further predicts that SYNT001 will have consequences for 
innate and adaptive cellular immunity.  In the first instance, blocking multimeric 
IgG IC interactions with FcRn within antigen presenting cells will result in 
inhibition of IC-stimulated inflammatory cytokine production and release by 
these cells.  In addition, as FcRn determines the intracellular itinerary of IgG 
immune complexes within and among compartments important in cellular 
immunity, it is further anticipated that SYNT001 will block antigen processing 
and presentation of antigens contained within IC that otherwise lead to CD8+ and 
CD4+ T cell activation. Thus, SYNT001 will specifically target immune 
functions associated with IgG and IC that are involved in many autoimmune 
conditions and dismantle their ability to cause disease. 
SYNT001 targets mechanisms contributing to pathology in a variety of IgG-
mediated autoimmune disorders, including warm antibody autoimmune 
hemolytic anemia (WAIHA), pemphigus, and chronic inflammatory 
demyelinating polyneuropathy (CIDP).     
While current treatments for certain autoimmune disorders including chronic 
steroids, immunosuppressants, intravenous immunoglobulin (IVIG), 
plasmapheresis, and anti-CD20 monoclonal antibodies (mAbs), such as 
rituximab, can be effective, they are frequently associated with significant 
adverse effects, and delayed or non-durable responses.  
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin 
and mucous membranes. Autoantibodies are thought to play an important 
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pathogenic role in the mucosal and cutaneous manifestations in patients with 
pemphigus. Administration of SYNT001, leading to a significant decrease in 
total IgG, and thereby a corresponding decrease in the level of the pathogenic 
autoantibodies as well as the ICs to which they are associated, should lead to a 
decrease in the mucosal and cutaneous manifestations in subjects with 
pemphigus. Moreover, the ability of SYNT001 to reduce circulating immune 
complexes (CICs) and the associated innate and adaptive immune responses may 
allow for further sustained disease modification. 
Study rationale 
This study is being conducted to further evaluate the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of 
intravenous (IV) SYNT001 as well as its effects on pemphigus disease activity 
markers. 
Study objectives 
Primary objective 
• 
To evaluate the safety and tolerability of 5 once-weekly IV infusions of 
SYNT001 at different dose levels in subjects with chronic pemphigus 
(vulgaris or foliaceus) 
Secondary objectives 
• 
To determine the PK of SYNT001 following 5 once-weekly 1-hour IV 
infusions at different dose levels 
• 
To assess the effect of 5 once-weekly doses of SYNT001 at different dose 
levels on the following PD biomarkers: 
o Immunoglobulins: IgG, IgG subtypes (IgG1-4), IgA, IgM 
o Albumin 
• 
To assess the effect of 5 once-weekly doses of SYNT001 at different dose 
levels on the following disease activity markers: 
o Serum anti-desmoglein (Dsg) (1 and 3) antibody levels 
o Pemphigus Disease Area Index (PDAI) 
• 
To assess immunogenicity (anti-SYNT001 antibodies) 
Exploratory objectives 
• 
To assess the effect of 5 once-weekly doses of SYNT001 at different dose 
levels on the following biomarkers, including: 
o Serum anti-epithelial cell antibody (AECA) levels by indirect 
immunofluorescence 
o Circulating immune complexes (CIC) 
o Complement component 3 (C3) 
o Exploratory biomarkers (FCGR2A (single nucleotide polymorphism-
SNP), RNAseq, urine IgG) 
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o Immune phenotyping by flow cytometry for CD3+CD4+ T, 
CD3+CD8+ T, monocytes, NK cells and B cells 
o SYNT001 levels in skin biopsies (optional) 
• 
To characterize corticosteroid use during the study 
Study design 
Phase 1b, multicenter, open-label, safety, tolerability, and activity study 
Methodology 
Two cohorts of 8 eligible subjects each will receive 5 once-weekly 60-minute 
infusions of SYNT001 in planned doses of 10 mg/kg or 30 mg/kg. Based on 
review of safety, PD, and clinical outcomes of these 2 cohorts, a third cohort of 
up to 8 subjects may be treated at another dose, with a maximum dose of 45 
mg/kg, but may also be lower than 10 mg/kg or between 10 and 30 mg/kg, 
inclusive.  
Cohort 
No. of subjects 
Dose 
1 
8 
SYNT001 10 mg/kg 
2 
8 
SYNT001 30 mg/kg 
Cohorts will be dosed sequentially beginning with Cohort 1.  The first 2 subjects 
will be dosed at least 24 hours apart.  A review of the 24-hour safety data for the 
first subject will be performed to ensure that there are no overt safety concerns 
before dosing the second subject.  A review of the 7-day safety data for the first 
2 subjects will be performed prior to dosing the remaining 6 subjects in the 
cohort.  This evaluation will include a review of AE/SAE reports, vital sign 
assessments, physical examinations, ECGs, and clinical laboratory testing.  The 
seriousness, severity, and relatedness of AEs/SAEs will also be considered in the 
safety evaluation.  Safety data will be reviewed on a continuous basis throughout 
the study.  All safety data and any available and relevant PD data through Day 
42 (2 weeks after the last subject’s last dose in Cohort 1) will be reviewed by a 
dose escalation committee before Cohort 2 is initiated.  Escalation to Cohort 2 
will proceed if there are no concerning safety signals and the review of available 
and relevant PD data supports advancing to a higher dose. The dose for Cohort 2 
will be finalized after review of the safety and PD data, but will not exceed 30 
mg/kg.  Cohort 2 and Cohort 3, if added, will be dosed per the same schedule as 
Cohort 1. 
On days where study drug is administered, vital sign and pulse oximetry 
measurements will be collected immediately prior to the infusion; 15, 30, and 45 
minutes after the start of the infusion; at completion of the infusion; and 
30 minutes, 1 hour and 2 hours following completion of the infusion.  
On Days 0 and 28, PK blood samples will be collected prior to infusion start and 
then over the subsequent 48 hours.  Subjects will remain at the clinic through the 
6-hour PK sample collection and will return to the clinic for the 24- and 48-hour 
collections.  Additional samples will be collected on Days 5 and 33. 
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On Day 0 photographs will be taken of active lesions.  Follow-up photographs 
will be taken of the same areas on Days 33, 56, 84 and 112.  If a subject begins a 
steroid taper, additional photographs will be taken at the clinic visit during which 
the decision to begin the taper is made. 
Subsequent visits will occur on Days 1, 2, 5, 7, 12, 14, 19, 21, 28, 29, 30, 33, 42 
and 56 for safety assessments, study drug dosing, sample collections, and other 
study procedures. 
Subjects will return to the clinic on Days 84 and 112 for follow-up visits.  
Subjects whose total IgG is not within 30% of their Day 0 baseline value and not 
above 500 mg/dL at the Day 112 visit will be referred for further management.  
See Table 1 for a schedule of all study events.  To assess safety and tolerability, 
subjects will undergo physical examinations (PEs; including weight), vital sign 
measurements, clinical (safety) laboratory tests, adverse event (AE) assessments, 
concomitant medication assessments, and electrocardiograms (ECG). 
 
Number of subjects 
Approximately 16; two cohorts of 8 subjects each.  An additional cohort of up to 
8 subjects may be enrolled.  Subjects who withdraw for any reason other than an 
AE and who do not receive study drug or have only received one dose of study 
drug may be replaced, up to one subject per cohort.   The maximum number of 
subjects who may be enrolled in this study is 27 (24 + up to 3 replacements, as 
necessary).  Within each dosing cohort, no more than 3 subjects with pemphigus 
foliaceus may be enrolled. 
Diagnosis and main 
entry criteria 
Inclusion criteria: 
Subjects must meet the following criteria to be included: 
1. Willing and able to read, understand and sign an informed consent form;  
2. Male or female ≥ 18 years of age at the time of screening;  
3. Documented diagnosis of pemphigus vulgaris or foliaceus based on all 3 of 
the following criteria: 
a. Documented clinical history consistent with pemphigus vulgaris or 
foliaceus (clinical presentation defined as mucosal and/ or skin 
lesions); 
b. Presence of Anti-Dsg 1 or 3 antibodies above the upper limit of 
normal;  
c. History of at least one positive tissue-based test (e.g., biopsy, direct 
immunofluorescence [DIF]) 
4. Active disease: Lesions lasting > 2 weeks, and 3 active lesions in skin or 
mucosa or 2 active lesions with at least one being a skin lesion > 1 cm 
diameter: 
a. If treated with rituximab or other anti-CD20 antibodies, last dose 
> 12 months prior to screening; 
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b. If being treated with other immunosuppressants (i.e., azathioprine, 
mycophenolate mofetil or cyclosporine), must be on stable dose 
(< 10% change in dose) for 6 weeks prior to screening; 
c. If being treated with corticosteroids, must be ≤ 1mg/kg/day and 
stable (< 10% change in dose) for 2 weeks prior to screening; 
d. Allowed topical therapies for pemphigus lesions upon entering the 
study include petroleum jelly or Aquaphor® for the skin or 
chlorhexidine for the mouth 
5. Body mass index (BMI) 18.5 – 35.0 kg/m2; 
6. Has a negative urine pregnancy test (for women of childbearing potential) 
documented prior to the first dose of study drug;     
7. Females of childbearing potential must agree to be abstinent or else use any 
two of the following medically acceptable forms of contraception (<1% per 
year failure rate) from the Screening Period through the final study visit: oral 
contraceptive, condom with or without spermicidal jelly, diaphragm or 
cervical cap with spermicidal jelly, or intra-uterine device (IUD). A female 
whose male partner has had a vasectomy must agree to use one additional 
form of medically acceptable contraception.  
8. Females of non-childbearing potential, defined as surgically sterile (status 
post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or 
post-menopausal for at least 12 months do not require contraception during 
the study. 
9. Males with female partners of childbearing potential, including males who 
are surgically sterile (post vasectomy), must agree to be abstinent or else use 
a medically acceptable form of contraception from the screening period 
through the final study visit. 
 
Exclusion criteria: 
Subjects meeting any of the following criteria are to be excluded:  
1. Subject unable or unwilling to comply with the protocol; 
2. Active non-hematologic malignancy or history of non-hematologic 
malignancy in the 3 years prior to screening (exclusive of non-melanoma 
skin cancer and cervical cancer in situ); 
3. Positive for HIV or hepatitis C antibody;  
4. Positive for hepatitis B surface antigen; 
5. Active infection or history of recurrent infections; 
6. IVIG use within 60 days of screening; 
7. Received any cytotoxic (other than azathioprine) or mAb therapy in the 3 
months prior to screening; 
8. Any exposure to an investigational drug or device within the 30 days prior to 
screening 
9. Plasmapheresis or immunoadsorption within 60 days of screening 
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10. Cellular therapy at any time prior to screening 
11. Use of any immunosuppressive drugs apart from corticosteroids, 
azathioprine, mycophenolate mofetil, or cyclosporine within 3 months of 
screening 
12. Serum total IgG < 600 mg/dL; 
13. Subject has any current medical condition that, in the opinion of the 
Investigator, may compromise their safety or compliance, preclude 
successful conduct of the study, or interfere with interpretation of the results 
(e.g., a significant pre-existing illness or other major comorbidity that the 
Investigator considers may confound the interpretation of the study results); 
14. Any vaccination within 2 weeks of screening 
 
Study drug, dosage, 
and administration 
 SYNT001 
 
Doses: 10 mg/kg and 30 mg/kg. A third cohort of up to 8 subjects may be treated 
at another dose, with a maximum dose of 45 mg/kg, but may also be lower than 
10 mg/kg or between 10 and 30 mg/kg, inclusive. 
SYNT001 is provided as a liquid at a nominal concentration of 50 mg/mL. 
SYNT001 is diluted in Dextrose 5% in Water (D5W) to prepare the solution for 
infusion. 
Route of administration: IV in 250 mL over 1 hour 
Control, dose, and 
route of 
administration 
 Not applicable 
Duration of subject 
participation and 
duration of study 
Up to 126 days (18 weeks): Screening of up to 2 weeks (14 days); Treatment 
period of 8 weeks (56 days); Follow-up period of 8 weeks (56 days) 
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Prohibited 
Concomitant 
treatments 
All treatments a subject receives within 14 days prior to enrollment through the 
end of the study will be documented.  Concomitant medication and treatment for 
co-existing conditions, including those for pemphigus, are permitted if not 
excluded below.  Topical antibiotics are permitted to treat active infections that 
occur on study.  Topical or systemic treatments for oral candidiasis are 
permitted.  Topical lidocaine for transient pain relief is acceptable as needed.  
Significant increases in anti-pemphigus medications will result in subjects being 
discontinued from the study.  Concomitant treatment that is medically indicated 
for any AEs the subject experiences during the study are permitted. 
Use of the following medications will not be permitted during the study unless 
otherwise specified: 
• 
Rituximab or other anti-CD20 antibody 
• 
Monoclonal antibodies other than study drug 
• 
Any immunosuppressive drugs apart from corticosteroids, azathioprine, 
mycophenolate mofetil, or cyclosporine 
• 
Topical steroids 
• 
Any dietary herbal supplements 
• 
Any investigational drug or device 
• 
Any vaccinations through Day 56.  Following Day 56, subjects may 
receive vaccinations at the discretion of the Investigator. 
If over a period of at least two weeks on study drug, a subject on corticosteroids 
shows the absence of new lesions and significant healing of lesions that existed 
at study baseline, a slow corticosteroid taper may be started as per the following 
suggested schedule  
• 
If on > 30 mg of prednisone per day, decrease by 10 mg every two 
weeks until a dose of 30 mg per day then decrease by 5 mg every two 
weeks 
• 
If on < 30 mg of prednisone per day, decrease by 5 mg every two weeks 
 
Safety assessments 
Safety assessments include AEs, serious adverse events (SAEs), PEs, vital sign 
measurements, clinical safety laboratory evaluations, ECGs, and reasons for 
treatment discontinuations due to toxicity. Safety assessments will be performed 
at specified time points and prior to discharge from the clinic.  Vital sign 
measurements, including blood pressure, pulse rate, respiratory rate, and 
temperature will be monitored throughout the study.  Pulse oximetry will be 
monitored during the study drug infusion and for 2 hours following the end of 
the infusion. 
The National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE; Version 4.03) will be used for grading clinical and 
laboratory AEs.    
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The AE reporting period for a subject enrolled in the study begins when the 
subject provides informed consent and is continued through the last study visit. 
All AEs that occur in the enrolled subjects during the AE reporting period must 
be recorded, regardless of the relationship of the AE to study drug. Any known 
untoward event that occurs beyond the AE reporting period that the Investigator 
assesses as related to study drug should also be recorded. 
Dose-escalation rules 
Dose escalation decisions will be made by a Dose Escalation Committee (DEC) 
and will be based on safety and pharmacodynamic evaluations including but not 
limited to, dose-limiting toxicities, AEs, SAEs, and total IgG levels. 
Dose-limiting toxicity (DLT) will be defined generally as severe (Grade 3) AEs 
occurring in ≥ 2 subjects that are determined to be clinically significant and 
considered related to study drug. 
If 2 or more subjects at any time in any cohort (8 total subjects per cohort) have 
Grade 3 AEs that are determined to be clinically significant and considered to be 
related to study drug, dosing will be halted within that cohort and dose-
escalation to a higher dose will not occur. If the dose-escalation stopping rule is 
met during Cohort 1 (10 mg/kg) all safety data and all available 
pharmacodynamics data will be reviewed and the cohort may resume (if 
applicable) or a new cohort may be added, at a dose at least 50% lower than the 
10 mg/kg dose.  If the stopping rule is not met in Cohort 1 (10 mg/kg), dose-
escalation may proceed up to a maximum of 30 mg/kg.  If the dose-escalation 
stopping rule is met for the first time during Cohort 2, all safety data and all 
available pharmacodynamics data will be reviewed and the cohort may resume 
(if applicable) or a new cohort may be added at a dose at least 30% lower than 
the Cohort 2 dose. If the stopping rule is not met in Cohort 2, dose-escalation 
may proceed up to a maximum of 45 mg/kg; however, this cohort may also 
receive a dose equal to or less than 30 mg/kg based on evaluation of all safety 
and pharmacodynamic data.   
Study stopping rule 
If any subject experiences a life-threatening AE (Grade 4) that is considered to 
be related to study drug, any further dosing in all enrolled subjects will be 
suspended until the DEC has evaluated the event and determined the next 
appropriate course of action.  At any time during the study, the study may be 
discontinued if the DEC determines that further drug exposure would pose an 
undue risk to subjects. 
 
Individual stopping 
rule 
 
Dosing for any individual subject will be discontinued (i.e., further treatment 
with the study drug will not be given) if the subject experiences any study drug-
related SAE or any study drug-related non-SAE adverse event that, in the 
judgement of the Investigator (following consultation with the Medical Monitor, 
if desired) suggest that it could be unsafe to administer further study drug to that 
subject.  Additionally, a subject will be discontinued from further treatment with 
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study drug, at the discretion of the Investigator with consultation with the 
Medical Monitor, if they require a significant increase in dose(s) of anti-
pemphigus medication(s) for the management of pemphigus. 
Pharmacokinetics 
The PK of SYNT001 will be evaluated following the first and last (fifth) doses 
of SYNT001.   
Starting on Days 0 and 28, serum samples will be collected just prior to the start 
of study drug infusion (pre-dose), at 5 minutes and 2, 4, 6, 24, and 48 hours after 
the end-of-study drug infusion.  Additional samples will be collected on Days 5 
and 33. 
Study drug concentration will be used to calculate the following PK parameters: 
t1/2, Cmax, Tmax, AUC0-24, and AUC0-∞. 
Pharmacodynamics/ 
Activity 
PD samples will be collected for analysis of IgG (serial assessment of IgG levels 
to identify Cmin, Tmin); IgG1-4 subtype levels; IgA levels; IgM levels; albumin 
levels; anti-Dsg (1 and 3) antibody levels; serum AECA by direct 
immunofluorescence; CIC; C3; exploratory biomarkers (FCGR2A SNP, 
RNAseq, urine IgG, CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B 
cells).  
Immunogenicity 
Samples will be collected for immunogenicity analyses on Days 0 (pre-dose), 14, 
28, 56, 84 and 112. 
Skin biopsy 
Optional skin biopsy samples will be collected on Day 0 pre-dose and on Days 1, 
2, 14, 33, 56 and 84 to analyze SYNT001 levels.   
Photography 
Photographs of active lesions will be taken at Day 0.  Follow-up photographs of 
the same areas will be taken on Days 33, 56, 84 and 112.  Subjects who begin a 
steroid taper will have additional photographs taken at the clinic visit during 
which the decision to begin the taper is made. 
Statistical methods 
Sample size consideration 
Formal sample size calculations were not performed.  The number of subjects 
was chosen based on feasibility and was considered sufficient to meet the study 
objectives. 
 
Data presentations/Descriptive statistics 
Three populations will be employed in the analysis of study data. 
• 
The intent-to-treat (ITT) population will consist of all subjects who have 
received at least one dose of study drug.  All safety analyses will be 
performed on the ITT population. 
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• 
The PK population will consist of all subjects who receive at least one 
dose of study drug and have sufficient post-dose blood samples to obtain 
PK parameters. 
• 
The PD population will consist of all subjects who receive at least one 
dose of study drug and have post-dose PD data available. 
 
Primary safety analyses will be performed on the ITT population. Demographics, 
subject disposition, and screening and baseline characteristics will be 
summarized for the PK and ITT populations, where appropriate. 
 
Criteria for evaluation 
Objective 
Endpoint 
Primary  
Safety and tolerability of 5 once-
weekly IV infusions of SYNT001 to 
subjects with pemphigus vulgaris or 
foliaceus 
AEs and clinical (safety) 
laboratory tests 
Secondary  
PK of SYNT001 following a 1-hour IV 
infusion 
PK parameters: t1/2, Cmax, Tmax, 
AUC0-24, and AUC0-∞. 
Effect of 5 once-weekly IV doses of 
SYNT001 on: 
• Total IgG (IgG1-4), IgA, IgM, and 
albumin 
• Serum anti-Dsg (1 and 3) antibodies 
Changes in levels of IgG, IgG 
subtypes (IgG1-4), IgA, IgM, 
albumin, serum anti-Dsg (1 and 
3) antibodies 
Assess immunogenicity  
Anti-SYNT001 antibodies 
Disease Activity 
PDAI Scores 
Exploratory  
Effect of 5 once-weekly IV doses of 
SYNT001 on biomarkers including: 
• CIC 
• C3 
• Serum anti-epithelial cell antibody 
(AECA) levels 
• Exploratory biomarkers (FCGR2A 
SNP, RNAseq, urine IgG) 
• Immune phenotyping by flow 
cytometry 
Changes in CIC; C3; AECA 
levels by indirect 
immunofluorescence; FCGR2A 
SNP; RNAseq; urine IgG, 
CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B 
cells; urine IgG levels; changes 
in blood transcriptome 
Concomitant Treatment 
Corticosteroid use during the 
study 
SYNT001 levels in skin biopsies  
Measures of SYNT001 levels in 
skin biopsies 
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Treatment-emergent AEs (TEAEs) will be summarized using the Medical 
Dictionary for Regulatory Activities (MedDRA®; Version 19 or higher) System 
Organ Class (SOC) and preferred term, classified from verbatim terms.  The 
incidence and percentage of subjects with at least 1 occurrence of a preferred 
term will be included, using the most severe grade.  The number of events per 
preferred term will also be summarized.  Causality (relationship to study 
treatment) will be summarized separately. 
TEAEs, SAEs, and AEs leading to withdrawal, or treatment discontinuation will 
be listed by subject, and cohort using SOC and preferred terms. Duration of AEs 
will be determined and included in listings, along with action taken, and 
outcome.   
Laboratory results will be summarized by time point and cohort.  The incidence 
of laboratory abnormalities will be summarized.  The worst on-study grade after 
the first dose of study drug will be summarized.  Results for variables that are 
not coded will be presented in the listings as below, within, and above the 
normal limits of the central laboratory.  Vital sign measurements will be 
summarized by cohort at each scheduled time point using descriptive statistics.    
Study drug concentrations will be used to calculate the following PK parameters:  
t1/2, Cmax, Tmax, and area under the curve (AUC).  PK parameters will be 
determined using non-compartmental method(s).   Descriptive statistics of PK 
parameters for SYNT001 will include mean, standard deviation (SD), coefficient 
of variation (CV), median, minimum, and maximum. Tmax will be reported as 
median and range. All descriptive statistics will be performed on untransformed 
PK parameters and after log10 transformation of PK parameters. 
PD results will be summarized by cohort.  Descriptive statistics of PD 
parameters for SYNT001 will include mean, SD, CV, median, minimum, and 
maximum. 
Immunogenicity results will be summarized by cohort.  Descriptive statistics will 
include mean, SD, CV, median, minimum, and maximum. 
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Table 1: 
Study Assessments  
 
Screening 
Treatment Period  
Follow-Up  
Timepoint (Study Day) 
-14 to -1 
0 
1 
(±1 
hr) 
2 
(± 2 
hr) 
5p 
(±4 
hr) 
7  
(±6 
hr) 
12p  
(±6 
hr) 
14  
(±6 
hr) 
19p  
(±6 
hr) 
21 
(±6 
hr) 
28 
(±6 
hr) 
29 
(±1 
hr) 
30 
(±2 
hr) 
33 
(±4 
hr) 
42 
(±3 
days) 
56 
(±5 
days) 
84 
(±5 
days) 
 
112 
(±5 days) or ET 
Visit 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationa 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
Vital Signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetryc 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Clinical Safety Labsd 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECGf 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Tetanus & VZV antibodies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
PDAI Score 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
PK Samplingh 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Immunogenicityi  
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
X 
Study Drug Administrationj 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Immunoglobulins (IgG, IgA, 
IgM) and IgG subtypes (IgG 1-4)k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
CIC 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Anti-Dsg (1 & 3) antibody titer 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
C3 and AECAl 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
FCGR2Am 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNAseqm 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Urine IgGm 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Immune phenotypingn 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Optional Skin Biopsy 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
Photographyo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Adverse Events 
To be collected from the date that the ICF is signed through the last study visit 
Concomitant Medications 
To be collected from within 14 days prior to Day 0 through  the last study visit 
ECG = electrocardiogram; ET= Early Termination; HIV = human immunodeficiency virus; ICF = informed consent form; PD = pharmacodynamic; PK = pharmacokinetic; VZV = 
varicella-zoster virus 
 
 
 
 
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a: Complete PE, including weight, to be performed.  Height and BMI will be additional assessments conducted at screening. 
b: Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and oral temperature) to be obtained after 5 minutes of seated rest.  Any abnormal measurements are to 
be repeated after 5 minutes of rest.  On Days 0, 7, 14, 21, and 28 vital sign measurements will be collected immediately prior to the infusion; 15, 30, and 45 minutes after the start 
of the infusion; at completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion.   
c: Pulse oximetry: On Days 0, 7, 14, 21, and 28, pulse oximetry to be measured immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at completion 
of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion. 
d: Clinical safety labs: hematology, clinical chemistry, and urinalysis (see Section 6.7 for a complete list).  Full clinical safety lab draws will be collected at Screening and on Days 
0, 7, 14, 21, 28, 33, 42, 56, 84 and 112. 
e: Pregnancy test:  To be performed at time of screening and prior to first dose of SYNT001 on Day 0 and on Days 56 and 112 (urine or serum test is acceptable, however, positive 
urine tests must be confirmed with serum testing.) 
f: Digital 12-lead ECG to be obtained after 5 minutes of rest in the supine position and in triplicate at least 1-2 minutes apart (see Section 6.6 for additional information).  On Days 0 
and 28 to be obtained 5 minutes after the completion of infusion. Day 12 ECG will be collected only if the visit is conducted at the study site.  
g: Serology:  Testing at Day 56 will not be done for any subject whose baseline titer is below the level of detection. If the Day 56 results are greater than 30% below the baseline 
value, or if the subject falls below the level of detection, the subject will be re-tested at Day 84; if still below the baseline value (or level of detection), the subject will be re-tested 
at Day 112. Any subject whose baseline value for tetanus or VZV was above the detectable level at baseline, and is not within 30% of the baseline value or is below the detectable 
level by Day 112, will be referred to their primary care physician for further management. See Section 6.7.3 for additional information. 
h: PK:  Starting on Days 0 and 28, serum samples will be collected just prior to the start of study drug infusion (pre-dose), and at 5 minutes and 2, 4, 6, 24, and 48 hours after the 
end-of-study drug infusion.  Additional samples will be collected on Days 5 and 33.  See Section 6.7.4 for additional information.  
i: Immunogenicity:  Blood samples will be collected pre-dose when collected on dosing days.  Samples will be collected on Days 0, 14, 28, 56, 84 and 112. See Section 6.7.6 for 
additional information. 
j: Prior to study drug infusion, SYNT001 drug product is to be diluted in Dextrose 5% in Water (D5W) to a total volume of 250 mL and administered intravenously over 1 hour 
using a 0.2-micron, inline filter.  See Section 9 for additional information. 
k: Immunoglobulins (IgG, IgA, IgM) and IgG subtypes (IgG 1-4): Collected for measurements of IgG, IgG subtypes (IgG1-4), IgA, and IgM at every visit. On Days 0, 7, 14, 21, 
and 28, samples are collected prior to infusion of study drug. See Section 6.7.5 for additional information   
l: Exploratory PD samples (C3 and AECA): collected pre-dose when collected on dosing days. See Section 6.7.5  for complete information. 
m: Samples to be collected and stored; pending review of clinical and pharmacodynamics assessments 
n: Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B cells 
o: Photographs of active lesions taken prior to first dose on Day 0.  Follow-up photographs will be taken at Days 33, 56, 84 and 112.  Subjects who begin a steroid taper will have 
additional photographs taken at the clinic visit during which the decision to begin the taper is made. 
p: Visit Days 5, 12 and 19 may be conducted via at-home nursing in lieu of a subject visit to the study site. 
q: Subjects will return to the clinic on Days 84 and 112 for follow-up visits.  Subjects whose total IgG is not within 30% of their Day 0 baseline value and not above 500 mg/dL at the 
Day 112 visit will be referred for further management. 
 
 
 
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Table 2: 
Timing Window Allowances for PK/PD Sampling, ECG, and Vital Sign Measurements 
Pharmacokinetic and Pharmacodynamic Sampling 
 
Timepoint 
Tolerance Window 
0 hour 
−240 min to 0 hour 
5 minutes post end-of-infusion 
± 5 minutes 
2, 4, & 6 hours post end-of-infusion 
± 15 minutes 
24 hours post end-of-infusion 
± 60 minutes 
48 hours post end-of-infusion  
± 120 minutes 
ECG 
 
Timepoint 
Tolerance Window 
5 minutes post end-of-infusion 
± 10 minutes 
Vital Signsa 
 
Timepoint 
Tolerance Window 
0 hour 
−240 min to 0 hour 
15, 30, and 45 minutes after start of infusion 
± 5 minutes 
60 minutes after start of infusion 
± 10 minutes 
30, 60 and 120 minutes post end-of-infusion 
± 10 minutes 
a:  Vital signs to include blood pressure, pulse rate, respiratory rate, oral temperature, and pulse oximetry.
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TABLE OF CONTENTS 
PROCEDURES IN CASE OF EMERGENCY ...................................................................3 
INVESTIGATOR SIGNATURE.........................................................................................4 
1 
SYNOPSIS ..................................................................................................................5 
LIST OF ABBREVIATIONS ............................................................................................24 
2 
BACKGROUND AND RATIONALE .....................................................................26 
2.1 
Study Rationale ................................................................................................27 
2.2 
Selection of Doses in this Study ......................................................................27 
2.3 
Compliance Statement .....................................................................................28 
3 
STUDY OBJECTIVES .............................................................................................29 
3.1 
Primary Objective ............................................................................................29 
3.2 
Secondary Objectives.......................................................................................29 
3.3 
Exploratory Objectives ....................................................................................29 
4 
STUDY DESIGN......................................................................................................30 
4.1 
Study Sites .......................................................................................................30 
4.2 
Study Endpoints ...............................................................................................30 
4.3 
Overview of Study Design ...............................................................................31 
4.4 
Randomization and Blinding ...........................................................................33 
5 
STUDY POPULATION ...........................................................................................34 
5.1 
Target Population .............................................................................................34 
5.2 
Inclusion Criteria .............................................................................................34 
5.3 
Exclusion Criteria ............................................................................................35 
6 
STUDY PROCEDURES ..........................................................................................37 
6.1 
Informed Consent.............................................................................................37 
6.2 
Demographics and Medical History ................................................................37 
6.3 
Physical Examination.......................................................................................37 
6.4 
Pemphigus Disease Area Index (PDAI) Scoring .............................................37 
6.5 
Vital Sign Measurements .................................................................................37 
6.6 
12-Lead Electrocardiogram (ECG) ..................................................................38 
6.7 
Clinical Laboratory Measurements ..................................................................39 
6.7.1 
Pregnancy Testing ................................................................................40 
6.7.2 
Virology ...............................................................................................40 
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6.7.3 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing40 
6.7.4 
Pharmacokinetics (PK) Sampling ........................................................40 
6.7.5 
Pharmacodynamic Sampling ...............................................................41 
6.7.6 
Immunogenicity Testing ......................................................................42 
6.8 
Study Drug Administration ..............................................................................43 
6.9 
Prior and Concomitant Medications ................................................................43 
6.10 
Adverse Event Assessments ............................................................................43 
6.11 
Photographs......................................................................................................44 
6.12 
Skin Biopsy ......................................................................................................44 
7 
STUDY ASSESSMENTS ........................................................................................45 
7.1 
Screening Period: Day -14 to Day -1 ...............................................................45 
7.2 
Enrollment and First Treatment: Day 0 ...........................................................45 
7.3 
Follow-up: Day 1 .............................................................................................47 
7.4 
Follow-up: Day 2 .............................................................................................47 
7.5 
Follow-up: Day 5 .............................................................................................48 
7.6 
Treatment Day 7 (Dose 2) ................................................................................48 
7.7 
Dose 2 Follow-up Day 12 ................................................................................49 
7.8 
Treatment Day 14 (Dose 3) ..............................................................................49 
7.9 
Dose 3 Follow-up Day 19 ................................................................................51 
7.10 
Treatment Day 21 (Dose 4) ..............................................................................51 
7.11 
Treatment Day 28 (Dose 5) ..............................................................................52 
7.12 
Follow-up Day 29 ............................................................................................53 
7.13 
Follow-up Day 30 ............................................................................................54 
7.14 
Follow-up Day 33 ............................................................................................54 
7.15 
Follow-up Day 42 ............................................................................................55 
7.16 
Follow-up Day 56 ............................................................................................55 
7.17 
Follow-up Day 84 ............................................................................................56 
7.18 
Follow-up Day 112 (End-of-Study) or Early Termination Visit .....................57 
8 
REMOVING SUBJECTS FROM STUDY ..............................................................58 
8.1 
Subject Withdrawal ..........................................................................................58 
8.2 
Study Discontinuation ......................................................................................59 
8.3 
Replacements ...................................................................................................59 
8.4 
Stopping Rule...................................................................................................59 
8.4.1 
Dose-Escalation Stopping Rule ...........................................................59 
8.4.2 
Study Stopping Rule ............................................................................60 
8.4.3 
Individual Stopping Rule .....................................................................60 
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9 
STUDY DRUG .........................................................................................................61 
9.1 
SYNT001 .........................................................................................................61 
9.2 
Cohort Dosing ..................................................................................................61 
9.3 
Timing of Dosing .............................................................................................61 
9.4 
Identity of Investigational Products .................................................................61 
9.5 
Investigational Product Retention at Study Site ..............................................62 
9.6 
Warnings and Precautions................................................................................62 
9.6.1 
Infusion Reaction .................................................................................62 
9.6.2 
Potential Immune Effects .....................................................................67 
10 
CONCOMITANT MEDICATION AND TREATMENT ........................................69 
11 
SAFETY ...................................................................................................................71 
11.1 
Safety Parameters.............................................................................................71 
11.2 
Adverse Event Definition ................................................................................71 
11.3 
Evaluating Adverse Events ..............................................................................72 
11.3.1 
Serious Adverse Events .......................................................................72 
11.3.2 
Overdose ..............................................................................................73 
11.3.3 
Non-Serious Adverse Events ...............................................................73 
11.3.4 
Protocol-Related Adverse Events ........................................................73 
11.3.5 
Assessment of Causality ......................................................................73 
11.3.6 
Recording Adverse Events ...................................................................74 
11.3.7 
Planned Hospitalization .......................................................................74 
11.3.8 
Reporting Pregnancies .........................................................................75 
11.3.9 
Serious Adverse Event Reporting ........................................................75 
11.3.9.1 Governing Regulatory Requirements ..................................................75 
11.3.9.2 Time Frame for Reporting ...................................................................76 
11.3.9.3 Information to be Provided by the Investigator ...................................77 
11.3.10 Regulatory Reporting ...........................................................................78 
11.3.11 Follow-up Information on a Serious Adverse Event (SAE) ................79 
11.4 
Other Safety Considerations ............................................................................79 
11.4.1 
Laboratory Data ...................................................................................79 
11.4.2 
Medication Errors ................................................................................79 
11.4.3 
Follow-Up of Adverse Events .............................................................79 
11.5 
Safety Monitoring for Dose Escalation............................................................79 
12 
STATISTICAL CONSIDERATIONS......................................................................81 
12.1 
General Design.................................................................................................81 
12.2 
Sample Size Justification .................................................................................81 
12.3 
Statistical Considerations .................................................................................81 
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12.3.1 
Study Populations ................................................................................81 
12.3.2 
Subject Accountability, Demographics, and Baseline Characteristics 82 
12.3.3 
Concomitant Medications ....................................................................82 
12.4 
Planned PK Analysis........................................................................................82 
12.5 
Safety Data .......................................................................................................83 
12.6 
Pharmacodynamic/Activity Data .....................................................................83 
12.7 
Immunogenicity Data.......................................................................................83 
12.8 
Interim Analysis ...............................................................................................84 
13 
DATA QUALITY ASSURANCE ............................................................................85 
14 
STUDY ADMINISTRATION..................................................................................86 
14.1 
Study Administrative Structure........................................................................86 
14.2 
Ethical Conduct of the Study ...........................................................................86 
14.3 
Informed Consent (ICF) ...................................................................................86 
14.4 
Institutional Review Board ..............................................................................87 
14.5 
Dose Escalation Committee .............................................................................87 
14.6 
Future Use of Subject Samples ........................................................................88 
15 
CONDITIONS FOR MODIFYING THE PROTOCOL...........................................89 
16 
CONDITIONS FOR TERMINATING THE STUDY .............................................90 
17 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING .......................91 
17.1 
Investigator’s Files and Retention of Documents ............................................91 
17.2 
Source Documents and Background Data .......................................................91 
17.3 
Audits and Inspections .....................................................................................92 
17.4 
Electronic Case Report Forms .........................................................................93 
18 
MONITORING THE STUDY ..................................................................................94 
19 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS ...95 
20 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS............96 
21 
REFERENCES .........................................................................................................97 
 
 
 
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LIST OF TABLES 
Table 1: 
Study Assessments .................................................................................... 16 
Table 2: 
Timing Window Allowances for PK/PD Sampling, ECG, and Vital Sign 
Measurements ........................................................................................... 18 
Table 3: 
Clinical Laboratory Panels ........................................................................ 39 
Table 4:  
Pharmacodynamic/ Activity Assessments ................................................ 42 
Table 5: 
Grading and Management of Allergic or Infusion-Related Reactions ..... 66 
Table 6 :  
Study Administrative Structure................................................................. 86 
 
LIST OF FIGURES 
Figure 1:  Management of Mild (Grade 1) to Moderate (Grade 2) Infusion Reactions .... 64 
Figure 2:  Management of Severe (Grade 3 or higher) Infusion Reactions ...................... 65 
 
 
LIST OF APPENDICES 
Appendix A: NCI CTCAE, Version 4.03 ......................................................................... 99 
Appendix B: Pemphigus Disease Area Index ................................................................. 100 
 
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LIST OF ABBREVIATIONS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AECA 
Anti-epithelial cell antibody 
ALT 
Alanine aminotransferase 
ANA 
Antinuclear antibody 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC0-24 
Area under the plasma concentration-time curve from pre-dose (time 0) to 24 hours post-dose 
AUC0-∞ 
Area under the plasma concentration-time curve from pre-dose (time 0) to infinity 
BLQ 
Below the limit of quantification  
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CAR-T 
Chimeric antigen receptor and T-cell 
CFR 
Code of Federal Regulations 
C3 
Complement component 3 
CBC 
Complete blood count 
CIC 
Circulating immune complexes 
CIDP 
Chronic inflammatory demyelinating polyneuropathy 
Cmax 
Maximum plasma concentration determined directly from the concentration-time profile 
CRO 
Contract research organization 
CV 
Coefficient of variation 
CVID 
Common variable immune deficiency 
DEC 
Dose escalation committee 
D5W 
Dextrose 5% in Water 
DIF 
Direct immunofluorescence 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ESR 
Erythrocyte sedimentation rate 
FcGR2a 
Fc Gamma R2a receptor 
FcRn 
Neonatal Fc receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
IC 
Immune complex 
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ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgG1-4 
Immunoglobulin G1-G4 
IgM 
Immunoglobulin M 
IL-12 
Interleukin 12 
IND 
Investigational new drug 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IUD 
Intrauterine devices 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHL 
Non-Hodgkin lymphoma 
PD 
Pharmacodynamics 
PE 
Physical examination 
PK 
Pharmacokinetic 
RBC 
RNAseq 
Red blood cells 
RNA sequencing 
QTcF 
Corrected QT interval using Fridericia's formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SD 
Standard deviation 
SNP 
Single nucleotide polymorphism 
SOC 
System Organ Class 
SOP 
Standard operating procedures 
SYNT001 
A humanized, affinity matured IgG4-kappa monoclonal antibody 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Observed time to reach peak plasma concentration 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
UNS 
Unscheduled 
VZV 
Varicella-zoster virus 
WAIHA 
Warm antibody autoimmune hemolytic anemia 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
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2 
BACKGROUND AND RATIONALE 
SYNT001, a humanized, affinity-matured IgG4-kappa monoclonal antibody (mAb), blocks IgG 
and IgG immune complex (IC) interactions with the neonatal Fc receptor (FcRn) and thereby the 
major functions of FcRn in protecting IgG and IgG ICs from degradation and their role in 
downstream signaling events. Specific and high affinity blockade of FcRn with SYNT001 has 
been shown to increase the catabolism of IgG and IgG IC in healthy volunteers. This predicts 
that SYNT001 will also accelerate degradation of endogenous circulating IgG autoantibodies and 
IgG-antigen IC specifically involved in the pathogenesis of autoimmunity.  Blocking FcRn 
interactions with IgG-containing ICs further predicts that SYNT001 will have consequences for 
innate and adaptive cellular immunity.  In the first instance, blocking multimeric IgG IC 
interactions with FcRn within antigen-presenting cells will result in inhibition of IC-stimulated 
inflammatory cytokine production and release by these cells.  In addition, as FcRn determines 
the intracellular itinerary of IgG ICs within and among compartments important in cellular 
immunity, it is anticipated that SYNT001 will block antigen processing and presentation of 
antigens contained within IC that otherwise lead to CD8+ and CD4+ T cell activation. Thus, 
SYNT001 will specifically target immune functions associated with IgG that are involved in 
certain autoimmune conditions and dismantle their ability to cause disease. 
SYNT001 targets key mechanisms contributing to pathology in a variety of IgG-mediated 
autoimmune disorders, including warm antibody autoimmune hemolytic anemia (WAIHA), 
pemphigus, and chronic inflammatory demyelinating polyneuropathy (CIDP).   
While current treatments for certain autoimmune disorders, including high-dose steroids, 
immunosuppressants, intravenous immunoglobulin (IVIG), plasmapheresis, and anti-CD20 
monoclonal antibodies (mAbs), such as rituximab, can be effective, they are associated with 
significant adverse effects, as well as delayed or non-durable responses.  
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous 
membranes. Autoantibodies have been shown to play an important pathogenic role in the 
mucosal and cutaneous manifestations in patients with pemphigus. Administration of SYNT001, 
which significantly decreases total IgG, including a corresponding decrease in the level of the 
pathogenic autoantibodies and the ICs to which they are associated, may lead to a decrease in the 
mucosal and cutaneous manifestations in patients with pemphigus. Moreover, the ability of 
SYNT001 to reduce circulating immune complexes (CICs) and the associated innate and 
adaptive immune responses may allow for further sustained disease modification. 
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2.1 
Study Rationale 
This study is being conducted to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD) and immunogenicity of intravenous (IV) SYNT001 as well as its 
effects on pemphigus disease activity markers. 
2.2 
Selection of Doses in this Study  
The planned dose levels of SYNT001 for this Phase 1b safety and proof-of-concept study of 10 
mg/kg and 30 mg/kg were selected from careful review of the safety, tolerability, and PD effect 
on total IgG levels after single and repeat dosing of SYNT001 in non-human primates (NHPs), 
as well as the safety, tolerability, and PD effect on total IgG levels after single ascending doses 
of SYNT001 in healthy volunteers. In addition, further consideration was given to the desired 
level of FcRn blockade to achieve suppression of IgG to a range that has been previously 
correlated with disease remission. Further, we considered the potential effects of inhibiting FcRn 
function as they relate to immune complex associated innate and adaptive immunity in choosing 
these dose levels based upon exploratory studies of a single ascending dose of SYNT001 in 
healthy volunteers. From the NHP studies, single doses of SYNT001 produced a dose-dependent 
decrease in total IgG and a further decrease was seen with repeated weekly doses up to a 
maximum 70% reduction at 100 mg/kg. This magnitude of total IgG reduction is approaching the 
expected maximal effect of 100% inhibition of FcRn function based on murine studies also 
performed by Syntimmune and others [Roopenian 2003, Nixon 2015]. In the recently completed 
Phase 1a trial with SYNT001 in healthy volunteers a single dose caused a maximum average 
50% drop in total IgG with IV dosing at 30 mg/kg. Based on the NHP studies further reductions 
are expected following multiple dosing. A comparable decrease in pathogenic autoantibodies is 
also anticipated. 
In the NHP studies, relevant adverse effects, mild-to-moderate infusion reactions, were observed 
only after the third weekly IV administration, concurrent with the development of anti-SYNT001 
antibodies. In the recently completed Phase 1a healthy male volunteer study, the doses of 
SYNT001 up to and including 30 mg/kg have been well tolerated. There were no dose limiting 
toxicities, serious adverse events, or any other safety concerns identified.  No AEs were observed 
in the 1 and 3 mg/kg dose cohorts. A single Grade 2 AE was observed; a headache in the 10 
mg/kg cohort, treated with acetaminophen. Other subjects had mild (Grade 1) AEs at 10 mg/kg. 
In Cohort 4 (30 mg/kg), 5 subjects received SYNT001. All five subjects experienced AEs; all 
were mild (Grade 1), transient and resolved spontaneously without intervention. Therefore, it is 
anticipated that the doses selected for this study should be well tolerated and have clinically 
relevant PD effects in patients with chronic pemphigus (vulgaris or foliaceus). For a summary of 
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findings from the single dose, clinical study in healthy subjects and further details on the 
nonclinical findings, please refer to the SYNT001 Investigator’s Brochure.  
2.3 
Compliance Statement 
This study will be conducted in compliance with Good Clinical Practice (GCP), including the 
International Conference on Harmonisation (ICH) Guidelines and FDA regulations, consistent 
with the principles outlined in the Declaration of Helsinki.  In addition, the Investigator agrees to 
adhere to all applicable local laws and regulatory requirements relevant to the use of new 
therapeutic agents. 
The study will be conducted in compliance with the protocol.  The appropriate Institutional 
Review Boards (IRBs) must approve the protocol, any amendments, and the subject informed 
consent form (ICF) prior to implementation.  
Freely given written informed consent must be obtained from every subject prior to participation 
in this clinical trial.  As part of this procedure, the Investigator must explain orally and in writing 
the nature, duration, and purpose of the study, and the action of the drug in such a manner that 
the study subject is aware of the potential risks, inconveniences, or AEs that may occur.  The 
study subject should be informed that he/she is free to withdraw from the study at any time.  
He/she will receive all information that is required by federal regulations and ICH guidelines.  
The Investigator or designee will provide the Sponsor with a copy of the IRB-approved informed 
consent form prior to the start of the study. The rights, safety, and well-being of participating 
subjects are the most important considerations and should prevail over interests of science and 
society. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s).  This trial will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct or 
fraud (e.g., loss of medical licensure, debarment). 
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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of 5 once-weekly IV 
infusions of SYNT001 at different dose levels in subjects with chronic pemphigus (vulgaris or 
foliaceus). 
3.2 
Secondary Objectives 
The secondary objectives of this study are as follow: 
• To determine the PK of SYNT001 following 5 once-weekly 1-hour IV infusions at 
different dose levels 
• To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the 
following PD biomarkers: 
o Immunoglobulins: IgG, IgG subtypes (IgG1-4), IgA, IgM  
o Albumin 
• To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the 
following disease activity markers: 
o Serum anti-desmoglein (Dsg) (1 and 3) antibody levels 
o Pemphigus Disease Area Index (PDAI) 
• To assess immunogenicity (anti-SYNT001 antibodies) 
3.3 
Exploratory Objectives 
The exploratory objectives of this study are as follow: 
• To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the 
following biomarkers, including: 
o Serum anti-epithelial cell antibody (AECA) levels by indirect immunofluorescence  
o Circulating immune complexes (CIC) 
o Complement component 3 (C3) 
o Exploratory biomarkers (FCGR2A single nucleotide polymorphism-SNP, RNAseq, 
urine IgG) 
o Immune phenotyping by flow cytometry for CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B cells 
o SYNT001 levels in skin biopsies (optional) 
• To characterize corticosteroid use during the study 
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4 
STUDY DESIGN 
4.1 
Study Sites 
This study will be conducted at approximately 10 sites in the United States (US). 
4.2 
Study Endpoints 
Primary Outcome Measures:  Assessment of safety data (adverse events [AEs], serious 
adverse events [SAEs], vital sign measurements, ECGs and clinical laboratory tests) will be the 
primary safety measure.   
Secondary Outcome Measures 
Pharmacokinetics: 
• Half-life (t1/2), maximum plasma concentration determined directly from the 
concentration-time profile (Cmax), observed time to reach peak plasma concentration 
(Tmax), area under the plasma concentration-time curve from pre-dose (time 0) to 
24 hours post-dose (AUC0-24), and area under the plasma concentration-time curve 
from pre-dose (time 0) to infinity (AUC0-∞) 
PD Biomarkers: 
• Ig Assessments: Serial assessments of total IgG and IgG subtypes (IgG1-4)  
o Serial assessments of total IgG and IgG subtypes (IgG1-4) 
o IgA levels 
o IgM levels 
• Albumin levels 
 
Disease activity markers: 
• Serum anti-desmoglein (Dsg) (1 and 3) antibody levels 
• Pemphigus Disease Area Index (PDAI) scores 
Immunogenicity: 
• Anti-SYNT001 antibodies 
Exploratory Outcome Measures 
Biomarkers, including: 
• CIC 
• C3 
• Serum AECA levels  
• Exploratory biomarkers (FCGR2A SNP, RNAseq, urine IgG) 
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• Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, 
CD3+CD8+ T, monocytes, NK cells and B cells 
• SYNT001 levels in skin biopsies (optional) 
 
Concomitant Treatments 
• Corticosteroid use 
 
Further details on the statistical and analytical plan for these endpoints are available in 
Section 12, Statistical Considerations.           
4.3 
Overview of Study Design 
This will be a multicenter, open-label study to assess the safety, tolerability, activity, PK, PD, 
and immunogenicity of 5 once-weekly IV infusions of SYNT001 to subjects with chronic 
pemphigus (vulgaris or foliaceus). 
Planned doses of SYNT001 to be studied are 10 mg/kg and up to 30 mg/kg.  Two cohorts of 8 
eligible subjects each will receive 5 once-weekly 60-minute infusions of SYNT001 10 mg/kg or 
up to 30 mg/kg. Based on review of safety, PD, and clinical outcomes of the first cohort, the dose 
for the second cohort may be adjusted, but with a maximum dose of 30 mg/kg.  Based on review 
of safety, PD and clinical outcomes from these 2 cohorts, a third cohort of up to 8 subjects may 
be treated at another dose, with a maximum dose of 45 mg/kg, but may also be lower than 10 
mg/kg or between 10 and 30 mg/kg, inclusive. 
Cohort 
No. of 
Subjects 
Dose 
1 
8 
SYNT001 10 mg/kg 
2 
8 
SYNT001 30 mg/kg 
Cohorts will be dosed sequentially beginning with Cohort 1.  The first 2 subjects will be dosed at 
least 24 hours apart.  A review of the 24-hour safety data for the first subject will be performed 
to ensure that there are no overt safety concerns before dosing the second subject.  A review of 
the 7-day safety data for the first 2 subjects will be performed prior to dosing the remaining 6 
subjects in the cohort.  This evaluation will include a review of AE/SAE reports, vital sign 
assessments, physical examinations, ECGs and clinical laboratory testing.  The seriousness, 
severity, and relatedness of AEs/SAEs will also be considered in the safety evaluation.  Safety 
data will be reviewed on a continuous basis throughout the study.  All data through Day 42 
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(2 weeks after the last subject’s last dose in Cohort 1) will be reviewed before Cohort 2 is 
initiated.  Cohort 2 and Cohort 3, if added, will be dosed per the same schedule.  
Safety evaluations will be conducted by a dose escalation committee (DEC). The DEC will 
consist of the Medical Monitor, an Independent Clinical Expert and a Syntimmune Medical 
Officer. To assist in the safety assessments, the DEC may request that Investigators, other 
experts, or members within their organizations review the data and participate in the 
discussions.  Dosing and dose escalation will proceed if the DEC has determined that it would be 
safe and appropriate to do so.  In addition, over the course of the study, the DEC will review any 
drug-related SAEs to determine if modifications to the study or other measures are necessary to 
ensure the safety of the subjects.   
On days where study drug is administered, vital sign and pulse oximetry measurements will be 
collected immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; 
at completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the 
infusion.  
On Days 0 and 28, PK blood samples will be collected prior to infusion start and then over the 
subsequent 48 hours.  Subjects will remain at the clinic through the 6-hour PK sample collection 
and will return to the clinic for the 24- and 48-hour collections.  Additional samples will be 
collected on Days 5 and 33.   
On Day 0 photographs will be taken of active lesions.  Follow-up photographs will be taken of 
the same areas on Days 33, 56, 84, and 112.  If a subject begins a steroid taper, additional 
photographs will be taken at the clinic visit during which the decision to begin the taper is made. 
Subsequent visits will occur on Days 1, 2, 5, 7, 12, 14, 19, 21, 28, 29, 30, 33, 42 and 56 for 
safety assessments, study drug dosing, sample collections, and other study procedures. 
Subjects also will return to the clinic on Days 84 and 112 for follow-up visits.  Subjects whose 
total IgG is not within 30% of their Day 0 baseline value and not above 500 mg/dL at the Day 
112 visit will be referred for further management. 
See Table 1 for a schedule of all study events.  To assess safety and tolerability, subjects will 
undergo physical examinations (PEs; including weight), vital sign measurements, clinical 
(safety) laboratory tests, AE assessments, concomitant medication assessments, and 
electrocardiograms (ECG). 
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Note:  No vaccinations may be given from within 2 weeks of screening through Day 56.  
Following Day 56, subjects may receive vaccinations at the discretion of the Investigator. 
4.4 
Randomization and Blinding 
This is an open-label study. 
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5 
STUDY POPULATION 
5.1 
Target Population 
This study will be conducted in approximately 16 male and female subjects (2 cohorts of 8 
subjects each) with a confirmed diagnosis of pemphigus (vulgaris or foliaceus); however, a third 
cohort of up to 8 subjects may be added.  Subjects will be enrolled only once in the study and 
will not be included in subsequent dosing cohorts. Subjects who withdraw for any reason other 
than an AE and who do not receive study drug or have only received one dose of study drug may 
be replaced, up to one subject per cohort. Subjects who do not receive all doses of study drug 
will continue to be followed through all scheduled visits.  The maximum number of subjects who 
may be enrolled in this study is 27 (24 + up to 3 replacements, as necessary).  Within each 
dosing cohort, no more than 3 subjects may be enrolled with pemphigus foliaceus. 
5.2 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for the study: 
1. Willing and able to read, understand and sign an informed consent form;  
2. Male or female ≥ 18 years of age;  
3. Documented diagnosis of pemphigus vulgaris or foliaceus based on all 3 of the following 
criteria: 
a. Documented clinical history consistent with pemphigus vulgaris or foliaceus 
(clinical presentation defined as mucosal and/ or skin lesions); 
b.  Presence of Anti-Dsg 1 or 3 antibodies above the upper limit of normal; 
c. History of at least one positive tissue based test (biopsy, DIF) 
4. Active disease: Lesions lasting > 2 weeks, and 3 active lesions in skin or mucosa or 2 
active lesions with at least one being a skin lesion > 1 cm diameter: 
a. If treated with rituximab or other anti-CD20 antibodies, last dose > 12 months 
prior to screening; 
b. If being treated with other immunosuppressants (i.e., azathioprine, mycophenolate 
mofetil or cyclosporine), must be on stable dose (< 10% change in dose) for 
6 weeks prior to screening; 
c. If being treated with corticosteroids, must be ≤ 1mg/kg/day and stable (< 10% 
change in dose) for 2 weeks prior to screening; 
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d. Allowed topical therapies for pemphigus lesions upon entering the study include 
petroleum jelly or Aquaphor® for the skin or chlorhexidine for the mouth  
5. Body mass index (BMI) 18.5 – 35.0 kg/m2; 
6. Has a negative urine pregnancy test (for women of childbearing potential) documented 
prior to the first dose of study drug;     
7. Females of childbearing potential must agree to be abstinent or else use any two of the 
following medically acceptable forms of contraception (<1% per year failure rate) from 
the Screening Period through the final study visit: oral contraceptive, condom with or 
without spermicidal jelly, diaphragm or cervical cap with spermicidal jelly, or intra-
uterine device (IUD). A female whose male partner has had a vasectomy must agree to 
use one additional form of medically acceptable contraception.  
8. Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for 
at least 12 months do not require contraception during the study. 
9. Males with female partners of childbearing potential, including males who are surgically 
sterile (post vasectomy), must agree to be abstinent or else use a medically acceptable 
form of contraception from the screening period through the final study visit.  
5.3 
Exclusion Criteria    
A subject who meets any of the following criteria is ineligible for the study: 
 
1. Unable or unwilling to comply with the protocol; 
2. Active non-hematologic malignancy or history of non-hematologic malignancy in the 
3 years prior to screening (exclusive of non-melanoma skin cancer and cervical cancer in 
situ); 
3. Positive for HIV or hepatitis C antibody;  
4. Positive for hepatitis B surface antigen; 
5. Active infection or history of recurrent infections; 
6. IVIG treatment within 60 days of screening; 
7. Received any cytotoxic (other than azathioprine) or mAb therapy in the 3 months prior to 
screening; 
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8. Any exposure to an investigational drug or device within 30 days prior to screening; 
9. Plasmapheresis or immunoadsorption within 60 days of screening 
10. Cellular therapy at any time prior to screening 
11. Use of any immunosuppressive drugs apart from corticosteroids, azathioprine, 
mycophenolate mofetil, or cyclosporine within 3 months of screening; 
12. Serum total IgG < 600 mg/dL; 
13. Subject has any current medical condition that, in the opinion of the Investigator, may 
compromise their safety or compliance, preclude successful conduct of the study, or 
interfere with interpretation of the results (e.g., a significant pre-existing illness or other 
major comorbidity that the Investigator considers may confound the interpretation of the 
study results); 
14. Any vaccination within 2 weeks of screening 
 
 
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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All subjects must take part in the informed consent process.  Adequate time must be allowed for 
the subject to ask questions and make a voluntary decision.  No protocol-specific procedures, 
including screening procedures, are to be performed until the subject has signed and dated an 
IRB-approved ICF.  Subjects may withdraw consent at any time. Participation in the study may 
be terminated at any time without the subject’s consent as determined by the Investigator.  
6.2 
Demographics and Medical History 
Demographics (age, gender, race and ethnicity) and medical history will be obtained from the 
subject and recorded on the source document and eCRF.  Medical history will capture the 
subject’s current medical history (current disease processes), past medical status (past disease 
processes), history of surgery and concomitant treatments.  
6.3 
Physical Examination 
A complete physical examination will be performed as outlined in Table 1.  The complete PE 
will include measurements of weight (in kg) and height (in cm; height to be measured only at 
screening visit) and a review of the following body systems: 
• General appearance 
• Head, eyes, ears, nose, and throat 
• Neck 
• Respiratory 
• Cardiovascular 
• Abdomen 
• Neurologic 
• Extremities 
• Dermatologic 
• Lymphatic 
Any abnormal and clinically significant findings from the PE must be recorded in the appropriate 
eCRF.  Findings at screening and Day 0 (pre-dose) will be recorded as medical history. 
6.4 
Pemphigus Disease Area Index (PDAI) Scoring 
Pemphigus severity and disease activity will be measured using the PDAI.  See Appendix B. 
6.5 
Vital Sign Measurements 
Vital sign measurements will be collected after the subject has been sitting for 5 minutes.  Vital 
sign assessments will include measurements of sitting blood pressure (mm Hg), heart rate (beats 
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per minute), respiration rate (breaths per minute), oral temperature (Celsius).  Abnormal results 
are to be repeated after 5 minutes of rest.  Pulse oximetry (%) also is to be measured.  See Table 
2 for timing window allowances with respect to measurement collection. 
On Days 0, 7, 14, 21, and 28, vital sign measurements are to be obtained immediately prior to the 
infusion; 15, 30, and 45 minutes after the start of the infusion; at completion of the infusion; and 
30 minutes, 1 hour and 2 hours following completion of the infusion.  Details on the 
management of mild to moderate and severe infusion reactions can be found in Figure 1 and 
Figure 2.  Abnormalities in vital sign measurements will be graded in severity per the NCI 
CTCAE scale Version 4.03. 
Subjects should be seated quietly for at least 5 minutes in a chair with their backs supported, 
their feet flat on floor (legs uncrossed), and their arms bared on a hard surface, with the arm 
slightly abducted and bent, with palm up and the midpoint of upper arm at heart level.  Correct 
cuff and bladder size should be utilized and the same cuff and arm should be used per subject 
throughout study.     
6.6 
12-Lead Electrocardiogram (ECG)   
Digital 12-lead ECG measurements will be obtained at screening, on Days 0 and 28 at 5 minutes 
after the completion of the infusion and at the Day 56 visit.  Subjects who conduct their Day 12 
visit at the investigative site, as opposed to an at-home nurse visit, will have an additional ECG 
performed.  ECGs are to be performed with the subject in a supine position having rested in this 
position for at least 5 minutes before each reading. ECGs are to be performed in triplicate, each 1 
to 2 minutes apart.  See Table 2 for timing window allowances with respect to performing ECG. 
The following ECG parameters will be collected: PR interval, RR interval, QRS interval, and QT 
interval.  The ECG findings will be evaluated by a qualified physician for the presence of 
abnormalities (qualitative assessment).  The physician will assess each ECG as normal, 
abnormal/not clinically significant, or abnormal/clinically significant.   
Normal QTcF is ≤ 450 msec.  
Abnormalities in the ECG that appear following therapy or that result in clinical signs and 
symptoms are considered clinically significant for the purposes of this study and will be recorded 
on the AE eCRF.   
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6.7 
Clinical Laboratory Measurements   
Collection time for all safety, PD, and exploratory labs are outlined in Table 1. 
Laboratory testing (hematology, urinalysis, serum chemistry, virology, serology, pregnancy tests, 
PD samples, PK samples, and anti-drug antibody samples) will be performed using established 
methods by a central laboratory. Safety laboratory panels are defined as listed in Table 3. Blood 
and urine samples for hematology, serum chemistry, and urinalysis will be prepared using 
standard procedures.  Results will be provided to the Investigator.  Aliquots from the PK, 
biomarker and anti-drug antibody samples may be retained as back-up for additional testing as 
necessary. Subjects will be in a seated or supine position during blood collection. Full clinical 
safety lab draws will be collected at Screening and on Days 0, 7, 14, 21, 28, 33, 42, 56, 84 and 
112.  The total blood draw for each subject who completes the study at Day 112, will be 
approximately 381 mL.  Please refer to the Laboratory Manual for more information.    
Table 3: 
Clinical Laboratory Panels 
Hematology 
Serum Chemistry 
Urinalysis 
• 
CBC with differential and blood 
smear 
• 
Erythrocyte Sedimentation Rate 
(ESR) 
 
• 
Albumin 
• 
Alkaline phosphatase 
• 
ALT 
• 
AST 
• 
BUN 
• 
Calcium 
• 
Carbon dioxide 
• 
Chloride 
• 
Creatinine 
• 
Glucose 
• 
LDH 
• 
Phosphorus 
• 
Potassium 
• 
Sodium 
• 
Total and direct bilirubin 
• 
Total protein 
• 
Uric acid 
• 
C-Reactive Protein 
 
• 
Appearance 
• 
Color 
• 
pH 
• 
Specific gravity 
• 
Ketones 
• 
Protein 
• 
Glucose 
• 
Nitrite 
• 
Urobilinogen 
• 
Blood/hemoglobin 
• 
Leukocyte esterase 
• 
Bilirubin 
• 
Microscopic examination of 
sediment: only if the results of 
the urinalysis dipstick evaluation 
are positive for 
blood/hemoglobin 
Virology 
 
 
• 
Hepatitis C 
• 
Hepatitis B 
 
 
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• 
HIV 
• 
VZV 
• 
Tetanus 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; BUN = blood urea 
nitrogen; HIV = human immunodeficiency virus; LDH = lactate dehydrogenase; VZV = varicella-zoster virus 
 
Abnormalities in clinical laboratory tests that are considered clinically significant are to be 
recorded on the AE electronic case report form (eCRF) page.   Laboratory results will be graded 
using the NCI CTCAE, Version 4.03. If laboratory values constitute part of an event that meets 
criteria defining it as serious, the event (and associated laboratory values) must be reported as an 
SAE (see Section 11.3.1). 
6.7.1 
Pregnancy Testing 
Pregnancy testing will be performed for women of childbearing potential at screening and prior 
to first dose of SYNT001 on Day 0 and Days 56 and 112 (urine or serum test is acceptable 
however, positive urine tests must be confirmed with serum testing.) 
6.7.2 
Virology 
Testing for HCV antibody, hepatitis B surface antigen, and HIV antibody will be performed at 
screening. 
6.7.3 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing 
Samples for serum tetanus antibody and varicella-zoster virus antibody testing are to be collected 
at baseline (pre-dose, Day 0) and on Day 56 (Follow-Up visit).  Testing at Day 56 will not be 
done for any subject whose baseline titer is below the level of detection. Specifically, if the 
baseline VZV titer is above the detectable level, but tetanus is not, only the VZV antibody titer 
will be tested on Day 56. If the Day 56 results are below the baseline value, defined as greater 
than 30% below the baseline value, or if the subject falls below the level of detection, the subject 
will be re-tested at Day 84; if still below the baseline value (or level of detection), the subject 
will be re-tested at Day 112. Any subject whose baseline value for tetanus or VZV was above the 
detectable level at baseline, and is not within 30% of the baseline value or is below the detectable 
level by Day 112, will be referred to their primary care physician for further management.  
6.7.4 
Pharmacokinetics (PK) Sampling 
Starting on Days 0 and 28, serum samples will be collected just prior to the start of study drug 
infusion (pre-dose), at 5 minutes and 2, 4, 6, 24, and 48 hours after the end-of-study drug 
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infusion.  Additional samples will be collected on Days 5 and 33.  The actual time and date of 
each blood draw is to be recorded.   
Study drug concentration will be used to calculate the following PK parameters: t1/2, Cmax, Tmax, 
AUC0-24, and AUC0-∞.   
Detailed instructions for sample collection and preparation will be provided in a separate 
laboratory manual 
6.7.5 
Pharmacodynamic Sampling 
PD samples will be collected for analyses throughout the study. On Days 0, 7, 14, 21, and 28, 
samples should be collected prior to infusion of study drug.  Measurements for albumin PD 
biomarkers will be derived from the clinical safety laboratory results.  Samples for each type of 
PD will be collected according to the schedule shown in Table 4. 
 
 
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Table 4: Pharmacodynamic/ Activity Assessments 
Parameter 
Collection Timepoints 
• 
IgG, IgG subtypes (IgG1-4), IgA, IgM  
Screening, and Days 0, 1, 2, 5, 7, 12, 14, 19, 
21, 28, 29, 30, 33, 42, 56, 84 and 112.   
• 
Circulating immune complexes (CIC) 
Days 0, 5, 7, 12, 14, 19, 21, 28, 33, 42, 56, 
84 and 112 
• 
Albumin 
Screening, and Days 0, 7, 14, 21, 28, 33, 42, 
56, 84 and 112 
• 
Anti-Dsg (1 and 3) antibody titer 
Screening, Days 0, 7, 14, 33, 56, 84 and 112 
• 
Complement component 3 (C3) 
• 
Anti-epithelial cell antibody (AECA) levels by 
indirect immunofluorescence 
 
Days 0, 14, 33, 56, 84 and 112 
• 
Exploratory biomarker (RNAseq, Urine IgG) 
 
Days 0, 14, 33, 56, 84 and 112 
• 
Immune phenotyping by flow cytometry for 
measurement of CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B cells 
Days 0, 28 and 56 
• 
Exploratory biomarker (FCGR2A SNP) 
Day 0 
 
See Table 2 for timing window allowances with respect to measurement collection. 
Detailed instructions for sample collection (including collection tubes) and preparation will be 
provided in a separate laboratory manual. 
6.7.6 
Immunogenicity Testing 
Serum samples will be collected for immunogenicity analyses on Days 0 (pre-dose), 14, 28, 56, 
84 and 112. 
SYNT001 is being developed for the acute and chronic therapy of autoimmune disorders. 
Although SYNT001 is a humanized IgG4 monoclonal antibody, exposure to SYNT001 in 
clinical trials could result in the development of anti-drug antibodies (ADAs), with potential 
consequences ranging from neutralization or lessening of drug efficacy to safety consequences 
such as allergic reactions.  Testing will first detect binding ADAs, then, for all confirmed 
positive samples, there will be testing for neutralizing effects.  
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Detailed instructions for sample collection and preparation will be provided in a separate 
laboratory manual. 
6.8 
Study Drug Administration 
Two cohorts of 8 eligible subjects each will receive 5 once-weekly 60-minute IV infusions of 
SYNT001 10 mg/kg or up to 30 mg/kg. SYNT001 will be given as a 250-mL IV infusion over 1 
hour using a 0.2-micron, inline filter. Based on review of safety data, as well as available and 
relevant PD results, and clinical outcomes of Cohort 1, a decision about proceeding with Cohort 
2 will be made.  Based on review of all safety data, available PD results, and clinical outcomes 
of these 2 cohorts, a third cohort of 8 subjects may be treated at another dose, with a maximum 
dose of 45 mg/kg, but may also be lower than 10 mg/kg or between 10 and 30 mg/kg, inclusive.   
Cohort No. 
Study Drug 
Dose Level 
(mg/kg/dose) 
1 
SYNT001 
10 mg/kg 
2 
SYNT001 
30 mg/kg 
See Section 9.1 for dosing schedule.   
6.9 
Prior and Concomitant Medications 
All medications a subject receives within 14 days prior to enrollment through the end of the 
study will be documented on the source document and eCRF.   
Note:  No vaccinations may be given from within 2 weeks of screening through Day 56.  
Following Day 56, subjects may receive vaccinations at the discretion of the Investigator. 
6.10 
Adverse Event Assessments 
Information regarding the occurrence of AEs will be collected from the time the subject signs the 
informed consent form and continuing through the last study visit.  Findings at screening and 
Day 0 (pre-dose) will be recorded as medical history.   Any known untoward event that occurs 
beyond the AE reporting period that the Investigator assesses as related to study drug also should 
be reported as an AE. 
Clinical AEs will be graded using the NCI CTCAE, Version 4.03 (Appendix A).   
Note:   AEs resulting in a subject’s permanent discontinuation from the study, regardless of 
seriousness or relationship to study drug, MUST be promptly reported to the sponsor.  
Additionally, subjects must be followed until return to normal and/or resolution of the AE. 
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See Section 11 for more information. 
6.11 
Photographs 
On Day 0 photographs will be taken of active lesions.  Follow-up photographs will be taken of 
the same areas on Days 33, 56, 84 and 112.  Subjects who begin a steroid taper will have 
additional photographs taken at the clinic visit during which the decision to begin the taper is 
made.  A separate manual describing the procedures for taking photographs will be provided. 
6.12 
Skin Biopsy 
Optional skin biopsy samples will be collected on Day 0 pre-dose and on Days 1, 2, 14, 33, 56 
and 84 to analyze SYNT001 levels. 
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7 
STUDY ASSESSMENTS 
7.1 
Screening Period: Day -14 to Day -1 
Informed consent must be obtained before any study-specific samples are taken or study-specific 
tests or evaluations are conducted.  The following assessments at the screening visit are to occur 
within 14 days before dosing.  Study eligibility will be based on satisfying all the study inclusion 
and exclusion criteria.   
At the screening visit, information will be collected and subjects will have clinical evaluations as 
follows: 
• Informed consent (Section 6.1) 
• Medical history and demographic data (Section 6.2) 
• Review inclusion and exclusion criteria (Section 5.2, Section 5.3) 
• Complete PE, including height and weight (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• 12-Lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position) 
(Section 6.6) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Pregnancy test (Section 6.7) 
• Hepatitis and HIV screen (Section 6.7) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• Anti-Dsg (1 and 3) antibody titer 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.2 
Enrollment and First Treatment: Day 0  
Study Day 0 is defined as the date the subject is administered their first dose of study drug. On 
Day 0, subjects will be asked to come to the clinic and the following procedures will be 
performed prior to the first dose of study drug: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
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• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Pregnancy test (Section 6.7) 
• Serum tetanus antibody and VZV antibody (Section 6.7) 
• PDAI Score (Section 6.4) 
• PK baseline sample collection (collected just prior to the start of the study drug infusion) 
(Section 6.7) 
• Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
(Section 6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• Anti-Dsg (1 and 3) antibody titer 
• CIC  
• C3 
• AECA 
• FCGR2A SNP 
• RNAseq 
• Urine IgG 
• Immune phenotyping 
• Optional skin biopsy (Section 6.12) 
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
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temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• PK sample collection at 5 minutes and 2, 4, 6 hours after the end-of-study drug infusion; 
record collection date and time for each PK sample (Section 6.7) 
• 12-Lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion (Section 6.6) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.3 
Follow-up: Day 1  
On Day 1 (24 hours ± 1 hour from end-of-infusion time on Day 0), the subject will return to the 
clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• PK sampling (record collection date and time) (Section 6.7) 
• Optional skin biopsy (Section 6.12) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.4 
Follow-up: Day 2 
On Day 2 (48 hours ± 2 hours from end-of-infusion time on Day 0), the subject will return to the 
clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• PK sampling (record collection date and time) (Section 6.7) 
• Optional skin biopsy (Section 6.12) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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7.5 
Follow-up: Day 5  
On Day 5 (120 hours ± 4 hours from end-of-infusion time on Day 0), subjects may return to the 
clinic or be visited by at-home nurse, and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PK sampling (record collection date and time) (Section 6.7) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.6 
Treatment Day 7 (Dose 2)  
On Day 7 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
• PDAI Score (Section 6.4) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
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and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.7 
Dose 2 Follow-up Day 12 
On Day 12 (± 6 hours) the subject may return to the clinic, or be visited by at-home nurse, and 
the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• If visit performed at the study site: 12-Lead ECG to be obtained in triplicate (Section 6.6) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.8 
Treatment Day 14 (Dose 3) 
On Day 14 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
• PDAI Score (Section 6.4) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
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• Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
(Section 6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• Anti-Dsg (1 and 3) antibody titer 
• CIC 
• C3 
• AECA 
• RNAseq 
• Urine IgG  
• Optional skin biopsy (Section 6.12) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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7.9 
Dose 3 Follow-up Day 19 
On Day 19 (± 6 hours) the subject may return to the clinic, or be visited by an at-home nurse, and 
the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.10 
Treatment Day 21 (Dose 4) 
On Day 21, (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
• PDAI Score (Section 6.4) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
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• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.11 
Treatment Day 28 (Dose 5) 
On Day 28 (± 6 hours), subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PDAI Score (Section 6.4) 
• PK sampling (collected just prior to the start of the study drug infusion; record collection 
date and time for each PK sample) (Section 6.7) 
• Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
(Section 6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Immune phenotyping 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
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and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• PK sample collection at 5 minutes and 2, 4, 6 hours after the end-of-study drug infusion; 
record collection date and time for each PK sample (Section 6.7) 
• 12-Lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion (Section 6.6) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.12 
Follow-up Day 29  
On Day 29 (24 hours ± 1 hour from end-of-infusion time on Day 28), the subject will return to 
the clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• PK sampling (record collection date and time) (Section 6.7) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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7.13 
Follow-up Day 30 
On Day 30 (48 hours ± 2 hours from end-of-infusion time on Day 28), the subject will return to 
the clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• PK sampling (record collection date and time) (Section 6.7) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.14 
Follow-up Day 33  
On Day 33 (120 hours ± 4 hours from end-of-infusion time on Day 28), subjects will return to 
the clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PDAI Score (Section 6.4) 
• PK sampling (record collection date and time) (Section 6.7) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• C3 
• AECA 
• RNAseq 
• Urine IgG  
• Optional skin biopsy (Section 6.12) 
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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7.15 
Follow-up Day 42  
On Day 42 (± 3 days), subjects will return to the clinic and the following procedures are to be 
performed: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PDAI Score (Section 6.4) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.16 
Follow-up Day 56 
On Day 56 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Pregnancy test (Section 6.7) 
• 12-Lead ECG (to be obtained in triplicate after 5 minutes of rest in the sitting position) 
(Section 6.6) 
• Serum tetanus antibody and VZV antibody; Testing at Day 56 will not be done for any 
subject whose baseline titer is below the level of detection. See Section 6.7.3 for 
additional information.   
• Immunogenicity sample collection (Section 6.7) 
• PDAI Score (Section 6.4) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
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• C3 
• AECA 
• RNAseq 
• Urine IgG 
• Immune phenotyping  
• Optional skin biopsy (Section 6.12) 
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.17 
Follow-up Day 84 
On Day 84 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Serum tetanus antibody and VZV antibody testing if required. See Section 6.7.3 for 
additional information.   
• Immunogenicity sample collection (Section 6.7) 
• PDAI Score (Section 6.4) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• C3 
• AECA 
• RNAseq 
• Urine IgG  
• Optional skin biopsy (Section 6.12) 
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
 
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7.18 
Follow-up Day 112 (End-of-Study) or Early Termination Visit 
On Day 112 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Pregnancy test (Section 6.7) 
• Serum tetanus antibody and VZV antibody testing if required. See Section 6.7.3 for 
additional information.   
• Immunogenicity sample collection (Section 6.7) 
• PDAI Score (Section 6.4) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• C3 
• AECA 
• RNAseq 
• Urine IgG  
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
 
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8 
REMOVING SUBJECTS FROM STUDY 
Every reasonable effort will be made to keep the subject in the study; however, if a subject is 
withdrawn from the study, every effort will be made by the Investigator to complete and report 
the reasons for withdrawal as thoroughly as possible.  The reason(s) for termination must be 
clearly documented on the appropriate page of the eCRF.  Once a subject discontinues from the 
study for any reason, every effort will be made to collect all clinical and laboratory data as 
scheduled for the Early Termination Visit (See Table 1).  A termination eCRF must be 
completed for all enrolled subjects. 
8.1 
Subject Withdrawal  
A subject’s participation in the study may be prematurely discontinued for any of the following 
reasons:  
1. The subject wishes to withdraw from the study. 
2. Request by a regulatory agency (e.g., Institutional Review Board). 
3. Subject experiences a significant or intolerable AE.   
4. The subject experiences a significant adverse change in vital signs, PE findings, or a 
clinical laboratory parameter. 
5. The subject has a need for a concomitant medication that is not permitted by the study 
protocol. 
6. The subject experiences generalized impairment or mental incompetence that would result 
in the subject being unable to understand his or her participation in the study. 
7. If, in the Investigator’s medical judgment, further participation would be injurious to the 
health and well-being of the subject, or is not in the best interest of the subject.  
8. Administrative reasons, such as subject non-compliance or a major protocol violation. 
Subjects who are withdrawn from this study due to an AE determined to be related to study drug 
are to be followed until there is either: 
• Resolution or stabilization of the AE determined to be related 
• The subject is lost to follow-up 
• The event is otherwise explained 
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If there is a persistent AE contributing to discontinuation that is determined to be related to 
SYNT001, subjects must be followed with appropriate medical management until resolution or 
stabilization. 
A reasonable effort should be made to contact any subject lost to follow-up during the study to 
complete assessments and retrieve any outstanding data.  If the subjects are unreachable by 
telephone after three (3) attempts, the minimum of a registered letter should be sent requesting 
that contact be made with the Investigator to report survival information.   
8.2 
Study Discontinuation 
Syntimmune Inc. has the right to terminate or to stop the study at any time.  Reasons for study 
discontinuation may include, but are not limited to the following:  
• The incidence or severity of AEs in this or other related studies indicates a potential health 
hazard to subjects  
• Subject enrollment is unsatisfactory 
• Drug supply issues 
• Excessive subject self-withdrawal 
• Significant protocol violations (e.g., violation of eligibility criteria, dosing errors, missing 
data for study endpoint analysis) 
8.3 
Replacements 
Enrolled subjects withdrawn for a reason other than an AE will be replaced if they have not been 
dosed or have only received one dose of study drug at the time of discontinuation, up to one 
subject per cohort. Subjects who do not receive all doses of study drug will continue to be 
followed through all scheduled study visits.   
8.4 
Stopping Rule 
8.4.1 
Dose-Escalation Stopping Rule 
Dose escalation decisions will be made by a Dose Escalation Committee (DEC) and will be 
based on safety and pharmacodynamic evaluations including but not limited to, dose-limiting 
toxicities, AEs, SAEs, and total IgG levels. 
Dose-limiting toxicity (DLT) will be defined generally as severe (Grade 3) AEs occurring in ≥2 
subjects that are determined to be clinically significant and considered related to study drug. 
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If 2 or more subjects at any time in any cohort (8 total subjects per cohort) have Grade 3 AEs 
that are determined to be clinically significant and considered to be related to study drug, dosing 
will be halted within that cohort and dose-escalation to a higher dose will not occur. If the dose-
escalation stopping rule is met during Cohort 1 (10 mg/kg) all safety data and all available 
pharmacodynamics will be reviewed and the cohort may resume (if applicable) or a new cohort 
may be added at a dose at least 50% lower than the 10 mg/kg dose.  If the stopping rule is not 
met in Cohort 1, dose-escalation may proceed up to a maximum of 30 mg/kg.  If the dose-
escalation stopping rule is met for the first time during Cohort 2, all safety data and all available 
pharmacodynamics will be reviewed and the cohort may resume (if applicable) or a new cohort 
may be added at a dose a minimum of 30% lower than the Cohort 2 dose. If the stopping rule is 
not met in Cohort 2, dose-escalation may proceed up to a maximum of 45 mg/kg; however, this 
cohort may also receive a dose equal to or less than 30 mg/kg based on evaluation of all safety 
and pharmacodynamic data.   
8.4.2 
Study Stopping Rule 
If any subject experiences a life-threatening AE (Grade 4) that is considered to be related to 
study drug, further dosing in all enrolled subjects will be suspended until the DEC has evaluated 
the event and determined the appropriate course of action.  At any time during the study, the 
study may be discontinued if the DEC determines that further drug exposure would pose an 
undue risk to subjects. 
8.4.3 
Individual Stopping Rule 
Dosing for any individual subject will be discontinued (i.e., no further study drug will be given 
to that subject) if the subject experiences any study drug-related SAE or any study drug-related 
non-SAE adverse event that, in the judgement of the Investigator (following consultation with 
the Medical Monitor, if desired) suggest that it could be unsafe to administer further study drug 
to that subject.  Additionally, a subject will be discontinued from further treatment with study 
drug, at the discretion of the Investigator with consultation with the Medical Monitor, if they 
require a significant increase in dose(s) of anti-pemphigus medication(s) for the management of 
pemphigus. 
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9 
STUDY DRUG 
For detailed information regarding SYNT001 preparation and administration, refer to the 
Pharmacy Manual. 
9.1 
SYNT001  
SYNT001 is provided in vials containing 5 mL SYNT001 (extractable volume) at a nominal 
concentration of 50 mg/mL.  The product is supplied as a liquid at pH 6.5 ± 0.5. SYNT001 is 
diluted in Dextrose 5% in Water (D5W) to prepare the solution for infusion.  SYNT001 will be 
infused via IV in 250 mL over 1 hour using a 0.2-micron, inline filter.   
Two cohorts of 8 eligible subjects each will receive 5 once-weekly 60-minute infusions of 
SYNT001 in planned doses of 10 mg/kg or 30 mg/kg. Based on review of safety, PD, and 
clinical outcomes of these two cohorts, a third cohort of up to 8 subjects may be treated at 
another dose, with a maximum dose of 45 mg/kg, but may also be lower than 10 mg/kg or 
between 10 and 30 mg/kg, inclusive.  
The specification for host cell DNA in SYNT001 is < 2 pg/mg, the limit of quantitation of the 
assay.  To comply with regulatory guidelines, which specify a maximum level of 10 ng host cell 
DNA per dose, dosing is limited to 5000 mg of SYNT001. Therefore, at the highest dose 
possible in this study (45 mg/kg), maximum subject weight will be limited to 111 kg.  
9.2 
Cohort Dosing 
Cohorts will be dosed sequentially beginning with Cohort 1.  The first 2 subjects will be dosed at 
least 24 hours apart.  A review of the 24-hour safety data for the first subject will be performed 
to ensure that there are no overt safety concerns before dosing the second subject.  A review of 
the 7-day safety data for the first 2 subjects will be performed prior to dosing the remaining 6 
subjects in the cohort.  Cohort 2, and Cohort 3 if added, will be dosed per the same schedule 
9.3 
Timing of Dosing  
On Days 0, 7, 14, 21, and 28, subjects will receive a 60-minute IV infusion of SYNT001 in the 
morning.  The date and time the dose is administered will be recorded.   
9.4 
Identity of Investigational Products 
All supplies of SYNT001 will be supplied by Syntimmune and must be stored refrigerated (2ºC 
to 8ºC/36ºF to 46ºF) in the carton and protected from light, in a securely locked area, accessible 
to authorized persons only, until needed for dose preparation.  Qualified site personnel will 
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inventory the investigational product received and will maintain records of disposition of the 
drug, including dates, quantity and use. 
9.5 
Investigational Product Retention at Study Site 
The Investigator (or designee) is responsible for maintaining accurate accountability records of 
the investigational product throughout the clinical study. All study drug received at the site must 
be inventoried and accounted for in an accountability log provided by the Sponsor. All 
dispensing and accountability records will be available for Sponsor review. Study drug 
accountability will be verified during on-site monitoring visits. 
Upon the completion or termination of the study, and upon written authorization from the 
Sponsor, or its representative, all unused and/or partially used study drug should be returned or 
destroyed at the investigational site, as specified by Sponsor.  It is the Investigator’s 
responsibility to ensure that the Sponsor, or its representative, has provided written authorization 
that procedures for proper disposal of the study drug have been established, and that appropriate 
records of the disposal are documented and maintained.  No unused study drug may be disposed 
until fully accounted for by the Sponsor monitor (or designee) 
9.6 
Warnings and Precautions  
Note: Subjects must not receive any vaccinations from within 2 weeks of screening until Day 56. 
9.6.1 
Infusion Reaction 
SYNT001 will be given as an IV infusion over 1 hour. As with all mAbs administered by IV 
infusion, infusion reactions are possible.  In nonclinical testing of SYNT001 in NHPs, clinical 
observations were limited to infusion reactions due to the immunogenicity of SYNT001 in 
NHPs. These reactions included transient emesis/vomitus which typically occurred within 1 hour 
of dosing at all dose groups, but only after the third weekly infusion following the development 
of ADAs. Transient histamine-type responses were noted 30 minutes post-dose in some animals 
in all dose groups, but only following the third weekly infusion as above.  These reactions were 
consistent with a histamine reaction (decreased activity, periocular swelling, erythema, facial 
flushing, eyelids partially/completely closed, and/or generalized weakness).  With the exception 
of vomitus/emesis and red skin discoloration associated with injection or blood draw sites, these 
observations spontaneously resolved within 1-hour post-dose. Subsequent pretreatment with 
intramuscular diphenhydramine prevented further histamine-type reactions.  All doses of 
SYNT001 were administered by bolus infusion over approximately 5 minutes in the NHP 
studies.  However, all of the observed infusion reactions (including vomitus/emesis and 
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histamine-type reactions) associated with ADAs are not at all predictive of what may occur in 
humans [Bugelski 2004, Ponce 2009] and furthermore, are not considered relevant to predicting 
responses in humans [ICH S6(R1) 2011].   
Typically, infusion reactions to monoclonal antibodies observed in human studies develop within 
30 minutes to 2 hours after the initiation of drug infusion, although symptoms may be delayed 
for up to 24 hours. Most are mild in severity, although severe and even fatal reactions can occur.  
Guidelines for Grading and Management of Allergic or Infusion-Related Reactions 
Allergic and/or infusion-related reactions include hypersensitivity reactions and cytokine release 
syndromes. These reactions are experienced by patients during or within hours of the infusion of 
monoclonal antibody therapy. Symptoms can include flushing, alterations in heart rate and blood 
pressure, dyspnea, bronchospasm, back pain, fever, urticaria, edema, nausea, and all types of 
rashes. Anaphylaxis is recognized as a severe, life-threatening, generalized, or systemic reaction. 
This is a medical emergency characterized by rapidly developing life-threatening airway and/or 
breathing and/or circulation problems usually associated with skin or mucosal changes.  
Management of Grade 1 infusion reactions include decreasing the rate of infusion by 50% and 
observing.  Symptoms may also be treated as needed with medications such as diphenhydramine, 
hydrocortisone or acetaminophen. 
Management of Grade 2 and higher infusion reactions should include stopping the infusion of 
study drug.  See Figure 1 and Figure 2 for details on the management of Grades 1-2 and Grade 3 
or higher infusion reactions. The severity of and management of allergic or infusion-related 
reactions will be graded and managed using NCI CTCAE Version 4.03 (see Table 5).   
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Figure 1:  Management of Mild (Grade 1) to Moderate (Grade 2) Infusion Reactions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stop  
Infusion 
Assess airway, breathing, circulation, and consciousness, and recline subject 
 
Start high flow oxygen 
Insert large bore IV and start IV fluids 
Initiate vital sign assessments at least every 15 minutes 
Any problem with airway, breathing 
circulation, or consciousness? 
NO: 
Initiate medical 
review 
YES:   
Initiate treatment per the 
Severe Infusion Reaction 
Flow Chart 
Monitor for symptom resolution 
If symptoms persist, proceed with medications as needed.  For example: 
diphenhydramine 25-50 mg IV and/ or hydrocortisone 200 mg IV 
Note:  If desaturation, 
hypotension, or urticaria 
present, refer to Severe 
Infusion Reaction Flow 
Chart. 
Subject presents with any of 
the below: 
• 
Altered vision 
• 
Impending feeling 
of doom 
• 
Pain:  Back, 
abdomen, chest 
• 
Flushing 
• 
Wheezing without 
desaturation 
• 
Pyrexia 
• 
Peripheral edema 
• 
GI symptoms 
 
If ongoing symptoms, consider ongoing 
observation or hospital admission 
If symptoms and signs resolve completely either spontaneously or after administration of diphenhydramine 
with or without hydrocortisone, consider rechallenge:   
Wait at least 20 minutes following medication administration before commencing rechallenge at an infusion 
rate of 50% or less of the initial infusion rate or 
Consider pre-medicating the subject with the same medication(s) 20-30 minutes in advance of subsequent 
administrations of SYNT001 and starting infusion at 50% of the planned infusion rate for the first 30 minutes, 
then returning to the intended infusion rate in the absence of any infusion reaction 
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Figure 2:  Management of Severe (Grade 3 or higher) Infusion Reactions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject presents with any of the below: 
• 
Urticaria 
• 
Airway threatened by angioedema 
• 
Angioedema: Lip, mouth, facial swelling 
• 
Respiratory compromise - wheezing, dyspnea, stridor or hypoxia 
(O2 saturation < 90%) 
• 
BP < 90 mmHg SBP or >30% decrease from patient baseline 
Stop  
Infusion 
Consider (under medial direction): 
 
Epinephrine 1:1000 
• 
0.3 mg (0.3 mL) IM into lateral thigh 
Transfer to Emergency Room/ICU 
Observe until all symptoms resolved. 
Start basic life support: 
• 
High oxygen flow 
• 
On bed, head down, legs up 
• 
Large bore IV cannula, 1 L normal saline STAT 
• 
Initiate vital signs at least every 15 minutes 
Airway Threatened: 
Nebulized epinephrine 1:1000, 3–5 mL (3–5 mg) 
Bronchospasm: 
Nebulized salbutamol 5 mg 
(Wheeze or Hypoxia) 
Consider: Intubation / nebulized epinephrine 
 
Hypotension: 
Place on cardiac monitor 
(Systolic BP <100 mmHg) 
Further epinephrine 1:1000, 0.3 mg IM and  
 
IV normal saline bolus 20 mL/kg STAT as needed 
 
Have vasopressin on hand 
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Table 5: 
Grading and Management of Allergic or Infusion-Related Reactions  
Adverse 
Event 
Grade 
1 
2 
3 
4 
5 
Infusion-
Related 
Reaction 
Mild transient 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤ 24 hours 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated for 
clinical sequelae 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Allergic 
Reaction 
Transient 
flushing or 
rash, drug 
fever 
< 38.0°C. 
Intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤ 24 hours 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated for 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Anaphylaxis 
- 
- 
Symptomatic 
bronchospasm, with or 
without urticarial; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Cytokine 
release 
syndrome 
Mild 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤ 24 hours 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated for 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Life-
threatening 
consequences; 
pressor or 
ventilator 
support 
indicated 
Death 
Abstracted from NCI CTCAE Version 4.03. 
 
 
 
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9.6.2 
Potential Immune Effects 
An antibody blocking FcRn is anticipated to have several effects.  These include acceleration of 
catabolism of IgG, but not other immunoglobulin isotypes such as IgA and IgM, leading to dose-
dependent decreases in circulating IgG levels by up to an estimated 50% from the baseline levels 
after a single dose and further decreases after multiple doses up to a 70% to 80% reduction. 
Based on studies in humans, it is expected that with a single dose, the nadir of this effect will 
occur approximately 5 days after dosing.  The time course of recovery of IgG following dosing 
in the Phase 1a study suggests that a return to within 30% of baseline levels observed at 
pretreatment occurs within 4 weeks after a single dose and within 4 weeks after multiple doses as 
shown in NHPs. 
Given the normal adult range of IgG of 500 to 1600 mg/dL (Agarwal and Cunningham-Rundles, 
2007; Furst, 2009; Gonzalez-Quintela et al, 2008; Joliff et al, 1982; Keystone et al, 2007; 
McMillan et al, 1997; van Vollenhoven et al, 2013), with a mean of 1150 mg/dL, a 50% decrease 
in the mean would be to 575 mg/dL and a 50% decrease from the low end of the normal range 
used for the inclusion criteria of 600 mg/dL would be to 300 mg/dL. An 80% decrease from 
baseline after multiple doses would result in IgG levels of 230 mg/dL and 120 mg/dL, 
respectively.  While these levels are in the range found in patients with primary humoral 
immunodeficiency [Ameratunga 2013], the levels will be transient. Further, as reported for other 
therapies used for pemphigus, the temporary (ie, less than 4 months) depletion of IgG (up to 95% 
reduction of total IgG as seen with immunoadsorption) does not appear to impart an increased 
risk of infection (Eming, 2006; Furst, 2009; Keystone et al, 2007; Schmaldienst et al, 2001; van 
Vollenhoven et al, 2013). Study subjects will be monitored clinically for any infection. Further, 
commercial IVIG can be given to reverse the low IgG levels in case of a bacterial infection 
occurring while their IgG levels are decreased. 
An antibody blocking FcRn is expected to also down modulate innate and adaptive immunity 
and the catabolism of IgG-containing immune complexes (IC). Specifically, it is expected that 
anti-FcRn will promote the clearance of IgG-containing ICs and the effects of these IC on 
stimulating innate immune cell production of inflammatory cytokines (e.g., IL-12, interferon-γ, 
and tumor necrosis factor [TNF]) and inhibit the processing and presentation of antigens 
contained within IC and thus the antigen-specific activation of CD4+ and CD8+ T-cells. 
Therefore, subjects with pre-existing conditions that are dependent upon IgG antibodies, such as 
chronic infections (e.g., HIV, HBV or HCV), will be excluded from this study, as will subjects 
with active infection in general. 
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SYNT001 administration could decrease the level of protective antibodies from prior 
vaccinations. Protective antibody levels for tetanus and varicella-zoster virus (chickenpox) are to 
be tested in accordance with Section 6.7.3.  
 
 
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10 
CONCOMITANT MEDICATION AND TREATMENT 
All treatments a subject receives within 14 days prior to enrollment through the end of the study 
will be documented.  Concomitant medication and treatment for co-existing conditions, 
including those for pemphigus, are permitted if not excluded below.  Topical antibiotics are 
permitted to treat active infections that occur on study.  Topical or systemic treatments for oral 
candidiasis are permitted.  Topical lidocaine for transient pain relief is acceptable as needed. 
Significant increases in anti-pemphigus medications will result in subjects being discontinued 
from the study.  Concomitant treatment that is medically indicated for any AEs the subject 
experiences during the study are permitted    
Use of the following treatments will not be permitted during the study unless otherwise 
specified: 
• Rituximab or other anti-CD20 antibody 
• Monoclonal antibodies other than study drug 
• Any immunosuppressive drugs apart from corticosteroids, azathioprine, mycophenolate 
mofetil, or cyclosporine. 
• Topical steroids 
• Any dietary herbal supplements 
• Any investigational drug or device 
• Any vaccinations through Day 56.  Following Day 56, subjects may be vaccinated at the 
discretion of the Investigator. 
If over a period of at least two weeks on study drug, a subject on corticosteroids shows the 
absence of new lesions and significant healing of lesions that existed at study baseline, a slow 
corticosteroid taper may be started as per the following suggested schedule  
• If on > 30 mg of prednisone per day, decrease by 10 mg every two weeks until a dose of 
30 mg per day then decrease by 5 mg every two weeks 
• If on < 30 mg of prednisone per day, decrease by 5 mg every two weeks 
In cases in which concomitant medications are used, details to be recorded include the following: 
medication name, start date and time, stop date and time, dose, route, frequency, and reason for 
use.  The concomitant medication names are to be coded using the World Health Organization 
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(WHO) Drug Dictionary (WHO-DD March 2013, Type B2 or later) and classified by anatomical 
therapeutic chemical (ATC) categories. 
 
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11 
SAFETY 
11.1 
Safety Parameters 
Clinical and laboratory AEs will be graded using the NCI CTCAE; Version 4.03 (See 
Appendix A).  
 Subjects will be monitored throughout the treatment and follow-up period for occurrence of AEs 
(acute, delayed, and/or cumulative), as well as for changes in clinical status, vital sign 
measurements, and laboratory data (including PD).  Safety parameters to be measured/assessed 
include PEs, vital sign measurements, hematology, serum chemistries, urinalysis, and ECG. 
11.2 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical trial subject associated with 
the use of a drug, whether considered drug related.  An AE can be an unfavorable and 
unintended sign (e.g., an abnormal laboratory value finding), a symptom, or a disease temporally 
associated with the use of a drug, without judgment as to causality.  An AE can arise from use of 
the drug (e.g., use in combination with another drug) and from any route of administration, 
formulation or dose, including an overdose.  An AE also includes, but is not limited to, any 
clinically significant worsening of a pre-existing condition.  Examples include: 
• Any sign, symptom, physical finding, or laboratory result that has worsened in nature, 
severity or frequency compared to baseline; 
• Reactions from an investigational drug, including those occurring because of an 
overdose, abuse of the study drug, withdrawal phenomena, sensitivity or toxicity; 
• Concurrent illness that was not present or worsens in nature, severity, or frequency 
compared to baseline;  
• Injury or accident; and/or 
• Exacerbation of a pre-existing condition. 
For data collection, all untoward events that occur after informed consent through the last study 
visit are to be recorded on eCRFs by the investigational site. 
While pregnancy alone is not considered as an AE or SAE, any pregnancy complication(s) 
should be recorded as an AE(s) or SAE(s) (if applicable).  Elective abortions without 
complications should not be regarded as AEs, unless they were therapeutic abortions (see 
below).  Hospitalization for normal delivery of a healthy newborn should not be considered an 
SAE.  If a female subject becomes pregnant during the conduct of the study, the Investigator 
must notify the Sponsor according to the procedures provided in Section 11.3.8). 
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11.3 
Evaluating Adverse Events 
The Investigator will determine the seriousness, intensity, and causality of an AE associated with 
the use of the study drug (i.e., events where there is a reasonable possibility that the event may 
have been caused by the study drug) based on the definitions that follow. 
11.3.1 
Serious Adverse Events 
(Notify Medpace Safety within 24 hours; document on eCRF) 
The SAE definition and reporting requirements are in accordance with Title 21 Part Code of 
Federal Regulations (CFR) 312.32 and the Guidance for Industry and Investigators Safety 
Reporting Requirements for Investigational New Drug (INDs) and Bioavailability 
/Bioequivalence Studies. 
SAE:  An AE is considered "serious" if, in the view of either the Investigator or sponsor, it 
results in any of the following outcomes: 
• Death:  This includes any death that occurs while the subject is “on study” through the 
last study visit.  
Note: Death is an outcome of an AE, and not an AE.  The event(s) that caused death 
(e.g., illness, accident) is the SAE.  Death due to any other cause(s) must also 
be reported as an outcome of the reportable SAE. 
• Life-threatening adverse drug event:  An AE or suspected adverse reaction is 
considered “life threatening” if, in the view of either the Investigator or sponsor, its 
occurrence places the patient or subject at immediate risk of death. It does not include an 
AE or suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death.   
• Inpatient hospitalization or prolongation of existing hospitalization: 
In the absence of an AE, the Investigator should not report hospitalization or prolongation 
of hospitalization.  This is the case in the following situations: 
o Hospitalization or prolongation of hospitalization is needed for a procedure 
required by the protocol 
o Hospitalization or prolongation of hospitalization is part of routine procedure 
followed by study center 
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o Hospitalization for survey visits or annual physicals 
o Hospitalization for observation with release within 24 hours 
In addition, a hospitalization planned before the start of the study for a pre-existing 
condition, which has not worsened, does not count as an SAE.  
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions    
• Congenital anomaly/birth defect 
• Important medical event:  An event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, it may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.   
11.3.2 
Overdose 
An overdose is defined as a significant variation from the recommended/scheduled dosage for a 
product. The dosing for this study will be conducted in a controlled clinical setting and an 
overdose is not anticipated. However, in the event of an accident, for this study, an overdose of 
SYNT001 is considered a dose that is two-fold higher than the intended dose for the subject. 
11.3.3 
Non-Serious Adverse Events  
(Document on eCRF) 
All other AEs, not fulfilling the previous definitions, are classified as non-serious. 
11.3.4 
Protocol-Related Adverse Events 
AEs that are not test drug related may nevertheless be considered by the Investigator or the 
Medical Monitor to be related to the conduct of the clinical study.  That is, the event may be 
related to the fact that a subject is participating in the study.  For example, a protocol-related AE 
may be an event that occurs during a screening period or that is related to a procedure required 
by the protocol. 
11.3.5 
Assessment of Causality 
A medically qualified Investigator must assess the relationship of any AE (including SAEs) to 
the use of the investigational product, as related or not related, based on clinical judgment and 
using all available information, and may include consideration of the following factors: 
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• Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic 
factors. 
• The temporal association between drug exposure and onset of the AE. 
• Whether the manifestations of the AE are consistent with known actions or toxicity of the 
investigational product. 
• The AE resolved or improved with decreasing the dose or stopping use of the 
investigational product (dechallenge).  Judgment should be used if multiple products are 
discontinued at the same time. 
The causal relationship between the study medication and the AE will be assessed using one of 
the following categories: 
Not Related:  Factors consistent with an assessment of Not Related include: 
• Temporal relationship is lacking (e.g., the event did not occur within a reasonable 
time frame following administration of the study medication); or 
• Other causative factors more likely explain the event (e.g., a pre-existing 
condition, other concomitant treatments). 
Related:  Factors consistent with an assessment of Related include: 
• There is a positive temporal relationship (e.g., the event occurred within a 
reasonable time frame following administration of study medication); or 
• The AE is more likely explained by the investigational product than by another 
cause (i.e., the AE shows a pattern consistent with previous knowledge of the 
investigational product or the class of the investigational product) 
11.3.6 
Recording Adverse Events 
All AEs (including SAEs) are to be accurately recorded on the Adverse Event page of the 
subject’s eCRF.  The severity of each AE will be graded using the NCI CTCAE, Version 4.03.  
The date of onset as well as the end date of the event also should be recorded or the event should 
be entered as “ongoing”.  In addition, the method used to treat the AE and the outcome of the AE 
also will be noted.  The Investigator will assess the relationship of the event to study drug.       
11.3.7 
Planned Hospitalization 
A hospitalization planned by the subject prior to the first dose of study medication is considered 
a therapeutic intervention and not the result of a new SAE and should be recorded as medical 
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history.  If the planned hospitalization or procedure is executed as planned, the record in the 
subject’s medical history is considered complete.  However, if the event/condition worsens 
during the trial, it must be reported as an AE. 
11.3.8 
Reporting Pregnancies 
If a female subject or the female partner of a male subject becomes pregnant during the course of 
the study, the Investigator must report the pregnancy to the Medpace Safety using the 
Pregnancy Reporting Form within 24 hours of becoming aware of the event.  The Investigator 
must obtain consent to collect pregnancy information (including the status of the newborn, if 
applicable). 
If some of the information required for completion of the Pregnancy Reporting Form is 
unavailable at the time of the initial report, follow-up reports will be completed and submitted 
within 24 hours of becoming aware of the new information.  Any pregnancy will be followed 
through delivery for the observation of any SAEs.  Any SAE that occurs during pregnancy must 
be recorded on the SAE report form in the EDC system (e.g., maternal serious complications, 
therapeutic or spontaneous abortion, ectopic pregnancy, stillbirth, neonatal death, congenital 
abnormality, birth defect) and reported within 24 hours in accordance with the procedure for 
reporting SAEs (See Section 11.3.9).   
11.3.9 
Serious Adverse Event Reporting 
11.3.9.1 
Governing Regulatory Requirements 
Compliance with this request for prompt reporting is essential in that the sponsor is responsible 
for informing the US Food and Drug Administration (FDA) and other regulatory authorities as 
well as all other participating Investigators of the event.  
Under FDA ruling (US Code of Federal Regulations, Title 21 CFR Part 312.32) and the ICH 
Guidelines for Clinical Safety Data Management Definitions and Standards for Expedited 
Reporting, the sponsor is required to submit written documentation, in the form of a safety 
report, detailing: 
• Any event associated with the use of the drug, that is both serious and unexpected, or  
• Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.  
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Written submission must be made by the sponsor to the FDA and the IRBs as soon as possible 
and in no event later than 15 calendar days after the sponsor’s initial notification of the event.  
The sponsor shall also inform all Investigators. 
11.3.9.2 
Time Frame for Reporting 
Any death, SAE, pregnancy, or unexpected (and severe) AE experienced by the subject after 
informed consent through the last study visit, regardless of relationship to study drug, , must be 
promptly reported (within 24 hours of the Investigator becoming aware of the event) by 
telephone or electronic transmission to the sponsor (or designee). 
 
 
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Contact information for SAE reporting: 
 
 
 
Medpace Clinical Safety  
Medpace SAE hotline:  
Telephone: 
 dial  or 
 dial   
Facsimile: 
 or 
  
e-mail:
 
 
Additionally, the Investigator will be able to contact the Medical Monitor: 
Medical Safety Contact 
  
Phone (US): 
 extension 
 
Mobile phone: 
 
Email: 
 
 
11.3.9.3 
Information to be Provided by the Investigator 
SAEs must be recorded on the SAE form in the EDC system.  This requirement includes all 
SAEs that occur after informed consent through the last study visit. 
The minimum information required for SAE reporting includes identity of Investigator, site 
number, subject number, an event description, SAE term(s), onset date, the reason why the event 
is serious (i.e., the seriousness criteria) and the Investigator’s assessment of the relationship of 
the event to study treatment.  Additional SAE information including medications or other 
therapeutic measures used to treat the event, action taken with the study treatment due to the 
event, and the outcome/resolution of the event will be recorded.  Paper forms for reporting SAEs 
will be provided to the study sites as back-up in case the EDC system is not accessible. 
In all cases, the Investigator should continue to monitor the clinical situation and report all 
material facts relating to the progression or outcome of the SAE.  Furthermore, the Investigator 
may be required to provide supplementary information as requested by Syntimmune or designee. 
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When reporting an SAE, the following additional points should be noted: 
• When the diagnosis of an SAE is known or suspected, the Investigator should report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms.  Signs 
and symptoms may then be described in the event description.  For example, dyspnea 
should not be used as an SAE term if the diagnosis, which caused the dyspnea, is known 
to be malignant pleural effusion.   
• Death should not be reported as an SAE, but as an outcome of a specific SAE, unless the 
event preceding the death is unknown.  In the exceptional case where the events leading 
to death are unknown, then death may be used as an event term.  If an autopsy was 
performed, the autopsy report should be provided.  
• While most hospitalizations necessitate reporting of an SAE, some hospitalizations do not 
require SAE reporting, as follows:  
• Elective or previously scheduled surgery, e.g., a previously scheduled ventral 
hernia repair 
• Procedures for pre-existing conditions that have not worsened after initiation of 
treatment 
• Pre-specified study hospitalizations for observation 
• Events that result in hospital stays of less than 24 hours and that do not require 
admission, e.g., an emergency room visit for hematuria that results in a diagnosis 
of cystitis and discharge to home on oral antibiotics 
• SAEs must, however, be reported for any surgical or procedural complication resulting in 
prolongation of the hospitalization. 
11.3.10 
Regulatory Reporting 
Syntimmune (or designee) will process and evaluate all SAEs as soon as the reports are received.  
For each SAE received, Syntimmune will decide as to whether the criteria for expedited 
reporting have been met. 
Syntimmune (or designee) will submit SAEs that meet the criteria for expedited reporting to the 
regulatory authorities in accordance with local regulations governing safety reporting.  Reporting 
of SAEs by the Investigator to his or her IRB will be done in accordance with the standard 
operating procedures and policies of the IRB.  Adequate documentation must be maintained 
showing that the IRB was properly notified. 
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11.3.11 
Follow-up Information on a Serious Adverse Event (SAE) 
Appropriate diagnostic tests should be performed and therapeutic measures, if indicated, should 
be instituted.  Appropriate consultation and follow-up evaluations should be carried out until the 
event has returned to baseline or is otherwise explained by the Investigator.   
If all required information on the SAE form is not available at the time of the initial report, 
follow-up information will be completed in the EDC system. 
11.4 
Other Safety Considerations 
11.4.1 
Laboratory Data 
All laboratory data obtained during the study should be reviewed.  Any abnormal value that leads 
to a change in subject management (e.g., requirement for additional medication or monitoring) or 
is of clinical significance by the Investigator should be reported as an AE and/or SAE as 
appropriate, unless this value is consistent with values obtained before entry into the study.   
11.4.2 
Medication Errors 
Any medication error that results in an AE, even if it does not meet the definition of serious, 
requires reporting within 24 hours to the safety Medical Monitor. 
11.4.3 
Follow-Up of Adverse Events 
Any SAE or AE assessed as related to study drug must be followed until either resolution of the 
event or determination by the Investigator that the event has become stable or irreversible.    The 
Investigator will follow all drug related AEs until there is a return to the subject’s baseline 
condition, or until a clinically satisfactory resolution has been achieved.  The appropriate follow-
up visits must be scheduled and the specific tests repeated or performed as necessary. The status 
of all AEs will be documented as of the last study visit. 
Where a diagnosis is possible, it is preferable to report this diagnosis rather than a series of terms 
(signs/symptoms) relating to the diagnosis. 
11.5 
Safety Monitoring for Dose Escalation 
Following dosing in each cohort, all safety/tolerability data (e.g., PEs, vital signs [including 
pulse oximetry], clinical safety laboratory tests, ECGs and AE/SAE assessments) as well as any 
available and relevant PD data collected through Day 42 will be reviewed by the DEC.  A 
decision to escalate to the next cohort will be made.  The recommendation may be to continue to 
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the next scheduled dose level, discontinue the study or to modify dosing to a dose less than the 
current dose or higher than the current dose but lower than the next planned dose.   
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12 
STATISTICAL CONSIDERATIONS  
All descriptive and inferential statistical analyses will be performed using the most recently 
released and available Statistical Analysis System (SAS) software, unless otherwise noted.  
Missing data will not be imputed unless otherwise stated.  All clinical data captured will be 
provided in data listings. A Statistical Analysis Plan (SAP) and a Pharmacokinetic Analysis Plan 
(PAP) will be finalized prior to database lock. 
12.1 
General Design  
All data for enrolled subjects will be presented in data listings by subject number.    
Continuous data will be described using descriptive statistics: number of observations (n), mean, 
standard deviation (SD), median, minimum, and maximum.  Frequencies and percentages will be 
used for summarizing discrete (categorical) data.  When categorical data are presented, the 
percent will be suppressed when the count is zero to draw attention to the non-zero counts.  The 
denominator for all percentages, unless otherwise specified, will be the number of subjects in the 
specified analysis population. 
12.2 
Sample Size Justification  
Formal sample size calculations were not performed. The number of subjects was chosen based 
on feasibility and was considered sufficient to meet the study objectives. 
12.3 
Statistical Considerations  
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP). The SAP may modify the plans outlined in 
the protocol; any deviations from the previously described statistical plan will be described and 
justified in an SAP amendment. Additional statistical analyses other than those described in this 
section may be performed if deemed appropriate and will be described in the SAP. Methods of 
handling of missing data for different endpoints will be further specified in the SAP. In general, 
where individual data points are missing because of insufficient samples, dropouts, or other 
reasons, the data will be analyzed based on reduced denominators unless specified otherwise in 
the SAP.  
Results will be summarized by cohorts.  
12.3.1 
Study Populations  
Three populations will be employed in the analysis of study data: 
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• The intent-to-treat (ITT) population will consist of all subjects who have received at least 
one dose of study drug.  All safety analyses will be performed on the ITT population. 
• The PK population will consist of all subjects who receive at least one dose of study drug 
and have sufficient post-dose blood samples to obtain PK parameters. 
• The PD population will consist of all subjects who receive at least one dose of study drug 
and have post-dose PD data available.  
Primary safety analyses will be performed on the ITT population.  Demographics, subject 
disposition, and screening and baseline characteristics will be summarized for the ITT, PK, and 
PD populations, where appropriate. 
12.3.2 
Subject Accountability, Demographics, and Baseline Characteristics  
Subject disposition, demographic information and baseline characteristics will be presented.  
Any discrepancy between treatment to be given and treatment received will be accounted for in 
these displays.  
12.3.3 
Concomitant Medications  
Concomitant medications will be coded using WHO Drug Dictionary (WHO-DD March 2013, 
Type B2 or later) and the data will be summarized and presented in tables and listings.  
12.4 
Planned PK Analysis 
Study drug concentrations will be used to calculate the following PK parameters: t1/2, Cmax, Tmax, 
and AUC0-24 and AUC0-∞.  PK parameters will be determined using noncompartmental 
method(s).  Descriptive statistics of PK parameters for SYNT001 will include mean, SD, 
coefficient of variation (CV), median, minimum, and maximum. Tmax will be reported as median 
and range. All descriptive statistics will be performed on untransformed PK parameters and after 
log10 transformation of PK parameters. 
For calculation of mean concentrations and generation of mean concentration-time profiles, all 
below the limit of quantification (BLQ) values will be set to zero except when an individual 
BLQ falls between 2 quantifiable values, in which case it will be omitted. 
If there are values above the BLQ, but too sparse to allow full analysis, descriptive statistics will 
be performed on available values. 
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12.5 
Safety Data  
Safety observations and measurements include AEs, safety laboratory tests, vital sign 
measurements, PEs, and ECGs.  
Treatment-emergent AEs will be summarized using the Medical Dictionary for Regulatory 
Activities (MedDRA®; Version 19 or higher) System Organ Class (SOC) and preferred term, 
classified from verbatim terms.  The incidence and percentage of subjects with at least 1 
occurrence of a preferred term will be included, using the most severe grade.  The number of 
events per preferred term will also be summarized.  Causality (relationship to study treatment) 
will be summarized separately.   
AEs, SAEs, and AEs leading to withdrawal, dose modification, or treatment discontinuation will 
be listed by subject, cohort, and overall per SOC and preferred terms. Duration of AEs will be 
determined and included in listings, along with action taken and outcome.   
Laboratory results will be summarized by cohort.  Incidence of laboratory abnormalities will be 
summarized.  The worst on-study grade after the first dose of study drug will be summarized.  
Results for variables that are not coded will be presented in the listings as below, within, and 
above the normal limits of the local laboratory. 
Vital sign measurements and change from baseline will be summarized at each scheduled time 
point by cohort using descriptive statistics.      
Arithmetic mean of parameters from triplicate ECG will be calculated first for each participant at 
each planned time point. Then summary statistics of ECG test parameters (mean of triplicate) 
and change from baseline to each post-dose time point will be calculated. Shift tables for ECG 
test result category change (normal, abnormal, clinically abnormal) from pre-dose to each post-
dose time point showing number and percentage of subjects with movement between categories 
will be presented by treatment group. Frequency and percentage of subjects experiencing 
potential QTc prolongation (QTcF > 450) will be summarized at each time point by cohort. 
12.6 
Pharmacodynamic/Activity Data  
PD results will be summarized by cohort. 
12.7 
Immunogenicity Data  
Immunogenicity results will be summarized by cohort. 
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12.8 
Interim Analysis 
No interim analysis is planned.  Safety results will be examined for making dose-escalation 
decisions; no statistical analyses are planned for aiding these dose-escalation decisions. 
 
 
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13 
DATA QUALITY ASSURANCE 
All data will be entered in a validated electronic data capture system using single data entry. 
Standard procedures (including following data review guidelines, manual clinical review based 
on subject profiles, computerized validation to produce queries, and maintenance of an audit file 
which includes all database modifications) will be followed to ensure accurate data. Clinical 
personnel will review all data listings for outliers, data inconsistencies, and spelling errors. 
During the study, a study site monitor will make site visits to review protocol compliance, 
compare electronic case report forms (eCRFs) against individual subject medical records, assess 
drug accountability, and ensure that the study is being conducted using pertinent regulatory 
requirements.  eCRF entries will be verified with source documentation. The review of medical 
records will be performed in a manner to ensure that subject confidentiality is maintained.  
Checking the eCRFs for completeness, clarity and cross checking with source documents is 
required to monitor the progress of the study. Direct access to source data is also required for 
inspections and audits, and will be carried out giving due consideration to data protection and 
medical confidentiality. Each Investigator will have assured Syntimmune of full access to 
complete source data for study participants and associated necessary support at all times. 
In addition to routine monitoring procedures, audits of clinical research activities in accordance 
with standard operating procedures (SOPs) may be performed to evaluate compliance with the 
principles of GCP.  A regulatory authority may also wish to conduct an inspection (during the 
study or even after its completion).  If a regulatory authority requests an inspection, the 
Investigator must immediately inform Syntimmune that this request has been made. Study 
conduct may be assessed during the study by a Clinical Quality Assurance representative(s) to 
ensure that the study is conducted in compliance with the protocol.  This designee, as well as the 
site monitor, will be permitted to inspect the study documents (study protocol, eCRFs, 
investigational product accountability, original study-relevant medical records).  All subject data 
will be treated confidentially.  During the clinical study, access will be available to Syntimmune 
or their designee (e.g., contract research organization [CRO]) to view the eCRFs after 
completion of the individual sections of the study. Furthermore, the study protocol, each step of 
the data-recording procedure and the handling of the data as well as the study report may be 
subject to independent review by a Quality Assurance representative.  Clinical site and study 
audits will be conducted as necessary to assure the validity of the study data. 
 
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14 
STUDY ADMINISTRATION 
14.1 
Study Administrative Structure 
The study administration structure is provided in Table 6. 
Table 6 :  
Study Administrative Structure 
Sponsor Contact: 
 
 
Phone: 
 
Email: 
 
Sponsor Medical Director: 
 
 
 
Phone: 
 
Email: 
 
Medical Monitor: 
 
Medpace 
43 Thorndike Street 
Cambridge, MA 01240 
Phone: 
 
Email: 
 
Study Monitoring: 
Medpace 
5375 Medpace Way 
Cincinnati, OH 45227 
Phone (Main): 
 
Email: 
 
 
14.2 
Ethical Conduct of the Study 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
ICH E6 Tripartite Guideline (January 1997), and in general, be conducted in a manner consistent 
with the principles described in the Declaration of Helsinki. The Investigator will ensure that the 
conduct of the study complies with the basic principles of GCP as outlined in the current version 
of 21 CFR, subpart D, Part 312, “Responsibilities of Sponsors and Investigators”, Part 50, 
“Protection of Human Subjects”, and Part 56, “Institutional Review Boards”. 
14.3 
Informed Consent (ICF) 
A properly executed, written informed consent document, in compliance with 21 CFR, Part 50 
and the ICH guidelines, will be obtained from each subject before the subject is entered into the 
study and before any study screening procedure is performed that involves risk.  Attention will 
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be directed to the basic elements required for incorporation into the informed consent under US 
Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a]) and (21 CFR 
50.25[b]), as necessary. 
Sample ICFs will be supplied to each site. Syntimmune or its designee must review any proposed 
deviations from the sample ICF. The final IRB-approved document must be provided to 
Syntimmune for regulatory purposes. 
It is the responsibility of the Investigator, or a person designated by the Investigator, to obtain 
written informed consent from each subject (or the subject’s legally authorized representative) 
participating in this study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study. In the case where the subject is unable to read, an impartial 
witness should be present during the entire informed consent discussion. After the subject has 
orally consented to participation in the trial, the witness’ signature on the form will attest that the 
information in the consent form was accurately explained and understood. A copy of the ICF 
must be provided to the subject or to the subject’s legally authorized representative. If applicable, 
it will be provided in a certified translation of the local language. 
The eCRF for this study contains a section for documenting informed subject consent, and this 
must be completed appropriately. Signed ICFs must remain in each subject’s study file and must 
be available for verification by site monitors at any time. If new safety information results in 
significant changes in the risk/benefit assessment, the consent form should be reviewed and 
updated as necessary. All subjects (including those already being treated) should be informed of 
the new information, should be given a copy of the revised form, and should give their consent to 
continue in the study. 
14.4 
Institutional Review Board 
This study is being conducted under US IND 128152. This protocol (and any modifications) and 
appropriate consent procedures must be reviewed and approved by an IRB. This board must 
operate in accordance with the current federal or local regulations. The Investigator will send a 
letter or certificate of IRB approval to Syntimmune (or designee) before subject enrollment and 
whenever subsequent modifications to the protocol are made. 
14.5 
Dose Escalation Committee 
The DEC will be responsible for confirming the safety of the investigative product prior to 
dose escalation, as well as the dose level for each successive cohort.  In addition, over the course 
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of the study, the DEC will review any drug-related SAEs to determine if modifications to the 
study or other measures are necessary to ensure the safety of the subjects.  The DEC will consist 
of the Medical Monitor, an Independent Clinical Expert and a Syntimmune Medical Officer.  To 
assist in the safety assessments, the DEC may request that Investigators, other experts, or 
members within their organizations review the data and participate in the discussions. 
14.6 
Future Use of Subject Samples 
Not all the tissue and blood components obtained during this study may be required for the tests 
that are part of the clinical trial. Available samples may be used for additional research. This 
research will help to understand disease subtypes, drug response and AE, and possibly identify 
new drug targets or biomarkers that predict subject response to treatment. The use of the samples 
for internal research will be done using the guidelines defined by the FDA guidance for In Vitro 
Diagnostic Device Studies Using Leftover Human Specimens that are Not Individual Identifiable 
(issued 25 April 2006) and the European Medicines Agency (EMA) Reflection Paper on 
Pharmacogenetic Samples, Testing and Data Handling (Doc. Ref. 
EMEA/CHMP/PGxWP/201914/2006; 15 November 2007).  If a subject requests destruction of 
their tissue and blood samples and the samples have not yet been de-identified, Syntimmune will 
destroy the samples as described in this FDA guidance. Syntimmune will notify the Investigator 
in writing that the samples have been destroyed. 
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CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between a 
Syntimmune representative and the Investigator. Protocol modifications will be prepared, 
reviewed, and approved by Syntimmune representatives. 
All protocol modifications must be submitted to the IRB for information and approval in 
accordance with local requirements, and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects, or when the change involves only logistical or administrative 
aspects of the trial (e.g., change in site monitor, change of telephone number). 
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CONDITIONS FOR TERMINATING THE STUDY 
Syntimmune has the right to terminate the study at any time. In terminating the study, 
Syntimmune and the Investigator will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 
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17 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
17.1 
Investigator’s Files and Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into 2 separate categories as follows: (1) Investigator’s study file and (2) subject 
clinical source documents. 
The Investigator’s study file will contain the protocol and protocol amendments, eCRFs, query 
forms, IRB and governmental approval with correspondence, sample informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
Subject clinical source documents (usually predefined by the project to record key efficacy and 
safety parameters independent of the eCRFs) may include subject hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, 
electroencephalogram, X-ray, pathology and special assessment reports, signed ICFs, consultant 
letters, and subject screening and enrollment logs. The Investigator must keep these 2 categories 
of documents on file for at least 2 years following the marketing application approval date for the 
study treatment and for the indication being investigated or for 2 years after the development 
program is discontinued and the FDA notified. After that period, the documents may be 
destroyed subject to local regulations with prior written permission from Syntimmune. If the 
Investigator wants to assign the study records to another party or move them to another location, 
Syntimmune must be notified in advance. 
If the Investigator cannot guarantee the archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and Syntimmune to 
store these in a sealed container outside of the study site so that they can be returned sealed to the 
Investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside of the study site. 
17.2 
Source Documents and Background Data 
Investigators must maintain adequate and accurate source documents on which the eCRFs for 
each subject are based. They are separate and distinct from the eCRFs. 
These records include detailed notes on the following: 
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• Medical history 
• Date and time of informed consent with Health Insurance Portability and Accountability 
Act (HIPAA) authorization either contained in the ICF or presented to the subject 
candidate as a standalone document 
• Description of the complete consenting process 
• The basic identifying information that linked the subject’s medical record with the 
eCRFs 
• The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject 
• The medical condition of the subject during their involvement in the study 
• All AEs 
• The subject’s exposure to the study medication 
• The subject’s exposure to any concomitant therapy 
• All relevant observations and data on the condition of the subject throughout the trial 
• Justification for all entries in the subject’s eCRF 
A subject log of all potentially eligible subjects considered, but not consented, for obvious 
deviations from the entry criteria, will be kept at each site. The log will contain subjects’ initials, 
diagnosis, eligibility, or, if not eligible, reason for not consenting.  All consented subjects will be 
logged, regardless of whether they ultimately enroll.  
Upon request, the Investigator will supply Syntimmune with any required background data from 
the study documentation or clinic records. This is particularly important when eCRFs are 
illegible or when errors in data transcription are suspected. In case of special problems or 
governmental queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected. 
17.3 
Audits and Inspections 
The Investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from Syntimmune (or designee), or to health 
authority inspectors after appropriate notification. The verification of the eCRF data must be by 
direct inspection of source documents. 
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17.4 
Electronic Case Report Forms 
Clinical trial data for this study will be captured on eCRF designed for computer processing and 
analysis.  This computerized system will be validated and compliant with 21 CFR Part 11. 
Corrections to data will be made using 21 CFR Part 11, Electronic Records; Electronic 
Signatures. If corrections are made after review and sign-off by the Investigator, he/she must be 
aware of the changes and provide written acknowledgement. There will also be an electronic 
audit trail. Corrections on paper CRFs must be initialed and dated by the person making the 
change. The Investigator agrees to provide all information requested on the eCRF in an accurate 
manner using instructions provided.  The Investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported to Syntimmune in the eCRF and in all required 
reports. 
An eCRF is required to be submitted for every subject who receives any amount of study drug.  
This includes submission of retrievable data on subjects who withdraw before completion of the 
study.  Prior to submission, eCRFs must be reviewed for completeness and accuracy, and signed 
and dated where either indicated, by the Principal Investigator or authorized delegate from the 
study staff.  If a subject stops treatment or terminates from the study, the dates and reasons must 
be noted on the eCRF. 
 
 
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MONITORING THE STUDY 
It is understood that the responsible Syntimmune site monitor (or designee) will contact and visit 
the Investigator regularly and will be allowed on request to inspect the various records of the trial 
(eCRFs and other pertinent data) if subject confidentiality is maintained in accordance with local 
requirements. 
It will be the site monitor’s responsibility to inspect the eCRFs at regular intervals throughout the 
study, to verify the adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The site monitor should have access to laboratory test reports 
and other subject records needed to verify the entries on the eCRF. The Investigator (or 
designee) must agree to cooperate with the site monitor to ensure that any problems detected 
during these monitoring visits are resolved. 
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CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS 
The Investigator must ensure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On eCRFs or other documents submitted to 
Syntimmune, subjects should be identified by an identification code and not by their names. The 
Investigator should keep a subject enrollment log showing codes, names, and addresses. The 
Investigator should maintain documents not for submission to Syntimmune (e.g., subjects’ 
written consent forms) in strict confidence. 
Authorized regulatory officials and Syntimmune personnel (or their representatives) will be 
allowed full access to inspect and copy the records.  All study drugs, subject bodily fluids and 
tissue, and/or other materials collected shall be used solely in accordance with this protocol, 
unless otherwise agreed to in writing by Syntimmune. 
The Principal Investigator also agrees that all information received from Syntimmune, including 
but not limited to the IB, this protocol, eCRFs, the INDs, and any other study information remain 
the sole and exclusive property of Syntimmune during the conduct of the study and thereafter.  
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from the 
sponsor. The Principal Investigator further agrees to take all reasonable precautions to prevent 
the disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain. 
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20 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. The Investigator 
agrees that any manuscript or abstract they author may be published only after receiving written 
permission from Syntimmune. 
If Syntimmune coordinates a publication or presentation of study results from all study sites, the 
participation of Investigator or other representatives of study site as a named author shall be 
determined in accordance with Syntimmune policy and generally accepted standards for 
authorship. 
 
 
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21 
REFERENCES 
Agarwal S and Cunningham-Rundles C. Assessment and clinical interpretation of reduced IgG 
values. Ann Allergy Asthma Immunol. 2007;99:281-283. 
Ameratunga R, Woon ST, Gillis D, Koopmans W, Steele R. New diagnostic criteria for common 
variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or 
subcutaneous immunoglobulin. Clin. Exp. Immunol. 2013;174: 203-211. 
Bugelski PJ and Treacy G. (2004) Predictive power of preclinical studies in animals for the 
immunogenicity of recombinant therapeutic proteins in humans. Curr Opin Mol Ther.  
2004;6:10−16. 
Eming R, Hertl M. Immunoadsorption in pemphigus. Autoimmunity. 2006;39:609-616. 
Furst DE. Serum immunoglobulins and risk of infection: how low can you go? Semin Arthritis 
Rheum. 2009;39:18-29. 
Gonzalez-Quintela A, Alende R, Gude R, Campos J, Rey J, Meijide LM, Fernandez-Merino C, 
Vidal C. Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and 
their relationship with alcohol consumption, smoking, and common metabolic abnormalities. 
Clin Exp Immunol. 2008;151:42-50. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) (2011). S6(R1) Preclinical Safety Evaluation of 
Biotechnology-Derived Pharmaceuticals. Accessed 03 June 2016. 
http://www.ich.org/products/guidelines/safety/safety-single/article/preclinical-safety-evaluation-
of-biotechnology-derived-pharmaceuticals.html     
Joliff CR, Cost KM, Stivrins PC, Grossman PP, Nolte CR, Franco SM, et al. Reference intervals 
for serum IgG, IgA, IgM, C3 and C4 as determined by rate nephelometry. Clin Chem. 
1982;28:126-128. 
Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, et al. Safety and 
efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-
label extension analysis. Arthritis Rheum. 2007;56:3896-3908. 
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McMillan SA, Douglas JP, Archbold GPR, McCrum EE, Evans AE. Effect of low to moderate 
levels of smoking and alcohol consumption on serum immunoglobulin concentrations. J Clin 
Pathol. 1997;50:819-822. 
Nixon AE, Chen J, Sexton DJ, Muruganandam A, Bitonti AJ, Dumont J, Viswanathan M, Martik 
D, Wassaf D, Mezo A, Wood CR, Biedenkapp JC, TenHoor C. (2015). Fully human monoclonal 
antibody inhibitors of the neonatal Fc receptor reduce circulating IgG in non-human 
primates. Front. Immun. 6:176 
Ponce R, Abad L, Amaravadi, L, et al. Immunogenicity of biologically-derived therapeutics: 
assessment and interpretation of nonclinical safety studies. Regul Toxicol Pharmacol. 
2009;54,164–182.   
Roopenian, D.C., Christianson, G.J., Sproule, T.J., Brown, A.C., Akilesh, S., Jung, N., Petkova, 
S., Avanessian, L., Choi, E.Y., Shaffer, D.J., Eden, P.A., Anderson, C. L. The MHC class I-like 
IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled 
drugs. 2003. J. Immun. 170 3528-3533 
 
Schmaldienst S, Müllner M, Goldammer A, Spitzauer S, Banyai S, Hörl WH, Derfler K. 
Intravenous immunoglobulin application following immunoadsorption: benefit or risk in patients 
with autoimmune disease? Rheumatology. 2001;40:513-521. 
 
van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann RM, Furst DE, et 
al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global 
clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum 
Dis. 2013;72:1496-502. 
 
 
 
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Appendix A: NCI CTCAE, Version 4.03 
 
 
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Appendix B: Pemphigus Disease Area Index (PDAI) 
 
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Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Syntimmune, Inc. and 
any unauthorized use or disclosure of such information without the prior written authorization of 
Syntimmune is expressly prohibited. 
Syntimmune, Inc. 
SUMMARY OF CHANGES TO CLINICAL STUDY PROTOCOL 
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and Activity 
Study of SYNT001 in Subjects with Chronic Pemphigus (Vulgaris or 
Foliaceus) 
Protocol Number: 
SYNT001-103 
 
IND Number: 
132727 
 
Study Drug: 
SYNT001 
 
Sponsor: 
Syntimmune, Inc. 
 
257 Park Avenue South 
 
15th Floor 
 
New York, NY 10010 
 
Medical Monitor: 
 
 
43 Thorndike Street, Cambridge, MA 01240 
 
Phone: 
 extension 
 
 
Mobile: 
 
 
  
 
Date of Protocol: 
Original, 18 January 2017 
Amendment 1.1 
21 March 2017 
Amendment 2.0 
12 April 2017 
 
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SUMMARY 
The SYNT001-103 protocol has been amended under version 2.0 as follows:   
 
• Lengthened subject follow-up to include study visits at Day 84 and Day 112 to follow 
pharmacodynamics (Serum IgG) and clinical effects out to 12 weeks from the last dose of 
SYNT001 
• Added immune phenotyping to Day 56 assessments 
• Contraception requirement in Inclusion and Exclusion criteria updated to correspond to 
additional study visits (out to Study Day 112; 12 weeks following last dose of SYNT001) 
for both females and males 
• Total blood draw for subjects completing the study at Day 112 updated to approximately 
381 mL from 311 mL in Section 6.7 
• Allowing vaccinations at the discretion of the Investigator after Day 56 
• AE reporting timelines updated to correspond to additional study visits 
• Clarifying language for Tetanus and Varicella-Zoster Virus antibody testing follow-up, 
specifying the actual study visit Days when additional testing will be performed 
• Clarifying language for Investigator removal of subjects from study to not require 
consultation with Medical Monitor but to allow it if desired 
• Clarifying language for dose escalation stopping rules; rules for stopping escalation are 
not changed 
• Additional text related to potential immune effects and corresponding references added 
• Various typographical and formatting corrections as well as corrections for consistency 
made throughout the document. 
 
 
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SPECIFIC CHANGES 
Text deletions are shown using strike through font; new text added in italic font. 
SECTION 1, STUDY SYNOPSIS 
In addition to the changes in the section below, the synopsis has been updated to reflect all 
changes in the body of the protocol.  
Duration of subject participation and duration of study 
• 
Up to 70 126 days (10 18 weeks): Screening of up to 2 weeks (14 days); Treatment dosing period 
of 8 weeks (56 days) 28 days; Follow-up period of and 4 8 weeks (56 28 days) 
Table 1, Schedule of Assessments 
• Table updated to show Treatment Period spanning Day 0 through Day 56 
• Table updated to show Follow-up Period spanning Day 84 through Day 112 
• Table updated by adding a Day 84 visit and a Day 112/ Early Termination visit, with 
associated assessments described in Section 7 
• Adverse Events and Concomitant Medications:  
o To be collected from the date that the ICF was signed through the last study visit 
until 28 days after the last dose of study drug 
• Footnote d: Clinical safety labs:  
o Hematology, clinical chemistry, and urinalysis (see Section 6.6 for a complete 
list).  Full clinical safety lab draws will be collected at Screening and on Days 0, 
7, 14, 21, 28, 33, 42, 56, 84 and 11256.  PD biomarkers (albumin levels, 
hematocrit, hemoglobin, platelet count, reticulocyte count, LDH, and total and 
direct bilirubin) will be derived from the clinical safety laboratory results. 
• Footnote e: Pregnancy Test:   
o To be performed at time of screening, prior to first dose of SYNT001 on Day 0 
and on Days 56 and 112 (urine or serum test is acceptable however, positive urine 
tests must be confirmed with serum testing.) 
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• Footnote g: Serology:  
o Testing at Day 56 will not be done for any subject whose baseline titer is below 
the level of detection. If the Day 56 results are greater than 30% below the 
baseline value, or if the subject falls below the level of detection, the subject will 
be re-tested at Day 841 month after the Follow-Up visit (approximately 2 months 
after the subject’s last dose); if still below the baseline value (or level of 
detection), the subject will be re-tested at Day 112after another month (3 months 
after last dose). Any subject whose baseline value for tetanus or VZV was above 
the detectable level at baseline, and is not within 30% of the baseline value or is 
below the detectable level by Day 112on Day 56 and upon 2 retests (2 and 3 
months following last dose of SYNT001), will be referred to their primary care 
physician for further management. See Section 6.7.3 for additional information. 
• Footnote i: Immunogenicity: 
o Blood samples will be collected pre-dose when collected on dosing days.  
Samples will be collected on Days 0, 14, 28, 56, 84 and 112. See Section 6.7.6 for 
additional information. 
• Footnote q: Subjects will return to the clinic on Days 84 and 112 for follow-up visits.  
Subjects whose total IgG is not within 30% of their Day 0 baseline value and not above 
500 mg/dL at the Day 112 visit will be referred for further management. Extended 
follow-up visits will occur only if additional testing for anti-tetanus and/ or anti-VZV 
titers are required.  These visits will occur as needed at approximately 2 months post last 
dose and 3 months post last dose. 
 
 
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SECTION 4 STUDY DESIGN 
Section 4.3, Overview of Study Design 
• On Day 0 photographs will be taken of active lesions.  Follow-up photographs will be 
taken of the same areas on Days 33, and 56, 84, and 112.  If a subject begins a steroid 
taper, additional photographs will be taken at the clinic visit during which the decision to 
begin the taper is made. 
• Subsequent visits will occur on Days 1, 2, 5, 7, 12, 14, 19, 21, 28, 29, 30, 33, 42 and 5642 
for safety assessments, study drug dosing, sample collections, and other study 
procedures. 
• Subjects also will return to the clinic on Days 84 and 112 for follow-up visits.  Subjects 
whose total IgG is not within 30% of their Day 0 baseline value and not above 500 mg/dL 
at the Day 112 visit will be referred for further management.56 (28 days after receiving 
their last dose of study drug) for an End-of-Study/Follow-Up visit. 
• Note:  No vaccinations may be given from within 2 weeks of screening through Day 56.  
Following Day 56, subjects may receive vaccinations at the discretion of the Investigator. 
until 2 months following the last dose of study drug 
SECTION 5 STUDY POPULATION 
Section 5.1, Target Population 
• This study will be conducted in approximately 16 male and female subjects (2 cohorts of 
8 subjects each) with a confirmed diagnosis of pemphigus (vulgaris or foliaceus); 
however, a third cohort of up to 8 subjects may be added.  Subjects will be enrolled only 
once in the study and will not be included in subsequent dosing cohorts. Subjects who 
withdraw for any reason other than an AE and who do not receive study drug or have 
only received one dose of study drug may be replaced, up to one subject per cohort. 
Subjects who do not receive all doses of study drug will continue to be followed through 
all scheduled visits28 days after last dose.  The maximum number of subjects who may 
be enrolled in this study is 27 (24 + up to 3 replacements, as necessary). Within each 
dosing cohort, no more than 3 subjects may be enrolled with pemphigus foliaceus. 
Section 5.2, Inclusion Criteria 
7. Females of childbearing potential must agree to be abstinent or else use any two of the 
following medically acceptable forms of contraception (<1% per year failure rate) from 
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the Screening Period through 30 days after the final dose of study visit drug: oral 
contraceptive, condom with or without spermicidal jelly, diaphragm or cervical cap with 
spermicidal jelly, or intra-uterine device (IUD). A female whose male partner has had a 
vasectomy must agree to use one additional form of medically acceptable contraception. 
9. Males with female partners of childbearing potential, including males who are surgically 
sterile (post vasectomy), must agree to be abstinent or else use a medically acceptable 
form of contraception from the screening period through 60 days after the final dose of 
study visit drug. 
SECTION 6 STUDY PROCEDURES 
Section 6.6, 12-Lead Electrocardiogram (ECG) 
• Digital 12-lead ECG measurements will be obtained at screening, on Days 0 and 28 at 5 
minutes after the completion of the infusion and at the Day 56 (Follow-up) visit.  
Subjects who conduct their Day 12 visit at the investigative site, as opposed to an at-
home nurse visit, will have an additional ECG performed.  ECGs are to be performed 
with the subject in a supine position having rested in this position for at least 5 minutes 
before each reading. ECGs are to be performed in triplicate, each 1–2 minutes apart.  See 
Table 2 for timing window allowances with respect to performing ECG. 
Section 6.7, Clinical Laboratory Measurements 
• Laboratory testing (hematology, urinalysis, serum chemistry, virology, serology, 
pregnancy tests, PD samples, PK samples, and anti-drug antibody samples) will be 
performed using established methods by a central laboratory. Safety laboratory panels are 
defined as listed in Table 3. Blood and urine samples for hematology, serum chemistry, 
and urinalysis will be prepared using standard procedures.  Results will be provided to 
the Investigator.   Aliquots from the PK, biomarker and anti-drug antibody samples may 
be retained as back-up for additional testing as necessary. Subjects will be in a seated or 
supine position during blood collection. Full clinical safety lab draws will be collected at 
Screening and on Days 0, 7, 14, 21, 28, 33, 42, 56, 84 and 11256.  The total blood draw 
for each subject who completes the study at Day 11256, will be approximately 311 381 
mL.  Please refer to the Laboratory Manual for more information. 
• Table 3: Clinical Laboratory Panels, Hematology 
o CBC with differential and blood smear 
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Section 6.7.1 Pregnancy Testing 
• Pregnancy testing will be performed for women of childbearing potential at screening and 
prior to first dose of SYNT001 on Day 0 and Days 56 and 112 (urine or serum test is 
acceptable however, positive urine tests must be confirmed with serum testing.) 
Section 6.7.3. Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing 
• Samples for serum tetanus antibody and Varicella-Zoster virus antibody testing are to be 
collected at baseline (pre-dose, Day 0) and on Day 56 (Follow-Up visit).  Testing at Day 
56 will not be done for any subject whose baseline titer is below the level of detection. 
Specifically, if the baseline VZV titer is above the detectable level, but Tetanus is not, 
only the VZV antibody titer will be tested on Day 56. If the Day 56 results are below the 
baseline value, defined as greater than 30% below the baseline value, or if the subject 
falls below the level of detection, the subject will be re-tested at Day 841 month after the 
Follow-Up visit (approximately 2 months after the subject’s last dose); if still below the 
baseline value (or level of detection), the subject will be re-tested at Day 112after another 
month (3 months after last dose). Any subject whose baseline value for tetanus or VZV 
was above the detectable level at baseline, and is not within 30% of the baseline value or 
is below the detectable level by Day 112on Days 56 and upon 2 retests (2 and 3 months 
following last dose of SYNT001), will be referred to their primary care physician for 
further management 
 
 
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Section 6.7.5 Pharmacodynamic (PD) Sampling 
Table 1:  
Pharmacodynamic/ Activity Assessments 
Parameter 
Collection Timepoints 
• 
IgG, IgG subtypes (IgG1-4), IgA, IgM  
Screening, and Days 0, 1, 2, 5, 7, 12, 14, 19, 
21, 28, 29, 30, 33, 42, 56, 84 and 11256.   
• 
Circulating immune complexes (CIC) 
Days 0, 5, 7, 12, 14, 19, 21, 28, 33, 42, 56, 
84 and 11256 
• 
Albumin 
Screening, and Days 0, 7, 14,21, 28, 33, 42, 
56, 84 and 11256 
• 
Anti-Dsg (1 and 3) antibody titer 
Screening, Days 0, 7, 14, 33, 56, 84 and 
11256 
• 
Complement component 3 (C3) 
• 
Anti-epithelial cell antibody (AECA) levels by 
indirect immunofluorescence 
 
Days 0, 14, 33, 56, 84 and 11256 
• 
Exploratory biomarker (RNAseq, Urine IgG) 
 
Days 0, 14, 33, 56, 84 and 11256 
• 
Immune phenotyping by flow cytometry for 
measurement of CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B cells 
Days 0, 28 and 2856 
• 
Exploratory biomarker (FCGR2A SNP) 
Day 0 
 
 
 
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Section 6.7.6 Immunogenicity Testing 
• Up to 4 sSerum samples will be collected for immunogenicity analyses.  Samples will be 
collected on Days 0 (pre-dose), 14, 28, 56, 84 and 56112 
Section 6.9 Prior and Concomitant Medication 
• All medications a subject receives within 14 days prior to enrollment through the end of 
the study (Day 56) will be documented on the source document and eCRF.   
Note:  No vaccinations may be given from within 2 weeks of screening through Day 56.  
Following Day 56, subjects may receive vaccinations at the discretion of the Investigator. 
until 2 months following the last dose of study drug. 
Section 6.10 Adverse Events Assessments 
• Information regarding the occurrence of AEs will be collected from the time the subject 
signs the informed consent form and is continuing through the last study visit throughout 
their participation in the study, including a period of 28 days after study drug dosing.  
Findings at screening and Day 0 (pre-dose) will be recorded as medical history.   Any 
known untoward event that occurs beyond the AE reporting period that the Investigator 
assesses as related to study drug also should be reported as an AE 
Section 6.11 Photographs 
• On Day 0 photographs will be taken of active lesions.  Follow-up photographs will be 
taken of the same areas on Days 33, 56, 84 and 11256.  Subjects who begin a steroid 
taper will have additional photographs taken at the clinic visit during which the decision 
to begin the taper is made.  A separate manual describing the procedures for taking 
photographs will be provided. 
Section 6.12 Skin Biopsies 
• Optional skin biopsy samples will be collected on Day 0 pre-dose and on Days 1, 2, 14, 
33, 56 and 8456 to analyze SYNT001 levels 
 
 
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SECTION 7 STUDY ASSESSMENTS 
Section 7.7 Dose 2 Follow-up Day 12 
• On Day 12 (± 6 hours) the subject may will return to the clinic, or be visited by an at-
home nurse, and the following procedures are to be performed: 
Section 7.11 Treatment Day 28 (Dose 5) 
• On Day 28 (± 6 hours1 Day), subjects will return to the clinic and the following 
procedures are to be performed prior to study drug infusion: 
Section 7.15 Follow-up Day 42 
• PDAI Score (Section 6.4) 
Section 7.16 Follow-up Day 56 (End-of-Study) or Early Termination Visit 
• 12-Lead ECG (to be obtained in triplicate after 5 minutes of rest in the sitting position) 
(Section 6.66.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• C3 
• AECA 
• RNAseq 
• Urine IgG 
• Immune phenotyping 
Section 7.17 Follow-up Day 84 
On Day 84 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of 
rest (Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Serum tetanus antibody and VZV antibody testing if required. See Section 6.7.3 for 
additional information.   
• Immunogenicity sample collection (Section 6.7) 
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• PDAI Score (Section 6.4) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• C3 
• AECA 
• RNAseq 
• Urine IgG  
• Optional skin biopsy (Section 6.12) 
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
Section 7.18 Follow-up Day 112 (End-of-Study) or Early Termination Visit 
On Day 112 (± 5 days), subjects are to return to the clinic and the following procedures are to 
be performed: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of 
rest (Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Pregnancy test (Section 6.7) 
• Serum tetanus antibody and VZV antibody testing if required. See Section 6.7.3 for 
additional information.   
• Immunogenicity sample collection (Section 6.7) 
• PDAI Score (Section 6.4) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• C3 
• AECA 
• RNAseq 
• Urine IgG  
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
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• AE assessment (Section 6.10) 
Section 7.16 Extended Follow-up Visits 
• Extended follow-up visits will occur only if additional testing for anti-tetanus and/ or 
anti-VZV titers are required.  These visits will occur as needed at approximately 2 
months post last dose and 3 months post last dose.  See Section 6.7.3. 
 
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SECTION 8 REMOVING SUBJECTS FROM STUDY 
Section 8.3 Replacements 
• Subjects withdrawn for a reason other than an AE will be replaced if they have not been 
dosed or have only received 1 dose of study drug at the time of discontinuation, up to one 
subject per cohort. Subjects who do not receive all doses of study drug will continue to be 
followed through all scheduled study visits28 days after their last dose. 
Section 8.4.1 Dose-Escalation Stopping Rule 
• Dose escalation decisions will be made by a Dose Escalation Committee (DEC) and will 
be based on safety and pharmacodynamic evaluations including but not limited to, dose-
limiting toxicities, AEs, SAEs, and total IgG levels. 
Dose-limiting toxicity (DLT) will be defined generally as clinically significant, severe 
(Grade 3) AEs occurring in ≥2 subjects that are determined to be clinically significant 
and considered related to study drug. 
If 2 or more subjects at any time in any cohort (8 total subjects per cohort) have Grade 3 
AEs that are determined to be clinically significant and considered to be related to study 
drug, dosing will be halted within that cohort and no further dose-escalation to a higher 
dose will not occur. If the dose-escalation stopping rule is met in during cohort 1 (10 
mg/kg) all safety data and all available pharmacodynamics will be reviewed and the 
cohort may resume (if applicable) or a new a cohort may be added at a dose at least 50% 
lower than the 10 mg/kg dose.  If the stopping rule is not met in after Cohort 1, dose-
escalation may proceed up to a maximum of 30 mg/kg.  If the dose-escalation stopping 
rule is met in for the first time during Cohort 2, all safety data and all available 
pharmacodynamics will be reviewed and the cohort may resume (if applicable) or a new 
a cohort may be added at a dose a minimum of 30% lower than the Cohort 2 dose. If the 
stopping rule is not met in after Cohort 2, dose-escalation may proceed up to a maximum 
of 45 mg/kg; however, this cohort may also receive a dose equal to or less than 30 mg/kg 
based on evaluation of all safety and pharmacodynamic data. 
 
 
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Section 8.4.3 Individual Stopping Rule 
• Dosing for any individual subject will be discontinued (i.e., no further study drug will be 
given to that subject) if the subject experiences any study drug-related SAE or any study 
drug-related non-SAE adverse event that, in the judgement of the Investigator and 
(following consultation with the Medical Monitor, if desired) suggest that it could be 
unsafe to administer further study drug to that subject.  Additionally, a subject may will 
be discontinued from further treatment with study drug, at the discretion of the 
Investigator with consultation with the Medical Monitor, if they require a significant 
increase in dose(s) of anti-pemphigus medication(s) for the management of pemphigus 
 
 
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SECTION 9 STUDY DRUG 
Section 9.6 Warnings and Precautions 
• Note: Subjects must not receive any vaccinations from within 2 weeks of screening until 
2 months after the last dose of study drug Day 56. 
Section 9.6.2 Potential Immune Effects 
• An antibody blocking FcRn is anticipated to have several effects.  These include 
acceleration of catabolism of IgG, but not other immunoglobulin isotypes such as IgA 
and IgM, leading to dose-dependent decreases in circulating IgG levels by up to an 
estimated 50% from the baseline levels after a single dose and further decreases after 
multiple doses up to a 70%-80% reduction.  Based on studies in humans, it is expected 
that with a single dose, the nadir of this effect will occur approximately 5 days after 
dosing. The time course of recovery of IgG following dosing in the Phase 1a study 
suggests that a return to within 30% of baseline levels observed at pretreatment normal 
limits occurs within 4 weeks after a single dose and within 4 weeks after multiple doses 
as shown in NHPs. 
• Given the normal adult range of total IgG of 700500-1600 mg/dL (Agarwal and 
Cunningham-Rundles, 2007; Furst, 2009; Gonzalez-Quintela et al, 2008; Joliff et al, 
1982; Keystone et al, 2007; McMillan et al, 1997; van Vollenhoven et al, 2013in some 
references), with a mean of 1150 mg/dL, a 50% decrease in the mean would be to 
575 mg/dL and a 50% decrease from the low end of the normal range used for the 
inclusion criteria of 700600 mg/dL in this study would be to 350300 mg/dL. An 80% 
decrease from baseline after multiple doses would result in IgG levels of 230 mg/dL and 
140120 mg/dL, respectively.  While these levels are in the range found in patients with 
primary humoral immunodeficiency [Ameratunga 2013], the levels will be transient. 
Further, in other conditions, the temporary (ie, less than 4 months) depletion of IgG (up 
to 95% reduction of total IgG as seen with immunoadsorption) does not appear to impart 
an increased risk of infection (Eming, 2006; Furst, 2009; Keystone et al, 2007; 
Schmaldienst et al, 2001; van Vollenhoven et al, 2013). Study subjects will be monitored 
clinically for any infection. Further, commercial IVIG can be given to reverse the low 
IgG levels in case of a bacterial infection occurring while their IgG levels are decreased. 
 
 
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SECTION 10 CONCOMITANT MEDICATION AND TREATMENT 
• Any medications a subject receives within 14 days prior to enrollment through the end of 
study (Day 56) will be documented. Concomitant medication and treatment for co-existing 
conditions, including those for pemphigus, are permitted if not excluded below.  Topical 
antibiotics are permitted to treat active infections that occur on study.  Topical or systemic 
treatments for oral candidiasis are permitted.  Topical lidocaine for transient pain relief is 
acceptable as needed. Significant increases in anti-pemphigus medications maywill result in 
subjects being discontinued from the study. Concomitant treatment that is medically 
indicated for any AEs the subject experiences during the study are permitted. 
• Use of the following treatments will not be permitted during the study unless otherwise 
specified: 
• Rituximab or other anti-CD20 antibody 
• Monoclonal antibodies other than study drug 
• Any immunosuppressive drugs apart from corticosteroids, azathioprine, 
mycophenolate mofetil, or cyclosporine. 
• Topical steroids 
• Any dietary herbal supplements 
• Any investigational drug or device 
• Any vaccinations through Day 56.  Following Day 56, subjects may be vaccinated at 
the discretion of the Investigator. 
SECTION 11 SAFETY 
Section 11.2 Adverse Event Definition 
• For data collection, all untoward events that occur after informed consent through the last 
study visit 28 days after study drug dosing are to be recorded on eCRFs by the 
investigational site 
Section 11.3.1 Serious Adverse Events 
• Death:  This includes any death that occurs while the subject is “on study” through the 
last study visit as well as any death that occurs within 28 days after study drug 
administration 
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Section 11.3.9.2 Time Frame for Reporting 
• Any death, SAE, pregnancy, or unexpected (and severe) AE experienced by the subject 
after informed consent through the last study visit or within 28 days of receiving study 
drug, regardless of relationship to study drug, or any death that occurs more than 28 days 
after receiving study drug, and is believed to be study drug related, must be promptly 
reported (within 24 hours of the Investigator becoming aware of the event) by telephone 
or electronic transmission to the sponsor (or designee) 
Section 11.3.9.3 Information to be Provided by the Investigator 
• SAEs must be recorded on the SAE form in the EDC system.  This requirement includes 
all SAEs that occur after informed consent through the last study visit and through 
28 days after study drug dosing, and in addition, any SAE that are assessed as related to 
study treatment by the Investigator, even if the SAE occurs more than 28 days after study 
drug dosing. 
Section 11.4.3 Follow-up of Adverse Events 
• Any SAE or AE assessed as related to study drug that led to treatment discontinuation 
(including clinically significant abnormal laboratory values that meet these criteria) and 
ongoing 28 days after study drug dosing must be followed until either resolution of the 
event or determination by the Investigator that the event has become stable or 
irreversible.  This follow-up guidance also applies to related SAE that occur more than 28 
days after study drug dosing. The status of all other continuing AEs will be documented 
as of 28 days after study drug dosing.  The Investigator will follow all subjects who 
experience drug related AEs until there is a return to the subject’s baseline condition, or 
until a clinically satisfactory resolution has been achieved.  The appropriate follow-up 
visits must be scheduled and the specific tests repeated or performed as necessary. The 
status of all AEs will be documented as of the last study visit. 
 
REFERENCES – The following were added: 
Agarwal S and Cunningham-Rundles C. Assessment and clinical interpretation of reduced IgG values. 
Ann Allergy Asthma Immunol. 2007;99:281-283. 
Eming R, Hertl M. Immunoadsorption in pemphigus. Autoimmunity. 2006;39:609-616. 
Furst DE. Serum immunoglobulins and risk of infection: how low can you go? Semin Arthritis Rheum. 
2009;39:18-29. 
Gonzalez-Quintela A, Alende R, Gude R, Campos J, Rey J, Meijide LM, Fernandez-Merino C, Vidal C. 
Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship 
with alcohol consumption, smoking, and common metabolic abnormalities. Clin Exp Immunol. 
2008;151:42-50. 
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Joliff CR, Cost KM, Stivrins PC, Grossman PP, Nolte CR, Franco SM, et al. Reference intervals for 
serum IgG, IgA, IgM, C3 and C4 as determined by rate nephelometry. Clin Chem. 1982;28:126-128. 
Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, et al. Safety and efficacy 
of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension 
analysis. Arthritis Rheum. 2007;56:3896-3908. 
McMillan SA, Douglas JP, Archbold GPR, McCrum EE, Evans AE. Effect of low to moderate levels of 
smoking and alcohol consumption on serum immunoglobulin concentrations. J Clin Pathol. 1997;50:819-
822. 
Schmaldienst S, Müllner M, Goldammer A, Spitzauer S, Banyai S, Hörl WH, Derfler K. 
Intravenous immunoglobulin application following immunoadsorption: benefit or risk in patients 
with autoimmune disease? Rheumatology. 2001;40:513-521. 
 
van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann RM, Furst DE, et 
al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global 
clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum 
Dis. 2013;72:1496-502. 
 
 
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SYNTIMMUNE
10-May-2017
Protocol Number: 
SYNT001-103
IND Number: 
132727
Study Drug: 
SYNTOOI
Protocol Version, Date: 2.A, 12-April-2017
Clarification Letter Version: 1.0
Subject:
Buccal swab for DNA testing
To Whom lt May Concern:
The purpose of this letter is to ctarify any question as to the method used for the
cotlection of a subject sampte to evatuate a FcGMA SNP (singte nucleotide
potymorphism) from ctinicat protocol SYNT001-103, titted "A Phase 1b, llutticenter,
Open-Label, Safety, Tolerability, and Activity Stufi of SYNT001 in Subjects with
Chronic Pemphigus (Vulgaris or Foliaceus)." The protocol inctudes an exptoratory
objective to evatuate FcGRZa SNP as an exptoratory biomarker. This objective witl be
evatuated through the cottection of a single buccal swab, from which DNA wiLl be
extracted and anatyzed. This buccal srab witt be cottected from the subject prior to
dosing on the day of first dose of 5YNT001.
The protcol does not specify the cottection witt be made via buccat swab; however,
the laboratory manua[ provides detailed instructions to the site on the cottection
materiats and methods to be used. Subjects are informed of the assessment and the
means by which it witt be cotlected and data generated from it in the lnformed
Consent Form. ln the event that there is a future protocol amendment, this
Syntimmune, lnc.
257 ParkAve S, 15ft Ftool; New York, New York, 10010
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PPD
PPD


257 Park Ave S, 15th Floor, New York, New York, 10010 
 
 
 
 
11-Aug-2017 
Protocol Number:    
 
 
SYNT001-103 
Protocol Name: 
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and 
Activity Study of SYNT001 in Subjects with Chronic Pemphigus 
(Vulgaris or Foliaceus) 
IND Number:   
 
 
 
 
132727 
Study Drug:   
 
 
 
 
SYNT001 
Protocol Version, Date:   
2.0, 12-April-2017 
Clarification Letter Version:  2.0 
Subjects:    
 
 
 
 
 
Infusion Reactions  
 
 
 
 
 
 
 
 
 
 
Concomitant Medications and Treatments 
Adverse Event Reporting 
 
 
The purpose of this memo is to present planned revisions and required corrections in the 
protocol text resulting from requests for clarification from Investigators.  Text regarding 
management of infusion reactions has been revised.  Text regarding pre-medications has been 
added and text regarding adverse events that require reporting within 24 hours has been 
corrected.  Deleted text is crossed through and new text is in italics. 
This text will be formally revised in the next forthcoming protocol amendment. In the interim 
please provide this correspondence to your Institutional Review Board as per local policy. 
 
Section 9.6.1 (page 63) 
Current Text: Management of Grade 1 infusion reactions include decreasing the rate of infusion 
by 50% and observing. Symptoms may also be treated as needed with medications such as 
diphenhydramine, hydrocortisone or acetaminophen. 
 
Revised text: Management of Grade 1 infusion reactions include interrupting the infusion or 
decreasing the rate of infusion by 50% and observing. Symptoms may also be treated as needed 
with medications such as diphenhydramine, hydrocortisone orand acetaminophen, either alone 
or in combination, depending on the subject’s signs and symptoms. If the infusion is interrupted 
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257 Park Ave S, 15th Floor, New York, New York, 10010 
 
or the infusion rate is decreased, it is important to note that all study drug infusions must be 
completed within 4 (four) hours of SYNT001 preparation. 
 
Rationale: Provides clarification for the management of a Grade 1 infusion reaction. Provides a 
maximum duration of infusion in accordance with the requirements for SYNT001 preparation 
and administration outlined in the pharmacy manual. 
  
Figure 1 (page 64) 
Title: 
Current text: Management of Mild (Grade 1) to Moderate (Grade 2) Infusion Reactions 
Revised Text: Management of Mild (Grade 1) to Moderate (Grade 2) Infusion Reactions 
 
Rationale: To be consistent with prior section regarding management of a Grade 1 infusion 
reaction and with CTCAE v4.03 definition of a Grade 1 infusion reaction.  
 
Last Box:  
 
Current text: Consider pre-medicating the subject with the same medication(s) 20-30 minutes 
in advance of subsequent administrations of SYNT001 and starting infusion at 50% of the 
planned infusion rate for the first 30 minutes, then returning to the intended infusion rate in 
the absence of any infusion reaction  
 
Revised Text: Consider pre-medicating the subject with the same medication(s) 20-30 minutes 
in advance of subsequent administrations of SYNT001 and starting infusion at 50% of the 
planned infusion rate for the first 30 minutes, then returning to the intended infusion rate in 
the absence of any infusion reaction. If the infusion is interrupted or the infusion rate is 
decreased, it is important to note that all study drug infusions must be completed within 4 hours 
of SYNT001 preparation.  
 
Rationale: Provision of a maximum duration of infusion in accordance with the requirements 
for SYNT001 preparation and administration as outlined in the pharmacy manual. 
 
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Section 10 (page 69) 
 
Current text: All treatments a subject receives within 14 days prior to enrollment through the 
end of the study will be documented.  Concomitant medication and treatment for co-existing 
conditions, including those for pemphigus, are permitted if not excluded below.  Topical 
antibiotics are permitted to treat active infections that occur on study.  Topical or systemic 
treatments for oral candidiasis are permitted.  Topical lidocaine for transient pain relief is 
acceptable as needed. Significant increases in anti-pemphigus medications will result in subjects 
being discontinued from the study.  Concomitant treatment that is medically indicated for any 
AEs the subject experiences during the study are permitted.    
 
Revised text: All treatments a subject receives within 14 days prior to enrollment through the 
end of the study will be documented.  Concomitant medications and treatments for co-existing 
conditions, including those for pemphigus, are permitted if not excluded below.  Topical 
antibiotics are permitted to treat active infections that occur on study.  Topical or systemic 
treatments for oral candidiasis are permitted.  Topical lidocaine for transient pain relief is 
acceptable as needed. Significant increases in anti-pemphigus medications will result in subjects 
being discontinued from the study (See Section 8.4.3).  Concomitant treatment that is medically 
indicated for any AEs the subject experiences during the study are permitted.  Premedication is 
discouraged as prophylaxis against AEs or infusion reactions unless medically indicated from 
either past medical history, prior infusion reactions or AEs resulting from SYNT001 infusions. 
 
Rationale: During recently conducted Site Initiation Visits for the Phase 1b studies of SYNT001, 
Syntimmune received questions about the possibility of infusion reactions with SYNT001.  
Indeed, infusion reactions are a common adverse effect of intravenous administration of 
monoclonal antibodies (mAb), even fully humanized mAbs.  Infusion reactions are common 
with some FDA-approved mAbs, including anti-CD20 antibodies (Rituxan® [rituximab], Arzerra® 
[ofatumumab], Gazyva® [obinutumumab]), as well as with Cyramza® (ramucirumab) for gastric 
cancer, Darzelex® (daratumumab) for multiple myeloma, and Herceptin® (trastuzumab) for 
breast cancer.  By contrast, infusion reactions are not reported in the package inserts for 
Soliris® (eculizumab) for paroxysmal nocturnal hemoglobinuria or Yervoy® (ipilimumab) for 
metastatic melanoma.  Infusion reactions most commonly occur with the first infusion and are 
often related to the rate of protein infusion.  For mAbs with frequent infusion reactions, it is 
typically recommended that pre-medications, such as corticosteroids, acetaminophen and an 
antihistamine, are administered prior to infusion, especially with the first infusion.  For mAbs 
without associated infusion reactions or with uncommon or mild infusion reactions, pre-
medications are not typically recommended and patients’ signs and symptoms are managed 
individually. 
While experience with SYNT001 is limited at this point, it is worth noting that there were no 
occurrences of infusion reactions in the recently completed healthy volunteer phase 1a single-
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257 Park Ave S, 15th Floor, New York, New York, 10010 
 
ascending dose study.  In that study, infusions of SYNT001 were given over 1 hour at doses up 
to 30 mg/kg.  No subject had their infusion interrupted or rate of infusion decreased.  No 
subject received premedication prior to SYNT001 infusion. 
While the phase 1a results for SYNT001 may not be indicative of what will be observed in future 
studies, Syntimmune does not currently believe that it is necessary or appropriate to administer 
pre-medications to patients who will be receiving SYNT001 at the same doses and same 
infusion rates as the healthy volunteers in the phase 1a study.  Of course, sites must be 
prepared to manage infusion reactions from mild to severe during every infusion given in this 
study.  Should an infusion reaction occur in any subject, their signs and symptoms should be 
managed as medically indicated, including the interruption of SYNT001 infusion or slowing of 
the rate of infusion.  If frequent infusion reactions are observed in the phase 1b study, the issue 
of pre-medication will certainly be discussed with the investigators. 
Section 11.3.9.2 (page 76) 
Current text: “Any death, SAE, pregnancy, or unexpected (and severe) AE experienced by the 
subject after informed consent through the last study visit, regardless of relationship to study 
drug, must be promptly reported (within 24 hours of the Investigator becoming aware of the 
event) by telephone or electronic transmission to the sponsor (or designee).”  
Revised text: “Any death, SAE, or pregnancy, or unexpected (and severe) AE experienced by the 
subject after informed consent through the last study visit, regardless of relationship to study 
drug, must be promptly reported (within 24 hours of the Investigator becoming aware of the 
event) by telephone or electronic transmission to the sponsor (or designee).”  
Rationale: To clarify, adverse (severe) events that are not considered SAEs do not need to be 
reported within 24 hours but reported per section 11.3.6. 
 
Sincerely,  
 
 
 
 
Syntimmune, Inc. 
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ProtocolNumber:
ProtocolName:
IND Number:
Study Drug:
Protocol Version, Date:
Clarification L€tter Version:
Subjects:
SYNTIMMUNE
21-Sep-2017
SYNT0o1-103
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and
Activity Study of SYNT001 in Subjects with Chronic Pemphigus
(Vulgaris or Foliaceus)
L32727
SYNTOOl
2.O,LZ-April-2OL7
3.0
lnclusion Criteria
The purpose of this memo is to present a planned revision ahead of the next forthcoming
protocol amendment. ln the interim, please provide this correspondence to your lnstitutional
Review Board as per local policy and request expedited review and approval.
Section 5.2lnclusion Criteria #5 (page 35)
Current Text: Body mass index (BMl) L8.5 - 35.0 kg/m2
Revised text: Body mass index (BMl) 18.5 - 39.9 kg/m2
Rationale: Patients who may be otherwise eligible to participate in the study are excluded due
would 
to
these individuals the opportunity to participate.
Syntimmune, lnc.
257 ParkAve S, L5th Floor, New York, New York, 10010
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Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Syntimmune, Inc. and 
any unauthorized use or disclosure of such information without the prior written authorization of 
Syntimmune is expressly prohibited. 
Syntimmune, Inc. 
CLINICAL STUDY PROTOCOL 
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and Activity 
Study of SYNT001 in Subjects with Chronic Pemphigus (Vulgaris or 
Foliaceus)  
Protocol Number: 
SYNT001-103 
 
IND Number: 
132727 
 
Study Drug: 
SYNT001 
 
Sponsor: 
Syntimmune, Inc. 
 
257 Park Avenue South 
 
15th Floor 
 
New York, NY 10010 
 
Medical Monitor: 
 
 
Wallace House 
 
17-21 Maxwell Place 
 
Stirling, Scotland FK81JU 
 
Mobile Phone: 
 
 
Office Phone: 
 ext. 
 
 
 
  
 
Original Protocol: 
18 January 2017 
Amendment 1.1: 
21 March 2017  
Amendment 2.0: 
12 April 2017 
Amendment 3.0: 
10 October 2017 
 
 
 
 
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2017 
 
SPONSOR SIGNATURE 
 
 
I have read and approve this protocol.  My signature, in conjunction with the signature of the 
Investigator, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Conference on Harmonisation Guideline for Good Clinical Practice (GCP), 
the Code of Federal Regulations (CFR), and the ethical principles that have their origins in the 
Declaration of Helsinki. 
 
 
 
Date of Signature 
(DD Mm YYYY) 
 
 
10-10-2017
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2017 
 
PROCEDURES IN CASE OF EMERGENCY 
 
Serious Adverse Events  
Any death or serious adverse event (SAE)* occurring in a subject while receiving study drug or 
within 7 days of receiving study drug, even though the event may not appear to be study drug 
related, must be promptly reported (within 24 hours) by telephone or electronic communication to 
the sponsor (or designee).   
 
Emergency Contact Information  
 
 
 
 
SAE CRITERIA 
* A serious adverse event (SAE) is any untoward medical occurrence that at any dose results in any of the following outcomes, regardless of 
relationship to study drug (see Section 11.3.1, Serious Adverse Events for additional information): 
• 
Death 
• 
Life-threatening adverse drug event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability/ incapacity 
• 
A congenital anomaly/birth defect 
• 
An important medical event that may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above. 
 
For SAE reporting: 
For any other questions or to  
contact the Medical Monitor: 
Medpace Clinical Safety  
Medpace SAE hotline:  
Telephone: 
 dial  or 
 dial   
Facsimile: 
 or 
  
e-mail:
 
 
 
 
 Mobile phone: 
 
 
Office phone: 
 ext. 
 
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2017 
 
 INVESTIGATOR SIGNATURE 
 
I have read and approve this protocol.  My signature, in conjunction with the signature of the 
sponsor, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Conference on Harmonization Guideline for Good Clinical Practice (GCP), 
the Code of Federal Regulations (CFR), and the ethical principles that have their origins in the 
Declaration of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations.  
 
 
Investigator Signature 
 
 
Date of Signature 
(DD Mm YYYY) 
Name of Investigator (please print) 
 
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2017 
 
1 
SYNOPSIS 
Study title 
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and Activity Study of 
SYNT001 in Subjects with Chronic Pemphigus (Vulgaris or Foliaceus) 
Protocol number 
SYNT001-103 
Number of study 
centers 
Approximately 10 (US) 
Clinical phase  
Phase 1b 
Study background 
SYNT001, a humanized, affinity-matured IgG4-kappa monoclonal antibody 
(mAb), blocks IgG and IgG immune complex (IC) interactions with the neonatal 
Fc receptor (FcRn) and thereby the major functions of FcRn in protecting IgG 
and IgG immune complexes from degradation and their role in downstream 
signaling events. Specific and high affinity blockade of FcRn with SYNT001 has 
been shown to increase the catabolism of IgG and IgG IC in healthy volunteers. 
This predicts that SYNT001 will also accelerate degradation of endogenous 
circulating IgG autoantibodies and IgG-antigen IC specifically involved in the 
pathogenesis of autoimmunity.  Blocking FcRn interactions with IgG containing 
immune complexes further predicts that SYNT001 will have consequences for 
innate and adaptive cellular immunity.  In the first instance, blocking multimeric 
IgG IC interactions with FcRn within antigen presenting cells will result in 
inhibition of IC-stimulated inflammatory cytokine production and release by 
these cells.  In addition, as FcRn determines the intracellular itinerary of IgG 
immune complexes within and among compartments important in cellular 
immunity, it is further anticipated that SYNT001 will block antigen processing 
and presentation of antigens contained within IC that otherwise lead to CD8+ and 
CD4+ T cell activation. Thus, SYNT001 will specifically target immune 
functions associated with IgG and IC that are involved in many autoimmune 
conditions and dismantle their ability to cause disease. 
SYNT001 targets mechanisms contributing to pathology in a variety of IgG-
mediated autoimmune disorders, including warm antibody autoimmune 
hemolytic anemia (WAIHA), pemphigus, and chronic inflammatory 
demyelinating polyneuropathy (CIDP).     
While current treatments for certain autoimmune disorders including chronic 
steroids, immunosuppressants, intravenous immunoglobulin (IVIG), 
plasmapheresis, and anti-CD20 monoclonal antibodies (mAbs), such as 
rituximab, can be effective, they are frequently associated with significant 
adverse effects, and delayed or non-durable responses.  
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin 
and mucous membranes. Autoantibodies are thought to play an important 
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pathogenic role in the mucosal and cutaneous manifestations in patients with 
pemphigus. Administration of SYNT001, leading to a significant decrease in 
total IgG, and thereby a corresponding decrease in the level of the pathogenic 
autoantibodies as well as the ICs to which they are associated, should lead to a 
decrease in the mucosal and cutaneous manifestations in subjects with 
pemphigus. Moreover, the ability of SYNT001 to reduce circulating immune 
complexes (CICs) and the associated innate and adaptive immune responses may 
allow for further sustained disease modification. 
Study rationale 
This study is being conducted to further evaluate the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of 
intravenous (IV) SYNT001 as well as its effects on pemphigus disease activity 
markers. 
Study objectives 
Primary objective 
• 
To evaluate the safety and tolerability of 5 once-weekly IV infusions of 
SYNT001 at different dose levels in subjects with chronic pemphigus 
(vulgaris or foliaceus) 
Secondary objectives 
• 
To determine the PK of SYNT001 following 5 once-weekly 1-hour IV 
infusions at different dose levels 
• 
To assess the effect of 5 once-weekly doses of SYNT001 at different dose 
levels on the following PD biomarkers: 
o Immunoglobulins: IgG, IgG subtypes (IgG1-4), IgA, IgM 
o Albumin 
• 
To assess the effect of 5 once-weekly doses of SYNT001 at different dose 
levels on the following disease activity markers: 
o Serum anti-desmoglein (Dsg) (1 and 3) antibody levels 
o Pemphigus Disease Area Index (PDAI) 
• 
To assess immunogenicity (anti-SYNT001 antibodies) 
Exploratory objectives 
• 
To assess the effect of 5 once-weekly doses of SYNT001 at different dose 
levels on the following biomarkers, including: 
o Serum anti-epithelial cell antibody (AECA) levels by indirect 
immunofluorescence 
o Circulating immune complexes (CIC) 
o Complement component 3 (C3) 
o Exploratory biomarkers (FCGR2A (single nucleotide polymorphism-
SNP), RNAseq, urine IgG) 
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o Immune phenotyping by flow cytometry for CD3+CD4+ T, 
CD3+CD8+ T, monocytes, NK cells and B cells 
o SYNT001 levels in skin biopsies (optional) 
o Exploratory biomarkers to investigate immune response associated 
with pemphigus 
• 
To characterize corticosteroid use during the study 
Study design 
Phase 1b, multicenter, open-label, safety, tolerability, and activity study 
Methodology 
Two cohorts of 8 eligible subjects each will receive 5 once-weekly 60-minute 
infusions of SYNT001 in planned doses of 10 mg/kg or 30 mg/kg. Based on 
review of safety, PD, and clinical outcomes of these 2 cohorts, a third cohort of 
up to 8 subjects may be treated at another dose, with a maximum dose of 45 
mg/kg, but may also be lower than 10 mg/kg or between 10 and 30 mg/kg, 
inclusive.  
Cohort 
No. of subjects 
Dose 
1 
8 
SYNT001 10 mg/kg 
2 
8 
SYNT001 30 mg/kg 
Cohorts will be dosed sequentially beginning with Cohort 1.  The first 2 subjects 
will be dosed at least 24 hours apart.  A review of the 24-hour safety data for the 
first subject will be performed to ensure that there are no overt safety concerns 
before dosing the second subject.  A review of the 7-day safety data for the first 
2 subjects will be performed prior to dosing the remaining 6 subjects in the 
cohort.  This evaluation will include a review of AE/SAE reports, vital sign 
assessments, physical examinations, ECGs, and clinical laboratory testing.  The 
seriousness, severity, and relatedness of AEs/SAEs will also be considered in the 
safety evaluation.  Safety data will be reviewed on a continuous basis throughout 
the study.  All safety data and any available and relevant PD data through Day 
42 (2 weeks after the last subject’s last dose in Cohort 1) will be reviewed by a 
dose escalation committee before Cohort 2 is initiated.  Escalation to Cohort 2 
will proceed if there are no concerning safety signals and the review of available 
and relevant PD data supports advancing to a higher dose. The dose for Cohort 2 
will be finalized after review of the safety and PD data, but will not exceed 30 
mg/kg.  Cohort 2 and Cohort 3, if added, will be dosed per the same schedule as 
Cohort 1. 
On days where study drug is administered, vital sign and pulse oximetry 
measurements will be collected immediately prior to the infusion; 15, 30, and 45 
minutes after the start of the infusion; at completion of the infusion; and 
30 minutes, 1 hour and 2 hours following completion of the infusion.  
On Days 0 and 28, PK blood samples will be collected prior to infusion start and 
then over the subsequent 48 hours.  Subjects will remain at the clinic through the 
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6-hour PK sample collection and will return to the clinic for the 24- and 48-hour 
collections.  Additional samples will be collected on Days 5 and 33. 
On Day 0 photographs will be taken of active lesions.  Follow-up photographs 
will be taken of the same areas on Days 33, 56, 84 and 112.  If a subject begins a 
steroid taper, additional photographs will be taken at the clinic visit during which 
the decision to begin the taper is made. 
Subsequent visits will occur on Days 1, 2, 5, 7, 12, 14, 19, 21, 28, 29, 30, 33, 42 
and 56 for safety assessments, study drug dosing, sample collections, and other 
study procedures. 
Subjects will return to the clinic on Days 84 and 112 for follow-up visits.  
Subjects whose total IgG is not within 30% of their Day 0 baseline value and not 
above 500 mg/dL at the Day 112 visit will be referred for further management.  
See Table 1 for a schedule of all study events.  To assess safety and tolerability, 
subjects will undergo physical examinations (PEs; including weight), vital sign 
measurements, clinical (safety) laboratory tests, adverse event (AE) assessments, 
concomitant medication assessments, and electrocardiograms (ECG). 
 
Number of subjects 
Approximately 16; two cohorts of 8 subjects each.  An additional cohort of up to 
8 subjects may be enrolled.  Subjects who withdraw for any reason other than an 
AE and who do not receive study drug or have only received one dose of study 
drug may be replaced, up to one subject per cohort.   The maximum number of 
subjects who may be enrolled in this study is 27 (24 + up to 3 replacements, as 
necessary).  Within each dosing cohort, no more than 3 subjects with pemphigus 
foliaceus may be enrolled. 
Diagnosis and main 
entry criteria 
Inclusion criteria: 
Subjects must meet the following criteria to be included: 
1. Willing and able to read, understand and sign an informed consent form;  
2. Male or female ≥ 18 years of age at the time of screening;  
3. Documented diagnosis of pemphigus vulgaris or foliaceus based on all 3 of 
the following criteria: 
a. Documented clinical history consistent with pemphigus vulgaris or 
foliaceus (clinical presentation defined as mucosal and/ or skin 
lesions); 
b. Presence of Anti-Dsg 1 or 3 antibodies above the upper limit of 
normal;  
c. History of at least one positive tissue-based test (e.g., biopsy, direct 
immunofluorescence [DIF]) 
4. Active disease: Lesions lasting > 2 weeks, and 3 active lesions in skin or 
mucosa or 2 active lesions with at least one being a skin lesion > 1 cm 
diameter: 
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a. If treated with rituximab or other anti-CD20 antibodies, last dose 
> 12 months prior to screening; 
b. If being treated with other immunosuppressants (i.e., azathioprine, 
mycophenolate mofetil or cyclosporine), must be on stable dose 
(< 10% change in dose) for 6 weeks prior to screening; 
c. If being treated with corticosteroids, must be ≤ 1mg/kg/day of 
prednisone or equivalent and stable (< 10% change in dose) for 2 
weeks prior to screening; 
d. Allowed topical therapies for pemphigus lesions upon entering the 
study include petroleum jelly or Aquaphor® for the skin or 
chlorhexidine for the mouth 
5. Body mass index (BMI) 18.5 – 39.0 kg/m2; 
6. Has a negative pregnancy test (for women of childbearing potential) 
documented prior to the first dose of study drug;     
7. Females of childbearing potential must agree to be abstinent or else use any 
two of the following medically acceptable forms of contraception (<1% per 
year failure rate) from the Screening Period through the final study visit: oral 
contraceptive, condom with or without spermicidal jelly, diaphragm or 
cervical cap with spermicidal jelly, or intra-uterine device (IUD). A female 
whose male partner has had a vasectomy must agree to use one additional 
form of medically acceptable contraception.  
8. Females of non-childbearing potential, defined as surgically sterile (status 
post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or 
post-menopausal for at least 12 months do not require contraception during 
the study. 
9. Males with female partners of childbearing potential, including males who 
are surgically sterile (post vasectomy), must agree to be abstinent or else use 
a medically acceptable form of contraception from the screening period 
through the final study visit. 
 
Exclusion criteria: 
Subjects meeting any of the following criteria are to be excluded:  
1. Subject unable or unwilling to comply with the protocol; 
2. Active non-hematologic malignancy or history of non-hematologic 
malignancy in the 3 years prior to screening (exclusive of non-melanoma 
skin cancer and cervical cancer in situ); 
3. Positive for HIV or hepatitis C antibody;  
4. Positive for hepatitis B surface antigen; 
5. Active infection or history of recurrent infections; 
6. IVIG use within 60 days of screening; 
7. Received any cytotoxic (other than azathioprine) or mAb therapy in the 3 
months prior to screening; 
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8. Any exposure to an investigational drug or device within the 30 days prior to 
screening 
9. Plasmapheresis or immunoadsorption within 60 days of screening 
10. Cellular therapy, including CAR-T, at any time prior to screening 
11. Use of any immunosuppressive drugs apart from corticosteroids, 
azathioprine, mycophenolate mofetil, or cyclosporine within 3 months of 
screening 
12. Serum total IgG < 600 mg/dL; 
13. Subject has any current medical condition that, in the opinion of the 
Investigator, may compromise their safety or compliance, preclude 
successful conduct of the study, or interfere with interpretation of the results 
(e.g., a significant pre-existing illness or other major comorbidity that the 
Investigator considers may confound the interpretation of the study results); 
14. Any vaccination within 2 weeks of screening 
 
Study drug, dosage, 
and administration 
 SYNT001 
 
Doses: 10 mg/kg and 30 mg/kg. A third cohort of up to 8 subjects may be treated 
at another dose, with a maximum dose of 45 mg/kg, but may also be lower than 
10 mg/kg or between 10 and 30 mg/kg, inclusive. 
SYNT001 is provided as a liquid at a nominal concentration of 50 mg/mL. 
SYNT001 is diluted in Dextrose 5% in Water (D5W) to prepare the solution for 
infusion. 
Route of administration: IV in 250 mL over 1 hour 
Control, dose, and 
route of 
administration 
Not applicable 
Duration of subject 
participation and 
duration of study 
Up to 126 days (18 weeks): Screening of up to 2 weeks (14 days); Treatment 
period of 8 weeks (56 days); Follow-up period of 8 weeks (56 days) 
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Prohibited 
Concomitant 
treatments 
All treatments a subject receives within 14 days prior to enrollment through the 
end of the study will be documented.  Concomitant medication and treatment for 
co-existing conditions, including those for pemphigus, are permitted if not 
excluded below.  Topical antibiotics are permitted to treat active infections that 
occur on study.  Topical or systemic treatments for oral candidiasis are 
permitted.  Topical lidocaine for transient pain relief is acceptable as needed.  
Significant increases in anti-pemphigus medications will result in subjects being 
discontinued from the study.  Concomitant treatment that is medically indicated 
for any AEs the subject experiences during the study are permitted. 
Premedication is discouraged as prophylaxis against AEs or infusion reactions 
unless medically indicated from either past medical history, prior infusion 
reactions or AEs resulting from SYNT001 infusions. 
Use of the following medications will not be permitted during the study unless 
otherwise specified: 
• 
Rituximab or other anti-CD20 antibody 
• 
Monoclonal antibodies other than study drug 
• 
Any immunosuppressive drugs apart from corticosteroids, azathioprine, 
mycophenolate mofetil, or cyclosporine 
• 
Topical steroids 
• 
Any dietary herbal supplements 
• 
Any investigational drug or device 
• 
Any vaccinations through Day 56.  Following Day 56, subjects may 
receive vaccinations at the discretion of the Investigator. 
If over a period of at least two weeks on study drug, a subject on corticosteroids 
shows the absence of new lesions and significant healing of lesions that existed 
at study baseline, a slow corticosteroid taper may be started as per the following 
suggested schedule  
• 
If on > 30 mg of prednisone per day, decrease by 10 mg every two 
weeks until a dose of 30 mg per day then decrease by 5 mg every two 
weeks 
• 
If on < 30 mg of prednisone per day, decrease by 5 mg every two weeks 
 
Safety assessments 
Safety assessments include AEs, serious adverse events (SAEs), PEs, vital sign 
measurements, clinical safety laboratory evaluations, ECGs, and reasons for 
treatment discontinuations due to toxicity. Safety assessments will be performed 
at specified time points and prior to discharge from the clinic.  Vital sign 
measurements, including blood pressure, pulse rate, respiratory rate, and 
temperature will be monitored throughout the study.  Pulse oximetry will be 
monitored during the study drug infusion and for 2 hours following the end of 
the infusion. 
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The National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE; Version 4.03) will be used for grading clinical and 
laboratory AEs.    
The AE reporting period for a subject enrolled in the study begins when the 
subject provides informed consent and is continued through the last study visit. 
All AEs that occur in the enrolled subjects during the AE reporting period must 
be recorded, regardless of the relationship of the AE to study drug. Any known 
untoward event that occurs beyond the AE reporting period that the Investigator 
assesses as related to study drug should also be recorded. 
Dose-escalation rules 
Dose escalation decisions will be made by a Dose Escalation Committee (DEC) 
and will be based on safety and pharmacodynamic evaluations including but not 
limited to, dose-limiting toxicities, AEs, SAEs, and total IgG levels. 
Dose-limiting toxicity (DLT) will be defined generally as severe (Grade 3) AEs 
occurring in ≥ 2 subjects that are determined to be clinically significant and 
considered related to study drug. 
If 2 or more subjects at any time in any cohort (8 total subjects per cohort) have 
Grade 3 AEs that are determined to be clinically significant and considered to be 
related to study drug, dosing will be halted within that cohort and dose-
escalation to a higher dose will not occur. If the dose-escalation stopping rule is 
met during Cohort 1 (10 mg/kg) all safety data and all available 
pharmacodynamics data will be reviewed and the cohort may resume (if 
applicable) or a new cohort may be added, at a dose at least 50% lower than the 
10 mg/kg dose.  If the stopping rule is not met in Cohort 1 (10 mg/kg), dose-
escalation may proceed up to a maximum of 30 mg/kg.  If the dose-escalation 
stopping rule is met for the first time during Cohort 2, all safety data and all 
available pharmacodynamics data will be reviewed and the cohort may resume 
(if applicable) or a new cohort may be added at a dose at least 30% lower than 
the Cohort 2 dose. If the stopping rule is not met in Cohort 2, dose-escalation 
may proceed up to a maximum of 45 mg/kg; however, this cohort may also 
receive a dose equal to or less than 30 mg/kg based on evaluation of all safety 
and pharmacodynamic data.   
Study stopping rule 
If any subject experiences a life-threatening AE (Grade 4) that is considered to 
be related to study drug, any further dosing in all enrolled subjects will be 
suspended until the DEC has evaluated the event and determined the next 
appropriate course of action.  At any time during the study, the study may be 
discontinued if the DEC determines that further drug exposure would pose an 
undue risk to subjects. 
 
Individual stopping 
rule 
Dosing for any individual subject will be discontinued (i.e., further treatment 
with the study drug will not be given) if the subject experiences any study drug-
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2017 
 
 
related SAE or any study drug-related non-SAE adverse event that, in the 
judgement of the Investigator (following consultation with the Medical Monitor, 
if desired) suggest that it could be unsafe to administer further study drug to that 
subject.  Additionally, a subject will be discontinued from further treatment with 
study drug, at the discretion of the Investigator with consultation with the 
Medical Monitor, if they require a significant increase in dose(s) of anti-
pemphigus medication(s) for the management of pemphigus. 
Pharmacokinetics 
The PK of SYNT001 will be evaluated following the first and last (fifth) doses 
of SYNT001.   
Starting on Days 0 and 28, serum samples will be collected just prior to the start 
of study drug infusion (pre-dose), at 5 minutes and 2, 4, 6, 24, and 48 hours after 
the end-of-study drug infusion.  Additional samples will be collected on Days 5 
and 33. 
Study drug concentration will be used to calculate the following PK parameters: 
t1/2, Cmax, Tmax, AUC0-24, and AUC0-∞. 
Pharmacodynamics/ 
Activity 
PD samples will be collected for analysis of IgG (serial assessment of IgG levels 
to identify Cmin, Tmin); IgG1-4 subtype levels; IgA levels; IgM levels; albumin 
levels; anti-Dsg (1 and 3) antibody levels; serum AECA by direct 
immunofluorescence; CIC; C3; exploratory biomarkers (FCGR2A SNP, 
RNAseq, urine IgG, CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B 
cells), and additional exploratory analyses to investigate immune response 
associated with pemphigus.  
Immunogenicity 
Samples will be collected for immunogenicity analyses on Days 0 (pre-dose), 14, 
28, 56, 84 and 112. 
Skin biopsy 
Optional skin biopsy samples from lesional or non-lesional skin will be collected 
on Day 0 pre-dose and on Days 1, 2, 14, 33, 56 and 84 to analyze SYNT001 
levels.   
Photography 
Photographs of active lesions will be taken at Day 0.  Follow-up photographs of 
the same areas will be taken on Days 33, 56, 84 and 112.  Subjects who begin a 
steroid taper will have additional photographs taken at the clinic visit during 
which the decision to begin the taper is made. 
Statistical methods 
Sample size consideration 
Formal sample size calculations were not performed.  The number of subjects 
was chosen based on feasibility and was considered sufficient to meet the study 
objectives. 
 
Data presentations/Descriptive statistics 
Three populations will be employed in the analysis of study data. 
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• 
The intent-to-treat (ITT) population will consist of all subjects who have 
received at least one dose of study drug.  All safety analyses will be 
performed on the ITT population. 
• 
The PK population will consist of all subjects who receive at least one 
dose of study drug and have sufficient post-dose blood samples to obtain 
PK parameters. 
• 
The PD population will consist of all subjects who receive at least one 
dose of study drug and have post-dose PD data available. 
 
Primary safety analyses will be performed on the ITT population. Demographics, 
subject disposition, and screening and baseline characteristics will be 
summarized for the PK and ITT populations, where appropriate. 
 
Criteria for evaluation 
Objective 
Endpoint 
Primary  
Safety and tolerability of 5 once-
weekly IV infusions of SYNT001 to 
subjects with pemphigus vulgaris or 
foliaceus 
AEs and clinical (safety) 
laboratory tests 
Secondary  
PK of SYNT001 following a 1-hour IV 
infusion 
PK parameters: t1/2, Cmax, Tmax, 
AUC0-24, and AUC0-∞. 
Effect of 5 once-weekly IV doses of 
SYNT001 on: 
• Total IgG (IgG1-4), IgA, IgM, and 
albumin 
• Serum anti-Dsg (1 and 3) antibodies 
Changes in levels of IgG, IgG 
subtypes (IgG1-4), IgA, IgM, 
albumin, serum anti-Dsg (1 and 
3) antibodies 
Assess immunogenicity  
Anti-SYNT001 antibodies 
Disease Activity 
PDAI Scores 
Exploratory  
Effect of 5 once-weekly IV doses of 
SYNT001 on biomarkers including: 
• CIC 
• C3 
• Serum anti-epithelial cell antibody 
(AECA) levels 
• Exploratory biomarkers (FCGR2A 
SNP, RNAseq, urine IgG) 
• Immune phenotyping by flow 
cytometry 
Changes in CIC; C3; AECA 
levels by indirect 
immunofluorescence; FCGR2A 
SNP; RNAseq; urine IgG, 
CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B 
cells; urine IgG levels; changes 
in blood transcriptome 
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• Exploratory biomarkers to 
investigate immune response 
associated with pemphigus 
Concomitant Treatment 
Corticosteroid use during the 
study 
SYNT001 levels in skin biopsies  
Measures of SYNT001 levels in 
skin biopsies 
Treatment-emergent AEs (TEAEs) will be summarized using the Medical 
Dictionary for Regulatory Activities (MedDRA®; Version 19 or higher) System 
Organ Class (SOC) and preferred term, classified from verbatim terms.  The 
incidence and percentage of subjects with at least 1 occurrence of a preferred 
term will be included, using the most severe grade.  The number of events per 
preferred term will also be summarized.  Causality (relationship to study 
treatment) will be summarized separately. 
TEAEs, SAEs, and AEs leading to withdrawal, or treatment discontinuation will 
be listed by subject, and cohort using SOC and preferred terms. Duration of AEs 
will be determined and included in listings, along with action taken, and 
outcome.   
Laboratory results will be summarized by time point and cohort.  The incidence 
of laboratory abnormalities will be summarized.  The worst on-study grade after 
the first dose of study drug will be summarized.  Results for variables that are 
not coded will be presented in the listings as below, within, and above the 
normal limits of the central laboratory.  Vital sign measurements will be 
summarized by cohort at each scheduled time point using descriptive statistics.    
Study drug concentrations will be used to calculate the following PK parameters:  
t1/2, Cmax, Tmax, and area under the curve (AUC).  PK parameters will be 
determined using non-compartmental method(s).   Descriptive statistics of PK 
parameters for SYNT001 will include mean, standard deviation (SD), coefficient 
of variation (CV), median, minimum, and maximum. Tmax will be reported as 
median and range. All descriptive statistics will be performed on untransformed 
PK parameters and after log10 transformation of PK parameters. 
PD results will be summarized by cohort.  Descriptive statistics of PD 
parameters for SYNT001 will include mean, SD, CV, median, minimum, and 
maximum. 
Immunogenicity results will be summarized by cohort.  Descriptive statistics will 
include mean, SD, CV, median, minimum, and maximum. 
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Table 1: 
Study Assessments  
 
Screening 
Treatment Period  
Follow‐Up  
Timepoint (Study Day) 
-14 to -1 
0 
1 
(±1 
hr) 
2 
(± 2 
hr) 
5p 
(±4 
hr) 
7  
(±6 
hr) 
12p  
(±6 
hr) 
14  
(±6 
hr) 
19p  
(±6 
hr) 
21 
(±6 
hr) 
28 
(±6 
hr) 
29 
(±1 
hr) 
30 
(±2 
hr) 
33 
(±4 
hr) 
42 
(±3 
days) 
56 
(±5 
days) 
84 
(±5 
days) 
 
112 
(±5 days) or ET 
Visit 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationa 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
Vital Signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetryc 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Clinical Safety Labsd 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECGf 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Tetanus & VZV antibodies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
PDAI Score 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
PK Samplingh 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Immunogenicityi  
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
X 
Study Drug Administrationj 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Immunoglobulins (IgG, IgA, 
IgM) and IgG subtypes (IgG 1-4)k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
CIC 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Anti-Dsg (1 & 3) antibody titer  
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
C3 and AECAl 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
FCGR2Am by buccal swab 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNAseqm 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Urine IgGm 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Immune phenotypingn 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Pemphigus immune response 
biomarkers  
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Optional Skin Biopsy 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
Photographyo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Adverse Events 
To be collected from the date that the ICF is signed through the last study visit 
Concomitant Medications 
To be collected from within 14 days prior to Day 0 through  the last study visit 
ECG = electrocardiogram; ET= Early Termination; HIV = human immunodeficiency virus; ICF = informed consent form; PD = pharmacodynamic; PK = pharmacokinetic; VZV = 
varicella-zoster virus 
 
 
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a: Complete PE, including weight, to be performed.  Height and BMI will be additional assessments conducted at screening. 
b: Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and oral temperature) to be obtained after 5 minutes of seated rest.  Any abnormal measurements are to 
be repeated after 5 minutes of rest.  On Days 0, 7, 14, 21, and 28 vital sign measurements will be collected immediately prior to the infusion; 15, 30, and 45 minutes after the start 
of the infusion; at completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion.   
c: Pulse oximetry: On Days 0, 7, 14, 21, and 28, pulse oximetry to be measured immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at completion 
of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion. 
d: Clinical safety labs: hematology, clinical chemistry, and urinalysis (see Section 6.7 for a complete list).  Full clinical safety lab draws will be collected at Screening and on Days 
0, 7, 14, 21, 28, 33, 42, 56, 84 and 112. 
e: Pregnancy test:  To be performed at time of screening and prior to first dose of SYNT001 on Day 0 and on Days 56 and 112 (urine or serum test is acceptable, however, positive 
urine tests must be confirmed with serum testing.) 
f: Digital 12-lead ECG to be obtained after 5 minutes of rest in the supine position and in triplicate at least 1-2 minutes apart (see Section 6.6 for additional information).  On Days 0 
and 28 to be obtained 5 minutes after the completion of infusion. Day 12 ECG will be collected only if the visit is conducted at the study site.  
g: Serology:  Testing at Day 56 will not be done for any subject whose baseline titer is below the level of detection. If the Day 56 results are greater than 30% below the baseline 
value, or if the subject falls below the level of detection, the subject will be re-tested at Day 84; if still below the baseline value (or level of detection), the subject will be re-tested 
at Day 112. Any subject whose baseline value for tetanus or VZV was above the detectable level at baseline, and is not within 30% of the baseline value or is below the detectable 
level by Day 112, will be referred to their primary care physician for further management. See Section 6.7.3 for additional information. 
h: PK:  Starting on Days 0 and 28, serum samples will be collected just prior to the start of study drug infusion (pre-dose), and at 5 minutes and 2, 4, 6, 24, and 48 hours after the 
end-of-study drug infusion.  Additional samples will be collected on Days 5 and 33.  See Section 6.7.4 for additional information.  
i: Immunogenicity:  Blood samples will be collected pre-dose when collected on dosing days.  Samples will be collected on Days 0, 14, 28, 56, 84 and 112. See Section 6.7.6 for 
additional information. 
j: Prior to study drug infusion, SYNT001 drug product is to be diluted in Dextrose 5% in Water (D5W) to a total volume of 250 mL and administered intravenously over 1 hour 
using a 0.2-micron, inline filter.  See Section 9 for additional information. 
k: Immunoglobulins (IgG, IgA, IgM) and IgG subtypes (IgG 1-4): Collected for measurements of IgG, IgG subtypes (IgG1-4), IgA, and IgM at every visit. On Days 0, 7, 14, 21, 
and 28, samples are collected prior to infusion of study drug. See Section 6.7.5 for additional information   
l: Exploratory PD samples (C3 and AECA): collected pre-dose when collected on dosing days. See Section 6.7.5  for complete information. 
m: Buccal samples to be collected and stored; pending review of clinical and pharmacodynamics assessments 
n: Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B cells 
o: Photographs of active lesions taken prior to first dose on Day 0.  Follow-up photographs will be taken at Days 33, 56, 84 and 112.  Subjects who begin a steroid taper will have 
additional photographs taken at the clinic visit during which the decision to begin the taper is made. 
p: Visit Days 5, 12 and 19 may be conducted via at-home nursing in lieu of a subject visit to the study site. 
q: Subjects will return to the clinic on Days 84 and 112 for follow-up visits.  Subjects whose total IgG is not within 30% of their Day 0 baseline value and not above 500 mg/dL at the 
Day 112 visit will be referred for further management. 
 
 
 
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Table 2: 
Timing Window Allowances for PK/PD Sampling, ECG, and Vital Sign Measurements 
Pharmacokinetic and Pharmacodynamic Sampling 
 
Timepoint 
Tolerance Window 
0 hour 
−240 min to 0 hour 
5 minutes post end-of-infusion 
± 5 minutes 
2, 4, & 6 hours post end-of-infusion 
± 15 minutes 
24 hours post end-of-infusion 
± 60 minutes 
48 hours post end-of-infusion  
± 120 minutes 
ECG 
 
Timepoint 
Tolerance Window 
5 minutes post end-of-infusion 
± 10 minutes 
Vital Signsa 
 
Timepoint 
Tolerance Window 
0 hour 
−240 min to 0 hour 
15, 30, and 45 minutes after start of infusion 
± 5 minutes 
60 minutes after start of infusion 
± 10 minutes 
30, 60 and 120 minutes post end-of-infusion 
± 10 minutes 
a:  Vital signs to include blood pressure, pulse rate, respiratory rate, oral temperature, and pulse oximetry.
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TABLE OF CONTENTS 
PROCEDURES IN CASE OF EMERGENCY ...................................................................3 
INVESTIGATOR SIGNATURE.........................................................................................4 
1 
SYNOPSIS ..................................................................................................................5 
LIST OF ABBREVIATIONS ............................................................................................24 
2 
BACKGROUND AND RATIONALE .....................................................................26 
2.1 
Study Rationale ................................................................................................27 
2.2 
Selection of Doses in this Study ......................................................................27 
2.3 
Compliance Statement .....................................................................................28 
3 
STUDY OBJECTIVES .............................................................................................29 
3.1 
Primary Objective ............................................................................................29 
3.2 
Secondary Objectives .......................................................................................29 
3.3 
Exploratory Objectives ....................................................................................29 
4 
STUDY DESIGN......................................................................................................30 
4.1 
Study Sites .......................................................................................................30 
4.2 
Study Endpoints ...............................................................................................30 
4.3 
Overview of Study Design ...............................................................................31 
4.4 
Randomization and Blinding ...........................................................................33 
5 
STUDY POPULATION ...........................................................................................34 
5.1 
Target Population .............................................................................................34 
5.2 
Inclusion Criteria .............................................................................................34 
5.3 
Exclusion Criteria ............................................................................................35 
6 
STUDY PROCEDURES ..........................................................................................37 
6.1 
Informed Consent.............................................................................................37 
6.2 
Demographics and Medical History ................................................................37 
6.3 
Physical Examination.......................................................................................37 
6.4 
Pemphigus Disease Area Index (PDAI) Scoring .............................................37 
6.5 
Vital Sign Measurements .................................................................................38 
6.6 
12-Lead Electrocardiogram (ECG) ..................................................................38 
6.7 
Clinical Laboratory Measurements ..................................................................39 
6.7.1 
Pregnancy Testing ................................................................................40 
6.7.2 
Virology ...............................................................................................40 
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6.7.3 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing40 
6.7.4 
Pharmacokinetics (PK) Sampling ........................................................41 
6.7.5 
Pharmacodynamic Sampling ...............................................................41 
6.7.6 
Immunogenicity Testing ......................................................................42 
6.8 
Study Drug Administration ..............................................................................43 
6.9 
Prior and Concomitant Medications ................................................................43 
6.10 
Adverse Event Assessments ............................................................................43 
6.11 
Photographs......................................................................................................44 
6.12 
Skin Biopsy ......................................................................................................44 
7 
STUDY ASSESSMENTS ........................................................................................45 
7.1 
Screening Period: Day -14 to Day -1 ...............................................................45 
7.2 
Enrollment and First Treatment: Day 0 ...........................................................45 
7.3 
Follow-up: Day 1 .............................................................................................47 
7.4 
Follow-up: Day 2 .............................................................................................47 
7.5 
Follow-up: Day 5 .............................................................................................48 
7.6 
Treatment Day 7 (Dose 2) ................................................................................48 
7.7 
Dose 2 Follow-up Day 12 ................................................................................49 
7.8 
Treatment Day 14 (Dose 3) ..............................................................................49 
7.9 
Dose 3 Follow-up Day 19 ................................................................................51 
7.10 
Treatment Day 21 (Dose 4) ..............................................................................51 
7.11 
Treatment Day 28 (Dose 5) ..............................................................................52 
7.12 
Follow-up Day 29 ............................................................................................53 
7.13 
Follow-up Day 30 ............................................................................................54 
7.14 
Follow-up Day 33 ............................................................................................54 
7.15 
Follow-up Day 42 ............................................................................................55 
7.16 
Follow-up Day 56 ............................................................................................55 
7.17 
Follow-up Day 84 ............................................................................................56 
7.18 
Follow-up Day 112 (End-of-Study) or Early Termination Visit .....................57 
8 
REMOVING SUBJECTS FROM STUDY ..............................................................58 
8.1 
Subject Withdrawal ..........................................................................................58 
8.2 
Study Discontinuation ......................................................................................59 
8.3 
Replacements ...................................................................................................59 
8.4 
Stopping Rule...................................................................................................59 
8.4.1 
Dose-Escalation Stopping Rule ...........................................................59 
8.4.2 
Study Stopping Rule ............................................................................60 
8.4.3 
Individual Stopping Rule .....................................................................60 
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9 
STUDY DRUG .........................................................................................................61 
9.1 
SYNT001 .........................................................................................................61 
9.2 
Cohort Dosing ..................................................................................................61 
9.3 
Timing of Dosing .............................................................................................61 
9.4 
Identity of Investigational Products .................................................................61 
9.5 
Investigational Product Retention at Study Site ..............................................62 
9.6 
Warnings and Precautions ................................................................................62 
9.6.1 
Infusion Reaction .................................................................................62 
9.6.2 
Potential Immune Effects .....................................................................67 
10 
CONCOMITANT MEDICATION AND TREATMENT ........................................69 
11 
SAFETY ...................................................................................................................71 
11.1 
Safety Parameters .............................................................................................71 
11.2 
Adverse Event Definition ................................................................................71 
11.3 
Evaluating Adverse Events ..............................................................................72 
11.3.1 
Serious Adverse Events .......................................................................72 
11.3.2 
Overdose ..............................................................................................73 
11.3.3 
Non-Serious Adverse Events ...............................................................73 
11.3.4 
Protocol-Related Adverse Events ........................................................73 
11.3.5 
Assessment of Causality ......................................................................73 
11.3.6 
Recording Adverse Events ...................................................................74 
11.3.7 
Planned Hospitalization .......................................................................74 
11.3.8 
Reporting Pregnancies .........................................................................75 
11.3.9 
Serious Adverse Event Reporting ........................................................75 
11.3.9.1  Governing Regulatory Requirements ..................................................75 
11.3.9.2  Time Frame for Reporting ...................................................................76 
11.3.9.3  Information to be Provided by the Investigator ...................................77 
11.3.10  Regulatory Reporting ...........................................................................78 
11.3.11  Follow-up Information on a Serious Adverse Event (SAE) ................79 
11.4 
Other Safety Considerations ............................................................................79 
11.4.1 
Laboratory Data ...................................................................................79 
11.4.2 
Medication Errors ................................................................................79 
11.4.3 
Follow-Up of Adverse Events .............................................................79 
11.5 
Safety Monitoring for Dose Escalation ............................................................79 
12 
STATISTICAL CONSIDERATIONS......................................................................81 
12.1 
General Design.................................................................................................81 
12.2 
Sample Size Justification .................................................................................81 
12.3 
Statistical Considerations .................................................................................81 
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12.3.1 
Study Populations ................................................................................81 
12.3.2 
Subject Accountability, Demographics, and Baseline Characteristics 82 
12.3.3 
Concomitant Medications ....................................................................82 
12.4 
Planned PK Analysis........................................................................................82 
12.5 
Safety Data .......................................................................................................83 
12.6 
Pharmacodynamic/Activity Data .....................................................................83 
12.7 
Immunogenicity Data .......................................................................................83 
12.8 
Interim Analysis ...............................................................................................84 
13 
DATA QUALITY ASSURANCE ............................................................................85 
14 
STUDY ADMINISTRATION .................................................................................86 
14.1 
Study Administrative Structure ........................................................................86 
14.2 
Ethical Conduct of the Study ...........................................................................86 
14.3 
Informed Consent (ICF) ...................................................................................86 
14.4 
Institutional Review Board ..............................................................................87 
14.5 
Dose Escalation Committee .............................................................................87 
14.6 
Future Use of Subject Samples ........................................................................88 
15 
CONDITIONS FOR MODIFYING THE PROTOCOL...........................................89 
16 
CONDITIONS FOR TERMINATING THE STUDY .............................................90 
17 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING .......................91 
17.1 
Investigator’s Files and Retention of Documents ............................................91 
17.2 
Source Documents and Background Data .......................................................91 
17.3 
Audits and Inspections .....................................................................................92 
17.4 
Electronic Case Report Forms .........................................................................93 
18 
MONITORING THE STUDY ..................................................................................94 
19 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS ...95 
20 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS............96 
21 
REFERENCES .........................................................................................................97 
 
 
 
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LIST OF TABLES 
Table 1: 
Study Assessments .................................................................................... 16 
Table 2: 
Timing Window Allowances for PK/PD Sampling, ECG, and Vital Sign 
Measurements ........................................................................................... 18 
Table 3: 
Clinical Laboratory Panels ........................................................................ 39 
Table 4: Pharmacodynamic/ Activity Assessments .......................................................... 42 
Table 5: 
Grading and Management of Allergic or Infusion-Related Reactions ..... 66 
Table 6 :  
Study Administrative Structure ................................................................. 86 
 
LIST OF FIGURES 
Figure 1:  Management of Mild (Grade 1) to Moderate (Grade 2) Infusion Reactions .... 64 
Figure 2:  Management of Severe (Grade 3 or higher) Infusion Reactions ...................... 65 
 
 
LIST OF APPENDICES 
Appendix A: NCI CTCAE, Version 4.03 ......................................................................... 99 
Appendix B: Pemphigus Disease Area Index ................................................................. 100 
 
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LIST OF ABBREVIATIONS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AECA 
Anti-epithelial cell antibody 
ALT 
Alanine aminotransferase 
ANA 
Antinuclear antibody 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC0-24 
Area under the plasma concentration-time curve from pre-dose (time 0) to 24 hours post-dose 
AUC0-∞ 
Area under the plasma concentration-time curve from pre-dose (time 0) to infinity 
BLQ 
Below the limit of quantification  
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CAR-T 
Chimeric antigen receptor and T-cell 
CFR 
Code of Federal Regulations 
C3 
Complement component 3 
CBC 
Complete blood count 
CIC 
Circulating immune complexes 
CIDP 
Chronic inflammatory demyelinating polyneuropathy 
Cmax 
Maximum plasma concentration determined directly from the concentration-time profile 
CRO 
Contract research organization 
CV 
Coefficient of variation 
CVID 
Common variable immune deficiency 
DEC 
Dose escalation committee 
D5W 
Dextrose 5% in Water 
DIF 
Direct immunofluorescence 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ESR 
Erythrocyte sedimentation rate 
FcGR2a 
Fc Gamma R2a receptor 
FcRn 
Neonatal Fc receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
IC 
Immune complex 
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ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgG1-4 
Immunoglobulin G1-G4 
IgM 
Immunoglobulin M 
IL-12 
Interleukin 12 
IND 
Investigational new drug 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IUD 
Intrauterine devices 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHL 
Non-Hodgkin lymphoma 
PD 
Pharmacodynamics 
PE 
Physical examination 
PK 
Pharmacokinetic 
RBC 
RNAseq 
Red blood cells 
RNA sequencing 
QTcF 
Corrected QT interval using Fridericia's formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SD 
Standard deviation 
SNP 
Single nucleotide polymorphism 
SOC 
System Organ Class 
SOP 
Standard operating procedures 
SYNT001 
A humanized, affinity matured IgG4-kappa monoclonal antibody 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Observed time to reach peak plasma concentration 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
UNS 
Unscheduled 
VZV 
Varicella-zoster virus 
WAIHA 
Warm antibody autoimmune hemolytic anemia 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
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2 
BACKGROUND AND RATIONALE 
SYNT001, a humanized, affinity-matured IgG4-kappa monoclonal antibody (mAb), blocks IgG 
and IgG immune complex (IC) interactions with the neonatal Fc receptor (FcRn) and thereby the 
major functions of FcRn in protecting IgG and IgG ICs from degradation and their role in 
downstream signaling events. Specific and high affinity blockade of FcRn with SYNT001 has 
been shown to increase the catabolism of IgG and IgG IC in healthy volunteers. This predicts 
that SYNT001 will also accelerate degradation of endogenous circulating IgG autoantibodies and 
IgG-antigen IC specifically involved in the pathogenesis of autoimmunity.  Blocking FcRn 
interactions with IgG-containing ICs further predicts that SYNT001 will have consequences for 
innate and adaptive cellular immunity.  In the first instance, blocking multimeric IgG IC 
interactions with FcRn within antigen-presenting cells will result in inhibition of IC-stimulated 
inflammatory cytokine production and release by these cells.  In addition, as FcRn determines 
the intracellular itinerary of IgG ICs within and among compartments important in cellular 
immunity, it is anticipated that SYNT001 will block antigen processing and presentation of 
antigens contained within IC that otherwise lead to CD8+ and CD4+ T cell activation. Thus, 
SYNT001 will specifically target immune functions associated with IgG that are involved in 
certain autoimmune conditions and dismantle their ability to cause disease. 
SYNT001 targets key mechanisms contributing to pathology in a variety of IgG-mediated 
autoimmune disorders, including warm antibody autoimmune hemolytic anemia (WAIHA), 
pemphigus, and chronic inflammatory demyelinating polyneuropathy (CIDP).   
While current treatments for certain autoimmune disorders, including high-dose steroids, 
immunosuppressants, intravenous immunoglobulin (IVIG), plasmapheresis, and anti-CD20 
monoclonal antibodies (mAbs), such as rituximab, can be effective, they are associated with 
significant adverse effects, as well as delayed or non-durable responses.  
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous 
membranes. Autoantibodies have been shown to play an important pathogenic role in the 
mucosal and cutaneous manifestations in patients with pemphigus. Administration of SYNT001, 
which significantly decreases total IgG, including a corresponding decrease in the level of the 
pathogenic autoantibodies and the ICs to which they are associated, may lead to a decrease in the 
mucosal and cutaneous manifestations in patients with pemphigus. Moreover, the ability of 
SYNT001 to reduce circulating immune complexes (CICs) and the associated innate and 
adaptive immune responses may allow for further sustained disease modification. 
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2.1 
Study Rationale 
This study is being conducted to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD) and immunogenicity of intravenous (IV) SYNT001 as well as its 
effects on pemphigus disease activity markers. 
2.2 
Selection of Doses in this Study  
The planned dose levels of SYNT001 for this Phase 1b safety and proof-of-concept study of 
10 mg/kg and 30 mg/kg were selected from careful review of the safety, tolerability, and PD 
effect on total IgG levels after single and repeat dosing of SYNT001 in non-human primates 
(NHPs), as well as the safety, tolerability, and PD effect on total IgG levels after single 
ascending doses of SYNT001 in healthy volunteers. In addition, further consideration was given 
to the desired level of FcRn blockade to achieve suppression of IgG to a range that has been 
previously correlated with disease remission. Further, we considered the potential effects of 
inhibiting FcRn function as they relate to immune complex associated innate and adaptive 
immunity in choosing these dose levels based upon exploratory studies of a single ascending 
dose of SYNT001 in healthy volunteers. From the NHP studies, single doses of SYNT001 
produced a dose-dependent decrease in total IgG and a further decrease was seen with repeated 
weekly doses up to a maximum 70% reduction at 100 mg/kg. This magnitude of total IgG 
reduction is approaching the expected maximal effect of 100% inhibition of FcRn function based 
on murine studies also performed by Syntimmune and others (Nixon et al., 2015; Roopenian et 
al., 2003). In the recently completed Phase 1a trial with SYNT001 in healthy volunteers a single 
dose caused a maximum average 50% drop in total IgG with IV dosing at 30 mg/kg. Based on 
the NHP studies further reductions are expected following multiple dosing. A comparable 
decrease in pathogenic autoantibodies is also anticipated. 
In the NHP studies, relevant adverse effects, mild-to-moderate infusion reactions, were observed 
only after the third weekly IV administration, concurrent with the development of anti-SYNT001 
antibodies. In the recently completed Phase 1a healthy male volunteer study, the doses of 
SYNT001 up to and including 30 mg/kg have been well tolerated. There were no dose limiting 
toxicities, serious adverse events, or any other safety concerns identified.  No AEs were observed 
in the 1 and 3 mg/kg dose cohorts. A single Grade 2 AE was observed; a headache in the 10 
mg/kg cohort. Other subjects had mild (Grade 1) AEs at 10 mg/kg. In Cohort 4 (30 mg/kg), 5 
subjects received SYNT001. All five subjects experienced AEs; all were mild (Grade 1), 
transient and resolved spontaneously without intervention. Therefore, it is anticipated that the 
doses selected for this study should be well tolerated and have clinically relevant PD effects in 
patients with chronic pemphigus (vulgaris or foliaceus). For a summary of findings from the 
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single dose, clinical study in healthy subjects and further details on the nonclinical findings, 
please refer to the SYNT001 Investigator’s Brochure.  
2.3 
Compliance Statement 
This study will be conducted in compliance with Good Clinical Practice (GCP), including the 
International Conference on Harmonisation (ICH) Guidelines and FDA regulations, consistent 
with the principles outlined in the Declaration of Helsinki.  In addition, the Investigator agrees to 
adhere to all applicable local laws and regulatory requirements relevant to the use of new 
therapeutic agents. 
The study will be conducted in compliance with the protocol.  The appropriate Institutional 
Review Boards (IRBs) must approve the protocol, any amendments, and the subject informed 
consent form (ICF) prior to implementation.  
Freely given written informed consent must be obtained from every subject prior to participation 
in this clinical trial.  As part of this procedure, the Investigator must explain orally and in writing 
the nature, duration, and purpose of the study, and the action of the drug in such a manner that 
the study subject is aware of the potential risks, inconveniences, or AEs that may occur.  The 
study subject should be informed that he/she is free to withdraw from the study at any time.  
He/she will receive all information that is required by federal regulations and ICH guidelines.  
The Investigator or designee will provide the Sponsor with a copy of the IRB-approved informed 
consent form prior to the start of the study. The rights, safety, and well-being of participating 
subjects are the most important considerations and should prevail over interests of science and 
society. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s).  This trial will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct or 
fraud (e.g., loss of medical licensure, debarment). 
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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of 5 once-weekly IV 
infusions of SYNT001 at different dose levels in subjects with chronic pemphigus (vulgaris or 
foliaceus). 
3.2 
Secondary Objectives 
The secondary objectives of this study are as follow: 
• To determine the PK of SYNT001 following 5 once-weekly 1-hour IV infusions at 
different dose levels 
• To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the 
following PD biomarkers: 
o Immunoglobulins: IgG, IgG subtypes (IgG1-4), IgA, IgM  
o Albumin 
• To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the 
following disease activity markers: 
o Serum anti-desmoglein (Dsg) (1 and 3) antibody levels 
o Pemphigus Disease Area Index (PDAI) 
• To assess immunogenicity (anti-SYNT001 antibodies) 
3.3 
Exploratory Objectives 
The exploratory objectives of this study are as follow: 
• To assess the effect of 5 once-weekly doses of SYNT001 at different dose levels on the 
following biomarkers, including: 
o Serum anti-epithelial cell antibody (AECA) levels by indirect immunofluorescence  
o Circulating immune complexes (CIC) 
o Complement component 3 (C3) 
o Exploratory biomarkers (FCGR2A single nucleotide polymorphism-SNP, RNAseq, 
urine IgG) 
o Immune phenotyping by flow cytometry for CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B cells 
o SYNT001 levels in skin biopsies (optional) 
o Exploratory biomarkers to investigate immune response associated with pemphigus 
• To characterize corticosteroid use during the study 
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4 
STUDY DESIGN 
4.1 
Study Sites 
This study will be conducted at approximately 10 sites in the United States (US). 
4.2 
Study Endpoints 
Primary Outcome Measures:  Assessment of safety data (adverse events [AEs], serious 
adverse events [SAEs], vital sign measurements, ECGs and clinical laboratory tests) will be the 
primary safety measure.   
Secondary Outcome Measures 
Pharmacokinetics: 
• Half-life (t1/2), maximum plasma concentration determined directly from the 
concentration-time profile (Cmax), observed time to reach peak plasma concentration 
(Tmax), area under the plasma concentration-time curve from pre-dose (time 0) to 
24 hours post-dose (AUC0-24), and area under the plasma concentration-time curve 
from pre-dose (time 0) to infinity (AUC0-∞) 
PD Biomarkers: 
• Ig Assessments: Serial assessments of total IgG and IgG subtypes (IgG1-4)  
o Serial assessments of total IgG and IgG subtypes (IgG1-4) 
o IgA levels 
o IgM levels 
• Albumin levels 
 
Disease activity markers: 
• Serum anti-desmoglein (Dsg) (1 and 3) antibody levels 
• Pemphigus Disease Area Index (PDAI) scores 
Immunogenicity: 
• Anti-SYNT001 antibodies 
Exploratory Outcome Measures 
Biomarkers, including: 
• CIC 
• C3 
• Serum AECA levels  
• Exploratory biomarkers (FCGR2A SNP, RNAseq, urine IgG) 
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• Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, 
CD3+CD8+ T, monocytes, NK cells and B cells 
• SYNT001 levels in skin biopsies (optional) 
• Exploratory biomarkers to investigate immune response associated with pemphigus 
 
Concomitant Treatments 
• Corticosteroid use 
 
Further details on the statistical and analytical plan for these endpoints are available in 
Section 12, Statistical Considerations.           
4.3 
Overview of Study Design 
This will be a multicenter, open-label study to assess the safety, tolerability, activity, PK, PD, 
and immunogenicity of 5 once-weekly IV infusions of SYNT001 to subjects with chronic 
pemphigus (vulgaris or foliaceus). 
Planned doses of SYNT001 to be studied are 10 mg/kg and up to 30 mg/kg.  Two cohorts of 8 
eligible subjects each will receive 5 once-weekly 60-minute infusions of SYNT001 10 mg/kg or 
up to 30 mg/kg. Based on review of safety, PD, and clinical outcomes of the first cohort, the dose 
for the second cohort may be adjusted, but with a maximum dose of 30 mg/kg.  Based on review 
of safety, PD and clinical outcomes from these 2 cohorts, a third cohort of up to 8 subjects may 
be treated at another dose, with a maximum dose of 45 mg/kg, but may also be lower than 10 
mg/kg or between 10 and 30 mg/kg, inclusive. 
Cohort 
No. of 
Subjects 
Dose 
1 
8 
SYNT001 10 mg/kg 
2 
8 
SYNT001 30 mg/kg 
Cohorts will be dosed sequentially beginning with Cohort 1.  The first 2 subjects will be dosed at 
least 24 hours apart.  A review of the 24-hour safety data for the first subject will be performed 
to ensure that there are no overt safety concerns before dosing the second subject.  A review of 
the 7-day safety data for the first 2 subjects will be performed prior to dosing the remaining 6 
subjects in the cohort.  This evaluation will include a review of AE/SAE reports, vital sign 
assessments, physical examinations, ECGs and clinical laboratory testing.  The seriousness, 
severity, and relatedness of AEs/SAEs will also be considered in the safety evaluation.  Safety 
data will be reviewed on a continuous basis throughout the study.  All data through Day 42 
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(2 weeks after the last subject’s last dose in Cohort 1) will be reviewed before Cohort 2 is 
initiated.  Cohort 2 and Cohort 3, if added, will be dosed per the same schedule.  
Safety evaluations will be conducted by a dose escalation committee (DEC). The DEC will 
consist of the Medical Monitor, an Independent Clinical Expert and a Syntimmune Medical 
Officer. To assist in the safety assessments, the DEC may request that Investigators, other 
experts, or members within their organizations review the data and participate in the 
discussions.  Dosing and dose escalation will proceed if the DEC has determined that it would be 
safe and appropriate to do so.  In addition, over the course of the study, the DEC will review any 
drug-related SAEs to determine if modifications to the study or other measures are necessary to 
ensure the safety of the subjects.   
On days where study drug is administered, vital sign and pulse oximetry measurements will be 
collected immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; 
at completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the 
infusion.  
On Days 0 and 28, PK blood samples will be collected prior to infusion start and then over the 
subsequent 48 hours.  Subjects will remain at the clinic through the 6-hour PK sample collection 
and will return to the clinic for the 24- and 48-hour collections.  Additional samples will be 
collected on Days 5 and 33.   
On Day 0 photographs will be taken of active lesions.  Follow-up photographs will be taken of 
the same areas on Days 33, 56, 84, and 112.  If a subject begins a steroid taper, additional 
photographs will be taken at the clinic visit during which the decision to begin the taper is made. 
Subsequent visits will occur on Days 1, 2, 5, 7, 12, 14, 19, 21, 28, 29, 30, 33, 42 and 56 for 
safety assessments, study drug dosing, sample collections, and other study procedures. 
Subjects also will return to the clinic on Days 84 and 112 for follow-up visits.  Subjects whose 
total IgG is not within 30% of their Day 0 baseline value and not above 500 mg/dL at the Day 
112 visit will be referred for further management. 
See Table 1 for a schedule of all study events.  To assess safety and tolerability, subjects will 
undergo physical examinations (PEs; including weight), vital sign measurements, clinical 
(safety) laboratory tests, AE assessments, concomitant medication assessments, and 
electrocardiograms (ECG). 
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Note:  No vaccinations may be given from within 2 weeks of screening through Day 56.  
Following Day 56, subjects may receive vaccinations at the discretion of the Investigator. 
4.4 
Randomization and Blinding 
This is an open-label study. 
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5 
STUDY POPULATION 
5.1 
Target Population 
This study will be conducted in approximately 16 male and female subjects (2 cohorts of 8 
subjects each) with a confirmed diagnosis of pemphigus (vulgaris or foliaceus); however, a third 
cohort of up to 8 subjects may be added.  Subjects will be enrolled only once in the study and 
will not be included in subsequent dosing cohorts. Subjects who withdraw for any reason other 
than an AE and who do not receive study drug or have only received one dose of study drug may 
be replaced, up to one subject per cohort. Subjects who do not receive all doses of study drug 
will continue to be followed through all scheduled visits.  The maximum number of subjects who 
may be enrolled in this study is 27 (24 + up to 3 replacements, as necessary).  Within each 
dosing cohort, no more than 3 subjects may be enrolled with pemphigus foliaceus. 
5.2 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for the study: 
1. Willing and able to read, understand and sign an informed consent form;  
2. Male or female ≥ 18 years of age;  
3. Documented diagnosis of pemphigus vulgaris or foliaceus based on all 3 of the following 
criteria: 
a. Documented clinical history consistent with pemphigus vulgaris or foliaceus 
(clinical presentation defined as mucosal and/ or skin lesions); 
b.  Presence of Anti-Dsg 1 or 3 antibodies above the upper limit of normal; 
c. History of at least one positive tissue based test (biopsy, DIF) 
4. Active disease: Lesions lasting > 2 weeks, and 3 active lesions in skin or mucosa or 2 
active lesions with at least one being a skin lesion > 1 cm diameter: 
a. If treated with rituximab or other anti-CD20 antibodies, last dose > 12 months 
prior to screening; 
b. If being treated with other immunosuppressants (i.e., azathioprine, mycophenolate 
mofetil or cyclosporine), must be on stable dose (< 10% change in dose) for 
6 weeks prior to screening; 
c. If being treated with corticosteroids, must be ≤ 1mg/kg/day of prednisone or 
equivalent and stable (< 10% change in dose) for 2 weeks prior to screening; 
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d. Allowed topical therapies for pemphigus lesions upon entering the study include 
petroleum jelly or Aquaphor® for the skin or chlorhexidine for the mouth  
5. Body mass index (BMI) 18.5 – 39.9 kg/m2; 
6. Has a negative pregnancy test (for women of childbearing potential) documented prior to 
the first dose of study drug;     
7. Females of childbearing potential must agree to be abstinent or else use any two of the 
following medically acceptable forms of contraception (<1% per year failure rate) from 
the Screening Period through the final study visit: oral contraceptive, condom with or 
without spermicidal jelly, diaphragm or cervical cap with spermicidal jelly, or intra-
uterine device (IUD). A female whose male partner has had a vasectomy must agree to 
use one additional form of medically acceptable contraception.  
8. Females of non-childbearing potential, defined as surgically sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for 
at least 12 months do not require contraception during the study. 
9. Males with female partners of childbearing potential, including males who are surgically 
sterile (post vasectomy), must agree to be abstinent or else use a medically acceptable 
form of contraception from the screening period through the final study visit.  
5.3 
Exclusion Criteria    
A subject who meets any of the following criteria is ineligible for the study: 
 
1. Unable or unwilling to comply with the protocol; 
2. Active non-hematologic malignancy or history of non-hematologic malignancy in the 
3 years prior to screening (exclusive of non-melanoma skin cancer and cervical cancer in 
situ); 
3. Positive for HIV or hepatitis C antibody;  
4. Positive for hepatitis B surface antigen; 
5. Active infection or history of recurrent infections; 
6. IVIG treatment within 60 days of screening; 
7. Received any cytotoxic (other than azathioprine) or mAb therapy in the 3 months prior to 
screening; 
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8. Any exposure to an investigational drug or device within 30 days prior to screening; 
9. Plasmapheresis or immunoadsorption within 60 days of screening 
10. Cellular therapy, including CAR-T, at any time prior to screening 
11. Use of any immunosuppressive drugs apart from corticosteroids, azathioprine, 
mycophenolate mofetil, or cyclosporine within 3 months of screening; 
12. Serum total IgG < 600 mg/dL; 
13. Subject has any current medical condition that, in the opinion of the Investigator, may 
compromise their safety or compliance, preclude successful conduct of the study, or 
interfere with interpretation of the results (e.g., a significant pre-existing illness or other 
major comorbidity that the Investigator considers may confound the interpretation of the 
study results); 
14. Any vaccination within 2 weeks of screening 
 
 
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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All subjects must take part in the informed consent process.  Adequate time must be allowed for 
the subject to ask questions and make a voluntary decision.  No protocol-specific procedures, 
including screening procedures, are to be performed until the subject has signed and dated an 
IRB-approved ICF.  Subjects may withdraw consent at any time. Participation in the study may 
be terminated at any time without the subject’s consent as determined by the Investigator.  
6.2 
Demographics and Medical History 
Demographics (age, gender, race and ethnicity) and medical history will be obtained from the 
subject and recorded on the source document and eCRF.  Medical history will capture the 
subject’s current medical history (current disease processes), past medical status (past disease 
processes), history of surgery and concomitant treatments, including relevant clinical response to 
past disease specific treatments and duration as well as dosing of such treatments.  
6.3 
Physical Examination 
A complete physical examination will be performed as outlined in Table 1.  The complete PE 
will include measurements of weight (in kg) and height (in cm; height to be measured only at 
screening visit) and a review of the following body systems: 
• General appearance 
• Head, eyes, ears, nose, and throat 
• Neck 
• Respiratory 
• Cardiovascular 
• Abdomen 
• Neurologic 
• Extremities 
• Dermatologic 
• Lymphatic 
Any abnormal and clinically significant findings from the PE must be recorded in the appropriate 
eCRF.  Findings at screening and Day 0 (pre-dose) will be recorded as medical history. 
6.4 
Pemphigus Disease Area Index (PDAI) Scoring 
Pemphigus severity and disease activity will be measured using the PDAI.  See Appendix B. 
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6.5 
Vital Sign Measurements 
Vital sign measurements will be collected after the subject has been sitting for 5 minutes.  Vital 
sign assessments will include measurements of sitting blood pressure (mm Hg), heart rate (beats 
per minute), respiration rate (breaths per minute), oral temperature (Celsius).  Abnormal results 
are to be repeated after 5 minutes of rest.  Pulse oximetry (%) also is to be measured.  See 
Table 2 for timing window allowances with respect to measurement collection. 
On Days 0, 7, 14, 21, and 28, vital sign measurements are to be obtained immediately prior to the 
infusion; 15, 30, and 45 minutes after the start of the infusion; at completion of the infusion; and 
30 minutes, 1 hour and 2 hours following completion of the infusion.  Details on the 
management of mild to moderate and severe infusion reactions can be found in Figure 1 and 
Figure 2.  Abnormalities in vital sign measurements will be graded in severity per the NCI 
CTCAE scale Version 4.03. 
Subjects should be seated quietly for at least 5 minutes in a chair with their backs supported, 
their feet flat on floor (legs uncrossed), and their arms bared on a hard surface, with the arm 
slightly abducted and bent, with palm up and the midpoint of upper arm at heart level.  Correct 
cuff and bladder size should be utilized and the same cuff and arm should be used per subject 
throughout study.     
6.6 
12-Lead Electrocardiogram (ECG)   
Digital 12-lead ECG measurements will be obtained at screening, on Days 0 and 28 at 5 minutes 
after the completion of the infusion and at the Day 56 visit.  Subjects who conduct their Day 12 
visit at the investigative site, as opposed to an at-home nurse visit, will have an additional ECG 
performed.  ECGs are to be performed with the subject in a supine position having rested in this 
position for at least 5 minutes before each reading. ECGs are to be performed in triplicate, each 1 
to 2 minutes apart.  See Table 2 for timing window allowances with respect to performing ECG. 
The following ECG parameters will be collected: PR interval, QRS interval, and QT interval.  
The ECG findings will be evaluated by a qualified physician for the presence of abnormalities 
(qualitative assessment).  The physician will assess each ECG as normal, abnormal/not clinically 
significant, or abnormal/clinically significant.   
Normal QTcF is ≤ 450 msec.  
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Abnormalities in the ECG that appear following therapy or that result in clinical signs and 
symptoms are considered clinically significant for the purposes of this study and will be recorded 
on the AE eCRF.   
6.7 
Clinical Laboratory Measurements   
Collection time for all safety, PD, and exploratory labs are outlined in Table 1. 
Laboratory testing (hematology, urinalysis, serum chemistry, virology, serology, pregnancy tests, 
PD samples, PK samples, and anti-drug antibody samples) will be performed using established 
methods by a central laboratory. Safety laboratory panels are defined as listed in Table 3. Blood 
and urine samples for hematology, serum chemistry, and urinalysis will be prepared using 
standard procedures.  Results will be provided to the Investigator.  Aliquots from the PK, 
biomarker and anti-drug antibody samples may be retained as back-up for additional testing as 
necessary. Subjects will be in a seated or supine position during blood collection. Full clinical 
safety lab draws will be collected at Screening and on Days 0, 7, 14, 21, 28, 33, 42, 56, 84 and 
112.  The total blood draw for each subject who completes the study at Day 112, will be 
approximately 433 mL.  Please refer to the Laboratory Manual for more information.    
Table 3: 
Clinical Laboratory Panels 
Hematology 
Serum Chemistry 
Urinalysis 
• 
CBC with differential and blood 
smear 
• 
Erythrocyte Sedimentation Rate 
(ESR) 
 
• 
Albumin 
• 
Alkaline phosphatase 
• 
ALT 
• 
AST 
• 
BUN 
• 
Calcium 
• 
Carbon dioxide 
• 
Chloride 
• 
Creatinine 
• 
Glucose 
• 
LDH 
• 
Phosphorus 
• 
Potassium 
• 
Sodium 
• 
Total and direct bilirubin 
• 
Total protein 
• 
Uric acid 
• 
C-Reactive Protein 
• 
Appearance 
• 
Color 
• 
pH 
• 
Specific gravity 
• 
Ketones 
• 
Protein 
• 
Glucose 
• 
Nitrite 
• 
Urobilinogen 
• 
Blood/hemoglobin 
• 
Leukocyte esterase 
• 
Bilirubin 
• 
Microscopic examination of 
sediment: only if the results of 
the urinalysis dipstick evaluation 
are positive for 
blood/hemoglobin 
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Virology 
 
 
• 
Hepatitis C 
• 
Hepatitis B 
• 
HIV 
• 
VZV 
• 
Tetanus 
 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; BUN = blood urea 
nitrogen; HIV = human immunodeficiency virus; LDH = lactate dehydrogenase; VZV = varicella-zoster virus 
 
Abnormalities in clinical laboratory tests that are considered clinically significant are to be 
recorded on the AE electronic case report form (eCRF) page.   Laboratory results will be graded 
using the NCI CTCAE, Version 4.03. If laboratory values constitute part of an event that meets 
criteria defining it as serious, the event (and associated laboratory values) must be reported as an 
SAE (see Section 11.3.1). 
6.7.1 
Pregnancy Testing 
Pregnancy testing will be performed for women of childbearing potential at screening and prior 
to first dose of SYNT001 on Day 0 and Days 56 and 112 (urine or serum test is acceptable 
however, positive urine tests must be confirmed with serum testing.) 
6.7.2 
Virology 
Testing for HCV antibody, hepatitis B surface antigen, and HIV antibody will be performed at 
screening. 
6.7.3 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing 
Samples for serum tetanus antibody and varicella-zoster virus antibody testing are to be collected 
at baseline (pre-dose, Day 0) and on Day 56 (Follow-Up visit).  Testing at Day 56 will not be 
done for any subject whose baseline titer is below the level of detection. Specifically, if the 
baseline VZV titer is above the detectable level, but tetanus is not, only the VZV antibody titer 
will be tested on Day 56. If the Day 56 results are below the baseline value, defined as greater 
than 30% below the baseline value, or if the subject falls below the level of detection, the subject 
will be re-tested at Day 84; if still below the baseline value (or level of detection), the subject 
will be re-tested at Day 112. Any subject whose baseline value for tetanus or VZV was above the 
detectable level at baseline, and is not within 30% of the baseline value or is below the detectable 
level by Day 112, will be referred to their primary care physician for further management.  
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6.7.4 
Pharmacokinetics (PK) Sampling 
Starting on Days 0 and 28, serum samples will be collected just prior to the start of study drug 
infusion (pre-dose), at 5 minutes and 2, 4, 6, 24, and 48 hours after the end-of-study drug 
infusion.  Additional samples will be collected on Days 5 and 33.  The actual time and date of 
each blood draw is to be recorded.   
Study drug concentration will be used to calculate the following PK parameters: t1/2, Cmax, Tmax, 
AUC0-24, and AUC0-∞.   
Detailed instructions for sample collection and preparation will be provided in a separate 
laboratory manual 
6.7.5 
Pharmacodynamic Sampling 
PD samples will be collected for analyses throughout the study. On Days 0, 7, 14, 21, and 28, 
samples should be collected prior to infusion of study drug.  Measurements for albumin PD 
biomarkers will be derived from the clinical safety laboratory results.  Samples for each type of 
PD will be collected according to the schedule shown in Table 4. 
 
 
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Table 4: Pharmacodynamic/ Activity Assessments 
Parameter 
Collection Timepoints 
• 
IgG, IgG subtypes (IgG1-4), IgA, IgM  
Screening, and Days 0, 1, 2, 5, 7, 12, 14, 19, 
21, 28, 29, 30, 33, 42, 56, 84 and 112.   
• 
Circulating immune complexes (CIC) 
Days 0, 5, 7, 12, 14, 19, 21, 28, 33, 42, 56, 
84 and 112 
• 
Albumin 
Screening, and Days 0, 7, 14, 21, 28, 33, 42, 
56, 84 and 112 
• 
Anti-Dsg (1 and 3) antibody titer 
Screening, Days 0, 7, 14, 33, 56, 84 and 112 
• 
Complement component 3 (C3) 
• 
Anti-epithelial cell antibody (AECA) levels by 
indirect immunofluorescence 
 
Days 0, 14, 33, 56, 84 and 112 
• 
Exploratory biomarker (RNAseq, Urine IgG) 
 
Days 0, 14, 33, 56, 84 and 112 
• 
Immune phenotyping by flow cytometry for 
measurement of CD3+CD4+ T, CD3+CD8+ T, 
monocytes, NK cells and B cells 
Days 0, 28 and 56 
• 
Exploratory biomarker (FCGR2A SNP, via 
buccal swab) 
Day 0 
• 
Exploratory pemphigus immune response 
biomarkers 
Days 0, 5, 7, 12, 14, 19, 21, 28, 33, 42, 56, 
84 and 112 
 
See Table 2 for timing window allowances with respect to measurement collection. 
Detailed instructions for sample collection (including collection tubes) and preparation will be 
provided in a separate laboratory manual. 
6.7.6 
Immunogenicity Testing 
Serum samples will be collected for immunogenicity analyses on Days 0 (pre-dose), 14, 28, 56, 
84 and 112. 
SYNT001 is being developed for the acute and chronic therapy of autoimmune disorders. 
Although SYNT001 is a humanized IgG4 monoclonal antibody, exposure to SYNT001 in 
clinical trials could result in the development of anti-drug antibodies (ADAs), with potential 
consequences ranging from neutralization or lessening of drug efficacy to safety consequences 
such as allergic reactions.  Testing will first detect binding ADAs, then, for all confirmed 
positive samples, there will be testing for neutralizing effects.  
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Detailed instructions for sample collection and preparation will be provided in a separate 
laboratory manual. 
6.8 
Study Drug Administration 
Two cohorts of 8 eligible subjects each will receive 5 once-weekly 60-minute IV infusions of 
SYNT001 10 mg/kg or up to 30 mg/kg. SYNT001 will be given as a 250-mL IV infusion over 1 
hour using a 0.2-micron, inline filter. Based on review of safety data, as well as available and 
relevant PD results, and clinical outcomes of Cohort 1, a decision about proceeding with Cohort 
2 will be made.  Based on review of all safety data, available PD results, and clinical outcomes 
of these 2 cohorts, a third cohort of 8 subjects may be treated at another dose, with a maximum 
dose of 45 mg/kg, but may also be lower than 10 mg/kg or between 10 and 30 mg/kg, inclusive.   
Cohort No. 
Study Drug 
Dose Level 
(mg/kg/dose) 
1 
SYNT001 
10 mg/kg 
2 
SYNT001 
30 mg/kg 
See Section 9.1 for dosing schedule.   
6.9 
Prior and Concomitant Medications 
All medications a subject receives within 14 days prior to enrollment through the end of the 
study will be documented on the source document and eCRF.  A history of treatments taken for 
primary disease, even if not taken within the 14 days prior to enrollment, will be collected. 
Note:  No vaccinations may be given from within 2 weeks of screening through Day 56.  
Following Day 56, subjects may receive vaccinations at the discretion of the Investigator. 
6.10 
Adverse Event Assessments 
Information regarding the occurrence of AEs will be collected from the time the subject signs the 
informed consent form and continuing through the last study visit.  Findings at screening and 
Day 0 (pre-dose) will be recorded as medical history.   Any known untoward event that occurs 
beyond the AE reporting period that the Investigator assesses as related to study drug also should 
be reported as an AE. 
Clinical AEs will be graded using the NCI CTCAE, Version 4.03 (Appendix A).   
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Note:   AEs resulting in a subject’s permanent discontinuation from the study, regardless of 
seriousness or relationship to study drug, MUST be promptly reported to the sponsor.  
Additionally, subjects must be followed until return to normal and/or resolution of the AE. 
See Section 11 for more information. 
6.11 
Photographs 
On Day 0 photographs will be taken of active lesions.  Follow-up photographs will be taken of 
the same areas on Days 33, 56, 84 and 112.  Subjects who begin a steroid taper will have 
additional photographs taken at the clinic visit during which the decision to begin the taper is 
made.  A separate manual describing the procedures for taking photographs will be provided. 
6.12 
Skin Biopsy 
Optional skin biopsy samples from lesional or non-lesional skin will be collected on Day 0 pre-
dose and on Days 1, 2, 14, 33, 56 and 84 to analyze SYNT001 levels. 
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7 
STUDY ASSESSMENTS 
7.1 
Screening Period: Day -14 to Day -1 
Informed consent must be obtained before any study-specific samples are taken or study-specific 
tests or evaluations are conducted.  The following assessments at the screening visit are to occur 
within 14 days before dosing.  Study eligibility will be based on satisfying all the study inclusion 
and exclusion criteria.   
At the screening visit, information will be collected and subjects will have clinical evaluations as 
follows: 
• Informed consent (Section 6.1) 
• Medical history and demographic data (Section 6.2) 
• Review inclusion and exclusion criteria (Section 5.2, Section 5.3) 
• Complete PE, including height and weight (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• 12-Lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position) 
(Section 6.6) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Pregnancy test (Section 6.7) 
• Hepatitis and HIV screen (Section 6.7) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• Anti-Dsg (1 and 3) antibody titer 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.2 
Enrollment and First Treatment: Day 0  
Study Day 0 is defined as the date the subject is administered their first dose of study drug. On 
Day 0, subjects will be asked to come to the clinic and the following procedures will be 
performed prior to the first dose of study drug: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
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• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Pregnancy test (Section 6.7) 
• Serum tetanus antibody and VZV antibody (Section 6.7) 
• PDAI Score (Section 6.4) 
• PK baseline sample collection (collected just prior to the start of the study drug infusion) 
(Section 6.7) 
• Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
(Section 6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• Anti-Dsg (1 and 3) antibody titer 
• CIC  
• C3 
• AECA 
• FCGR2A SNP, via buccal swab 
• RNAseq 
• Urine IgG 
• Immune phenotyping 
• Exploratory pemphigus immune response biomarkers 
• Optional skin biopsy (Section 6.12) 
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
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• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• PK sample collection at 5 minutes and 2, 4, 6 hours after the end-of-study drug infusion; 
record collection date and time for each PK sample (Section 6.7) 
• 12-Lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion (Section 6.6) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.3 
Follow-up: Day 1  
On Day 1 (24 hours ± 1 hour from end-of-infusion time on Day 0), the subject will return to the 
clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• PK sampling (record collection date and time) (Section 6.7) 
• Optional skin biopsy (Section 6.12) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.4 
Follow-up: Day 2 
On Day 2 (48 hours ± 2 hours from end-of-infusion time on Day 0), the subject will return to the 
clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• PK sampling (record collection date and time) (Section 6.7) 
• Optional skin biopsy (Section 6.12) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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7.5 
Follow-up: Day 5  
On Day 5 (120 hours ± 4 hours from end-of-infusion time on Day 0), subjects may return to the 
clinic or be visited by at-home nurse, and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PK sampling (record collection date and time) (Section 6.7) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Exploratory pemphigus immune response biomarkers 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.6 
Treatment Day 7 (Dose 2)  
On Day 7 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
• PDAI Score (Section 6.4) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• Exploratory pemphigus immune response biomarkers 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
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temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.7 
Dose 2 Follow-up Day 12 
On Day 12 (± 6 hours) the subject may return to the clinic, or be visited by at-home nurse, and 
the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Exploratory pemphigus immune response biomarkers 
• If visit performed at the study site: 12-Lead ECG to be obtained in triplicate (Section 6.6) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.8 
Treatment Day 14 (Dose 3) 
On Day 14 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
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• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
• PDAI Score (Section 6.4) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
(Section 6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• Anti-Dsg (1 and 3) antibody titer 
• CIC 
• C3 
• AECA 
• RNAseq 
• Urine IgG 
• Exploratory pemphigus immune response biomarkers 
• Optional skin biopsy (Section 6.12) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
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• AE assessment (Section 6.10) 
7.9 
Dose 3 Follow-up Day 19 
On Day 19 (± 6 hours) the subject may return to the clinic, or be visited by an at-home nurse, and 
the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Exploratory pemphigus immune response biomarkers 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.10 
Treatment Day 21 (Dose 4) 
On Day 21, (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
• PDAI Score (Section 6.4) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Exploratory pemphigus immune response biomarkers 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
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and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.11 
Treatment Day 28 (Dose 5) 
On Day 28 (± 6 hours), subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature); to be measured immediately prior to the infusion (Section 6.5) 
• Pulse oximetry (to be measured immediately prior to the infusion) (Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PDAI Score (Section 6.4) 
• PK sampling (collected just prior to the start of the study drug infusion; record collection 
date and time for each PK sample) (Section 6.7) 
• Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
(Section 6.7) 
• PD sample collection (collected just prior to the start of the study drug infusion) (Section 
6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Immune phenotyping 
• Exploratory pemphigus immune response biomarkers 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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After the preceding procedures and assessments are completed: 
• Study drug administration (record date and time of dose of study drug) (Section 9) 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Pulse oximetry will be measured at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion (Section 6.5) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
• Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature): 30 minutes, 1 hour and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest (Section 6.5) 
• Pulse oximetry: 30 minutes, 1 hour and 2 hours following completion of the infusion 
(Section 6.5) 
• PK sample collection at 5 minutes and 2, 4, 6 hours after the end-of-study drug infusion; 
record collection date and time for each PK sample (Section 6.7) 
• 12-Lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion (Section 6.6) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.12 
Follow-up Day 29  
On Day 29 (24 hours ± 1 hour from end-of-infusion time on Day 28), the subject will return to 
the clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• PK sampling (record collection date and time) (Section 6.7) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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7.13 
Follow-up Day 30 
On Day 30 (48 hours ± 2 hours from end-of-infusion time on Day 28), the subject will return to 
the clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• PK sampling (record collection date and time) (Section 6.7) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.14 
Follow-up Day 33  
On Day 33 (120 hours ± 4 hours from end-of-infusion time on Day 28), subjects will return to 
the clinic and the following procedures are to be performed: 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PDAI Score (Section 6.4) 
• PK sampling (record collection date and time) (Section 6.7) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• C3 
• AECA 
• RNAseq 
• Urine IgG 
• Exploratory pemphigus immune response biomarkers  
• Optional skin biopsy (Section 6.12) 
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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7.15 
Follow-up Day 42  
On Day 42 (± 3 days), subjects will return to the clinic and the following procedures are to be 
performed: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• PDAI Score (Section 6.4) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Exploratory pemphigus immune response biomarkers 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.16 
Follow-up Day 56 
On Day 56 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Pregnancy test (Section 6.7) 
• 12-Lead ECG (to be obtained in triplicate after 5 minutes of rest in the sitting position) 
(Section 6.6) 
• Serum tetanus antibody and VZV antibody; Testing at Day 56 will not be done for any 
subject whose baseline titer is below the level of detection. See Section 6.7.3 for 
additional information.   
• Immunogenicity sample collection (Section 6.7) 
• PDAI Score (Section 6.4) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
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• Anti-Dsg (1 and 3) antibody titer 
• C3 
• AECA 
• RNAseq 
• Urine IgG 
• Immune phenotyping 
• Exploratory pemphigus immune response biomarkers  
• Optional skin biopsy (Section 6.12) 
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
7.17 
Follow-up Day 84 
On Day 84 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Serum tetanus antibody and VZV antibody testing if required. See Section 6.7.3 for 
additional information.   
• Immunogenicity sample collection (Section 6.7) 
• PDAI Score (Section 6.4) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• C3 
• AECA 
• RNAseq 
• Urine IgG 
• Exploratory pemphigus immune response biomarkers  
• Optional skin biopsy (Section 6.12) 
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
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7.18 
Follow-up Day 112 (End-of-Study) or Early Termination Visit 
On Day 112 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed: 
• Complete physical exam (Section 6.3) 
• Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
(Section 6.5) 
• Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) (Section 
6.7) 
• Pregnancy test (Section 6.7) 
• Serum tetanus antibody and VZV antibody testing if required. See Section 6.7.3 for 
additional information.   
• Immunogenicity sample collection (Section 6.7) 
• PDAI Score (Section 6.4) 
• PD sample collection (Section 6.7) 
• IgG, IgG subtypes (IgG1-4), IgA, IgM 
• CIC 
• Anti-Dsg (1 and 3) antibody titer 
• C3 
• AECA 
• RNAseq 
• Urine IgG 
• Exploratory pemphigus immune response biomarkers  
• Photography (Section 6.11) 
• Concomitant medication assessment (Section 6.9) 
• AE assessment (Section 6.10) 
 
 
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8 
REMOVING SUBJECTS FROM STUDY 
Every reasonable effort will be made to keep the subject in the study; however, if a subject is 
withdrawn from the study, every effort will be made by the Investigator to complete and report 
the reasons for withdrawal as thoroughly as possible.  The reason(s) for termination must be 
clearly documented on the appropriate page of the eCRF.  Once a subject discontinues from the 
study for any reason, every effort will be made to collect all clinical and laboratory data as 
scheduled for the Early Termination Visit (See Table 1).  A termination eCRF must be 
completed for all enrolled subjects. 
8.1 
Subject Withdrawal  
A subject’s participation in the study may be prematurely discontinued for any of the following 
reasons:  
1. The subject wishes to withdraw from the study. 
2. Request by a regulatory agency (e.g., Institutional Review Board). 
3. Subject experiences a significant or intolerable AE.   
4. The subject experiences a significant adverse change in vital signs, PE findings, or a 
clinical laboratory parameter. 
5. The subject has a need for a concomitant medication that is not permitted by the study 
protocol. 
6. The subject experiences generalized impairment or mental incompetence that would result 
in the subject being unable to understand his or her participation in the study. 
7. If, in the Investigator’s medical judgment, further participation would be injurious to the 
health and well-being of the subject, or is not in the best interest of the subject.  
8. Administrative reasons, such as subject non-compliance or a major protocol violation. 
Subjects who are withdrawn from this study due to an AE determined to be related to study drug 
are to be followed until there is either: 
• Resolution or stabilization of the AE determined to be related 
• The subject is lost to follow-up 
• The event is otherwise explained 
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If there is a persistent AE contributing to discontinuation that is determined to be related to 
SYNT001, subjects must be followed with appropriate medical management until resolution or 
stabilization. 
A reasonable effort should be made to contact any subject lost to follow-up during the study to 
complete assessments and retrieve any outstanding data.  If the subjects are unreachable by 
telephone after three (3) attempts, the minimum of a registered letter should be sent requesting 
that contact be made with the Investigator to report survival information.   
8.2 
Study Discontinuation 
Syntimmune Inc. has the right to terminate or to stop the study at any time.  Reasons for study 
discontinuation may include, but are not limited to the following:  
• The incidence or severity of AEs in this or other related studies indicates a potential health 
hazard to subjects  
• Subject enrollment is unsatisfactory 
• Drug supply issues 
• Excessive subject self-withdrawal 
• Significant protocol violations (e.g., violation of eligibility criteria, dosing errors, missing 
data for study endpoint analysis) 
8.3 
Replacements 
Enrolled subjects withdrawn for a reason other than an AE will be replaced if they have not been 
dosed or have only received one dose of study drug at the time of discontinuation, up to one 
subject per cohort. Subjects who do not receive all doses of study drug will continue to be 
followed through all scheduled study visits.   
8.4 
Stopping Rule 
8.4.1 
Dose-Escalation Stopping Rule 
Dose escalation decisions will be made by a Dose Escalation Committee (DEC) and will be 
based on safety and pharmacodynamic evaluations including but not limited to, dose-limiting 
toxicities, AEs, SAEs, and total IgG levels. 
Dose-limiting toxicity (DLT) will be defined generally as severe (Grade 3) AEs occurring in ≥2 
subjects that are determined to be clinically significant and considered related to study drug. 
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If 2 or more subjects at any time in any cohort (8 total subjects per cohort) have Grade 3 AEs 
that are determined to be clinically significant and considered to be related to study drug, dosing 
will be halted within that cohort and dose-escalation to a higher dose will not occur. If the dose-
escalation stopping rule is met during Cohort 1 (10 mg/kg) all safety data and all available 
pharmacodynamics will be reviewed and the cohort may resume (if applicable) or a new cohort 
may be added at a dose at least 50% lower than the 10 mg/kg dose.  If the stopping rule is not 
met in Cohort 1, dose-escalation may proceed up to a maximum of 30 mg/kg.  If the dose-
escalation stopping rule is met for the first time during Cohort 2, all safety data and all available 
pharmacodynamics will be reviewed and the cohort may resume (if applicable) or a new cohort 
may be added at a dose a minimum of 30% lower than the Cohort 2 dose. If the stopping rule is 
not met in Cohort 2, dose-escalation may proceed up to a maximum of 45 mg/kg; however, this 
cohort may also receive a dose equal to or less than 30 mg/kg based on evaluation of all safety 
and pharmacodynamic data.   
8.4.2 
Study Stopping Rule 
If any subject experiences a life-threatening AE (Grade 4) that is considered to be related to 
study drug, further dosing in all enrolled subjects will be suspended until the DEC has evaluated 
the event and determined the appropriate course of action.  At any time during the study, the 
study may be discontinued if the DEC determines that further drug exposure would pose an 
undue risk to subjects. 
8.4.3 
Individual Stopping Rule 
Dosing for any individual subject will be discontinued (i.e., no further study drug will be given 
to that subject) if the subject experiences any study drug-related SAE or any study drug-related 
non-SAE adverse event that, in the judgement of the Investigator (following consultation with 
the Medical Monitor, if desired) suggest that it could be unsafe to administer further study drug 
to that subject.  Additionally, a subject will be discontinued from further treatment with study 
drug, at the discretion of the Investigator with consultation with the Medical Monitor, if they 
require a significant increase in dose(s) of anti-pemphigus medication(s) for the management of 
pemphigus. 
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9 
STUDY DRUG 
For detailed information regarding SYNT001 preparation and administration, refer to the 
Pharmacy Manual. 
9.1 
SYNT001  
SYNT001 is provided in vials containing 5 mL SYNT001 (extractable volume) at a nominal 
concentration of 50 mg/mL.  The product is supplied as a liquid at pH 6.5 ± 0.5. SYNT001 is 
diluted in Dextrose 5% in Water (D5W) to prepare the solution for infusion.  SYNT001 will be 
infused via IV in 250 mL over 1 hour using a 0.2-micron, inline filter.   
Two cohorts of 8 eligible subjects each will receive 5 once-weekly 60-minute infusions of 
SYNT001 in planned doses of 10 mg/kg or 30 mg/kg. Based on review of safety, PD, and 
clinical outcomes of these two cohorts, a third cohort of up to 8 subjects may be treated at 
another dose, with a maximum dose of 45 mg/kg, but may also be lower than 10 mg/kg or 
between 10 and 30 mg/kg, inclusive.  
The specification for host cell DNA in SYNT001 is < 2 pg/mg, the limit of quantitation of the 
assay.  To comply with regulatory guidelines, which specify a maximum level of 10 ng host cell 
DNA per dose, dosing is limited to 5000 mg of SYNT001. Therefore, the maximum subject 
weight allowed for enrollment into the 30 mg/kg dose cohort is 166 kg and the maximum subject 
weight allowed for enrollment into the highest dose possible in this study (45 mg/kg)is 111 kg.  
9.2 
Cohort Dosing 
Cohorts will be dosed sequentially beginning with Cohort 1.  The first 2 subjects will be dosed at 
least 24 hours apart.  A review of the 24-hour safety data for the first subject will be performed 
to ensure that there are no overt safety concerns before dosing the second subject.  A review of 
the 7-day safety data for the first 2 subjects will be performed prior to dosing the remaining 6 
subjects in the cohort.  Cohort 2, and Cohort 3 if added, will be dosed per the same schedule 
9.3 
Timing of Dosing  
On Days 0, 7, 14, 21, and 28, subjects will receive a 60-minute IV infusion of SYNT001 in the 
morning.  The date and time the dose is administered will be recorded.   
9.4 
Identity of Investigational Products 
All supplies of SYNT001 will be supplied by Syntimmune and must be stored refrigerated (2ºC 
to 8ºC/36ºF to 46ºF) in the carton and protected from light, in a securely locked area, accessible 
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to authorized persons only, until needed for dose preparation.  Qualified site personnel will 
inventory the investigational product received and will maintain records of disposition of the 
drug, including dates, quantity and use. 
9.5 
Investigational Product Retention at Study Site 
The Investigator (or designee) is responsible for maintaining accurate accountability records of 
the investigational product throughout the clinical study. All study drug received at the site must 
be inventoried and accounted for in an accountability log provided by the Sponsor. All 
dispensing and accountability records will be available for Sponsor review. Study drug 
accountability will be verified during on-site monitoring visits. 
Upon the completion or termination of the study, and upon written authorization from the 
Sponsor, or its representative, all unused and/or partially used study drug should be returned or 
destroyed at the investigational site, as specified by Sponsor.  It is the Investigator’s 
responsibility to ensure that the Sponsor, or its representative, has provided written authorization 
that procedures for proper disposal of the study drug have been established, and that appropriate 
records of the disposal are documented and maintained.  No unused study drug may be disposed 
until fully accounted for by the Sponsor monitor (or designee) 
9.6 
Warnings and Precautions  
Note: Subjects must not receive any vaccinations from within 2 weeks of screening until Day 56. 
9.6.1 
Infusion Reaction 
SYNT001 will be given as an IV infusion over 1 hour. As with all mAbs administered by IV 
infusion, infusion reactions are possible.  In nonclinical testing of SYNT001 in NHPs, clinical 
observations were limited to infusion reactions due to the immunogenicity of SYNT001 in 
NHPs. These reactions included transient emesis/vomitus which typically occurred within 1 hour 
of dosing at all dose groups, but only after the third weekly infusion following the development 
of ADAs. Transient histamine-type responses were noted 30 minutes post-dose in some animals 
in all dose groups, but only following the third weekly infusion as above.  These reactions were 
consistent with a histamine reaction (decreased activity, periocular swelling, erythema, facial 
flushing, eyelids partially/completely closed, and/or generalized weakness).  With the exception 
of vomitus/emesis and red skin discoloration associated with injection or blood draw sites, these 
observations spontaneously resolved within 1-hour post-dose. Subsequent pretreatment with 
intramuscular diphenhydramine prevented further histamine-type reactions.  All doses of 
SYNT001 were administered by bolus infusion over approximately 5 minutes in the NHP 
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studies.  However, all of the observed infusion reactions (including vomitus/emesis and 
histamine-type reactions) associated with ADAs are not at all predictive of what may occur in 
humans (Bugelski and Treacy, 2004; Ponce et al., 2009) and furthermore, are not considered 
relevant to predicting responses in humans [ICH S6(R1) 2011].   
Typically, infusion reactions to monoclonal antibodies observed in human studies develop within 
30 minutes to 2 hours after the initiation of drug infusion, although symptoms may be delayed 
for up to 24 hours. Most are mild in severity, although severe and even fatal reactions can occur.  
Guidelines for Grading and Management of Allergic or Infusion-Related Reactions 
Allergic and/or infusion-related reactions include hypersensitivity reactions and cytokine release 
syndromes. These reactions are experienced by patients during or within hours of the infusion of 
monoclonal antibody therapy. Symptoms can include flushing, alterations in heart rate and blood 
pressure, dyspnea, bronchospasm, back pain, fever, urticaria, edema, nausea, and all types of 
rashes. Anaphylaxis is recognized as a severe, life-threatening, generalized, or systemic reaction. 
This is a medical emergency characterized by rapidly developing life-threatening airway and/or 
breathing and/or circulation problems usually associated with skin or mucosal changes.  
Management of Grade 1 infusion reactions include interrupting the infusion or decreasing the 
rate of infusion by 50% and observing.  Symptoms may also be treated as needed with 
medications such as diphenhydramine, hydrocortisone or acetaminophen, either alone or in 
combination, depending on the subject’s signs and symptoms. If the infusion is interrupted or the 
infusion rate is decreased, it is important to note that all study drug infusions must be completed 
within 4 hours of SYNT001 administration. 
Management of Grade 2 and higher infusion reactions should include stopping the infusion of 
study drug.  See Figure 1 and Figure 2 for details on the management of Grade 2 and Grade 3 or 
higher infusion reactions. The severity of and management of allergic or infusion-related 
reactions will be graded and managed using NCI CTCAE Version 4.03 (see Table 5).   
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Figure 1:  Management of Moderate (Grade 2) Infusion Reactions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stop  
Infusion 
Assess airway, breathing, circulation, and consciousness, and recline subject 
 
Start high flow oxygen 
Insert large bore IV and start IV fluids 
Initiate vital sign assessments at least every 15 minutes 
Any problem with airway, breathing 
circulation, or consciousness? 
NO: 
Initiate medical 
review 
YES:   
Initiate treatment per the 
Severe Infusion Reaction 
Flow Chart 
Monitor for symptom resolution 
If symptoms persist, proceed with medications as needed.  For example: 
diphenhydramine 25-50 mg IV and/ or hydrocortisone 200 mg IV 
Note:  If desaturation, 
hypotension, or urticaria 
present, refer to Severe 
Infusion Reaction Flow 
Chart. 
Subject presents with any of 
the below: 
• 
Altered vision 
• 
Impending feeling 
of doom 
• 
Pain:  Back, 
abdomen, chest 
• 
Flushing 
• 
Wheezing without 
desaturation 
• 
Pyrexia 
• 
Peripheral edema 
• 
GI symptoms 
 
If ongoing symptoms, consider ongoing 
observation or hospital admission 
If symptoms and signs resolve completely either spontaneously or after administration of diphenhydramine with or without 
hydrocortisone, consider rechallenge:   
Wait at least 20 minutes following medication administration before commencing rechallenge at an infusion rate of 50% or less of 
the initial infusion rate or 
Consider pre-medicating the subject with the same medication(s) 20-30 minutes in advance of subsequent administrations of 
SYNT001 and starting infusion at 50% of the planned infusion rate for the first 30 minutes, then returning to the intended infusion 
rate in the absence of any infusion reaction. If the infusion is interrupted or the infusion rate is decreased, it is important to note 
that all study drug infusions must be completed within 4 hours of SYNT001 administration. 
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Figure 2:  Management of Severe (Grade 3 or higher) Infusion Reactions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject presents with any of the below: 
• 
Urticaria 
• 
Airway threatened by angioedema 
• 
Angioedema: Lip, mouth, facial swelling 
• 
Respiratory compromise - wheezing, dyspnea, stridor or hypoxia 
(O2 saturation < 90%) 
• 
BP < 90 mmHg SBP or >30% decrease from patient baseline 
Stop  
Infusion 
Consider (under medial direction): 
 
Epinephrine 1:1000 
• 
0.3 mg (0.3 mL) IM into lateral thigh 
Transfer to Emergency Room/ICU 
Observe until all symptoms resolved. 
Start basic life support: 
• 
High oxygen flow 
• 
On bed, head down, legs up 
• 
Large bore IV cannula, 1 L normal saline STAT 
• 
Initiate vital signs at least every 15 minutes 
Airway Threatened: 
Nebulized epinephrine 1:1000, 3–5 mL (3–5 mg) 
Bronchospasm: 
Nebulized salbutamol 5 mg 
(Wheeze or Hypoxia) 
Consider: Intubation / nebulized epinephrine 
 
Hypotension: 
Place on cardiac monitor 
(Systolic BP <100 mmHg) 
Further epinephrine 1:1000, 0.3 mg IM and  
 
IV normal saline bolus 20 mL/kg STAT as needed 
 
Have vasopressin on hand 
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Table 5: 
Grading and Management of Allergic or Infusion-Related Reactions  
Adverse 
Event 
Grade 
1 
2 
3 
4 
5 
Infusion-
Related 
Reaction 
Mild transient 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤ 24 hours 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated for 
clinical sequelae 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Allergic 
Reaction 
Transient 
flushing or 
rash, drug 
fever 
< 38.0°C. 
Intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤ 24 hours 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated for 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Anaphylaxis 
- 
- 
Symptomatic 
bronchospasm, with or 
without urticarial; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Cytokine 
release 
syndrome 
Mild 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤ 24 hours 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated for 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Life-
threatening 
consequences; 
pressor or 
ventilator 
support 
indicated 
Death 
Abstracted from NCI CTCAE Version 4.03. 
 
 
 
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9.6.2 
Potential Immune Effects 
An antibody blocking FcRn is anticipated to have several effects.  These include acceleration of 
catabolism of IgG, but not other immunoglobulin isotypes such as IgA and IgM, leading to dose-
dependent decreases in circulating IgG levels by up to an estimated 50% from the baseline levels 
after a single dose and further decreases after multiple doses up to a 70% to 80% reduction. 
Based on studies in humans, it is expected that with a single dose, the nadir of this effect will 
occur approximately 5 days after dosing.  The time course of recovery of IgG following dosing 
in the Phase 1a study suggests that a return to within 30% of baseline levels observed at 
pretreatment occurs within 4 weeks after a single dose and within 4 weeks after multiple doses as 
shown in NHPs. 
Given the normal adult range of IgG of 500 to 1600 mg/dL (Agarwal and Cunningham-Rundles, 
2007; Furst, 2009; Gonzalez-Quintela et al., 2008; Jolliff et al., 1982; Keystone et al., 2007; 
McMillan et al., 1997; van Vollenhoven et al., 2013), with a mean of 1150 mg/dL, a 50% 
decrease in the mean would be to 575 mg/dL and a 50% decrease from the low end of the normal 
range used for the inclusion criteria of 600 mg/dL would be to 300 mg/dL. An 80% decrease 
from baseline after multiple doses would result in IgG levels of 230 mg/dL and 120 mg/dL, 
respectively.  While these levels are in the range found in patients with primary humoral 
immunodeficiency (Ameratunga et al., 2013), the levels will be transient. Further, as reported for 
other therapies used for pemphigus, the temporary (ie, less than 4 months) depletion of IgG (up 
to 95% reduction of total IgG as seen with immunoadsorption) does not appear to impart an 
increased risk of infection (Eming and Hertl, 2006; Furst, 2009; Keystone et al., 2007; 
Schmaldienst et al., 2001; van Vollenhoven et al., 2013). Study subjects will be monitored 
clinically for any infection. Further, commercial IVIG can be given to reverse the low IgG levels 
in case of a bacterial infection occurring while their IgG levels are decreased. 
An antibody blocking FcRn is expected to also down modulate innate and adaptive immunity 
and the catabolism of IgG-containing immune complexes (IC). Specifically, it is expected that 
anti-FcRn will promote the clearance of IgG-containing ICs and the effects of these IC on 
stimulating innate immune cell production of inflammatory cytokines (e.g., IL-12, interferon-γ, 
and tumor necrosis factor [TNF]) and inhibit the processing and presentation of antigens 
contained within IC and thus the antigen-specific activation of CD4+ and CD8+ T-cells. 
Therefore, subjects with pre-existing conditions that are dependent upon IgG antibodies, such as 
chronic infections (e.g., HIV, HBV or HCV), will be excluded from this study, as will subjects 
with active infection in general. 
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SYNT001 administration could decrease the level of protective antibodies from prior 
vaccinations. Protective antibody levels for tetanus and varicella-zoster virus (chickenpox) are to 
be tested in accordance with Section 6.7.3.  
 
 
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10 
CONCOMITANT MEDICATION AND TREATMENT 
All treatments a subject receives within 14 days prior to enrollment through the end of the study 
will be documented.  Concomitant medication and treatment for co-existing conditions, 
including those for pemphigus, are permitted if not excluded below.  Topical antibiotics are 
permitted to treat active infections that occur on study.  Topical or systemic treatments for oral 
candidiasis are permitted.  Topical lidocaine for transient pain relief is acceptable as needed. 
Significant increases in anti-pemphigus medications will result in subjects being discontinued 
from the study.  Concomitant treatment that is medically indicated for any AEs the subject 
experiences during the study are permitted. Premedication is discouraged as prophylaxis against 
AEs or infusion reactions unless medically indicated from either past medical history, prior 
infusion reactions or AEs resulting from SYNT001 infusions.    
Use of the following treatments will not be permitted during the study unless otherwise 
specified: 
• Rituximab or other anti-CD20 antibody 
• Monoclonal antibodies other than study drug 
• Any immunosuppressive drugs apart from corticosteroids, azathioprine, mycophenolate 
mofetil, or cyclosporine. 
• Topical steroids 
• Any dietary herbal supplements 
• Any investigational drug or device 
• Any vaccinations through Day 56.  Following Day 56, subjects may be vaccinated at the 
discretion of the Investigator. 
If over a period of at least two weeks on study drug, a subject on corticosteroids shows the 
absence of new lesions and significant healing of lesions that existed at study baseline, a slow 
corticosteroid taper may be started as per the following suggested schedule  
• If on > 30 mg of prednisone per day, decrease by 10 mg every two weeks until a dose of 
30 mg per day then decrease by 5 mg every two weeks 
• If on < 30 mg of prednisone per day, decrease by 5 mg every two weeks 
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In cases in which concomitant medications are used, details to be recorded include the following: 
medication name, start date and time, stop date and time, dose, route, frequency, and reason for 
use.  The concomitant medication names are to be coded using the World Health Organization 
(WHO) Drug Dictionary (WHO-DD March 2013, Type B2 or later) and classified by anatomical 
therapeutic chemical (ATC) categories. 
 
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11 
SAFETY 
11.1 
Safety Parameters 
Clinical and laboratory AEs will be graded using the NCI CTCAE; Version 4.03 (See 
Appendix A).  
 Subjects will be monitored throughout the treatment and follow-up period for occurrence of AEs 
(acute, delayed, and/or cumulative), as well as for changes in clinical status, vital sign 
measurements, and laboratory data (including PD).  Safety parameters to be measured/assessed 
include PEs, vital sign measurements, hematology, serum chemistries, urinalysis, and ECG. 
11.2 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical trial subject associated with 
the use of a drug, whether considered drug related.  An AE can be an unfavorable and 
unintended sign (e.g., an abnormal laboratory value finding), a symptom, or a disease temporally 
associated with the use of a drug, without judgment as to causality.  An AE can arise from use of 
the drug (e.g., use in combination with another drug) and from any route of administration, 
formulation or dose, including an overdose.  An AE also includes, but is not limited to, any 
clinically significant worsening of a pre-existing condition.  Examples include: 
• Any sign, symptom, physical finding, or laboratory result that has worsened in nature, 
severity or frequency compared to baseline; 
• Reactions from an investigational drug, including those occurring because of an 
overdose, abuse of the study drug, withdrawal phenomena, sensitivity or toxicity; 
• Concurrent illness that was not present or worsens in nature, severity, or frequency 
compared to baseline;  
• Injury or accident; and/or 
• Exacerbation of a pre-existing condition. 
For data collection, all untoward events that occur after informed consent through the last study 
visit are to be recorded on eCRFs by the investigational site. 
While pregnancy alone is not considered as an AE or SAE, any pregnancy complication(s) 
should be recorded as an AE(s) or SAE(s) (if applicable).  Elective abortions without 
complications should not be regarded as AEs, unless they were therapeutic abortions (see 
below).  Hospitalization for normal delivery of a healthy newborn should not be considered an 
SAE.  If a female subject becomes pregnant during the conduct of the study, the Investigator 
must notify the Sponsor according to the procedures provided in Section 11.3.8). 
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11.3 
Evaluating Adverse Events 
The Investigator will determine the seriousness, intensity, and causality of an AE associated with 
the use of the study drug (i.e., events where there is a reasonable possibility that the event may 
have been caused by the study drug) based on the definitions that follow. 
11.3.1 
Serious Adverse Events 
(Notify Medpace Safety within 24 hours; document on eCRF) 
The SAE definition and reporting requirements are in accordance with Title 21 Part Code of 
Federal Regulations (CFR) 312.32 and the Guidance for Industry and Investigators Safety 
Reporting Requirements for Investigational New Drug (INDs) and Bioavailability 
/Bioequivalence Studies. 
SAE:  An AE is considered "serious" if, in the view of either the Investigator or sponsor, it 
results in any of the following outcomes: 
• Death:  This includes any death that occurs while the subject is “on study” through the 
last study visit.  
Note: Death is an outcome of an AE, and not an AE.  The event(s) that caused death 
(e.g., illness, accident) is the SAE.  Death due to any other cause(s) must also 
be reported as an outcome of the reportable SAE. 
• Life-threatening adverse drug event:  An AE or suspected adverse reaction is 
considered “life threatening” if, in the view of either the Investigator or sponsor, its 
occurrence places the patient or subject at immediate risk of death. It does not include an 
AE or suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death.   
• Inpatient hospitalization or prolongation of existing hospitalization: 
In the absence of an AE, the Investigator should not report hospitalization or prolongation 
of hospitalization.  This is the case in the following situations: 
o Hospitalization or prolongation of hospitalization is needed for a procedure 
required by the protocol 
o Hospitalization or prolongation of hospitalization is part of routine procedure 
followed by study center 
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o Hospitalization for survey visits or annual physicals 
o Hospitalization for observation with release within 24 hours 
In addition, a hospitalization planned before the start of the study for a pre-existing 
condition, which has not worsened, does not count as an SAE.  
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions    
• Congenital anomaly/birth defect 
• Important medical event:  An event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, it may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.   
11.3.2 
Overdose 
An overdose is defined as a significant variation from the recommended/scheduled dosage for a 
product. The dosing for this study will be conducted in a controlled clinical setting and an 
overdose is not anticipated. However, in the event of an accident, for this study, an overdose of 
SYNT001 is considered a dose that is two-fold higher than the intended dose for the subject. 
11.3.3 
Non-Serious Adverse Events  
(Document on eCRF) 
All other AEs, not fulfilling the previous definitions, are classified as non-serious. 
11.3.4 
Protocol-Related Adverse Events 
AEs that are not test drug related may nevertheless be considered by the Investigator or the 
Medical Monitor to be related to the conduct of the clinical study.  That is, the event may be 
related to the fact that a subject is participating in the study.  For example, a protocol-related AE 
may be an event that occurs during a screening period or that is related to a procedure required 
by the protocol. 
11.3.5 
Assessment of Causality 
A medically qualified Investigator must assess the relationship of any AE (including SAEs) to 
the use of the investigational product, as related or not related, based on clinical judgment and 
using all available information, and may include consideration of the following factors: 
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• Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic 
factors. 
• The temporal association between drug exposure and onset of the AE. 
• Whether the manifestations of the AE are consistent with known actions or toxicity of the 
investigational product. 
• The AE resolved or improved with decreasing the dose or stopping use of the 
investigational product (dechallenge).  Judgment should be used if multiple products are 
discontinued at the same time. 
The causal relationship between the study medication and the AE will be assessed using one of 
the following categories: 
Not Related:  Factors consistent with an assessment of Not Related include: 
• Temporal relationship is lacking (e.g., the event did not occur within a reasonable 
time frame following administration of the study medication); or 
• Other causative factors more likely explain the event (e.g., a pre-existing 
condition, other concomitant treatments). 
Related:  Factors consistent with an assessment of Related include: 
• There is a positive temporal relationship (e.g., the event occurred within a 
reasonable time frame following administration of study medication); or 
• The AE is more likely explained by the investigational product than by another 
cause (i.e., the AE shows a pattern consistent with previous knowledge of the 
investigational product or the class of the investigational product) 
11.3.6 
Recording Adverse Events 
All AEs (including SAEs) are to be accurately recorded on the Adverse Event page of the 
subject’s eCRF.  The severity of each AE will be graded using the NCI CTCAE, Version 4.03.  
The date of onset as well as the end date of the event also should be recorded or the event should 
be entered as “ongoing”.  In addition, the method used to treat the AE and the outcome of the AE 
also will be noted.  The Investigator will assess the relationship of the event to study drug.       
11.3.7 
Planned Hospitalization 
A hospitalization planned by the subject prior to the first dose of study medication is considered 
a therapeutic intervention and not the result of a new SAE and should be recorded as medical 
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history.  If the planned hospitalization or procedure is executed as planned, the record in the 
subject’s medical history is considered complete.  However, if the event/condition worsens 
during the trial, it must be reported as an AE. 
11.3.8 
Reporting Pregnancies 
If a female subject or the female partner of a male subject becomes pregnant during the course of 
the study, the Investigator must report the pregnancy to the Medpace Safety using the 
Pregnancy Reporting Form within 24 hours of becoming aware of the event.  The Investigator 
must obtain consent to collect pregnancy information (including the status of the newborn, if 
applicable). 
If some of the information required for completion of the Pregnancy Reporting Form is 
unavailable at the time of the initial report, follow-up reports will be completed and submitted 
within 24 hours of becoming aware of the new information.  Any pregnancy will be followed 
through delivery for the observation of any SAEs.  Any SAE that occurs during pregnancy must 
be recorded on the SAE report form in the EDC system (e.g., maternal serious complications, 
therapeutic or spontaneous abortion, ectopic pregnancy, stillbirth, neonatal death, congenital 
abnormality, birth defect) and reported within 24 hours in accordance with the procedure for 
reporting SAEs (See Section 11.3.9).   
11.3.9 
Serious Adverse Event Reporting 
11.3.9.1 
Governing Regulatory Requirements 
Compliance with this request for prompt reporting is essential in that the sponsor is responsible 
for informing the US Food and Drug Administration (FDA) and other regulatory authorities as 
well as all other participating Investigators of the event.  
Under FDA ruling (US Code of Federal Regulations, Title 21 CFR Part 312.32) and the ICH 
Guidelines for Clinical Safety Data Management Definitions and Standards for Expedited 
Reporting, the sponsor is required to submit written documentation, in the form of a safety 
report, detailing: 
• Any event associated with the use of the drug, that is both serious and unexpected, or  
• Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.  
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Written submission must be made by the sponsor to the FDA as soon as possible and in no event 
later than 15 calendar days after the sponsor’s initial notification of the event.  The sponsor shall 
also inform all Investigators. 
11.3.9.2 
Time Frame for Reporting 
Any death, SAE or pregnancy experienced by the subject after informed consent through the last 
study visit, regardless of relationship to study drug, , must be promptly reported (within 24 hours 
of the Investigator becoming aware of the event) by telephone or electronic transmission to the 
sponsor (or designee). 
 
 
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Contact information for SAE reporting: 
 
 
 
Medpace Clinical Safety  
Medpace SAE hotline:  
Telephone: 
 dial  or 
 dial   
Facsimile: 
 or 
  
e-mail:
 
 
Additionally, the Investigator will be able to contact the Medical Monitor: 
Medical Safety Contact 
  
Phone (EU): 
 extension 
  
Mobile phone: 
 
Email: 
 
 
11.3.9.3 
Information to be Provided by the Investigator 
SAEs must be recorded on the SAE form in the EDC system.  This requirement includes all 
SAEs that occur after informed consent through the last study visit. 
The minimum information required for SAE reporting includes identity of Investigator, site 
number, subject number, an event description, SAE term(s), onset date, the reason why the event 
is serious (i.e., the seriousness criteria) and the Investigator’s assessment of the relationship of 
the event to study treatment.  Additional SAE information including medications or other 
therapeutic measures used to treat the event, action taken with the study treatment due to the 
event, and the outcome/resolution of the event will be recorded.  Paper forms for reporting SAEs 
will be provided to the study sites as back-up in case the EDC system is not accessible. 
In all cases, the Investigator should continue to monitor the clinical situation and report all 
material facts relating to the progression or outcome of the SAE.  Furthermore, the Investigator 
may be required to provide supplementary information as requested by Syntimmune or designee. 
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When reporting an SAE, the following additional points should be noted: 
• When the diagnosis of an SAE is known or suspected, the Investigator should report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms.  Signs 
and symptoms may then be described in the event description.  For example, dyspnea 
should not be used as an SAE term if the diagnosis, which caused the dyspnea, is known 
to be malignant pleural effusion.   
• Death should not be reported as an SAE, but as an outcome of a specific SAE, unless the 
event preceding the death is unknown.  In the exceptional case where the events leading 
to death are unknown, then death may be used as an event term.  If an autopsy was 
performed, the autopsy report should be provided.  
• While most hospitalizations necessitate reporting of an SAE, some hospitalizations do not 
require SAE reporting, as follows:  
• Elective or previously scheduled surgery, e.g., a previously scheduled ventral 
hernia repair 
• Procedures for pre-existing conditions that have not worsened after initiation of 
treatment 
• Pre-specified study hospitalizations for observation 
• Events that result in hospital stays of less than 24 hours and that do not require 
admission, e.g., an emergency room visit for hematuria that results in a diagnosis 
of cystitis and discharge to home on oral antibiotics 
• SAEs must, however, be reported for any surgical or procedural complication resulting in 
prolongation of the hospitalization. 
11.3.10 
Regulatory Reporting 
Syntimmune (or designee) will process and evaluate all SAEs as soon as the reports are received.  
For each SAE received, Syntimmune will decide as to whether the criteria for expedited 
reporting have been met. 
Syntimmune (or designee) will submit SAEs that meet the criteria for expedited reporting to the 
regulatory authorities in accordance with local regulations governing safety reporting.  Reporting 
of SAEs by the Investigator to his or her IRB will be done in accordance with the standard 
operating procedures and policies of the IRB.  Adequate documentation must be maintained 
showing that the IRB was properly notified. 
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11.3.11 
Follow-up Information on a Serious Adverse Event (SAE) 
Appropriate diagnostic tests should be performed and therapeutic measures, if indicated, should 
be instituted.  Appropriate consultation and follow-up evaluations should be carried out until the 
event has returned to baseline or is otherwise explained by the Investigator.   
If all required information on the SAE form is not available at the time of the initial report, 
follow-up information will be completed in the EDC system. 
11.4 
Other Safety Considerations 
11.4.1 
Laboratory Data 
All laboratory data obtained during the study should be reviewed.  Any abnormal value that leads 
to a change in subject management (e.g., requirement for additional medication or monitoring) or 
is of clinical significance by the Investigator should be reported as an AE and/or SAE as 
appropriate, unless this value is consistent with values obtained before entry into the study.   
11.4.2 
Medication Errors 
Any medication error that results in an AE, even if it does not meet the definition of serious, 
requires reporting within 24 hours to the safety Medical Monitor. 
11.4.3 
Follow-Up of Adverse Events 
Any SAE or AE assessed as related to study drug must be followed until either resolution of the 
event or determination by the Investigator that the event has become stable or irreversible.    The 
Investigator will follow all drug related AEs until there is a return to the subject’s baseline 
condition, or until a clinically satisfactory resolution has been achieved.  The appropriate follow-
up visits must be scheduled and the specific tests repeated or performed as necessary. The status 
of all AEs will be documented as of the last study visit. 
Where a diagnosis is possible, it is preferable to report this diagnosis rather than a series of terms 
(signs/symptoms) relating to the diagnosis. 
11.5 
Safety Monitoring for Dose Escalation 
Following dosing in each cohort, all safety/tolerability data (e.g., PEs, vital signs [including 
pulse oximetry], clinical safety laboratory tests, ECGs and AE/SAE assessments) as well as any 
available and relevant PD data collected through Day 42 will be reviewed by the DEC.  A 
decision to escalate to the next cohort will be made.  The recommendation may be to continue to 
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the next scheduled dose level, discontinue the study or to modify dosing to a dose less than the 
current dose or higher than the current dose but lower than the next planned dose.   
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12 
STATISTICAL CONSIDERATIONS  
All descriptive and inferential statistical analyses will be performed using the most recently 
released and available Statistical Analysis System (SAS) software, unless otherwise noted.  
Missing data will not be imputed unless otherwise stated.  All clinical data captured will be 
provided in data listings. A Statistical Analysis Plan (SAP) and a Pharmacokinetic Analysis Plan 
(PAP) will be finalized prior to database lock. 
12.1 
General Design  
All data for enrolled subjects will be presented in data listings by subject number.    
Continuous data will be described using descriptive statistics: number of observations (n), mean, 
standard deviation (SD), median, minimum, and maximum.  Frequencies and percentages will be 
used for summarizing discrete (categorical) data.  When categorical data are presented, the 
percent will be suppressed when the count is zero to draw attention to the non-zero counts.  The 
denominator for all percentages, unless otherwise specified, will be the number of subjects in the 
specified analysis population. 
12.2 
Sample Size Justification  
Formal sample size calculations were not performed. The number of subjects was chosen based 
on feasibility and was considered sufficient to meet the study objectives. 
12.3 
Statistical Considerations  
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP). The SAP may modify the plans outlined in 
the protocol; any deviations from the previously described statistical plan will be described and 
justified in an SAP amendment. Additional statistical analyses other than those described in this 
section may be performed if deemed appropriate and will be described in the SAP. Methods of 
handling of missing data for different endpoints will be further specified in the SAP. In general, 
where individual data points are missing because of insufficient samples, dropouts, or other 
reasons, the data will be analyzed based on reduced denominators unless specified otherwise in 
the SAP.  
Results will be summarized by cohorts.  
12.3.1 
Study Populations  
Three populations will be employed in the analysis of study data: 
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• The intent-to-treat (ITT) population will consist of all subjects who have received at least 
one dose of study drug.  All safety analyses will be performed on the ITT population. 
• The PK population will consist of all subjects who receive at least one dose of study drug 
and have sufficient post-dose blood samples to obtain PK parameters. 
• The PD population will consist of all subjects who receive at least one dose of study drug 
and have post-dose PD data available.  
Primary safety analyses will be performed on the ITT population.  Demographics, subject 
disposition, and screening and baseline characteristics will be summarized for the ITT, PK, and 
PD populations, where appropriate. 
12.3.2 
Subject Accountability, Demographics, and Baseline Characteristics  
Subject disposition, demographic information and baseline characteristics will be presented.  
Any discrepancy between treatment to be given and treatment received will be accounted for in 
these displays.  
12.3.3 
Concomitant Medications  
Concomitant medications will be coded using WHO Drug Dictionary (WHO-DD March 2013, 
Type B2 or later) and the data will be summarized and presented in tables and listings.  
12.4 
Planned PK Analysis 
Study drug concentrations will be used to calculate the following PK parameters: t1/2, Cmax, Tmax, 
and AUC0-24 and AUC0-∞.  PK parameters will be determined using noncompartmental 
method(s).  Descriptive statistics of PK parameters for SYNT001 will include mean, SD, 
coefficient of variation (CV), median, minimum, and maximum. Tmax will be reported as median 
and range. All descriptive statistics will be performed on untransformed PK parameters and after 
log10 transformation of PK parameters. 
For calculation of mean concentrations and generation of mean concentration-time profiles, all 
below the limit of quantification (BLQ) values will be set to zero except when an individual 
BLQ falls between 2 quantifiable values, in which case it will be omitted. 
If there are values above the BLQ, but too sparse to allow full analysis, descriptive statistics will 
be performed on available values. 
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12.5 
Safety Data  
Safety observations and measurements include AEs, safety laboratory tests, vital sign 
measurements, PEs, and ECGs.  
Treatment-emergent AEs will be summarized using the Medical Dictionary for Regulatory 
Activities (MedDRA®; Version 19 or higher) System Organ Class (SOC) and preferred term, 
classified from verbatim terms.  The incidence and percentage of subjects with at least 1 
occurrence of a preferred term will be included, using the most severe grade.  The number of 
events per preferred term will also be summarized.  Causality (relationship to study treatment) 
will be summarized separately.   
AEs, SAEs, and AEs leading to withdrawal, dose modification, or treatment discontinuation will 
be listed by subject, cohort, and overall per SOC and preferred terms. Duration of AEs will be 
determined and included in listings, along with action taken and outcome.   
Laboratory results will be summarized by cohort.  Incidence of laboratory abnormalities will be 
summarized.  The worst on-study grade after the first dose of study drug will be summarized.  
Results for variables that are not coded will be presented in the listings as below, within, and 
above the normal limits of the local laboratory. 
Vital sign measurements and change from baseline will be summarized at each scheduled time 
point by cohort using descriptive statistics.      
Arithmetic mean of parameters from triplicate ECG will be calculated first for each participant at 
each planned time point. Then summary statistics of ECG test parameters (mean of triplicate) 
and change from baseline to each post-dose time point will be calculated. Shift tables for ECG 
test result category change (normal, abnormal, clinically abnormal) from pre-dose to each post-
dose time point showing number and percentage of subjects with movement between categories 
will be presented by treatment group. Frequency and percentage of subjects experiencing 
potential QTc prolongation (QTcF > 450) will be summarized at each time point by cohort. 
12.6 
Pharmacodynamic/Activity Data  
PD results will be summarized by cohort. 
12.7 
Immunogenicity Data  
Immunogenicity results will be summarized by cohort. 
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12.8 
Interim Analysis 
No interim analysis is planned.  Safety results will be examined for making dose-escalation 
decisions; no statistical analyses are planned for aiding these dose-escalation decisions. 
 
 
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13 
DATA QUALITY ASSURANCE 
All data will be entered in a validated electronic data capture system using single data entry. 
Standard procedures (including following data review guidelines, manual clinical review based 
on subject profiles, computerized validation to produce queries, and maintenance of an audit file 
which includes all database modifications) will be followed to ensure accurate data. Clinical 
personnel will review all data listings for outliers, data inconsistencies, and spelling errors. 
During the study, a study site monitor will make site visits to review protocol compliance, 
compare electronic case report forms (eCRFs) against individual subject medical records, assess 
drug accountability, and ensure that the study is being conducted using pertinent regulatory 
requirements.  eCRF entries will be verified with source documentation. The review of medical 
records will be performed in a manner to ensure that subject confidentiality is maintained.  
Checking the eCRFs for completeness, clarity and cross checking with source documents is 
required to monitor the progress of the study. Direct access to source data is also required for 
inspections and audits, and will be carried out giving due consideration to data protection and 
medical confidentiality. Each Investigator will have assured Syntimmune of full access to 
complete source data for study participants and associated necessary support at all times. 
In addition to routine monitoring procedures, audits of clinical research activities in accordance 
with standard operating procedures (SOPs) may be performed to evaluate compliance with the 
principles of GCP.  A regulatory authority may also wish to conduct an inspection (during the 
study or even after its completion).  If a regulatory authority requests an inspection, the 
Investigator must immediately inform Syntimmune that this request has been made. Study 
conduct may be assessed during the study by a Clinical Quality Assurance representative(s) to 
ensure that the study is conducted in compliance with the protocol.  This designee, as well as the 
site monitor, will be permitted to inspect the study documents (study protocol, eCRFs, 
investigational product accountability, original study-relevant medical records).  All subject data 
will be treated confidentially.  During the clinical study, access will be available to Syntimmune 
or their designee (e.g., contract research organization [CRO]) to view the eCRFs after 
completion of the individual sections of the study. Furthermore, the study protocol, each step of 
the data-recording procedure and the handling of the data as well as the study report may be 
subject to independent review by a Quality Assurance representative.  Clinical site and study 
audits will be conducted as necessary to assure the validity of the study data. 
 
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14 
STUDY ADMINISTRATION 
14.1 
Study Administrative Structure 
The study administration structure is provided in Table 6. 
Table 6 :  
Study Administrative Structure 
Sponsor Contact and Medical Director: 
 
 
 
Phone: 
 
Email: 
 
Medical Monitor: 
 
Medpace 
Wallace House 
17-21 Maxwell Place 
Stirling, Scotland FK81JU 
Phone: 
 extension 
 
Email: 
  
Study Monitoring: 
Medpace 
5375 Medpace Way 
Cincinnati, OH 45227 
Phone (Main): 
 
Email: 
 
 
14.2 
Ethical Conduct of the Study 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
ICH E6 Tripartite Guideline (January 1997), and in general, be conducted in a manner consistent 
with the principles described in the Declaration of Helsinki. The Investigator will ensure that the 
conduct of the study complies with the basic principles of GCP as outlined in the current version 
of 21 CFR, subpart D, Part 312, “Responsibilities of Sponsors and Investigators”, Part 50, 
“Protection of Human Subjects”, and Part 56, “Institutional Review Boards”. 
14.3 
Informed Consent (ICF) 
A properly executed, written informed consent document, in compliance with 21 CFR, Part 50 
and the ICH guidelines, will be obtained from each subject before the subject is entered into the 
study and before any study screening procedure is performed that involves risk.  Attention will 
be directed to the basic elements required for incorporation into the informed consent under US 
Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a]) and (21 CFR 
50.25[b]), as necessary. 
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Sample ICFs will be supplied to each site. Syntimmune or its designee must review any proposed 
deviations from the sample ICF. The final IRB-approved document must be provided to 
Syntimmune for regulatory purposes. 
It is the responsibility of the Investigator, or a person designated by the Investigator, to obtain 
written informed consent from each subject (or the subject’s legally authorized representative) 
participating in this study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study. In the case where the subject is unable to read, an impartial 
witness should be present during the entire informed consent discussion. After the subject has 
orally consented to participation in the trial, the witness’ signature on the form will attest that the 
information in the consent form was accurately explained and understood. A copy of the ICF 
must be provided to the subject or to the subject’s legally authorized representative. If applicable, 
it will be provided in a certified translation of the local language. 
The eCRF for this study contains a section for documenting informed subject consent, and this 
must be completed appropriately. Signed ICFs must remain in each subject’s study file and must 
be available for verification by site monitors at any time. If new safety information results in 
significant changes in the risk/benefit assessment, the consent form should be reviewed and 
updated as necessary. All subjects (including those already being treated) should be informed of 
the new information, should be given a copy of the revised form, and should give their consent to 
continue in the study. 
14.4 
Institutional Review Board 
This study is being conducted under US IND 128152. This protocol (and any modifications) and 
appropriate consent procedures must be reviewed and approved by an IRB. This board must 
operate in accordance with the current federal or local regulations. The Investigator will send a 
letter or certificate of IRB approval to Syntimmune (or designee) before subject enrollment and 
whenever subsequent modifications to the protocol are made. 
14.5 
Dose Escalation Committee 
The DEC will be responsible for confirming the safety of the investigative product prior to 
dose escalation, as well as the dose level for each successive cohort.  In addition, over the course 
of the study, the DEC will review any drug-related SAEs to determine if modifications to the 
study or other measures are necessary to ensure the safety of the subjects.  The DEC will consist 
of the Medical Monitor, an Independent Clinical Expert and a Syntimmune Medical Officer.  To 
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assist in the safety assessments, the DEC may request that Investigators, other experts, or 
members within their organizations review the data and participate in the discussions. 
14.6 
Future Use of Subject Samples 
Not all the tissue and blood components obtained during this study may be required for the tests 
that are part of the clinical trial. Available samples may be used for additional research. This 
research will help to understand disease subtypes, drug response and AE, and possibly identify 
new drug targets or biomarkers that predict subject response to treatment. The use of the samples 
for internal research will be done using the guidelines defined by the FDA guidance for In Vitro 
Diagnostic Device Studies Using Leftover Human Specimens that are Not Individual Identifiable 
(issued 25 April 2006) and the European Medicines Agency (EMA) Reflection Paper on 
Pharmacogenetic Samples, Testing and Data Handling (Doc. Ref. 
EMEA/CHMP/PGxWP/201914/2006; 15 November 2007).  If a subject requests destruction of 
their tissue and blood samples and the samples have not yet been de-identified, Syntimmune will 
destroy the samples as described in this FDA guidance. Syntimmune will notify the Investigator 
in writing that the samples have been destroyed. 
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15 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between a 
Syntimmune representative and the Investigator. Protocol modifications will be prepared, 
reviewed, and approved by Syntimmune representatives. 
All protocol modifications must be submitted to the IRB for information and approval in 
accordance with local requirements, and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects, or when the change involves only logistical or administrative 
aspects of the trial (e.g., change in site monitor, change of telephone number). 
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16 
CONDITIONS FOR TERMINATING THE STUDY 
Syntimmune has the right to terminate the study at any time. In terminating the study, 
Syntimmune and the Investigator will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 
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17 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
17.1 
Investigator’s Files and Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into 2 separate categories as follows: (1) Investigator’s study file and (2) subject 
clinical source documents. 
The Investigator’s study file will contain the protocol and protocol amendments, eCRFs, query 
forms, IRB and governmental approval with correspondence, sample informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
Subject clinical source documents (usually predefined by the project to record key efficacy and 
safety parameters independent of the eCRFs) may include subject hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, 
electroencephalogram, X-ray, pathology and special assessment reports, signed ICFs, consultant 
letters, and subject screening and enrollment logs. The Investigator must keep these 2 categories 
of documents on file for at least 2 years following the marketing application approval date for the 
study treatment and for the indication being investigated or for 2 years after the development 
program is discontinued and the FDA notified. After that period, the documents may be 
destroyed subject to local regulations with prior written permission from Syntimmune. If the 
Investigator wants to assign the study records to another party or move them to another location, 
Syntimmune must be notified in advance. 
If the Investigator cannot guarantee the archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and Syntimmune to 
store these in a sealed container outside of the study site so that they can be returned sealed to the 
Investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside of the study site. 
17.2 
Source Documents and Background Data 
Investigators must maintain adequate and accurate source documents on which the eCRFs for 
each subject are based. They are separate and distinct from the eCRFs. 
These records include detailed notes on the following: 
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• Medical history 
• Date and time of informed consent with Health Insurance Portability and Accountability 
Act (HIPAA) authorization either contained in the ICF or presented to the subject 
candidate as a standalone document 
• Description of the complete consenting process 
• The basic identifying information that linked the subject’s medical record with the 
eCRFs 
• The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject 
• The medical condition of the subject during their involvement in the study 
• All AEs 
• The subject’s exposure to the study medication 
• The subject’s exposure to any concomitant therapy 
• All relevant observations and data on the condition of the subject throughout the trial 
• Justification for all entries in the subject’s eCRF 
A subject log of all potentially eligible subjects considered, but not consented, for obvious 
deviations from the entry criteria, will be kept at each site. The log will contain subjects’ initials, 
diagnosis, eligibility, or, if not eligible, reason for not consenting.  All consented subjects will be 
logged, regardless of whether they ultimately enroll.  
Upon request, the Investigator will supply Syntimmune with any required background data from 
the study documentation or clinic records. This is particularly important when eCRFs are 
illegible or when errors in data transcription are suspected. In case of special problems or 
governmental queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected. 
17.3 
Audits and Inspections 
The Investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from Syntimmune (or designee), or to health 
authority inspectors after appropriate notification. The verification of the eCRF data must be by 
direct inspection of source documents. 
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17.4 
Electronic Case Report Forms 
Clinical trial data for this study will be captured on eCRF designed for computer processing and 
analysis.  This computerized system will be validated and compliant with 21 CFR Part 11. 
Corrections to data will be made using 21 CFR Part 11, Electronic Records; Electronic 
Signatures. If corrections are made after review and sign-off by the Investigator, he/she must be 
aware of the changes and provide written acknowledgement. There will also be an electronic 
audit trail. Corrections on paper CRFs must be initialed and dated by the person making the 
change. The Investigator agrees to provide all information requested on the eCRF in an accurate 
manner using instructions provided.  The Investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported to Syntimmune in the eCRF and in all required 
reports. 
An eCRF is required to be submitted for every subject who receives any amount of study drug.  
This includes submission of retrievable data on subjects who withdraw before completion of the 
study.  Prior to submission, eCRFs must be reviewed for completeness and accuracy, and signed 
and dated where either indicated, by the Principal Investigator or authorized delegate from the 
study staff.  If a subject stops treatment or terminates from the study, the dates and reasons must 
be noted on the eCRF. 
 
 
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18 
MONITORING THE STUDY 
It is understood that the responsible Syntimmune site monitor (or designee) will contact and visit 
the Investigator regularly and will be allowed on request to inspect the various records of the trial 
(eCRFs and other pertinent data) if subject confidentiality is maintained in accordance with local 
requirements. 
It will be the site monitor’s responsibility to inspect the eCRFs at regular intervals throughout the 
study, to verify the adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The site monitor should have access to laboratory test reports 
and other subject records needed to verify the entries on the eCRF. The Investigator (or 
designee) must agree to cooperate with the site monitor to ensure that any problems detected 
during these monitoring visits are resolved. 
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19 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS 
The Investigator must ensure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On eCRFs or other documents submitted to 
Syntimmune, subjects should be identified by an identification code and not by their names. The 
Investigator should keep a subject enrollment log showing codes, names, and addresses. The 
Investigator should maintain documents not for submission to Syntimmune (e.g., subjects’ 
written consent forms) in strict confidence. 
Authorized regulatory officials and Syntimmune personnel (or their representatives) will be 
allowed full access to inspect and copy the records.  All study drugs, subject bodily fluids and 
tissue, and/or other materials collected shall be used solely in accordance with this protocol, 
unless otherwise agreed to in writing by Syntimmune. 
The Principal Investigator also agrees that all information received from Syntimmune, including 
but not limited to the IB, this protocol, eCRFs, the INDs, and any other study information remain 
the sole and exclusive property of Syntimmune during the conduct of the study and thereafter.  
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from the 
sponsor. The Principal Investigator further agrees to take all reasonable precautions to prevent 
the disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain. 
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20 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. The Investigator 
agrees that any manuscript or abstract they author may be published only after receiving written 
permission from Syntimmune. 
If Syntimmune coordinates a publication or presentation of study results from all study sites, the 
participation of Investigator or other representatives of study site as a named author shall be 
determined in accordance with Syntimmune policy and generally accepted standards for 
authorship. 
 
 
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21 
REFERENCES 
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values. Ann Allergy Asthma Immunol. 2007;99(3):281-283. Epub 2007/10/04. 
Ameratunga R, Woon ST, Gillis D, Koopmans W, Steele R. New diagnostic criteria for common 
variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or 
subcutaneous immunoglobulin. Clin Exp Immunol. 2013;174(2):203-211. Epub 2013/07/19. 
Bugelski PJ, Treacy G. Predictive power of preclinical studies in animals for the immunogenicity 
of recombinant therapeutic proteins in humans. Curr Opin Mol Ther. 2004;6(1):10-16. Epub 
2004/03/12. 
Eming R, Hertl M. Immunoadsorption in pemphigus. Autoimmunity. 2006;39(7):609-616. Epub 
2006/11/15. 
Furst DE. Serum immunoglobulins and risk of infection: how low can you go? Semin Arthritis 
Rheum. 2009;39(1):18-29. Epub 2008/07/16. 
Gonzalez-Quintela A, Alende R, Gude F, et al. Serum levels of immunoglobulins (IgG, IgA, 
IgM) in a general adult population and their relationship with alcohol consumption, smoking and 
common metabolic abnormalities. Clin Exp Immunol. 2008;151(1):42-50. Epub 2007/11/17. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) (2011). S6(R1) Preclinical Safety Evaluation of 
Biotechnology-Derived Pharmaceuticals. Accessed 03 June 2016. 
http://www.ich.org/products/guidelines/safety/safety-single/article/preclinical-safety-evaluation-
of-biotechnology-derived-pharmaceuticals.html.     
Jolliff CR, Cost KM, Stivrins PC, et al. Reference intervals for serum IgG, IgA, IgM, C3, and C4 
as determined by rate nephelometry. Clin Chem. 1982;28(1):126-128. Epub 1982/01/01. 
Keystone E, Fleischmann R, Emery P, et al. Safety and efficacy of additional courses of 
rituximab in patients with active rheumatoid arthritis: an open-label extension analysis. Arthritis 
Rheum. 2007;56(12):3896-3908. Epub 2007/12/01. 
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McMillan SA, Douglas JP, Archbold GP, McCrum EE, Evans AE. Effect of low to moderate 
levels of smoking and alcohol consumption on serum immunoglobulin concentrations. J Clin 
Pathol. 1997;50(10):819-822. Epub 1998/02/14. 
Nixon AE, Chen J, Sexton DJ, et al. Fully human monoclonal antibody inhibitors of the neonatal 
fc receptor reduce circulating IgG in non-human primates. Front Immunol. 2015;6:176. Epub 
2015/05/09. 
Ponce R, Abad L, Amaravadi L, et al. Immunogenicity of biologically-derived therapeutics: 
assessment and interpretation of nonclinical safety studies. Regul Toxicol Pharmacol. 
2009;54(2):164-182. Epub 2009/04/07. 
Roopenian DC, Christianson GJ, Sproule TJ, et al. The MHC class I-like IgG receptor controls 
perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol. 
2003;170(7):3528-3533. Epub 2003/03/21. 
Schmaldienst S, Mullner M, Goldammer A, et al. Intravenous immunoglobulin application 
following immunoadsorption: benefit or risk in patients with autoimmune diseases? 
Rheumatology. 2001;40(5):513-521. Epub 2001/05/24. 
van Vollenhoven RF, Emery P, Bingham CO, 3rd, et al. Long-term safety of rituximab in 
rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on 
adverse events of interest in RA patients. Ann Rheum Dis. 2013;72(9):1496-1502. Epub 
2012/11/09. 
 
 
 
 
 
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Appendix A: NCI CTCAE, Version 4.03 
 
 
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1. CTCAE 4.03
Common Terminology Criteria for
Adverse Events (CTCAE)
Version 4.0
Published: May 28, 2009 (v4.03: June 14, 2010)
U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Cancer Institute
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Alexion Confidential
Page 503 of 979


CONTENTS
SOC
Page
Blood and lymphatic system disorders
3
Cardiac disorders
4
Congenital, familial and genetic disorders
7
Ear and labyrinth disorders
8
Endocrine disorders
9
Eye disorders
10
Gastrointestinal disorders
12
General disorders and administration site conditions
22
Hepatobiliary disorders
24
Immune system disorders
26
Infections and infestations
27
Injury, poisoning and procedural complications
34
Investigations
41
Metabolism and nutrition disorders
44
Musculoskeletal and connective tissue disorders
46
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
50
Nervous system disorders
51
Pregnancy, puerperium and perinatal conditions
56
Psychiatric disorders
57
Renal and urinary disorders
59
Reproductive system and breast disorders
61
Respiratory, thoracic and mediastinal disorders
65
Skin and subcutaneous tissue disorders
71
Social circumstances
75
Surgical and medical procedures
76
Vascular disorders
77
Alexion Confidential
Page 504 of 979


CTCAE 4.03 - June 14, 2010 : Blood and lymphatic system disorders
3
2. Blood and lymphatic system disorders
Blood and lymphatic system disorders
Grade
Adverse Event
1
2
3
4
5
Anemia
Hemoglobin (Hgb) <LLN - 10.0
g/dL; <LLN - 6.2 mmol/L; <LLN -
100 g/L
Hgb <10.0 - 8.0 g/dL; <6.2 - 4.9
mmol/L;  <100 - 80g/L
Hgb <8.0 g/dL; <4.9 mmol/L;
<80 g/L; transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an reduction in the amount of hemoglobin in 100 ml of blood. Signs and symptoms of anemia may include pallor of the skin and mucous
membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.
Bone marrow hypocellular
Mildly hypocellular or <=25%
reduction from normal cellularity
for age
Moderately hypocellular or >25 -
<50% reduction from normal
cellularity for age
Severely hypocellular or >50 -
<=75% reduction cellularity from
normal for age
Aplastic persistent for longer
than 2 weeks
Death
Definition: A disorder characterized by the inability of the bone marrow to produce hematopoietic elements.
Disseminated intravascular
coagulation
 -
Laboratory findings with no
bleeding
Laboratory findings and
bleeding
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by systemic pathological activation of blood clotting mechanisms which results in clot formation throughout the body. There is an increase in the
risk of hemorrhage as the body is depleted of platelets and coagulation factors.
Febrile neutropenia
 -
 -
ANC <1000/mm3 with a single
temperature of >38.3 degrees C
(101 degrees F) or a sustained
temperature of >=38 degrees C
(100.4 degrees F) for more than
one hour.
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an ANC <1000/mm3 and a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >=38 degrees C (100.4
degrees F) for more than one hour.
Hemolysis
Laboratory evidence of
hemolysis only (e.g., direct
antiglobulin test; DAT; Coombs';
schistocytes; decreased
haptoglobin)
Evidence of hemolysis and >=2
gm decrease in hemoglobin.
Transfusion or medical
intervention indicated (e.g.,
steroids)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate widespread erythrocyte cell membrane destruction.
Hemolytic uremic syndrome
Evidence of RBC destruction
(schistocytosis) without clinical
consequences
 -
Laboratory findings with clinical
consequences (e.g., renal
insufficiency, petechiae)
Life-threatening consequences,
(e.g., CNS hemorrhage or
thrombosis/embolism or renal
failure)
Death
Definition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, hemolytic anemia, and severe thrombocytopenia.
Leukocytosis
 -
 -
>100,000/mm3
Clinical manifestations of
leucostasis; urgent intervention
indicated
Death
Definition: A disorder characterized by laboratory test results that indicate an increased number of white blood cells in the blood.
Lymph node pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in a lymph node.
Spleen disorder
Incidental findings (e.g., Howell-
Jolly bodies); mild degree of
thrombocytosis and
leukocytosis
Prophylactic antibiotics
indicated
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder of the spleen.
Thrombotic thrombocytopenic
purpura
Evidence of RBC destruction
(schistocytosis) without clinical
consequences
 -
Laboratory findings with clinical
consequences (e.g., renal
insufficiency, petechiae)
Life-threatening consequences,
(e.g., CNS hemorrhage or
thrombosis/embolism or renal
failure)
Death
Definition: A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic purpura, fever, renal abnormalities and neurological abnormalities such
as seizures, hemiplegia, and visual disturbances. It is an acute or subacute condition.
Blood and lymphatic system
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 505 of 979


CTCAE 4.03 - June 14, 2010 : Cardiac disorders
4
3. Cardiac disorders
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Acute coronary syndrome
 -
Symptomatic, progressive
angina; cardiac enzymes
normal; hemodynamically stable
Symptomatic, unstable angina
and/or acute myocardial
infarction, cardiac enzymes
abnormal, hemodynamically
stable
Symptomatic, unstable angina
and/or acute myocardial
infarction, cardiac enzymes
abnormal, hemodynamically
unstable
Death
Definition: A disorder characterized by signs and symptoms related to acute ischemia of the myocardium secondary to coronary artery disease. The clinical presentation covers a
spectrum of heart diseases from unstable angina to myocardial infarction.
Aortic valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in aortic valve function or structure.
Asystole
Periods of asystole; non-urgent
medical management indicated
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without cardiac electrical activity. Typically, this is accompanied by cessation of the pumping function of the heart.
Atrial fibrillation
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker), or ablation
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without discernible P waves and an irregular ventricular response due to multiple reentry circuits. The rhythm disturbance
originates above the ventricles.
Atrial flutter
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker), or ablation
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with organized rhythmic atrial contractions with a rate of 200-300 beats per minute. The rhythm disturbance originates in the
atria.
Atrioventricular block complete
 -
Non-urgent intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with complete failure of atrial electrical impulse conduction through the AV node to the ventricles.
Atrioventricular block first
degree
Asymptomatic, intervention not
indicated
Non-urgent intervention
indicated
 -
 -
 -
Definition: A disorder characterized by a dysrhythmia with a delay in the time required for the conduction of an electrical impulse through the atrioventricular (AV) node beyond 0.2
seconds; prolongation of the PR interval greater than 200 milliseconds.
Cardiac arrest
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by cessation of the pumping function of the heart.
Chest pain - cardiac
Mild pain
Moderate pain; limiting
instrumental ADL
Pain at rest; limiting self care
ADL
 -
 -
Definition: A disorder characterized by substernal discomfort due to insufficient myocardial oxygenation.
Conduction disorder
Mild symptoms; intervention not
indicated
Moderate symptoms
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by pathological irregularities in the cardiac conduction system.
Constrictive pericarditis
 -
 -
Symptomatic heart failure or
other cardiac symptoms,
responsive to intervention
Refractory heart failure or other
poorly controlled cardiac
symptoms
Death
Definition: A disorder characterized by a thickened and fibrotic pericardial sac; these fibrotic changes impede normal myocardial function by restricting myocardial muscle action.
Heart failure
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe with symptoms at rest or
with minimal activity or exertion;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., continuous IV therapy or
mechanical hemodynamic
support)
Death
Definition: A disorder characterized by the inability of the heart to pump blood at an adequate volume to meet tissue metabolic requirements, or, the ability to do so only at an elevation
in the filling pressure.
Alexion Confidential
Page 506 of 979


CTCAE 4.03 - June 14, 2010 : Cardiac disorders
5
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Left ventricular systolic
dysfunction
 -
 -
Symptomatic due to drop in
ejection fraction responsive to
intervention
Refractory or poorly controlled
heart failure due to drop in
ejection fraction; intervention
such as ventricular assist
device, intravenous vasopressor
support, or heart transplant
indicated
Death
Definition: A disorder characterized by failure of the left ventricle to produce adequate output despite an increase in distending pressure and in end-diastolic volume. Clinical
manifestations mayinclude dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema.
Mitral valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in mitral valve function or structure.
Mobitz (type) II atrioventricular
block
Asymptomatic, intervention not
indicated
Symptomatic; medical
intervention indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with relatively constant PR interval prior to the block of an atrial impulse. This is the result of intermittent failure of atrial electrical
impulse conduction through the atrioventricular (AV) node to the ventricles.
Mobitz type I
Asymptomatic, intervention not
indicated
Symptomatic; medical
intervention indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a progressively lengthening PR interval prior to the blocking of an atrial impulse. This is the result of intermittent failure of
atrial electrical impulse conduction through the atrioventricular (AV) node to the ventricles.
Myocardial infarction
 -
Asymptomatic and cardiac
enzymes minimally abnormal
and no evidence of ischemic
ECG changes
Severe symptoms; cardiac
enzymes abnormal;
hemodynamically stable; ECG
changes consistent with
infarction
Life-threatening consequences;
hemodynamically unstable
Death
Definition: A disorder characterized by gross necrosis of the myocardium; this is due to an interruption of blood supply to the area.
Myocarditis
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe with symptoms at rest or
with minimal activity or exertion;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., continuous IV therapy or
mechanical hemodynamic
support)
Death
Definition: A disorder characterized by inflammation of the muscle tissue of the heart.
Palpitations
Mild symptoms; intervention not
indicated
Intervention indicated
 -
 -
 -
Definition: A disorder characterized by an unpleasant sensation of irregular and/or forceful beating of the heart.
Paroxysmal atrial tachycardia
Asymptomatic, intervention not
indicated
Symptomatic; medical
management indicated
IV medication indicated
Life-threatening consequences;
incompletely controlled
medically; cardioversion
indicated
Death
Definition: A disorder characterized by a dysrhythmia with abrupt onset and sudden termination of atrial contractions with a rate of 150-250 beats per minute. The rhythm disturbance
originates in the atria.
Pericardial effusion
 -
Asymptomatic effusion size
small to moderate
Effusion with physiologic
consequences
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by fluid collection within the pericardial sac, usually due to inflammation.
Pericardial tamponade
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in intrapericardial pressure due to the collection of blood or fluid in the pericardium.
Pericarditis
Asymptomatic, ECG or physical
findings (e.g., rub) consistent
with pericarditis
Symptomatic pericarditis (e.g.,
chest pain)
Pericarditis with physiologic
consequences (e.g., pericardial
constriction)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by irritation to the layers of the pericardium (the protective sac around the heart).
Alexion Confidential
Page 507 of 979


CTCAE 4.03 - June 14, 2010 : Cardiac disorders
6
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Pulmonary valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in pulmonary valve function or structure.
Restrictive cardiomyopathy
 -
 -
Symptomatic heart failure or
other cardiac symptoms,
responsive to intervention
Refractory heart failure or other
poorly controlled cardiac
symptoms
Death
Definition: A disorder characterized by an inability of the ventricles to fill with blood because the myocardium (heart muscle) stiffens and loses its flexibility.
Right ventricular dysfunction
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe symptoms, associated
with hypoxemia, right heart
failure; oxygen indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., ventricular assist device);
heart transplant indicated
Death
Definition: A disorder characterized by impairment of right ventricular function associated with low ejection fraction and a decrease in motility of the right ventricular wall.
Sick sinus syndrome
Asymptomatic, intervention not
indicated
Non-urgent intervention
indicated
Severe, medically significant;
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with alternating periods of bradycardia and atrial tachycardia accompanied by syncope, fatigue and dizziness.
Sinus bradycardia
Asymptomatic, intervention not
indicated
Symptomatic, medical
intervention indicated
Severe, medically significant,
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate less than 60 beats per minute that originates in the sinus node.
Sinus tachycardia
Asymptomatic, intervention not
indicated
Symptomatic; non-urgent
medical intervention indicated
Urgent medical intervention
indicated
 -
 -
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates in the sinus node.
Supraventricular tachycardia
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates above the ventricles.
Tricuspid valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis;
symptoms controlled with
medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in tricuspid valve function or structure.
Ventricular arrhythmia
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia that originates in the ventricles.
Ventricular fibrillation
 -
 -
 -
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without discernible QRS complexes due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the
ventricles.
Ventricular tachycardia
 -
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates distal to the bundle of His.
Wolff-Parkinson-White
syndrome
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically or
controlled with procedure
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the presence of an accessory conductive pathway between the atria and the ventricles that causes premature ventricular activation.
Cardiac disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 508 of 979


CTCAE 4.03 - June 14, 2010 : Congenital, familial and genetic disorders
7
4. Congenital, familial and genetic disorders
Congenital, familial and genetic disorders
Grade
Adverse Event
1
2
3
4
5
Congenital, familial and genetic
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 509 of 979


CTCAE 4.03 - June 14, 2010 : Ear and labyrinth disorders
8
5. Ear and labyrinth disorders
Ear and labyrinth disorders
Grade
Adverse Event
1
2
3
4
5
Ear pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the ear.
External ear inflammation
External otitis with erythema or
dry desquamation
External otitis with moist
desquamation, edema,
enhanced cerumen or
discharge; tympanic membrane
perforation; tympanostomy
External otitis with mastoiditis;
stenosis or osteomyelitis;
necrosis of soft tissue or bone
Urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation, swelling and redness to the outer ear and ear canal.
External ear pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the external ear region.
Hearing impaired
Adults enrolled on a Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift of 15 - 25 dB averaged at 2
contiguous test frequencies in at
least one ear.
Adults not enrolled in Monitoring
Program: subjective change in
hearing in the absence of
documented hearing loss.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift >20 dB at 8 kHz in at least
one ear.
Adults enrolled in Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz  audiogram):  Threshold
shift of >25 dB averaged at 2
contiguous test frequencies in at
least one ear.
Adults not enrolled in Monitoring
Program: hearing loss but
hearing aid or intervention not
indicated; limiting instrumental
ADL.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift >20 dB at 4 kHz and above
in at least one ear.
Adults enrolled in Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift of >25 dB averaged at 3
contiguous test frequencies in at
least one ear; therapeutic
intervention indicated.
Adults not enrolled in Monitoring
Program:  hearing loss with
hearing aid or intervention
indicated; limiting self care ADL.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): hearing loss
sufficient to indicate therapeutic
intervention, including hearing
aids; threshold shift >20 dB at 3
kHz and above in at least one
ear; additional speech-language
related services indicated.
Adults: Decrease in hearing to
profound bilateral loss (absolute
threshold >80 dB HL  at 2 kHz
and above); non-servicable
hearing.
Pediatric: Audiologic indication
for cochlear implant and
additional speech-language
related services indicated.
 -
Definition: A disorder characterized by partial or complete loss of the ability to detect or understand sounds resulting from damage to ear structures.
Middle ear inflammation
Serous otitis
Serous otitis, medical
intervention indicated
Mastoiditis; necrosis of canal
soft tissue or bone
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation (physiologic response to irritation), swelling and redness to the middle ear.
Tinnitus
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by noise in the ears, such as ringing, buzzing, roaring or clicking.
Vertigo
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective
vertigo).
Vestibular disorder
 -
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by dizziness, imbalance, nausea, and vision problems.
Ear and labyrinth disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 510 of 979


CTCAE 4.03 - June 14, 2010 : Endocrine disorders
9
6. Endocrine disorders
Endocrine disorders
Grade
Adverse Event
1
2
3
4
5
Adrenal insufficiency
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms;
hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder that occurs when the adrenal cortex does not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. It may be due to a disorder
of the adrenal cortex as in Addison's disease or primary adrenal insufficiency.
Cushingoid
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms, medical
intervention or hospitalization
indicated
 -
 -
Definition: A disorder characterized by signs and symptoms that resemble Cushing's disease or syndrome: buffalo hump obesity, striations, adiposity, hypertension, diabetes, and
osteoporosis, usually due to exogenous corticosteroids.
Delayed puberty
 -
No breast development by age
13 yrs for females; testes
volume of <3 cc or no Tanner
Stage 2 development by age
14.5 yrs for males
No breast development by age
14 yrs for females; no increase
in testes volume or no Tanner
Stage 2 by age 16 yrs for
males; hormone replacement
indicated
 -
 -
Definition: A disorder characterized by unusually late sexual maturity.
Growth accelerated
 -
>= +2 SD (standard deviation)
above mid parental height or
target height
 -
 -
 -
Definition: A disorder characterized by greater growth than expected for age.
Hyperparathyroidism
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by an increase in production of parathyroid hormone by the parathyroid glands. This results in hypercalcemia (abnormally high levels of calcium in
the blood).
Hyperthyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thyroid
suppression therapy indicated;
limiting instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by excessive levels of thyroid hormone in the body. Common causes include an overactive thyroid gland or thyroid hormone overdose.
Hypoparathyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; medical
intervention or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a decrease in production of parathyroid hormone by the parathyroid glands.
Hypothyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thyroid
replacement indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a decrease in production of thyroid hormone by the thyroid gland.
Precocious puberty
Physical signs of puberty with
no biochemical markers for
females <8 years and males <9
years
Physical signs and biochemical
markers of puberty for females
<8 years and males <9 years
 -
 -
 -
Definition: A disorder characterized by unusually early development of secondary sexual features; the onset of sexual maturation begins usually before age 8 for girls and before age
9 for boys.
Virilization
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by inappropriate masculinization occurring in a female or prepubertal male.
Endocrine disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Eye disorders
10
7. Eye disorders
Eye disorders
Grade
Adverse Event
1
2
3
4
5
Blurred vision
Intervention not indicated
Symptomatic; limiting
instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by visual perception of unclear or fuzzy images.
Cataract
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; moderate
decrease in visual acuity
(20/40 or better)
Symptomatic with marked
decrease in visual acuity
(worse than 20/40 but better
than 20/200); operative
intervention indicated (e.g.,
cataract surgery)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by partial or complete opacity of the crystalline lens of one or both eyes. This results in a decrease in visual acuity and eventual blindness if
untreated.
Conjunctivitis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; topical
intervention indicated (e.g.,
antibiotics); limiting
instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by inflammation, swelling and redness to the conjunctiva of the eye.
Corneal ulcer
 -
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Limiting self care ADL;
declining vision (worse than
20/40 but better than 20/200)
Perforation or blindness
(20/200 or worse) in the
affected eye
 -
Definition: A disorder characterized by an area of epithelial tissue loss on the surface of the cornea. It is associated with inflammatory cells in the cornea and anterior chamber.
Dry eye
Asymptomatic; clinical or
diagnostic observations only;
mild symptoms relieved by
lubricants
Symptomatic; multiple
agents indicated; limiting
instrumental ADL
Decrease in visual acuity
(<20/40); limiting self care
ADL
 -
 -
Definition: A disorder characterized by dryness of the cornea and conjunctiva.
Extraocular muscle paresis
Asymptomatic; clinical or
diagnostic observations only
Symptomatic; limiting
instrumental ADL
Limiting self care ADL;
disabling
 -
 -
Definition: A disorder characterized by incomplete paralysis of an extraocular muscle.
Eye pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the eye.
Eyelid function disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; nonoperative
intervention indicated;
limiting instrumental ADL
Limiting self care ADL;
operative intervention
indicated
 -
 -
Definition: A disorder characterized by impaired eyelid function.
Flashing lights
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by a sudden or brief burst of light.
Floaters
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by an individual seeing spots before their eyes. The spots are shadows of opaque cell fragments in the vitreous humor or lens.
Glaucoma
Elevated intraocular
pressure (EIOP) with single
topical agent for intervention;
no visual field deficit
EIOP causing early visual
field deficits; multiple topical
or oral agents indicated;
limiting instrumental ADL
EIOP causing marked visual
field deficits (e.g., involving
both superior and inferior
visual fields); operative
intervention indicated;
limiting self care ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by an increase in pressure in the eyeball due to obstruction of the aqueous humor outflow.
Keratitis
 -
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Decline in vision (worse than
20/40 but better than
20/200); limiting self care
ADL
Perforation or blindness
(20/200 or worse) in the
affected eye
 -
Definition: A disorder characterized by inflammation to the cornea of the eye.
Night blindness
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by an inability to see clearly in dim light.
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CTCAE 4.03 - June 14, 2010 : Eye disorders
11
Eye disorders
Grade
Adverse Event
1
2
3
4
5
Optic nerve disorder
Asymptomatic; clinical or
diagnostic observations only
Limiting vision of the affected
eye (20/40 or better)
Limiting vision in the affected
eye (worse than 20/40 but
better than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by involvement of the optic nerve (second cranial nerve).
Papilledema
Asymptomatic; no visual field
defects
Symptomatic decline in
vision; visual field defect
present sparing the central
20 degrees
Marked visual field defect
(worse than 20/40 but better
than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by swelling around the optic disc.
Photophobia
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by fear and avoidance of light.
Retinal detachment
Asymptomatic
Exudative and visual acuity
20/40 or better
Rhegmatogenous or
exudative detachment;
operative intervention
indicated; decline in vision
(worse than 20/40 but better
than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by the separation of the inner retina layers from the underlying pigment epithelium.
Retinal tear
 -
Laser therapy or
pneumopexy indicated
Vitroretinal surgical repair
indicated
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by a small laceration of the retina, this occurs when the vitreous separates from the retina. Symptoms include flashes and floaters.
Retinal vascular disorder
 -
Topical medication indicated
Intravitreal medication;
operative intervention
indicated
 -
 -
Definition: A disorder characterized by pathological retinal blood vessels that adversely affects vision.
Retinopathy
Asymptomatic; clinical or
diagnostic observations only
Symptomatic with moderate
decrease in visual acuity
(20/40 or better); limiting
instrumental ADL
Symptomatic with marked
decrease in visual acuity
(worse than 20/40);
disabling; limiting self care
ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder involving the retina.
Scleral disorder
Asymptomatic; clinical or
diagnostic observations only
Symptomatic, limiting
instrumental ADL; moderate
decrease in visual acuity
(20/40 or better)
Symptomatic, limiting self
care ADL; marked decrease
in visual acuity (worse than
20/40)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by involvement of the sclera of the eye.
Uveitis
Asymptomatic; clinical or
diagnostic observations only
Anterior uveitis; medical
intervention indicated
Posterior or pan-uveitis
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by inflammation to the uvea of the eye.
Vitreous hemorrhage
Asymptomatic or mild
symptoms; clinical or
diagnostic observations only
Symptomatic; limiting
instrumental ADL
Limiting self care ADL;
vitrectomy indicated
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by blood extravasation into the vitreous humor.
Watering eyes
Intervention not indicated
Intervention indicated
Operative intervention
indicated
 -
 -
Definition: A disorder of excessive tearing in the eyes; it can be caused by overproduction of tears or impaired drainage of the tear duct.
Eye disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or
diagnostic observations only;
intervention not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental
ADL
Severe or medically
significant but not
immediately sight-
threatening; hospitalization
or prolongation of existing
hospitalization indicated;
disabling;  limiting self care
ADL
Sight-threatening
consequences; urgent
intervention indicated;
blindness (20/200 or worse)
in the affected eye
 -
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders
12
8. Gastrointestinal disorders
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Abdominal distension
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe discomfort; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling of the abdomen.
Abdominal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the abdominal region.
Anal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the opening in the anal canal to the perianal skin.
Anal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the anal region.
Anal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the anus.
Anal necrosis
 -
 -
TPN or hospitalization indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the anal region.
Anal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the anal region.
Anal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Symptomatic and severely
altered GI function; non-
emergent operative intervention
indicated; TPN or hospitalization
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the anal canal.
Anal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the anal canal.
Ascites
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; invasive
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by accumulation of serous or hemorrhagic fluid in the peritoneal cavity.
Bloating
No change in bowel function or
oral intake
Symptomatic, decreased oral
intake; change in bowel function
 -
 -
 -
Definition: A disorder characterized by subject-reported feeling of uncomfortable fullness of the abdomen.
Cecal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the cecum.
Cheilitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; intervention indicated
 -
 -
Definition: A disorder characterized by inflammation of the lip.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders
13
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Colitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Abdominal pain; mucus or blood
in stool
Severe abdominal pain; change
in bowel habits; medical
intervention indicated;
peritoneal signs
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the colon.
Colonic fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
bowel rest, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the large intestine and another organ or anatomic site.
Colonic hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the colon.
Colonic obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Hospitalization indicated;
elective operative intervention
indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the colon.
Colonic perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the colonic wall.
Colonic stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the colon.
Colonic ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the colon.
Constipation
Occasional or intermittent
symptoms; occasional use of
stool softeners, laxatives,
dietary modification, or enema
Persistent symptoms with
regular use of laxatives or
enemas; limiting instrumental
ADL
Obstipation with manual
evacuation indicated; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by irregular and infrequent or difficult evacuation of the bowels.
Dental caries
One or more dental caries, not
involving the root
Dental caries involving the root
Dental caries resulting in pulpitis
or periapical abscess or
resulting in tooth loss
 -
 -
Definition: A disorder characterized by the decay of a tooth, in which it becomes softened, discolored and/or porous.
Diarrhea
Increase of <4 stools per day
over baseline; mild increase in
ostomy output compared to
baseline
Increase of 4 - 6 stools per day
over baseline; moderate
increase in ostomy output
compared to baseline
Increase of >=7 stools per day
over baseline; incontinence;
hospitalization indicated; severe
increase in ostomy output
compared to baseline; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by frequent and watery bowel movements.
Dry mouth
Symptomatic (e.g., dry or thick
saliva) without significant dietary
alteration; unstimulated saliva
flow >0.2 ml/min
Moderate symptoms; oral intake
alterations (e.g., copious water,
other lubricants, diet limited to
purees and/or soft, moist foods);
unstimulated saliva 0.1 to 0.2
ml/min
Inability to adequately aliment
orally; tube feeding or TPN
indicated; unstimulated saliva
<0.1 ml/min
 -
 -
Definition: A disorder characterized by reduced salivary flow in the oral cavity.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders
14
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Duodenal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the duodenum and another organ or anatomic site.
Duodenal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the duodenum.
Duodenal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Hospitalization or elective
operative intervention indicated;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of stomach contents through the duodenum.
Duodenal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the duodenal wall.
Duodenal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the duodenum.
Duodenal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the duodenal wall.
Dyspepsia
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; surgical
intervention indicated
 -
 -
Definition: A disorder characterized by an uncomfortable, often painful feeling in the stomach, resulting from impaired digestion. Symptoms include burning stomach, bloating,
heartburn, nausea and vomiting.
Dysphagia
Symptomatic, able to eat
regular diet
Symptomatic and altered
eating/swallowing
Severely altered
eating/swallowing; tube feeding
or TPN or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by difficulty in swallowing.
Enterocolitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Abdominal pain; mucus or blood
in stool
Severe or persistent abdominal
pain; fever; ileus; peritoneal
signs
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the small and large intestines.
Enterovesical fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; noninvasive
intervention indicated
Severe, medically significant;
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the urinary bladder and the intestine.
Esophageal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the esophagus and another organ or anatomic site.
Esophageal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the esophagus.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders
15
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Esophageal necrosis
 -
 -
Inability to aliment adequately
by GI tract; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the esophageal wall.
Esophageal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents in the esophagus.
Esophageal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the esophageal region.
Esophageal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the wall of the esophagus.
Esophageal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the esophagus.
Esophageal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the esophageal wall.
Esophageal varices
hemorrhage
 -
Self-limited; intervention not
indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from esophageal varices.
Esophagitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered
eating/swallowing;  oral
supplements indicated
Severely altered
eating/swallowing; tube feeding,
TPN or hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the esophageal wall.
Fecal incontinence
Occasional use of pads required Daily use of pads required
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by inability to control the escape of stool from the rectum.
Flatulence
Mild symptoms; intervention not
indicated
Moderate; persistent;
psychosocial sequelae
 -
 -
 -
Definition: A disorder characterized by a state of excessive gas in the alimentary canal.
Gastric fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
bowel rest; tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the stomach and another organ or anatomic site.
Gastric hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the gastric wall.
Gastric necrosis
 -
 -
Inability to aliment adequately
by GI tract; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the gastric wall.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders
16
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Gastric perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the stomach wall.
Gastric stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the stomach.
Gastric ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; medical intervention
indicated; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the stomach.
Gastritis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; medical intervention
indicated
Severely altered eating or
gastric function; TPN or
hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the stomach.
Gastroesophageal reflux
disease
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; surgical
intervention indicated
 -
 -
Definition: A disorder characterized by reflux of the gastric and/or duodenal contents into the distal esophagus. It is chronic in nature and usually caused by incompetence of the lower
esophageal sphincter, and may result in injury to the esophageal mucosal. Symptoms include heartburn and acid indigestion.
Gastrointestinal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between any part of the gastrointestinal system and another organ or anatomic site.
Gastrointestinal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gastrointestinal region.
Gastroparesis
Mild nausea, early satiety and
bloating, able to maintain caloric
intake on regular diet
Moderate symptoms; able to
maintain nutrition with dietary
and lifestyle modifications; may
need pharmacologic
intervention
Weight loss; refractory to
medical intervention; unable to
maintain nutrition orally
 -
 -
Definition: A disorder characterized by an incomplete paralysis of the muscles of the stomach wall resulting in delayed emptying of the gastric contents into the small intestine.
Gingival pain
Mild pain
Moderate pain interfering with
oral intake
Severe pain; inability to aliment
orally
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gingival region.
Hemorrhoidal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the hemorrhoids.
Hemorrhoids
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; banding or
medical intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by the presence of dilated veins in the rectum and surrounding area.
Ileal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the ileum and another organ or anatomic site.
Ileal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the ileal wall.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders
17
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Ileal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the ileum.
Ileal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the ileal wall.
Ileal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the ileum.
Ileal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the ileum.
Ileus
 -
Symptomatic; altered GI
function; bowel rest indicated
Severely altered GI function;
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by failure of the ileum to transport intestinal contents.
Intra-abdominal hemorrhage
 -
Medical intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding in the abdominal cavity.
Jejunal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the jejunum and another organ or anatomic site.
Jejunal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the jejunal wall.
Jejunal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the jejunum.
Jejunal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the jejunal wall.
Jejunal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the jejunum.
Jejunal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the jejunum.
Lip pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort of the lip.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders
18
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Lower gastrointestinal
hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the lower gastrointestinal tract (small intestine, large intestine, and anus).
Malabsorption
 -
Altered diet; oral intervention
indicated
Inability to aliment adequately;
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inadequate absorption of nutrients in the small intestine. Symptoms include abdominal marked discomfort, bloating and diarrhea.
Mucositis oral
Asymptomatic or mild
symptoms; intervention not
indicated
Moderate pain; not interfering
with oral intake; modified diet
indicated
Severe pain; interfering with oral
intake
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the oral mucosal.
Nausea
Loss of appetite without
alteration in eating habits
Oral intake decreased without
significant weight loss,
dehydration or malnutrition
Inadequate oral caloric or fluid
intake; tube feeding, TPN, or
hospitalization indicated
 -
 -
Definition: A disorder characterized by a queasy sensation and/or the urge to vomit.
Obstruction gastric
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents in the stomach.
Oral cavity fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the oral cavity and another organ or anatomic site.
Oral dysesthesia
Mild discomfort; not interfering
with oral intake
Moderate pain; interfering with
oral intake
Disabling pain; tube feeding or
TPN indicated
 -
 -
Definition: A disorder characterized by a burning or tingling sensation on the lips, tongue or entire mouth.
Oral hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the mouth.
Oral pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the mouth, tongue or lips.
Pancreatic duct stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the pancreatic duct.
Pancreatic fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the pancreas and another organ or anatomic site.
Pancreatic hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the pancreas.
Pancreatic necrosis
 -
 -
Tube feeding or TPN indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the pancreas.
Pancreatitis
 -
Enzyme elevation or radiologic
findings only
Severe pain; vomiting; medical
intervention indicated (e.g.,
analgesia, nutritional support)
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders
19
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by inflammation of the pancreas.
Periodontal disease
Gingival recession or gingivitis;
limited bleeding on probing; mild
local bone loss
Moderate gingival recession or
gingivitis; multiple sites of
bleeding on probing; moderate
bone loss
Spontaneous bleeding; severe
bone loss with or without tooth
loss; osteonecrosis of maxilla or
mandible
 -
 -
Definition: A disorder in the gingival tissue around the teeth.
Peritoneal necrosis
 -
 -
Tube feeding or TPN  indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the peritoneum.
Proctitis
Rectal discomfort, intervention
not indicated
Symptoms (e.g., rectal
discomfort, passing blood or
mucus); medical intervention
indicated; limiting instrumental
ADL
Severe symptoms; fecal
urgency or stool incontinence;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the rectum.
Rectal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the rectum and another organ or anatomic site.
Rectal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the rectal wall and discharged from the anus.
Rectal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the rectum.
Rectal necrosis
 -
 -
Tube feeding or TPN indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the rectal wall.
Rectal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the rectum.
Rectal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the rectal region.
Rectal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the rectal wall.
Rectal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the rectum.
Rectal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function (e.g. altered dietary
habits, vomiting, diarrhea)
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the rectum.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders
20
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Retroperitoneal hemorrhage
 -
Self-limited; intervention
indicated
Transfusion, medical, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the retroperitoneal area.
Salivary duct inflammation
Slightly thickened saliva; slightly
altered taste (e.g., metallic)
Thick, ropy, sticky saliva;
markedly altered taste;
alteration in diet indicated;
secretion-induced symptoms;
limiting instrumental ADL
Acute salivary gland necrosis;
severe secretion-induced
symptoms (e.g., thick saliva/oral
secretions or gagging);  tube
feeding or TPN indicated;
limiting self care ADL; disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the salivary duct.
Salivary gland fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; tube feeding indicated
Severely altered GI function;
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between a salivary gland and another organ or anatomic site.
Small intestinal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe pain; interfering with oral
intake; tube feeding, TPN or
hospitalization indicated; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the small intestine.
Small intestinal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents.
Small intestinal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the small intestine wall.
Small intestinal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Symptomatic and severely
altered GI function; tube
feeding, TPN or hospitalization
indicated; non-emergent
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the small intestine.
Small intestine ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the small intestine.
Stomach pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the stomach.
Tooth development disorder
Asymptomatic; hypoplasia of
tooth or enamel
Impairment correctable with oral
surgery
Maldevelopment with
impairment not surgically
correctable; disabling
 -
 -
Definition: A disorder characterized by a pathological process of the teeth occurring during tooth development.
Tooth discoloration
Surface stains
 -
 -
 -
 -
Definition: A disorder characterized by a change in tooth hue or tint.
Toothache
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the tooth.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders
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Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Typhlitis
 -
 -
Symptomatic (e.g., abdominal
pain, fever, change in bowel
habits with ileus); peritoneal
signs
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the cecum.
Upper gastrointestinal
hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the upper gastrointestinal tract (oral cavity, pharynx, esophagus, and stomach).
Vomiting
1 - 2 episodes (separated by 5
minutes) in 24 hrs
3 - 5 episodes (separated by 5
minutes) in 24 hrs
>=6 episodes (separated by 5
minutes) in 24 hrs; tube feeding,
TPN or hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
Gastrointestinal disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : General disorders and administration site conditions
22
9. General disorders and administration site conditions
General disorders and administration site conditions
Grade
Adverse Event
1
2
3
4
5
Chills
Mild sensation of cold;
shivering; chattering of teeth
Moderate tremor of the entire
body; narcotics indicated
Severe or prolonged, not
responsive to narcotics
 -
 -
Definition: A disorder characterized by a sensation of cold that often marks a physiologic response to sweating after a fever.
Death neonatal
 -
 -
 -
 -
Death
Definition: A disorder characterized by cessation of life occurring during the first 28 days of life.
Death NOS
 -
 -
 -
 -
Death
Definition: A cessation of life that cannot be attributed to a CTCAE term associated with Grade 5.
Edema face
Localized facial edema
Moderate localized facial
edema; limiting instrumental
ADL
Severe swelling; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in facial tissues.
Edema limbs
5 - 10% inter-limb discrepancy
in volume or circumference at
point of greatest visible
difference; swelling or
obscuration of anatomic
architecture on close inspection
>10 - 30% inter-limb
discrepancy in volume or
circumference at point of
greatest visible difference;
readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour; limiting
instrumental ADL
>30% inter-limb discrepancy in
volume; gross deviation from
normal anatomic contour;
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the upper or lower extremities.
Edema trunk
Swelling or obscuration of
anatomic architecture on close
inspection
Readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour; limiting
instrumental ADL
Gross deviation from normal
anatomic contour; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the trunk area.
Facial pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the face.
Fatigue
Fatigue relieved by rest
Fatigue not relieved by rest;
limiting instrumental ADL
Fatigue not relieved by rest,
limiting self care ADL
 -
 -
Definition: A disorder characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities.
Fever
38.0 - 39.0 degrees C  (100.4 -
102.2 degrees F)
>39.0 - 40.0 degrees C (102.3 -
104.0 degrees F)
>40.0 degrees C (>104.0
degrees F) for <=24 hrs
>40.0 degrees C (>104.0
degrees F) for >24 hrs
Death
Definition: A disorder characterized by elevation of the body's temperature above the upper limit of normal.
Flu like symptoms
Mild flu-like symptoms present
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a group of symptoms similar to those observed in patients with the flu. It includes fever, chills, body aches, malaise, loss of appetite and dry
cough.
Gait disturbance
Mild change in gait (e.g., wide-
based, limping or hobbling)
Moderate change in gait (e.g.,
wide-based, limping or
hobbling); assistive device
indicated; limiting instrumental
ADL
Disabling; limiting self care ADL
 -
 -
Definition: A disorder characterized by walking difficulties.
Hypothermia
 -
35 - >32 degrees C;  95 - >89.6
degrees F
32 - >28 degrees C;  89.6 -
>82.4 degrees F
<=28 degrees C; 82.4 degrees
F; life-threatening
consequences (e.g., coma,
hypotension, pulmonary edema,
acidemia, ventricular fibrillation)
Death
Definition: A disorder characterized by an abnormally low body temperature. Treatment is required when the body temperature is 35C (95F) or below.
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CTCAE 4.03 - June 14, 2010 : General disorders and administration site conditions
23
General disorders and administration site conditions
Grade
Adverse Event
1
2
3
4
5
Infusion related reaction
Mild transient reaction; infusion
interruption not indicated;
intervention not indicated
Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.,
antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic
medications indicated for <=24
hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by adverse reaction to the infusion of pharmacological or biological substances.
Infusion site extravasation
 -
Erythema with associated
symptoms (e.g., edema, pain,
induration, phlebitis)
Ulceration or necrosis; severe
tissue damage; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by leakage of a pharmacologic or a biologic substance from the infusion site into the surrounding tissue. Signs and symptoms include induration,
erythema, swelling, burning sensation and marked discomfort at the infusion site.
Injection site reaction
Tenderness with or without
associated symptoms (e.g.,
warmth, erythema, itching)
Pain; lipodystrophy; edema;
phlebitis
Ulceration or necrosis; severe
tissue damage; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an intense adverse reaction (usually immunologic) developing at the site of an injection.
Irritability
Mild; easily consolable
Moderate; limiting instrumental
ADL; increased attention
indicated
Severe abnormal or excessive
response; limiting self care ADL;
inconsolable
 -
 -
Definition: A disorder characterized by an abnormal responsiveness to stimuli or physiological arousal; may be in response to pain, fright, a drug, an emotional situation or a medical
condition.
Localized edema
Localized to dependent areas,
no disability or functional
impairment
Moderate localized edema and
intervention indicated; limiting
instrumental ADL
Severe localized edema and
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation at a specific anatomic site.
Malaise
Uneasiness or lack of well being Uneasiness or lack of well
being; limiting instrumental ADL
 -
 -
 -
Definition: A disorder characterized by a feeling of general discomfort or uneasiness, an out-of-sorts feeling.
Multi-organ failure
 -
 -
Shock with azotemia and acid-
base disturbances; significant
coagulation abnormalities
Life-threatening consequences
(e.g., vasopressor dependent
and oliguric or anuric or
ischemic colitis or lactic
acidosis)
Death
Definition: A disorder characterized by progressive deterioration of the lungs, liver, kidney and clotting mechanisms.
Neck edema
Asymptomatic localized neck
edema
Moderate neck edema; slight
obliteration of anatomic
landmarks; limiting instrumental
ADL
Generalized neck edema (e.g.,
difficulty in turning neck);
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to an accumulation of excessive fluid in the neck.
Non-cardiac chest pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by discomfort in the chest unrelated to a heart disorder.
Pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by the sensation of marked discomfort, distress or agony.
Sudden death NOS
 -
 -
 -
 -
Death
Definition: An unexpected cessation of life that cannot be attributed to a CTCAE term associated with Grade 5.
General disorders and
administration site conditions -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Hepatobiliary disorders
24
10. Hepatobiliary disorders
Hepatobiliary disorders
Grade
Adverse Event
1
2
3
4
5
Bile duct stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; IV fluids indicated <24
hrs
Severely altered GI function;
radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the bile duct.
Biliary fistula
 -
Symptomatic and intervention
not indicated
Severely altered GI function;
TPN indicated; endoscopic
intervention indicated; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the bile ducts and another organ or anatomic site.
Cholecystitis
 -
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation involving the gallbladder. It may be associated with the presence of gallstones.
Gallbladder fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Symptomatic or severely altered
GI function; TPN indicated;
radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the gallbladder and another organ or anatomic site.
Gallbladder necrosis
 -
 -
 -
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the gallbladder.
Gallbladder obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; IV fluids indicated  <24
hrs
Symptomatic and severely
altered GI function; tube
feeding, TPN or hospitalization
indicated; non-emergent
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents of the gallbladder.
Gallbladder pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gallbladder region.
Gallbladder perforation
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the gallbladder wall.
Hepatic failure
 -
 -
Asterixis; mild encephalopathy;
limiting self care ADL
Moderate to severe
encephalopathy; coma; life-
threatening consequences
Death
Definition: A disorder characterized by the inability of the liver to metabolize chemicals in the body. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic
dehydrogenase, and alkaline phosphatase.
Hepatic hemorrhage
Mild; intervention not indicated
Symptomatic; medical
intervention indicated
Transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the liver.
Hepatic necrosis
 -
 -
 -
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the hepatic parenchyma.
Hepatic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the liver region.
Perforation bile duct
 -
 -
Radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the wall of the extrahepatic or intrahepatic bile duct.
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CTCAE 4.03 - June 14, 2010 : Hepatobiliary disorders
25
Hepatobiliary disorders
Grade
Adverse Event
1
2
3
4
5
Portal hypertension
 -
Decreased portal vein flow
Reversal/retrograde portal vein
flow; associated with varices
and/or ascites
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in blood pressure in the portal venous system.
Portal vein thrombosis
 -
Intervention not indicated
Medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the formation of a thrombus (blood clot) in the portal vein.
Hepatobiliary disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Immune system disorders
26
11. Immune system disorders
Immune system disorders
Grade
Adverse Event
1
2
3
4
5
Allergic reaction
Transient flushing or rash, drug
fever <38 degrees C (<100.4
degrees F); intervention not
indicated
Intervention or infusion
interruption indicated; responds
promptly to symptomatic
treatment (e.g., antihistamines,
NSAIDS, narcotics);
prophylactic medications
indicated for <=24 hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae (e.g., renal
impairment, pulmonary
infiltrates)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
 -
 -
Symptomatic bronchospasm,
with or without urticaria;
parenteral intervention
indicated; allergy-related
edema/angioedema;
hypotension
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivity
immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death.
Autoimmune disorder
Asymptomatic; serologic or
other evidence of autoimmune
reaction, with normal organ
function;  intervention not
indicated
Evidence of autoimmune
reaction involving a non-
essential organ or function (e.g.,
hypothyroidism)
Autoimmune reactions involving
major organ (e.g., colitis,
anemia, myocarditis, kidney)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder resulting from loss of function or tissue destruction of an organ or multiple organs, arising from humoral or cellular immune responses of the individual to his own
tissue constituents.
Cytokine release syndrome
Mild reaction; infusion
interruption not indicated;
intervention not indicated
Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.,
antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic
medications indicated for <=24
hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae (e.g., renal
impairment, pulmonary
infiltrates)
Life-threatening consequences;
pressor or ventilatory support
indicated
Death
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused by the release of cytokines from the cells.
Serum sickness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate arthralgia; fever, rash,
urticaria, antihistamines
indicated
Severe arthralgia or arthritis;
extensive rash; steroids or IV
fluids indicated
Life-threatening consequences;
pressor or ventilatory support
indicated
Death
Definition: A disorder characterized by a delayed-type hypersensitivity reaction to foreign proteins derived from an animal serum. It occurs approximately six to twenty-one days
following the administration of the foreign antigen. Symptoms include fever, arthralgias, myalgias, skin eruptions, lymphadenopathy, chest marked discomfort and dyspnea.
Immune system disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations
27
12. Infections and infestations
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Abdominal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the abdominal cavity.
Anorectal infection
Localized; local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the anal area and the rectum.
Appendicitis
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent.
Appendicitis perforated
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent with gangrenous changes resulting in the rupture of the
appendiceal wall. The appendiceal wall rupture causes the release of inflammatory and bacterial contents from the appendiceal lumen into the abdominal cavity.
Arteritis infective
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving an artery.
Biliary tract infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the biliary tract.
Bladder infection
 -
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bladder.
Bone infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bones.
Breast infection
 -
Local infection with moderate
symptoms; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral)
Severe infection; axillary
adenitis;  IV antibacterial,
antifungal, or antiviral
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the breast.
Bronchial infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bronchi.
Catheter related infection
 -
Localized; local intervention
indicated; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process that arises secondary to catheter use.
Cecal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations
28
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the cecum.
Cervicitis infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the uterine cervix.
Conjunctivitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the conjunctiva. Clinical manifestations include pink or red color in the eyes.
Corneal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the cornea.
Cranial nerve infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a cranial nerve.
Device related infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the use of a medical device.
Duodenal infection
 -
Moderate symptoms; medical
intervention indicated (e.g., oral
antibiotics)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the duodenum.
Encephalitis infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
severe changes in mental
status; self-limited seizure
activity; focal neurologic
abnormalities
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the brain tissue.
Encephalomyelitis infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the brain and spinal cord tissues.
Endocarditis infective
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the endocardial layer of the heart.
Endophthalmitis
 -
Local intervention indicated
Systemic intervention or
hospitalization indicated
Blindness (20/200 or worse)
 -
Definition: A disorder characterized by an infectious process involving the internal structures of the eye.
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CTCAE 4.03 - June 14, 2010 : Infections and infestations
29
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Enterocolitis infectious
 -
Passage of >3 unformed stools
per 24 hrs or duration of illness
>48 hrs; moderate abdominal
pain
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated;
profuse watery diarrhea with
signs of hypovolemia;  bloody
diarrhea; fever; severe
abdominal pain; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the small and large intestines.
Esophageal infection
 -
Local intervention indicated
(e.g., oral antibiotic, antifungal,
antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the esophagus.
Eye infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated;
enucleation
Death
Definition: A disorder characterized by an infectious process involving the eye.
Gallbladder infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the gallbladder.
Gum infection
Local therapy indicated (swish
and swallow)
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the gums.
Hepatic infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the liver.
Hepatitis viral
Asymptomatic, treatment not
indicated
 -
Symptomatic liver dysfunction;
fibrosis by biopsy; compensated
cirrhosis; reactivation of chronic
hepatitis
Decompensated liver function
(e.g., ascites, coagulopathy,
encephalopathy, coma)
Death
Definition: A disorder characterized by a viral pathologic process involving the liver parenchyma.
Infective myositis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the skeletal muscles.
Joint infection
 -
Localized; local intervention
indicated; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral); needle
aspiration indicated (single or
multiple)
Arthroscopic intervention
indicated (e.g., drainage) or
arthrotomy (e.g., open surgical
drainage)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a joint.
Kidney infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the kidney.
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CTCAE 4.03 - June 14, 2010 : Infections and infestations
30
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Laryngitis
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammatory process involving the larynx.
Lip infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by an infectious process involving the lips.
Lung infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the lungs.
Lymph gland infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the lymph nodes.
Mediastinal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the mediastinum.
Meningitis
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated; focal
neurologic deficit
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation of the meninges of the brain and/or spinal cord.
Mucosal infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a mucosal surface.
Nail infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by an infectious process involving the nail.
Otitis externa
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the outer ear and ear canal. Contributory factors include excessive water exposure (swimmer's ear infection)
and cuts in the ear canal. Symptoms include fullness, itching, swelling and marked discomfort in the ear and ear drainage.
Otitis media
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the middle ear.
Ovarian infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the ovary.
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CTCAE 4.03 - June 14, 2010 : Infections and infestations
31
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Pancreas infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pancreas.
Papulopustular rash
Papules and/or pustules
covering <10% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness
Papules and/or pustules
covering 10-30% BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness; associated with
psychosocial impact; limiting
instrumental ADL
Papules and/or pustules
covering >30% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness; limiting self-care
ADL; associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering  any % BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness and are associated
with extensive superinfection
with IV antibiotics indicated; life-
threatening consequences
Death
Definition: A disorder characterized by an eruption consisting of papules (a small, raised pimple) and pustules (a small pus filled blister), typically appearing in face, scalp, and upper
chest and back Unlike acne, this rash does not present with whiteheads or blackheads, and can be symptomatic, with itchy or tender lesions.
Paronychia
Nail fold edema or erythema;
disruption of the cuticle
Localized intervention indicated;
oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral);
nail fold edema or erythema
with pain; associated with
discharge or nail plate
separation; limiting instrumental
ADL
Surgical intervention or IV
antibiotics indicated; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an infectious process involving the soft tissues around the nail.
Pelvic infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pelvic cavity.
Penile infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the penis.
Periorbital infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the orbit of the eye.
Peripheral nerve infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the peripheral nerves.
Peritoneal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the peritoneum.
Pharyngitis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the throat.
Phlebitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations
32
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the vein. Clinical manifestations include erythema, marked discomfort, swelling, and induration along the course
of the infected vein.
Pleural infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pleura.
Prostate infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the prostate gland.
Rash pustular
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by a circumscribed and elevated skin lesion filled with pus.
Rhinitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
 -
 -
 -
Definition: A disorder characterized by an infectious process involving the nasal mucosal.
Salivary gland infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the salivary gland.
Scrotal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the scrotum.
Sepsis
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the presence of pathogenic microorganisms in the blood stream that cause a rapidly progressing systemic reaction that may lead to shock.
Sinusitis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the mucous membranes of the paranasal sinuses.
Skin infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the skin.
Small intestine infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the small intestine.
Soft tissue infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving soft tissues.
Splenic infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations
33
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the spleen.
Stoma site infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a stoma (surgically created opening on the surface of the body).
Tooth infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a tooth.
Tracheitis
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the trachea.
Upper respiratory infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the upper respiratory tract (nose, paranasal sinuses, pharynx, larynx, or trachea).
Urethral infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the urethra.
Urinary tract infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the urinary tract, most commonly the bladder and the urethra.
Uterine infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the endometrium. It may extend to the myometrium and parametrial tissues.
Vaginal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the vagina.
Vulval infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the vulva.
Wound infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the wound.
Infections and infestations -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications
34
13. Injury, poisoning and procedural complications
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Ankle fracture
Mild; non-surgical intervention
indicated
Limiting instrumental ADL;
operative intervention indicated
Limiting self care ADL; elective
surgery indicated
 -
 -
Definition: A finding of damage to the ankle joint characterized by a break in the continuity of the ankle bone. Symptoms include marked discomfort, swelling and difficulty moving the
affected leg and foot.
Aortic injury
 -
 -
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to the aorta.
Arterial injury
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic (e.g.,
claudication); repair or revision
not indicated
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to an artery.
Biliary anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of bile due to breakdown of a biliary anastomosis (surgical connection of two separate anatomic structures).
Bladder anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of urine due to breakdown of a bladder anastomosis (surgical connection of two separate anatomic structures).
Bruising
Localized or in a dependent
area
Generalized
 -
 -
 -
Definition: A finding of injury of the soft tissues or bone characterized by leakage of blood into surrounding tissues.
Burn
Minimal symptoms; intervention
not indicated
Medical intervention; minimal
debridement indicated
Moderate to major debridement
or reconstruction indicated
Life-threatening consequences
Death
Definition: A finding of impaired integrity to the anatomic site of an adverse thermal reaction. Burns can be caused by exposure to chemicals, direct heat, electricity, flames and
radiation. The extent of damage depends on the length and intensity of exposure and time until provision of treatment.
Dermatitis radiation
Faint erythema or dry
desquamation
Moderate to brisk erythema;
patchy moist desquamation,
mostly confined to skin folds
and creases; moderate edema
Moist desquamation in areas
other than skin folds and
creases; bleeding induced by
minor trauma or abrasion
Life-threatening consequences;
skin necrosis or ulceration of full
thickness dermis; spontaneous
bleeding from involved site; skin
graft indicated
Death
Definition: A finding of cutaneous inflammatory reaction occurring as a result of exposure to biologically effective levels of ionizing radiation.
Esophageal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an esophageal anastomosis (surgical connection of two separate anatomic structures).
Fall
Minor with no resultant injuries;
intervention not indicated
Symptomatic; noninvasive
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding of sudden movement downward, usually resulting in injury.
Fallopian tube anastomotic leak
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a fallopian tube anastomosis (surgical connection of two separate anatomic structures).
Fallopian tube perforation
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated (e.g., organ resection)
Death
Definition: A finding of rupture of the fallopian tube wall.
Fracture
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic but non-displaced;
immobilization indicated
Severe symptoms; displaced or
open wound with bone
exposure; disabling; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of traumatic injury to the bone in which the continuity of the bone is broken.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications
35
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Gastric anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a gastric anastomosis (surgical connection of two separate anatomic structures).
Gastrointestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a gastrointestinal anastomosis (surgical connection of two separate anatomic structures).
Gastrointestinal stoma necrosis
 -
Superficial necrosis;
intervention not indicated
Severe symptoms;
hospitalization or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of a necrotic process occurring in the gastrointestinal tract stoma.
Hip fracture
 -
Hairline fracture; mild pain;
limiting instrumental ADL; non-
surgical intervention indicated
Severe pain; hospitalization or
intervention indicated for pain
control (e.g., traction); operative
intervention indicated
Life-threatening consequences;
symptoms associated with
neurovascular compromise
 -
Definition: A finding of traumatic injury to the hip in which the continuity of either the femoral head, femoral neck, intertrochanteric or subtrochanteric regions is broken.
Injury to carotid artery
 -
 -
Severe symptoms; limiting self
care ADL (e.g., transient
cerebral ischemia); repair or
revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the carotid artery.
Injury to inferior vena cava
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the inferior vena cava.
Injury to jugular vein
 -
 -
Symptomatic limiting self care
ADL; disabling; repair or
revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the jugular vein.
Injury to superior vena cava
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic; repair or revision
not indicated
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to the superior vena cava.
Intestinal stoma leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of contents from an intestinal stoma (surgically created opening on the surface of the body).
Intestinal stoma obstruction
 -
Self-limited; intervention not
indicated
Severe symptoms; IV fluids,
tube feeding, or TPN indicated
>=24 hrs; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of blockage of the normal flow of the contents of the intestinal stoma.
Intestinal stoma site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of blood leakage from the intestinal stoma.
Intraoperative arterial injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to an artery during a surgical procedure.
Intraoperative breast injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications
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Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of damage to the breast parenchyma during a surgical procedure.
Intraoperative cardiac injury
 -
 -
Primary repair of injured
organ/structure indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the heart during a surgical procedure.
Intraoperative ear injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection of injured
organ/structure indicated;
disabling (e.g., impaired
hearing; impaired balance)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the ear during a surgical procedure.
Intraoperative endocrine injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the endocrine gland during a surgical procedure.
Intraoperative gastrointestinal
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the gastrointestinal system during a surgical procedure.
Intraoperative head and neck
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the head and neck during a surgical procedure.
Intraoperative hemorrhage
 -
 -
Postoperative radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of uncontrolled bleeding during a surgical procedure.
Intraoperative hepatobiliary
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the hepatic parenchyma and/or biliary tract during a surgical procedure.
Intraoperative musculoskeletal
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the musculoskeletal system during a surgical procedure.
Intraoperative neurological
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the nervous system during a surgical procedure.
Intraoperative ocular injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the eye during a surgical procedure.
Intraoperative renal injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the kidney during a surgical procedure.
Intraoperative reproductive tract
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
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Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of damage to the reproductive organs during a surgical procedure.
Intraoperative respiratory injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the respiratory system during a surgical procedure.
Intraoperative skin injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the skin during a surgical procedure.
Intraoperative splenic injury
 -
Primary repair of injured
organ/structure indicated
Resection or reconstruction of
injured organ/structure
indicated; disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the spleen during a surgical procedure.
Intraoperative urinary injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the urinary system during a surgical procedure.
Intraoperative venous injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to a vein during a surgical procedure.
Kidney anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of urine due to breakdown of a kidney anastomosis (surgical connection of two separate anatomic structures).
Large intestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the large intestine.
Pancreatic anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a pancreatic anastomosis (surgical connection of two separate anatomic structures).
Pharyngeal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a pharyngeal anastomosis (surgical connection of two separate anatomic structures).
Postoperative hemorrhage
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; radiologic,
endoscopic, or operative
intervention indicated
Transfusion indicated of >=2
units (10 cc/kg for pediatrics)
pRBCs beyond protocol
specification; urgent radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding occurring after a surgical procedure.
Postoperative thoracic
procedure complication
 -
Extubated within 24 - 72 hrs
postoperatively
Extubated >72 hrs
postoperatively, but before
tracheostomy indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A finding of a previously undocumented problem that occurs after a thoracic procedure.
Prolapse of intestinal stoma
Asymptomatic; reducible
Recurrent after manual
reduction; local irritation or stool
leakage; difficulty to fit
appliance; limiting instrumental
ADL
Severe symptoms; elective
operative intervention indicated;
limiting self care ADL
Life-threatening consequences;
urgent operative intervention
indicated
Death
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Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of protrusion of the intestinal stoma (surgically created opening on the surface of the body) above the abdominal surface.
Prolapse of urostomy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Local care or maintenance;
minor revision indicated
Dysfunctional stoma; elective
operative intervention or major
stomal revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of displacement of the urostomy.
Radiation recall reaction
(dermatologic)
Faint erythema or dry
desquamation
Moderate to brisk erythema;
patchy moist desquamation,
mostly confined to skin folds
and creases; moderate edema
Moist desquamation in areas
other than skin folds and
creases; bleeding induced by
minor trauma or abrasion
Life-threatening consequences;
skin necrosis or ulceration of full
thickness dermis; spontaneous
bleeding from involved site; skin
graft indicated
Death
Definition: A finding of acute skin inflammatory reaction caused by drugs, especially chemotherapeutic agents, for weeks or months following radiotherapy. The inflammatory reaction
is confined to the previously irradiated skin and the symptoms disappear after the removal of the pharmaceutical agent.
Rectal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a rectal anastomosis (surgical connection of two separate anatomic structures).
Seroma
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; simple aspiration
indicated
Symptomatic, elective radiologic
or operative intervention
indicated
 -
 -
Definition: A finding of tumor-like collection of serum in the tissues.
Small intestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the small bowel.
Spermatic cord anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a spermatic cord anastomosis (surgical connection of two separate anatomic structures).
Spinal fracture
Mild back pain; nonprescription
analgesics indicated
Moderate back pain;
prescription analgesics
indicated; limiting instrumental
ADL
Severe back pain;
hospitalization or intervention
indicated for pain control (e.g.,
vertebroplasty); limiting self care
ADL; disability
Life-threatening consequences;
symptoms associated with
neurovascular compromise
Death
Definition: A finding of traumatic injury to the spine in which the continuity of a vertebral bone is broken.
Stenosis of gastrointestinal
stoma
 -
Symptomatic; IV fluids indicated
<24 hrs; manual dilation at
bedside
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of narrowing of the gastrointestinal stoma (surgically created opening on the surface of the body).
Stomal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the jejunal mucosal surface close to the anastomosis site following a
gastroenterostomy procedure.
Tracheal hemorrhage
Minimal bleeding identified on
clinical or diagnostic exam;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding from the trachea.
Tracheal obstruction
Partial asymptomatic
obstruction on examination
(e.g., visual, radiologic or
endoscopic)
Symptomatic (e.g., noisy airway
breathing), no respiratory
distress; medical intervention
indicated (e.g., steroids); limiting
instrumental ADL
Stridor; radiologic or endoscopic
intervention indicated (e.g.,
stent, laser); limiting self care
ADL
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A finding of blockage of the lumen of the trachea.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications
39
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Tracheostomy site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of blood leakage from the tracheostomy site.
Ureteric anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a ureteral anastomosis (surgical connection of two separate anatomic structures).
Urethral anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a urethral anastomosis (surgical connection of two separate anatomic structures).
Urostomy leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of contents from a urostomy.
Urostomy obstruction
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; dilation or
endoscopic repair or stent
placement indicated
Altered organ function (e.g.,
sepsis or hydronephrosis, or
renal dysfunction); elective
operative intervention indicated
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A finding of blockage of the urostomy.
Urostomy site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding from the urostomy site.
Urostomy stenosis
 -
Symptomatic but no
hydronephrosis, no sepsis or no
renal dysfunction; dilation or
endoscopic repair or stent
placement indicated
Symptomatic (e.g.,
hydronephrosis, or renal
dysfunction); elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of narrowing of the opening of a urostomy.
Uterine anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a uterine anastomosis (surgical connection of two separate anatomic structures).
Uterine perforation
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the uterine wall.
Vaginal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a vaginal anastomosis (surgical connection of two separate anatomic structures).
Vas deferens anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a vas deferens anastomosis (surgical connection of two separate anatomic structures).
Vascular access complication
 -
Device dislodgement, blockage,
leak, or malposition; device
replacement indicated
Deep vein or cardiac
thrombosis; intervention
indicated (e.g., anticoagulation,
lysis, filter, invasive procedure)
Embolic event including
pulmonary embolism or life-
threatening thrombus
Death
Definition: A finding of a previously undocumented problem related to the vascular access site.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications
40
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Venous injury
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic (e.g.,
claudication); repair or revision
not indicated
Severe symptoms; limiting self
care ADL; repair or revision
indicated; disabling
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to a vein.
Wound complication
Incisional separation of <=25%
of wound, no deeper than
superficial fascia
Incisional separation >25% of
wound; local care indicated
Hernia without evidence of
strangulation; fascial
disruption/dehiscence; primary
wound closure or revision by
operative intervention indicated
Hernia with evidence of
strangulation; major
reconstruction flap, grafting,
resection, or amputation
indicated
Death
Definition: A finding of development of a new problem at the site of an existing wound.
Wound dehiscence
Incisional separation of <=25%
of wound, no deeper than
superficial fascia
Incisional separation >25% of
wound with local care;
asymptomatic hernia or
symptomatic hernia without
evidence of strangulation
Fascial disruption or dehiscence
without evisceration; primary
wound closure or revision by
operative intervention indicated
Life-threatening consequences;
symptomatic hernia with
evidence of strangulation;
fascial disruption with
evisceration; major
reconstruction flap, grafting,
resection, or amputation
indicated
Death
Definition: A finding of separation of the approximated margins of a surgical wound.
Wrist fracture
Mild; non-surgical intervention
indicated
Limiting instrumental ADL;
operative intervention indicated
Limiting self care ADL; elective
surgery indicated
 -
 -
Definition: A finding of traumatic injury to the wrist joint in which the continuity of a wrist bone is broken.
Injury, poisoning and procedural
complications - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Investigations
41
14. Investigations
Investigations
Grade
Adverse Event
1
2
3
4
5
Activated partial thromboplastin
time prolonged
>ULN - 1.5 x ULN
>1.5 - 2.5 x ULN
>2.5 x ULN; hemorrhage
 -
 -
Definition: An abnormal laboratory test result in which the partial thromboplastin time is found to be greater than the control value. As a possible indicator of coagulopathy, a prolonged
partial thromboplastin time (PTT) may occur in a variety of diseases and disorders, both primary and related to treatment.
Alanine aminotransferase
increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT or SGPT) in the blood specimen.
Alkaline phosphatase increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of alkaline phosphatase in a blood specimen.
Aspartate aminotransferase
increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of aspartate aminotransferase (AST or SGOT) in a blood specimen.
Blood antidiuretic hormone
abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of antidiuretic hormone in the blood specimen.
Blood bilirubin increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an abnormally high level of bilirubin in the blood. Excess bilirubin is associated with jaundice.
Blood corticotrophin decreased
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of corticotrophin in a blood specimen.
Blood gonadotrophin abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of gonadotrophin hormone in a blood specimen.
Blood prolactin abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
 -
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of prolactin hormone in a blood specimen.
Carbon monoxide diffusing
capacity decreased
3 - 5 units below LLN; for follow-
up, a decrease of 3 - 5 units
(ml/min/mm Hg) below the
baseline value
6 - 8 units below LLN; for follow-
up, an asymptomatic decrease
of >5 - 8 units (ml/min/mm Hg)
below the baseline value
Asymptomatic decrease  of >8
units drop;  >5 units drop along
with the presence of pulmonary
symptoms (e.g. , >Grade 2
hypoxia or >Grade 2 or higher
dyspnea)
 -
 -
Definition: A finding based on lung function test results that indicate  a decrease in the lung capacity to absorb carbon monoxide.
Cardiac troponin I increased
Levels above the upper limit of
normal and below the level of
myocardial infarction as defined
by the manufacturer
 -
Levels consistent with
myocardial infarction as defined
by the manufacturer
 -
 -
Definition: A laboratory test result which indicates increased levels of cardiac troponin I in a biological specimen.
Cardiac troponin T increased
Levels above the upper limit of
normal and below the level of
myocardial infarction as defined
by the manufacturer
 -
Levels consistent with
myocardial infarction as defined
by the manufacturer
 -
 -
Definition: A laboratory test result which indicates increased levels of cardiac troponin T in a biological specimen.
CD4 lymphocytes decreased
<LLN - 500/mm3;  <LLN - 0.5 x
10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x
10e9 /L
<200 - 50/mm3; <0.2 x 0.05 -
10e9 /L
<50/mm3; <0.05 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of CD4 lymphocytes in a blood specimen.
Cholesterol high
>ULN - 300 mg/dL; >ULN - 7.75
mmol/L
>300 - 400 mg/dL; >7.75 - 10.34
mmol/L
>400 - 500 mg/dL; >10.34 -
12.92 mmol/L
>500 mg/dL; >12.92 mmol/L
 -
Definition: A finding based on laboratory test results that indicate higher than normal levels of cholesterol in a blood specimen.
CPK increased
>ULN - 2.5 x ULN
>2.5 x ULN - 5 x ULN
>5 x ULN - 10 x ULN
>10 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in levels of creatine phosphokinase in a blood specimen.
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CTCAE 4.03 - June 14, 2010 : Investigations
42
Investigations
Grade
Adverse Event
1
2
3
4
5
Creatinine increased
>1 - 1.5 x baseline; >ULN - 1.5
x ULN
>1.5 - 3.0 x baseline; >1.5 - 3.0
x ULN
>3.0 baseline; >3.0 - 6.0 x ULN
>6.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate increased levels of creatinine in a biological specimen.
Ejection fraction decreased
 -
Resting ejection fraction (EF) 50
- 40%; 10 - 19% drop from
baseline
Resting ejection fraction (EF) 39
- 20%; >20% drop from baseline
Resting ejection fraction (EF)
<20%
 -
Definition: The percentage computed when the amount of blood ejected during a ventricular contraction of the heart is compared to the amount that was present prior to the
contraction.
Electrocardiogram QT corrected
interval prolonged
QTc 450 - 480 ms
QTc 481 - 500 ms
QTc >= 501 ms on at least two
separate ECGs
QTc >= 501 or >60 ms change
from baseline and Torsade de
pointes or polymorphic
ventricular tachycardia or
signs/symptoms of serious
arrhythmia
 -
Definition: A finding of a cardiac dysrhythmia characterized by an abnormally long corrected QT interval.
Fibrinogen decreased
<1.0 - 0.75 x LLN  or <25%
decrease from baseline
<0.75 - 0.5 x LLN or 25 - <50%
decrease from baseline
<0.5 - 0.25 x LLN or 50 - <75%
decrease from baseline
<0.25 x LLN  or 75% decrease
from baseline or absolute value
<50 mg/dL
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of fibrinogen in a blood specimen.
Forced expiratory volume
decreased
FEV1% (percentages of
observed FEV1 and FVC
related to their respective
predicted values)  99 - 70%
predicted
FEV1 60 - 69%
50 - 59%
<= 49%
 -
Definition: A finding based on test results that indicate a relative decrease in the fraction of the forced vital capacity that is exhaled in a specific number of seconds.
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate higher than normal levels of the enzyme gamma-glutamyltransferase in the blood specimen. GGT (gamma-
glutamyltransferase ) catalyzes the transfer of a gamma glutamyl group from a gamma glutamyl peptide to another peptide, amino acids or water.
Growth hormone abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
 -
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of growth hormone in a biological specimen.
Haptoglobin decreased
<LLN
 -
 -
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of haptoglobin in a blood specimen.
Hemoglobin increased
Increase in >0 - 2 gm/dL above
ULN or above baseline if
baseline is above ULN
Increase in >2 - 4 gm/dL above
ULN or above baseline if
baseline is above ULN
Increase in >4 gm/dL above
ULN or above baseline if
baseline is above ULN
 -
 -
Definition: A finding based on laboratory test results that indicate increased levels of hemoglobin in a biological specimen.
INR increased
>1 - 1.5 x ULN; >1 - 1.5 times
above baseline if on
anticoagulation
>1.5 - 2.5 x ULN; >1.5 - 2.5
times above baseline if on
anticoagulation
>2.5 x ULN; >2.5 times above
baseline if on anticoagulation
 -
 -
Definition: A finding based on laboratory test results that indicate an increase in the ratio of the patient's prothrombin time to a control sample in the blood.
Lipase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of lipase in a biological specimen.
Lymphocyte count decreased
 <LLN - 800/mm3; <LLN - 0.8 x
10e9 /L
<800 - 500/mm3; <0.8 - 0.5 x
10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x
10e9 /L
<200/mm3; <0.2 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of lymphocytes in a blood specimen.
Lymphocyte count increased
 -
>4000/mm3 - 20,000/mm3
>20,000/mm3
 -
 -
Definition: A finding based on laboratory test results that indicate an abnormal increase in the number of lymphocytes in the blood, effusions or bone marrow.
Neutrophil count decreased
<LLN - 1500/mm3; <LLN - 1.5 x
10e9 /L
<1500 - 1000/mm3; <1.5 - 1.0 x
10e9 /L
<1000 - 500/mm3; <1.0 - 0.5 x
10e9 /L
<500/mm3; <0.5 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of neutrophils in a blood specimen.
Pancreatic enzymes decreased
<LLN and asymptomatic
Increase in stool frequency,
bulk, or odor; steatorrhea
Sequelae of absorption
deficiency
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of pancreatic enzymes in a biological specimen.
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CTCAE 4.03 - June 14, 2010 : Investigations
43
Investigations
Grade
Adverse Event
1
2
3
4
5
Platelet count decreased
<LLN - 75,000/mm3; <LLN -
75.0 x 10e9 /L
<75,000 - 50,000/mm3; <75.0 -
50.0 x 10e9 /L
<50,000 - 25,000/mm3; <50.0 -
25.0 x 10e9 /L
<25,000/mm3; <25.0 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.
Serum amylase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the levels of amylase in a serum specimen.
Urine output decreased
 -
 -
Oliguria (<80 ml in 8 hr)
Anuria (<240 ml in 24 hr)
 -
Definition: A finding based on test results that indicate urine production is less relative to previous output.
Vital capacity abnormal
90 - 75% of predicted value
<75 - 50% of predicted value;
limiting instrumental ADL
<50% of predicted value;
limiting self care ADL
 -
 -
Definition: A finding based on pulmonary function test results that indicate an abnormal vital capacity (amount of exhaled after a maximum inhalation) when compared to the predicted
value.
Weight gain
5 - <10% from baseline
10 - <20% from baseline
>=20% from baseline
 -
 -
Definition: A finding characterized by an increase in overall body weight; for pediatrics, greater than the baseline growth curve.
Weight loss
5 to <10% from baseline;
intervention not indicated
10 - <20% from baseline;
nutritional support indicated
>=20% from baseline; tube
feeding or TPN indicated
 -
 -
Definition: A finding characterized by a decrease in overall body weight; for pediatrics, less than the baseline growth curve.
White blood cell decreased
<LLN - 3000/mm3; <LLN - 3.0 x
10e9 /L
<3000 - 2000/mm3; <3.0 - 2.0 x
10e9 /L
<2000 - 1000/mm3; <2.0 - 1.0 x
10e9 /L
<1000/mm3; <1.0 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate an decrease in number of white blood cells in a blood specimen.
Investigations - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Metabolism and nutrition disorders
44
15. Metabolism and nutrition disorders
Metabolism and nutrition disorders
Grade
Adverse Event
1
2
3
4
5
Acidosis
pH <normal, but >=7.3
 -
pH <7.3
Life-threatening consequences
Death
Definition: A disorder characterized by abnormally high acidity (high hydrogen-ion concentration) of the blood and other body tissues.
Alcohol intolerance
 -
Present
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in sensitivity to the adverse effects of alcohol, which can include nasal congestion, skin flushes, heart dysrhythmias, nausea,
vomiting, indigestion and headaches.
Alkalosis
pH >normal, but <=7.5
 -
pH >7.5
Life-threatening consequences
Death
Definition: A disorder characterized by abnormally high alkalinity (low hydrogen-ion concentration) of the blood and other body tissues.
Anorexia
Loss of appetite without
alteration in eating habits
Oral intake altered without
significant weight loss or
malnutrition; oral nutritional
supplements indicated
Associated with significant
weight loss or malnutrition (e.g.,
inadequate oral caloric and/or
fluid intake); tube feeding or
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a loss of appetite.
Dehydration
Increased oral fluids indicated;
dry mucous membranes;
diminished skin turgor
IV fluids indicated <24 hrs
IV fluids or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Glucose intolerance
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; dietary
modification or oral agent
indicated
Severe symptoms; insulin
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inability to properly metabolize glucose.
Hypercalcemia
Corrected serum calcium of
>ULN - 11.5 mg/dL; >ULN - 2.9
mmol/L;  Ionized calcium  >ULN
- 1.5 mmol/L
Corrected serum calcium of
>11.5 - 12.5 mg/dL; >2.9 - 3.1
mmol/L;  Ionized calcium >1.5 -
1.6 mmol/L; symptomatic
Corrected serum calcium of
>12.5 - 13.5 mg/dL; >3.1 - 3.4
mmol/L;  Ionized calcium  >1.6 -
1.8 mmol/L; hospitalization
indicated
Corrected serum calcium of
>13.5 mg/dL; >3.4 mmol/L;
Ionized calcium  >1.8 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of calcium (corrected for albumin) in blood.
Hyperglycemia
Fasting glucose value >ULN -
160 mg/dL; Fasting glucose
value >ULN - 8.9 mmol/L
Fasting glucose value >160 -
250 mg/dL; Fasting glucose
value >8.9 - 13.9 mmol/L
>250 - 500 mg/dL; >13.9 - 27.8
mmol/L; hospitalization
indicated
>500 mg/dL; >27.8 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of blood sugar. It is usually an indication of diabetes mellitus or glucose
intolerance.
Hyperkalemia
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L
>6.0 - 7.0 mmol/L;
hospitalization indicated
>7.0 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of potassium in the blood; associated with kidney failure or sometimes with
the use of diuretic drugs.
Hypermagnesemia
>ULN - 3.0 mg/dL; >ULN - 1.23
mmol/L
 -
>3.0 - 8.0 mg/dL; >1.23 - 3.30
mmol/L
>8.0 mg/dL; >3.30 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of magnesium in the  blood.
Hypernatremia
>ULN - 150 mmol/L
>150 - 155 mmol/L
>155 - 160 mmol/L;
hospitalization indicated
>160 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of sodium in the  blood.
Hypertriglyceridemia
150 mg/dL - 300 mg/dL; 1.71
mmol/L - 3.42 mmol/L
>300 mg/dL - 500 mg/dL;  >3.42
mmol/L - 5.7 mmol/L
>500 mg/dL - 1000 mg/dL;  >5.7
mmol/L - 11.4 mmol/L
>1000 mg/dL; >11.4 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of triglyceride concentration in the blood.
Hyperuricemia
>ULN - 10 mg/dL (0.59 mmol/L)
without physiologic
consequences
 -
>ULN - 10 mg/dL (0.59 mmol/L)
with physiologic consequences
>10 mg/dL; >0.59 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of uric acid.
Hypoalbuminemia
<LLN - 3 g/dL; <LLN - 30 g/L
<3 - 2 g/dL; <30 - 20 g/L
<2 g/dL; <20 g/L
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of albumin in the blood.
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CTCAE 4.03 - June 14, 2010 : Metabolism and nutrition disorders
45
Metabolism and nutrition disorders
Grade
Adverse Event
1
2
3
4
5
Hypocalcemia
Corrected serum calcium of
<LLN - 8.0 mg/dL; <LLN - 2.0
mmol/L; Ionized calcium  <LLN -
1.0 mmol/L
Corrected serum calcium of
<8.0 - 7.0 mg/dL; <2.0 - 1.75
mmol/L; Ionized calcium  <1.0 -
0.9 mmol/L; symptomatic
Corrected serum calcium of
<7.0 - 6.0 mg/dL; <1.75 - 1.5
mmol/L;  Ionized calcium  <0.9 -
0.8 mmol/L; hospitalization
indicated
Corrected serum calcium of
<6.0 mg/dL; <1.5 mmol/L;
Ionized calcium  <0.8 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of calcium (corrected for albumin) in the  blood.
Hypoglycemia
<LLN - 55 mg/dL; <LLN - 3.0
mmol/L
<55 - 40 mg/dL; <3.0 - 2.2
mmol/L
<40 - 30 mg/dL; <2.2 - 1.7
mmol/L
<30 mg/dL; <1.7 mmol/L; life-
threatening consequences;
seizures
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of glucose in the blood.
Hypokalemia
<LLN - 3.0 mmol/L
<LLN - 3.0 mmol/L;
symptomatic; intervention
indicated
<3.0 - 2.5 mmol/L;
hospitalization indicated
<2.5 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of potassium in the  blood.
Hypomagnesemia
<LLN - 1.2 mg/dL; <LLN - 0.5
mmol/L
<1.2 - 0.9 mg/dL; <0.5 - 0.4
mmol/L
<0.9 - 0.7 mg/dL; <0.4 - 0.3
mmol/L
<0.7 mg/dL; <0.3 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of magnesium in the  blood.
Hyponatremia
<LLN - 130 mmol/L
 -
<130 - 120 mmol/L
<120 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of sodium in the blood.
Hypophosphatemia
<LLN - 2.5 mg/dL; <LLN - 0.8
mmol/L
<2.5 - 2.0 mg/dL; <0.8 - 0.6
mmol/L
<2.0 - 1.0 mg/dL; <0.6 - 0.3
mmol/L
<1.0 mg/dL; <0.3 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of phosphates in the  blood.
Iron overload
 -
Moderate symptoms;
intervention not indicated
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by accumulation of iron in the tissues.
Obesity
 -
BMI 25 - 29.9 kg/m2
BMI 30 - 39.9 kg/m2
BMI >=40 kg/m2
 -
Definition: A disorder characterized by having a high amount of body fat.
Tumor lysis syndrome
 -
 -
Present
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by metabolic abnormalities that result from a spontaneous or therapy-related cytolysis of tumor cells.
Metabolism and nutrition
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders
46
16. Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Abdominal soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g. tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the abdominal wall.
Arthralgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in a joint.
Arthritis
Mild pain with inflammation,
erythema, or joint swelling
Moderate pain associated with
signs of inflammation,
erythema, or joint swelling;
limiting instrumental ADL
Severe pain associated with
signs of inflammation,
erythema, or joint swelling;
irreversible joint damage;
disabling; limiting self care ADL
 -
 -
Definition: A disorder characterized by inflammation involving a joint.
Avascular necrosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by necrotic changes in the bone tissue due to interruption of blood supply. Most often affecting the epiphysis of the long bones, the necrotic
changes result in the collapse and the destruction of the bone structure.
Back pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the back region.
Bone pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the bones.
Buttock pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the buttocks.
Chest wall pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the chest wall region.
Exostosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by non-neoplastic overgrowth of bone.
Fibrosis deep connective tissue
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration; unable to
slide or pinch skin; limiting joint
or orifice movement (e.g.
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by fibrotic degeneration of the deep connective tissues.
Flank pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation on the lateral side of the body in the region below the ribs and above the hip.
Generalized muscle weakness
Symptomatic; weakness
perceived by patient but not
evident on physical exam
Symptomatic; weakness evident
on physical exam; weakness
limiting instrumental ADL
Weakness limiting self care
ADL; disabling
 -
 -
Definition: A disorder characterized by a reduction in the strength of muscles in multiple anatomic sites.
Growth suppression
Reduction in growth velocity by
10 - 29% ideally measured over
the period of a year
Reduction in growth velocity by
30 - 49% ideally measured over
the period of a year or 0 - 49%
reduction in growth from the
baseline growth curve
Reduction in growth velocity of
>=50% ideally measured over
the period of a year
 -
 -
Definition: A disorder characterized by of stature that is smaller than normal as expected for age.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders
47
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Head soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the head.
Joint effusion
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated; disabling
 -
 -
Definition: A disorder characterized by excessive fluid in a joint, usually as a result of joint inflammation.
Joint range of motion decreased <=25% loss of ROM (range of
motion); decreased ROM
limiting athletic activity
>25 - 50% decrease in ROM;
limiting instrumental ADL
>50% decrease in ROM; limiting
self care ADL; disabling
 -
 -
Definition: A disorder characterized by a decrease in joint flexibility of any joint.
Joint range of motion decreased
cervical spine
Mild restriction of rotation or
flexion between 60 - 70 degrees
Rotation <60 degrees to right or
left; <60 degrees of flexion
Ankylosed/fused over multiple
segments with no C-spine
rotation
 -
 -
Definition: A disorder characterized by a decrease in flexibility of a cervical spine joint.
Joint range of motion decreased
lumbar spine
Stiffness; difficulty bending to
the floor to pick up a very light
object but able to do athletic
activity
Pain with range of motion
(ROM) in lumbar spine; requires
a reaching aid to pick up a very
light object from the floor
<50% lumbar spine flexion;
associated with symptoms of
ankylosis or fused over multiple
segments with no L-spine
flexion (e.g., unable to reach to
floor to pick up a very light
object)
 -
 -
Definition: A disorder characterized by a decrease in flexibility of a lumbar spine joint.
Kyphosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate accentuation; limiting
instrumental ADL
Severe accentuation; operative
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an abnormal increase in the curvature of the thoracic portion of the spine.
Lordosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate accentuation; limiting
instrumental ADL
Severe accentuation; operative
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an abnormal increase in the curvature of the lumbar portion of the spine.
Muscle weakness left-sided
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the muscles on the left side of the body.
Muscle weakness lower limb
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the lower limb muscles.
Muscle weakness right-sided
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the muscles on the right side of the body.
Muscle weakness trunk
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the trunk muscles.
Muscle weakness upper limb
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the upper limb muscles.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders
48
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Musculoskeletal deformity
Cosmetically and functionally
insignificant hypoplasia
Deformity, hypoplasia, or
asymmetry able to be
remediated by prosthesis (e.g.,
shoe insert) or covered by
clothing
Significant deformity,
hypoplasia, or asymmetry,
unable to be remediated by
prosthesis or covered by
clothing; disabling
 -
 -
Definition: A disorder characterized by of a malformation of the musculoskeletal system.
Myalgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation originating from a muscle or group of muscles.
Myositis
Mild pain
Moderate pain associated with
weakness; pain limiting
instrumental ADL
Pain associated with severe
weakness; limiting self care
ADL
 -
 -
Definition: A disorder characterized by inflammation involving the skeletal muscles.
Neck pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the neck area.
Neck soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the neck.
Osteonecrosis of jaw
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the bone of the mandible.
Osteoporosis
Radiologic evidence of
osteoporosis or Bone Mineral
Density (BMD) t-score -1 to -2.5
(osteopenia); no loss of height
or intervention indicated
BMD t-score <-2.5; loss of
height <2 cm; anti-osteoporotic
therapy indicated; limiting
instrumental ADL
Loss of height >=2 cm;
hospitalization indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by reduced bone mass, with a decrease in cortical thickness and in the number and size of the trabeculae of cancellous bone (but normal chemical
composition), resulting in increased fracture incidence.
Pain in extremity
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the upper or lower extremities.
Pelvic soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the pelvis.
Scoliosis
<20 degrees; clinically
undetectable
>20 - 45 degrees; visible by
forward flexion; limiting
instrumental ADL
>45 degrees; scapular
prominence in forward flexion;
operative intervention indicated;
limiting self care ADL; disabling
 -
 -
Definition: A disorder characterized by a malformed, lateral curvature of the spine.
Soft tissue necrosis lower limb
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the lower extremity.
Soft tissue necrosis upper limb
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the upper extremity.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders
49
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Superficial soft tissue fibrosis
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration; unable to
slide or pinch skin; limiting joint
or orifice movement (e.g.,
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by fibrotic degeneration of the superficial soft tissues.
Trismus
Decreased ROM (range of
motion) without impaired eating
Decreased ROM requiring small
bites, soft foods or purees
Decreased ROM with inability to
adequately aliment or hydrate
orally
 -
 -
Definition: A disorder characterized by lack of ability to open the mouth fully due to a decrease in the range of motion of the muscles of mastication.
Unequal limb length
Mild length discrepancy <2 cm
Moderate length discrepancy 2 -
5 cm; shoe lift indicated; limiting
instrumental ADL
Severe length discrepancy >5
cm; limiting self care ADL;
disabling; operative intervention
indicated
 -
 -
Definition: A disorder characterized by of a discrepancy between the lengths of the lower or upper extremities.
Musculoskeletal and connective
tissue disorder -  Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Neoplasms benign, malignant and unspecified (incl cysts and polyps)
50
17. Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Grade
Adverse Event
1
2
3
4
5
Leukemia secondary to
oncology chemotherapy
 -
 -
 -
Present
Death
Definition: A disorder characterized by leukemia arising as a result of the mutagenic effect of chemotherapy agents.
Myelodysplastic syndrome
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by insufficiently healthy hematapoietic cell production by the bone marrow.
Treatment related secondary
malignancy
 -
 -
Non life-threatening secondary
malignancy
Acute life-threatening secondary
malignancy; blast crisis in
leukemia
Death
Definition: A disorder characterized by development of a malignancy most probably as a result of treatment for a previously existing malignancy.
Tumor pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort from a neoplasm that may be pressing on a nerve, blocking blood vessels, inflamed or fractured from metastasis.
Neoplasms benign, malignant
and unspecified (incl cysts and
polyps) - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders
51
18. Nervous system disorders
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Abducens nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the abducens nerve (sixth cranial nerve).
Accessory nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the accessory nerve (eleventh cranial nerve).
Acoustic nerve disorder NOS
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the acoustic nerve (eighth cranial nerve).
Akathisia
Mild restlessness or increased
motor activity
Moderate restlessness or
increased motor activity; limiting
instrumental ADL
Severe restlessness or
increased motor activity; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an uncomfortable feeling of inner restlessness and inability to stay still; this is a side effect of some psychotropic drugs.
Amnesia
Mild; transient memory loss
Moderate; short term memory
loss; limiting instrumental ADL
Severe; long term memory loss;
limiting self care ADL
 -
 -
Definition: A disorder characterized by systematic and extensive loss of memory.
Aphonia
 -
 -
Voicelessness; unable to speak
 -
 -
Definition: A disorder characterized by the inability to speak. It may result from injuries to the vocal cords or may be functional (psychogenic).
Arachnoiditis
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the arachnoid membrane and adjacent subarachnoid space.
Ataxia
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; mechanical
assistance indicated
 -
 -
Definition: A disorder characterized by lack of coordination of muscle movements resulting in the impairment or inability to perform voluntary activities.
Brachial plexopathy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by regional paresthesia of the brachial plexus, marked discomfort and muscle weakness, and limited movement in the arm or hand.
Central nervous system
necrosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms;
corticosteroids indicated
Severe symptoms; medical
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the brain and/or spinal cord.
Cerebrospinal fluid leakage
Post-craniotomy: asymptomatic;
Post-lumbar puncture: transient
headache; postural care
indicated
Post-craniotomy: moderate
symptoms; medical intervention
indicated; Post-lumbar
puncture: persistent moderate
symptoms; blood patch
indicated
Severe symptoms; medical
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by loss of cerebrospinal fluid into the surrounding tissues.
Cognitive disturbance
Mild cognitive disability; not
interfering with work/school/life
performance; specialized
educational services/devices
not indicated
Moderate cognitive disability;
interfering with work/school/life
performance but capable of
independent living; specialized
resources on part time basis
indicated
Severe cognitive disability;
significant impairment of
work/school/life performance
 -
 -
Definition: A disorder characterized by a conspicuous change in cognitive function.
Concentration impairment
Mild inattention or decreased
level of concentration
Moderate impairment in
attention or decreased level of
concentration; limiting
instrumental ADL
Severe impairment in attention
or decreased level of
concentration; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a deterioration in the ability to concentrate.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders
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Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Depressed level of
consciousness
Decreased level of alertness
Sedation; slow response to
stimuli; limiting instrumental
ADL
Difficult to arouse
Life-threatening consequences
Death
Definition: A disorder characterized by a decrease in ability to perceive and respond.
Dizziness
Mild unsteadiness or sensation
of movement
Moderate unsteadiness or
sensation of movement; limiting
instrumental ADL
Severe unsteadiness or
sensation of movement; limiting
self care ADL
 -
 -
Definition: A disorder characterized by a disturbing sensation of lightheadedness, unsteadiness, giddiness, spinning or rocking.
Dysarthria
Mild slurred speech
Moderate impairment of
articulation or slurred speech
Severe impairment of
articulation or slurred speech
 -
 -
Definition: A disorder characterized by slow and slurred speech resulting from an inability to coordinate the muscles used in speech.
Dysesthesia
Mild sensory alteration
Moderate sensory alteration;
limiting instrumental ADL
Severe sensory alteration;
limiting self care ADL
 -
 -
Definition: A disorder characterized by distortion of sensory perception, resulting in an abnormal and unpleasant sensation.
Dysgeusia
Altered taste but no change in
diet
Altered taste with change in diet
(e.g., oral supplements);
noxious or unpleasant taste;
loss of taste
 -
 -
 -
Definition: A disorder characterized by abnormal sensual experience with the taste of foodstuffs; it can be related to a decrease in the sense of smell.
Dysphasia
Awareness of receptive or
expressive characteristics; not
impairing ability to communicate
Moderate receptive or
expressive characteristics;
impairing ability to communicate
spontaneously
Severe receptive or expressive
characteristics; impairing ability
to read, write or communicate
intelligibly
 -
 -
Definition: A disorder characterized by impairment of verbal communication skills, often resulting from brain damage.
Edema cerebral
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the brain.
Encephalopathy
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a pathologic process involving the brain.
Extrapyramidal disorder
Mild involuntary movements
Moderate involuntary
movements; limiting
instrumental ADL
Severe involuntary movements
or torticollis; limiting self care
ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormal, repetitive, involuntary muscle movements, frenzied speech and extreme restlessness.
Facial muscle weakness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a reduction in the strength of the facial muscles.
Facial nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the facial nerve (seventh cranial nerve).
Glossopharyngeal nerve
disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the glossopharyngeal nerve (ninth cranial nerve).
Headache
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in various parts of the head, not confined to the area of distribution of any nerve.
Hydrocephalus
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms;
intervention not indicated
Severe symptoms or
neurological deficit; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal increase of cerebrospinal fluid in the ventricles of the brain.
Hypersomnia
Mild increased need for sleep
Moderate increased need for
sleep
Severe increased need for
sleep
 -
 -
Definition: A disorder characterized by characterized by excessive sleepiness during the daytime.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders
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Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Hypoglossal nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the hypoglossal nerve (twelfth cranial nerve).
Intracranial hemorrhage
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Ventriculostomy, ICP
monitoring, intraventricular
thrombolysis, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the cranium.
Ischemia cerebrovascular
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms
 -
 -
 -
Definition: A disorder characterized by a decrease or absence of blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurological
damage.
IVth nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the trochlear nerve (fourth cranial nerve).
Lethargy
Mild symptoms; reduced
alertness and awareness
Moderate symptoms; limiting
instrumental ADL
 -
 -
 -
Definition: A disorder characterized by a decrease in consciousness characterized by mental and physical inertness.
Leukoencephalopathy
Asymptomatic; small focal
T2/FLAIR hyperintensities;
involving periventricular white
matter or <1/3 of susceptible
areas of cerebrum +/- mild
increase in subarachnoid space
(SAS) and/or mild
ventriculomegaly
Moderate symptoms; focal
T2/FLAIR hyperintensities,
involving periventricular white
matter extending into centrum
semiovale or involving 1/3 to 2/3
of susceptible areas of
cerebrum +/- moderate increase
in SAS and/or moderate
ventriculomegaly
Severe symptoms; extensive
T2/FLAIR hyperintensities,
involving periventricular white
matter involving 2/3 or more of
susceptible areas of cerebrum
+/- moderate to severe increase
in SAS and/or moderate to
severe ventriculomegaly
Life-threatening consequences;
extensive T2/FLAIR
hyperintensities, involving
periventricular white matter
involving most of susceptible
areas of cerebrum +/- moderate
to severe increase in SAS
and/or moderate to severe
ventriculomegaly
Death
Definition: A disorder characterized by diffuse reactive astrocytosis with multiple areas of necrotic foci without inflammation.
Memory impairment
Mild memory impairment
Moderate memory impairment;
limiting instrumental ADL
Severe memory impairment;
limiting self care ADL
 -
 -
Definition: A disorder characterized by a deterioration in memory function.
Meningismus
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by neck stiffness, headache, and photophobia resulting from irritation of the cerebral meninges.
Movements involuntary
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by uncontrolled and purposeless movements.
Myelitis
Asymptomatic; mild signs (e.g.,
Babinski's reflex or Lhermitte's
sign)
Moderate weakness or sensory
loss; limiting instrumental ADL
Severe weakness or sensory
loss; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving the spinal cord. Symptoms include weakness, paresthesia, sensory loss, marked discomfort and incontinence.
Neuralgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by intense painful sensation along a nerve or group of nerves.
Nystagmus
 -
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involuntary movements of the eyeballs.
Oculomotor nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the oculomotor nerve (third cranial nerve).
Olfactory nerve disorder
 -
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the olfactory nerve (first cranial nerve).
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders
54
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Paresthesia
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by functional disturbances of sensory neurons resulting in abnormal cutaneous sensations of tingling, numbness, pressure, cold, and warmth that
are experienced in the absence of a stimulus.
Peripheral motor neuropathy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; assistive device
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation or degeneration of the peripheral motor nerves.
Peripheral sensory neuropathy
Asymptomatic; loss of deep
tendon reflexes or paresthesia
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation or degeneration of the peripheral sensory nerves.
Phantom pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort related to a limb or an organ that is removed from or is not physically part of the body.
Presyncope
 -
Present (e.g., near fainting)
 -
 -
 -
Definition: A disorder characterized by an episode of lightheadedness and dizziness which may precede an episode of syncope.
Pyramidal tract syndrome
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by dysfunction of the corticospinal (pyramidal) tracts of the spinal cord. Symptoms include  an increase in the muscle tone in the lower extremities,
hyperreflexia, positive Babinski and a decrease in fine motor coordination.
Radiculitis
Mild symptoms
Moderate symptoms; limiting
instrumental ADL; medical
intervention indicated
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving a nerve root. Patients experience marked discomfort radiating along a nerve path because of spinal pressure on the
connecting nerve root.
Recurrent laryngeal nerve palsy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms
Severe symptoms; medical
intervention indicated (e.g.,
thyroplasty, vocal cord injection)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by paralysis of the recurrent laryngeal nerve.
Reversible posterior
leukoencephalopathy syndrome
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; abnormal
imaging studies; limiting
instrumental ADL
Severe symptoms; very
abnormal imaging studies;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by headaches, mental status changes, visual disturbances, and seizures associated with imaging findings of posterior leukoencephalopathy. It has
been observed in association with hypertensive encephalopathy, eclampsia, and immunosuppressive and cytotoxic drug treatment. It is an acute or subacute reversible condition.
Seizure
Brief partial seizure; no loss of
consciousness
Brief generalized seizure
Multiple seizures despite
medical intervention
Life-threatening; prolonged
repetitive seizures
Death
Definition: A disorder characterized by a sudden, involuntary skeletal muscular contractions of cerebral or brain stem origin.
Sinus pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort in the face, between the eyes, or upper teeth originating from the sinuses.
Somnolence
Mild but more than usual
drowsiness or sleepiness
Moderate sedation; limiting
instrumental ADL
Obtundation or stupor
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by characterized by excessive sleepiness and drowsiness.
Spasticity
Mild or slight increase in muscle
tone
Moderate increase in muscle
tone and increase in resistance
through range of motion
Severe increase in muscle tone
and increase in resistance
through range of motion
Life-threatening; unable to move
active or passive range of
motion
Death
Definition: A disorder characterized by increased involuntary muscle tone that affects the regions interfering with voluntary movement. It results in gait, movement, and speech
disturbances.
Stroke
Asymptomatic or mild
neurologic deficit; radiographic
findings only
Moderate neurologic deficit
Severe neurologic deficit
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a sudden loss of sensory function due to an intracranial vascular event.
Syncope
 -
 -
Fainting; orthostatic collapse
 -
 -
Definition: A disorder characterized by spontaneous loss of consciousness caused by insufficient blood supply to the brain.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders
55
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Transient ischemic attacks
Mild neurologic deficit with or
without imaging confirmation
Moderate neurologic deficit with
or without imaging confirmation
 -
 -
 -
Definition: A disorder characterized by a brief attack (less than 24 hours) of cerebral dysfunction of vascular origin, with no persistent neurological deficit.
Tremor
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by the uncontrolled shaking movement of the whole body or individual parts.
Trigeminal nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the trigeminal nerve (fifth cranial nerve).
Vagus nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the vagus nerve (tenth cranial nerve).
Vasovagal reaction
 -
 -
Present
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a sudden drop of the blood pressure, bradycardia, and peripheral vasodilation that may lead to loss of consciousness. It results from an
increase in the stimulation of the vagus nerve.
Nervous system disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Pregnancy, puerperium and perinatal conditions
56
19. Pregnancy, puerperium and perinatal conditions
Pregnancy, puerperium and perinatal conditions
Grade
Adverse Event
1
2
3
4
5
Fetal death
 -
 -
 -
 -
Fetal loss at
any
gestational
age
Definition: A disorder characterized by death in utero; failure of the product of conception to show evidence of respiration, heartbeat, or definite movement of a voluntary muscle after
expulsion from the uterus, without possibility of resuscitation.
Fetal growth retardation
 -
<10% percentile of weight for
gestational age
<5% percentile of weight for
gestational age
<1% percentile of weight for
gestational age
 -
Definition: A disorder characterized by inhibition of fetal growth resulting in the inability of the fetus to achieve its potential weight.
Premature delivery
Delivery of a liveborn infant at
>34 to 37 weeks gestation
Delivery of a liveborn infant at
>28 to 34 weeks gestation
Delivery of a liveborn infant at
24 to 28 weeks gestation
Delivery of a liveborn infant at
24 weeks of gestation or less
 -
Definition: A disorder characterized by delivery of a viable infant before the normal end of gestation. Typically, viability is achievable between the twentieth and thirty-seventh week of
gestation.
Unintended pregnancy
 -
 -
Unintended pregnancy
 -
 -
Definition: A disorder characterized by an unexpected pregnancy at the time of conception.
Pregnancy, puerperium and
perinatal conditions - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate, local or noninvasive
intervention indicated; limiting
instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Psychiatric disorders
57
20. Psychiatric disorders
Psychiatric disorders
Grade
Adverse Event
1
2
3
4
5
Agitation
Mild mood alteration
Moderate mood alteration
Severe agitation; hospitalization
not indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a state of restlessness associated with unpleasant feelings of irritability and tension.
Anorgasmia
Inability to achieve orgasm not
adversely affecting relationship
Inability to achieve orgasm
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by an inability to achieve orgasm.
Anxiety
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization not
indicated
Life-threatening; hospitalization
indicated
Death
Definition: A disorder characterized by apprehension of danger and dread accompanied by restlessness, tension, tachycardia, and dyspnea unattached to a clearly identifiable
stimulus.
Confusion
Mild disorientation
Moderate disorientation; limiting
instrumental ADL
Severe disorientation; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a lack of clear and orderly thought and behavior.
Delayed orgasm
Delay in achieving orgasm not
adversely affecting relationship
Delay in achieving orgasm
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by sexual dysfunction characterized by a delay in climax.
Delirium
Mild acute confusional state
Moderate and acute confusional
state; limiting instrumental ADL
Severe and acute confusional
state; limiting self care ADL;
hospitalization indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by the acute and sudden development of confusion, illusions, movement changes, inattentiveness, agitation, and hallucinations. Usually, it is a
reversible condition.
Delusions
 -
Moderate delusional symptoms
Severe delusional symptoms;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by false personal beliefs held contrary to reality, despite contradictory evidence and common sense.
Depression
Mild depressive symptoms
Moderate depressive
symptoms; limiting instrumental
ADL
Severe depressive symptoms;
limiting self care ADL;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by melancholic feelings of grief or unhappiness.
Euphoria
Mild mood elevation
Moderate mood elevation
Severe mood elevation (e.g.,
hypomania)
 -
 -
Definition: A disorder characterized by an exaggerated feeling of well-being which is disproportionate to events and stimuli.
Hallucinations
Mild hallucinations (e.g.,
perceptual distortions)
Moderate hallucinations
Severe hallucinations;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by a false sensory perception in the absence of an external stimulus.
Insomnia
Mild difficulty falling asleep,
staying asleep or waking up
early
Moderate difficulty falling
asleep, staying asleep or
waking up early
Severe difficulty in falling
asleep, staying asleep or
waking up early
 -
 -
Definition: A disorder characterized by difficulty in falling asleep and/or remaining asleep.
Libido decreased
Decrease in sexual interest not
adversely affecting relationship
Decrease in sexual interest
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by a decrease in sexual desire.
Libido increased
Mild increase in sexual interest
not adversely affecting
relationship
Moderate increase in sexual
interest adversely affecting
relationship
Severe increase in sexual
interest leading to dangerous
behavior
 -
 -
Definition: A disorder characterized by an increase in sexual desire.
Mania
Mild manic symptoms (e.g.,
elevated mood, rapid thoughts,
rapid speech, decreased need
for sleep)
Moderate manic symptoms
(e.g., relationship and work
difficulties; poor hygiene)
Severe manic symptoms (e.g.,
hypomania; major sexual or
financial indiscretions);
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behavior and elevation of mood.
Personality change
Mild personality change
Moderate personality change
Severe personality change;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
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CTCAE 4.03 - June 14, 2010 : Psychiatric disorders
58
Psychiatric disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by a conspicuous change in a person's behavior and thinking.
Psychosis
Mild psychotic symptoms
Moderate psychotic symptoms
(e.g., disorganized speech;
impaired reality testing)
Severe psychotic symptoms
(e.g., paranoid; extreme
disorganization); hospitalization
not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by personality change, impaired functioning, and loss of touch with reality. It may be a manifestation of schizophrenia, bipolar disorder or brain
tumor.
Restlessness
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an inability to rest, relax or be still.
Suicidal ideation
Increased thoughts of death but
no wish to kill oneself
Suicidal ideation with no specific
plan or intent
Specific plan to commit suicide
without serious intent to die
which may not require
hospitalization
Specific plan to commit suicide
with serious intent to die which
requires hospitalization
 -
Definition: A disorder characterized by thoughts of taking one's own life.
Suicide attempt
 -
 -
Suicide attempt or gesture
without intent to die which may
not require hospitalization
Suicide attempt with intent to
die which requires
hospitalization
Death
Definition: A disorder characterized by self-inflicted harm in an attempt to end one's own life.
Psychiatric disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; disabling;  limiting
self care ADL
Life-threatening consequences;
hospitalization or urgent
intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Renal and urinary disorders
59
21. Renal and urinary disorders
Renal and urinary disorders
Grade
Adverse Event
1
2
3
4
5
Acute kidney injury
Creatinine level increase of >0.3
mg/dL; creatinine 1.5 - 2.0 x
above baseline
Creatinine 2 - 3 x above
baseline
Creatinine >3 x baseline or >4.0
mg/dL; hospitalization indicated
Life-threatening consequences;
dialysis indicated
Death
Definition: A disorder characterized by the acute loss of renal function and is traditionally classified as pre-renal (low blood flow into kidney), renal (kidney damage) and post-renal
causes (ureteral or bladder outflow obstruction).
Bladder perforation
 -
Extraperitoneal perforation,
indwelling catheter indicated
Intraperitoneal perforation;
elective radiologic, endoscopic
or operative intervention
indicated
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A disorder characterized by a rupture in the bladder wall.
Bladder spasm
Intervention not indicated
Antispasmodics indicated
Hospitalization indicated
 -
 -
Definition: A disorder characterized by a sudden and involuntary contraction of the bladder wall.
Chronic kidney disease
eGFR (estimated Glomerular
Filtration Rate) or CrCl
(creatinine clearance) <LLN - 60
ml/min/1.73 m2 or proteinuria
2+ present; urine
protein/creatinine >0.5
eGFR or CrCl 59 - 30
ml/min/1.73 m2
eGFR or CrCl 29 - 15
ml/min/1.73 m2
eGFR or CrCl <15 ml/min/1.73
m2; dialysis or renal transplant
indicated
Death
Definition: A disorder characterized by gradual and usually permanent loss of kidney function resulting in renal failure.
Cystitis noninfective
Microscopic hematuria; minimal
increase in frequency, urgency,
dysuria, or nocturia; new onset
of incontinence
Moderate hematuria; moderate
increase in frequency, urgency,
dysuria, nocturia or
incontinence; urinary catheter
placement or bladder irrigation
indicated; limiting instrumental
ADL
Gross hematuria; transfusion, IV
medications or hospitalization
indicated; elective endoscopic,
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by inflammation of the bladder which is not caused by an infection of the urinary tract.
Hematuria
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; urinary catheter
or bladder irrigation indicated;
limiting instrumental ADL
Gross hematuria; transfusion, IV
medications or hospitalization
indicated; elective endoscopic,
radiologic or operative
intervention indicated; limiting
self care ADL
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate blood in the urine.
Hemoglobinuria
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by laboratory test results that indicate the presence of free hemoglobin in the urine.
Proteinuria
1+ proteinuria; urinary protein
<1.0 g/24 hrs
Adults: 2+ proteinuria; urinary
protein 1.0 - 3.4 g/24 hrs;
Pediatric: urine P/C
(Protein/Creatinine) ratio 0.5 -
1.9
Adults: urinary protein >=3.5
g/24 hrs;
Pediatric: urine P/C >1.9
 -
 -
Definition: A disorder characterized by laboratory test results that indicate the presence of excessive protein in the urine. It is predominantly albumin, but also globulin.
Renal calculi
Asymptomatic or mild
symptoms; occasional use of
nonprescription analgesics
indicated
Symptomatic; oral antiemetics
indicated; around the clock
nonprescription analgesics or
any oral narcotic analgesics
indicated
Hospitalization indicated; IV
intervention (e.g., analgesics,
antiemetics); elective
endoscopic or radiologic
intervention indicated
Life-threatening consequences;
urgent radiologic, endoscopic or
operative intervention indicated
Death
Definition: A disorder characterized by the formation of crystals in the pelvis of the kidney.
Renal colic
Mild pain not interfering with
activity; nonprescription
medication indicated
Moderate pain; limiting
instrumental ADL; prescription
medication indicated
Hospitalization indicated;
limiting self care ADL
 -
 -
Definition: A disorder characterized by paroxysmal and severe flank marked discomfort radiating to the inguinal area. Often, the cause is the passage of kidney stones.
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CTCAE 4.03 - June 14, 2010 : Renal and urinary disorders
60
Renal and urinary disorders
Grade
Adverse Event
1
2
3
4
5
Renal hemorrhage
Mild symptoms; intervention not
indicated
Analgesics and hematocrit
monitoring indicated
Transfusion, radiation, or
hospitalization indicated;
elective radiologic, endoscopic
or operative intervention
indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by bleeding from the kidney.
Urinary fistula
 -
Noninvasive intervention
indicated; urinary or suprapubic
catheter placement indicated
Limiting self care ADL; elective
radiologic, endoscopic or
operative intervention indicated;
permanent urinary diversion
indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between any part of the urinary system and another organ or anatomic site.
Urinary frequency
Present
Limiting instrumental ADL;
medical management indicated
 -
 -
 -
Definition: A disorder characterized by urination at short intervals.
Urinary incontinence
Occasional (e.g., with coughing,
sneezing, etc.), pads not
indicated
Spontaneous; pads indicated;
limiting instrumental ADL
Intervention indicated (e.g.,
clamp, collagen injections);
operative intervention indicated;
limiting self care ADL
 -
 -
Definition: A disorder characterized by inability to control the flow of urine from the bladder.
Urinary retention
Urinary, suprapubic or
intermittent catheter placement
not indicated; able to void with
some residual
Placement of urinary,
suprapubic or intermittent
catheter placement indicated;
medication indicated
Elective operative or radiologic
intervention indicated;
substantial loss of affected
kidney function or mass
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A disorder characterized by accumulation of urine within the bladder because of the inability to urinate.
Urinary tract obstruction
Asymptomatic; clinical or
diagnostic observations only
Symptomatic but no
hydronephrosis, sepsis or renal
dysfunction; urethral dilation,
urinary or suprapubic catheter
indicated
Symptomatic and altered organ
function (e.g., hydronephrosis,
or renal dysfunction); elective
radiologic, endoscopic or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the normal flow of contents of the urinary tract.
Urinary tract pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the urinary tract.
Urinary urgency
Present
Limiting instrumental ADL;
medical management indicated
 -
 -
 -
Definition: A disorder characterized by a sudden compelling urge to urinate.
Urine discoloration
Present
 -
 -
 -
 -
Definition: A disorder characterized by a change in the color of the urine.
Renal and urinary disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate, local or noninvasive
intervention indicated; limiting
instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders
61
22. Reproductive system and breast disorders
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Azoospermia
 -
 -
Absence of sperm in ejaculate
 -
 -
Definition: A disorder characterized by laboratory test results that indicate complete absence of spermatozoa in the semen.
Breast atrophy
Minimal asymmetry; minimal
atrophy
Moderate asymmetry; moderate
atrophy
Asymmetry >1/3 of breast
volume; severe atrophy
 -
 -
Definition: A disorder characterized by underdevelopment of the breast.
Breast pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the breast region.
Dysmenorrhea
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by abnormally painful abdominal cramps during menses.
Dyspareunia
Mild discomfort or pain
associated with vaginal
penetration; discomfort relieved
with use of vaginal lubricants or
estrogen
Moderate discomfort or pain
associated with vaginal
penetration; discomfort or pain
partially relieved with use of
vaginal lubricants or estrogen
Severe discomfort or pain
associated with vaginal
penetration; discomfort or pain
unrelieved by vaginal lubricants
or estrogen
 -
 -
Definition: A disorder characterized by painful or difficult coitus.
Ejaculation disorder
Diminished ejaculation
Anejaculation or retrograde
ejaculation
 -
 -
 -
Definition: A disorder characterized by problems related to ejaculation. This category includes premature, delayed, retrograde and painful ejaculation.
Erectile dysfunction
Decrease in erectile function
(frequency or rigidity of
erections) but intervention not
indicated (e.g., medication or
use of mechanical device,
penile pump)
Decrease in erectile function
(frequency/rigidity of erections),
erectile intervention indicated,
(e.g., medication or mechanical
devices such as penile pump)
Decrease in erectile function
(frequency/rigidity of erections)
but erectile intervention not
helpful (e.g., medication or
mechanical devices such as
penile pump); placement of a
permanent penile prosthesis
indicated (not previously
present)
 -
 -
Definition: A disorder characterized by the persistent or recurrent inability to achieve or to maintain an erection during sexual activity.
Fallopian tube obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the normal flow of the contents in the fallopian tube.
Fallopian tube stenosis
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated (e.g., organ resection)
Death
Definition: A disorder characterized by a narrowing of the fallopian tube lumen.
Female genital tract fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between a female reproductive system organ and another organ or anatomic site.
Feminization acquired
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by the development of secondary female sex characteristics in males due to extrinsic factors.
Genital edema
Mild swelling or obscuration of
anatomic architecture on close
inspection
Readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour
Lymphorrhea; gross deviation
from normal anatomic contour;
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the genitals.
Gynecomastia
Asymptomatic breast
enlargement
Symptomatic (e.g., pain or
psychosocial impact)
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by excessive development of the breasts in males.
Hematosalpinx
Minimal bleeding identified on
imaging study or laparoscopy;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by the presence of blood in a fallopian tube.
Irregular menstruation
Intermittent menses with
skipped menses for no more
than 1 to 3 months
Intermittent menses with
skipped menses for more than 4
to 6 months
Persistent amenorrhea for more
than 6 months
 -
 -
Definition: A disorder characterized by irregular cycle or duration of menses.
Lactation disorder
Mild changes in lactation, not
significantly affecting production
or expression of breast milk
Changes in lactation,
significantly affecting breast
production or expression of
breast milk
 -
 -
 -
Definition: A disorder characterized by disturbances of milk secretion. It is not necessarily related to pregnancy that is observed in females and can be observed in males.
Menorrhagia
Mild; iron supplements indicated Moderate symptoms; medical
intervention indicated (e.g.,
hormones)
Severe; transfusion indicated;
surgical intervention indicated
(e.g., hysterectomy)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormally heavy vaginal bleeding during menses.
Nipple deformity
Asymptomatic; asymmetry with
slight retraction and/or
thickening of the nipple areolar
complex
Symptomatic; asymmetry of
nipple areolar complex with
moderate retraction and/or
thickening of the nipple areolar
complex
 -
 -
 -
Definition: A disorder characterized by a malformation of the nipple.
Oligospermia
Sperm concentration >48
million/mL or motility >68%
Sperm concentration 13 - 48
million/mL or motility 32 - 68%
Sperm concentration <13
million/mL or motility <32%
 -
 -
Definition: A disorder characterized by a decrease in the number of spermatozoa in the semen.
Ovarian hemorrhage
Minimal bleeding identified on
imaging study or laproscopy;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic  intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the ovary.
Ovarian rupture
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by tearing or disruption of the ovarian tissue.
Ovulation pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in one side of the abdomen between menstrual cycles, around the time of the discharge of the ovum from the
ovarian follicle.
Pelvic floor muscle weakness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic, not interfering
with bladder, bowel, or vaginal
function; limiting instrumental
ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a reduction in the strength of the muscles of the pelvic floor.
Pelvic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pelvis.
Penile pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the penis.
Perineal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the area between the genital organs and the anus.
Premature menopause
 -
 -
Present
 -
 -
Definition: A disorder characterized by ovarian failure before the age of 40. Symptoms include hot flashes, night sweats, mood swings and a decrease in sex drive.
Prostatic hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by bleeding from the prostate gland.
Prostatic obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by compression of the urethra secondary to enlargement of the prostate gland. This results in voiding difficulties (straining to void, slow urine
stream, and incomplete emptying of the bladder).
Prostatic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the prostate gland.
Scrotal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the scrotal area.
Spermatic cord hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the spermatic cord.
Spermatic cord obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the normal flow of the contents of the spermatic cord.
Testicular disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic but not interfering
with urination or sexual
activities; intervention not
indicated; limiting instrumental
ADL
Severe symptoms; interfering
with urination or sexual function;
limiting self care ADL;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the testis.
Testicular hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the testis.
Testicular pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the testis.
Uterine fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the uterus and another organ or anatomic site.
Uterine hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the uterus.
Uterine obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the uterine outlet.
Uterine pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the uterus.
Vaginal discharge
Mild vaginal discharge (greater
than baseline for patient)
Moderate to heavy vaginal
discharge; use of perineal pad
or tampon indicated
 -
 -
 -
Definition: A disorder characterized by vaginal secretions. Mucus produced by the cervical glands is discharged from the vagina naturally, especially during the childbearing years.
Vaginal dryness
Mild vaginal dryness not
interfering with sexual function
Moderate vaginal dryness
interfering with sexual function
or causing frequent discomfort
Severe vaginal dryness
resulting in dyspareunia or
severe discomfort
 -
 -
Definition: A disorder characterized by an uncomfortable feeling of itching and burning in the vagina.
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Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Vaginal fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the vagina and another organ or anatomic site.
Vaginal hemorrhage
Minimal bleeding identified on
clinical exam or imaging study;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the vagina.
Vaginal inflammation
Mild discomfort or pain, edema,
or redness
Moderate discomfort or pain,
edema, or redness; limiting
instrumental ADL
Severe discomfort or pain,
edema, or redness; limiting self
care ADL; small areas of
mucosal ulceration
Widespread areas of mucosal
ulceration; life-threatening
consequences; urgent
intervention indicated
Death
Definition: A disorder characterized by inflammation involving the vagina. Symptoms may include redness, edema, marked discomfort and an increase in vaginal discharge.
Vaginal obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of vaginal canal.
Vaginal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the vagina.
Vaginal perforation
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the vaginal wall.
Vaginal stricture
Asymptomatic; mild vaginal
shortening or narrowing
Vaginal narrowing and/or
shortening not interfering with
physical examination
Vaginal narrowing and/or
shortening interfering with the
use of tampons, sexual activity
or physical examination
 -
Death
Definition: A disorder characterized by a narrowing of the vaginal canal.
Vaginismus
Mild discomfort or pain
associated with vaginal
spasm/tightening; no impact
upon sexual function or physical
examination
Moderate discomfort or pain
associated with vaginal
spasm/tightening; disruption in
sexual function and physical
examination
Severe discomfort or pain
associated with vaginal
spasm/tightening; unable to
tolerate vaginal penetration or
physical examination
 -
 -
Definition: A disorder characterized by involuntary spasms of the pelvic floor muscles, resulting in pathologic tightness of the vaginal wall during penetration such as during sexual
intercourse.
Reproductive system and breast
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders
65
23. Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Adult respiratory distress
syndrome
 -
 -
Present with radiologic findings;
intubation not indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by progressive and life-threatening pulmonary distress in the absence of an underlying pulmonary condition, usually following major trauma or
surgery.
Allergic rhinitis
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by an inflammation of the nasal mucous membranes caused by an IgE-mediated response to external allergens. The inflammation may also
involve the mucous membranes of the sinuses, eyes, middle ear, and pharynx. Symptoms include sneezing, nasal congestion, rhinorrhea and itching.
Apnea
 -
 -
Present; medical intervention
indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by cessation of breathing.
Aspiration
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Altered eating habits; coughing
or choking episodes after eating
or swallowing; medical
intervention indicated (e.g.,
suction or oxygen)
Dyspnea and pneumonia
symptoms (e.g., aspiration
pneumonia); hospitalization
indicated; unable to aliment
orally
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by inhalation of solids or liquids into the lungs.
Atelectasis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., dyspnea,
cough); medical intervention
indicated (e.g., chest
physiotherapy, suctioning);
bronchoscopic suctioning
Oxygen indicated;
hospitalization or elective
operative intervention indicated
(e.g., stent, laser)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by the collapse of part or the entire lung.
Bronchial fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
with thoracoplasty, chronic open
drainage or multiple
thoracotomies indicated
Death
Definition: A disorder characterized by an abnormal communication between the bronchus and another organ or anatomic site.
Bronchial obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., mild
wheezing); endoscopic
evaluation indicated;
radiographic evidence of
atelectasis/lobar collapse;
medical management indicated
(e.g., steroids, bronchodilators)
Shortness of breath with stridor;
endoscopic intervention
indicated (e.g., laser, stent
placement)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by blockage of a bronchus passage, most often by bronchial secretions and exudates.
Bronchial stricture
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., rhonchi or
wheezing) but without
respiratory distress; medical
intervention indicated (e.g.,
steroids, bronchodilators)
Shortness of breath with stridor;
endoscopic intervention
indicated (e.g., laser, stent
placement)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the bronchial tube.
Bronchopleural fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
with thoracoplasty, chronic open
drainage or multiple
thoracotomies indicated
Death
Definition: A disorder characterized by an abnormal communication between a bronchus and the pleural cavity.
Bronchopulmonary hemorrhage
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the bronchial wall and/or lung parenchyma.
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Bronchospasm
Mild symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Limiting self care ADL; oxygen
saturation decreased
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by a sudden contraction of the smooth muscles of the bronchial wall.
Chylothorax
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thoracentesis or
tube drainage indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by milky pleural effusion (abnormal collection of fluid) resulting from accumulation of lymph fluid in the pleural cavity.
Cough
Mild symptoms; nonprescription
intervention indicated
Moderate symptoms, medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by sudden, often repetitive, spasmodic contraction of the thoracic cavity, resulting in violent release of air from the lungs and usually accompanied
by a distinctive sound.
Dyspnea
Shortness of breath with
moderate exertion
Shortness of breath with
minimal exertion; limiting
instrumental ADL
Shortness of breath at rest;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an uncomfortable sensation of difficulty breathing.
Epistaxis
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated (e.g.,
nasal packing, cauterization;
topical vasoconstrictors)
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the nose.
Hiccups
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; interfering
with sleep; limiting self care
ADL
 -
 -
Definition: A disorder characterized by repeated gulp sounds that result from an involuntary opening and closing of the glottis. This is attributed to a spasm of the diaphragm.
Hoarseness
Mild or intermittent voice
change; fully understandable;
self-resolves
Moderate or persistent voice
changes; may require
occasional repetition but
understandable on telephone;
medical evaluation indicated
Severe voice changes including
predominantly whispered
speech
 -
 -
Definition: A disorder characterized by harsh and raspy voice arising from or spreading to the larynx.
Hypoxia
 -
Decreased oxygen saturation
with exercise (e.g., pulse
oximeter <88%); intermittent
supplemental oxygen
Decreased oxygen saturation at
rest (e.g., pulse oximeter <88%
or PaO2 <=55 mm Hg)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a decrease in the level of oxygen in the body.
Laryngeal edema
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated (e.g.,
dexamethasone, epinephrine,
antihistamines)
Stridor; respiratory distress;
hospitalization indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the larynx.
Laryngeal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
indicated (e.g., thoracoplasty,
chronic open drainage or
multiple thoracotomies)
Death
Definition: A disorder characterized by an abnormal communication between the larynx and another organ or anatomic site.
Laryngeal hemorrhage
Mild cough or trace hemoptysis;
laryngoscopic findings
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by bleeding from the larynx.
Laryngeal inflammation
Mild sore throat; raspy voice
Moderate sore throat;
analgesics indicated
Severe throat pain; endoscopic
intervention indicated
 -
 -
Definition: A disorder characterized by an inflammation involving the larynx.
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67
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Laryngeal mucositis
Endoscopic findings only; mild
discomfort with normal intake
Moderate discomfort; altered
oral intake
Severe pain; severely altered
eating/swallowing; medical
intervention indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the larynx.
Laryngeal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids); limiting instrumental
ADL
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the laryngeal airway.
Laryngeal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids)
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a narrowing of the laryngeal airway.
Laryngopharyngeal dysesthesia
Mild symptoms; no anxiety;
intervention not indicated
Moderate symptoms; mild
anxiety, but no dyspnea; short
duration of observation and or
anxiolytic indicated; limiting
instrumental ADL
Severe symptoms; dyspnea and
swallowing difficulty; limiting self
care ADL
Life-threatening consequences
Death
Definition: A disorder characterized by an uncomfortable persistent sensation in the area of the laryngopharynx.
Laryngospasm
 -
Transient episode; intervention
not indicated
Recurrent episodes;
noninvasive intervention
indicated (e.g., breathing
technique, pressure point
massage)
Persistent or severe episodes
associated with syncope; urgent
intervention indicated (e.g.,
fiberoptic laryngoscopy,
intubation, botox injection)
Death
Definition: A disorder characterized by paroxysmal spasmodic muscular contraction of the vocal cords.
Mediastinal hemorrhage
Radiologic evidence only;
minimal symptoms; intervention
not indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
(e.g., hemostasis of bleeding
site)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the mediastinum.
Nasal congestion
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Associated with bloody nasal
discharge or epistaxis
 -
 -
Definition: A disorder characterized by obstruction of the nasal passage due to mucosal edema.
Pharyngeal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the pharynx and another organ or anatomic site.
Pharyngeal hemorrhage
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the pharynx.
Pharyngeal mucositis
Endoscopic findings only;
minimal symptoms with normal
oral intake; mild pain but
analgesics not indicated
Moderate pain and analgesics
indicated; altered oral intake;
limiting instrumental ADL
Severe pain; unable to
adequately aliment or hydrate
orally; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the pharynx.
Pharyngeal necrosis
 -
 -
Inability to aliment adequately
by GI tract; tube feeding or TPN
indicated; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by a necrotic process occurring in the pharynx.
Pharyngeal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids); limiting instrumental
ADL
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a narrowing of the pharyngeal airway.
Pharyngolaryngeal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pharyngolaryngeal region.
Pleural effusion
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; intervention
indicated (e.g., diuretics or
limited therapeutic
thoracentesis)
Symptomatic with respiratory
distress and hypoxia; surgical
intervention including chest tube
or pleurodesis indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by an increase in amounts of fluid within the pleural cavity. Symptoms include shortness of breath, cough and marked chest discomfort.
Pleural hemorrhage
Asymptomatic; mild hemorrhage
confirmed by thoracentesis
Symptomatic or associated with
pneumothorax; chest tube
drainage indicated
>1000 ml of blood evacuated;
persistent bleeding (150-200
ml/hr for 2 - 4 hr); persistent
transfusion indicated; elective
operative intervention indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the pleural cavity.
Pleuritic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pleura.
Pneumonitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; oxygen indicated
Life-threatening respiratory
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma.
Pneumothorax
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; intervention
indicated (e.g., tube placement
without sclerosis)
Sclerosis and/or operative
intervention indicated;
hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormal presence of air in the pleural cavity resulting in the collapse of the lung.
Postnasal drip
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by excessive mucous secretion in the back of the nasal cavity or throat, causing sore throat and/or coughing.
Productive cough
Occasional/minimal production
of sputum with cough
Moderate sputum production;
limiting instrumental ADL
Persistent or copious production
of sputum; limiting self care ADL
 -
 -
Definition: A disorder characterized by expectorated secretions upon coughing.
Pulmonary edema
Radiologic findings only;
minimal dyspnea on exertion
Moderate dyspnea on exertion;
medical intervention indicated;
limiting instrumental ADL
Severe dyspnea or dyspnea at
rest; oxygen indicated; limiting
self care ADL
Life-threatening respiratory
compromise; urgent intervention
or intubation with ventilatory
support indicated
Death
Definition: A disorder characterized by accumulation of fluid in the lung tissues that causes a disturbance of the gas exchange that may lead to respiratory failure.
Pulmonary fibrosis
Mild hypoxemia; radiologic
pulmonary fibrosis <25% of lung
volume
Moderate hypoxemia; evidence
of pulmonary hypertension;
radiographic pulmonary fibrosis
25 - 50%
Severe hypoxemia; evidence of
right-sided heart failure;
radiographic pulmonary fibrosis
>50 - 75%
Life-threatening consequences
(e.g., hemodynamic/pulmonary
complications); intubation with
ventilatory support indicated;
radiographic pulmonary fibrosis
>75% with severe
honeycombing
Death
Definition: A disorder characterized by the replacement of the lung tissue by connective tissue, leading to progressive dyspnea, respiratory failure or right heart failure.
Pulmonary fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Limiting self care ADL;
endoscopic stenting or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an abnormal communication between the lung and another organ or anatomic site.
Pulmonary hypertension
Minimal dyspnea; findings on
physical exam or other
evaluation
Moderate dyspnea, cough;
requiring evaluation by cardiac
catheterization and medical
intervention
Severe symptoms, associated
with hypoxemia, right heart
failure; oxygen indicated
Life-threatening airway
consequences; urgent
intervention indicated (e.g.,
tracheotomy or intubation)
Death
Definition: A disorder characterized by an increase in pressure within the pulmonary circulation due to lung or heart disorder.
Respiratory failure
 -
 -
 -
Life-threatening consequences;
urgent intervention, intubation,
or ventilatory support indicated
Death
Definition: A disorder characterized by impaired gas exchange by the respiratory system resulting in hypoxemia and a decrease in oxygenation of the tissues that may be associated
with an increase in arterial levels of carbon dioxide.
Retinoic acid syndrome
Fluid retention; <3 kg of weight
gain; intervention with fluid
restriction and/or diuretics
indicated
Moderate signs or symptoms;
steroids indicated
Severe symptoms;
hospitalization indicated
Life-threatening consequences;
ventilatory support indicated
Death
Definition: A disorder characterized by weight gain, dyspnea, pleural and pericardial effusions, leukocytosis and/or renal failure originally described in patients treated with all-trans
retinoic acid.
Sinus disorder
Asymptomatic mucosal crusting;
blood-tinged secretions
Symptomatic stenosis or
edema/narrowing interfering
with airflow; limiting instrumental
ADL
Stenosis with significant nasal
obstruction; limiting self care
ADL
Necrosis of soft tissue or bone;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by involvement of the paranasal sinuses.
Sleep apnea
Snoring and nocturnal sleep
arousal without apneic periods
Moderate apnea and oxygen
desaturation; excessive daytime
sleepiness; medical evaluation
indicated; limiting instrumental
ADL
Oxygen desaturation;
associated with hypertension;
medical intervention indicated;
limiting self care ADL
Cardiovascular or
neuropsychiatric symptoms;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by cessation of breathing for short periods during sleep.
Sneezing
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by the involuntary expulsion of air from the nose.
Sore throat
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL; limiting ability to swallow
 -
 -
Definition: A disorder characterized by of marked discomfort in the throat
Stridor
 -
 -
Respiratory distress limiting self
care ADL; medical intervention
indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a high pitched breathing sound due to laryngeal or upper airway obstruction.
Tracheal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
indicated (e.g., thoracoplasty,
chronic open drainage or
multiple thoracotomies)
Death
Definition: A disorder characterized by an abnormal communication between the trachea and another organ or anatomic site.
Tracheal mucositis
Endoscopic findings only;
minimal hemoptysis, pain, or
respiratory symptoms
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe pain; hemorrhage or
respiratory symptoms; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the trachea.
Tracheal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids)
Stridor or respiratory distress
limiting self care ADL;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a narrowing of the trachea.
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Voice alteration
Mild or intermittent change from
normal voice
Moderate or persistent change
from normal voice; still
understandable
Severe voice changes including
predominantly whispered
speech; may require frequent
repetition or face-to-face contact
for understandability; may
require assistive technology
 -
 -
Definition: A disorder characterized by a change in the sound and/or speed of the voice.
Wheezing
Detectable airway noise with
minimal symptoms
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe respiratory symptoms
limiting self care ADL; oxygen
therapy or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a high-pitched, whistling sound during breathing. It results from the narrowing or obstruction of the respiratory airways.
Respiratory, thoracic and
mediastinal disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders
71
24. Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Alopecia
Hair loss of <50% of normal for
that individual that is not
obvious from a distance but only
on close inspection; a different
hair style may be required to
cover the hair loss but it does
not require a wig or hair piece to
camouflage
Hair loss of >=50% normal for
that individual that is readily
apparent to others; a wig or hair
piece is necessary if the patient
desires to completely
camouflage the hair loss;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by a decrease in density of hair compared to normal for a given individual at a given age and body location.
Body odor
Mild odor; physician intervention
not indicated; self care
interventions
Pronounced odor; psychosocial
impact; patient seeks medical
intervention
 -
 -
 -
Definition: A disorder characterized by an abnormal body smell resulting from the growth of bacteria on the body.
Bullous dermatitis
Asymptomatic; blisters covering
<10% BSA
Blisters covering 10 - 30% BSA;
painful blisters; limiting
instrumental ADL
Blisters covering >30% BSA;
limiting self care ADL
Blisters covering >30% BSA;
associated with fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by inflammation of the skin characterized by the presence of bullae which are filled with fluid.
Dry skin
Covering <10% BSA and no
associated erythema or pruritus
Covering 10 - 30% BSA and
associated with erythema or
pruritus; limiting instrumental
ADL
Covering >30% BSA and
associated with pruritus; limiting
self care ADL
 -
 -
Definition: A disorder characterized by flaky and dull skin; the pores are generally fine, the texture is a papery thin texture.
Erythema multiforme
Target lesions covering <10%
BSA and not associated with
skin tenderness
Target lesions covering 10 -
30% BSA and associated with
skin tenderness
Target lesions covering >30%
BSA and associated with oral or
genital erosions
Target lesions covering >30%
BSA; associated with fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by target lesions (a pink-red ring around a pale center).
Erythroderma
 -
Erythema covering >90% BSA
without associated symptoms;
limiting instrumental ADL
Erythema covering >90% BSA
with associated symptoms (e.g.,
pruritus or tenderness); limiting
self care ADL
Erythema covering >90% BSA
with associated fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by generalized inflammatory erythema and exfoliation. The inflammatory process involves > 90% of the body surface area.
Fat atrophy
Covering <10% BSA and
asymptomatic
Covering 10 - 30% BSA and
associated with erythema or
tenderness; limiting instrumental
ADL
Covering >30% BSA;
associated with erythema or
tenderness; limiting self-care
ADL
 -
 -
Definition: A disorder characterized by shrinking of adipose tissue.
Hirsutism
In women, increase in length,
thickness or density of hair in a
male distribution that the patient
is able to camouflage by
periodic shaving, bleaching, or
removal of hair
In women, increase in length,
thickness or density of hair in a
male distribution that requires
daily shaving or consistent
destructive means of hair
removal to camouflage;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by the presence of excess hair growth in women in anatomic sites where growth is considered to be a secondary male characteristic and under
androgen control (beard, moustache, chest, abdomen)
Hyperhidrosis
Limited to one site (palms,
soles, or axillae); self care
interventions
Involving >1 site; patient seeks
medical intervention; associated
with psychosocial impact
Generalized involving sites
other than palms, soles, or
axillae; associated with
electrolyte/hemodynamic
imbalance
 -
 -
Definition: A disorder characterized by excessive perspiration.
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders
72
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Hypertrichosis
Increase in length, thickness or
density of hair that the patient is
either able to camouflage by
periodic shaving or removal of
hairs or is not concerned
enough about the overgrowth to
use any form of hair removal
Increase in length, thickness or
density of hair at least on the
usual exposed areas of the
body [face (not limited to
beard/moustache area)
plus/minus arms] that requires
frequent  shaving or use of
destructive means of hair
removal to camouflage;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by hair density or length beyond the accepted limits of normal in a particular body region, for a particular age or race.
Hypohidrosis
 -
Symptomatic; limiting
instrumental ADL
Increase in body temperature;
limiting self care ADL
Heat stroke
Death
Definition: A disorder characterized by reduced sweating.
Lipohypertrophy
Asymptomatic and covering
<10% BSA
Covering 10 - 30% BSA and
associated tenderness; limiting
instrumental ADL
Covering >30% BSA and
associated tenderness and
narcotics or NSAIDs indicated;
lipohypertrophy; limiting self
care ADL
 -
 -
Definition: A disorder characterized by hypertrophy of the subcutaneous adipose tissue at the site of multiple subcutaneous injections of insulin.
Nail discoloration
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by a change in the color of the nail plate.
Nail loss
Asymptomatic separation of the
nail bed from the nail plate or
nail loss
Symptomatic separation of the
nail bed from the nail plate or
nail loss; limiting instrumental
ADL
 -
 -
 -
Definition: A disorder characterized by loss of all or a portion of the nail.
Nail ridging
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by vertical or horizontal ridges on the nails.
Pain of skin
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the skin.
Palmar-plantar
erythrodysesthesia syndrome
Minimal skin changes or
dermatitis (e.g., erythema,
edema, or hyperkeratosis)
without pain
Skin changes (e.g., peeling,
blisters, bleeding, edema, or
hyperkeratosis) with pain;
limiting instrumental ADL
Severe skin changes (e.g.,
peeling, blisters, bleeding,
edema, or hyperkeratosis) with
pain; limiting self care ADL
 -
 -
Definition: A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet.
Periorbital edema
Soft or non-pitting
Indurated or pitting edema;
topical intervention indicated
Edema associated with visual
disturbance; increased
intraocular pressure, glaucoma
or retinal hemorrhage; optic
neuritis; diuretics indicated;
operative intervention indicated
 -
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid around the orbits of the face.
Photosensitivity
Painless erythema and
erythema covering <10% BSA
Tender erythema covering 10 -
30% BSA
Erythema covering >30% BSA
and erythema with blistering;
photosensitivity; oral
corticosteroid therapy indicated;
pain control indicated (e.g.,
narcotics or NSAIDs)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in sensitivity of the skin to light.
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders
73
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Pruritus
Mild or localized; topical
intervention indicated
Intense or widespread;
intermittent; skin changes from
scratching (e.g., edema,
papulation, excoriations,
lichenification, oozing/crusts);
oral intervention indicated;
limiting instrumental ADL
Intense or widespread;
constant; limiting self care ADL
or sleep; oral corticosteroid or
immunosuppressive therapy
indicated
 -
 -
Definition: A disorder characterized by an intense itching sensation.
Purpura
Combined area of lesions
covering <10% BSA
Combined area of lesions
covering 10 - 30% BSA;
bleeding with trauma
Combined area of lesions
covering >30% BSA;
spontaneous bleeding
 -
 -
Definition: A disorder characterized by hemorrhagic areas of the skin and mucous membrane. Newer lesions appear reddish in color. Older lesions are usually a darker purple color
and eventually become a brownish-yellow color.
Rash acneiform
Papules and/or pustules
covering <10% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness
Papules and/or pustules
covering 10 - 30% BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness; associated with
psychosocial impact; limiting
instrumental ADL
Papules and/or pustules
covering >30% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness; limiting self care
ADL; associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering any % BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness and are associated
with extensive superinfection
with IV antibiotics indicated; life-
threatening consequences
Death
Definition: A disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest and back.
Rash maculo-papular
Macules/papules covering
<10% BSA with or without
symptoms (e.g., pruritus,
burning, tightness)
Macules/papules covering 10 -
30% BSA with or without
symptoms (e.g., pruritus,
burning, tightness); limiting
instrumental ADL
Macules/papules covering
>30% BSA with or without
associated symptoms; limiting
self care ADL
 -
 -
Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbillform rash, it is one of the most common cutaneous adverse
events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus.
Scalp pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the skin covering the top and the back of the head.
Skin atrophy
Covering <10% BSA;
associated with telangiectasias
or changes in skin color
Covering 10 - 30% BSA;
associated with striae or
adnexal structure loss
Covering >30% BSA;
associated with ulceration
 -
 -
Definition: A disorder characterized by the degeneration and thinning of the epidermis and dermis.
Skin hyperpigmentation
Hyperpigmentation covering
<10% BSA; no psychosocial
impact
Hyperpigmentation covering
>10% BSA; associated
psychosocial impact
 -
 -
 -
Definition: A disorder characterized by darkening of the skin due to excessive melanin deposition.
Skin hypopigmentation
Hypopigmentation or
depigmentation covering <10%
BSA; no psychosocial impact
Hypopigmentation or
depigmentation covering >10%
BSA; associated psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by loss of skin pigment.
Skin induration
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration, unable to
slide or pinch skin; limiting joint
movement or orifice (e.g.,
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by an area of hardness in the skin.
Skin ulceration
Combined area of ulcers <1 cm;
nonblanchable erythema of
intact skin with associated
warmth or edema
Combined area of ulcers 1 - 2
cm; partial thickness skin loss
involving skin or subcutaneous
fat
Combined area of ulcers >2 cm;
full-thickness skin loss involving
damage to or necrosis of
subcutaneous tissue that may
extend down to fascia
Any size ulcer with extensive
destruction, tissue necrosis, or
damage to muscle, bone, or
supporting structures with or
without full thickness skin loss
Death
Definition: A disorder characterized by circumscribed, inflammatory and necrotic erosive lesion on the skin.
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74
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Stevens-Johnson syndrome
 -
 -
Skin sloughing covering <10%
BSA with associated signs (e.g.,
erythema, purpura, epidermal
detachment and mucous
membrane detachment)
Skin sloughing covering 10 -
30% BSA with associated signs
(e.g., erythema, purpura,
epidermal detachment and
mucous membrane
detachment)
Death
Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the
mucous membranes.
Telangiectasia
Telangiectasias covering <10%
BSA
Telangiectasias covering >10%
BSA; associated with
psychosocial impact
 -
 -
 -
Definition: A disorder characterized by local dilatation of small vessels resulting in red discoloration of the skin or mucous membranes.
Toxic epidermal necrolysis
 -
 -
 -
Skin sloughing covering >=30%
BSA with associated symptoms
(e.g., erythema, purpura, or
epidermal detachment)
Death
Definition: A disorder characterized by greater than 30% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the
mucous membranes.
Urticaria
Urticarial lesions covering <10%
BSA; topical intervention
indicated
Urticarial lesions covering 10 -
30% BSA; oral intervention
indicated
Urticarial lesions covering >30%
BSA; IV intervention indicated
 -
 -
Definition: A disorder characterized by an itchy skin eruption characterized by wheals with pale interiors and well-defined red margins.
Skin and subcutaneous tissue
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Social circumstances
75
25. Social circumstances
Social circumstances
Grade
Adverse Event
1
2
3
4
5
Menopause
Menopause occurring at age 46
- 53 years of age
Menopause occurring at age 40
- 45 years of age
Menopause occurring before
age 40 years of age
 -
 -
Definition: A disorder characterized by the permanent cessation of menses, usually defined by 12 consecutive months of amenorrhea in a woman over 45 years of age.
Social circumstances - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Surgical and medical procedures
76
26. Surgical and medical procedures
Surgical and medical procedures
Grade
Adverse Event
1
2
3
4
5
Surgical and medical
procedures - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Vascular disorders
77
27. Vascular disorders
Vascular disorders
Grade
Adverse Event
1
2
3
4
5
Capillary leak syndrome
 -
Symptomatic; medical
intervention indicated
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by leakage of intravascular fluids into the extravascular space. This syndrome is observed in patients who demonstrate a state of generalized
leaky capillaries following shock syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. It can lead to generalized edema and multiple organ
failure.
Flushing
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Symptomatic, associated with
hypotension and/or tachycardia;
limiting self care ADL
 -
 -
Definition: A disorder characterized by episodic reddening of the face.
Hematoma
Mild symptoms; intervention not
indicated
Minimally invasive evacuation or
aspiration indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel.
Hot flashes
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an uncomfortable and temporary sensation of intense body warmth, flushing, sometimes accompanied by sweating upon cooling.
Hypertension
Prehypertension (systolic BP
120 - 139 mm Hg or diastolic
BP  80 - 89 mm Hg)
Stage 1 hypertension (systolic
BP 140 - 159 mm Hg or
diastolic BP 90 - 99 mm Hg);
medical intervention indicated;
recurrent or persistent (>=24
hrs); symptomatic increase by
>20 mm Hg (diastolic) or to
>140/90 mm Hg if previously
WNL; monotherapy indicated
Pediatric: recurrent or persistent
(>=24 hrs) BP >ULN;
monotherapy indicated
Stage 2 hypertension (systolic
BP >=160 mm Hg or diastolic
BP >=100 mm Hg); medical
intervention indicated; more
than one drug or more intensive
therapy than previously used
indicated
Pediatric: Same as adult
Life-threatening consequences
(e.g., malignant hypertension,
transient or permanent
neurologic deficit, hypertensive
crisis); urgent intervention
indicated
Pediatric: Same as adult
Death
Definition: A disorder characterized by a pathological increase in blood pressure; a repeatedly elevation in the blood pressure exceeding 140 over 90 mm Hg.
Hypotension
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention or
hospitalization indicated
Life-threatening and urgent
intervention indicated
Death
Definition: A disorder characterized by a blood pressure that is below the normal expected for an individual in a given environment.
Lymph leakage
 -
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the loss of lymph fluid into the surrounding tissue or body cavity.
Lymphedema
Trace thickening or faint
discoloration
Marked discoloration; leathery
skin texture; papillary formation;
limiting instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by excessive fluid collection in tissues that causes swelling.
Lymphocele
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by a cystic lesion containing lymph.
Peripheral ischemia
 -
Brief (<24 hrs) episode of
ischemia managed non-
surgically and without
permanent deficit
Recurring or prolonged (>=24
hrs) and/or invasive intervention
indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by impaired circulation to an extremity.
Phlebitis
 -
Present
 -
 -
 -
Definition: A disorder characterized by inflammation of the wall of a vein.
Superficial thrombophlebitis
 -
Present
 -
 -
 -
Definition: A disorder characterized by a blood clot and inflammation involving a superficial vein of the extremities.
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CTCAE 4.03 - June 14, 2010 : Vascular disorders
78
Vascular disorders
Grade
Adverse Event
1
2
3
4
5
Superior vena cava syndrome
Asymptomatic; incidental finding
of SVC thrombosis
Symptomatic; medical
intervention indicated (e.g.,
anticoagulation, radiation or
chemotherapy)
Severe symptoms; multi-
modality intervention indicated
(e.g., anticoagulation,
chemotherapy, radiation,
stenting)
Life-threatening consequences;
urgent multi-modality
intervention indicated (e.g.,
lysis, thrombectomy, surgery)
Death
Definition: A disorder characterized by obstruction of the blood flow in the superior vena cava. Signs and symptoms include swelling and cyanosis of the face, neck, and upper arms,
cough, orthopnea and headache.
Thromboembolic event
Venous thrombosis (e.g.,
superficial thrombosis)
Venous thrombosis (e.g.,
uncomplicated deep vein
thrombosis), medical
intervention indicated
Thrombosis (e.g.,
uncomplicated pulmonary
embolism [venous], non-embolic
cardiac mural [arterial]
thrombus), medical intervention
indicated
Life-threatening (e.g.,
pulmonary embolism,
cerebrovascular event, arterial
insufficiency); hemodynamic or
neurologic instability; urgent
intervention indicated
Death
Definition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via the blood stream.
Vasculitis
Asymptomatic, intervention not
indicated
Moderate symptoms, medical
intervention indicated
Severe symptoms, medical
intervention indicated (e.g.,
steroids)
Life-threatening; evidence of
peripheral or visceral ischemia;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving the wall of a vessel.
Visceral arterial ischemia
 -
Brief (<24 hrs) episode of
ischemia managed medically
and without permanent deficit
Prolonged (>=24 hrs) or
recurring symptoms and/or
invasive intervention indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a decrease in blood supply due to narrowing or blockage of a visceral (mesenteric) artery.
Vascular disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
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28. Publication Information
NIH Publication No. 09-5410
Revised June 2010
Reprinted June 2010
Alexion Confidential
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SYNT001 
Pemphigus 
Protocol SYNT001-103 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 100 of 100 
Confidential and Proprietary 
Amendment 3.0 Final  10 October 
2017 
 
Appendix B: Pemphigus Disease Area Index (PDAI) 
 
Alexion Confidential
Page 582 of 979


Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Syntimmune, Inc. and 
any unauthorized use or disclosure of such information without the prior written authorization of 
Syntimmune is expressly prohibited. 
Syntimmune, Inc. 
SUMMARY OF CHANGES TO CLINICAL STUDY PROTOCOL 
A Phase 1b, Multicenter, Open-Label, Safety, Tolerability, and Activity 
Study of SYNT001 in Subjects with Chronic Pemphigus (Vulgaris or 
Foliaceus) 
Protocol Number: 
SYNT001-103 
 
IND Number: 
132727 
 
Study Drug: 
SYNT001 
 
Sponsor: 
Syntimmune, Inc. 
 
257 Park Avenue South 
 
15th Floor 
 
New York, NY 10010 
 
Medical Monitor: 
 
 
Wallace House 
 
17-21 Maxwell Place 
 
Stirling, Scotland FK81JU 
 
Mobile Phone: 
 
 
Office Phone: 
 ext. 
 
 
  
 
Original Protocol: 
19 December 2016 
Amendment 1.1 
18 January 2017 
Amendment 2.0 
12 April 2017 
Amendment 3.0 
10 October 2017 
 
Alexion Confidential
Page 583 of 979
PPD
PPD
PPD
PPD


SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 2 of 16 
Confidential and Proprietary 
10 October 2017 
 
SUMMARY 
The SYNT001-103 protocol has been amended under version 3.0 as follows:   
 
• Medical Monitor and emergency contact information has been updated 
• Clarification of allowable corticosteroids 
• Additional exploratory biomarker and subsequent increase in total blood volume included 
• Increase maximum BMI from 35.0 to 39.9 mg/m2 
• Allowance of urine or serum pregnancy tests for women of childbearing potential at 
screening 
• Clarification of the restriction on cellular therapy  
• Provide guidance on the use of premedications for SYNT001 dosing 
• Clarification of the type of skin the optional biopsies may be taken from 
• Clarification of the method of sample collection for FCGR2A 
• Clarification of the treatment for the single Grade 2 AE in the Phase 1a study 
• Clarification of the data collected as part of the patient relevant medical history 
• Removal of RR Interval as a required part of the ECG assessments 
• Clarification that subjects exceeding a specific weight are not to be enrolled into the 30 
mg/kg or higher dose groups based on theoretical host cell DNA levels per dose 
• Clarification for the management of a Grade 1 infusion reaction.  
• Provides a maximum duration of infusion in accordance with the requirements for 
SYNT001 preparation and administration outlined in the pharmacy manual 
• Clarification of SAE reporting requirements and IRB notifications 
• Sponsor contact information has been updated 
• Various typographical and formatting corrections as well as corrections for consistency 
made throughout the document. 
 
Alexion Confidential
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SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 3 of 16 
Confidential and Proprietary 
10 October 2017 
 
SPECIFIC CHANGES 
Text deletions are shown using strike through font; new text added in italic font. Listed page numbers are based on Protocol 
Amendment 2.0, dated 12 April 2017.  
Alexion Confidential
Page 585 of 979


SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 4 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Cover, page 1 
Blythe Thomson, MD 
43 Thornd
reet,  
Cambridg
01240 
Richard Kay, MD 
Wallace House 
17-21 Maxwell Place 
Stirling, Scotland FK81JU 
Mobile Phone: (+44) 7747 621 827 
Office Phone: (+44) 1786 460 400 ext. 
24461 
Medical Monitor information updated 
Eme
cy Contact 
Infor
tion, page 3 
Bly
om
, MD 
b.th
@medpace.com 
Mo
one: 1-513-748-2122 
ne: 1-
-579-9911 ext. 
Richard Kay, MD 
 r.kay@medpace.com 
Mobile phone: (+44) 7747 621 827 
Office phone: (+44) 1786 460 400 ext. 
24461 
Medical Monitor information updated 
Synopsis, 
Exploratory 
Objectives, page 7 
 
• 
Exploratory biomarkers to 
investigate immune response 
associated with pemphigus  
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response  
Synopsis, Diagnosis 
and main entry 
criteria, page 9 
c.  If bein
d with corticosteroids, 
dose m
mg/kg/day and stable 
(< 10
n dose) for 2 weeks 
pri
g 
c.  If being treated with corticosteroids, 
dose must be ≤ 1mg/kg/day of 
prednisone or equivalent and stable (< 
10% change in dose) for 2 weeks prior 
to screening 
Clarification of allowable corticosteroids 
Syno
s, Diagnosis 
and 
 entry 
criter
page 9 
5.  
ass index (BMI) 18.5 – 35.0 
kg/
5.  Body mass index (BMI) 18.5 –
39.935.0 kg/m2; 
Patients who may be otherwise eligible to 
participate in the study are excluded due to BMI.  
We would like to be able to offer these 
individuals the opportunity to participate 
Syno
s, Diagnosis 
and main entry 
criteria, page 9 
6.  
egativ
rine pregnancy test 
(for women of childbearing potential) 
documented prior to the first dose of 
study drug; 
6  Has a negative urine pregnancy test 
(for women of childbearing potential) 
documented prior to the first dose of 
study drug; 
Allows for serum or urine tests as per 
institutional standards 
Synopsis, Diagnosis 
and main entry 
criteria, page 10 
10.  Cellular therapy at any time prior 
to screening 
10.  Cellular therapy, including CAR-T, 
therapy at any time prior to screening 
To further clarify the restriction on all cellular 
therapy 
Alexion Confidential
Page 586 of 979
PP
D
PP
D
PP
D
PP
D
PP
D
PP
D
PP
D
PP
D
PP
D
PP
D
PP
D
PP
D
PP
D
PP
D
PP
D


SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 5 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Synopsis, Prohibited 
Concomitant 
Treatments, page 11 
All treatments a subject receives within 
14 days prior to enrollment through the 
end of the study will be documented.  
Concomitant medication and treatment 
for co-existing conditions, including 
those for pemphigus, are permitted if 
not excluded below.  Topical 
antibiotics are permitted to treat active 
infections that occur on study.  Topical 
or systemic treatments for oral 
candidiasis are permitted.  Topical 
lidocaine for transient pain relief is 
acceptable as needed.  Significant 
increases in anti-pemphigus 
medications will result in subjects 
being discontinued from the study.  
Concomitant treatment that is 
medically indicated for any AEs the 
subject experiences during the study 
are permitted. 
All treatments a subject receives within 
14 days prior to enrollment through the 
end of the study will be documented.  
Concomitant medication and treatment 
for co-existing conditions, including 
those for pemphigus, are permitted if 
not excluded below.  Topical 
antibiotics are permitted to treat active 
infections that occur on study.  Topical 
or systemic treatments for oral 
candidiasis are permitted.  Topical 
lidocaine for transient pain relief is 
acceptable as needed.  Significant 
increases in anti-pemphigus 
medications will result in subjects 
being discontinued from the study.  
Concomitant treatment that is 
medically indicated for any AEs the 
subject experiences during the study are 
permitted. Premedication is 
discouraged as prophylaxis against 
AEs or infusion reactions unless 
medically indicated from either past 
medical history, prior infusion 
reactions or AEs resulting from 
SYNT001 infusions.  
Infusion reactions are a common adverse effect 
of IV administration of some, but not all 
monoclonal antibodies (mAb).  Infusion 
reactions most commonly occur with the first 
infusion and are often related to the infusion 
rate.  For mAbs with frequent infusion reactions, 
it is recommended that pre-medications, such as 
corticosteroids, acetaminophen and/or 
antihistamines, are administered prior to 
infusion, especially with the first infusion.  
However, pre-medications are generally not 
recommended for mAbs associated with no or 
mild infusion reactions. 
No infusion reactions occurred in the recently 
completed healthy volunteer phase 1a single-
ascending dose study, where infusions were 
given over 1 hour at doses up to 30 mg/kg. As 
such, Syntimmune does not currently believe 
that it is necessary or appropriate to administer 
pre-medications to patients who will be 
receiving SYNT001 at the same doses and 
infusion rate as in the phase 1a study.  If 
frequent infusion reactions are observed in the 
phase 1b study, the issue of pre-medication will 
be revisited. 
Alexion Confidential
Page 587 of 979


SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 6 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Pharmacodynamics/ 
Activity, page 13 
PD samples will be collected for 
analysis of IgG (serial assessment of 
IgG levels to identify Cmin, Tmin); 
IgG1-4 subtype levels; IgA levels; IgM 
levels; albumin levels; anti-Dsg (1 and 
3) antibody levels; serum AECA by 
direct immunofluorescence; CIC; C3; 
exploratory biomarkers (FCGR2A 
SNP, RNAseq, urine IgG, CD3+CD4+ 
T, CD3+CD8+ T, monocytes, NK cells 
and B cells). 
PD samples will be collected for 
analysis of IgG (serial assessment of 
IgG levels to identify Cmin, Tmin); 
IgG1-4 subtype levels; IgA levels; IgM 
levels; albumin levels; anti-Dsg (1 and 
3) antibody levels; serum AECA by 
direct immunofluorescence; CIC; C3; 
exploratory biomarkers (FCGR2A 
SNP, RNAseq, urine IgG, CD3+CD4+ 
T, CD3+CD8+ T, monocytes, NK cells 
and B cells) and additional exploratory 
analyses to investigate immune 
response associated with pemphigus. 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Synopsis, Skin 
Biopsy, page 13 
Optional skin biopsy samples will be 
collected on Day 0 pre-dose and on 
Days 1, 2, 14, 33, 56 and 84 to analyze 
SYNT001 levels. 
Optional skin biopsy samples from 
lesional or non-lesional skin will be 
collected on Day 0 pre-dose and on 
Days 1, 2, 14, 33, 56 and 84 to analyze 
SYNT001 levels. 
Clarifies type of skin the optional biopsies may 
be taken from 
Criteria for 
Evaluation, page 14 
 
• Exploratory biomarkers to investigate 
immune response associated with 
pemphigus 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Table 1, Study 
Assessments, page 16 
 
Pemphigus immune response 
biomarkers 
Sample collection for exploratory pemphigus 
immune response biomarkers added at Days 0, 
5, 7, 12, 14, 19, 21, 28, 33, 42, 56, 84 and 112 
Table 1, Study 
Assessments, page 16 
FCGR2Am 
FCGR2Am by buccal swab 
Clarifies method of sample collection 
Table 1, Study 
Assessments, page 17 
m:  Samples to be collected and stored; 
pending review of clinical and 
pharmacodynamics assessments 
m:  Buccal Ssamples to be collected 
and stored; pending review of clinical 
and pharmacodynamics assessments 
Clarifies method of sample collection 
Alexion Confidential
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SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 7 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Section 2.2, Selection 
of Doses in this 
Study, page 27 
No AEs were observed in the 1 and 3 
mg/kg dose cohorts. A single Grade 2 
AE was observed; a headache in the 10 
mg/kg cohort., treated with 
acetaminophen. 
No AEs were observed in the 1 and 3 
mg/kg dose cohorts. A single Grade 2 
AE was observed; a headache in the 10 
mg/kg cohort treated with 
acetaminophen  
Clarifies that no treatment was given for the 
Grade 2 AE of headache in the Phase 1a study. 
Section 3.3, 
Exploratory 
Objectives, Page 29 
 
o 
Exploratory biomarkers to 
investigate immune response associated 
with pemphigus 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 4.2, 
Exploratory Outcome 
Measures, page 31 
 
• Exploratory biomarkers to investigate 
immune response associated with 
pemphigus 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 5.2, Inclusion 
Criteria, page 34 
c.  If being treated with corticosteroids, 
dose must be ≤ 1mg/kg/day and stable 
(< 10% change in dose) for 2 weeks 
prior to screening 
c.  If being treated with corticosteroids, 
dose must be ≤ 1mg/kg/day of 
prednisone or equivalent and stable (< 
10% change in dose) for 2 weeks prior 
to screening 
Clarification of allowable corticosteroids 
Section 5.2, Inclusion 
Criteria, page 35 
5.  Body mass index (BMI) 18.5 – 35.0 
kg/m2; 
5.  Body mass index (BMI) 18.5 –
39.935.0 kg/m2; 
Patients who may be otherwise eligible to 
participate in the study are excluded due to BMI.  
We would like to be able to offer these 
individuals the opportunity to participate 
Section 5.2, Inclusion 
Criteria, page 35 
6.  Has a negative urine pregnancy test 
(for women of childbearing potential) 
documented prior to the first dose of 
study drug; 
6.  Has a negative urine pregnancy test 
(for women of childbearing potential) 
documented prior to the first dose of 
study drug; 
Allows for serum or urine tests as per 
institutional standards 
Section 5.3, 
Exclusion Criteria, 
page 36 
10.  Cellular therapy at any time prior 
to screening 
10.  Cellular therapy, including CAR-T,  
at any time prior to screening 
To further clarify the restriction on all cellular 
therapy 
Alexion Confidential
Page 589 of 979


SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 8 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Section 6.2, 
Demographics and 
Medical History, 
page 37 
Demographics (age, gender, race and 
ethnicity) and medical history will be 
obtained from the subject and recorded 
on the source document and eCRF.  
Medical history will capture the 
subject’s current medical history 
(current disease processes), past 
medical status (past disease processes), 
history of surgery, transfusions and 
concomitant treatments. 
Demographics (age, gender, race and 
ethnicity) and medical history will be 
obtained from the subject and recorded 
on the source document and eCRF.  
Medical history will capture the 
subject’s current medical history 
(current disease processes), past 
medical status (past disease processes), 
history of surgery, transfusions and 
concomitant treatments, including 
relevant clinical response to past 
disease specific treatments and 
duration as well as dosing of such 
treatments.   
Clarifies data collected as part of the patient 
relevant medical history 
Section 6.6, 12-Lead 
Electrocardiogram 
(ECG), page 38 
The following ECG parameters will be 
collected: PR interval, RR interval, 
QRS interval, and QT interval.  The 
ECG findings will be evaluated by a 
qualified physician for the presence of 
abnormalities (qualitative assessment).  
The physician will assess each ECG as 
normal, abnormal/not clinically 
significant, or abnormal/clinically 
significant. 
The following ECG parameters will be 
collected: PR interval, RR interval, 
QRS interval, and QT interval.  The 
ECG findings will be evaluated by a 
qualified physician for the presence of 
abnormalities (qualitative assessment).  
The physician will assess each ECG as 
normal, abnormal/not clinically 
significant, or abnormal/clinically 
significant. 
Not all study sites have ECG machines that 
report the RR interval. As heart rate is already 
being collected as part of clinical evaluation of 
vital signs, this measure does not provide 
additional information. ECG machines do 
provide an estimated heart rate over a 10-second 
recording and this is a more clinically 
meaningful outcome measure. 
Section 6.7, Clinical 
Laboratory 
Measurements, page 
39 
The total blood draw for each subject 
who completes the study at Day 112, 
will be approximately 381 mL. 
The total blood draw for each subject 
who completes the study at Day 112, 
will be approximately 381 433 mL. 
Increase due to additional sample collection  
Section 6.7.5, Table 
4, Pharmacodynamic 
Sampling, page 42 
• Exploratory biomarker (FCGR2A 
SNP) 
• Exploratory biomarker (FCGR2A 
SNP, via buccal swab) 
Clarifies method of sample collection 
Alexion Confidential
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SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 9 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Section 6.7.5, Table 
4, Pharmacodynamic 
Sampling, page 42 
 
• 
Exploratory pemphigus immune 
response Days, 0, 7, 14, 21, 28, 33, 
42, 56, 84, 112 
Sample collection for exploratory pemphigus 
immune response biomarkers added at Days 0, 
5, 7, 12, 14, 19, 21, 28, 33, 42, 56, 84 and 112 
Section 6.9, Prior and 
Concomitant 
Medications, page 43 
All medications a subject receives 
within 14 days prior to enrollment 
through the end of the study will be 
documented on the source document 
and eCRF. 
All medications a subject receives 
within 14 days prior to enrollment 
through the end of the study will be 
documented on the source document 
and eCRF. A history of treatments 
taken for primary disease, even if not 
taken within the 14 days prior to 
enrollment, will be collected.  
Clarifies data collected as part of the patient 
relevant medical history 
Section 6.12, Skin 
Biopsy, page 44 
Optional skin biopsy samples will be 
collected on Day 0 pre-dose and on 
Days 1, 2, 14, 33, 56 and 84 to analyze 
SYNT001 levels 
Optional skin biopsy samples from 
lesional or non-lesional skin will be 
collected on Day 0 pre-dose and on 
Days 1, 2, 14, 33, 56 and 84 to analyze 
SYNT001 levels 
Clarifies type of skin biopsies may be taken 
from 
Section 7.2, 
Enrollment and First 
Treatment: Dose 0, 
page 46 
•  FCGR2A SNP 
•  FCGR2A SNP via buccal swab 
Clarifies method of sample collection 
Section 7.2, 
Enrollment and First 
Treatment: Dose 0, 
page 46 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 7.5, Follow-
up Day 5, page 48 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 7.6, 
Treatment Day 7 
(Dose 2), page 48 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Alexion Confidential
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SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 10 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Section 7.7, Dose 2 
Follow-up Day 12, 
page 49 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 7.8, 
Treatment Day 14 
(Dose 3), page 50 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 7.9, Dose 3 
Follow-up Day 19, 
page 51 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 7.10, 
Treatment Day 21 
(Dose 4), page 51 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 7.11, 
Treatment Day 28 
(Dose 5), page 52 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 7.14, Follow-
up Day 33, page 54 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 7.15, Follow-
up Day 42, page 55 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 7.16, Follow-
up Day 56, page 56 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 7.17, Follow-
up Day 84, page 56 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Section 7.18, Follow-
up Day 112, page 57 
 
• 
Exploratory pemphigus immune 
response biomarkers 
Added an additional exploratory objective to 
investigate other possible biomarkers associated 
with the pemphigus immune response 
Alexion Confidential
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SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 11 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Section 9.1, 
SYNT001, page 61 
The specification for host cell DNA in 
SYNT001 is < 2 pg/mg, the limit of 
quantitation of the assay.  To comply 
with regulatory guidelines, which 
specify a maximum level of 10 ng host 
cell DNA per dose, dosing is limited to 
5000 mg SYNT001. Therefore, at the 
highest dose possible in this study (45 
mg/kg), maximum subject weight will 
be limited to 111 kg. 
The specification for host cell DNA in 
SYNT001 is < 2 pg/mg, the limit of 
quantitation of the assay.  To comply 
with regulatory guidelines, which 
specify a maximum level of 10 ng host 
cell DNA per dose, dosing is limited to 
5000 mg SYNT001. Therefore, the 
maximum subject weight allowed for 
enrollment into the 30 mg/kg dose 
cohort is 166 kg and the maximum 
subject weight allowed for enrollment 
into the highest dose possible in this 
study (45 mg/kg), maximum subject 
weight will be limited to is 111 kg. 
Clarifies that subjects exceeding a specific 
weight are not to be enrolled into the 30 mg/kg 
or higher dose groups based on theoretical host 
cell DNA levels per dose. 
Alexion Confidential
Page 593 of 979


SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 12 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Section 9.6.1, 
Infusion Reaction, 
page 63 
Management of Grade 1 infusion 
reactions include decreasing the rate of 
infusion by 50% and observing.  
Symptoms may also be treated as 
needed with medications such as 
diphenhydramine, hydrocortisone or 
acetaminophen. 
Management of Grade 2 and higher 
infusion reactions should include 
stopping the infusion of study drug.  
See Figure 1 and Figure 2 for details on 
the management of Grades 1- 2 and 
Grade 3 infusion reactions. The 
severity of and management of allergic 
or infusion-related reactions will be 
graded and managed using NCI 
CTCAE Version 4.03 (see Table 5). 
Management of Grade 1 infusion 
reactions include interrupting the 
infusion or decreasing the rate of 
infusion by 50% and observing.  
Symptoms may also be treated as 
needed with medications such as 
diphenhydramine, hydrocortisone or 
acetaminophen., either alone or in 
combination, depending on the 
subject’s signs and symptoms. If the 
infusion is interrupted or the infusion 
rate is decreased, it is important to note 
that all study drug infusions must be 
completed within 4 hours of SYNT001 
administration. 
Management of Grade 2 and higher 
infusion reactions should include 
stopping the infusion of study drug.  
See Figure 1 and Figure 2 for details on 
the management of Grades 1- 2 and 
Grade 3 infusion reactions. The 
severity of and management of allergic 
or infusion-related reactions will be 
graded and managed using NCI 
CTCAE Version 4.03 (see Table 5). 
Provides clarification for the management of a 
Grade 1 infusion reaction. Provides a maximum 
duration of infusion in accordance with the 
requirements for SYNT001 preparation and 
administration outlined in the pharmacy manual. 
Section 9.6.1, Figure 
1 Title, page 64 
Management of Mild (Grade 1) to 
Moderate (Grade 2) Infusion Reactions 
Management of Mild (Grade 1) to 
Moderate (Grade 2) Infusion Reaction 
To be consistent with prior section regarding 
management of a Grade 1 infusion reaction and 
with CTCAE v4.03 definition of a Grade 1 
infusion reaction. 
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SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 13 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Section 9.6.1, Figure 
1, last box, page 64 
Consider pre-medicating the subject 
with the same medication(s) 20-30 
minutes in advance of subsequent 
administrations of SYNT001 and 
starting infusion at 50% of the planned 
infusion rate for the first 30 minutes, 
then returning to the intended infusion 
rate in the absence of any infusion 
reaction 
Consider pre-medicating the subject 
with the same medication(s) 20-30 
minutes in advance of subsequent 
administrations of SYNT001 and 
starting infusion at 50% of the planned 
infusion rate for the first 30 minutes, 
then returning to the intended infusion 
rate in the absence of any infusion 
reaction. If the infusion is interrupted 
or the infusion rate is decreased, it is 
important to note that all study drug 
infusions must be completed within 4 
hours of SYNT001 administration. 
Provision of a maximum duration of infusion in 
accordance with the requirements for SYNT001 
preparation and administration as outlined in the 
pharmacy manual. 
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SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 14 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Section 10, 
Concomitant 
Medication and 
Treatment, page 69 
All treatments a subject receives within 
14 days prior to enrollment through the 
end of the study will be documented.  
Concomitant medication and treatment 
for co-existing conditions, including 
those for pemphigus, are permitted if 
not excluded below.  Topical 
antibiotics are permitted to treat active 
infections that occur on study.  Topical 
or systemic treatments for oral 
candidiasis are permitted.  Topical 
lidocaine for transient pain relief is 
acceptable as needed.  Significant 
increases in anti-pemphigus 
medications will result in subjects 
being discontinued from the study.  
Concomitant treatment that is 
medically indicated for any AEs the 
subject experiences during the study 
are permitted. 
All treatments a subject receives within 
14 days prior to enrollment through the 
end of the study will be documented.  
Concomitant medication and treatment 
for co-existing conditions, including 
those for pemphigus, are permitted if 
not excluded below.  Topical 
antibiotics are permitted to treat active 
infections that occur on study.  Topical 
or systemic treatments for oral 
candidiasis are permitted.  Topical 
lidocaine for transient pain relief is 
acceptable as needed.  Significant 
increases in anti-pemphigus 
medications will result in subjects 
being discontinued from the study.  
Concomitant treatment that is 
medically indicated for any AEs the 
subject experiences during the study are 
permitted. Premedication is 
discouraged as prophylaxis against 
AEs or infusion reactions unless 
medically indicated from either past 
medical history, prior infusion 
reactions or AEs resulting from 
SYNT001 infusions. 
Infusion reactions are a common adverse effect 
of IV administration of some, but not all 
monoclonal antibodies (mAb).  Infusion 
reactions most commonly occur with the first 
infusion and are often related to the infusion 
rate.  For mAbs with frequent infusion reactions, 
it is recommended that pre-medications, such as 
corticosteroids, acetaminophen and/or 
antihistamines, are administered prior to 
infusion, especially with the first infusion.  
However, pre-medications are generally not 
recommended for mAbs associated with no or 
mild infusion reactions. 
No infusion reactions occurred in the recently 
completed healthy volunteer phase 1a single-
ascending dose study, where infusions were 
given over 1 hour at doses up to 30 mg/kg. As 
such, Syntimmune does not currently believe 
that it is necessary or appropriate to administer 
pre-medications to patients who will be 
receiving SYNT001 at the same doses and 
infusion rate as in the phase 1a study.  If 
frequent infusion reactions are observed in the 
phase 1b study, the issue of pre-medication will 
be revisited. 
Alexion Confidential
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SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 15 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Section 11.3.9.1, 
Governing 
Regulatory 
Requirements, page 
76 
Written submission must be made by 
the sponsor to the FDA and the IRBs as 
soon as possible and in no event later 
than 15 calendar days after the 
sponsor’s initial notification of the 
event.  The sponsor shall also inform 
all Investigators. 
Written submission must be made by 
the sponso
 the F
 the IRBs as 
soo
 po
le 
ve
ater 
than
 ca
the
spo
’s 
n o
 
eve
Th
rm 
sti
Clarifies that notification to IRBs is not a 
responsibility of the sponsor. 
Section 11.3.9.2, 
Time Frame for 
Reporting, page 76 
Any death, SAE, pregnancy, or 
unexpected (and severe) AE 
experienced by the subject after 
informed consent through the last study 
visit, regardless of relationship to study 
drug, must be promptly reported 
(within 24 hours of the Investigator 
becoming aware of the event) by 
telephone or electronic transmission to 
the sponsor (or designee). 
, S
 or 
 
xpe
d (a
sev
erienced b
he s
e
rmed consent th
he last study 
t, regardless of re
hip to study 
drug, must be promptly reported 
(within 24 hours of the Investigator 
becoming aw
nt) by 
tele
ne 
sm
on to 
the 
nso
Clarifies that adverse (severe) events that are not 
considered SAEs do not need to be reported 
within 24 hours but reported per section 11.3.6. 
Section 11.3.9.2, 
Time Frame for 
Reporting, page 77 
Medical Safety Contact 
Blythe Thomson MD  
Medical Monitor 
Phone (US):  1-513-579-9911 
extension 27201 
Mobile phone: 1-513-748-2122 
Email: b.thomson@medpace.com 
Me
l S
 K
M
 
): (
) 1
nsi
244
 
bile phone
44)
1 827 
ail: r.kay@medp
 
Medical Monitor information updated 
Section 14, Study 
Administration, 
Table 6, page 86 
Sponsor Contact: Ryan Iarrobino 
SVP Clinical Operations and Data 
Management 
Phone: 617-913-1681 
Email:  ryan@syntimmune.com 
nsor Contact: Ry
robino 
SVP Clinical Operations and Data 
Management 
Phone: 617-913-1681 
Email:  ryan@syntimmune.com 
Sponsor contact information updated  
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SYNT001 
 
Protocol SYNT001-103 
Amendment 3.0 
 
 
 
 
 
 
Syntimmune, Inc. 
Page 16 of 16 
Confidential and Proprietary 
10 October 2017 
 
Section, Page 
Number 
Original Text 
Revised Text 
Rationale 
Section 14,
dy 
Administra
, 
Table 6, pa
6 
Sponsor Medical Director: 
Laurence Blumberg, MD 
Founder and Chief Operating Officer 
Phone:  917-4
-22
Email:  laur
nti
ne.com 
Sponsor Contact and Medical Director: 
Laurence Blumberg, MD 
President and Chief Operating Officer 
Phone:  917-415-2210 
Email:  laur@syntimmune.com 
Sponsor contact information updated 
Section 
Admini
Table 6,
Blythe Thom
 
Medpace 
43 Thorndike
eet
Cambridge, 
01
 
Phone: 513-5
991
xt.27201 
Email:  b.thoms
medpace.com 
Richard Kay, MD 
Medpace 
Wallace House 
17-21 Maxwell Place 
Stirling, Scotland FK81JU 
Phone: (+44) 1786 460 400 extension 
24461 
Email: r.kay@medpace.com  
Medical Monitor information updated 
 
Alexion Confidential
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SYNT001 
 
8 June 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 4.0 
 
Confidential 
Page 1 of 96 
Syntimmune, Inc. 
SYNTIMMUNE, INC. 
CLINICAL STUDY PROTOCOL 
A Phase 1b/2, Multicenter, Open-Label, Safety, and Dose-Finding Study of 
SYNT001 in Subjects with Pemphigus (Vulgaris or Foliaceus) 
 
Protocol Number: 
SYNT001-103 
IND Number: 
132727 
Study Drug: 
SYNT001 
Sponsor: 
Syntimmune, Inc. 
116 Huntington Avenue 
Suite 301 
Boston, MA 02116 
 
Medical Monitor: 
 
Wallace House 
17-21 Maxwell Place 
Stirling, Scotland FK81JU 
Mobile Phone: 
 
Office Phone: 
 ext. 
 
 
Original Protocol: 
18 January 2017 
Amendment 1.1: 
21 March 2017 
Amendment 2.0 
12 April 2017 
Amendment 3.0 
10 October 2017 
Amendment 4.0 
8 June 2018 
 
CONFIDENTIALITY STATEMENT 
The information contained herein is confidential and the proprietary property of Syntimmune, Inc. Any unauthorized 
use or disclosure of such information without the prior written authorization of Syntimmune is expressly prohibited. 
Alexion Confidential
Page 601 of 979
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SYNTOOI 
Protocol SYNTOOI -I03 for Pemphigus 
SPONSOR SIGNATURE 
8 June 2018 
Amendment 4.0 
I have read and approve this protocol. My signature, in conjunction with the signature of the 
Investigator, confinns the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Conference on Hannonisation (ICH) Guideline for Good Clinical Practice 
(GCP), the United States Code of Federal Regulations (CFR), and the ethical principles that have 
their origins in the Declaration of Helsinki. 
Syntimmune, Inc. 
Confidential 
Page 2 of96 
Date of Signature 
Syntimmune, Inc. 
Alexion Confidential
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SYNT001 
 
8 June 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 4.0 
 
Confidential 
Page 3 of 96 
Syntimmune, Inc. 
INVESTIGATOR SIGNATURE 
I have read and approve this protocol. My signature, in conjunction with the signature of the 
Sponsor, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP), the United States Code of Federal Regulations (CFR), and the ethical principles that have 
their origins in the Declaration of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations. 
 
 
 
 
Investigator Signature 
 
Date of Signature 
 
 
 
Name of Investigator (please print) 
 
 
 
Alexion Confidential
Page 603 of 979


SYNT001 
 
8 June 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 4.0 
 
Confidential 
Page 4 of 96 
Syntimmune, Inc. 
1. 
SYNOPSIS 
Study title 
A Phase 1b/2, Multicenter, Open-Label, Safety, and Dose-Finding Study of 
SYNT001 in Subjects with Pemphigus (Vulgaris or Foliaceus) 
Sponsor 
Syntimmune, Inc. 
Protocol number 
SYNT001-103 
Clinical phase  
Phase 1b/2 
Number of study 
centers 
Approximately 10 global study sites 
Study rationale 
Pemphigus is a potentially life-threatening group of rare blistering 
autoimmune diseases that affect the skin and mucous membranes. The exact 
cause is unknown, though autoantibodies are thought to play an important 
pathogenic role in the mucosal and cutaneous manifestations in patients with 
pemphigus. 
The prognosis of pemphigus has markedly improved over the last decades with 
steroid therapy. Nevertheless, mortality remains an issue (1.6% to 12% of 
cases) (Hsu et al., 2016; Kasperkiewicz et al., 2017; Langan et al., 2008). In 
these cases, death typically occurs as a consequence of treatment-related 
systemic infections and in a smaller proportion, as a consequence of 
superinfected lesions. While steroids have greatly improved patient outcomes, 
they are associated with serious and long-lasting side effects; therefore, their 
use should be limited as much as possible. Although other currently available 
treatments for certain autoimmune disorders, including immunosuppressants, 
intravenous immunoglobulin (IVIG), plasmapheresis, and anti-CD20 
monoclonal antibodies (mAbs), such as rituximab, can be effective, they can 
be associated with significant adverse effects and delayed or non-durable 
responses.  
SYNT001 targets key mechanisms contributing to pathology in a variety of 
immunoglobulin G (IgG)-mediated autoimmune disorders. When administered 
to healthy subjects, SYNT001 has been shown to significantly decrease total 
IgG, as well as immune complexes with which IgG is associated. Based on 
these results, it is predicted that SYNT001 will also reduce the levels of 
pathogenic autoantibodies. This could lead to a decrease in the mucosal and 
cutaneous manifestations in patients with pemphigus. Moreover, the ability of 
SYNT001 to reduce circulating immune complexes (CICs) and the associated 
innate and adaptive immune responses may allow for sustained disease 
modification. Thus, this study is being conducted to evaluate the safety and 
immunogenicity and determine a minimally effective dose (MED) of 
intravenous (IV) SYNT001 in pemphigus patients.  
Study objectives 
and endpoints 
The study objectives and their corresponding endpoints (primary, secondary, 
and exploratory) are detailed below. 
 
 
 
 
 
 
Alexion Confidential
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SYNT001 
 
8 June 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 4.0 
 
Confidential 
Page 5 of 96 
Syntimmune, Inc. 
Primary Objectives 
Primary Endpoints 
Safety: To evaluate the safety of 
once-weekly IV infusions of 
SYNT001 at different dose levels 
and dosing durations in subjects 
with pemphigus (vulgaris or 
foliaceus) 
Safety: The evaluation of SYNT001 
safety based on vital signs, physical 
examinations, electrocardiograms 
(ECGs), clinical safety laboratory 
tests, the incidence of adverse events 
(AEs), treatment-emergent adverse 
events (TEAEs) and serious adverse 
events (SAEs) summarized by 
cohort, severity, and relationship to 
study product 
Dose Selection: To determine a 
MED of SYNT001 as assessed by (i) 
total IgG level nadir and (ii) the 
proportion of subjects that meet the 
criteria for response by Pemphigus 
Disease Area Index total activity 
score (PDAI) 
Dose Selection: The determination 
of dose and dosing duration of 
SYNT001 that achieves (i) total IgG 
level nadir decrease by ≥60% and 
≤90% from baseline and (ii) a PDAI 
total activity score of ≥50% 
reduction from baseline to allow 
further clinical development in 
subjects with pemphigus (vulgaris or 
foliaceus) 
Secondary Objectives 
Secondary Endpoints 
To determine the pharmacokinetics 
(PK) of SYNT001 following once-
weekly IV infusions at different 
dose levels and dosing durations 
The determination of PK parameters 
including half-life (t1/2), maximum 
serum concentration determined 
directly from the concentration-time 
profile (Cmax), observed time of peak 
plasma concentration (Tmax), area 
under the serum concentration-time 
curve from pre-dose (time0) to 
24 hours post-dose (AUC0-24), and 
area under the serum concentration-
time curve from pre-dose (time0) to 
infinity (AUC0-∞), (Cohort 1); 
maximum plasma concentration 
determined directly from the 
concentration-time profile (Cmax) and 
Tmax (Cohort 2 onwards) 
summarized by cohort and timepoint 
To evaluate the effect of once-
weekly doses of SYNT001 at 
different dose levels and dosing 
durations on pharmacodynamics 
(PD) biomarkers 
The evaluation of PD biomarkers 
based on absolute serum levels and 
percent change from baseline in 
serum levels of total 
immunoglobulin G (IgG), IgG 
subtypes (IgG1-4), immunoglobulin 
A (IgA), immunoglobulin M (IgM), 
albumin, and CIC summarized by 
cohort and timepoint 
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SYNT001 
 
8 June 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 4.0 
 
Confidential 
Page 6 of 96 
Syntimmune, Inc. 
To assess the effect of once-weekly 
doses of SYNT001 at different dose 
levels and dosing durations on 
disease markers 
 
The assessment of pemphigus 
disease activity by responses on 
PDAI based on absolute and 
percent change from baseline 
will be summarized by cohort 
and timepoint. 
 
The assessment of pemphigus 
disease pathogenic antibody 
levels based on absolute and 
percent change from baseline of 
serum anti-desmoglein 1 and 3 
antibody (anti-Dsg 1 and anti-
Dsg 3) levels that will be 
summarized by cohort and 
timepoint
To measure the immunogenicity of 
once-weekly administered 
SYNT001 at different dose levels 
and dosing durations 
The immunogenicity of once-weekly 
administered SYNT001 as 
determined by presence of anti-
SYNT001 binding antibodies and 
neutralizing antibodies summarized 
by cohort and timepoint 
Exploratory Objectives 
Exploratory Endpoints 
To explore the effect of once-weekly 
doses of SYNT001 at different dose 
levels and dosing durations on 
biomarkers to understand the 
pathophysiology of the disease and 
the SYNT001 mechanisms of action  
The exploration of SYNT001 
mechanisms of action and effects of 
SYNT001 on pathophysiology 
summarized by cohort and timepoint 
as determined by:  
 
Complement component 3 (C3) 
levels by nephelometry 
 
Anti-epithelial cell antibody 
(AECA) titers by indirect 
immunofluorescence 
 
Fc gamma R2A receptor 
(FCGR2A) single nucleotide 
polymorphisms (SNP) by 
genotyping 
 
Presence of disease and 
inflammatory markers by 
RNAseq (RNA sequencing) 
 
Immunophenotyping via 
measures of T cells, monocytes, 
NK cells and B cells by flow 
cytometry 
 
Urine IgG levels to explore 
SYNT001 distribution and 
elimination 
 
Exploratory biomarkers to 
investigate immune response 
associated with pemphigus
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SYNT001 
 
8 June 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 4.0 
 
Confidential 
Page 7 of 96 
Syntimmune, Inc. 
To determine the impact of different 
SYNT001 dose levels and dosing 
durations on the subject’s use of 
corticosteroids to treat their 
pemphigus (vulgaris or foliaceus) 
The evaluation of corticosteroid use 
during the study will be summarized 
by cohort and timepoint 
To assess the impact of once-weekly 
doses of SYNT001 on the subject’s 
health-related quality of life 
(HR-QoL) at different dose levels 
and dosing durations 
The assessment of SYNT001 impact 
on subject’s health-related quality of 
life (HR-QoL) by responses to the 
Autoimmune Bullous Diseases 
Quality of Life (ABQoL) 
questionnaire and Skindex-29 scores 
summarized by cohort and timepoint 
To assess the effect of once-weekly 
doses of SYNT001 on the 
appearance of skin and mucosal 
lesions at different dose levels and 
dosing durations 
The qualitative assessment of 
changes in appearance of skin and 
mucosal lesions as determined by 
photography presented by cohort 
and timepoint 
To quantify the amount of 
SYNT001 in skin (skin biopsies 
optional) 
The determination of SYNT001 
levels in skin biopsies across 
timepoints (skin biopsies optional) 
 
Study design 
This is a multicenter, open-label safety study to determine the dose regimen of 
SYNT001 administered intravenously in subjects with pemphigus (vulgaris or 
foliaceus). Approximately 20 (up to a maximum of 32) eligible subjects with a 
diagnosis of active pemphigus vulgaris or pemphigus foliaceus will receive 
planned doses of 10 mg/kg up to 45 mg/kg of SYNT001.  
Eligible subjects will be enrolled in Cohort 1 and then sequential cohorts, 
pending recommendation received from the scheduled Dose Escalation 
Committee (DEC) review.  
The DEC will consist of the Medical Monitor, an Independent Clinical Expert 
and a Syntimmune Medical Officer. To assist in the safety assessments, the 
DEC may request that Investigators, other experts, or members within their 
organization review the data and participate in the discussions. 
Each cohort must be fully enrolled before a successive cohort will be opened 
for enrollment. Cohort 4 is optional and will be added at the discretion of the 
sponsor and/or DEC. 
An overview of the study cohorts is provided in Table 1 and Figure 1 shows a 
schematic of the study design. 
 
 
 
 
 
 
 
 
 
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SYNT001 
 
8 June 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 4.0 
 
Confidential 
Page 8 of 96 
Syntimmune, Inc. 
Table 1. 
Cohort Overview 
Cohort 
No. 
No. of 
Subjects 
SYNT001 
Dose  
No. of 
Doses 
DEC Review Timepoint 
1a 
up to 8 
10 mg/kg 
5 
NA 
2b 
4c 
≤30 mg/kgd 
5 
When 100% of Cohort 1 
subjects reach Day 42 
3b 
4c 
≤30 mg/kgd 
14 
When 50% of Cohort 2 
subjects reach Day 42 
4b 
(optional)  
4c 
≤45 mg/kgd 
≤14 
When 50% of Cohort 3 
subjects reach Day 42e 
Abbreviations: DEC = Dose Escalation Committee; NA = not applicable 
a. 
No more than 3 subjects with pemphigus foliaceus may be enrolled 
b. 
Two or fewer subjects with pemphigus foliaceus may be enrolled 
c. 
Up to 4 additional subjects may be added following DEC’s evaluation. 
d. 
Dose will be recommended by the DEC and will be based on both an ongoing and set 
timepoint review of safety and pharmacodynamic evaluations including but not limited 
to, dose-limiting toxicities (DLTs), adverse events (AEs), treatment-emergent adverse 
events (TEAEs), serious adverse events (SAEs), and total IgG levels. 
e. 
All available data will be considered. 
 
The first 2 subjects in Cohorts 1 and 2 will be enrolled at staggered intervals to 
facilitate adequate safety evaluation before dosing of subsequent subjects may 
proceed. A staggered dosing interval for the first 2 subjects enrolled in 
successive cohorts will not be required if the planned dose is equal to or lower 
than that previously administered. 
At 24-hour and 7-day intervals described below, the DEC will review all 
available safety data (including but not limited to dose limiting toxicities 
[DLTs], AEs, TEAEs, and SAEs, PD (including but not limited to total IgG 
levels), and clinical outcomes. 
 
DEC Safety Review of 24-hour Data for Cohorts 1 and 2, Subject 1 
 
The first 2 subjects will be dosed at least 24 hours apart. A DEC review of 
the 24-hour safety data for the first subject will be performed to ensure that 
there are no overt safety concerns before dosing the second subject. 
 
DEC Safety Review of 7-day Data for Cohorts 1 and 2, Subjects 1 and 2 
 
The 7-day safety data for the first 2 subjects will be performed prior to 
dosing the remaining subjects in the cohort.  
 
The 24-hour and 7-day reviews will consider seriousness and severity of 
AEs/TEAEs/SAEs and relatedness to study drug, vital sign assessments, 
physical examinations, and clinical laboratory testing. 
At scheduled reviews, the DEC may recommend increasing the number of 
subjects to be enrolled (from 4 up to 8 as shown in Table 1) and advise on the 
planned dose for each successive cohort. Further, the DEC may recommend 
pausing and resuming or halting enrollment.  
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Further, at any time during the study, the DEC may review all available safety 
data (including but not limited to DLTs, AEs, TEAEs, and SAEs), PD 
(including but not limited to IgG levels), and clinical outcomes. 
 
If 2 or more subjects at any time in any cohort have Grade 3 AEs that are 
determined to be clinically significant and considered to be related to study 
drug, dosing will be halted within that cohort and dose-escalation to a 
higher dose will not occur. Upon review of the available information, the 
DEC may reduce the dose prior to enrolling additional subjects using the 
guidelines below: 
 
Cohort 1: Dose may be reduced by at least 50%.  
 
Cohort 2: Dose may be reduced by at least 33%. 
 
Cohort 3: Dose may be reduced to a level lower than the Cohort 2 
dose. 
 
Cohort 4 (optional cohort): Dose may be reduced to level lower than 
the Cohort 3 dose. 
NOTE: DLT will be defined generally as severe (Grade 3) AEs occurring 
in ≥2 subjects that are determined to be clinically significant and 
considered related to study drug. 
 
If any subject at any time during the study experiences a life-threatening 
AE (Grade 4) that is related to study drug, further dosing in all enrolled 
subjects will be suspended until the DEC has evaluated the event and 
determined the appropriate course of action.  
 
At any time during the study, the study or any ongoing study cohort may 
be discontinued if the DEC determines that further drug exposure would 
pose an undue risk to subjects. 
 
Additional information on the DEC’s responsibilities as they pertain to data 
review, dose selection, opening and closing a cohort, individual and study 
stopping recommendations is provided in Section 9 and the DEC charter. 
Study methodology 
Study participation requires that the subject will have completed the following 
periods of assessment to be performed on a weekly basis: Screening, 
Treatment (Baseline [Day 0], Major and Minor Dosing Visit days), and a 
Follow-Up (Major and Minor Visit days). 
Throughout the study, during each period of assessment to evaluate safety and 
tolerability, subjects will undergo physical examinations (including weight), 
vital sign measurements (including pulse oximetry), clinical (safety) laboratory 
tests, AEs, concomitant medication assessments, and ECGs. 
 
Screening Period (up to 14 days) 
After the subject has provided written informed consent, the Investigator or 
other qualified study personnel will determine if the subject is eligible for the 
study. This will be accomplished by reviewing the inclusion and exclusion 
criteria, and the subject’s demographic profile, screening PDAI total activity 
score, and medical history.  
 
Treatment Period (28 or 91 days) 
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The treatment period includes the Baseline (Day 0) Dosing Visit day, and 
Major and Minor Dosing Visit days. Refer to Table 2, Table 3, Table 4, and 
Section 7. 
Baseline (Day 0) Visit Day 
In addition to the safety and tolerability assessments described above, the 
subject will be administered the study drug and the following procedures will 
be conducted: pregnancy test (if applicable), PDAI, PK, PD, and 
immunogenicity sample collection, photography of lesions, and serum tetanus 
and varicella zoster virus (VZV) antibody tests. An optional skin biopsy may 
be collected. HR-QoL is assessed in all cohorts except Cohort 1. A complete 
list of assessments is provided in Table 2, Table 3, Table 4, and Section 7. 
Major Dosing Visit Days 
In addition to the safety and tolerability assessments described above, the 
subject will be administered the study drug, and the following procedures will 
be conducted: PDAI, PD, and immunogenicity sample collection. A complete 
list of assessments is provided in Table 2, Table 3, Table 4, and Section 7. 
Minor Dosing Visit Days  
In addition to the safety and tolerability assessments described above, the 
subject will be administered the study drug, and the following procedures will 
be conducted: PDAI and PD sample collection. A complete list of assessments 
is provided in Table 2, Table 3, Table 4, and Section 7. 
 
Follow-up Period/End of Study (84 days) 
The follow-up period includes the Major and Minor Follow-up Visit days. 
Subjects are encouraged to participate in all visits up to and including Day 112 
(Cohorts 1 and 2) or Day 175 (Cohort 3) to ensure study completion. Refer to 
Table 2, Table 3, Table 4, and Section 7. 
Major Follow-up Visit Days 
In addition to the safety and tolerability assessments described above, the 
following procedures will be conducted: PDAI, PD sample collection, 
photography of lesions and HR-QoL assessments. A complete list of 
assessments is provided in Table 2, Table 3, Table 4, and Section 7. 
Minor Follow-up Visit Days 
In addition to the safety and tolerability assessments described above, the 
following procedures will be conducted: PDAI and PD sample collection. A 
complete list of assessments is provided in Table 2, Table 3, Table 4, and 
Section 7. 
 
Dosing for any individual subject will be discontinued (ie, further treatment 
with the study drug will not be given) if the subject experiences any study 
drug-related SAE or any study drug-related non-serious adverse event that, in 
the judgement of the Investigator (following consultation with the Medical 
Monitor, if desired) suggests that it could be unsafe to administer further study 
drug to that subject. Additionally, a subject will be discontinued from further 
treatment with study drug at the discretion of the Investigator, with 
consultation with the Medical Monitor if desired, if they require a significant 
increase in anti-pemphigus medications for the management of pemphigus. 
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Study population 
Male or female subjects aged 18 and older with pemphigus (vulgaris or 
foliaceus) in active stage 
Inclusion criteria 
Subjects must meet the following criteria to be included: 
1. Willing and able to read, understand, and sign an informed consent form. 
2. Male or female ≥18 years of age at the time of screening. 
3. Documented diagnosis of pemphigus vulgaris or foliaceus based on all 3 
of the following criteria: 
a. Documented clinical history consistent with pemphigus vulgaris or 
foliaceus (clinical presentation defined as mucosal and/or skin 
lesions). 
b. Presence of Anti-Dsg 1 or 3 antibodies above the upper limit of 
normal (ULN).  
c. History of at least one positive tissue-based test (eg, biopsy, direct 
immunofluorescence [DIF]). 
4. Active disease defined as lesions lasting >2 weeks, and 3 active lesions in 
skin or mucosa or 2 active lesions with at least one being a skin lesion 
>1 cm diameter: 
a. If treated with rituximab or other anti-CD20 mAb, last dose 
>12 months prior to screening. 
b. If being treated with other immunosuppressants (ie, azathioprine, 
mycophenolate mofetil, methotrexate, dapsone, cyclosporine, 
tacrolimus, sirolimus, or low-dose cyclophosphamide 
[≤100 mg/day]), dose must be stable, defined as <25% change in 
dose, for 4 weeks prior to screening. 
c. On stable dose of corticosteroids, defined as ≤1 mg/kg of 
prednisone or equivalent and may not be increased by more than 
50% in the 2 weeks prior to screening.  
d. Allowed topical therapies for pemphigus lesions upon entering the 
study include petroleum jelly or Aquaphor® for the skin or 
chlorhexidine for the mouth.  
e. Stable use of topical low strength hydrocortisone (≤1%), 
tacrolimus, sirolimus, or pimecrolimus for lesions contributing 
<10% of the PDAI total activity score for the 4 weeks prior to 
screening is allowed. Stable use of dexamethasone elixir solution 
(swish and spit only) for oral lesions for the 4 weeks prior to 
screening is allowed. 
f. If not on regular corticosteroids, no pulse corticosteroids are 
allowed in the 2 weeks prior to screening. 
5. Body mass index (BMI) >18.5 kg/m2. 
6. Has a negative pregnancy test documented prior to the first dose of study 
drug (for women of childbearing potential). 
7. Females of childbearing potential must agree to be abstinent or else use 
any two of the following medically acceptable forms of contraception 
(<1% per year failure rate) from the screening period through the final 
study visit: oral contraceptive, condom with or without spermicidal jelly, 
diaphragm or cervical cap with spermicidal jelly, or intrauterine device 
(IUD). A female whose male partner has had a vasectomy must agree to 
use one additional form of medically acceptable contraception.  
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8. Females of non-childbearing potential, defined as surgically sterile (status 
post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or 
post-menopausal for at least 12 months do not require contraception 
during the study. 
9. Males with female partners of childbearing potential, including males who 
are surgically sterile (post vasectomy), must agree to be abstinent or else 
use a medically acceptable form of contraception from the screening 
period through 60 days after the final study visit. 
10. A PDAI total activity score of >4 at screening.
Exclusion criteria 
Subjects meeting any of the following criteria are to be excluded:  
1. Subject unable or unwilling to comply with the protocol. 
2. Active non-hematologic malignancy or history of non-hematologic 
malignancy in the 3 years prior to screening (exclusive of non-melanoma 
skin cancer and cervical cancer in situ). 
3. Positive for human immunodeficiency virus (HIV) or hepatitis C antibody. 
4. Positive for hepatitis B surface antigen. 
5. Active infection or history of recurrent infections. 
6. IVIG treatment within 30 days of screening. 
7. Received any cytotoxic (other than azathioprine) or any non-anti-CD20 
mAb therapy in the 3 months prior to screening. 
8. Any exposure to an investigational drug or device within the 30 days prior 
to screening. 
9. Plasmapheresis or immunoadsorption within 30 days of screening. 
10. Cellular therapy, including chimeric antigen receptor and T-cell (CAR-T), 
at any time prior to screening. 
11. Use of any systemic or topical immunosuppressive drugs within 3 months 
of screening not including dose allowed by the inclusion criteria. 
12. Serum total IgG <600 mg/dL. 
13. Subject has any current medical condition that, in the opinion of the 
Investigator, may compromise their safety or compliance, preclude 
successful conduct of the study, or interfere with interpretation of the 
results (eg, a significant pre-existing illness or other major comorbidity 
that the Investigator considers may confound the interpretation of the 
study results). 
14. Any vaccination within 2 weeks of screening.
Study drug, dosage, 
and administration 
Study drug: SYNT001 
Dosage:  
Cohort 1: 10 mg/kg, 5 weekly IV doses 
Cohort 2: ≤30 mg/kg, 5 weekly IV doses  
Cohort 3: ≤30 mg/kg, 14 weekly IV doses 
Cohort 4 (optional cohort): ≤45 mg/kg, ≤14 weekly IV doses  
Product presentation and preparation: 
SYNT001 provided as a liquid at a nominal concentration of 50 mg/mL. 
SYNT001 is diluted in dextrose 5% in water (D5W) to prepare the solution for 
infusion. 
Route of administration: IV in 250 mL over 1 hour ± 15 minutes 
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Control, dose, and 
route of 
administration 
Not applicable 
Duration of subject 
participation 
The duration of subject participation for each cohort is as follows: 
Cohorta 
Screening 
Treatment 
Follow-up 
Maximum Total 
Days 
Weeks 
1 
≤14 days 
28 days 
84 days 
126 days 
18 weeks 
2  
≤14 days 
28 days 
84 days 
126 days 
18 weeks 
3 
≤14 days 
91 days 
84 days 
189 days 
27 weeks 
a. 
Planned dose and duration of subject participation for Cohort 4 (optional cohort) will be 
determined following DEC data review. All available data will be considered. 
 
Permitted and 
prohibited 
concomitant 
treatments 
All treatments a subject receives within 14 days prior to enrollment through 
the end of the study will be documented.  
Permitted Medications 
Concomitant medication and treatment for co-existing conditions, including 
those for pemphigus, are permitted if not listed as prohibited.  
1. Topical antibiotics to treat active infections that occur during the study.  
2. Topical or systemic treatments for oral candidiasis.  
3. Topical lidocaine for transient pain relief as needed.  
4. Concomitant treatment that is medically indicated for any AEs the subject 
experiences during the study.  
5. Medication for potential infusion reactions: The Investigator may 
recommend prophylactic use of acetaminophen, IV hydration, 
diphenhydramine, histamine2 (H2) blockers (eg, ranitidine, famotidine), etc 
to manage potential infusion reactions. 
6. Low-strength corticosteroids (eg, hydrocortisone ≤1%) applied to a single 
lesion contributing <10% of the PDAI total activity score. 
7. Topical tacrolimus, sirolimus or pimecrolimus applied to a single lesion 
contributing <10% of the PDAI total activity score. 
8. Dexamethasone elixir solution for oral lesions if dose remains stable 
throughout trial participation (swish and spit only). 
9. Stable regimen of the following systemic immunosuppressants: 
azathioprine, mycophenolate mofetil, methotrexate, dapsone, cyclosporine, 
tacrolimus, sirolimus, or low dose oral cyclophosphamide (≤100 mg/day).  
One month after the final dose of SYNT001, corticosteroids may be tapered at 
the Investigator’s discretion. Prohibited Medications 
Use of the following medications will not be permitted during the study unless 
specified above as permitted: 
1. Rituximab or other anti-CD20 antibody  
2. Monoclonal antibodies other than study drug  
3. Any topical or systemic immunosuppressive drugs apart from those that 
are listed as permitted.  
4. IV corticosteroids prior to infusion (except in subjects who received 
corticosteroids for treatment of a prior infusion reaction to SYNT001) 
5. Any dietary herbal supplements 
6. Any investigational drug or device 
7. Vaccinations within 2 weeks of screening through 28 days following final 
dose of study drug
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Statistical 
considerations 
Three populations will be employed in the analysis of study data: 
 
The safety population will consist of all subjects who have received at 
least one dose of study drug.  
 
The PD population will consist of all subjects who receive at least one 
dose of study drug and have post-dose PD data available.  
 
The PK population will consist of all subjects who receive at least one 
dose of study drug and have post-dose PK data available. 
 
Primary safety analyses will be performed on the safety population. 
Demographics, subject disposition, screening, and baseline characteristics will 
be summarized for the safety and PD/PK populations, where appropriate. 
 
Sample size  
Formal sample size calculations were not performed. The number of subjects 
was chosen based on feasibility and was considered sufficient to meet the 
study objectives.  
 
Criteria for evaluation 
Baseline analysis 
Baseline characteristics to include medical history, physical examination, vital 
signs, and ECG will be summarized using descriptive statistics by cohort. 
 
Safety analysis 
The evaluation of SYNT001 based on vital signs, physical examination, ECGs, 
clinical safety laboratory tests, the incidence of AEs, TEAEs, and SAEs 
summarized by cohort, severity, and relationship to study product. 
 
Dose-finding analysis 
The evaluation of SYNT001 based on total IgG levels and responses on the 
PDAI total activity score from baseline will be summarized using descriptive 
statistics by cohort.  
 
Statistical methodology 
Treatment-emergent AEs (TEAEs) will be summarized using the Medical 
Dictionary for Regulatory Activities (MedDRA®; Version 19 or higher) 
System Organ Class (SOC) and preferred term, classified from verbatim terms. 
The incidence and percentage of subjects with at least one occurrence of a 
preferred term will be included, using the most severe grade. The number of 
events per preferred term will also be summarized. Causality (relationship to 
study treatment) will be summarized separately. 
TEAEs, SAEs, and AEs leading to withdrawal, dose modification, or treatment 
discontinuation will be listed by subject and dose using SOC and preferred 
terms. Duration of AEs will be determined and included in listings, along with 
action taken and outcome.  
Laboratory results will be summarized by time point and cohort. The incidence 
of laboratory abnormalities will be summarized. The worst on-study grade 
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after the first dose of study drug will be summarized. Results for variables that 
are not coded will be presented in the listings as below, within, or above the 
normal limits of the central laboratory. Vital sign measurements will be 
summarized by cohort at each scheduled time point using descriptive statistics. 
PD/PK results will be summarized by cohort. Descriptive statistics of PD/PK 
parameters for SYNT001 will include mean, standard deviation (SD), 
coefficient of variation (CV), median, minimum, and maximum  
Immunogenicity results will be summarized by cohort and timepoint. 
Descriptive statistics will include mean, SD, median, minimum, and 
maximum. 
PDAI results will be summarized by score (total activity score, total damage 
score), cohort, and timepoint. Descriptive statistics will include absolute 
change from baseline and percent change from baseline. 
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Figure 1. 
Cohort Enrollment 
 
 
 
tttt 
tttt 
Pemphigus 
Vulga ris and 
Foliaceus 
patients with 
active disease 
Patient 
Selectial 
Cohort 1 
Cohort 2 
Cohort 3 
(optional) 
• • • • 
• • • • U- TTTT 
W- TTTT 
• • • • 
TTTT 
Maximum 45 mgfkg 
tttt 
r 
s 30mg/kg 
Ma)limum 14 doses 
t 
14 W1lekly IV doses 
t 
n_4, optional +4 
S 30mg/kg 
I 
• • • • 
5 weekly IV dosing 
I 
n-4, optional +4 
TTTT 
I 
I 
• 
I 
n-4, optional +4 
I 
I 
I 
I 
I 
I 
I 
I 
lOmg/kg 
I 
I 
I 
5 weekly IV doses 
r-J.----- ] 
r---L--- r------L-------I 
I 
1 
I 
I I 
DECO. tll Review 3 
n-upto 8 
J 
I Cohorts 1, 2, and/or 
3 Iny 42 1 
______________ J 
Following doro reviews or rhe occurrence% 
DL T, rhe DEC may lower dose, holt or closecohOfTs. Of odd up r04 porienrs ro Cohorts 2-4 
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Table 2. 
Study Assessments for Cohort 1 
 
Screening 
Treatment Period 
Follow-Up 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Time point (study day) 
−14 to −1 
0 
1 
(±1 h)
2 
(±2 h)
5p 
(±4 h)
7 
(±6 h)
12p 
(±6 h)
14 
(±6 h)
19p 
(±6 h)
21 
(±6 h) 
28 
(±6 h)
29 
(±1 h)
30 
(±2 h)
33 
(±4 h)
42 
(±3 d)
56 
(±5 d)
84 
(±5 d)
112 or 
ET 
(±5 d)
Informed consent 
X 
 
 
Demographics/medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationa 
X 
X
X
X
X 
X
X
X
X
X
Vital signsb 
X 
X
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
X
X
Pulse oximetryc 
 
X
X
X
X 
X
Clinical safety labsd 
X 
X
X
X
X 
X
X
X
X
X
X
Pregnancy teste 
X 
X
 
X
X
Hepatitis and HIV screen 
X 
 
 
12-lead ECGf 
X 
X
X
 
X
X
Tetanus and VZV antibodiesg 
 
X
 
X
X
X
PDAI 
 
X
X
X
X 
X 
X
X
X
X
X
PK samplingh 
 
X
X
X
X
 
X
X
X
X
Immunogenicityi 
 
X
X
 
X
X
X
X
Study drug administrationj 
 
X
X
X
X 
X
Immunoglobulins (IgG, IgA, 
IgM) and IgG subtypes 
(IgG1-4)k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
CIC 
 
X
X
X
X
X
X
X 
X
X
X
X
X
X
Anti-Dsg (1 and 3) antibody 
titers 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
C3 and AECAl 
 
X
X
 
X
X
X
X
FCGR2A by buccal swabm 
 
X
 
RNAseq 
 
X
X
 
X
X
X
X
Urine IgG 
 
X
X
 
X
X
X
X
Immunophenotypingn 
 
X
 
X
X
Exploratory pemphigus 
immune response biomarkers 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Optional skin biopsy 
 
X
X
X
X
 
X
X
X
Photographyo 
 
X
 
X
X
X
X
Adverse events 
To be collected from the date that the ICF is signed through the last study visit
Concomitant medications 
To be collected from within 14 days prior to Day 0 through the last study visit
Abbreviations: CIC = circulating immune complexes; d = days; ECG = electrocardiogram; ET = early termination; h = hour(s); HIV = human immunodeficiency virus; 
ICF = informed consent form; PDAI = Pemphigus Disease Area Index; PK = pharmacokinetic; VZV = varicella zoster virus. 
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a. 
Complete physical examination, including weight, to be performed. Height and BMI will be additional assessments conducted at screening.  
b. 
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and oral temperature) to be obtained after 5 minutes of seated rest. Any abnormal 
measurements are to be repeated after 5 minutes of rest. On Days 0, 7, 14, 21, and 28, vital sign measurements will be collected immediately prior to the infusion; 15, 30, 
and 45 minutes after the start of the infusion; at completion of the infusion; and 30 minutes, 1 hour, and 2 hours following completion of the infusion.  
c. 
Pulse oximetry: On Days 0, 7, 14, 21, and 28, pulse oximetry to be measured immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at 
completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion. 
d. 
Clinical safety labs: hematology, clinical chemistry, and urinalysis (see Section 7.5 for a complete list). Full clinical safety laboratory draws will be collected at screening 
and on Days 0, 7, 14, 21, 28, 33, 42, 56, 84, and 112.  
e. 
Pregnancy test: To be performed at time of screening, prior to first dose of SYNT001 on Day 0, and on Days 56 and 112. Urine or serum test is acceptable; however, 
positive urine tests must be confirmed with serum testing. 
f. 
Digital 12-lead ECG to be obtained in triplicate at least 1 to 2 minutes apart and after 5 minutes of rest in a supine position. See Section 7.6 for additional information. On 
Days 0 and 28 to be obtained 5 minutes after the completion of infusion. Day 12 ECG will be collected only if the visit is conducted at the study site.  
g. 
Serology: Testing at Day 56 will not be done for any subject whose baseline titer is below the level of detection. If the Day 56 results are greater than 30% below the 
baseline value, or if the subject falls below the level of detection, the subject will be re-tested at Day 84; if still below the baseline value (or level of detection), the subject 
will be re-tested at Day 112. Any subject whose baseline value for tetanus or VZV was above the detectable level at baseline, and is not within 30% of the baseline value or 
is below the detectable level by Day 112, will be referred to their primary care physician for further management. See Section 7.5.3 for additional information. 
h. 
PK: Starting on Days 0 and 28, serum samples will be collected just prior to the start of study drug infusion (pre-dose), and at 5 minutes and 2, 4, 6, 24, and 48 hours after 
the end-of-study drug infusion. Additional samples will be collected on Days 5 and 33. See Section 7.5.4 for additional information.  
i. 
Immunogenicity: Samples will be collected pre-dose when collected on dosing days. Samples will be collected on Days 0, 14, 28, 56, 84 and 112. See Section 7.5.6 for 
additional information. 
j. 
Prior to study drug infusion, SYNT001 drug product is to be diluted in dextrose 5% in water (D5W) to a total volume of 250 mL and administered intravenously over 
1 hour using a 0.2-micron inline filter. See Section 4 and Section 7.8 for additional information.  
k. 
Immunoglobulins (IgG, IgA, IgM) and IgG subtypes (IgG1-4): Collected for measurements of IgG, IgG subtypes (IgG1-4), IgA, IgM at every visit. On Days 0, 7, 14, 
21, and 28, samples are collected prior to infusion of study drug. See Section 7.5.5 for additional information. 
l. 
Exploratory pharmacodynamic samples (C3 and AECA): Collected pre-dose when collected on dosing days. See Section 7.5.5 for complete information. 
m. Buccal samples to be collected and stored; pending review of clinical and pharmacodynamics assessments. 
n. 
Immunophenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B cells. 
o. 
Photographs of active lesions taken prior to first dose on Day 0. Follow-up photographs will be taken at Days 33, 56, 84 and 112. Subjects who begin a steroid taper will 
have additional photographs taken at the clinic visit during which the decision to begin the taper is made. 
p. 
Visit Days 5, 12, and 19 may be conducted via at-home nurse in lieu of a subject visit to the study site. 
q. 
Subjects will return to the clinic on Days 84 and 112 for follow-up visits. Subjects whose total IgG is not within 30% of their Day 0 baseline value and not above 
500 mg/dL at the Day 112 visit will be referred for further management. 
 
 
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Table 3. 
Study Assessments for Cohort 2 
 
Screening 
Treatment Period 
Follow-Up 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Time point (study day) 
−14 to −1 
0 
7  
(±1 d) 
14  
(±1 d) 
21  
(±1 d) 
28  
(±1 d) 
35  
(±1 d) 
42  
(±1 d) 
56  
(±3 d) 
84  
(±5 d) 
112 or ET
 (±5 d) 
Informed consent 
X 
 
Demographics/medical history 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinationa 
X 
X
X
X
X
X 
X
X
X
X
X
Vital signsb 
X 
X
X
X
X
X 
X
X
X
X
X
Pulse oximetryc 
 
X
X
X
X
X 
Clinical safety labsd 
X 
X
X
X
X
X 
X
X
X
X
X
Pregnancy teste 
X 
X
 
X
X
Hepatitis and HIV screen 
X 
 
12-lead ECGf 
X 
X
X
X 
X
Tetanus and VZV antibodiesg 
 
X
 
X
X
PDAIh 
X 
X
X
X
X
X 
X
X
X
X
X
PK samplingi 
 
X
X 
Immunogenicityj 
 
X
X
X 
X
X
Study drug administrationk 
 
X
X
X
X
X 
Immunoglobulins (IgG, IgA, 
IgM) and IgG subtypes (IgG1-4)l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
CIC 
 
X
X
X
X
X 
X
X
X
X
X
Anti-Dsg (1 and 3) antibody 
titers 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C3 and AECAm 
 
X
 
X
X
FCGR2A by buccal swabn 
 
X
 
RNAseq 
 
X
 
X
X
Urine IgG 
 
X
 
X
X
Immunophenotypingo 
 
X
 
X
X
Exploratory pemphigus immune 
response biomarkers 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photographyp 
 
X
 
X
X
X
HR-QoL assessments 
 
X
 
X
X
X
Adverse events 
To be collected from the date that the ICF is signed through the last study visit
Concomitant medications 
To be collected from within 14 days prior to Day 0 through the last study visit
Abbreviations: CIC = circulating immune complexes; d = day(s); ECG = electrocardiogram; ET = early termination; HIV = human immunodeficiency virus; HR-QoL = health-
related quality of life; ICF = informed consent form; PDAI = Pemphigus Disease Area Index; PK = pharmacokinetic; VZV = varicella zoster virus. 
a. 
Complete physical examination, including weight, to be performed. Height and BMI will be additional assessments conducted at screening.  
b. 
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and oral temperature) to be obtained after 5 minutes of seated rest. Any abnormal 
measurements are to be repeated after 5 minutes of rest. Vital sign measurements will be taken on all study visits. On Days 0, 7, 14, 21, and 28, vital sign measurements 
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will be collected immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at completion of the infusion; and 30 minutes, 1 hour, and 2 hours 
following completion of the infusion.  
c. 
Pulse oximetry: On Days 0, 7, 14, 21, and 28, pulse oximetry to be measured immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at 
completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion. 
d. 
Clinical safety labs: hematology, clinical chemistry, and urinalysis (see Section 7.5 for a complete list). Full clinical safety laboratory draws will be collected at screening 
and on all study visits.  
e. 
Pregnancy test: To be performed at time of screening, prior to first dose of SYNT001 on Day 0, and on Days 56 and 112. Urine or serum test is acceptable; however, 
positive urine tests must be confirmed with serum testing. 
f. 
Digital 12-lead ECG to be obtained in triplicate at least 1 to 2 minutes apart and after 5 minutes of rest in a supine position. See Section 7.6 for additional information. On 
treatment days to be obtained 5 minutes after the completion of infusion.  
g. 
Serology: Any subject whose baseline value for tetanus or VZV was above the detectable level at baseline and is not within 30% of the baseline value or is below the 
protective level by End of Treatment will be referred to their primary care physician for further management. See Section 7.5.3 for additional information. 
h. 
PDAI will be administered at screening. Subject eligibility requires a PDAI total activity score >4. Thereafter, assuming eligibility, the PDAI will be administered during 
Treatment Period and Follow-up Period. See Section 7.7 for additional information. 
i. 
PK: On Days 0 and 28, serum samples will be collected just prior to the start of study drug infusion (pre-dose), and at 5 minutes, 1 and 2 hours after the end of study drug 
infusion. See Section 7.5.4 for additional information.  
j. 
Immunogenicity: Samples will be collected pre-dose when collected on dosing days. Samples will be collected on Days 0, 14, 28, 56, and 112. See Section 7.5.6 for 
additional information. 
k. 
Prior to study drug infusion, SYNT001 drug product is to be diluted in dextrose 5% in water (D5W) to a total volume of 250 mL and administered intravenously over 
1 hour ± 15 minutes using a 0.2-micron inline filter. See Section 4 and Section 7.8 for additional information.  
l. 
Immunoglobulins (IgG, IgA, IgM) and IgG subtypes (IgG1-4): Collected for measurements of IgG, IgG subtypes (IgG1-4), IgA, IgM at every visit. On Days 0, 7, 14, 
21, and 28, samples are collected prior to infusion of study drug. See Section 7.5.5 for additional information. 
m. Exploratory pharmacodynamic samples (C3 and AECA): Collected pre-dose when collected on dosing days. See Section 7.5.5 for complete information. 
n. 
Buccal samples to be collected and stored; pending review of clinical and pharmacodynamics assessments. 
o. 
Immunophenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B cells. 
p. 
Photographs of active lesions taken prior to first dose on Day 0. Follow-up photographs will be taken at Days 35, 56, and 112. Subjects who begin a steroid taper will have 
additional photographs taken at the clinic visit during which the decision to begin the taper is made. 
q. 
Subjects will return to the clinic on Days 84 and 112 for follow-up visits. Subjects whose total IgG is not within 30% of their Day 0 baseline value and not above 
500 mg/dL at the Day 112 visit will be referred for further management. 
 
 
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Table 4. 
Study Assessments for Cohort 3 
 
Screening 
Treatment Period 
Follow-Up 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Time point (study day) 
−14 to −1 
0 
7  
(±1 d)
14 
(±1 d)
21 
(±1 d)
28 
(±1 d)
35 
(±1 d)
42 
(±1 d)
49 
(±1 d)
56 
(±1 d)
63  
(±1 d) 
70 
(±1 d)
77 
(±1 d)
84 
(±1 d)
91 
(±1 d)
98 
(±1 d)
105 
(±1 d)
119 
(±3 d)
147 
(±5 d)
175 or 
ET
 (±5 d)
Informed consent 
X 
 
 
Demographics/medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
Physical examinationa 
X 
X 
X
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
X
X
X
Vital signsb 
X 
X 
X
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
X
X
X
Pulse oximetryc 
 
X 
X
X
X
X
X
X
X
X
X 
X
X
X
X
Clinical safety labsd 
X 
X 
X
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
X
X
X
Pregnancy teste 
X 
X 
X
 
X
X
X
Hepatitis and HIV screen 
X 
 
 
12-lead ECGf 
X 
X 
X
 
X
X
Tetanus and VZV antibodiesg 
 
X 
 
X
X
PDAIh 
X 
X 
X
X
X
X
X
X
X
X 
X 
X
X
X
X
X
X
X
X
X
PK samplingi 
 
X 
 
X
Immunogenicityj 
 
X 
X
 
X
X
X
Study drug administrationk 
 
X 
X
X
X
X
X
X
X
X
X 
X
X
X
X
Immunoglobulinsl 
X 
X 
X
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
X
X
Xq
CIC 
 
X 
X
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
X
X
X
Anti-Dsg (1 and 3) antibody 
titers 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C3 and AECAm 
 
X 
 
X
X
FCGR2A by buccal swabn 
 
X 
 
RNAseq 
 
X 
 
X
X
Urine IgG 
 
X 
 
X
X
Immunophenotypingo 
 
X 
 
X
X
Exploratory pemphigus 
immune response biomarkers 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photographyp 
 
X 
X
 
X
X
X
HR-QoL assessments 
 
X 
 
X
X
X
Adverse events 
To be collected from the date that the ICF is signed through the last study visit
Concomitant medications 
To be collected from within 14 days prior to Day 0 through the last study visit
Abbreviations: CIC = circulating immune complexes; d = days; ECG = electrocardiogram; ET = early termination; HIV = human immunodeficiency virus; ICF = informed 
consent form; PDAI = Pemphigus Disease Area Index; PK = pharmacokinetic; VZV = varicella zoster virus. 
a. 
Complete physical examination, including weight, to be performed. Height and BMI will be additional assessments conducted at screening.  
b. 
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and oral temperature) to be obtained after 5 minutes of seated rest. Any abnormal 
measurements are to be repeated after 5 minutes of rest. Vital sign measurements will be taken on all study visits. On Days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 
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and 91, vital sign measurements will be collected immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at completion of the infusion; and 
30 minutes, 1 hour, and 2 hours following completion of the infusion.  
c. 
Pulse oximetry: On Days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, and 91, pulse oximetry to be measured immediately prior to the infusion; 15, 30, and 45 minutes 
after the start of the infusion; at completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion. 
d. 
Clinical safety labs: hematology, clinical chemistry, and urinalysis (see Section 7.5 for a complete list). Full clinical safety laboratory draws will be collected at screening 
and on all study visits.  
e. 
Pregnancy test: To be performed at time of screening, prior to dosing of SYNT001 on Days 0, 42, and 91, and on Days 119 and 175. Urine or serum test is acceptable; 
however, positive urine tests must be confirmed with serum testing. 
f. 
Digital 12-lead ECG to be obtained in triplicate at least 1 to 2 minutes apart and after 5 minutes of rest in a supine position. See Section 7.6 for additional information. On 
treatment days to be obtained 5 minutes after the completion of infusion.  
g. 
Serology: Any subject whose baseline value for tetanus or VZV was above the detectable level at baseline, and is not within 30% of the baseline value or is below the 
protective level by End of Treatment will be referred to their primary care physician for further management. See Section 7.5.3 for additional information. 
h. 
PDAI will be administered at screening. Subject eligibility requires a PDAI total activity score >4. Thereafter, assuming eligibility, the PDAI will be administered during 
Treatment Period and Follow-up Period. See Section 7.7 for additional information. 
i. 
PK: Starting on Days 0 and 91, serum samples will be collected just prior to the start of study drug infusion (pre-dose), and at 5 minutes, 1 hour and 2 hours after the end 
of study drug infusion. Section 7.5.4 for additional information.  
j. 
Immunogenicity: Samples will be collected pre-dose when collected on dosing days. Samples will be collected on Days 0, 42, 91, 119 and 175. See Section 7.5.6 for 
additional information. 
k. 
Prior to study drug infusion, SYNT001 drug product is to be diluted in dextrose 5% in water (D5W) to a total volume of 250 mL and administered intravenously over 
1 hour ± 15 minutes using a 0.2-micron inline filter. See Section 4 and Section 7.8 for additional information.  
l. 
Immunoglobulins (IgG, IgA, IgM) and IgG subtypes (IgG1-4): Collected for measurements of IgG, IgG subtypes (IgG1-4), IgA, IgM at every visit. On Days 0, 7, 14, 
21, 28, 35, 42, 49, 56, 63, 70, 77, 84, and 91, samples are collected prior to infusion of study drug. See Section 7.5.5 for additional information. 
m. Exploratory pharmacodynamic samples (C3 and AECA): Collected pre-dose when collected on dosing days. See Section 7.5.5 for complete information. 
n. 
Buccal samples to be collected and stored; pending review of clinical and pharmacodynamics assessments. 
o. 
Immunophenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B cells. 
p. 
Photographs of active lesions taken prior to first dose on Day 0. Follow-up photographs will be taken at Days 42, 98, 119, and 175. Subjects who begin a steroid taper will 
have additional photographs taken at the clinic visit during which the decision to begin the taper is made. 
q. 
Subjects will return to the clinic on Days 147 and 175 for follow-up visits. Subjects whose total IgG is not within 30% of their Day 0 baseline value and not above 
500 mg/dL at the Day 175 visit will be referred for further management. 
 
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TABLE OF CONTENTS 
1. 
SYNOPSIS .........................................................................................................................4 
LIST OF TABLES ...................................................................................................................27 
LIST OF FIGURES .................................................................................................................27 
LIST OF APPENDICES ..........................................................................................................27 
LIST OF ABBREVIATIONS ..................................................................................................28 
2. 
BACKGROUND AND RATIONALE ............................................................................31 
2.1 
Study Rationale ......................................................................................................31 
2.2 
Selection of Doses in this Study ............................................................................32 
2.3 
Compliance Statement ...........................................................................................33 
3. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................34 
3.1 
Primary Objective ..................................................................................................34 
3.2 
Secondary Objectives .............................................................................................34 
3.3 
Exploratory Objectives ..........................................................................................34 
3.4 
Primary Endpoints .................................................................................................34 
3.5 
Secondary Endpoints .............................................................................................35 
3.6 
Exploratory Endpoints ...........................................................................................35 
4. 
STUDY DRUG ................................................................................................................37 
4.1 
Description of SYNT001 .......................................................................................37 
4.2 
Dose Requirements ................................................................................................37 
4.3 
Handling and Storage of SYNT001 .......................................................................37 
4.4 
Study Drug Accountability ....................................................................................37 
5. 
STUDY DESIGN .............................................................................................................39 
5.1 
Study Sites .............................................................................................................39 
5.2 
Overview of Study Design .....................................................................................39 
5.3 
Randomization and Blinding .................................................................................40 
6. 
STUDY POPULATION ..................................................................................................41 
6.1 
Target Population ...................................................................................................41 
6.2 
Inclusion Criteria ...................................................................................................41 
6.3 
Exclusion Criteria ..................................................................................................42 
7. 
STUDY PROCEDURES .................................................................................................44 
7.1 
Informed Consent...................................................................................................44 
7.2 
Demographics and Medical History ......................................................................44 
7.3 
Physical Examination.............................................................................................44 
7.4 
Vital Sign Measurements .......................................................................................44 
7.5 
Clinical Laboratory Measurements ........................................................................46 
7.5.1 
Pregnancy Testing ........................................................................................47 
7.5.2 
Virology .......................................................................................................47 
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7.5.3 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing ....47 
7.5.4 
Pharmacokinetics (PK) Sampling ................................................................47 
7.5.5 
Pharmacodynamic Sampling .......................................................................47 
7.5.6 
Immunogenicity Testing ..............................................................................48 
7.6 
12-Lead Electrocardiogram (ECG) ........................................................................49 
7.7 
Pemphigus Disease Area Index (PDAI) ................................................................49 
7.8 
Study Drug Administration ....................................................................................49 
7.9 
Photographs............................................................................................................49 
7.10 
Health-Related Quality of Life Assessments .........................................................50 
7.11 
Adverse Event Assessments ..................................................................................50 
7.12 
Prior and Concomitant Medications ......................................................................50 
7.13 
Skin Biopsy ............................................................................................................51 
8. 
STUDY ASSESSMENTS ...............................................................................................52 
8.1 
All Cohorts: Screening Period and First Treatment (Day 0) .................................52 
8.1.1 
All Cohorts: Screening Period (Day −14 to Day −1) ..................................52 
8.1.2 
All Cohorts: Enrollment and First Treatment (Day 0) .................................52 
8.2 
Cohort 1: Day 1 to 84.............................................................................................54 
8.2.1 
Cohort 1: Follow-up Day 1 ..........................................................................54 
8.2.2 
Cohort 1: Follow-up Day 2 ..........................................................................54 
8.2.3 
Cohort 1: Follow-up Day 5 ..........................................................................54 
8.2.4 
Cohort 1: Treatment Day 7 (Dose 2) ...........................................................55 
8.2.5 
Cohort 1: Follow-up Day 12 ........................................................................55 
8.2.6 
Cohort 1: Treatment Day 14 (Dose 3) .........................................................56 
8.2.7 
Cohort 1: Follow-up Day 19 ........................................................................57 
8.2.8 
Cohort 1: Treatment Day 21 (Dose 4) .........................................................57 
8.2.9 
Cohort 1: Treatment Day 28 (Dose 5) .........................................................58 
8.2.10 
Cohort 1: Follow-up Day 29 ........................................................................59 
8.2.11 
Cohort 1: Follow-up Day 30 ........................................................................59 
8.2.12 
Cohort 1: Follow-up Day 33 ........................................................................59 
8.2.13 
Cohort 1: Follow-up Day 42 ........................................................................60 
8.2.14 
Cohort 1: Follow-up Day 56 ........................................................................60 
8.2.15 
Cohort 1: Follow-up Day 84 ........................................................................61 
8.3 
Cohorts 2 and 3: Subsequent Treatments to Follow-up .........................................61 
8.3.1 
Cohort 2: Treatment Days 7 and 21; Cohort 3: Treatment Days 7, 14, 21, 
28, 35, 49, 56, 63, 70, 77, and 84 .................................................................61 
8.3.2 
Cohort 2: Treatment Days 14 and 28; Cohort 3: Treatment Days 42 and 9162 
8.3.3 
Cohort 2: Follow-up Days 35 and 56; Cohort 3: Follow-up Days 98 and 11963 
8.3.4 
Cohort 2: Follow-up Days 42 and 84; Cohort 3: Follow-up Days 105 and 
147 ...............................................................................................................64 
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8.4 
All Cohorts: End of Study or Early Termination Visit; Cohorts 1 and 2, Day 112; 
Cohort 3, Day 175 ..................................................................................................64 
9. 
STUDY RULES ...............................................................................................................66 
9.1 
Subject Withdrawal ................................................................................................66 
9.2 
Subject Replacement ..............................................................................................66 
9.3 
Study Discontinuation ............................................................................................67 
9.4 
Lost to Follow-up ...................................................................................................67 
9.5 
Stopping Rules .......................................................................................................67 
9.5.1 
Dose-Escalation Stopping Rule ...................................................................67 
9.5.2 
Study Stopping Rule ....................................................................................68 
9.5.3 
Individual Stopping Rule .............................................................................68 
10.  EVALUATION OF SAFETY .........................................................................................69 
10.1 
Safety Parameters ...................................................................................................69 
10.2 
Adverse Events ......................................................................................................69 
10.2.1 
Recording an Adverse Event .......................................................................70 
10.2.2 
Assessment of Causality ..............................................................................70 
10.2.3 
Serious Adverse Events ...............................................................................70 
10.2.3.1 
Recording a Serious Adverse Event...................................................71 
10.2.3.2 
Reporting a Serious Adverse Event ...................................................72 
10.2.4 
Follow-Up of Adverse Events and Serious Adverse Events .......................73 
10.3 
Warnings and Precautions ......................................................................................73 
10.3.1 
Vaccinations .................................................................................................73 
10.3.2 
Management of Allergic or Infusion-Related Reactions .............................73 
10.3.3 
Potential Immune Effects .............................................................................77 
10.4 
Events of Special Interest.......................................................................................78 
10.5 
Other Safety Considerations ..................................................................................78 
10.5.1 
Laboratory Data ...........................................................................................78 
10.5.2 
Medication Errors ........................................................................................79 
10.5.3 
Overdose ......................................................................................................79 
10.5.4 
Pregnancy .....................................................................................................79 
11.  STATISTICAL CONSIDERATIONS .............................................................................80 
11.1 
General Design.......................................................................................................80 
11.2 
Study Populations ..................................................................................................80 
11.3 
Sample Size Justification .......................................................................................80 
11.4 
Statistical Analysis .................................................................................................80 
11.4.1 
Statistical Analysis Plan ...............................................................................80 
11.4.2 
Statistical Methodology ...............................................................................81 
11.4.3 
Analysis of Primary Endpoints ....................................................................81 
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11.4.3.1 
Safety Data .........................................................................................81 
11.4.3.2 
Dose Selection Data ...........................................................................82 
11.4.4 
Analysis of Secondary Endpoints ................................................................82 
11.4.4.1 
Pharmacokinetic Data ........................................................................82 
11.4.4.2 
Pharmacodynamic/Activity Data .......................................................82 
11.4.4.3 
Immunogenicity Data .........................................................................82 
11.4.4.4 
PDAI Data ..........................................................................................83 
11.4.5 
Analysis of Exploratory Endpoints ..............................................................83 
11.4.5.1 
Corticosteroid Use .............................................................................83 
11.4.5.2 
Health-Related Quality of Life Data ..................................................83 
11.4.5.3 
Photography .......................................................................................83 
11.5 
Interim Analysis .....................................................................................................83 
12.  STUDY MANAGEMENT ..............................................................................................84 
12.1 
Regulatory and Ethical Considerations ..................................................................84 
12.1.1 
Ethical Conduct ............................................................................................84 
12.1.2 
Informed Consent ........................................................................................84 
12.1.3 
Subject Confidentiality and Privacy ............................................................84 
12.1.4 
Future Use of Stored Specimens ..................................................................85 
12.2 
Study Administration .............................................................................................85 
12.2.1 
Institutional Review Board Approval ..........................................................86 
12.2.2 
Data Handling and Record Keeping ............................................................86 
12.2.3 
Data Protection ............................................................................................86 
12.2.4 
Study Site Regulatory Documentation ........................................................86 
12.2.5 
Subject Clinical Source Documents and Background Data .........................87 
12.2.6 
Electronic Case Report Forms .....................................................................88 
12.3 
Clinical Monitoring, Audits, and Inspections ........................................................88 
12.3.1 
Clinical Monitoring ......................................................................................88 
12.3.2 
Audits and Inspections .................................................................................89 
12.4 
Changes to the Protocol .........................................................................................89 
12.5 
Study Discontinuation and Closure .......................................................................89 
13.  PUBLICATION AND DATA SHARING POLICY .......................................................90 
14.  REFERENCES ................................................................................................................91 
 
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LIST OF TABLES 
Table 1.Cohort Overview ...........................................................................................................8 
Table 2.Study Assessments for Cohort 1 .................................................................................17 
Table 3.Study Assessments for Cohort 2 .................................................................................19 
Table 4.Study Assessments for Cohort 3 .................................................................................21 
Table 5.Cohort Overview .........................................................................................................39 
Table 6.Timing Windows for PK/PD Sampling, ECG, and Vital Sign Measurements ...........45 
Table 7.Clinical Safety Laboratory Panels ..............................................................................46 
Table 8.Pharmacodynamic Assessments .................................................................................48 
Table 9.Grading and Management of Allergic or Infusion-Related Reactions .......................77 
Table 10.Study Administrative Structure ................................................................................86 
 
LIST OF FIGURES 
Figure 1.Cohort Enrollment .....................................................................................................16 
Figure 2.Management of Moderate (Grade 2) Infusion Reactions ..........................................75 
Figure 3.Management of Severe (Grade 3 or Higher) Infusion Reactions ..............................76 
 
LIST OF APPENDICES 
APPENDIX 1.NCI CTCAE, Version 4.03 ..............................................................................93 
APPENDIX 2.Pemphigus Disease Area Index (PDAI) .........................................................174 
APPENDIX 3.Autoimmune Bullous Disease Quality of Life (ABQoL) Questionnaire .......175 
APPENDIX 4.Skindex-29 .....................................................................................................179 
 
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LIST OF ABBREVIATIONS 
ABQoL 
Autoimmune Bullous Disease Quality of Life 
ADA 
anti-drug antibodies 
AE 
adverse event 
AECA 
Anti-epithelial cell antibody 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-24 
area under the plasma concentration-time curve from pre-dose (time0) to 24 hours 
post-dose 
AUC0-∞ 
area under the plasma concentration-time curve from pre-dose (time0) to infinity 
BLQ 
below the limit of quantification  
BMI 
body mass index 
BUN 
blood urea nitrogen 
C1q 
complement component 1q 
C3 
complement component 3 
CAR-T 
chimeric antigen receptor and T-cell 
CFR 
Code of Federal Regulations 
CIC 
circulating immune complexes 
Cmax 
maximum plasma concentration determined directly from the concentration-time 
profile 
CRO 
contract research organization 
CV 
coefficient of variation 
CVID 
common variable immune deficiency 
D5W 
dextrose 5% in water 
DEC 
Dose Escalation Committee 
DIF 
direct immunofluorescence 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
Dsg 
desmoglein 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ET 
early termination 
FCGR2A 
Fc gamma R2a receptor 
FcRn 
neonatal Fc receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
H2 
histamine2 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
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HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR-QoL 
health-related quality of life 
IB 
Investigator’s Brochure 
IC 
immune complex 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IgG1-4 
immunoglobulin G1-G4 
IgM 
immunoglobulin M 
IND 
investigational new drug 
IRB 
institutional review board 
IUD 
intrauterine 
IV 
intravenous 
IVIG 
intravenous immunoglobulin 
mAb 
monoclonal antibody 
MED 
minimum effective dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHP 
nonhuman primate 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamics 
PDAI 
Pemphigus Disease Area Index 
PK 
pharmacokinetic 
QTcF 
corrected QT interval using Fridericia's formula 
RNAseq 
RNA sequencing 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
SD 
standard deviation 
SNP 
single nucleotide polymorphism 
SOC 
system organ class 
SYNT001 
a humanized, affinity matured IgG4-kappa monoclonal antibody 
t1/2 
Half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
observed time to reach peak plasma concentration 
ULN 
upper limit of normal 
US 
United States of America 
VZV 
varicella zoster virus 
WAIHA 
warm autoimmune hemolytic anemia 
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WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
 
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2. 
BACKGROUND AND RATIONALE 
SYNT001, a humanized, affinity-matured IgG4-kappa monoclonal antibody (mAb), blocks 
immunoglobulin G (IgG) and circulating IgG immune complex (CIC) interactions with the 
neonatal crystallizable fragment receptor (FcRn), and inhibits the varied roles played by FcRn in 
the immune response.  
Through specific and high affinity blockade of FcRn, SYNT001 has been shown to increase the 
catabolism of IgG and CIC in healthy volunteers and is predicted to block the ability of CIC to 
activate intracellular signaling events associated with binding to FcRn. This predicts that 
SYNT001 will also accelerate degradation of endogenous circulating IgG autoantibodies and 
IgG-IC specifically involved in the pathogenesis of autoimmunity. Blocking FcRn interactions 
with CICs further predicts that SYNT001 will have consequences for innate and adaptive cellular 
immunity. In the first instance, blocking multimeric CIC interactions with FcRn within antigen-
presenting cells should result in inhibition of CIC inflammatory cytokine production and release 
by these cells. In addition, as FcRn determines the intracellular itinerary of CICs within and 
among compartments important in cellular immunity, it is further anticipated that SYNT001 will 
block antigen processing and presentation of antigens contained within CIC that otherwise lead 
to CD8+ and CD4+ T cell activation. Thus, SYNT001 is expected to specifically target immune 
functions associated with IgG and CIC that are involved in certain IgG-mediated autoimmune 
conditions. 
SYNT001 targets key mechanisms contributing to pathology in a variety of IgG-mediated 
autoimmune disorders, including warm autoimmune hemolytic anemia (WAIHA) pemphigus, 
pemphigoid, myasthenia gravis, immune thrombocytopenic purpura (ITP), and chronic 
inflammatory demyelinating polyneuropathy (CIDP).  
While current treatments for certain autoimmune disorders, including chronic steroids, 
immunosuppressants, intravenous immunoglobulin (IVIG), plasmapheresis, and anti-CD20 
mAbs, such as rituximab, can be effective, they are associated with significant adverse effects, 
and delayed or non-durable responses.  
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous 
membranes. Autoantibodies are thought to play an important pathogenic role in the mucosal and 
cutaneous manifestations in patients with pemphigus. Administration of SYNT001, which 
significantly decreases total IgG levels, including a predicted corresponding decrease in the 
levels of the pathogenic autoantibodies, may lead to a decrease in the mucosal and cutaneous 
manifestations in patients with pemphigus. Moreover, the ability of SYNT001 to reduce CICs 
and the associated innate and adaptive immune responses may allow for further sustained disease 
modification. 
2.1 
Study Rationale 
This study is being conducted to evaluate the safety, dose, pharmacokinetics (PK), 
pharmacodynamics (PD) and immunogenicity of intravenous (IV) SYNT001 as well as its 
effects on pemphigus disease activity markers. 
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2.2 
Selection of Doses in this Study  
The SYNT001 dose levels for study SYNT001-103 were selected following careful review of the 
safety, tolerability, and PD effect on total IgG levels studied in non-human primates (NHP) and 
healthy male subjects. 
Four repeat-dose toxicology studies in cynomolgus monkeys examined 2 to 14 repeat weekly IV 
doses 5 to 100 mg/kg SYNT001 with up to a 4-week follow-up.  There was one death in the 14-
week study attributed to an immune-evoked infusion reaction, which correlated with the 
development of ADAs, circulating immune complexes, circulating complement depletion, and 
deposition of immune complexes containing SYTN001 and complement in tissues. Across 
studies, clinical signs were limited to reports of transient emesis/vomitus following dosing and 
facial flushing and periocular swelling observed in the 5-week study after the third dose 
coincident with the first appearance of ADAs. With the exception of emesis/vomitus, these 
clinical signs were effectively controlled with diphenhydramine pretreatment in the 5-week study 
and the subsequent 14-week study . There were no adverse SYNT001-related changes in weight 
gain, clinical chemistry, gross or histo-pathology. The No Observed Adverse Effect Level 
(NOAEL) was the highest dose tested in all 4 studies and the overall NOAEL following repeat 
weekly exposure to STYNT001 of up to 14 doses in cynomolgus monkeys was 100 mg/kg . 
The safety, tolerability, and PD effect on total IgG levels in study SYNT-101—a Phase 1a study 
that assessed single ascending doses of SYNT001 in healthy male subjects—were also reviewed. 
In study SYNT-101, the doses of SYNT001 up to and including 30 mg/kg were well tolerated. 
There were no dose-limiting toxicities, serious adverse events (SAEs), or any other safety 
concerns. No adverse events (AEs) were observed in the 1 and 3 mg/kg dose cohorts. Headache 
was the most commonly reported treatment-emergent adverse event (TEAE), occurring in 8 of 
11 subjects treated with 10 or 30 mg/kg SYNT001. One headache in the 10 mg/kg cohort was 
moderate (Grade 2) in severity; all other headaches were mild (Grade 1). One mild headache was 
treated with a single dose of acetaminophen; all other headaches resolved without treatment. 
Therefore, it is anticipated that the doses selected for this study should be well tolerated and have 
clinically relevant PD effects in patients with pemphigus.  
Further consideration was given to the desired level of FcRn blockade to achieve suppression of 
IgG to a range that has been previously correlated with disease remission induced by 
immunoadsorption in autoimmune disorders such as pemphigus vulgaris and myasthenia gravis 
(ie, >50% decrease in total IgG from baseline) (Blaha et al., 2011; Eming and Hertl, 2006; 
Kohler et al., 2011).  
The Sponsor also considered the potential effects of inhibiting FcRn function as they relate to IC 
associated innate and adaptive immunity. From the NHP studies, single doses of SYNT001 
produced a dose-dependent decrease in total IgG and a further decrease was seen with repeated 
weekly doses up to a maximum 70% reduction at 100 mg/kg. This magnitude of total IgG 
reduction is approaching the expected maximal effect of 100% inhibition of FcRn function based 
on murine studies performed by the Sponsor and others (Nixon et al., 2015; Roopenian et al., 
2003). In the recently completed Phase 1a trial with SYNT001 in healthy volunteers a single 
dose caused a maximum average 50% drop in total IgG with IV dosing at 30 mg/kg. Based on 
the NHP studies further reductions are expected following multiple dosing. A comparable 
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decrease in pathogenic autoantibodies is anticipated. In study SYNT-101, a single dose caused a 
maximum average 50% drop in total IgG with IV dosing at 30 mg/kg. Based on the NHP studies, 
further reductions may occur following multiple dosing.  
For more information on the findings from the clinical and nonclinical findings with SYNT001, 
please refer to the Investigator’s Brochure (IB).  
2.3 
Compliance Statement 
This study will be conducted in compliance with Good Clinical Practice (GCP), including the 
International Conference on Harmonisation (ICH) Guidelines and FDA regulations, consistent 
with the principles outlined in the Declaration of Helsinki. In addition, the Investigator agrees to 
adhere to all applicable local laws and regulatory requirements relevant to the use of new 
therapeutic agents. 
The study will be conducted in compliance with the protocol. The appropriate Institutional 
Review Boards (IRBs) must approve the protocol, any amendments, and the subject informed 
consent form (ICF) prior to implementation.  
Freely given written informed consent must be obtained from every subject prior to participation 
in this clinical trial. As part of this procedure, the Investigator must explain orally and in writing 
the nature, duration, and purpose of the study, and the action of the drug in such a manner that 
the study subject is aware of the potential risks, inconveniences, or AEs that may occur. The 
study subject should be informed that he/she is free to withdraw from the study at any time. 
He/she will receive all information that is required by federal regulations and ICH guidelines. 
The Investigator or designee will provide the Sponsor with a copy of the IRB-approved informed 
consent form prior to the start of the study. The rights, safety, and well-being of participating 
subjects are the most important considerations and should prevail over interests of science and 
society. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct or 
fraud (eg, loss of medical licensure, debarment). 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective 
The primary objectives of this study are as follows: 
 Safety: To evaluate the safety of once-weekly IV infusions of SYNT001 at different dose 
levels and dosing durations in subjects with pemphigus (vulgaris or foliaceus)  
 Dose Selection: To determine a Minimum Effective Dose (MED) of SYNT001 as assessed 
by (i) total IgG level nadir and (ii) the proportion of subjects that meet the criteria for 
response by Pemphigus Disease Area Index total activity score (PDAI) 
 
3.2 
Secondary Objectives 
The secondary objectives of this study are as follows: 
 To determine the pharmacokinetics (PK) of SYNT001 following once-weekly IV infusions at 
different dose levels and dosing durations 
 To evaluate the effect of once-weekly doses of SYNT001 at different dose levels and dosing 
durations on PD biomarkers 
 To assess the effect of once-weekly doses of SYNT001 at different dose levels and dosing 
durations on disease markers 
 To measure the immunogenicity of once-weekly doses of SYNT001 at different dose levels 
and dosing durations 
 
3.3 
Exploratory Objectives 
The exploratory objectives of this study are as follow: 
 To explore the effect of once-weekly doses of SYNT001 at different dose levels and dosing 
durations on biomarkers to understand the pathophysiology of the disease and the SYNT001 
mechanisms of action 
 To determine the impact of different SYNT001 dose levels and dosing durations on the 
subject’s use of corticosteroids to treat their pemphigus (vulgaris or foliaceus) 
 To assess the impact of once-weekly doses of SYNT001 on the subject’s health-related 
quality of life (HR-QoL) at different dose levels and dosing durations  
 To assess the effect of once-weekly doses of SYNT001 on the appearance of skin and 
mucosal lesions at different dose levels and dosing durations 
 To quantify the amount of SYNT001 in skin (skin biopsies optional)  
 
3.4 
Primary Endpoints 
The primary endpoints of this study are as follows: 
Safety: The evaluation of SYNT001 safety based on vital signs, physical examinations, 
electrocardiograms (ECGs), clinical safety laboratory tests, the incidence of adverse events 
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(AEs), treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) 
summarized by cohort, severity, and relationship to study product 
Dose Selection: The determination of dose and dosing duration of SYNT001 that achieves (i) 
total IgG level nadir decrease by ≥60% and ≤90% from baseline and (ii) a PDAI total activity 
score of ≥50% reduction from baseline to allow further clinical development in subject with 
pemphigus (vulgaris or foliaceus) 
3.5 
Secondary Endpoints  
The secondary endpoints of this study are as follows: 
 The determination of PK parameters including half-life (t1/2), maximum serum concentration 
determined directly from the concentration-time profile (Cmax), observed time of peak plasma 
concentration (Tmax), area under the serum concentration-time curve from pre-dose (time0) to 
24 hours post-dose (AUC0-24), and area under the serum concentration-time curve from pre-
dose (time0) to infinity (AUC0-∞), (Cohort 1); maximum plasma concentration determined 
directly from the concentration-time profile (Cmax) and Tmax (Cohort 2 onwards) summarized 
by cohort and timepoint 
 The evaluation of PD biomarkers based on absolute serum levels and percent change from 
baseline in serum levels of total immunoglobulin G (IgG), IgG subtypes (IgG1-4), 
immunoglobulin A (IgA), immunoglobulin M (IgM), albumin, and CIC summarized by 
cohort and timepoint 
 The assessment of pemphigus disease activity by responses on PDAI based on absolute and 
percent change from baseline will be summarized by cohort and timepoint 
 The assessment of pemphigus disease pathogenic antibody levels based on absolute and 
percent change from baseline of serum anti-desmoglein 1 and 3 antibody (anti-Dsg 1 and 
anti-Dsg 3) levels that will be summarized by cohort and timepoint 
 The immunogenicity of once-weekly administered SYNT001 as determined by presence of 
anti-SYNT001 binding antibodies and neutralizing antibodies summarized by cohort and 
timepoint 
 
3.6 
Exploratory Endpoints 
The exploratory endpoints of this study are as follows: 
 The exploration of SYNT001 mechanisms of action and effects of SYNT001 on 
pathophysiology summarized by cohort and timepoint as determined by: 
 Complement component 3 (C3) levels by nephelometry  
 Anti-epithelial cell antibody (AECA) titers by indirect immunofluorescence  
 Fc gamma R2A receptor (FCGR2A) single-nucleotide polymorphisms (SNP) by 
genotyping 
 Presence of disease and inflammatory markers by RNAseq (RNA sequencing) 
 Immunophenotyping via measures of T cells, monocytes, NK cells and B cells by flow 
cytometry  
 Urine IgG levels to explore SYNT001 distribution and elimination 
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 Exploratory biomarkers to investigate immune response associated with pemphigus 
 The evaluation of corticosteroid use during the study will be summarized by cohort and 
timepoint 
 The assessment of SYNT001 impact on subject’s HR-QoL by responses to the Autoimmune 
Bullous Disease Quality of Life (ABQoL) questionnaire and Skindex-29 scores summarized 
by cohort and timepoint 
 The qualitative assessment of changes in appearance of skin and mucosal lesions as 
determined by photography presented by cohort and timepoint 
 The determination of SYNT001 levels in skin biopsies across timepoints (skin biopsies 
optional) 
 
Further details on the statistical and analytical plans for these endpoints are available in 
Section 11.  
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4. 
STUDY DRUG 
4.1 
Description of SYNT001 
SYNT001 is provided in vials containing 5 mL SYNT001 (extractable volume) at a nominal 
concentration of 50 mg/mL. The product is supplied as a liquid at pH 6.5 ± 0.5. SYNT001 is 
diluted in dextrose 5% in water (D5W) to prepare the solution for infusion. SYNT001 will be 
infused via IV in 250 mL over 1 hour ± 15 minutes using a 0.2-micron, inline filter.  
For detailed information regarding SYNT001 preparation and administration, refer to the 
Pharmacy Manual. 
4.2 
Dose Requirements 
The specification for host cell deoxyribonucleic acid (DNA) in SYNT001 is <2 pg/mg, the limit 
of quantitation of the assay. To comply with regulatory guidelines, which specify a maximum 
level of 10 ng host cell DNA per dose, dosing per subject is limited to 5000 mg SYNT001.  
For example, a subject with a body weight of 166 kg and enrolled in the ≤30 mg/kg dose cohort 
will receive ≤4960 mg SYNT001 per dose. If a subject’s body weight extrapolates to an expected 
dose ≥5000 mg SYNT001, the dose will be capped to ensure the 5000 mg SYNT001 per dose 
limit is not exceeded.  
A subject with a body weight of 111 kg and enrolled in the ≤45 mg/kg dose cohort will receive 
≤4995 mg SYNT001 per dose. If a subject’s body weight extrapolates to an expected dose 
≥5000 mg SYNT001, the dose will be capped to ensure the 5000 mg SYNT001 per dose limit is 
not exceeded. 
4.3 
Handling and Storage of SYNT001 
All supplies of SYNT001 will be provided by the Sponsor and must be stored refrigerated 
(2ºC to 8ºC/36ºF to 46ºF) in the carton and protected from light, in a securely locked area, 
accessible to authorized persons only, until needed for dose preparation. 
4.4 
Study Drug Accountability 
The Investigator (or designee) is responsible for maintaining accurate accountability records of 
the study drug throughout the clinical study. Qualified site personnel will inventory the study 
drug received and will maintain records of disposition of the drug, including dates, quantity and 
use. All study drug received at the site must be accounted for on an accountability log provided 
by the Sponsor. All dispensing and accountability records will be available for Sponsor review. 
Study drug accountability will be verified during on-site monitoring visits. 
Upon the completion or termination of the study, and upon written authorization from the 
Sponsor, or its representative, all unused and/or partially used study drug should be returned or 
destroyed at the investigational site, as specified by Sponsor. It is the Investigator’s 
responsibility to ensure that the Sponsor, or its representative, has provided written authorization 
that procedures for proper disposal of the study drug have been established, and that appropriate 
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records of the disposal are documented and maintained. No unused study drug may be disposed 
of until fully accounted for by the Sponsor monitor (or designee). 
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5. 
STUDY DESIGN 
5.1 
Study Sites 
This study will be conducted at approximately 10 global study sites. 
5.2 
Overview of Study Design 
This is a multicenter, open-label safety study to determine the dose regimen of SYNT001 
administered intravenously in subjects with pemphigus (vulgaris or foliaceus). Approximately 20 
(up to a maximum of 32) eligible subjects will receive planned doses of 10 mg/kg up to 
45 mg/kg of SYNT001.  
Cohorts will be dosed sequentially beginning with Cohort 1. Up to 8 eligible subjects will be 
enrolled in Cohort 1 and will receive 5 once-weekly 60-minute infusions of SYNT001 10 mg/kg. 
Based on review of safety, PD, and clinical outcomes of Cohort 1, sequential cohorts will enroll, 
pending recommendation received from a scheduled Dose Escalation Committee (DEC) review.  
The DEC will consist of the Medical Monitor, an Independent Clinical Expert and a Syntimmune 
Medical Officer. To assist in the safety assessments, the DEC may request that Investigators, 
other experts, or members within their organization review the data and participate in the 
discussions. 
Each cohort must be fully enrolled before a successive cohort will be opened for enrollment. An 
overview of the study cohorts is provided in Table 5 and Figure 1 shows a schematic of the study 
design. 
Table 5. 
Cohort Overview 
Cohort No. 
No. of Subjects 
SYNT001 Dose  
No. of Doses 
DEC Review Timepoint 
1a 
up to 8 
10 mg/kg 
5 
NA 
2b 
4c 
≤30 mg/kgd 
5 
When 100% of Cohort 1 subjects 
reach Day 42 
3b 
4c 
≤30 mg/kgd 
14 
When 50% of Cohort 2 subjects 
reach Day 42 
4b (optional)  
4c 
≤45 mg/kgd 
≤14 
When 50% of Cohort 3 subjects 
reach Day 42e 
Abbreviations: DEC = Dose Escalation Committee; NA = not applicable 
a. 
No more than 3 subjects with pemphigus foliaceus may be enrolled 
b. 
Two or fewer subjects with pemphigus foliaceus may be enrolled 
c. 
Up to 4 additional subjects may be added following DEC’s evaluation. 
d. 
Dose will be recommended by the DEC and will be based on both an ongoing and set timepoint review of safety and 
pharmacodynamic evaluations including but not limited to, dose-limiting toxicities (DLTs), adverse events (AEs), 
treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and total IgG levels. 
e. 
All available data will be considered. 
 
The first 2 subjects in Cohorts 1 and 2 will be enrolled at staggered intervals to facilitate 
adequate safety evaluation before dosing of subsequent subjects may proceed. A staggered 
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dosing interval for the first 2 subjects enrolled in successive cohorts will not be required if the 
planned dose is equal to or lower than that previously administered. 
At 24-hour and 7-day intervals described below, the DEC will review of all available safety data 
(including but not limited to dose limiting toxicities [DLTs], AEs, TEAEs, and SAEs, PD 
(including but not limited to IgG levels), and clinical outcomes. 
DEC Safety Review of 24-hour Data for Cohorts 1 and 2, Subject 1 
The first 2 subjects will be dosed at least 24 hours apart. A DEC review of the 24-hour safety 
data for the first subject will be performed to ensure that there are no overt safety concerns 
before dosing the second subject. 
Safety Review of 7-day Data for Cohorts 1 and 2, Subjects 1 and 2 
The 7-day safety data for the first 2 subjects will be performed prior to dosing the remaining 
subjects in the cohort.  
The 24-hour and 7-day reviews will consider seriousness and severity of AEs/TEAEs/SAEs and 
relatedness to study drug, vital sign assessments, physical examinations, and clinical laboratory 
testing. 
For further information about dose escalation and study stopping rules, refer to Section 9.5.1  and 
Section 9.5.2, respectively. 
5.3 
Randomization and Blinding 
This is an open-label study. 
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6. 
STUDY POPULATION 
6.1 
Target Population 
This study will be conducted in approximately 20 male and female subjects aged 18 and older 
with a confirmed diagnosis of pemphigus (vulgaris or foliaceus).  
Up to 8 subjects may be enrolled in Cohort 1. Four subjects will be enrolled sequentially in 
Cohort 2, 3, and 4 (optional cohort). An additional 4 subjects may be enrolled in Cohorts 2, 3 and 
4 (optional cohort) following DEC’s evaluation and recommendation. 
Subjects who withdraw for any reason other than an AE and who do not receive study drug or 
have only received one dose of study drug may be replaced, up to one subject per cohort. Thus, 
the maximum number of subjects who may be enrolled in this study is 36 (20 + up to 12 
additional subjects, + up to 4 replacements, as necessary).  
Within Cohort 1, no more than 3 subjects may be enrolled with pemphigus foliaceus. Within 
successive cohorts, ≤2 subjects with pemphigus foliaceus may be enrolled.  
Subjects will be enrolled only once in the study and will not be included in subsequent dosing 
cohorts. Subjects who do not receive all doses of study drug will continue to be followed through 
all scheduled visits. 
6.2 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for the study: 
1. Willing and able to read, understand, and sign an informed consent form. 
2. Male or female ≥18 years of age at the time of screening. 
3. Documented diagnosis of pemphigus vulgaris or foliaceus based on all 3 of the following 
criteria: 
a. Documented clinical history consistent with pemphigus vulgaris or foliaceus (clinical 
presentation defined as mucosal and/or skin lesions). 
b. Presence of Anti-Dsg 1 or 3 antibodies above the upper limit of normal (ULN).  
c. History of at least one positive tissue-based test (eg, biopsy, direct 
immunofluorescence [DIF]). 
4. Active disease defined as lesions lasting >2 weeks, and 3 active lesions in skin or mucosa or 
2 active lesions with at least one being a skin lesion >1 cm diameter: 
a. If treated with rituximab or other anti-CD20 mAb, last dose >12 months prior to 
screening. 
b. If being treated with other immunosuppressants (ie, azathioprine, mycophenolate 
mofetil, methotrexate, dapsone, cyclosporine, tacrolimus, sirolimus, or low-dose 
cyclophosphamide [≤100 mg/day]), dose must be stable, defined as <25% change in 
dose, for 4 weeks prior to screening. 
c. On stable dose of corticosteroids, defined as ≤1 mg/kg of prednisone or equivalent 
and may not be increased by more than 50% in the 2 weeks prior to screening.  
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d. Allowed topical therapies for pemphigus lesions upon entering the study include 
petroleum jelly or Aquaphor® for the skin or chlorhexidine for the mouth.  
e. Stable use of topical low strength hydrocortisone (≤1%), tacrolimus, sirolimus, or 
pimecrolimus for lesions contributing <10% of the PDAI total activity score for the 4 
weeks prior to screening is allowed. Stable use of dexamethasone elixir solution 
(swish and spit only) for oral lesions for the 4 weeks prior to screening is allowed. 
f. If not on regular corticosteroids, no pulse corticosteroids are allowed in the 2 weeks 
prior to screening. 
5. Body mass index (BMI) >18.5 kg/m2. 
6. Has a negative pregnancy test documented prior to the first dose of study drug (for women of 
childbearing potential). 
7. Females of childbearing potential must agree to be abstinent or else use any two of the 
following medically acceptable forms of contraception (<1% per year failure rate) from the 
screening period through the final study visit: oral contraceptive, condom with or without 
spermicidal jelly, diaphragm or cervical cap with spermicidal jelly, or intrauterine device 
(IUD). A female whose male partner has had a vasectomy must agree to use one additional 
form of medically acceptable contraception.  
8. Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, 
bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months 
do not require contraception during the study. 
9. Males with female partners of childbearing potential, including males who are surgically 
sterile (post vasectomy), must agree to be abstinent or else use a medically acceptable form 
of contraception from the screening period through 60 days after the final study visit. 
10. A PDAI total activity score of >4 at screening. 
 
6.3 
Exclusion Criteria 
A subject who meets any of the following criteria is ineligible for the study: 
1. Subject unable or unwilling to comply with the protocol. 
2. Active non-hematologic malignancy or history of non-hematologic malignancy in the 3 years 
prior to screening (exclusive of non-melanoma skin cancer and cervical cancer in situ). 
3. Positive for human immunodeficiency virus (HIV) or hepatitis C antibody. 
4. Positive for hepatitis B surface antigen. 
5. Active infection or history of recurrent infections. 
6. IVIG treatment within 30 days of screening. 
7. Received any cytotoxic (other than azathioprine) or any non-anti-CD20 mAb therapy in the 
3 months prior to screening. 
8. Any exposure to an investigational drug or device within the 30 days prior to screening. 
9. Plasmapheresis or immunoadsorption within 30 days of screening. 
10. Cellular therapy, including chimeric antigen receptor and T-cell (CAR-T), at any time prior 
to screening. 
11. Use of any systemic or topical immunosuppressive drugs within 3 months of screening not 
including dose allowed by the inclusion criteria. 
12. Serum total IgG <600 mg/dL. 
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13. Subject has any current medical condition that, in the opinion of the Investigator, may 
compromise their safety or compliance, preclude successful conduct of the study, or interfere 
with interpretation of the results (eg, a significant pre-existing illness or other major 
comorbidity that the Investigator considers may confound the interpretation of the study 
results). 
14. Any vaccination within 2 weeks of screening. 
 
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7. 
STUDY PROCEDURES 
7.1 
Informed Consent 
All subjects must take part in the informed consent process. Adequate time must be allowed for 
the subject to ask questions and make a voluntary decision. No protocol-specific procedures, 
including screening procedures are to be performed until the subject has signed and dated an 
IRB-approved ICF. Subjects may withdraw consent at any time. Participation in the study may 
be terminated at any time without the subject’s consent as determined by the Investigator.  
7.2 
Demographics and Medical History 
Demographics (age, gender, race and ethnicity) and medical history will be obtained from the 
subject and recorded on the source document and electronic case report form (eCRF). Medical 
history will capture the subject’s current medical history (current disease processes), past 
medical status (past disease processes), history of surgery, concomitant treatments, and relevant 
clinical response to past disease specific treatments including duration and dosing of such 
treatments.  
7.3 
Physical Examination 
A complete physical examination will include measurements of weight (in kg) and height (in cm; 
height to be measured only at screening visit) and a review of the following body systems: 
 General appearance 
 Head, eyes, ears, nose, and throat 
 Neck 
 Respiratory 
 Cardiovascular 
 Abdomen 
 Neurologic 
 Extremities 
 Dermatologic 
 Lymphatic 
 
Any abnormal and clinically significant findings from the physical examination must be recorded 
in the appropriate eCRF. Findings at screening and Day 0 (pre-dose) will be recorded as medical 
history. 
7.4 
Vital Sign Measurements 
Vital sign assessments will include measurements of sitting blood pressure (mm Hg), heart rate 
(beats per minute), respiration rate (breaths per minute), pulse oximetry, and oral temperature 
(Celsius). Abnormal results are to be repeated after 5 minutes of rest. See Table 6 for timing 
window allowances with respect to measurement collection.  
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Vital sign measurements will be collected after the subject has been sitting for 5 minutes. 
Subjects should be seated quietly for at least 5 minutes in a chair with their backs supported, 
their feet flat on the floor (legs uncrossed), and their arms bared on a hard surface, with the arm 
slightly abducted and bent, with palm up and the midpoint of upper arm at heart level. Correct 
cuff and bladder size should be utilized and the same cuff and arm should be used per subject 
throughout study.  
Vital sign measurements are to be obtained immediately prior to the infusion; 15, 30, and 
45 minutes after the start of the infusion; at completion of the infusion; 30 minutes, 1 hour, and 
2 hours following completion of the infusion. Abnormalities in vital sign measurements will be 
graded in severity per the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) scale Version 4.03.  
Table 6. 
Timing Windows for PK/PD Sampling, ECG, and Vital Sign 
Measurements 
Time Point 
Tolerance Window 
 
Cohort 1 
Cohorts 2, 3, and 4 
(Optional Cohort) 
Pharmacokinetic Sampling 
 
 
0 hour 
−240 minutes to 0 hour 
−240 minutes to 0 hour 
5 minutes post end-of-infusion 
±5 minutes 
±5 minutes 
1 hour post end-of-infusion 
N/A 
±15 minutes 
2 hours post end-of-infusion 
±15 minutes 
±15 minutes 
4 and 6 hours post end-of-infusion 
±15 minutes 
N/A 
24 hours (1 day) post end-of-infusion 
±60 minutes 
N/A 
48 hours (2 days) post end-of-infusion 
±120 minutes 
N/A 
 
 
 
Pharmacodynamic Sampling 
 
 
0 hour 
−240 minutes to 0 hour 
−240 minutes to 0 hour 
24 hours (1 day) post end-of-infusion 
±60 minutes 
N/A 
48 hours (2 days) post end-of-infusion 
±120 minutes 
N/A 
 
 
 
ECG 
 
 
5 minutes post end-of-infusion 
±10 minutes 
±10 minutes 
 
 
 
Vital Signsa 
 
 
0 hour 
−240 minutes to 0 hour 
−240 minutes to 0 hour 
15, 30, and 45 minutes after start of infusion 
±5 minutes 
±5 minutes 
1 hour after start of infusion 
±10 minutes 
±10 minutes 
30 minutes, 1 and 2 hours post end-of-infusion 
±10 minutes 
±10 minutes 
Abbreviations: ECG = electrocardiogram; N/A = not applicable; PD = pharmacodynamic; PK = pharmacokinetic. 
a. 
Vital signs to include blood pressure, pulse rate, respiratory rate, oral temperature, and pulse oximetry. 
 
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7.5 
Clinical Laboratory Measurements   
Laboratory testing (hematology, urinalysis, serum chemistry, virology, serology, pregnancy tests, 
PD samples, PK samples, and ADA samples) will be performed using established methods by a 
central laboratory. Clinical safety laboratory panels are listed in Table 7. Blood and urine 
samples for hematology, serum chemistry, and urinalysis will be prepared using standard 
procedures. Results will be provided to the Investigator. Aliquots from the PK, biomarker and 
ADA samples may be retained as back-up for additional testing as necessary. Subjects will be in 
a seated or supine position during blood collection. Collection times for all safety, PD, and 
exploratory labs are outlined in Table 2, Table 3, and Table 4.  
Table 7. 
Clinical Safety Laboratory Panels 
Hematology 
Serum Chemistry 
Urinalysis 
Virology 
 
CBC with 
differential and 
blood smear 
 
Erythrocyte 
sedimentation rate 
 
Albumin 
 
Alkaline 
phosphatase 
 
ALT 
 
AST 
 
BUN 
 
C-Reactive Protein  
 
Calcium 
 
Carbon dioxide 
 
Chloride 
 
Creatinine 
 
Glucose 
 
LDH 
 
Phosphorus 
 
Potassium 
 
Sodium 
 
Total and direct 
bilirubin 
 
Total protein 
 
Uric acid
 
Appearance 
 
Color 
 
pH 
 
Specific gravity 
 
Ketones 
 
Protein 
 
Glucose 
 
Nitrite 
 
Urobilinogen 
 
Blood/hemoglobin 
 
Leukocyte esterase 
 
Bilirubin 
 
Microscopic 
examination of 
sediment: only if 
the results of the 
urinalysis dipstick 
evaluation are 
positive for 
blood/hemoglobin 
 
Hepatitis C 
 
Hepatitis B 
 
HIV 
 
Tetanus  
 
VZV 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CBC = complete blood count; HIV = human immunodeficiency virus; LDH = lactate dehydrogenase; VZV = Varicella-
Zoster virus. 
 
Abnormalities in clinical laboratory tests that are considered clinically significant are to be 
recorded on the AE eCRF page. Laboratory results will be graded using the NCI CTCAE, 
Version 4.03. If laboratory values constitute part of an event that meets criteria defining it as 
serious, the event (and associated laboratory values) must be reported as an SAE (see 
Section 10.2.3). 
For Cohort 1, the total blood draw for each subject who completes the study at Day 112 will be 
approximately 420 mL. For Cohort 2 the total blood draw for each subject who completes the 
study at Day 112 will be approximately 380 mL. For Cohort 3 and Cohort 4 (Optional), the total 
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blood draw for each subject who completes the study at Day 175 will be 656 mL. Please refer to 
the Laboratory Manual for more information. 
7.5.1 
Pregnancy Testing 
Pregnancy testing will be performed for women of childbearing potential. Urine or serum test is 
acceptable; however, positive urine tests must be confirmed with serum testing. 
7.5.2 
Virology 
Testing for hepatitis C antibody, hepatitis B surface antigen, and HIV antibody will be performed 
at screening. 
7.5.3 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing 
Samples for serum tetanus antibody and VZV antibody testing are to be collected at baseline 
(pre-dose, Day 0), during the follow-up period, and at the end-of-study visit. Any subject whose 
baseline value for tetanus or VZV was above the detectable level at baseline, and is not within 
30% of the baseline value or is below the protective level by the end-of-study visit, will be 
referred to their primary care physician for further management. 
7.5.4 
Pharmacokinetics (PK) Sampling 
The following PK parameters will be studied in Cohort 1: t1/2, Cmax, Tmax, AUC0-24, and AUC0-∞. 
For all successive cohorts, the PK parameters studied will be Cmax and Tmax. 
Specific collection times are detailed in Table 6. Detailed instructions for sample collection and 
preparation will be provided in a separate laboratory manual 
7.5.5 
Pharmacodynamic Sampling 
PD samples will be collected for analyses throughout the study. Measurements for albumin will 
be derived from the clinical safety laboratory results. Specific collection times are detailed in. 
Samples for each type of PD will be collected according to the schedule shown in Table 8. 
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Table 8. 
Pharmacodynamic Assessments 
Parameter 
Collection Time Points 
 
 
 
Cohort 1 
Cohort 2 
Cohort 3 
 
IgG 
 
IgG subtypes (IgG1-4) 
 
IgA 
 
IgM 
Screening and Days 0, 1, 
2, 5, 7, 12, 14, 19, 21, 
28, 29, 30, 33, 42, 56, 
84, and 112 
Screening and Days 0, 7, 
14, 21, 28, 35, 42, 56, 84, 
and 112 
Screening and Days 0, 7, 
14, 21, 28, 35, 42, 49, 56, 
63, 70, 77, 84, 91, 98, 
105, 119, 147, and 175 
 
Circulating immune 
complexes (CIC) 
Days 0, 5, 7, 12, 14, 19, 
21, 28, 33, 42, 56, 84, 
and 112 
Days 0, 7, 14, 21, 28, 35, 
42, 56, 84, and 112 
Days 0, 7, 14, 21, 28, 35, 
42, 49, 56, 63, 70, 77, 84, 
91, 98, 105, 119, 147, and 
175 
 
Albumin 
Screening and Days 0, 7, 
14, 21, 28, 33, 42, 56, 
84, and 112 
Screening and Days 0, 7, 
14, 21, 28, 35, 42, 56, 84, 
and 112 
Screening and Days 0, 7, 
14, 21, 28, 35, 42, 49, 56, 
63, 70, 77, 84, 91, 98, 
105, 119, 147, and 175 
 
Anti-Dsg (1 and 3) 
antibody titers 
Screening and Days 0, 7, 
14, 33, 56, 84, and 112 
Screening and Days 0, 7, 
14, 21, 28, 35, 42, 56, 84, 
and 112 
Screening and Days 0, 7, 
14, 21, 28, 35, 42, 49, 56, 
63, 70, 77, 84, 91, 98, 
105, 119, 147, and 175 
 
C3 and AECA levels 
by indirect 
immunofluorescence 
Days 0, 14, 33, 56, 84, 
and 112 
Days 0, 35, and 56 
Days 0, 98, and 119 
 
Exploratory 
biomarkers (RNAseq, 
urine IgG) 
Days 0, 14, 33, 56, 84, 
and 112 
Days 0, 35, and 56 
Days 0, 98, and 119 
 
Immunophenotyping 
by flow cytometry for 
measurement of T 
cells, monocytes, NK 
cells, and B cells 
Days 0, 28, and 56 
Days 0, 35, and 56 
Days 0, 98, and 119 
 
Exploratory biomarker 
(FCGR2A SNP, via 
buccal swab) 
Day 0 
Day 0 
Day 0 
 
Exploratory 
pemphigus immune 
response biomarkers 
Days 0, 5, 7, 12, 14, 19, 
21, 28, 33, 42, 56, 84, 
and 112 
Days 0, 7, 14, 21, 28, 35, 
42, 56, 84, and 112 
Days 0, 7, 14, 21, 28, 35, 
42, 49, 56, 63, 70, 77, 84, 
91, 98, 105, 119, 147, and 
175 
 
See Table 6 for timing window allowances with respect to measurement collection. More 
information, including detailed instructions for sample collection (including collection tubes) and 
preparation will be provided in a separate laboratory manual. 
7.5.6 
Immunogenicity Testing 
SYNT001 is being developed for the acute and chronic therapy of autoimmune disorders. 
Although SYNT001 is a humanized IgG4 mAb, exposure to SYNT001 in clinical trials could 
result in the development of ADAs, with potential consequences ranging from neutralization 
with possible lessening of drug efficacy to safety consequences such as allergic reactions. 
Testing will first detect binding ADAs. Then, for all confirmed positive samples, an ADA titer 
will be determined and there will be testing for neutralizing effects.  
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More information, including detailed instructions for sample collection and preparation will be 
provided in a separate laboratory manual. 
7.6 
12-Lead Electrocardiogram (ECG) 
On dose administration days, digital 12-lead ECG measurements will be obtained at 5 minutes 
after the completion of the infusion. All ECGs are to be performed with the subject in a supine 
position having rested in this position for at least 5 minutes before each reading. ECGs are to be 
performed in triplicate, each at an interval of 1 to 2 minutes apart. See Table 6 for timing 
window allowances with respect to performing ECG. 
The following ECG parameters will be collected: PR interval, RR interval, QRS interval, and QT 
interval. The ECG findings will be evaluated by a qualified physician for the presence of 
abnormalities (qualitative assessment). The physician will assess each ECG as normal, 
abnormal/not clinically significant, or abnormal/clinically significant.  
Normal corrected QT interval using Fridericia’s formula (QTcF) is ≤450 msec.  
Abnormalities in the ECG that appear following therapy or that result in clinical signs and 
symptoms are considered clinically significant for the purposes of this study and will be recorded 
on the AE eCRF.  
7.7 
Pemphigus Disease Area Index (PDAI) 
Pemphigus severity and disease activity will be measured using the PDAI in regions where a 
validated questionnaire is available. A PDAI total activity score will be determined at screening. 
To be eligible for study participation, the patient’s grade by disease severity must be >4. 
Assuming subject eligibility, the PDAI will be administered during Treatment Period and 
Follow-up Period. Disease severity categories by PDAI are mild (0 to 8), moderate (9 to 24), and 
severe (≥25) (Shimizu et al., 2014). The Investigator will determine a PDAI score as follows: 0 
to 250 points for disease activity (≤120 for skin, ≤10 for scalp, and ≤120 for mucosa), and 0 to 
13 points for damage (≤12 for skin and ≤1 for scalp) (Rosenbach et al., 2009). See Appendix 2. 
7.8 
Study Drug Administration 
SYNT001 will be given as a 250-mL IV infusion over 1 hour ± 15 minutes using a 0.2-micron, 
inline filter.  
7.9 
Photographs 
Photographs will be taken of active lesions and follow-up photographs will be taken of the same 
areas at timepoints indicated in Table 2, Table 3, and Table 4. Subjects who begin a steroid taper 
will have additional photographs taken at the clinic visit during which the decision to begin the 
taper is made. A separate manual describing the procedures for taking photographs will be 
provided. 
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7.10 
Health-Related Quality of Life Assessments 
For Cohorts 2, 3 and 4 (optional cohort), health-related quality of life will be assessed using 
ABQoL and Skindex-29 in regions where a validated questionnaire is available. The ABQoL 
questionnaire was developed in Australia as a patient-based measure to quantify disease burden, 
monitor disease activity and evaluate response to therapeutic intervention in patients with 
autoimmune bullous disease (Sebaratnam et al., 2013; Sebaratnam et al., 2015) (Appendix 3). 
Skindex-29 was developed to measure the effects of skin disease on patients’ quality of life using 
a self-administered 30 question dermatology survey (Chren et al., 1996) (Appendix 4). 
7.11 
Adverse Event Assessments 
Information regarding the occurrence of AEs will be collected from the time the subject signs the 
informed consent form and continuing through the last study visit. Findings at screening and Day 
0 (pre-dose) will be recorded as medical history. Any known untoward event that occurs beyond 
the AE reporting period that the Investigator assesses as related to study drug also should be 
reported as an AE. Clinical AEs will be graded using the NCI CTCAE, Version 4.03 (Appendix 
1).  
Note: AEs resulting in a subject’s permanent discontinuation from the study, regardless of 
seriousness or relationship to study drug, MUST be promptly reported to the Sponsor. 
Additionally, subjects must be followed until return to normal and/or resolution of the AE. 
See Section 10 for more information. 
7.12 
Prior and Concomitant Medications 
All treatments a subject receives within 14 days prior to enrollment through the end of the study 
will be documented on the source document and eCRF. A history of treatments taken for the 
primary disease, even if not taken within the 14 days prior to enrollment, will be collected.  
Permitted Medications 
Concomitant medication and treatment for co-existing conditions, including those for 
pemphigus, are permitted if not listed as prohibited.  
1. Topical antibiotics to treat active infections that occur during the study.  
2. Topical or systemic treatments for oral candidiasis.  
3. Topical lidocaine for transient pain relief as needed.  
4. Concomitant treatment that is medically indicated for any AEs the subject experiences during 
the study.  
5. Medication for potential infusion reactions: The Investigator may recommend prophylactic 
use of acetaminophen, IV hydration, diphenhydramine, histamine2 (H2) blockers (eg, 
ranitidine, famotidine), etc to manage potential infusion reactions. 
6. Low-strength corticosteroids (eg, hydrocortisone ≤1%) applied to a single lesion contributing 
<10% of the PDAI total activity score. 
7. Topical tacrolimus, sirolimus or pimecrolimus applied to a single lesion contributing <10% 
of the PDAI total activity score. 
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8. Dexamethasone elixir solution for oral lesions if dose remains stable throughout trial 
participation (swish and spit only). 
9. Stable regimen of the following systemic immunosuppressants: azathioprine, mycophenolate 
mofetil, methotrexate, dapsone, cyclosporine, tacrolimus, sirolimus, or low dose oral 
cyclophosphamide (≤100 mg/day).  
One month after the final dose of SYNT001, corticosteroids may be tapered at the Investigator’s 
discretion.  
Prohibited Medications 
Use of the following medications will not be permitted during the study unless specified above 
as permitted: 
1. Rituximab or other anti-CD20 antibody  
2. Monoclonal antibodies other than study drug  
3. Any topical or systemic immunosuppressive drugs apart from those that are listed as 
permitted.  
4. IV corticosteroids prior to infusion (except in subjects who received corticosteroids for 
treatment of a prior infusion reaction to SYNT001) 
5. Any dietary herbal supplements 
6. Any investigational drug or device 
7. Vaccinations within 2 weeks of screening through 28 days following final dose of study drug 
 
7.13 
Skin Biopsy 
Optional skin biopsy samples from lesional or non-lesional skin will be collected to analyze 
SYNT001 levels. 
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8. 
STUDY ASSESSMENTS 
Study assessments are performed on a weekly basis and will be comprised of the following 
periods: Screening, Treatment (including Baseline [Day 0]), and Follow-Up (including End-Of 
Study). For those subjects that complete all periods in Cohorts 1 and 2, study duration is 112 
days. For those subjects that complete all periods in Cohort 3, study duration is 175 days.  
Further detail on specific study assessments is provided in Section 7. 
8.1 
All Cohorts: Screening Period and First Treatment (Day 0) 
8.1.1 
All Cohorts: Screening Period (Day −14 to Day −1) 
For all cohorts, informed consent must be obtained before any study-specific samples are taken 
or study-specific tests or evaluations are conducted. The following assessments at the screening 
visit are to occur within 14 days before dosing. Study eligibility will be based on satisfying all 
the study inclusion and exclusion criteria (see Section 6).  
At the screening visit, information will be collected and subjects will have clinical evaluations as 
follows: 
 Informed consent 
 Medical history and demographic data 
 Review inclusion and exclusion criteria 
 Complete physical examination, including height and weight 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis)  
 Pregnancy test 
 Hepatitis and HIV screen 
 12-lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position) 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 Anti-Dsg1 and Dsg3 antibody titers 
 Concomitant medication assessment 
 AE assessment 
 
8.1.2 
All Cohorts: Enrollment and First Treatment (Day 0)  
For all cohorts, study Day 0 is defined as the date the subject is administered their first dose of 
study drug. On Day 0, subjects will be asked to come to the clinic and the following procedures 
will be performed prior to the first dose of study drug: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry; to be measured immediately prior to the infusion 
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 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 Pregnancy test 
 Serum tetanus antibody and VZV antibody 
 PDAI 
 PK baseline sample collection (collected just prior to the start of the study drug infusion) 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3 
 AECA 
 FCGR2A SNP via buccal swab  
 RNAseq 
 Urine IgG 
 Immunophenotyping  
 Exploratory pemphigus immune response biomarkers 
 Skin biopsy (optional) (Cohort 1 only) 
 Photography 
 HR-QoL assessments (ABQoL, Skindex-29) (Cohorts 2 and 3 only) 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest  
 PK sample collection at 5 minutes. Thereafter at 2, 4, 6 hours (Cohort 1) or 1 and 2 hours 
(Cohorts 2 and 3) after the completion of study drug infusion; record collection date and time 
for each PK sample 
 12-lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion 
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
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8.2 
Cohort 1: Day 1 to 84 
8.2.1 
Cohort 1: Follow-up Day 1  
On Day 1 (24 hours ± 1 hour from end-of-infusion time on Day 0), the subject will return to the 
clinic and the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PK sample collection (record collection date and time) 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 Skin biopsy (optional) 
 Concomitant medication assessment 
 AE assessment 
 
8.2.2 
Cohort 1: Follow-up Day 2  
On Day 2 (48 hours ± 2 hours from end-of-infusion time on Day 0), the subject will return to the 
clinic and the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PK sample collection (record collection date and time) 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 Skin biopsy (optional) 
 Concomitant medication assessment 
 AE assessment 
 
8.2.3 
Cohort 1: Follow-up Day 5  
On Day 5 (120 hours ± 4 hours from end-of-infusion time on Day 0), subjects may return to the 
clinic or be visited by an at-home nurse, and the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PK sample collection (record collection date and time 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 CIC 
 Exploratory pemphigus immune response biomarkers 
 Concomitant medication assessment 
 AE assessment 
 
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8.2.4 
Cohort 1: Treatment Day 7 (Dose 2) 
On Day 7 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 Exploratory pemphigus immune response biomarkers 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest  
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
8.2.5 
Cohort 1: Follow-up Day 12  
On Day 12 (± 6 hours), subjects may return to the clinic or be visited by an at-home nurse, and 
the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 CIC 
 Exploratory pemphigus immune response biomarkers 
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 If visit performed at the study site: 12-lead ECG to be obtained in triplicate 
 Concomitant medication assessment 
 AE assessment 
 
8.2.6 
Cohort 1: Treatment Day 14 (Dose 3) 
On Day 14 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3 
 AECA 
 RNAseq 
 Urine IgG 
 Exploratory pemphigus immune response biomarkers 
 Skin biopsy (optional) 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest  
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
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8.2.7 
Cohort 1: Follow-up Day 19  
On Day 19 (± 6 hours), subjects may return to the clinic or be visited by an at-home nurse, and 
the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 CIC 
 Exploratory pemphigus immune response biomarkers 
 Concomitant medication assessment 
 AE assessment 
 
8.2.8 
Cohort 1: Treatment Day 21 (Dose 4) 
On Day 21 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Exploratory pemphigus immune response biomarkers 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest  
 
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Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
8.2.9 
Cohort 1: Treatment Day 28 (Dose 5) 
On Day 28 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 PK sample collection (collected just prior to the start of the study drug infusion) 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Immunophenotyping  
 Exploratory pemphigus immune response biomarkers 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest  
 PK sample collection at 5 minutes and 2, 4, and 6 hours after the completion of study drug 
infusion; record collection date and time for each PK sample 
 12-lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion 
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
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8.2.10 
Cohort 1: Follow-up Day 29  
On Day 29 (24 hours ± 1 hour from end-of-infusion time on Day 28), the subject will return to 
the clinic and the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PK sample collection (record collection date and time) 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 Concomitant medication assessment 
 AE assessment 
 
8.2.11 
Cohort 1: Follow-up Day 30 
On Day 30 (48 hours ± 2 hours from end-of-infusion time on Day 28), the subject will return to 
the clinic and the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PK sample collection (record collection date and time) 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 Concomitant medication assessment 
 AE assessment 
 
8.2.12 
Cohort 1: Follow-up Day 33  
On Day 33 (120 hours ± 4 hours from end-of-infusion time on Day 28), subjects will return to 
the clinic and the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 PK sample collection (record collection date and time) 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3 
 AECA 
 RNAseq 
 Urine IgG 
 Exploratory pemphigus immune response biomarkers 
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 Skin biopsy (optional) 
 Photography 
 Concomitant medication assessment 
 AE assessment 
 
8.2.13 
Cohort 1: Follow-up Day 42 
On Day 42 (± 3 days), subjects will return to the clinic and the following procedures are to be 
performed: 
 Complete physical exam 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Exploratory pemphigus immune response biomarkers 
 Concomitant medication assessment 
 AE assessment 
 
8.2.14 
Cohort 1: Follow-up Day 56  
On Day 56 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed: 
 Complete physical exam 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 Pregnancy test 
 12-lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position) 
 Serum tetanus antibody and VZV antibody 
 PDAI 
 Immunogenicity sample collection 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3 
 AECA 
 RNAseq 
 Urine IgG 
 Immunophenotyping  
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 Exploratory pemphigus immune response biomarkers 
 Skin biopsy (optional) 
 Photography 
 Concomitant medication assessment 
 AE assessment 
 
8.2.15 
Cohort 1: Follow-up Day 84  
On Day 84 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed: 
 Complete physical exam 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 Serum tetanus antibody and VZV antibody 
 PDAI 
 Immunogenicity sample collection 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3 
 AECA 
 RNAseq 
 Urine IgG 
 Exploratory pemphigus immune response biomarkers 
 Skin biopsy (optional) 
 Photography 
 Concomitant medication assessment 
 AE assessment 
 
Note: Cohort 1 End-of-Study visit is detailed in Section 8.4. 
8.3 
Cohorts 2 and 3: Subsequent Treatments to Follow-up 
8.3.1 
Cohort 2: Treatment Days 7 and 21; Cohort 3: Treatment Days 7, 14, 21, 28, 
35, 49, 56, 63, 70, 77, and 84 
For Cohort 2 Days 7 and 21 (± 1 day) and Cohort 3 Days 7, 14, 21, 28, 35, 49, 56, 63, 70, 77, 
and 84 (± 1 day), subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
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 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 Exploratory pemphigus immune response biomarkers 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest  
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
8.3.2 
Cohort 2: Treatment Days 14 and 28; Cohort 3: Treatment Days 42 and 91 
For Cohort 2 Days 14 and 28 (± 1 day) and Cohort 3 Days 42 and 91 (± 1 day), subjects will 
return to the clinic and the following procedures are to be performed prior to study drug infusion: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 Pregnancy test (Cohort 3, Days 42 and 91 only) 
 PDAI 
 PK sample collection (collected just prior to the start of the study drug infusion) (Cohort 2, 
Day 28 only; Cohort 3, Day 91 only) 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
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 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 Exploratory pemphigus immune response biomarkers 
 Photography (Cohort 3, Day 42 only) 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry will be performed at 15, 30, and 45 minutes after the start of the infusion 
and at completion of the infusion 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral temperature) 
and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion of the infusion; 
abnormal results to be repeated after 5 minutes of rest 
 PK sample collection at 5 minutes and 1 and 2 hours after the completion of study drug 
infusion; record collection date and time for each PK sample (Cohort 2, Day 28 only; 
Cohort 3, Day 91 only) 
 12-lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion 
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
8.3.3 
Cohort 2: Follow-up Days 35 and 56; Cohort 3: Follow-up Days 98 and 119 
For Cohort 2 Days 35 (± 1 day) and 56 (± 3 days) and Cohort 3 Days 98 (± 1 day) and 119 (± 3 
days), subjects are to return to the clinic and the following procedures are to be performed: 
 Complete physical exam 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 Pregnancy test (Cohort 2, Day 56 only; Cohort 3, Day 119 only) 
 12-lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position) 
(Cohort 2, Day 56 only; Cohort 3, Day 119 only) 
 Serum tetanus antibody and VZV antibody (Cohort 2, Day 56 only; Cohort 3, Day 119 only) 
 PDAI 
 Immunogenicity sample collection (Cohort 2, Day 56 only; Cohort 3, Day 119 only) 
 PD sample collection 
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 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3 
 AECA 
 RNAseq 
 Urine IgG 
 Immunophenotyping  
 Exploratory pemphigus immune response biomarkers 
 Photography 
 HR-Qol (ABQoL, Skindex-29) 
 Concomitant medication assessment 
 AE assessment 
 
8.3.4 
Cohort 2: Follow-up Days 42 and 84; Cohort 3: Follow-up Days 105 and 147 
For Cohort 2 Days 42 (± 1 day) and 84 (± 5 days) and Cohort 3 Days 105 (± 1 day) and 147 (± 5 
days), subjects are to return to the clinic and the following procedures are to be performed: 
 Complete physical exam 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 Exploratory pemphigus immune response biomarkers 
 Concomitant medication assessment 
 AE assessment 
 
8.4 
All Cohorts: End of Study or Early Termination Visit; Cohorts 1 and 2, 
Day 112; Cohort 3, Day 175  
For Cohorts 1 and 2 Day 112 (± 5 days) and Cohort 3 Day 175 (± 5 days), subjects are to return 
to the clinic and the following procedures are to be performed: 
 Complete physical exam 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, respiratory 
rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 Pregnancy test  
 Serum tetanus antibody and VZV antibody 
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 PDAI 
 Immunogenicity sample collection 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3 (Cohort 1 only) 
 AECA (Cohort 1 only) 
 RNAseq (Cohort 1 only) 
 Urine IgG (Cohort 1 only) 
 Exploratory pemphigus immune response biomarkers 
 Photography 
 HR-Qol (ABQoL, Skindex-29) (Cohorts 2 and 3 only) 
 Concomitant medication assessment 
 AE assessment 
 
Note: a subject may choose to terminate participation in the study at any time. Under this 
circumstance, the subject will be encouraged to return as soon as possible for an early treatment 
visit and to receive assessments otherwise scheduled on Day 112 (Cohorts 1 and 2) or Day 175 
(Cohort 3). 
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9. 
STUDY RULES 
9.1 
Subject Withdrawal  
Every reasonable effort will be made to keep the subject in the study; however, if a subject 
withdraws from the study, the Investigator should complete and report the reasons for 
withdrawal as thoroughly as possible. The reason(s) for termination must be clearly documented 
on the appropriate page of the eCRF.  
If a subject discontinues from the study for any reason, every effort will be made to collect all 
clinical and laboratory data as scheduled for the Early Termination Visit (see Section 8.4). If the 
subject fails to return for these assessments for unknown reasons, every effort (eg, telephone, 
email, and letter) should be made to contact them.  
The reason(s) for a subject’s participation in the study may be prematurely discontinued will be 
documented and include:  
1. The subject wishes to withdraw from the study. 
2. Request by a regulatory agency (eg, Institutional Review Board). 
3. The subject experiences a significant or intolerable AE.  
4. The subject experiences a significant adverse change in vital signs, physical examination 
findings, or clinical laboratory parameter. 
5. The subject has a need for a concomitant medication that is not permitted by the study 
protocol. 
6. The subject experiences generalized impairment or mental incompetence that would result in 
the subject being unable to understand his or her participation in the study. 
7. If, in the Investigator’s medical judgment, further participation would be injurious to the 
health and well-being of the subject, or is not in the best interest of the subject.  
8. Administrative reasons, such as subject non-compliance or a major protocol violation. 
9. The subject requires a significant increase in dose(s) of anti-pemphigus medication(s) for the 
management of pemphigus (at the discretion of the Investigator with consultation with the 
Medical Monitor). 
 
If at the discretion of the Investigator with consultation with the Medical Monitor, a subject 
requires a significant increase in dose(s) of anti-pemphigus medication(s) for the management of 
pemphigus, the subject will be encouraged to continue their study visits to allow collection of 
safety data. 
9.2 
Subject Replacement 
Enrolled subjects withdrawn for a reason other than an AE will be replaced if they have not been 
dosed or have only received one dose of study drug at the time of discontinuation, up to one 
subject per cohort. Subjects who do not receive all doses of study drug will continue to be 
followed through all scheduled study visits.  
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9.3 
Study Discontinuation 
The Sponsor has the right to terminate or to stop the study at any time. Reasons for study 
discontinuation may include, but are not limited to, the following:  
 The incidence or severity of AEs in this or other related studies indicates a potential health 
hazard to subjects  
 Subject enrollment is unsatisfactory 
 Drug supply issues 
 Excessive subject self-withdrawal 
 Significant protocol violations (eg, violation of eligibility criteria, dosing errors, missing data 
for study endpoint analysis) 
 
9.4 
Lost to Follow-up 
All reasonable effort should be made to contact any subject lost to follow-up during the study to 
complete assessments and retrieve any outstanding data. If the subject is unreachable after three 
good faith attempts, at a minimum, the Investigator should follow up with a registered letter 
requesting contact so safety data may be collected, recorded, and reported (if necessary).  
9.5 
Stopping Rules 
9.5.1 
Dose-Escalation Stopping Rule 
Dose recommendations will be made by a DEC based upon a review of all available safety data, 
on a continuous basis as well as at discrete timepoints. Available data will be based on safety and 
pharmacodynamic evaluations including but not limited to, DLTs, AEs, TEAEs, SAEs, PD 
(including but not limited to IgG levels), and clinical outcomes. 
Dose-limiting toxicity (DLT) will be defined generally as severe (Grade 3) AEs occurring in 
≥2 subjects in any cohort that are determined to be clinically significant and considered related to 
study drug. 
If 2 or more subjects at any time in any cohort have Grade 3 AEs that are determined to be 
clinically significant and considered to be related to study drug, dosing will be halted within that 
cohort and dose-escalation to a higher dose will not occur. Upon review of the available 
information, the DEC may reduce the dose prior to enrolling additional subjects using the 
guidelines below:  
 Cohort 1: Dose may be reduced by at least 50%.  
 Cohort 2: Dose may be reduced by at least 33%. 
 Cohort 3: Dose may be reduced to a level lower than the Cohort 2 dose. 
 Cohort 4 (optional cohort): Dose may be reduced to level lower than the Cohort 3 dose. 
 
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9.5.2 
Study Stopping Rule 
If any subject experiences a life-threatening AE (Grade 4) that is considered to be related to 
study drug, any further dosing in all enrolled subjects will be suspended until the DEC has 
evaluated the event and determined the next appropriate course of action. At any time during the 
study, the study may be discontinued if the DEC determines that further drug exposure would 
pose an undue risk to subjects. 
9.5.3 
Individual Stopping Rule 
Dosing for any individual subject will be discontinued (ie, no further study drug will be given to 
that subject) if the subject experiences any study drug-related SAE or any study drug-related 
non-serious AE that, in the judgement of the Investigator (following consultation with the 
Medical Monitor, if desired) suggest that it could be unsafe to administer further study drug to 
that subject. 
Subjects who are withdrawn from this study due to an AE determined to be related to study drug 
are to be followed until there is: 
 Resolution or stabilization of the AE determined to be related 
 The subject is lost to follow-up 
 The event is otherwise explained 
 
If there is a persistent AE contributing to discontinuation that is determined to be related to 
SYNT001, subjects must be followed with appropriate medical management until resolution or 
stabilization. Refer to Section 10 for more information.  
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10. 
EVALUATION OF SAFETY 
10.1 
Safety Parameters 
Subjects will be monitored continuously throughout the treatment and follow-up period for AEs 
(acute, delayed, and/or cumulative), as well as for changes in clinical status. Parameters 
measure/assess safety include physical examinations, vital sign measurements (including pulse 
oximetry), clinical (safety) laboratory tests (hematology, serum chemistries, urinalysis), 
concomitant medication assessments, and ECG. Clinical and laboratory AEs will be graded using 
the NCI CTCAE; Version 4.03 (see Appendix 1).  
10.2 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical trial subject associated with 
the use of a drug, whether considered drug related or not. An AE can be an unfavorable and 
unintended sign (eg, an abnormal laboratory value finding), a symptom, or a disease temporally 
associated with the use of a drug, without judgment as to causality. An AE can arise from use of 
the drug (eg, use in combination with another drug) and from any route of administration, 
formulation or dose, including an overdose. An AE also includes, but is not limited to, any 
clinically significant worsening of a pre-existing condition. Examples include: 
 Any sign, symptom, physical finding, or laboratory result that has worsened in nature, 
severity or frequency compared to baseline 
 Reactions from an investigational drug, including those occurring because of an overdose, 
abuse of the study drug, withdrawal phenomena, sensitivity or toxicity 
 Concurrent illness that was not present or worsens in nature, severity, or frequency compared 
to baseline  
 Injury or accident 
 Exacerbation of a pre-existing condition 
 
Pregnancy is not considered an AE or SAE; however, any pregnancy complication(s) should be 
recorded as an AE(s) or SAE(s) (if applicable). Elective abortions without complications should 
not be regarded as AEs, unless they were therapeutic abortions. Hospitalization for normal 
delivery of a healthy newborn should not be considered an SAE. If a female subject becomes 
pregnant during the conduct of the study, the Investigator must notify the Sponsor according to 
the procedures provided in Section 10.5.4. 
Planned hospitalization admissions or surgical procedures for a condition known to exist before 
the subject signed the informed consent are not an AE and should be recorded as medical history. 
If the planned hospitalization or procedure is executed as planned and without complication, the 
record in the subject’s medical history is considered complete. However, if the event/condition 
deteriorates in an unexpected manner during the study or following surgery, it must be reported 
as an AE according to the procedures provided in Section 10.2.1. 
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10.2.1 
Recording an Adverse Event 
For data collection, all untoward events that occur after informed consent through the last study 
visit are to be recorded on eCRFs by the investigational site. All AEs are to be accurately 
recorded on the Adverse Event page of the subject’s eCRF. The severity of each AE will be 
graded using the NCI CTCAE, Version 4.03 (see Appendix 1). The date of onset as well as the 
end date of the event should be recorded or the event should be entered as “ongoing”. In 
addition, the method used to treat the AE and the outcome of the AE will be noted. The 
Investigator will assess the relationship of the event to study drug.  
10.2.2 
Assessment of Causality 
A medically qualified Investigator must assess the relationship of any AE (including SAEs) to 
the use of the study drug, as related or not related, based on clinical judgment and using all 
available information. The causal relationship between the study medication and the AE will be 
assessed using one of the following categories: 
Not Related: Factors consistent with an assessment of Not Related include: 
 Temporal relationship is lacking (eg, the event did not occur within a reasonable time frame 
following administration of the study medication); or 
 Other causative factors more likely explain the event (eg, a pre-existing condition, other 
concomitant treatments). 
 
Related: Factors consistent with an assessment of Related include: 
 There is a positive temporal relationship (eg, the event occurred within a reasonable time 
frame following administration of study medication); or 
 The AE is more likely explained by the investigational product than by another cause (ie, the 
AE shows a pattern consistent with previous knowledge of the investigational product or the 
class of the investigational product) 
 
10.2.3 
Serious Adverse Events 
(Notify Medpace Safety within 24 hours; document on eCRF) 
The SAE definition and reporting requirements are in accordance with Title 21 Part Code of 
Federal Regulations (CFR) 312.32 and the Guidance for Industry and Investigators Safety 
Reporting Requirements for Investigational New Drug (INDs) and Bioavailability 
/Bioequivalence Studies. 
An AE is considered "serious" if, in the view of either the Investigator or sponsor, it results in 
any of the following outcomes: 
 Death: This includes any death that occurs while the subject is “on study” through the last 
study visit.  
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Note: Death is an outcome of an AE and not an AE. The event(s) that caused death (eg, 
illness, accident) is the SAE. Death due to any other cause(s) must also be reported as an 
outcome of the reportable SAE. 
 Life-threatening adverse drug event: An AE or suspected adverse reaction is considered 
“life threatening” if, in the view of either the Investigator or Sponsor, its occurrence places 
the patient or subject at immediate risk of death. It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused death.  
 Inpatient hospitalization or prolongation of existing hospitalization: an AE that requires 
admission to a hospital for medical and/or surgical intervention. 
 In the absence of an AE, the Investigator should not report hospitalization or prolongation 
of hospitalization as an SAE, as detailed in the following examples: 
o An elective or previously scheduled surgery for a pre-existing condition that has not 
deteriorated unexpectedly after initiation of treatment (eg, a previously scheduled 
ventral hernia repair) 
o Hospitalization or prolongation of hospitalization is needed for a procedure required 
by the protocol 
o Hospitalization or prolongation of hospitalization is part of routine procedure 
followed by study center 
o Hospitalization for survey visits, annual physicals, or planned observation 
o Hospitalization for observation with release within 24 hours (eg, an emergency room 
visit for hematuria that results in a diagnosis of cystitis and discharge to home on oral 
antibiotics 
 Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 Congenital anomaly/birth defect 
 Important medical event: An event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, it may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
 
10.2.3.1 
Recording a Serious Adverse Event 
When the diagnosis of an SAE is known or suspected, the Investigator should record the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms. Signs and 
symptoms may then be described in the event description. For example, dyspnea should not be 
used as an SAE term if the diagnosis, which caused the dyspnea, is known to be malignant 
pleural effusion.  
Death should not be recorded as an SAE, but as an outcome of a specific SAE, unless the event 
preceding the death is unknown. In the exceptional case where the events leading to death are 
unknown, then death may be used as an event term. If an autopsy was performed, the autopsy the 
autopsy report should be provided. 
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10.2.3.2 
Reporting a Serious Adverse Event 
RESPONSIBILITIES OF THE INVESTIGATOR 
Any death, SAE, or pregnancy, experienced by the subject after informed consent through the 
last study visit, regardless of relationship to study drug, must be promptly reported (within 
24 hours of the Investigator becoming aware of the event) by telephone or electronic 
transmission to the Sponsor (or designee). 
Contact information for SAE reporting: 
Medpace Clinical Safety 
Medpace SAE hotline: 
Telephone: 
 dial  or 
 dial  
Facsimile: 
 or 
 
e-mail:
 
 
Additionally, the Investigator will be able to contact the Medical Monitor: 
Medical Safety Contact 
 
 
Phone (EU): 
 extension 
 
Mobile phone: 
 
Email: 
 
 
The Investigator will report the SAE to his or her IRB in accordance with IRB’s standard 
operating procedures and policies. Adequate documentation must be maintained showing that the 
IRB was properly notified. 
SAEs must be recorded on the SAE form in the electronic data capture (EDC) system. This 
requirement includes all SAEs that occur after informed consent through the last study visit. The 
minimum information required for SAE reporting includes identity of investigator, site number, 
subject number, an event description, SAE term(s), onset date, the reason why the event is 
serious (ie, the seriousness criteria), and the Investigator’s assessment of the relationship of the 
event to study treatment. Additional SAE information including medications or other therapeutic 
measures used to treat the event, action taken with the study treatment due to the event, and the 
outcome/resolution of the event will be recorded. Paper forms for reporting SAEs will be 
provided to the study sites as back-up in case the EDC system is not accessible. 
In all cases, the Investigator should continue to monitor the clinical situation and report all 
material facts relating to the progression or outcome of the SAE. Furthermore, the Investigator 
may be required to provide supplementary information as requested by the Sponsor (or 
designee). 
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RESPONSIBILITIES OF THE SPONSOR (OR DESIGNEE) 
The Sponsor (or designee) will process and evaluate all SAE as soon as the reports are received. 
For each SAE received, the Sponsor will decide as to whether the criteria for expedited reporting 
have been met. 
The Sponsor (or designee) is responsible for promptly informing the FDA and other regulatory 
authorities as well as other participating Investigators of the event. Written submission must be 
made by the Sponsor to the FDA as soon as possible and in no event later than 15 calendar days 
after the Sponsor’s initial notification of the event, or for an event that is fatal or life-threatening 
no later than 7 calendar days after the Sponsor’s initial notification.  
EXPEDITED REPORTING  
Under FDA ruling (US Code of Federal Regulations, Title 21 CFR Part 312.32) and the ICH 
Guideline “Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting E2A,” the Sponsor is required to submit written documentation, in the form of a safety 
report, detailing: 
 Any event associated with the use of the drug, that is both serious and unexpected, or  
 Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.  
 
The Sponsor will submit SAEs that meet the criteria for expedited reporting to the regulatory 
authorities in accordance with local regulations governing safety reporting. 
10.2.4 
Follow-Up of Adverse Events and Serious Adverse Events 
Any SAE or AE must be followed until either resolution of the event or determination by the 
Investigator that the event has become stable or irreversible. Appropriate diagnostic tests should 
be performed and therapeutic measures, if indicated, should be instituted until the event has 
returned to baseline or until a clinically satisfactory resolution has been achieved. The 
appropriate follow-up visits must be scheduled and the specific tests repeated or performed as 
necessary. The status of all AEs will be documented as of the last study visit. If all required 
information is not available at the time of the initial report, follow-up information will be 
completed in the EDC system.  
10.3 
Warnings and Precautions 
10.3.1 
Vaccinations 
Subjects must not receive any vaccinations from within 2 weeks of screening until 28 days 
following final dose at the discretion of the Investigator. 
10.3.2 
Management of Allergic or Infusion-Related Reactions 
As observed with all mAbs administered by IV infusion, infusion reactions to SYNT001 are 
possible. In general, infusion reactions to mAbs observed in human studies typically develop 
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within 30 minutes to 2 hours after the initiation of drug infusion, although symptoms may be 
delayed for up to 24 hours. These infusion reactions can occur with the first dose of a mAb and 
are generally mild in severity, although severe and even fatal reactions can occur.  
Allergic and/or infusion-related reactions include hypersensitivity reactions and cytokine release 
syndromes. These reactions are experienced by subjects during or within hours of the infusion of 
mAb therapy. Symptoms can include flushing, alterations in heart rate and blood pressure, 
dyspnea, bronchospasm, back pain, fever, urticaria, edema, nausea, and all types of rashes. 
Anaphylaxis is recognized as a severe, life-threatening, generalized, or systemic reaction. This is 
a medical emergency characterized by rapidly developing life-threatening airway and/or 
breathing and/or circulation problems usually associated with skin or mucosal changes.  
Management of Grade 1 infusion reactions include interrupting the infusion or decreasing the 
rate of infusion by 50% and observing. Symptoms may also be treated as needed with 
medications such as diphenhydramine, hydrocortisone, or acetaminophen, either alone or in 
combination, depending on the subject’s signs and symptoms. If the infusion is interrupted or the 
infusion rate is decreased, it is important to note that all study drug infusions must be completed 
within 4 hours of SYNT001 preparation. 
Management of Grade 2 and higher infusion reactions should include stopping the infusion of 
study drug. Continued treatment with SYNT001 is prohibited following Grade 2 or higher 
infusion reactions. See Figure 2 and Figure 3 for details on the management of Grade 2 and 
Grade 3 infusion reactions. Allergic or infusion-related reactions will be graded in severity and 
managed based on NCI CTCAE Version 4.03 (see Table 9). 
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Figure 2. 
Management of Moderate (Grade 2) Infusion Reactions 
 
Stop  
Infusion
Assess airway, breathing, circulation, and consciousness, and 
recline subject 
Start high flow oxygen 
Insert large bore IV and start IV fluids 
Initiate vital sign assessments at least every 15 minutes
Any problem with airway, 
breathing circulation, or 
consciousness?
NO: 
Initiate medical 
review 
YES:  
Initiate treatment per 
the Severe Infusion 
Reaction Flow Chart 
Monitor for symptom resolution 
If symptoms persist, proceed with medications as needed. For 
example: diphenhydramine 25-50 mg IV and/ or 
hydrocortisone 200 mg IV 
Note: If desaturation, 
hypotension, or urticaria 
present, refer to Severe 
Infusion Reaction Flow 
Chart. 
Subject presents with any of the below: 

Impending feeling 
of doom 

Flushing 

Pyrexia 

GI symptoms 

Altered vision 

Pain: back, 
abdomen, chest 

Wheezing without 
desaturation 

Peripheral edema
If ongoing symptoms, consider 
ongoing observation or hospital 
admission 
If symptoms and signs resolve completely either spontaneously or after administration of diphenhydramine 
with or without hydrocortisone, consider rechallenge:  
Wait at least 20 minutes following medication administration before commencing rechallenge at an infusion 
rate of 50% or less of the initial infusion rate or 
Consider pre-medicating the subject with the same medication(s) 20-30 minutes in advance of subsequent 
administrations of SYNT001 and starting infusion at 50% of the planned infusion rate for the first 30 minutes, 
then returning to the intended infusion rate in the absence of any infusion reaction. If the infusion is interrupted 
or the infusion rate is decreased, it is important to note that all study drug infusions must be completed within 4 
hours of SYNT001 adminstration. 
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Figure 3. 
Management of Severe (Grade 3 or Higher) Infusion Reactions 
 
 
Subject presents with any of the below: 

Urticaria 

Airway threatened by angioedema 

Angioedema: Lip, mouth, facial swelling 

Respiratory compromise - wheezing, dyspnea, stridor or hypoxia 
(O2 saturation <90%) 

BP <90 mmHg SBP or >30% decrease from patient baseline 
Stop  
Infusion 
Consider (under medial direction): 
Epinephrine 1:1000 

0.3 mg (0.3 mL) IM into lateral thigh 
Transfer to Emergency Room/ICU 
Observe until all symptoms resolved. 
Start basic life support: 

High oxygen flow 

On bed, head down, legs up 

Large bore IV cannula, 1 L normal saline STAT 

Initiate vital signs at least every 15 minutes
Airway Threatened:  
Bronchospasm: 
(Wheeze or Hypoxia) 
 
Hypotension: 
(Systolic BP <100 mmHg) 
Nebulized epinephrine 1:1000, 3–5 mL (3–5 mg) 
Nebulized salbutamol 5 mg 
Consider: Intubation / nebulized epinephrine 
 
Place on cardiac monitor 
Further epinephrine 1:1000, 0.3 mg IM and  
IV normal saline bolus 20 mL/kg STAT as needed 
Have vasopressin on hand 
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Table 9. 
Grading and Management of Allergic or Infusion-Related Reactions 
Adverse 
Event 
Grade 
1 
2 
3 
4 
5 
Infusion-
related 
reaction 
Mild transient 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤24 hours 
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated 
for clinical sequelae 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Allergic 
reaction 
Transient 
flushing or 
rash, drug 
fever 
<38.0°C. 
Intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤24 hours 
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Anaphylaxis 
– 
– 
Symptomatic 
bronchospasm, with or 
without urticarial; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Cytokine 
release 
syndrome 
Mild reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤24 hours 
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
Life-
threatening 
consequences; 
pressor or 
ventilator 
support 
indicated 
Death 
Abstracted from NCI CTCAE Version 4.03. 
 
10.3.3 
Potential Immune Effects 
An antibody blocking FcRn is anticipated to have several effects. These include acceleration of 
catabolism of IgG, but not other immunoglobulin isotypes such as IgA and IgM, leading to dose-
dependent decreases in circulating IgG levels by up to an estimated 50% from the baseline levels 
after a single dose and further decreases after multiple doses up to a 70% to 80% reduction. 
Based on studies in humans, it is expected that with a single dose, the nadir of this effect will 
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occur approximately 5 days after dosing. The time course of recovery of IgG following dosing in 
the Phase 1a study suggests that a return to within 30% of baseline levels observed at 
pretreatment occurs within 4 weeks after a single dose and within 4 weeks after multiple doses as 
shown in NHPs.  
Given the normal adult range of total IgG of 500 to 1600 mg/dL (Agarwal and Cunningham-
Rundles, 2007; Furst, 2009; Gonzalez-Quintela et al., 2008; Jolliff et al., 1982; Keystone et al., 
2007; McMillan et al., 1997; van Vollenhoven et al., 2013), with a mean of 1150 mg/dL, a 50% 
decrease in the mean would be to 575 mg/dL and a 50% decrease from the low end of the normal 
range used for the inclusion criteria of 600 mg/dL in this study would be to 300 mg/dL. An 80% 
decrease from baseline after multiple doses would result in IgG levels of 230 mg/dL and 
120 mg/dL, respectively. While these levels are in the range found in patients with primary 
humoral immunodeficiency (Ameratunga et al., 2013), the levels will be transient. Further, as 
reported for other therapies used for pemphigus, the temporary (ie, less than 4 months) depletion 
of IgG (up to 95% reduction of total IgG as seen with immunoadsorption) does not appear to 
impart an increased risk of infection (Eming and Hertl, 2006; Furst, 2009; Keystone et al., 2007; 
Schmaldienst et al., 2001; van Vollenhoven et al., 2013). Study subjects will be monitored 
clinically for any infection. Further, commercial IVIG can be given to reverse the low IgG levels 
in case of a bacterial infection occurring while their IgG levels are decreased. 
An antibody that blocks FcRn is expected to also down-modulate innate and adaptive immunity 
and the catabolism of IgG-containing immune complexes (IC). Specifically, it is expected that 
anti-FcRn will promote the clearance of IgG-containing ICs and the effects of these ICs on 
stimulating innate immune cell production of inflammatory cytokines (eg, interleukin 12 [IL-12], 
interferon-γ, and tumor necrosis factor [TNF]) and inhibit the processing and presentation of 
antigens contained within ICs and thus the antigen-specific activation of CD4+ and CD8+ T-cells. 
Therefore, subjects with pre-existing conditions that are dependent upon IgG antibodies, such as 
chronic infections (eg, HIV, HBV or HCV), will be excluded from this study, as will subjects 
with active infection, in general. 
10.4 
Events of Special Interest 
Not applicable. 
10.5 
Other Safety Considerations 
10.5.1 
Laboratory Data 
All laboratory data obtained during the study should be reviewed. Any abnormal value that leads 
to a change in subject management (eg, requirement for additional medication or monitoring) or 
is determined to be of clinical significance by the Investigator should be reported as an AE 
and/or SAE as appropriate, unless this value is consistent with values obtained before entry into 
the study.  
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10.5.2 
Medication Errors 
Any medication error that results in an AE, even if it does not meet the definition of serious, 
requires reporting within 24 hours to the safety Medical Monitor. Refer to Section 10.2.3.2 for 
more information. 
10.5.3 
Overdose 
For the purposes of this study, an overdose of SYNT001 is defined as a dose that is two-fold 
higher than the intended dose for the subject. As all dosing for this study will be conducted in a 
controlled clinical setting, an overdose is not anticipated. In the unlikely event an overdose 
should occur, it should be reported as an AE.  
10.5.4 
Pregnancy 
If a female subject or the female partner of a male subject becomes pregnant during the course of 
the study, the Investigator must report the pregnancy to Medpace Safety using the Pregnancy 
Reporting Form within 24 hours of becoming aware of the event. The Investigator must obtain 
consent to collect pregnancy information (including the status of the newborn, if applicable). 
If some of the information required for completion of the Pregnancy Reporting Form is 
unavailable at the time of the initial report, follow-up reports will be completed and submitted 
within 24 hours of becoming aware of the new information. Any pregnancy will be followed 
through delivery for the observation of any SAEs. Any SAE that occurs during pregnancy must 
be recorded on the SAE report form in the EDC system (eg, maternal serious complications, 
therapeutic or spontaneous abortion, ectopic pregnancy, stillbirth, neonatal death, congenital 
abnormality, birth defect) and reported within 24 hours in accordance with the procedure for 
reporting SAEs (see Section 10.2.3.2).  
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11. 
STATISTICAL CONSIDERATIONS  
11.1 
General Design  
This study is being conducted to evaluate the safety, tolerability, PK, PD, activity, and 
immunogenicity of SYNT001 in pemphigus patients. 
11.2 
Study Populations  
Three populations will be employed in the analysis of study data: 
 The Safety population will consist of all subjects who have received at least one dose of 
study drug.  
 The PD population will consist of all subjects who receive at least one dose of study drug 
and have post-dose PD data available. 
 The PK population will consist of all subjects who receive at least one dose of study drug 
and have post-dose PK data available. 
 
Primary safety analyses will be performed on the safety population. Demographics, subject 
disposition, screening, and baseline characteristics will be summarized for the safety and PD/PK 
populations, where appropriate. 
11.3 
Sample Size Justification  
Formal sample size calculations were not performed. The number of subjects was chosen based 
on feasibility and was considered sufficient to meet the study objectives. 
11.4 
Statistical Analysis  
11.4.1 
Statistical Analysis Plan 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP). The SAP may modify the plans outlined in 
the protocol; however, any deviations from the previously approved statistical plan will be 
described and justified in a SAP amendment. Additional statistical analyses other than those 
described in this section may be performed if deemed appropriate and will be described in the 
SAP. The SAP including pharmacokinetic data analysis methodologies will be finalized prior to 
database lock. 
All descriptive and inferential statistical analyses will be performed using Statistical Analysis 
System (SAS) version 9.4 or later. Missing data will not be imputed unless otherwise stated. All 
clinical data captured will be provided in data listings.  
Methods of handling of missing data for different endpoints will be further specified in the SAP. 
In general, where individual data points are missing because of insufficient samples, dropouts, or 
other reasons, the data will be analyzed based on reduced denominators unless specified 
otherwise in the SAP.  
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11.4.2 
Statistical Methodology 
All clinical data captured will be provided in data listings. Subject disposition, demographic 
information, and baseline characteristics will be presented. Baseline will be defined at the last 
value obtained prior to the first dose of study drug. Results will be summarized by dose level and 
cohort. Any discrepancy between treatment to be given and treatment received will be accounted 
for in these displays.  
Continuous data will be summarized using descriptive statistics: number of subjects (N), number 
of observations (n), mean, median, standard deviation (SD), minimum, and maximum.  
Categorical data will be summarized using frequencies and percentages. When categorical data 
will be presented, the percent will be suppressed when the count is zero to draw attention to the 
non-zero counts. The denominator for all percentages, unless otherwise specified, will be the 
number of subjects in the specified analysis population. 
11.4.3 
Analysis of Primary Endpoints 
11.4.3.1 
Safety Data  
All statistical analysis of safety outcomes will be descriptive. Safety observations and 
measurements include AEs, treatment-emergent AEs (TEAEs), SAEs, clinical safety laboratory 
tests, vital sign measurements, physical examinations, and ECGs. The incidence of AEs, TEAEs 
and SAEs will be summarized by cohort, severity and relationship to study product. 
TEAEs will be summarized using the Medical Dictionary for Regulatory Activities (MedDRA®; 
Version 19 or higher) System Organ Class (SOC) and preferred term, classified from verbatim 
terms. The incidence and percentage of subjects with at least one occurrence of a preferred term 
will be included, using the most severe grade. The number of events per preferred term will also 
be summarized. Causality (relationship to study treatment) will be summarized separately.  
TEAEs, SAEs, and AEs leading to withdrawal, dose modification, or treatment discontinuation 
will be listed by subject, dose, and overall per SOC and preferred terms. Duration of AEs will be 
determined and included in listings, along with action taken and outcome.  
Laboratory results will be summarized by cohort and time point. The incidence of laboratory 
abnormalities will be summarized. The worst on-study grade after the first dose of study drug 
will be summarized. Results for variables that are not coded will be presented in the listings as 
below, within, and above the normal limits of the local laboratory. 
Vital sign measurements and change from baseline will be summarized at each scheduled time 
point by cohort using descriptive statistics.  
Arithmetic mean of parameters from triplicate ECG will be calculated first for each subject at 
each planned time point. Then summary statistics of ECG test parameters (mean of triplicate) 
and change from baseline to each post-dose time point will be calculated. Shift tables for ECG 
test result category change (normal, abnormal, clinically abnormal) from pre-dose to each post-
dose time point showing number and percentage of subjects with movement between categories 
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will be presented by treatment group. Frequency and percentage of subjects experiencing 
potential QTc prolongation (QTcF > 450) will be summarized at each time point by cohort. 
Concomitant medications will be coded using WHO Drug Dictionary (WHO-DD March 2013, 
Type B2 or later) and the data will be summarized and presented in tables and listings.  
11.4.3.2 
Dose Selection Data 
The evaluation of SYNT001 based on total IgG levels and responses on the PDAI total activity 
score from baseline will be summarized using descriptive statistics. Descriptive statistics will 
include mean, SD, coefficient of variation (CV), median, minimum, and maximum. The 
determination of dose and dosing duration of SYNT001 that achieves (i) total IgG level nadir 
decrease by ≥60% and ≤90% from baseline and (ii) a PDAI total activity score of ≥50% 
reduction from baseline to allow further clinical development in subject with pemphigus 
(vulgaris or foliaceus). 
11.4.4 
Analysis of Secondary Endpoints 
11.4.4.1 
Pharmacokinetic Data 
PK results for SYNT001 will be summarized by cohort and timepoint. 
Study drug serum concentrations will be used to calculate the following PK parameters: t1/2, 
Cmax, Tmax, and AUC0-24 and AUC0-∞ in Cohort 1 and Cmax for Cohorts 2, 3, and 4 (optional 
cohort). PK parameters will be determined using noncompartmental method(s). Descriptive 
statistics will be provided for the PK parameters including mean, SD, CV, median, minimum, 
and maximum. Tmax will be reported as median and range. All descriptive statistics will be 
performed on untransformed PK parameters and after log10 transformation of PK parameters. 
For calculation of mean concentrations and generation of mean concentration-time profiles, all 
below the limit of quantification (BLQ) values will be set to zero except when an individual 
BLQ falls between 2 quantifiable values, in which case it will be omitted. 
If there are values above the BLQ, but too sparse to allow full analysis, descriptive statistics will 
be performed on available values. 
11.4.4.2 
Pharmacodynamic/Activity Data  
The evaluation of PD biomarkers will be based on absolute and percent change from baseline in 
serum levels of total IgG, IgG subtypes (IgG1-4), immunoglobulin A (IgA), immunoglobulin M 
(IgM), albumin, and CIC that will be summarized by cohort and timepoint. 
11.4.4.3 
Immunogenicity Data  
Immunogenicity results will be summarized by cohort and timepoint. Descriptive statistics will 
include mean, SD, CV, median, minimum, and maximum.  
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11.4.4.4 
PDAI Data 
PDAI results will be summarized by score (total activity score, total damage score), cohort, and 
timepoint. Descriptive statistics will include absolute change from baseline, and percent change 
from baseline. PDAI will also be summarized by disease severity category, mild (0 to 8), 
moderate (9 to 24), and severe (≥25). 
11.4.5 
Analysis of Exploratory Endpoints 
11.4.5.1 
Corticosteroid Use 
The evaluation of corticosteroid use during the study will be summarized by cohort and 
timepoint. 
11.4.5.2 
Health-Related Quality of Life Data 
HR-QoL results from the ABQoL and Skindex-29 assessments will be summarized by cohort 
and timepoint 
11.4.5.3 
Photography 
The qualitative assessment of changes in appearance of skin and mucosal lesions as determined 
by photography presented by cohort and timepoint. 
11.5 
Interim Analysis 
No interim analysis is planned. 
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12. 
STUDY MANAGEMENT 
12.1 
Regulatory and Ethical Considerations 
12.1.1 
Ethical Conduct 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
ICH E6 Tripartite Guideline (January 1997), and in general, be conducted in a manner consistent 
with the principles described in the Declaration of Helsinki. The Investigator will ensure that the 
conduct of the study complies with the basic principles of GCP as outlined in the current version 
of 21 CFR, subpart D, Part 312, “Responsibilities of Sponsors and Investigators”, Part 50, 
“Protection of Human Subjects”, and Part 56, “Institutional Review Boards”. 
12.1.2 
Informed Consent  
A signed informed consent form (ICF) in compliance with 21 CFR, Part 50.25(a) and Part 
50.25(b) and the ICH guidelines, will be obtained from each subject before the subject is entered 
into the study and before any study screening procedure is performed that involves risk. The 
method of obtaining and documenting the informed consent will comply with ICH GCP and all 
applicable laws and regulations and will be subject to approval by the Sponsor. 
The Investigator, or designee, is responsible for obtaining written informed consent from each 
subject (or the subject’s legally authorized representative) participating in this study after a 
thorough and clear explanation of the objectives, procedures, anticipated benefits, and potential 
hazards of the study. In the case where the subject is unable to read, an impartial witness should 
be present during the entire informed consent discussion. After the subject has orally consented 
to participation in the trial, the witness’ signature on the form will attest that the information in 
the consent form was accurately explained and understood. The study site must retain the 
original ICF and a copy must be provided to the subject or to the subject’s legally authorized 
representative. If applicable, it will be provided in a certified translation of the local language. 
The Sponsor, or designee, must review the signed ICF against any proposed deviations from a 
sample ICF the Sponsor has supplied to each site. The final IRB-approved document must be 
provided to the Sponsor for regulatory purposes. 
The eCRF for this study contains a section for documenting informed subject consent, and this 
must be completed appropriately. Signed ICFs must remain in each subject’s study file and must 
be available for verification by site monitors at any time. If new safety information results in 
significant changes in the risk/benefit assessment, the consent form should be reviewed and 
updated as necessary. All subjects (including those already being treated) should be informed of 
the new information, should be given a copy of the revised form, and should give their consent to 
continue in the study. 
12.1.3 
Subject Confidentiality and Privacy 
As applicable, in accordance with the Health Insurance Portability and Accountability Act 
(HIPAA), and associated privacy regulations, a patient authorization to use personally 
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identifiable health information may be required from each patient before research activities 
begin.  
The Investigator must ensure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On eCRFs or other documents submitted to the Sponsor, 
subjects should be identified by an identification code and not by their names. The Investigator 
should keep a subject enrollment log showing codes, names, and addresses. The Investigator 
should maintain documents intended for storing onsite (eg, subjects’ written consent forms) in 
strict confidence. 
All study drugs, subject bodily fluids and tissue, and/or other materials collected shall be used 
solely in accordance with this protocol, unless otherwise agreed to in writing by the Sponsor. 
12.1.4 
Future Use of Stored Specimens 
Not all the tissue and blood components obtained during this study may be required for the tests 
that are part of the clinical trial. Available samples may be used for additional research. This 
research will help to understand disease subtypes, drug response, and AEs, and possibly identify 
new drug targets or biomarkers that predict subject response to treatment. The use of the samples 
for internal research will adhere to the guidelines defined by the FDA in “Guidance on Informed 
Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not 
Individual Identifiable” (issued 25 April 2006) and the European Medicines Agency (EMA) 
“Reflection Paper on Pharmacogenetic Samples, Testing and Data Handling” (Doc. Ref. 
EMEA/CHMP/PGxWP/201914/2006; 15 November 2007). If a subject requests destruction of 
their tissue and blood samples and the samples have not yet been de-identified, the Sponsor will 
destroy the samples as described in the FDA guidance. The Sponsor will notify the Investigator 
in writing that the samples have been destroyed. 
12.2 
Study Administration 
The study administration structure is provided in Table 10. 
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Table 10. 
Study Administrative Structure 
Sponsor Contact and Medical Director: 
 
 
Phone: 
 
Email: 
 
Medical Monitor: 
 
Medpace 
Wallace House 
Stirling, Scotland FK81JU 
Phone: 
 extension 
 
Email: 
 
Study Monitoring: 
Medpace 
5375 Medpace Way 
Cincinnati, OH 45227 USA 
Phone (Main): 
 
Email: 
 
 
12.2.1 
Institutional Review Board Approval 
This study is being conducted under US IND 132727. This protocol (and any modifications) and 
appropriate consent procedures must be reviewed and approved by the site-specific IRB before 
the study is initiated. The IRB must operate in accordance with the current federal or local 
regulations. The Investigator will send a letter or certificate of IRB approval to the Sponsor (or 
designee) before subject enrollment and whenever subsequent modifications to the protocol are 
made. 
12.2.2 
Data Handling and Record Keeping 
All data will be entered in a validated electronic data capture system using single data entry. 
Standard procedures (including following data review guidelines, manual clinical review based 
on subject profiles, computerized validation to produce queries, and maintenance of an audit file, 
which includes all database modifications) will be followed to ensure accurate data. Clinical 
personnel will review all data listings for outliers, data inconsistencies, and spelling errors. 
12.2.3 
Data Protection 
The Investigator agrees that all information received from the Sponsor, including but not limited 
to the IB, this protocol, eCRFs, the INDs, and any other study information remain the sole and 
exclusive property of the Sponsor during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) or otherwise into the public domain 
without prior written consent from the Sponsor. 
12.2.4 
Study Site Regulatory Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
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be classified into 2 separate categories as follows: (1) Investigator’s study file and (2) subject 
clinical source documents (see Section 12.2.5). 
The Investigator’s study file will contain the protocol and protocol amendments, eCRFs, query 
forms, IRB and governmental approval with correspondence, sample informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
Subject clinical source documents (usually predefined by the project to record key efficacy and 
safety parameters independent of the eCRFs) may include subject hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, 
electroencephalogram, X-ray, pathology and special assessment reports, signed ICFs, consultant 
letters, and subject screening and enrollment logs. The Investigator must keep these two 
categories of documents on file for at least 2 years following the marketing application approval 
date for the study treatment and for the indication being investigated or for 2 years after the 
development program is discontinued and the FDA notified. After that period, the documents 
may be destroyed subject to local regulations with prior written permission from the Sponsor. If 
the Investigator wants to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee the archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and the Sponsor to 
store these in a sealed container outside of the study site so that they can be returned sealed to the 
Investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside of the study site. 
12.2.5 
Subject Clinical Source Documents and Background Data 
Investigators must maintain adequate and accurate source documents on which the eCRFs for 
each subject are based. They are separate and distinct from the eCRFs. 
These records include detailed notes on the following: 
 Medical history 
 Informed consent 
 HIPAA authorization, if applicable (either contained in the ICF or presented to the subject 
candidate as a standalone document) 
 Description of the complete consenting process 
 The basic identifying information that linked the subject’s medical record with the eCRFs 
 The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject 
 The medical condition of the subject during their involvement in the study 
 All AEs 
 The subject’s exposure to the study medication 
 The subject’s exposure to any concomitant therapy 
 All relevant observations and data on the condition of the subject throughout the trial 
 Justification for all entries in the subject’s eCRF 
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A subject log of all potentially eligible subjects considered, but not consented, for obvious 
deviations from the entry criteria, will be kept at each site. The log will contain subjects’ initials, 
diagnosis, eligibility, or, if not eligible, reason for not consenting. All consented subjects will be 
logged, regardless of whether they ultimately enroll.  
Upon request, the Investigator will supply the Sponsor with any required background data from 
the study documentation or clinic records. This is particularly important when eCRFs are 
illegible or when errors in data transcription are suspected. In case of special problems or 
governmental queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected. 
12.2.6 
Electronic Case Report Forms 
Clinical trial data for this study will be captured on eCRF designed for computer processing and 
analysis. This computerized system will be validated and compliant with 21 CFR Part 11, as 
described in the FDA guidance “Use of Electronic Records and Electronic Signatures in Clinical 
Investigations Under 21 CFR Part 11 – Questions and Answers.” If corrections are made after 
review and sign-off by the Investigator, he/she must be aware of the changes and provide written 
acknowledgement. There will also be an electronic audit trail. Corrections on paper CRFs must 
be initialed and dated by the person making the change. The Investigator agrees to provide all 
information requested on the eCRF in an accurate manner using instructions provided. The 
Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to Syntimmune in the eCRF and in all required reports. 
An eCRF is required to be submitted for every subject who receives any amount of study drug. 
This includes submission of retrievable data on subjects who withdraw before completion of the 
study. Prior to submission, eCRFs must be reviewed for completeness and accuracy, and signed 
and dated where indicated, by the Investigator or designee. If a subject stops treatment or 
terminates from the study, the dates and reasons must be noted on the eCRF. 
12.3 
Clinical Monitoring, Audits, and Inspections 
The Investigator and study staff are responsible for maintaining a comprehensive and accurate 
filing system of all study-related documentation that will be suitable for inspection for routine 
monitoring, audit, or inspection at any time by the Sponsor (or designee) and/or a regulatory 
authority. 
12.3.1 
Clinical Monitoring 
During the clinical study, it is understood that the responsible Sponsor site monitor or designee 
(eg, contract research organization [CRO]) will contact and visit the study site at regular 
intervals for routine monitoring of various records. Routine monitoring activities will be 
conducted to verify adherence to the protocol, completeness, consistency and accuracy of the 
data, and to review study source documents and drug accountability records. Regular review of 
the eCRFs for completeness, clarity, and to cross-check against source documents is required to 
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monitor the progress of the study. Data will be reviewed and verified against the source 
documents (eg, original medical records and laboratory results) to ensure validity. 
The Investigator will provide the Sponsor or designee with full access to all source data 
(including laboratory tests) and provide administrative support if requested. The Investigator (or 
designee) must agree to cooperate with the site monitor to ensure that any problems detected 
during these monitoring visits are resolved. 
Site-specific study procedures, such data-recording and handling of the data, may be assessed 
during the study by a Clinical Quality Assurance representative(s) authorized by the Sponsor. 
Further, this designee, as well as the site monitor, will be permitted to inspect the study 
documents (study protocol, eCRFs, study drug accountability, original study-relevant medical 
records) to ensure that the study is conducted in compliance with the protocol.  
During these visits, all representatives of the Sponsor will be responsible for ensuring data 
integrity and subject confidentiality is protected. 
12.3.2 
Audits and Inspections 
Clinical site and study audits will be conducted as necessary to assure the validity of the study 
data. The Sponsor (or designee) may perform a quality assurance audit to ensure compliance 
with GCP, this protocol, and all applicable regulatory requirements. The Investigator should 
ensure that study documents (protocol, eCRFs, study drug record-keeping, original study-
relevant medical records) are made available to the Sponsor (or designee) for examination. All 
subject data will be treated as confidential. 
A regulatory authority, after appropriate notification, may also wish to conduct an inspection 
during the study or even after its completion. If a regulatory authority requests an inspection, the 
Investigator must immediately inform the Sponsor. 
12.4 
Changes to the Protocol 
Protocol modifications to ongoing studies must be made only after consultation between a 
Sponsor representative and the Investigator. Protocol modifications will be prepared, reviewed, 
and approved by Sponsor representatives. 
All protocol modifications must be submitted to the IRB for information and approval in 
accordance with local requirements, and to regulatory agencies, if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects, or when the change involves only logistical or administrative 
aspects of the trial (eg, change in site monitor, change of telephone number). 
12.5 
Study Discontinuation and Closure 
The Sponsor has the right to terminate the study at any time. In terminating the study, the 
Sponsor and the Investigator will ensure that adequate consideration is given to the protection of 
the subjects’ interests. 
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13. 
PUBLICATION AND DATA SHARING POLICY 
The results of this study may be published or presented at scientific meetings. The Investigator 
agrees that any manuscript or abstract they author may be published only after receiving written 
permission from the Sponsor. 
If the Sponsor coordinates a publication or presentation of study results from all study sites, the 
participation of Investigator or other representatives of study site as a named author shall be 
determined in accordance with the Sponsor’s policy and generally accepted standards for 
authorship as developed by the International Committee of Medical Journal Editors (ICMJE) and 
in accordance with Good Publication Practices. 
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14. 
REFERENCES 
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Eming R, Hertl M. Immunoadsorption in pemphigus. Autoimmunity. 2006;39(7):609-16. 
Furst DE. Serum immunoglobulins and risk of infection: how low can you go?  Semin Arthritis 
Rheum. 2009;39(1):18-29. 
Gonzalez-Quintela A, Alende R, Gude F, Campos J, Rey J, Meijide LM, et al. Serum levels of 
immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with 
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Hsu DY, Brieva J, Sinha AA, Langan SM, Silverberg JI. Comorbidities and inpatient mortality 
for pemphigus in the U.S.A. Br J Dermatol. 2016;174(6):1290-8. 
Jolliff CR, Cost KM, Stivrins PC, Grossman PP, Nolte CR, Franco SM, et al. Reference intervals 
for serum IgG, IgA, IgM, C3, and C4 as determined by rate nephelometry. Clin Chem. 
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Kasperkiewicz M, Ellebrecht CT, Takahashi H, Yamagami J, Zillikens D, Payne AS, et al. 
Pemphigus. Nat Rev Dis Primers. 2017;3:17026. 
Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, et al. Safety and 
efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-
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Kohler W, Bucka C, Klingel R. A randomized and controlled study comparing 
immunoadsorption and plasma exchange in myasthenic crisis. J Clin Apher. 2011;26(6):347-55. 
Langan SM, Smeeth L, Hubbard R, Fleming KM, Smith CJ, West J. Bullous pemphigoid and 
pemphigus vulgaris--incidence and mortality in the UK: population based cohort study. BMJ. 
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McMillan SA, Douglas JP, Archbold GP, McCrum EE, Evans AE. Effect of low to moderate 
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monoclonal antibody inhibitors of the neonatal fc receptor reduce circulating IgG in non-human 
primates. Front Immunol. 2015;6:176. 
Roopenian DC, Christianson GJ, Sproule TJ, Brown AC, Akilesh S, Jung N, et al. The MHC 
class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-
coupled drugs. J Immunol. 2003;170(7):3528-33. 
Rosenbach M, Murrell DF, Bystryn JC, Dulay S, Dick S, Fakharzadeh S, et al. Reliability and 
convergent validity of two outcome instruments for pemphigus. J Invest Dermatol. 
2009;129(10):2404-10. 
Schmaldienst S, Mullner M, Goldammer A, Spitzauer S, Banyai S, Horl WH, et al. Intravenous 
immunoglobulin application following immunoadsorption: benefit or risk in patients with 
autoimmune diseases?  Rheumatology. 2001;40(5):513-21. 
Sebaratnam DF, Hanna AM, Chee SN, Frew JW, Venugopal SS, Daniel BS, et al. Development 
of a quality-of-life instrument for autoimmune bullous disease: the Autoimmune Bullous Disease 
Quality of Life questionnaire. JAMA Dermatol. 2013;149(10):1186-91. 
Sebaratnam DF, Okawa J, Payne A, Murrell DF, Werth VP. Reliability of the autoimmune 
bullous disease quality of life (ABQOL) questionnaire in the USA. Qual Life Res. 
2015;24(9):2257-60. 
Shimizu T, Takebayashi T, Sato Y, Niizeki H, Aoyama Y, Kitajima Y, et al. Grading criteria for 
disease severity by pemphigus disease area index. J Dermatol. 2014;41(11):969-73. 
van Vollenhoven RF, Emery P, Bingham CO, 3rd, Keystone EC, Fleischmann RM, Furst DE, et 
al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global 
clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum 
Dis. 2013;72(9):1496-502. 
 
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APPENDIX 1. NCI CTCAE, VERSION 4.03 
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1. CTCAE 4.03
 
 
Common Terminology Criteria for
Adverse Events (CTCAE)
Version 4.0
Published: May 28, 2009 (v4.03: June 14, 2010)
U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Cancer Institute
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C o m m o n  T er mi n ol o g y  Crit eri a  f or A d v ers e  E v e nts  v 4. 0  ( C T C A E) 
P u blis h D at e: M a y 2 8, 2 0 0 9  
Q uic k R ef er e nc e  
T h e  N CI  C o m m o n  T er mi n ol o g y  Crit eri a f or 
A d v ers e  E v e nts  is a  d escri pti v e  t er mi n ol o g y w hic h 
c a n b e utiliz e d f or A d v ers e E v e nt ( A E) r e p orti n g. 
A gr a di n g (s e v erit y) sc al e is pr o vi d e d f or e ac h A E 
t er m. 
C o m p o n e nts a n d Or g a niz ati o n 
S O C  
S yst e m  Or g a n Cl ass, t h e hi g h est l e v el of t h e 
M e d D R A hi er arc h y, is i d e ntifi e d b y a n at o mic al or 
p h ysi ol o gic al sys t e m, eti ol o g y, or p ur p os e ( e. g., 
S O C I n v esti g ati o ns f or l a b or at or y t est r es ults). 
C T C A E t er ms ar e gr o u p e d b y  M e d D R A Pri m ar y 
S O Cs.  Wit hi n e ac h S O C,  A Es ar e list e d a n d 
acc o m p a ni e d by d escri pti o ns of s e v erit y ( Gr a d e).  
C T C A E T er ms  
A n A d v ers e E v e nt ( A E) is a n y u nf a v or a bl e a n d 
u ni nt e n d e d   si g n   (i ncl u di n g   a n   a b n or m al 
l a b or at or y  fi n di n g),  s y m pt o m,   or   dis e as e 
t e m p or all y ass oci at e d wit h t h e us e of a m e dic al 
tr e at m e nt or pr oc e d ur e t h at m a y or m a y n ot b e 
c o nsi d er e d r el at e d t o t h e m e dic al tr e at m e nt or 
pr oc e d ur e. A n A E is  a t er m t h at is a u ni q u e 
r e pr es e nt ati o n  of a s p ecific e v e nt  us e d f or 
m e dic al d oc u m e nt ati o n a n d sci e ntific a n al ys es. 
E ac h C T C A E v 4. 0 t er m is a M e d D R A LL T (L o w est 
L e v el T er m).  
D efi niti o ns  
A bri ef d efi niti o n is pr o vi d e d 
m e a ni n g of e ac h A E t er m.  
Gr a d es  
N ot all  Gr a d es ar e a p pr o pri at e f or all  A Es. 
T h er ef or e, s o m e A Es ar e list e d wit h f e w er t h a n 
fi v e o pti o ns f or Gr a d e s el ecti o n. 
Gr a d e 5  
Gr a d e 5 ( D e at h) is n ot a p pr o pri at e f or s o m e A Es 
a n d t h er ef or e is n ot a n  o pti o n.  
Acti viti es  of  D ail y  Li vi n g ( A DL) 
*I nstr u m e n t al  A DL r ef er t o pr e p ari n g  m e als, 
s h o p pi n g f or gr oc eri es or cl ot h es, usi n g t h e 
t el e p h o n e, m a n a gi n g m o n e y, etc. 
* * S elf c ar e A DL r ef er t o b at hi n g, dr essi n g a n d 
u n dr essi n g, f e e di n g s elf, usi n g t h e t oil et, t a ki n g 
m e dic ati o ns, a n d n ot b e dri d d e n.  
t o cl arify  t h e 
Gr a d e r ef ers t o t h e s e v erit y of t h e A E. T h e  C T C A E 
dis pl a ys Gr a d es 1 t hr o u g h 5 wit h u ni q u e cli nic al 
d escri pti o ns of s e v erit y f or e ac h A E b as e d o n t his 
g e n er al  g ui d eli n e:  
Gr a d e 1  
Mil d;   as y m pt o m atic   or   
mil d 
s y m pt o ms; cli nic al  or  di a g n ostic 
o bs er v ati o ns o nl y; i nt er v e nti o n  n ot 
i n dic at e d. 
M o d er at e;   mi ni m al,   l oc al   or 
n o ni nv asi v e i nt er v e nti o n  i n dic at e d; 
Gr a d e 2  
li miti n g 
i nstr u m e nt al A DL *.  
a g e -a p pr o pri at e  
Gr a d e 3  
S e v er e or m e dic all y si g nific a nt b ut  
n ot i m m e di at el y lif e -t hr e at e ni n g; 
h os pit aliz ati o n or pr ol o n g ati o n of 
h os pit aliz ati o n i n dic at e d;  dis a bli n g; 
li miti n g s elf c ar e A DL * *.  
Gr a d e 4   Lif e-t hr e at e ni n g  
c o ns e q u e nc es; 
ur g e nt  i nt er v e nti o n i n dic at e d. 
D e at h r el at e d t o A E.  
Gr a d e 5  
A S e mi -c ol o n i n dic at es ‘ or’ wit hi n t h e d escri pti o n 
of t h e gr a d e.  
A  si n gl e d as h  (-) i n dic at es a  gr a d e  is n ot  a v ail a bl e.  
†  C T C A E  v 4. 0 i nc or p or at es c ert ai n el e m e nts  of  t h e M e d D R A  t er mi n ol o g y. F or  f urt h er d et ails  o n  M e d D R A  r ef er t o t h e M e d D R A  M S S O  W e b  sit e (htt p:// w w w. m e d dr a mss o.c o m ).  
Pa ge 6 9 5 of 9 7 9  
Ale xi o n C o nfi de ntial  
 
 


C O N T E N T S
S O C
P a g e
Bl o o d  a n d l y m p h ati c s yst e m  dis or d ers
3
C ar di a c  dis or d ers
4
C o n g e nit al, f a mili al  a n d  g e n eti c  dis or d ers
7
E ar  a n d l a b yri nt h  dis or d ers
8
E n d o cri n e  dis or d ers
9
E y e  dis or d ers
1 0
G astr oi nt esti n al  dis or d ers
1 2
G e n er al  dis or d ers  a n d  a d mi nistr ati o n sit e  c o n diti o ns
2 2
H e p at o bili ar y  dis or d ers
2 4
I m m u n e s yst e m  dis or d ers
2 6
I nf e cti o ns  a n d i nf est ati o ns
2 7
I nj ur y,  p ois o ni n g  a n d  pr o c e d ur al  c o m pli c ati o ns
3 4
I n v esti g ati o ns
4 1
M et a b olis m  a n d  n utriti o n  dis or d ers
4 4
M us c ul os k el et al  a n d  c o n n e cti v e tiss u e  dis or d ers
4 6
N e o pl as ms  b e ni g n,  m ali g n a nt  a n d  u ns p e cifi e d (i n cl  c ysts  a n d  p ol y ps)
5 0
N er v o us s yst e m  dis or d ers
5 1
Pr e g n a n c y,  p u er p eri u m  a n d  p eri n at al  c o n diti o ns
5 6
Ps y c hi atri c  dis or d ers
5 7
R e n al  a n d  uri n ar y  dis or d ers
5 9
R e pr o d u cti v e s yst e m  a n d  br e ast  dis or d ers
6 1
R es pir at or y, t h or a ci c  a n d  m e di asti n al  dis or d ers
6 5
S ki n  a n d s u b c ut a n e o us tiss u e  dis or d ers
7 1
S o ci al  cir c u mst a n c es
7 5
S ur gi c al  a n d  m e di c al  pr o c e d ur es
7 6
V as c ul ar  dis or d ers
7 7
Al e xi o n  C o nfi d e nti al
P a g e  6 9 6  of  9 7 9


CTCAE 4.03 - June 14, 2010 : Blood and lymphatic system disorders 
3
2. Blood and lymphatic system disorders
Blood and lymphatic system disorders
Grade
Adverse Event
1
2
3
4
5
Anemia
Hemoglobin (Hgb) <LLN - 10.0
g/dL; <LLN - 6.2 mmol/L; <LLN -
100 g/L
Hgb <10.0 - 8.0 g/dL; <6.2 - 4.9
mmol/L;  <100 - 80g/L
Hgb <8.0 g/dL; <4.9 mmol/L;
<80 g/L; transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an reduction in the amount of hemoglobin in 100 ml of blood. Signs and symptoms of anemia may include pallor of the skin and mucous
membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.
Bone marrow hypocellular
Mildly hypocellular or <=25%
reduction from normal cellularity
for age
Moderately hypocellular or >25 -
<50% reduction from normal
cellularity for age
Severely hypocellular or >50 -
<=75% reduction cellularity from
normal for age
Aplastic persistent for longer
than 2 weeks
Death
Definition: A disorder characterized by the inability of the bone marrow to produce hematopoietic elements.
Disseminated intravascular
coagulation
 -
Laboratory findings with no
bleeding
Laboratory findings and
bleeding
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by systemic pathological activation of blood clotting mechanisms which results in clot formation throughout the body. There is an increase in the
risk of hemorrhage as the body is depleted of platelets and coagulation factors.
Febrile neutropenia
 -
 -
ANC <1000/mm3 with a single
temperature of >38.3 degrees C
(101 degrees F) or a sustained
temperature of >=38 degrees C
(100.4 degrees F) for more than
one hour.
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an ANC <1000/mm3 and a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >=38 degrees C (100.4
degrees F) for more than one hour.
Hemolysis
Laboratory evidence of
hemolysis only (e.g., direct
antiglobulin test; DAT; Coombs';
schistocytes; decreased
haptoglobin)
Evidence of hemolysis and >=2
gm decrease in hemoglobin.
Transfusion or medical
intervention indicated (e.g.,
steroids)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate widespread erythrocyte cell membrane destruction.
Hemolytic uremic syndrome
Evidence of RBC destruction
(schistocytosis) without clinical
consequences
 -
Laboratory findings with clinical
consequences (e.g., renal
insufficiency, petechiae)
Life-threatening consequences,
(e.g., CNS hemorrhage or
thrombosis/embolism or renal
failure)
Death
Definition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, hemolytic anemia, and severe thrombocytopenia.
Leukocytosis
 -
 -
>100,000/mm3
Clinical manifestations of
leucostasis; urgent intervention
indicated
Death
Definition: A disorder characterized by laboratory test results that indicate an increased number of white blood cells in the blood.
Lymph node pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in a lymph node.
Spleen disorder
Incidental findings (e.g., Howell-
Jolly bodies); mild degree of
thrombocytosis and
leukocytosis
Prophylactic antibiotics
indicated
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder of the spleen.
Thrombotic thrombocytopenic
purpura
Evidence of RBC destruction
(schistocytosis) without clinical
consequences
 -
Laboratory findings with clinical
consequences (e.g., renal
insufficiency, petechiae)
Life-threatening consequences,
(e.g., CNS hemorrhage or
thrombosis/embolism or renal
failure)
Death
Definition: A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic purpura, fever, renal abnormalities and neurological abnormalities such
as seizures, hemiplegia, and visual disturbances. It is an acute or subacute condition.
Blood and lymphatic system
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 697 of 979


CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
4
3. Cardiac disorders
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Acute coronary syndrome
 -
Symptomatic, progressive
angina; cardiac enzymes
normal; hemodynamically stable
Symptomatic, unstable angina
and/or acute myocardial
infarction, cardiac enzymes
abnormal, hemodynamically
stable
Symptomatic, unstable angina
and/or acute myocardial
infarction, cardiac enzymes
abnormal, hemodynamically
unstable
Death
Definition: A disorder characterized by signs and symptoms related to acute ischemia of the myocardium secondary to coronary artery disease. The clinical presentation covers a
spectrum of heart diseases from unstable angina to myocardial infarction.
Aortic valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in aortic valve function or structure.
Asystole
Periods of asystole; non-urgent
medical management indicated
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without cardiac electrical activity. Typically, this is accompanied by cessation of the pumping function of the heart.
Atrial fibrillation
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker), or ablation
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without discernible P waves and an irregular ventricular response due to multiple reentry circuits. The rhythm disturbance
originates above the ventricles.
Atrial flutter
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker), or ablation
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with organized rhythmic atrial contractions with a rate of 200-300 beats per minute. The rhythm disturbance originates in the
atria.
Atrioventricular block complete
 -
Non-urgent intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with complete failure of atrial electrical impulse conduction through the AV node to the ventricles.
Atrioventricular block first
degree
Asymptomatic, intervention not
indicated
Non-urgent intervention
indicated
 -
 -
 -
Definition: A disorder characterized by a dysrhythmia with a delay in the time required for the conduction of an electrical impulse through the atrioventricular (AV) node beyond 0.2
seconds; prolongation of the PR interval greater than 200 milliseconds.
Cardiac arrest
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by cessation of the pumping function of the heart.
Chest pain - cardiac
Mild pain
Moderate pain; limiting
instrumental ADL
Pain at rest; limiting self care
ADL
 -
 -
Definition: A disorder characterized by substernal discomfort due to insufficient myocardial oxygenation.
Conduction disorder
Mild symptoms; intervention not
indicated
Moderate symptoms
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by pathological irregularities in the cardiac conduction system.
Constrictive pericarditis
 -
 -
Symptomatic heart failure or
other cardiac symptoms,
responsive to intervention
Refractory heart failure or other
poorly controlled cardiac
symptoms
Death
Definition: A disorder characterized by a thickened and fibrotic pericardial sac; these fibrotic changes impede normal myocardial function by restricting myocardial muscle action.
Heart failure
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe with symptoms at rest or
with minimal activity or exertion;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., continuous IV therapy or
mechanical hemodynamic
support)
Death
Definition: A disorder characterized by the inability of the heart to pump blood at an adequate volume to meet tissue metabolic requirements, or, the ability to do so only at an elevation
in the filling pressure.
Alexion Confidential
Page 698 of 979


CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
5
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Left ventricular systolic
dysfunction
 -
 -
Symptomatic due to drop in
ejection fraction responsive to
intervention
Refractory or poorly controlled
heart failure due to drop in
ejection fraction; intervention
such as ventricular assist
device, intravenous vasopressor
support, or heart transplant
indicated
Death
Definition: A disorder characterized by failure of the left ventricle to produce adequate output despite an increase in distending pressure and in end-diastolic volume. Clinical
manifestations mayinclude dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema.
Mitral valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in mitral valve function or structure.
Mobitz (type) II atrioventricular
block
Asymptomatic, intervention not
indicated
Symptomatic; medical
intervention indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with relatively constant PR interval prior to the block of an atrial impulse. This is the result of intermittent failure of atrial electrical
impulse conduction through the atrioventricular (AV) node to the ventricles.
Mobitz type I
Asymptomatic, intervention not
indicated
Symptomatic; medical
intervention indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a progressively lengthening PR interval prior to the blocking of an atrial impulse. This is the result of intermittent failure of
atrial electrical impulse conduction through the atrioventricular (AV) node to the ventricles.
Myocardial infarction
 -
Asymptomatic and cardiac
enzymes minimally abnormal
and no evidence of ischemic
ECG changes
Severe symptoms; cardiac
enzymes abnormal;
hemodynamically stable; ECG
changes consistent with
infarction
Life-threatening consequences;
hemodynamically unstable
Death
Definition: A disorder characterized by gross necrosis of the myocardium; this is due to an interruption of blood supply to the area.
Myocarditis
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe with symptoms at rest or
with minimal activity or exertion;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., continuous IV therapy or
mechanical hemodynamic
support)
Death
Definition: A disorder characterized by inflammation of the muscle tissue of the heart.
Palpitations
Mild symptoms; intervention not
indicated
Intervention indicated
 -
 -
 -
Definition: A disorder characterized by an unpleasant sensation of irregular and/or forceful beating of the heart.
Paroxysmal atrial tachycardia
Asymptomatic, intervention not
indicated
Symptomatic; medical
management indicated
IV medication indicated
Life-threatening consequences;
incompletely controlled
medically; cardioversion
indicated
Death
Definition: A disorder characterized by a dysrhythmia with abrupt onset and sudden termination of atrial contractions with a rate of 150-250 beats per minute. The rhythm disturbance
originates in the atria.
Pericardial effusion
 -
Asymptomatic effusion size
small to moderate
Effusion with physiologic
consequences
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by fluid collection within the pericardial sac, usually due to inflammation.
Pericardial tamponade
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in intrapericardial pressure due to the collection of blood or fluid in the pericardium.
Pericarditis
Asymptomatic, ECG or physical
findings (e.g., rub) consistent
with pericarditis
Symptomatic pericarditis (e.g.,
chest pain)
Pericarditis with physiologic
consequences (e.g., pericardial
constriction)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by irritation to the layers of the pericardium (the protective sac around the heart).
Alexion Confidential
Page 699 of 979


CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
6
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Pulmonary valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in pulmonary valve function or structure.
Restrictive cardiomyopathy
 -
 -
Symptomatic heart failure or
other cardiac symptoms,
responsive to intervention
Refractory heart failure or other
poorly controlled cardiac
symptoms
Death
Definition: A disorder characterized by an inability of the ventricles to fill with blood because the myocardium (heart muscle) stiffens and loses its flexibility.
Right ventricular dysfunction
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe symptoms, associated
with hypoxemia, right heart
failure; oxygen indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., ventricular assist device);
heart transplant indicated
Death
Definition: A disorder characterized by impairment of right ventricular function associated with low ejection fraction and a decrease in motility of the right ventricular wall.
Sick sinus syndrome
Asymptomatic, intervention not
indicated
Non-urgent intervention
indicated
Severe, medically significant;
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with alternating periods of bradycardia and atrial tachycardia accompanied by syncope, fatigue and dizziness.
Sinus bradycardia
Asymptomatic, intervention not
indicated
Symptomatic, medical
intervention indicated
Severe, medically significant,
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate less than 60 beats per minute that originates in the sinus node.
Sinus tachycardia
Asymptomatic, intervention not
indicated
Symptomatic; non-urgent
medical intervention indicated
Urgent medical intervention
indicated
 -
 -
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates in the sinus node.
Supraventricular tachycardia
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates above the ventricles.
Tricuspid valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis;
symptoms controlled with
medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in tricuspid valve function or structure.
Ventricular arrhythmia
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia that originates in the ventricles.
Ventricular fibrillation
 -
 -
 -
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without discernible QRS complexes due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the
ventricles.
Ventricular tachycardia
 -
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates distal to the bundle of His.
Wolff-Parkinson-White
syndrome
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically or
controlled with procedure
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the presence of an accessory conductive pathway between the atria and the ventricles that causes premature ventricular activation.
Cardiac disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 700 of 979


CTCAE 4.03 - June 14, 2010 : Congenital, familial and genetic disorders 
7
4. Congenital, familial and genetic disorders
Congenital, familial and genetic disorders
Grade
Adverse Event
1
2
3
4
5
Congenital, familial and genetic
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 701 of 979


CTCAE 4.03 - June 14, 2010 : Ear and labyrinth disorders 
8
5. Ear and labyrinth disorders
Ear and labyrinth disorders
Grade
Adverse Event
1
2
3
4
5
Ear pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the ear.
External ear inflammation
External otitis with erythema or
dry desquamation
External otitis with moist
desquamation, edema,
enhanced cerumen or
discharge; tympanic membrane
perforation; tympanostomy
External otitis with mastoiditis;
stenosis or osteomyelitis;
necrosis of soft tissue or bone
Urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation, swelling and redness to the outer ear and ear canal.
External ear pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the external ear region.
Hearing impaired
Adults enrolled on a Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift of 15 - 25 dB averaged at 2
contiguous test frequencies in at
least one ear.
Adults not enrolled in Monitoring
Program: subjective change in
hearing in the absence of
documented hearing loss.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift >20 dB at 8 kHz in at least
one ear.
Adults enrolled in Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz  audiogram):  Threshold
shift of >25 dB averaged at 2
contiguous test frequencies in at
least one ear.
Adults not enrolled in Monitoring
Program: hearing loss but
hearing aid or intervention not
indicated; limiting instrumental
ADL.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift >20 dB at 4 kHz and above
in at least one ear.
Adults enrolled in Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift of >25 dB averaged at 3
contiguous test frequencies in at
least one ear; therapeutic
intervention indicated.
Adults not enrolled in Monitoring
Program:  hearing loss with
hearing aid or intervention
indicated; limiting self care ADL.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): hearing loss
sufficient to indicate therapeutic
intervention, including hearing
aids; threshold shift >20 dB at 3
kHz and above in at least one
ear; additional speech-language
related services indicated.
Adults: Decrease in hearing to
profound bilateral loss (absolute
threshold >80 dB HL  at 2 kHz
and above); non-servicable
hearing.
Pediatric: Audiologic indication
for cochlear implant and
additional speech-language
related services indicated.
 -
Definition: A disorder characterized by partial or complete loss of the ability to detect or understand sounds resulting from damage to ear structures.
Middle ear inflammation
Serous otitis
Serous otitis, medical
intervention indicated
Mastoiditis; necrosis of canal
soft tissue or bone
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation (physiologic response to irritation), swelling and redness to the middle ear.
Tinnitus
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by noise in the ears, such as ringing, buzzing, roaring or clicking.
Vertigo
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective
vertigo).
Vestibular disorder
 -
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by dizziness, imbalance, nausea, and vision problems.
Ear and labyrinth disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
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CTCAE 4.03 - June 14, 2010 : Endocrine disorders 
9
6. Endocrine disorders
Endocrine disorders
Grade
Adverse Event
1
2
3
4
5
Adrenal insufficiency
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms;
hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder that occurs when the adrenal cortex does not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. It may be due to a disorder
of the adrenal cortex as in Addison's disease or primary adrenal insufficiency.
Cushingoid
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms, medical
intervention or hospitalization
indicated
 -
 -
Definition: A disorder characterized by signs and symptoms that resemble Cushing's disease or syndrome: buffalo hump obesity, striations, adiposity, hypertension, diabetes, and
osteoporosis, usually due to exogenous corticosteroids.
Delayed puberty
 -
No breast development by age
13 yrs for females; testes
volume of <3 cc or no Tanner
Stage 2 development by age
14.5 yrs for males
No breast development by age
14 yrs for females; no increase
in testes volume or no Tanner
Stage 2 by age 16 yrs for
males; hormone replacement
indicated
 -
 -
Definition: A disorder characterized by unusually late sexual maturity.
Growth accelerated
 -
>= +2 SD (standard deviation)
above mid parental height or
target height
 -
 -
 -
Definition: A disorder characterized by greater growth than expected for age.
Hyperparathyroidism
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by an increase in production of parathyroid hormone by the parathyroid glands. This results in hypercalcemia (abnormally high levels of calcium in
the blood).
Hyperthyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thyroid
suppression therapy indicated;
limiting instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by excessive levels of thyroid hormone in the body. Common causes include an overactive thyroid gland or thyroid hormone overdose.
Hypoparathyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; medical
intervention or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a decrease in production of parathyroid hormone by the parathyroid glands.
Hypothyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thyroid
replacement indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a decrease in production of thyroid hormone by the thyroid gland.
Precocious puberty
Physical signs of puberty with
no biochemical markers for
females <8 years and males <9
years
Physical signs and biochemical
markers of puberty for females
<8 years and males <9 years
 -
 -
 -
Definition: A disorder characterized by unusually early development of secondary sexual features; the onset of sexual maturation begins usually before age 8 for girls and before age
9 for boys.
Virilization
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by inappropriate masculinization occurring in a female or prepubertal male.
Endocrine disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Eye disorders 
10
7. Eye disorders
Eye disorders
Grade
Adverse Event
1
2
3
4
5
Blurred vision
Intervention not indicated
Symptomatic; limiting
instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by visual perception of unclear or fuzzy images.
Cataract
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; moderate
decrease in visual acuity
(20/40 or better)
Symptomatic with marked
decrease in visual acuity
(worse than 20/40 but better
than 20/200); operative
intervention indicated (e.g.,
cataract surgery)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by partial or complete opacity of the crystalline lens of one or both eyes. This results in a decrease in visual acuity and eventual blindness if
untreated.
Conjunctivitis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; topical
intervention indicated (e.g.,
antibiotics); limiting
instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by inflammation, swelling and redness to the conjunctiva of the eye.
Corneal ulcer
 -
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Limiting self care ADL;
declining vision (worse than
20/40 but better than 20/200)
Perforation or blindness
(20/200 or worse) in the
affected eye
 -
Definition: A disorder characterized by an area of epithelial tissue loss on the surface of the cornea. It is associated with inflammatory cells in the cornea and anterior chamber.
Dry eye
Asymptomatic; clinical or
diagnostic observations only;
mild symptoms relieved by
lubricants
Symptomatic; multiple
agents indicated; limiting
instrumental ADL
Decrease in visual acuity
(<20/40); limiting self care
ADL
 -
 -
Definition: A disorder characterized by dryness of the cornea and conjunctiva.
Extraocular muscle paresis
Asymptomatic; clinical or
diagnostic observations only
Symptomatic; limiting
instrumental ADL
Limiting self care ADL;
disabling
 -
 -
Definition: A disorder characterized by incomplete paralysis of an extraocular muscle.
Eye pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the eye.
Eyelid function disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; nonoperative
intervention indicated;
limiting instrumental ADL
Limiting self care ADL;
operative intervention
indicated
 -
 -
Definition: A disorder characterized by impaired eyelid function.
Flashing lights
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by a sudden or brief burst of light.
Floaters
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by an individual seeing spots before their eyes. The spots are shadows of opaque cell fragments in the vitreous humor or lens.
Glaucoma
Elevated intraocular
pressure (EIOP) with single
topical agent for intervention;
no visual field deficit
EIOP causing early visual
field deficits; multiple topical
or oral agents indicated;
limiting instrumental ADL
EIOP causing marked visual
field deficits (e.g., involving
both superior and inferior
visual fields); operative
intervention indicated;
limiting self care ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by an increase in pressure in the eyeball due to obstruction of the aqueous humor outflow.
Keratitis
 -
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Decline in vision (worse than
20/40 but better than
20/200); limiting self care
ADL
Perforation or blindness
(20/200 or worse) in the
affected eye
 -
Definition: A disorder characterized by inflammation to the cornea of the eye.
Night blindness
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by an inability to see clearly in dim light.
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CTCAE 4.03 - June 14, 2010 : Eye disorders 
11
Eye disorders
Grade
Adverse Event
1
2
3
4
5
Optic nerve disorder
Asymptomatic; clinical or
diagnostic observations only
Limiting vision of the affected
eye (20/40 or better)
Limiting vision in the affected
eye (worse than 20/40 but
better than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by involvement of the optic nerve (second cranial nerve).
Papilledema
Asymptomatic; no visual field
defects
Symptomatic decline in
vision; visual field defect
present sparing the central
20 degrees
Marked visual field defect
(worse than 20/40 but better
than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by swelling around the optic disc.
Photophobia
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by fear and avoidance of light.
Retinal detachment
Asymptomatic
Exudative and visual acuity
20/40 or better
Rhegmatogenous or
exudative detachment;
operative intervention
indicated; decline in vision
(worse than 20/40 but better
than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by the separation of the inner retina layers from the underlying pigment epithelium.
Retinal tear
 -
Laser therapy or
pneumopexy indicated
Vitroretinal surgical repair
indicated
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by a small laceration of the retina, this occurs when the vitreous separates from the retina. Symptoms include flashes and floaters.
Retinal vascular disorder
 -
Topical medication indicated
Intravitreal medication;
operative intervention
indicated
 -
 -
Definition: A disorder characterized by pathological retinal blood vessels that adversely affects vision.
Retinopathy
Asymptomatic; clinical or
diagnostic observations only
Symptomatic with moderate
decrease in visual acuity
(20/40 or better); limiting
instrumental ADL
Symptomatic with marked
decrease in visual acuity
(worse than 20/40);
disabling; limiting self care
ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder involving the retina.
Scleral disorder
Asymptomatic; clinical or
diagnostic observations only
Symptomatic, limiting
instrumental ADL; moderate
decrease in visual acuity
(20/40 or better)
Symptomatic, limiting self
care ADL; marked decrease
in visual acuity (worse than
20/40)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by involvement of the sclera of the eye.
Uveitis
Asymptomatic; clinical or
diagnostic observations only
Anterior uveitis; medical
intervention indicated
Posterior or pan-uveitis
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by inflammation to the uvea of the eye.
Vitreous hemorrhage
Asymptomatic or mild
symptoms; clinical or
diagnostic observations only
Symptomatic; limiting
instrumental ADL
Limiting self care ADL;
vitrectomy indicated
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by blood extravasation into the vitreous humor.
Watering eyes
Intervention not indicated
Intervention indicated
Operative intervention
indicated
 -
 -
Definition: A disorder of excessive tearing in the eyes; it can be caused by overproduction of tears or impaired drainage of the tear duct.
Eye disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or
diagnostic observations only;
intervention not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental
ADL
Severe or medically
significant but not
immediately sight-
threatening; hospitalization
or prolongation of existing
hospitalization indicated;
disabling;  limiting self care
ADL
Sight-threatening
consequences; urgent
intervention indicated;
blindness (20/200 or worse)
in the affected eye
 -
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
12
8. Gastrointestinal disorders
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Abdominal distension
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe discomfort; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling of the abdomen.
Abdominal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the abdominal region.
Anal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the opening in the anal canal to the perianal skin.
Anal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the anal region.
Anal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the anus.
Anal necrosis
 -
 -
TPN or hospitalization indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the anal region.
Anal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the anal region.
Anal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Symptomatic and severely
altered GI function; non-
emergent operative intervention
indicated; TPN or hospitalization
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the anal canal.
Anal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the anal canal.
Ascites
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; invasive
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by accumulation of serous or hemorrhagic fluid in the peritoneal cavity.
Bloating
No change in bowel function or
oral intake
Symptomatic, decreased oral
intake; change in bowel function
 -
 -
 -
Definition: A disorder characterized by subject-reported feeling of uncomfortable fullness of the abdomen.
Cecal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the cecum.
Cheilitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; intervention indicated
 -
 -
Definition: A disorder characterized by inflammation of the lip.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
13
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Colitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Abdominal pain; mucus or blood
in stool
Severe abdominal pain; change
in bowel habits; medical
intervention indicated;
peritoneal signs
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the colon.
Colonic fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
bowel rest, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the large intestine and another organ or anatomic site.
Colonic hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the colon.
Colonic obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Hospitalization indicated;
elective operative intervention
indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the colon.
Colonic perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the colonic wall.
Colonic stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the colon.
Colonic ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the colon.
Constipation
Occasional or intermittent
symptoms; occasional use of
stool softeners, laxatives,
dietary modification, or enema
Persistent symptoms with
regular use of laxatives or
enemas; limiting instrumental
ADL
Obstipation with manual
evacuation indicated; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by irregular and infrequent or difficult evacuation of the bowels.
Dental caries
One or more dental caries, not
involving the root
Dental caries involving the root
Dental caries resulting in pulpitis
or periapical abscess or
resulting in tooth loss
 -
 -
Definition: A disorder characterized by the decay of a tooth, in which it becomes softened, discolored and/or porous.
Diarrhea
Increase of <4 stools per day
over baseline; mild increase in
ostomy output compared to
baseline
Increase of 4 - 6 stools per day
over baseline; moderate
increase in ostomy output
compared to baseline
Increase of >=7 stools per day
over baseline; incontinence;
hospitalization indicated; severe
increase in ostomy output
compared to baseline; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by frequent and watery bowel movements.
Dry mouth
Symptomatic (e.g., dry or thick
saliva) without significant dietary
alteration; unstimulated saliva
flow >0.2 ml/min
Moderate symptoms; oral intake
alterations (e.g., copious water,
other lubricants, diet limited to
purees and/or soft, moist foods);
unstimulated saliva 0.1 to 0.2
ml/min
Inability to adequately aliment
orally; tube feeding or TPN
indicated; unstimulated saliva
<0.1 ml/min
 -
 -
Definition: A disorder characterized by reduced salivary flow in the oral cavity.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
14
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Duodenal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the duodenum and another organ or anatomic site.
Duodenal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the duodenum.
Duodenal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Hospitalization or elective
operative intervention indicated;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of stomach contents through the duodenum.
Duodenal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the duodenal wall.
Duodenal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the duodenum.
Duodenal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the duodenal wall.
Dyspepsia
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; surgical
intervention indicated
 -
 -
Definition: A disorder characterized by an uncomfortable, often painful feeling in the stomach, resulting from impaired digestion. Symptoms include burning stomach, bloating,
heartburn, nausea and vomiting.
Dysphagia
Symptomatic, able to eat
regular diet
Symptomatic and altered
eating/swallowing
Severely altered
eating/swallowing; tube feeding
or TPN or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by difficulty in swallowing.
Enterocolitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Abdominal pain; mucus or blood
in stool
Severe or persistent abdominal
pain; fever; ileus; peritoneal
signs
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the small and large intestines.
Enterovesical fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; noninvasive
intervention indicated
Severe, medically significant;
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the urinary bladder and the intestine.
Esophageal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the esophagus and another organ or anatomic site.
Esophageal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the esophagus.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
15
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Esophageal necrosis
 -
 -
Inability to aliment adequately
by GI tract; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the esophageal wall.
Esophageal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents in the esophagus.
Esophageal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the esophageal region.
Esophageal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the wall of the esophagus.
Esophageal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the esophagus.
Esophageal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the esophageal wall.
Esophageal varices
hemorrhage
 -
Self-limited; intervention not
indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from esophageal varices.
Esophagitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered
eating/swallowing;  oral
supplements indicated
Severely altered
eating/swallowing; tube feeding,
TPN or hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the esophageal wall.
Fecal incontinence
Occasional use of pads required Daily use of pads required
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by inability to control the escape of stool from the rectum.
Flatulence
Mild symptoms; intervention not
indicated
Moderate; persistent;
psychosocial sequelae
 -
 -
 -
Definition: A disorder characterized by a state of excessive gas in the alimentary canal.
Gastric fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
bowel rest; tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the stomach and another organ or anatomic site.
Gastric hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the gastric wall.
Gastric necrosis
 -
 -
Inability to aliment adequately
by GI tract; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the gastric wall.
Alexion Confidential
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
16
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Gastric perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the stomach wall.
Gastric stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the stomach.
Gastric ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; medical intervention
indicated; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the stomach.
Gastritis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; medical intervention
indicated
Severely altered eating or
gastric function; TPN or
hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the stomach.
Gastroesophageal reflux
disease
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; surgical
intervention indicated
 -
 -
Definition: A disorder characterized by reflux of the gastric and/or duodenal contents into the distal esophagus. It is chronic in nature and usually caused by incompetence of the lower
esophageal sphincter, and may result in injury to the esophageal mucosal. Symptoms include heartburn and acid indigestion.
Gastrointestinal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between any part of the gastrointestinal system and another organ or anatomic site.
Gastrointestinal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gastrointestinal region.
Gastroparesis
Mild nausea, early satiety and
bloating, able to maintain caloric
intake on regular diet
Moderate symptoms; able to
maintain nutrition with dietary
and lifestyle modifications; may
need pharmacologic
intervention
Weight loss; refractory to
medical intervention; unable to
maintain nutrition orally
 -
 -
Definition: A disorder characterized by an incomplete paralysis of the muscles of the stomach wall resulting in delayed emptying of the gastric contents into the small intestine.
Gingival pain
Mild pain
Moderate pain interfering with
oral intake
Severe pain; inability to aliment
orally
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gingival region.
Hemorrhoidal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the hemorrhoids.
Hemorrhoids
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; banding or
medical intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by the presence of dilated veins in the rectum and surrounding area.
Ileal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the ileum and another organ or anatomic site.
Ileal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the ileal wall.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
17
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Ileal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the ileum.
Ileal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the ileal wall.
Ileal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the ileum.
Ileal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the ileum.
Ileus
 -
Symptomatic; altered GI
function; bowel rest indicated
Severely altered GI function;
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by failure of the ileum to transport intestinal contents.
Intra-abdominal hemorrhage
 -
Medical intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding in the abdominal cavity.
Jejunal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the jejunum and another organ or anatomic site.
Jejunal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the jejunal wall.
Jejunal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the jejunum.
Jejunal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the jejunal wall.
Jejunal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the jejunum.
Jejunal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the jejunum.
Lip pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort of the lip.
Alexion Confidential
Page 711 of 979


CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
18
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Lower gastrointestinal
hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the lower gastrointestinal tract (small intestine, large intestine, and anus).
Malabsorption
 -
Altered diet; oral intervention
indicated
Inability to aliment adequately;
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inadequate absorption of nutrients in the small intestine. Symptoms include abdominal marked discomfort, bloating and diarrhea.
Mucositis oral
Asymptomatic or mild
symptoms; intervention not
indicated
Moderate pain; not interfering
with oral intake; modified diet
indicated
Severe pain; interfering with oral
intake
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the oral mucosal.
Nausea
Loss of appetite without
alteration in eating habits
Oral intake decreased without
significant weight loss,
dehydration or malnutrition
Inadequate oral caloric or fluid
intake; tube feeding, TPN, or
hospitalization indicated
 -
 -
Definition: A disorder characterized by a queasy sensation and/or the urge to vomit.
Obstruction gastric
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents in the stomach.
Oral cavity fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the oral cavity and another organ or anatomic site.
Oral dysesthesia
Mild discomfort; not interfering
with oral intake
Moderate pain; interfering with
oral intake
Disabling pain; tube feeding or
TPN indicated
 -
 -
Definition: A disorder characterized by a burning or tingling sensation on the lips, tongue or entire mouth.
Oral hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the mouth.
Oral pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the mouth, tongue or lips.
Pancreatic duct stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the pancreatic duct.
Pancreatic fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the pancreas and another organ or anatomic site.
Pancreatic hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the pancreas.
Pancreatic necrosis
 -
 -
Tube feeding or TPN indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the pancreas.
Pancreatitis
 -
Enzyme elevation or radiologic
findings only
Severe pain; vomiting; medical
intervention indicated (e.g.,
analgesia, nutritional support)
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
19
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by inflammation of the pancreas.
Periodontal disease
Gingival recession or gingivitis;
limited bleeding on probing; mild
local bone loss
Moderate gingival recession or
gingivitis; multiple sites of
bleeding on probing; moderate
bone loss
Spontaneous bleeding; severe
bone loss with or without tooth
loss; osteonecrosis of maxilla or
mandible
 -
 -
Definition: A disorder in the gingival tissue around the teeth.
Peritoneal necrosis
 -
 -
Tube feeding or TPN  indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the peritoneum.
Proctitis
Rectal discomfort, intervention
not indicated
Symptoms (e.g., rectal
discomfort, passing blood or
mucus); medical intervention
indicated; limiting instrumental
ADL
Severe symptoms; fecal
urgency or stool incontinence;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the rectum.
Rectal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the rectum and another organ or anatomic site.
Rectal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the rectal wall and discharged from the anus.
Rectal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the rectum.
Rectal necrosis
 -
 -
Tube feeding or TPN indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the rectal wall.
Rectal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the rectum.
Rectal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the rectal region.
Rectal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the rectal wall.
Rectal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the rectum.
Rectal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function (e.g. altered dietary
habits, vomiting, diarrhea)
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the rectum.
Alexion Confidential
Page 713 of 979


CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
20
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Retroperitoneal hemorrhage
 -
Self-limited; intervention
indicated
Transfusion, medical, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the retroperitoneal area.
Salivary duct inflammation
Slightly thickened saliva; slightly
altered taste (e.g., metallic)
Thick, ropy, sticky saliva;
markedly altered taste;
alteration in diet indicated;
secretion-induced symptoms;
limiting instrumental ADL
Acute salivary gland necrosis;
severe secretion-induced
symptoms (e.g., thick saliva/oral
secretions or gagging);  tube
feeding or TPN indicated;
limiting self care ADL; disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the salivary duct.
Salivary gland fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; tube feeding indicated
Severely altered GI function;
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between a salivary gland and another organ or anatomic site.
Small intestinal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe pain; interfering with oral
intake; tube feeding, TPN or
hospitalization indicated; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the small intestine.
Small intestinal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents.
Small intestinal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the small intestine wall.
Small intestinal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Symptomatic and severely
altered GI function; tube
feeding, TPN or hospitalization
indicated; non-emergent
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the small intestine.
Small intestine ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the small intestine.
Stomach pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the stomach.
Tooth development disorder
Asymptomatic; hypoplasia of
tooth or enamel
Impairment correctable with oral
surgery
Maldevelopment with
impairment not surgically
correctable; disabling
 -
 -
Definition: A disorder characterized by a pathological process of the teeth occurring during tooth development.
Tooth discoloration
Surface stains
 -
 -
 -
 -
Definition: A disorder characterized by a change in tooth hue or tint.
Toothache
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the tooth.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
21
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Typhlitis
 -
 -
Symptomatic (e.g., abdominal
pain, fever, change in bowel
habits with ileus); peritoneal
signs
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the cecum.
Upper gastrointestinal
hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the upper gastrointestinal tract (oral cavity, pharynx, esophagus, and stomach).
Vomiting
1 - 2 episodes (separated by 5
minutes) in 24 hrs
3 - 5 episodes (separated by 5
minutes) in 24 hrs
>=6 episodes (separated by 5
minutes) in 24 hrs; tube feeding,
TPN or hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
Gastrointestinal disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : General disorders and administration site conditions 
22
9. General disorders and administration site conditions
General disorders and administration site conditions
Grade
Adverse Event
1
2
3
4
5
Chills
Mild sensation of cold;
shivering; chattering of teeth
Moderate tremor of the entire
body; narcotics indicated
Severe or prolonged, not
responsive to narcotics
 -
 -
Definition: A disorder characterized by a sensation of cold that often marks a physiologic response to sweating after a fever.
Death neonatal
 -
 -
 -
 -
Death
Definition: A disorder characterized by cessation of life occurring during the first 28 days of life.
Death NOS
 -
 -
 -
 -
Death
Definition: A cessation of life that cannot be attributed to a CTCAE term associated with Grade 5.
Edema face
Localized facial edema
Moderate localized facial
edema; limiting instrumental
ADL
Severe swelling; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in facial tissues.
Edema limbs
5 - 10% inter-limb discrepancy
in volume or circumference at
point of greatest visible
difference; swelling or
obscuration of anatomic
architecture on close inspection
>10 - 30% inter-limb
discrepancy in volume or
circumference at point of
greatest visible difference;
readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour; limiting
instrumental ADL
>30% inter-limb discrepancy in
volume; gross deviation from
normal anatomic contour;
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the upper or lower extremities.
Edema trunk
Swelling or obscuration of
anatomic architecture on close
inspection
Readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour; limiting
instrumental ADL
Gross deviation from normal
anatomic contour; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the trunk area.
Facial pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the face.
Fatigue
Fatigue relieved by rest
Fatigue not relieved by rest;
limiting instrumental ADL
Fatigue not relieved by rest,
limiting self care ADL
 -
 -
Definition: A disorder characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities.
Fever
38.0 - 39.0 degrees C  (100.4 -
102.2 degrees F)
>39.0 - 40.0 degrees C (102.3 -
104.0 degrees F)
>40.0 degrees C (>104.0
degrees F) for <=24 hrs
>40.0 degrees C (>104.0
degrees F) for >24 hrs
Death
Definition: A disorder characterized by elevation of the body's temperature above the upper limit of normal.
Flu like symptoms
Mild flu-like symptoms present
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a group of symptoms similar to those observed in patients with the flu. It includes fever, chills, body aches, malaise, loss of appetite and dry
cough.
Gait disturbance
Mild change in gait (e.g., wide-
based, limping or hobbling)
Moderate change in gait (e.g.,
wide-based, limping or
hobbling); assistive device
indicated; limiting instrumental
ADL
Disabling; limiting self care ADL
 -
 -
Definition: A disorder characterized by walking difficulties.
Hypothermia
 -
35 - >32 degrees C;  95 - >89.6
degrees F
32 - >28 degrees C;  89.6 -
>82.4 degrees F
<=28 degrees C; 82.4 degrees
F; life-threatening
consequences (e.g., coma,
hypotension, pulmonary edema,
acidemia, ventricular fibrillation)
Death
Definition: A disorder characterized by an abnormally low body temperature. Treatment is required when the body temperature is 35C (95F) or below.
Alexion Confidential
Page 716 of 979


CTCAE 4.03 - June 14, 2010 : General disorders and administration site conditions 
23
General disorders and administration site conditions
Grade
Adverse Event
1
2
3
4
5
Infusion related reaction
Mild transient reaction; infusion
interruption not indicated;
intervention not indicated
Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.,
antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic
medications indicated for <=24
hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by adverse reaction to the infusion of pharmacological or biological substances.
Infusion site extravasation
 -
Erythema with associated
symptoms (e.g., edema, pain,
induration, phlebitis)
Ulceration or necrosis; severe
tissue damage; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by leakage of a pharmacologic or a biologic substance from the infusion site into the surrounding tissue. Signs and symptoms include induration,
erythema, swelling, burning sensation and marked discomfort at the infusion site.
Injection site reaction
Tenderness with or without
associated symptoms (e.g.,
warmth, erythema, itching)
Pain; lipodystrophy; edema;
phlebitis
Ulceration or necrosis; severe
tissue damage; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an intense adverse reaction (usually immunologic) developing at the site of an injection.
Irritability
Mild; easily consolable
Moderate; limiting instrumental
ADL; increased attention
indicated
Severe abnormal or excessive
response; limiting self care ADL;
inconsolable
 -
 -
Definition: A disorder characterized by an abnormal responsiveness to stimuli or physiological arousal; may be in response to pain, fright, a drug, an emotional situation or a medical
condition.
Localized edema
Localized to dependent areas,
no disability or functional
impairment
Moderate localized edema and
intervention indicated; limiting
instrumental ADL
Severe localized edema and
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation at a specific anatomic site.
Malaise
Uneasiness or lack of well being Uneasiness or lack of well
being; limiting instrumental ADL
 -
 -
 -
Definition: A disorder characterized by a feeling of general discomfort or uneasiness, an out-of-sorts feeling.
Multi-organ failure
 -
 -
Shock with azotemia and acid-
base disturbances; significant
coagulation abnormalities
Life-threatening consequences
(e.g., vasopressor dependent
and oliguric or anuric or
ischemic colitis or lactic
acidosis)
Death
Definition: A disorder characterized by progressive deterioration of the lungs, liver, kidney and clotting mechanisms.
Neck edema
Asymptomatic localized neck
edema
Moderate neck edema; slight
obliteration of anatomic
landmarks; limiting instrumental
ADL
Generalized neck edema (e.g.,
difficulty in turning neck);
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to an accumulation of excessive fluid in the neck.
Non-cardiac chest pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by discomfort in the chest unrelated to a heart disorder.
Pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by the sensation of marked discomfort, distress or agony.
Sudden death NOS
 -
 -
 -
 -
Death
Definition: An unexpected cessation of life that cannot be attributed to a CTCAE term associated with Grade 5.
General disorders and
administration site conditions -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 717 of 979


CTCAE 4.03 - June 14, 2010 : Hepatobiliary disorders 
24
10. Hepatobiliary disorders
Hepatobiliary disorders
Grade
Adverse Event
1
2
3
4
5
Bile duct stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; IV fluids indicated <24
hrs
Severely altered GI function;
radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the bile duct.
Biliary fistula
 -
Symptomatic and intervention
not indicated
Severely altered GI function;
TPN indicated; endoscopic
intervention indicated; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the bile ducts and another organ or anatomic site.
Cholecystitis
 -
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation involving the gallbladder. It may be associated with the presence of gallstones.
Gallbladder fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Symptomatic or severely altered
GI function; TPN indicated;
radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the gallbladder and another organ or anatomic site.
Gallbladder necrosis
 -
 -
 -
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the gallbladder.
Gallbladder obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; IV fluids indicated  <24
hrs
Symptomatic and severely
altered GI function; tube
feeding, TPN or hospitalization
indicated; non-emergent
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents of the gallbladder.
Gallbladder pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gallbladder region.
Gallbladder perforation
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the gallbladder wall.
Hepatic failure
 -
 -
Asterixis; mild encephalopathy;
limiting self care ADL
Moderate to severe
encephalopathy; coma; life-
threatening consequences
Death
Definition: A disorder characterized by the inability of the liver to metabolize chemicals in the body. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic
dehydrogenase, and alkaline phosphatase.
Hepatic hemorrhage
Mild; intervention not indicated
Symptomatic; medical
intervention indicated
Transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the liver.
Hepatic necrosis
 -
 -
 -
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the hepatic parenchyma.
Hepatic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the liver region.
Perforation bile duct
 -
 -
Radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the wall of the extrahepatic or intrahepatic bile duct.
Alexion Confidential
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CTCAE 4.03 - June 14, 2010 : Hepatobiliary disorders 
25
Hepatobiliary disorders
Grade
Adverse Event
1
2
3
4
5
Portal hypertension
 -
Decreased portal vein flow
Reversal/retrograde portal vein
flow; associated with varices
and/or ascites
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in blood pressure in the portal venous system.
Portal vein thrombosis
 -
Intervention not indicated
Medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the formation of a thrombus (blood clot) in the portal vein.
Hepatobiliary disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 719 of 979


CTCAE 4.03 - June 14, 2010 : Immune system disorders 
26
11. Immune system disorders
Immune system disorders
Grade
Adverse Event
1
2
3
4
5
Allergic reaction
Transient flushing or rash, drug
fever <38 degrees C (<100.4
degrees F); intervention not
indicated
Intervention or infusion
interruption indicated; responds
promptly to symptomatic
treatment (e.g., antihistamines,
NSAIDS, narcotics);
prophylactic medications
indicated for <=24 hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae (e.g., renal
impairment, pulmonary
infiltrates)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
 -
 -
Symptomatic bronchospasm,
with or without urticaria;
parenteral intervention
indicated; allergy-related
edema/angioedema;
hypotension
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivity
immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death.
Autoimmune disorder
Asymptomatic; serologic or
other evidence of autoimmune
reaction, with normal organ
function;  intervention not
indicated
Evidence of autoimmune
reaction involving a non-
essential organ or function (e.g.,
hypothyroidism)
Autoimmune reactions involving
major organ (e.g., colitis,
anemia, myocarditis, kidney)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder resulting from loss of function or tissue destruction of an organ or multiple organs, arising from humoral or cellular immune responses of the individual to his own
tissue constituents.
Cytokine release syndrome
Mild reaction; infusion
interruption not indicated;
intervention not indicated
Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.,
antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic
medications indicated for <=24
hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae (e.g., renal
impairment, pulmonary
infiltrates)
Life-threatening consequences;
pressor or ventilatory support
indicated
Death
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused by the release of cytokines from the cells.
Serum sickness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate arthralgia; fever, rash,
urticaria, antihistamines
indicated
Severe arthralgia or arthritis;
extensive rash; steroids or IV
fluids indicated
Life-threatening consequences;
pressor or ventilatory support
indicated
Death
Definition: A disorder characterized by a delayed-type hypersensitivity reaction to foreign proteins derived from an animal serum. It occurs approximately six to twenty-one days
following the administration of the foreign antigen. Symptoms include fever, arthralgias, myalgias, skin eruptions, lymphadenopathy, chest marked discomfort and dyspnea.
Immune system disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 720 of 979


CTCAE 4.03 - June 14, 2010 : Infections and infestations 
27
12. Infections and infestations
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Abdominal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the abdominal cavity.
Anorectal infection
Localized; local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the anal area and the rectum.
Appendicitis
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent.
Appendicitis perforated
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent with gangrenous changes resulting in the rupture of the
appendiceal wall. The appendiceal wall rupture causes the release of inflammatory and bacterial contents from the appendiceal lumen into the abdominal cavity.
Arteritis infective
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving an artery.
Biliary tract infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the biliary tract.
Bladder infection
 -
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bladder.
Bone infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bones.
Breast infection
 -
Local infection with moderate
symptoms; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral)
Severe infection; axillary
adenitis;  IV antibacterial,
antifungal, or antiviral
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the breast.
Bronchial infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bronchi.
Catheter related infection
 -
Localized; local intervention
indicated; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process that arises secondary to catheter use.
Cecal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
28
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the cecum.
Cervicitis infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the uterine cervix.
Conjunctivitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the conjunctiva. Clinical manifestations include pink or red color in the eyes.
Corneal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the cornea.
Cranial nerve infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a cranial nerve.
Device related infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the use of a medical device.
Duodenal infection
 -
Moderate symptoms; medical
intervention indicated (e.g., oral
antibiotics)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the duodenum.
Encephalitis infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
severe changes in mental
status; self-limited seizure
activity; focal neurologic
abnormalities
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the brain tissue.
Encephalomyelitis infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the brain and spinal cord tissues.
Endocarditis infective
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the endocardial layer of the heart.
Endophthalmitis
 -
Local intervention indicated
Systemic intervention or
hospitalization indicated
Blindness (20/200 or worse)
 -
Definition: A disorder characterized by an infectious process involving the internal structures of the eye.
Alexion Confidential
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
29
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Enterocolitis infectious
 -
Passage of >3 unformed stools
per 24 hrs or duration of illness
>48 hrs; moderate abdominal
pain
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated;
profuse watery diarrhea with
signs of hypovolemia;  bloody
diarrhea; fever; severe
abdominal pain; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the small and large intestines.
Esophageal infection
 -
Local intervention indicated
(e.g., oral antibiotic, antifungal,
antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the esophagus.
Eye infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated;
enucleation
Death
Definition: A disorder characterized by an infectious process involving the eye.
Gallbladder infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the gallbladder.
Gum infection
Local therapy indicated (swish
and swallow)
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the gums.
Hepatic infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the liver.
Hepatitis viral
Asymptomatic, treatment not
indicated
 -
Symptomatic liver dysfunction;
fibrosis by biopsy; compensated
cirrhosis; reactivation of chronic
hepatitis
Decompensated liver function
(e.g., ascites, coagulopathy,
encephalopathy, coma)
Death
Definition: A disorder characterized by a viral pathologic process involving the liver parenchyma.
Infective myositis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the skeletal muscles.
Joint infection
 -
Localized; local intervention
indicated; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral); needle
aspiration indicated (single or
multiple)
Arthroscopic intervention
indicated (e.g., drainage) or
arthrotomy (e.g., open surgical
drainage)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a joint.
Kidney infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the kidney.
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
30
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Laryngitis
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammatory process involving the larynx.
Lip infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by an infectious process involving the lips.
Lung infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the lungs.
Lymph gland infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the lymph nodes.
Mediastinal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the mediastinum.
Meningitis
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated; focal
neurologic deficit
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation of the meninges of the brain and/or spinal cord.
Mucosal infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a mucosal surface.
Nail infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by an infectious process involving the nail.
Otitis externa
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the outer ear and ear canal. Contributory factors include excessive water exposure (swimmer's ear infection)
and cuts in the ear canal. Symptoms include fullness, itching, swelling and marked discomfort in the ear and ear drainage.
Otitis media
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the middle ear.
Ovarian infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the ovary.
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
31
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Pancreas infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pancreas.
Papulopustular rash
Papules and/or pustules
covering <10% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness
Papules and/or pustules
covering 10-30% BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness; associated with
psychosocial impact; limiting
instrumental ADL
Papules and/or pustules
covering >30% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness; limiting self-care
ADL; associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering  any % BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness and are associated
with extensive superinfection
with IV antibiotics indicated; life-
threatening consequences
Death
Definition: A disorder characterized by an eruption consisting of papules (a small, raised pimple) and pustules (a small pus filled blister), typically appearing in face, scalp, and upper
chest and back Unlike acne, this rash does not present with whiteheads or blackheads, and can be symptomatic, with itchy or tender lesions.
Paronychia
Nail fold edema or erythema;
disruption of the cuticle
Localized intervention indicated;
oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral);
nail fold edema or erythema
with pain; associated with
discharge or nail plate
separation; limiting instrumental
ADL
Surgical intervention or IV
antibiotics indicated; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an infectious process involving the soft tissues around the nail.
Pelvic infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pelvic cavity.
Penile infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the penis.
Periorbital infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the orbit of the eye.
Peripheral nerve infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the peripheral nerves.
Peritoneal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the peritoneum.
Pharyngitis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the throat.
Phlebitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
32
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the vein. Clinical manifestations include erythema, marked discomfort, swelling, and induration along the course
of the infected vein.
Pleural infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pleura.
Prostate infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the prostate gland.
Rash pustular
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by a circumscribed and elevated skin lesion filled with pus.
Rhinitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
 -
 -
 -
Definition: A disorder characterized by an infectious process involving the nasal mucosal.
Salivary gland infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the salivary gland.
Scrotal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the scrotum.
Sepsis
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the presence of pathogenic microorganisms in the blood stream that cause a rapidly progressing systemic reaction that may lead to shock.
Sinusitis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the mucous membranes of the paranasal sinuses.
Skin infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the skin.
Small intestine infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the small intestine.
Soft tissue infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving soft tissues.
Splenic infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
33
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the spleen.
Stoma site infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a stoma (surgically created opening on the surface of the body).
Tooth infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a tooth.
Tracheitis
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the trachea.
Upper respiratory infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the upper respiratory tract (nose, paranasal sinuses, pharynx, larynx, or trachea).
Urethral infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the urethra.
Urinary tract infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the urinary tract, most commonly the bladder and the urethra.
Uterine infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the endometrium. It may extend to the myometrium and parametrial tissues.
Vaginal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the vagina.
Vulval infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the vulva.
Wound infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the wound.
Infections and infestations -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
34
13. Injury, poisoning and procedural complications
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Ankle fracture
Mild; non-surgical intervention
indicated
Limiting instrumental ADL;
operative intervention indicated
Limiting self care ADL; elective
surgery indicated
 -
 -
Definition: A finding of damage to the ankle joint characterized by a break in the continuity of the ankle bone. Symptoms include marked discomfort, swelling and difficulty moving the
affected leg and foot.
Aortic injury
 -
 -
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to the aorta.
Arterial injury
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic (e.g.,
claudication); repair or revision
not indicated
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to an artery.
Biliary anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of bile due to breakdown of a biliary anastomosis (surgical connection of two separate anatomic structures).
Bladder anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of urine due to breakdown of a bladder anastomosis (surgical connection of two separate anatomic structures).
Bruising
Localized or in a dependent
area
Generalized
 -
 -
 -
Definition: A finding of injury of the soft tissues or bone characterized by leakage of blood into surrounding tissues.
Burn
Minimal symptoms; intervention
not indicated
Medical intervention; minimal
debridement indicated
Moderate to major debridement
or reconstruction indicated
Life-threatening consequences
Death
Definition: A finding of impaired integrity to the anatomic site of an adverse thermal reaction. Burns can be caused by exposure to chemicals, direct heat, electricity, flames and
radiation. The extent of damage depends on the length and intensity of exposure and time until provision of treatment.
Dermatitis radiation
Faint erythema or dry
desquamation
Moderate to brisk erythema;
patchy moist desquamation,
mostly confined to skin folds
and creases; moderate edema
Moist desquamation in areas
other than skin folds and
creases; bleeding induced by
minor trauma or abrasion
Life-threatening consequences;
skin necrosis or ulceration of full
thickness dermis; spontaneous
bleeding from involved site; skin
graft indicated
Death
Definition: A finding of cutaneous inflammatory reaction occurring as a result of exposure to biologically effective levels of ionizing radiation.
Esophageal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an esophageal anastomosis (surgical connection of two separate anatomic structures).
Fall
Minor with no resultant injuries;
intervention not indicated
Symptomatic; noninvasive
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding of sudden movement downward, usually resulting in injury.
Fallopian tube anastomotic leak
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a fallopian tube anastomosis (surgical connection of two separate anatomic structures).
Fallopian tube perforation
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated (e.g., organ resection)
Death
Definition: A finding of rupture of the fallopian tube wall.
Fracture
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic but non-displaced;
immobilization indicated
Severe symptoms; displaced or
open wound with bone
exposure; disabling; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of traumatic injury to the bone in which the continuity of the bone is broken.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
35
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Gastric anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a gastric anastomosis (surgical connection of two separate anatomic structures).
Gastrointestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a gastrointestinal anastomosis (surgical connection of two separate anatomic structures).
Gastrointestinal stoma necrosis
 -
Superficial necrosis;
intervention not indicated
Severe symptoms;
hospitalization or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of a necrotic process occurring in the gastrointestinal tract stoma.
Hip fracture
 -
Hairline fracture; mild pain;
limiting instrumental ADL; non-
surgical intervention indicated
Severe pain; hospitalization or
intervention indicated for pain
control (e.g., traction); operative
intervention indicated
Life-threatening consequences;
symptoms associated with
neurovascular compromise
 -
Definition: A finding of traumatic injury to the hip in which the continuity of either the femoral head, femoral neck, intertrochanteric or subtrochanteric regions is broken.
Injury to carotid artery
 -
 -
Severe symptoms; limiting self
care ADL (e.g., transient
cerebral ischemia); repair or
revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the carotid artery.
Injury to inferior vena cava
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the inferior vena cava.
Injury to jugular vein
 -
 -
Symptomatic limiting self care
ADL; disabling; repair or
revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the jugular vein.
Injury to superior vena cava
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic; repair or revision
not indicated
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to the superior vena cava.
Intestinal stoma leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of contents from an intestinal stoma (surgically created opening on the surface of the body).
Intestinal stoma obstruction
 -
Self-limited; intervention not
indicated
Severe symptoms; IV fluids,
tube feeding, or TPN indicated
>=24 hrs; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of blockage of the normal flow of the contents of the intestinal stoma.
Intestinal stoma site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of blood leakage from the intestinal stoma.
Intraoperative arterial injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to an artery during a surgical procedure.
Intraoperative breast injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
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Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of damage to the breast parenchyma during a surgical procedure.
Intraoperative cardiac injury
 -
 -
Primary repair of injured
organ/structure indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the heart during a surgical procedure.
Intraoperative ear injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection of injured
organ/structure indicated;
disabling (e.g., impaired
hearing; impaired balance)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the ear during a surgical procedure.
Intraoperative endocrine injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the endocrine gland during a surgical procedure.
Intraoperative gastrointestinal
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the gastrointestinal system during a surgical procedure.
Intraoperative head and neck
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the head and neck during a surgical procedure.
Intraoperative hemorrhage
 -
 -
Postoperative radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of uncontrolled bleeding during a surgical procedure.
Intraoperative hepatobiliary
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the hepatic parenchyma and/or biliary tract during a surgical procedure.
Intraoperative musculoskeletal
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the musculoskeletal system during a surgical procedure.
Intraoperative neurological
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the nervous system during a surgical procedure.
Intraoperative ocular injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the eye during a surgical procedure.
Intraoperative renal injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the kidney during a surgical procedure.
Intraoperative reproductive tract
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
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Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of damage to the reproductive organs during a surgical procedure.
Intraoperative respiratory injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the respiratory system during a surgical procedure.
Intraoperative skin injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the skin during a surgical procedure.
Intraoperative splenic injury
 -
Primary repair of injured
organ/structure indicated
Resection or reconstruction of
injured organ/structure
indicated; disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the spleen during a surgical procedure.
Intraoperative urinary injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the urinary system during a surgical procedure.
Intraoperative venous injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to a vein during a surgical procedure.
Kidney anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of urine due to breakdown of a kidney anastomosis (surgical connection of two separate anatomic structures).
Large intestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the large intestine.
Pancreatic anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a pancreatic anastomosis (surgical connection of two separate anatomic structures).
Pharyngeal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a pharyngeal anastomosis (surgical connection of two separate anatomic structures).
Postoperative hemorrhage
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; radiologic,
endoscopic, or operative
intervention indicated
Transfusion indicated of >=2
units (10 cc/kg for pediatrics)
pRBCs beyond protocol
specification; urgent radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding occurring after a surgical procedure.
Postoperative thoracic
procedure complication
 -
Extubated within 24 - 72 hrs
postoperatively
Extubated >72 hrs
postoperatively, but before
tracheostomy indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A finding of a previously undocumented problem that occurs after a thoracic procedure.
Prolapse of intestinal stoma
Asymptomatic; reducible
Recurrent after manual
reduction; local irritation or stool
leakage; difficulty to fit
appliance; limiting instrumental
ADL
Severe symptoms; elective
operative intervention indicated;
limiting self care ADL
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
38
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of protrusion of the intestinal stoma (surgically created opening on the surface of the body) above the abdominal surface.
Prolapse of urostomy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Local care or maintenance;
minor revision indicated
Dysfunctional stoma; elective
operative intervention or major
stomal revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of displacement of the urostomy.
Radiation recall reaction
(dermatologic)
Faint erythema or dry
desquamation
Moderate to brisk erythema;
patchy moist desquamation,
mostly confined to skin folds
and creases; moderate edema
Moist desquamation in areas
other than skin folds and
creases; bleeding induced by
minor trauma or abrasion
Life-threatening consequences;
skin necrosis or ulceration of full
thickness dermis; spontaneous
bleeding from involved site; skin
graft indicated
Death
Definition: A finding of acute skin inflammatory reaction caused by drugs, especially chemotherapeutic agents, for weeks or months following radiotherapy. The inflammatory reaction
is confined to the previously irradiated skin and the symptoms disappear after the removal of the pharmaceutical agent.
Rectal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a rectal anastomosis (surgical connection of two separate anatomic structures).
Seroma
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; simple aspiration
indicated
Symptomatic, elective radiologic
or operative intervention
indicated
 -
 -
Definition: A finding of tumor-like collection of serum in the tissues.
Small intestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the small bowel.
Spermatic cord anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a spermatic cord anastomosis (surgical connection of two separate anatomic structures).
Spinal fracture
Mild back pain; nonprescription
analgesics indicated
Moderate back pain;
prescription analgesics
indicated; limiting instrumental
ADL
Severe back pain;
hospitalization or intervention
indicated for pain control (e.g.,
vertebroplasty); limiting self care
ADL; disability
Life-threatening consequences;
symptoms associated with
neurovascular compromise
Death
Definition: A finding of traumatic injury to the spine in which the continuity of a vertebral bone is broken.
Stenosis of gastrointestinal
stoma
 -
Symptomatic; IV fluids indicated
<24 hrs; manual dilation at
bedside
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of narrowing of the gastrointestinal stoma (surgically created opening on the surface of the body).
Stomal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the jejunal mucosal surface close to the anastomosis site following a
gastroenterostomy procedure.
Tracheal hemorrhage
Minimal bleeding identified on
clinical or diagnostic exam;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding from the trachea.
Tracheal obstruction
Partial asymptomatic
obstruction on examination
(e.g., visual, radiologic or
endoscopic)
Symptomatic (e.g., noisy airway
breathing), no respiratory
distress; medical intervention
indicated (e.g., steroids); limiting
instrumental ADL
Stridor; radiologic or endoscopic
intervention indicated (e.g.,
stent, laser); limiting self care
ADL
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A finding of blockage of the lumen of the trachea.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
39
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Tracheostomy site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of blood leakage from the tracheostomy site.
Ureteric anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a ureteral anastomosis (surgical connection of two separate anatomic structures).
Urethral anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a urethral anastomosis (surgical connection of two separate anatomic structures).
Urostomy leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of contents from a urostomy.
Urostomy obstruction
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; dilation or
endoscopic repair or stent
placement indicated
Altered organ function (e.g.,
sepsis or hydronephrosis, or
renal dysfunction); elective
operative intervention indicated
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A finding of blockage of the urostomy.
Urostomy site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding from the urostomy site.
Urostomy stenosis
 -
Symptomatic but no
hydronephrosis, no sepsis or no
renal dysfunction; dilation or
endoscopic repair or stent
placement indicated
Symptomatic (e.g.,
hydronephrosis, or renal
dysfunction); elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of narrowing of the opening of a urostomy.
Uterine anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a uterine anastomosis (surgical connection of two separate anatomic structures).
Uterine perforation
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the uterine wall.
Vaginal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a vaginal anastomosis (surgical connection of two separate anatomic structures).
Vas deferens anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a vas deferens anastomosis (surgical connection of two separate anatomic structures).
Vascular access complication
 -
Device dislodgement, blockage,
leak, or malposition; device
replacement indicated
Deep vein or cardiac
thrombosis; intervention
indicated (e.g., anticoagulation,
lysis, filter, invasive procedure)
Embolic event including
pulmonary embolism or life-
threatening thrombus
Death
Definition: A finding of a previously undocumented problem related to the vascular access site.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
40
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Venous injury
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic (e.g.,
claudication); repair or revision
not indicated
Severe symptoms; limiting self
care ADL; repair or revision
indicated; disabling
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to a vein.
Wound complication
Incisional separation of <=25%
of wound, no deeper than
superficial fascia
Incisional separation >25% of
wound; local care indicated
Hernia without evidence of
strangulation; fascial
disruption/dehiscence; primary
wound closure or revision by
operative intervention indicated
Hernia with evidence of
strangulation; major
reconstruction flap, grafting,
resection, or amputation
indicated
Death
Definition: A finding of development of a new problem at the site of an existing wound.
Wound dehiscence
Incisional separation of <=25%
of wound, no deeper than
superficial fascia
Incisional separation >25% of
wound with local care;
asymptomatic hernia or
symptomatic hernia without
evidence of strangulation
Fascial disruption or dehiscence
without evisceration; primary
wound closure or revision by
operative intervention indicated
Life-threatening consequences;
symptomatic hernia with
evidence of strangulation;
fascial disruption with
evisceration; major
reconstruction flap, grafting,
resection, or amputation
indicated
Death
Definition: A finding of separation of the approximated margins of a surgical wound.
Wrist fracture
Mild; non-surgical intervention
indicated
Limiting instrumental ADL;
operative intervention indicated
Limiting self care ADL; elective
surgery indicated
 -
 -
Definition: A finding of traumatic injury to the wrist joint in which the continuity of a wrist bone is broken.
Injury, poisoning and procedural
complications - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Investigations 
41
14. Investigations
Investigations
Grade
Adverse Event
1
2
3
4
5
Activated partial thromboplastin
time prolonged
>ULN - 1.5 x ULN
>1.5 - 2.5 x ULN
>2.5 x ULN; hemorrhage
 -
 -
Definition: An abnormal laboratory test result in which the partial thromboplastin time is found to be greater than the control value. As a possible indicator of coagulopathy, a prolonged
partial thromboplastin time (PTT) may occur in a variety of diseases and disorders, both primary and related to treatment.
Alanine aminotransferase
increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT or SGPT) in the blood specimen.
Alkaline phosphatase increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of alkaline phosphatase in a blood specimen.
Aspartate aminotransferase
increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of aspartate aminotransferase (AST or SGOT) in a blood specimen.
Blood antidiuretic hormone
abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of antidiuretic hormone in the blood specimen.
Blood bilirubin increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an abnormally high level of bilirubin in the blood. Excess bilirubin is associated with jaundice.
Blood corticotrophin decreased
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of corticotrophin in a blood specimen.
Blood gonadotrophin abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of gonadotrophin hormone in a blood specimen.
Blood prolactin abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
 -
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of prolactin hormone in a blood specimen.
Carbon monoxide diffusing
capacity decreased
3 - 5 units below LLN; for follow-
up, a decrease of 3 - 5 units
(ml/min/mm Hg) below the
baseline value
6 - 8 units below LLN; for follow-
up, an asymptomatic decrease
of >5 - 8 units (ml/min/mm Hg)
below the baseline value
Asymptomatic decrease  of >8
units drop;  >5 units drop along
with the presence of pulmonary
symptoms (e.g. , >Grade 2
hypoxia or >Grade 2 or higher
dyspnea)
 -
 -
Definition: A finding based on lung function test results that indicate  a decrease in the lung capacity to absorb carbon monoxide.
Cardiac troponin I increased
Levels above the upper limit of
normal and below the level of
myocardial infarction as defined
by the manufacturer
 -
Levels consistent with
myocardial infarction as defined
by the manufacturer
 -
 -
Definition: A laboratory test result which indicates increased levels of cardiac troponin I in a biological specimen.
Cardiac troponin T increased
Levels above the upper limit of
normal and below the level of
myocardial infarction as defined
by the manufacturer
 -
Levels consistent with
myocardial infarction as defined
by the manufacturer
 -
 -
Definition: A laboratory test result which indicates increased levels of cardiac troponin T in a biological specimen.
CD4 lymphocytes decreased
<LLN - 500/mm3;  <LLN - 0.5 x
10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x
10e9 /L
<200 - 50/mm3; <0.2 x 0.05 -
10e9 /L
<50/mm3; <0.05 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of CD4 lymphocytes in a blood specimen.
Cholesterol high
>ULN - 300 mg/dL; >ULN - 7.75
mmol/L
>300 - 400 mg/dL; >7.75 - 10.34
mmol/L
>400 - 500 mg/dL; >10.34 -
12.92 mmol/L
>500 mg/dL; >12.92 mmol/L
 -
Definition: A finding based on laboratory test results that indicate higher than normal levels of cholesterol in a blood specimen.
CPK increased
>ULN - 2.5 x ULN
>2.5 x ULN - 5 x ULN
>5 x ULN - 10 x ULN
>10 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in levels of creatine phosphokinase in a blood specimen.
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CTCAE 4.03 - June 14, 2010 : Investigations 
42
Investigations
Grade
Adverse Event
1
2
3
4
5
Creatinine increased
>1 - 1.5 x baseline; >ULN - 1.5
x ULN
>1.5 - 3.0 x baseline; >1.5 - 3.0
x ULN
>3.0 baseline; >3.0 - 6.0 x ULN
>6.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate increased levels of creatinine in a biological specimen.
Ejection fraction decreased
 -
Resting ejection fraction (EF) 50
- 40%; 10 - 19% drop from
baseline
Resting ejection fraction (EF) 39
- 20%; >20% drop from baseline
Resting ejection fraction (EF)
<20%
 -
Definition: The percentage computed when the amount of blood ejected during a ventricular contraction of the heart is compared to the amount that was present prior to the
contraction.
Electrocardiogram QT corrected
interval prolonged
QTc 450 - 480 ms
QTc 481 - 500 ms
QTc >= 501 ms on at least two
separate ECGs
QTc >= 501 or >60 ms change
from baseline and Torsade de
pointes or polymorphic
ventricular tachycardia or
signs/symptoms of serious
arrhythmia
 -
Definition: A finding of a cardiac dysrhythmia characterized by an abnormally long corrected QT interval.
Fibrinogen decreased
<1.0 - 0.75 x LLN  or <25%
decrease from baseline
<0.75 - 0.5 x LLN or 25 - <50%
decrease from baseline
<0.5 - 0.25 x LLN or 50 - <75%
decrease from baseline
<0.25 x LLN  or 75% decrease
from baseline or absolute value
<50 mg/dL
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of fibrinogen in a blood specimen.
Forced expiratory volume
decreased
FEV1% (percentages of
observed FEV1 and FVC
related to their respective
predicted values)  99 - 70%
predicted
FEV1 60 - 69%
50 - 59%
<= 49%
 -
Definition: A finding based on test results that indicate a relative decrease in the fraction of the forced vital capacity that is exhaled in a specific number of seconds.
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate higher than normal levels of the enzyme gamma-glutamyltransferase in the blood specimen. GGT (gamma-
glutamyltransferase ) catalyzes the transfer of a gamma glutamyl group from a gamma glutamyl peptide to another peptide, amino acids or water.
Growth hormone abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
 -
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of growth hormone in a biological specimen.
Haptoglobin decreased
<LLN
 -
 -
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of haptoglobin in a blood specimen.
Hemoglobin increased
Increase in >0 - 2 gm/dL above
ULN or above baseline if
baseline is above ULN
Increase in >2 - 4 gm/dL above
ULN or above baseline if
baseline is above ULN
Increase in >4 gm/dL above
ULN or above baseline if
baseline is above ULN
 -
 -
Definition: A finding based on laboratory test results that indicate increased levels of hemoglobin in a biological specimen.
INR increased
>1 - 1.5 x ULN; >1 - 1.5 times
above baseline if on
anticoagulation
>1.5 - 2.5 x ULN; >1.5 - 2.5
times above baseline if on
anticoagulation
>2.5 x ULN; >2.5 times above
baseline if on anticoagulation
 -
 -
Definition: A finding based on laboratory test results that indicate an increase in the ratio of the patient's prothrombin time to a control sample in the blood.
Lipase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of lipase in a biological specimen.
Lymphocyte count decreased
 <LLN - 800/mm3; <LLN - 0.8 x
10e9 /L
<800 - 500/mm3; <0.8 - 0.5 x
10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x
10e9 /L
<200/mm3; <0.2 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of lymphocytes in a blood specimen.
Lymphocyte count increased
 -
>4000/mm3 - 20,000/mm3
>20,000/mm3
 -
 -
Definition: A finding based on laboratory test results that indicate an abnormal increase in the number of lymphocytes in the blood, effusions or bone marrow.
Neutrophil count decreased
<LLN - 1500/mm3; <LLN - 1.5 x
10e9 /L
<1500 - 1000/mm3; <1.5 - 1.0 x
10e9 /L
<1000 - 500/mm3; <1.0 - 0.5 x
10e9 /L
<500/mm3; <0.5 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of neutrophils in a blood specimen.
Pancreatic enzymes decreased
<LLN and asymptomatic
Increase in stool frequency,
bulk, or odor; steatorrhea
Sequelae of absorption
deficiency
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of pancreatic enzymes in a biological specimen.
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CTCAE 4.03 - June 14, 2010 : Investigations 
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Investigations
Grade
Adverse Event
1
2
3
4
5
Platelet count decreased
<LLN - 75,000/mm3; <LLN -
75.0 x 10e9 /L
<75,000 - 50,000/mm3; <75.0 -
50.0 x 10e9 /L
<50,000 - 25,000/mm3; <50.0 -
25.0 x 10e9 /L
<25,000/mm3; <25.0 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.
Serum amylase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the levels of amylase in a serum specimen.
Urine output decreased
 -
 -
Oliguria (<80 ml in 8 hr)
Anuria (<240 ml in 24 hr)
 -
Definition: A finding based on test results that indicate urine production is less relative to previous output.
Vital capacity abnormal
90 - 75% of predicted value
<75 - 50% of predicted value;
limiting instrumental ADL
<50% of predicted value;
limiting self care ADL
 -
 -
Definition: A finding based on pulmonary function test results that indicate an abnormal vital capacity (amount of exhaled after a maximum inhalation) when compared to the predicted
value.
Weight gain
5 - <10% from baseline
10 - <20% from baseline
>=20% from baseline
 -
 -
Definition: A finding characterized by an increase in overall body weight; for pediatrics, greater than the baseline growth curve.
Weight loss
5 to <10% from baseline;
intervention not indicated
10 - <20% from baseline;
nutritional support indicated
>=20% from baseline; tube
feeding or TPN indicated
 -
 -
Definition: A finding characterized by a decrease in overall body weight; for pediatrics, less than the baseline growth curve.
White blood cell decreased
<LLN - 3000/mm3; <LLN - 3.0 x
10e9 /L
<3000 - 2000/mm3; <3.0 - 2.0 x
10e9 /L
<2000 - 1000/mm3; <2.0 - 1.0 x
10e9 /L
<1000/mm3; <1.0 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate an decrease in number of white blood cells in a blood specimen.
Investigations - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Metabolism and nutrition disorders 
44
15. Metabolism and nutrition disorders
Metabolism and nutrition disorders
Grade
Adverse Event
1
2
3
4
5
Acidosis
pH <normal, but >=7.3
 -
pH <7.3
Life-threatening consequences
Death
Definition: A disorder characterized by abnormally high acidity (high hydrogen-ion concentration) of the blood and other body tissues.
Alcohol intolerance
 -
Present
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in sensitivity to the adverse effects of alcohol, which can include nasal congestion, skin flushes, heart dysrhythmias, nausea,
vomiting, indigestion and headaches.
Alkalosis
pH >normal, but <=7.5
 -
pH >7.5
Life-threatening consequences
Death
Definition: A disorder characterized by abnormally high alkalinity (low hydrogen-ion concentration) of the blood and other body tissues.
Anorexia
Loss of appetite without
alteration in eating habits
Oral intake altered without
significant weight loss or
malnutrition; oral nutritional
supplements indicated
Associated with significant
weight loss or malnutrition (e.g.,
inadequate oral caloric and/or
fluid intake); tube feeding or
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a loss of appetite.
Dehydration
Increased oral fluids indicated;
dry mucous membranes;
diminished skin turgor
IV fluids indicated <24 hrs
IV fluids or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Glucose intolerance
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; dietary
modification or oral agent
indicated
Severe symptoms; insulin
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inability to properly metabolize glucose.
Hypercalcemia
Corrected serum calcium of
>ULN - 11.5 mg/dL; >ULN - 2.9
mmol/L;  Ionized calcium  >ULN
- 1.5 mmol/L
Corrected serum calcium of
>11.5 - 12.5 mg/dL; >2.9 - 3.1
mmol/L;  Ionized calcium >1.5 -
1.6 mmol/L; symptomatic
Corrected serum calcium of
>12.5 - 13.5 mg/dL; >3.1 - 3.4
mmol/L;  Ionized calcium  >1.6 -
1.8 mmol/L; hospitalization
indicated
Corrected serum calcium of
>13.5 mg/dL; >3.4 mmol/L;
Ionized calcium  >1.8 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of calcium (corrected for albumin) in blood.
Hyperglycemia
Fasting glucose value >ULN -
160 mg/dL; Fasting glucose
value >ULN - 8.9 mmol/L
Fasting glucose value >160 -
250 mg/dL; Fasting glucose
value >8.9 - 13.9 mmol/L
>250 - 500 mg/dL; >13.9 - 27.8
mmol/L; hospitalization
indicated
>500 mg/dL; >27.8 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of blood sugar. It is usually an indication of diabetes mellitus or glucose
intolerance.
Hyperkalemia
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L
>6.0 - 7.0 mmol/L;
hospitalization indicated
>7.0 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of potassium in the blood; associated with kidney failure or sometimes with
the use of diuretic drugs.
Hypermagnesemia
>ULN - 3.0 mg/dL; >ULN - 1.23
mmol/L
 -
>3.0 - 8.0 mg/dL; >1.23 - 3.30
mmol/L
>8.0 mg/dL; >3.30 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of magnesium in the  blood.
Hypernatremia
>ULN - 150 mmol/L
>150 - 155 mmol/L
>155 - 160 mmol/L;
hospitalization indicated
>160 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of sodium in the  blood.
Hypertriglyceridemia
150 mg/dL - 300 mg/dL; 1.71
mmol/L - 3.42 mmol/L
>300 mg/dL - 500 mg/dL;  >3.42
mmol/L - 5.7 mmol/L
>500 mg/dL - 1000 mg/dL;  >5.7
mmol/L - 11.4 mmol/L
>1000 mg/dL; >11.4 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of triglyceride concentration in the blood.
Hyperuricemia
>ULN - 10 mg/dL (0.59 mmol/L)
without physiologic
consequences
 -
>ULN - 10 mg/dL (0.59 mmol/L)
with physiologic consequences
>10 mg/dL; >0.59 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of uric acid.
Hypoalbuminemia
<LLN - 3 g/dL; <LLN - 30 g/L
<3 - 2 g/dL; <30 - 20 g/L
<2 g/dL; <20 g/L
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of albumin in the blood.
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CTCAE 4.03 - June 14, 2010 : Metabolism and nutrition disorders 
45
Metabolism and nutrition disorders
Grade
Adverse Event
1
2
3
4
5
Hypocalcemia
Corrected serum calcium of
<LLN - 8.0 mg/dL; <LLN - 2.0
mmol/L; Ionized calcium  <LLN -
1.0 mmol/L
Corrected serum calcium of
<8.0 - 7.0 mg/dL; <2.0 - 1.75
mmol/L; Ionized calcium  <1.0 -
0.9 mmol/L; symptomatic
Corrected serum calcium of
<7.0 - 6.0 mg/dL; <1.75 - 1.5
mmol/L;  Ionized calcium  <0.9 -
0.8 mmol/L; hospitalization
indicated
Corrected serum calcium of
<6.0 mg/dL; <1.5 mmol/L;
Ionized calcium  <0.8 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of calcium (corrected for albumin) in the  blood.
Hypoglycemia
<LLN - 55 mg/dL; <LLN - 3.0
mmol/L
<55 - 40 mg/dL; <3.0 - 2.2
mmol/L
<40 - 30 mg/dL; <2.2 - 1.7
mmol/L
<30 mg/dL; <1.7 mmol/L; life-
threatening consequences;
seizures
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of glucose in the blood.
Hypokalemia
<LLN - 3.0 mmol/L
<LLN - 3.0 mmol/L;
symptomatic; intervention
indicated
<3.0 - 2.5 mmol/L;
hospitalization indicated
<2.5 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of potassium in the  blood.
Hypomagnesemia
<LLN - 1.2 mg/dL; <LLN - 0.5
mmol/L
<1.2 - 0.9 mg/dL; <0.5 - 0.4
mmol/L
<0.9 - 0.7 mg/dL; <0.4 - 0.3
mmol/L
<0.7 mg/dL; <0.3 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of magnesium in the  blood.
Hyponatremia
<LLN - 130 mmol/L
 -
<130 - 120 mmol/L
<120 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of sodium in the blood.
Hypophosphatemia
<LLN - 2.5 mg/dL; <LLN - 0.8
mmol/L
<2.5 - 2.0 mg/dL; <0.8 - 0.6
mmol/L
<2.0 - 1.0 mg/dL; <0.6 - 0.3
mmol/L
<1.0 mg/dL; <0.3 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of phosphates in the  blood.
Iron overload
 -
Moderate symptoms;
intervention not indicated
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by accumulation of iron in the tissues.
Obesity
 -
BMI 25 - 29.9 kg/m2
BMI 30 - 39.9 kg/m2
BMI >=40 kg/m2
 -
Definition: A disorder characterized by having a high amount of body fat.
Tumor lysis syndrome
 -
 -
Present
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by metabolic abnormalities that result from a spontaneous or therapy-related cytolysis of tumor cells.
Metabolism and nutrition
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
46
16. Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Abdominal soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g. tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the abdominal wall.
Arthralgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in a joint.
Arthritis
Mild pain with inflammation,
erythema, or joint swelling
Moderate pain associated with
signs of inflammation,
erythema, or joint swelling;
limiting instrumental ADL
Severe pain associated with
signs of inflammation,
erythema, or joint swelling;
irreversible joint damage;
disabling; limiting self care ADL
 -
 -
Definition: A disorder characterized by inflammation involving a joint.
Avascular necrosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by necrotic changes in the bone tissue due to interruption of blood supply. Most often affecting the epiphysis of the long bones, the necrotic
changes result in the collapse and the destruction of the bone structure.
Back pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the back region.
Bone pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the bones.
Buttock pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the buttocks.
Chest wall pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the chest wall region.
Exostosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by non-neoplastic overgrowth of bone.
Fibrosis deep connective tissue
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration; unable to
slide or pinch skin; limiting joint
or orifice movement (e.g.
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by fibrotic degeneration of the deep connective tissues.
Flank pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation on the lateral side of the body in the region below the ribs and above the hip.
Generalized muscle weakness
Symptomatic; weakness
perceived by patient but not
evident on physical exam
Symptomatic; weakness evident
on physical exam; weakness
limiting instrumental ADL
Weakness limiting self care
ADL; disabling
 -
 -
Definition: A disorder characterized by a reduction in the strength of muscles in multiple anatomic sites.
Growth suppression
Reduction in growth velocity by
10 - 29% ideally measured over
the period of a year
Reduction in growth velocity by
30 - 49% ideally measured over
the period of a year or 0 - 49%
reduction in growth from the
baseline growth curve
Reduction in growth velocity of
>=50% ideally measured over
the period of a year
 -
 -
Definition: A disorder characterized by of stature that is smaller than normal as expected for age.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
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Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Head soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the head.
Joint effusion
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated; disabling
 -
 -
Definition: A disorder characterized by excessive fluid in a joint, usually as a result of joint inflammation.
Joint range of motion decreased <=25% loss of ROM (range of
motion); decreased ROM
limiting athletic activity
>25 - 50% decrease in ROM;
limiting instrumental ADL
>50% decrease in ROM; limiting
self care ADL; disabling
 -
 -
Definition: A disorder characterized by a decrease in joint flexibility of any joint.
Joint range of motion decreased
cervical spine
Mild restriction of rotation or
flexion between 60 - 70 degrees
Rotation <60 degrees to right or
left; <60 degrees of flexion
Ankylosed/fused over multiple
segments with no C-spine
rotation
 -
 -
Definition: A disorder characterized by a decrease in flexibility of a cervical spine joint.
Joint range of motion decreased
lumbar spine
Stiffness; difficulty bending to
the floor to pick up a very light
object but able to do athletic
activity
Pain with range of motion
(ROM) in lumbar spine; requires
a reaching aid to pick up a very
light object from the floor
<50% lumbar spine flexion;
associated with symptoms of
ankylosis or fused over multiple
segments with no L-spine
flexion (e.g., unable to reach to
floor to pick up a very light
object)
 -
 -
Definition: A disorder characterized by a decrease in flexibility of a lumbar spine joint.
Kyphosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate accentuation; limiting
instrumental ADL
Severe accentuation; operative
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an abnormal increase in the curvature of the thoracic portion of the spine.
Lordosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate accentuation; limiting
instrumental ADL
Severe accentuation; operative
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an abnormal increase in the curvature of the lumbar portion of the spine.
Muscle weakness left-sided
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the muscles on the left side of the body.
Muscle weakness lower limb
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the lower limb muscles.
Muscle weakness right-sided
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the muscles on the right side of the body.
Muscle weakness trunk
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the trunk muscles.
Muscle weakness upper limb
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the upper limb muscles.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
48
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Musculoskeletal deformity
Cosmetically and functionally
insignificant hypoplasia
Deformity, hypoplasia, or
asymmetry able to be
remediated by prosthesis (e.g.,
shoe insert) or covered by
clothing
Significant deformity,
hypoplasia, or asymmetry,
unable to be remediated by
prosthesis or covered by
clothing; disabling
 -
 -
Definition: A disorder characterized by of a malformation of the musculoskeletal system.
Myalgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation originating from a muscle or group of muscles.
Myositis
Mild pain
Moderate pain associated with
weakness; pain limiting
instrumental ADL
Pain associated with severe
weakness; limiting self care
ADL
 -
 -
Definition: A disorder characterized by inflammation involving the skeletal muscles.
Neck pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the neck area.
Neck soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the neck.
Osteonecrosis of jaw
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the bone of the mandible.
Osteoporosis
Radiologic evidence of
osteoporosis or Bone Mineral
Density (BMD) t-score -1 to -2.5
(osteopenia); no loss of height
or intervention indicated
BMD t-score <-2.5; loss of
height <2 cm; anti-osteoporotic
therapy indicated; limiting
instrumental ADL
Loss of height >=2 cm;
hospitalization indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by reduced bone mass, with a decrease in cortical thickness and in the number and size of the trabeculae of cancellous bone (but normal chemical
composition), resulting in increased fracture incidence.
Pain in extremity
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the upper or lower extremities.
Pelvic soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the pelvis.
Scoliosis
<20 degrees; clinically
undetectable
>20 - 45 degrees; visible by
forward flexion; limiting
instrumental ADL
>45 degrees; scapular
prominence in forward flexion;
operative intervention indicated;
limiting self care ADL; disabling
 -
 -
Definition: A disorder characterized by a malformed, lateral curvature of the spine.
Soft tissue necrosis lower limb
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the lower extremity.
Soft tissue necrosis upper limb
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the upper extremity.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
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Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Superficial soft tissue fibrosis
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration; unable to
slide or pinch skin; limiting joint
or orifice movement (e.g.,
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by fibrotic degeneration of the superficial soft tissues.
Trismus
Decreased ROM (range of
motion) without impaired eating
Decreased ROM requiring small
bites, soft foods or purees
Decreased ROM with inability to
adequately aliment or hydrate
orally
 -
 -
Definition: A disorder characterized by lack of ability to open the mouth fully due to a decrease in the range of motion of the muscles of mastication.
Unequal limb length
Mild length discrepancy <2 cm
Moderate length discrepancy 2 -
5 cm; shoe lift indicated; limiting
instrumental ADL
Severe length discrepancy >5
cm; limiting self care ADL;
disabling; operative intervention
indicated
 -
 -
Definition: A disorder characterized by of a discrepancy between the lengths of the lower or upper extremities.
Musculoskeletal and connective
tissue disorder -  Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
50
17. Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Grade
Adverse Event
1
2
3
4
5
Leukemia secondary to
oncology chemotherapy
 -
 -
 -
Present
Death
Definition: A disorder characterized by leukemia arising as a result of the mutagenic effect of chemotherapy agents.
Myelodysplastic syndrome
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by insufficiently healthy hematapoietic cell production by the bone marrow.
Treatment related secondary
malignancy
 -
 -
Non life-threatening secondary
malignancy
Acute life-threatening secondary
malignancy; blast crisis in
leukemia
Death
Definition: A disorder characterized by development of a malignancy most probably as a result of treatment for a previously existing malignancy.
Tumor pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort from a neoplasm that may be pressing on a nerve, blocking blood vessels, inflamed or fractured from metastasis.
Neoplasms benign, malignant
and unspecified (incl cysts and
polyps) - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
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18. Nervous system disorders
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Abducens nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the abducens nerve (sixth cranial nerve).
Accessory nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the accessory nerve (eleventh cranial nerve).
Acoustic nerve disorder NOS
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the acoustic nerve (eighth cranial nerve).
Akathisia
Mild restlessness or increased
motor activity
Moderate restlessness or
increased motor activity; limiting
instrumental ADL
Severe restlessness or
increased motor activity; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an uncomfortable feeling of inner restlessness and inability to stay still; this is a side effect of some psychotropic drugs.
Amnesia
Mild; transient memory loss
Moderate; short term memory
loss; limiting instrumental ADL
Severe; long term memory loss;
limiting self care ADL
 -
 -
Definition: A disorder characterized by systematic and extensive loss of memory.
Aphonia
 -
 -
Voicelessness; unable to speak
 -
 -
Definition: A disorder characterized by the inability to speak. It may result from injuries to the vocal cords or may be functional (psychogenic).
Arachnoiditis
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the arachnoid membrane and adjacent subarachnoid space.
Ataxia
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; mechanical
assistance indicated
 -
 -
Definition: A disorder characterized by lack of coordination of muscle movements resulting in the impairment or inability to perform voluntary activities.
Brachial plexopathy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by regional paresthesia of the brachial plexus, marked discomfort and muscle weakness, and limited movement in the arm or hand.
Central nervous system
necrosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms;
corticosteroids indicated
Severe symptoms; medical
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the brain and/or spinal cord.
Cerebrospinal fluid leakage
Post-craniotomy: asymptomatic;
Post-lumbar puncture: transient
headache; postural care
indicated
Post-craniotomy: moderate
symptoms; medical intervention
indicated; Post-lumbar
puncture: persistent moderate
symptoms; blood patch
indicated
Severe symptoms; medical
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by loss of cerebrospinal fluid into the surrounding tissues.
Cognitive disturbance
Mild cognitive disability; not
interfering with work/school/life
performance; specialized
educational services/devices
not indicated
Moderate cognitive disability;
interfering with work/school/life
performance but capable of
independent living; specialized
resources on part time basis
indicated
Severe cognitive disability;
significant impairment of
work/school/life performance
 -
 -
Definition: A disorder characterized by a conspicuous change in cognitive function.
Concentration impairment
Mild inattention or decreased
level of concentration
Moderate impairment in
attention or decreased level of
concentration; limiting
instrumental ADL
Severe impairment in attention
or decreased level of
concentration; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a deterioration in the ability to concentrate.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
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Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Depressed level of
consciousness
Decreased level of alertness
Sedation; slow response to
stimuli; limiting instrumental
ADL
Difficult to arouse
Life-threatening consequences
Death
Definition: A disorder characterized by a decrease in ability to perceive and respond.
Dizziness
Mild unsteadiness or sensation
of movement
Moderate unsteadiness or
sensation of movement; limiting
instrumental ADL
Severe unsteadiness or
sensation of movement; limiting
self care ADL
 -
 -
Definition: A disorder characterized by a disturbing sensation of lightheadedness, unsteadiness, giddiness, spinning or rocking.
Dysarthria
Mild slurred speech
Moderate impairment of
articulation or slurred speech
Severe impairment of
articulation or slurred speech
 -
 -
Definition: A disorder characterized by slow and slurred speech resulting from an inability to coordinate the muscles used in speech.
Dysesthesia
Mild sensory alteration
Moderate sensory alteration;
limiting instrumental ADL
Severe sensory alteration;
limiting self care ADL
 -
 -
Definition: A disorder characterized by distortion of sensory perception, resulting in an abnormal and unpleasant sensation.
Dysgeusia
Altered taste but no change in
diet
Altered taste with change in diet
(e.g., oral supplements);
noxious or unpleasant taste;
loss of taste
 -
 -
 -
Definition: A disorder characterized by abnormal sensual experience with the taste of foodstuffs; it can be related to a decrease in the sense of smell.
Dysphasia
Awareness of receptive or
expressive characteristics; not
impairing ability to communicate
Moderate receptive or
expressive characteristics;
impairing ability to communicate
spontaneously
Severe receptive or expressive
characteristics; impairing ability
to read, write or communicate
intelligibly
 -
 -
Definition: A disorder characterized by impairment of verbal communication skills, often resulting from brain damage.
Edema cerebral
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the brain.
Encephalopathy
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a pathologic process involving the brain.
Extrapyramidal disorder
Mild involuntary movements
Moderate involuntary
movements; limiting
instrumental ADL
Severe involuntary movements
or torticollis; limiting self care
ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormal, repetitive, involuntary muscle movements, frenzied speech and extreme restlessness.
Facial muscle weakness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a reduction in the strength of the facial muscles.
Facial nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the facial nerve (seventh cranial nerve).
Glossopharyngeal nerve
disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the glossopharyngeal nerve (ninth cranial nerve).
Headache
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in various parts of the head, not confined to the area of distribution of any nerve.
Hydrocephalus
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms;
intervention not indicated
Severe symptoms or
neurological deficit; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal increase of cerebrospinal fluid in the ventricles of the brain.
Hypersomnia
Mild increased need for sleep
Moderate increased need for
sleep
Severe increased need for
sleep
 -
 -
Definition: A disorder characterized by characterized by excessive sleepiness during the daytime.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
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Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Hypoglossal nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the hypoglossal nerve (twelfth cranial nerve).
Intracranial hemorrhage
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Ventriculostomy, ICP
monitoring, intraventricular
thrombolysis, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the cranium.
Ischemia cerebrovascular
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms
 -
 -
 -
Definition: A disorder characterized by a decrease or absence of blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurological
damage.
IVth nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the trochlear nerve (fourth cranial nerve).
Lethargy
Mild symptoms; reduced
alertness and awareness
Moderate symptoms; limiting
instrumental ADL
 -
 -
 -
Definition: A disorder characterized by a decrease in consciousness characterized by mental and physical inertness.
Leukoencephalopathy
Asymptomatic; small focal
T2/FLAIR hyperintensities;
involving periventricular white
matter or <1/3 of susceptible
areas of cerebrum +/- mild
increase in subarachnoid space
(SAS) and/or mild
ventriculomegaly
Moderate symptoms; focal
T2/FLAIR hyperintensities,
involving periventricular white
matter extending into centrum
semiovale or involving 1/3 to 2/3
of susceptible areas of
cerebrum +/- moderate increase
in SAS and/or moderate
ventriculomegaly
Severe symptoms; extensive
T2/FLAIR hyperintensities,
involving periventricular white
matter involving 2/3 or more of
susceptible areas of cerebrum
+/- moderate to severe increase
in SAS and/or moderate to
severe ventriculomegaly
Life-threatening consequences;
extensive T2/FLAIR
hyperintensities, involving
periventricular white matter
involving most of susceptible
areas of cerebrum +/- moderate
to severe increase in SAS
and/or moderate to severe
ventriculomegaly
Death
Definition: A disorder characterized by diffuse reactive astrocytosis with multiple areas of necrotic foci without inflammation.
Memory impairment
Mild memory impairment
Moderate memory impairment;
limiting instrumental ADL
Severe memory impairment;
limiting self care ADL
 -
 -
Definition: A disorder characterized by a deterioration in memory function.
Meningismus
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by neck stiffness, headache, and photophobia resulting from irritation of the cerebral meninges.
Movements involuntary
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by uncontrolled and purposeless movements.
Myelitis
Asymptomatic; mild signs (e.g.,
Babinski's reflex or Lhermitte's
sign)
Moderate weakness or sensory
loss; limiting instrumental ADL
Severe weakness or sensory
loss; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving the spinal cord. Symptoms include weakness, paresthesia, sensory loss, marked discomfort and incontinence.
Neuralgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by intense painful sensation along a nerve or group of nerves.
Nystagmus
 -
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involuntary movements of the eyeballs.
Oculomotor nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the oculomotor nerve (third cranial nerve).
Olfactory nerve disorder
 -
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the olfactory nerve (first cranial nerve).
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
54
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Paresthesia
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by functional disturbances of sensory neurons resulting in abnormal cutaneous sensations of tingling, numbness, pressure, cold, and warmth that
are experienced in the absence of a stimulus.
Peripheral motor neuropathy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; assistive device
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation or degeneration of the peripheral motor nerves.
Peripheral sensory neuropathy
Asymptomatic; loss of deep
tendon reflexes or paresthesia
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation or degeneration of the peripheral sensory nerves.
Phantom pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort related to a limb or an organ that is removed from or is not physically part of the body.
Presyncope
 -
Present (e.g., near fainting)
 -
 -
 -
Definition: A disorder characterized by an episode of lightheadedness and dizziness which may precede an episode of syncope.
Pyramidal tract syndrome
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by dysfunction of the corticospinal (pyramidal) tracts of the spinal cord. Symptoms include  an increase in the muscle tone in the lower extremities,
hyperreflexia, positive Babinski and a decrease in fine motor coordination.
Radiculitis
Mild symptoms
Moderate symptoms; limiting
instrumental ADL; medical
intervention indicated
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving a nerve root. Patients experience marked discomfort radiating along a nerve path because of spinal pressure on the
connecting nerve root.
Recurrent laryngeal nerve palsy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms
Severe symptoms; medical
intervention indicated (e.g.,
thyroplasty, vocal cord injection)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by paralysis of the recurrent laryngeal nerve.
Reversible posterior
leukoencephalopathy syndrome
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; abnormal
imaging studies; limiting
instrumental ADL
Severe symptoms; very
abnormal imaging studies;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by headaches, mental status changes, visual disturbances, and seizures associated with imaging findings of posterior leukoencephalopathy. It has
been observed in association with hypertensive encephalopathy, eclampsia, and immunosuppressive and cytotoxic drug treatment. It is an acute or subacute reversible condition.
Seizure
Brief partial seizure; no loss of
consciousness
Brief generalized seizure
Multiple seizures despite
medical intervention
Life-threatening; prolonged
repetitive seizures
Death
Definition: A disorder characterized by a sudden, involuntary skeletal muscular contractions of cerebral or brain stem origin.
Sinus pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort in the face, between the eyes, or upper teeth originating from the sinuses.
Somnolence
Mild but more than usual
drowsiness or sleepiness
Moderate sedation; limiting
instrumental ADL
Obtundation or stupor
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by characterized by excessive sleepiness and drowsiness.
Spasticity
Mild or slight increase in muscle
tone
Moderate increase in muscle
tone and increase in resistance
through range of motion
Severe increase in muscle tone
and increase in resistance
through range of motion
Life-threatening; unable to move
active or passive range of
motion
Death
Definition: A disorder characterized by increased involuntary muscle tone that affects the regions interfering with voluntary movement. It results in gait, movement, and speech
disturbances.
Stroke
Asymptomatic or mild
neurologic deficit; radiographic
findings only
Moderate neurologic deficit
Severe neurologic deficit
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a sudden loss of sensory function due to an intracranial vascular event.
Syncope
 -
 -
Fainting; orthostatic collapse
 -
 -
Definition: A disorder characterized by spontaneous loss of consciousness caused by insufficient blood supply to the brain.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
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Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Transient ischemic attacks
Mild neurologic deficit with or
without imaging confirmation
Moderate neurologic deficit with
or without imaging confirmation
 -
 -
 -
Definition: A disorder characterized by a brief attack (less than 24 hours) of cerebral dysfunction of vascular origin, with no persistent neurological deficit.
Tremor
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by the uncontrolled shaking movement of the whole body or individual parts.
Trigeminal nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the trigeminal nerve (fifth cranial nerve).
Vagus nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the vagus nerve (tenth cranial nerve).
Vasovagal reaction
 -
 -
Present
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a sudden drop of the blood pressure, bradycardia, and peripheral vasodilation that may lead to loss of consciousness. It results from an
increase in the stimulation of the vagus nerve.
Nervous system disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Pregnancy, puerperium and perinatal conditions 
56
19. Pregnancy, puerperium and perinatal conditions
Pregnancy, puerperium and perinatal conditions
Grade
Adverse Event
1
2
3
4
5
Fetal death
 -
 -
 -
 -
Fetal loss at
any
gestational
age
Definition: A disorder characterized by death in utero; failure of the product of conception to show evidence of respiration, heartbeat, or definite movement of a voluntary muscle after
expulsion from the uterus, without possibility of resuscitation.
Fetal growth retardation
 -
<10% percentile of weight for
gestational age
<5% percentile of weight for
gestational age
<1% percentile of weight for
gestational age
 -
Definition: A disorder characterized by inhibition of fetal growth resulting in the inability of the fetus to achieve its potential weight.
Premature delivery
Delivery of a liveborn infant at
>34 to 37 weeks gestation
Delivery of a liveborn infant at
>28 to 34 weeks gestation
Delivery of a liveborn infant at
24 to 28 weeks gestation
Delivery of a liveborn infant at
24 weeks of gestation or less
 -
Definition: A disorder characterized by delivery of a viable infant before the normal end of gestation. Typically, viability is achievable between the twentieth and thirty-seventh week of
gestation.
Unintended pregnancy
 -
 -
Unintended pregnancy
 -
 -
Definition: A disorder characterized by an unexpected pregnancy at the time of conception.
Pregnancy, puerperium and
perinatal conditions - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate, local or noninvasive
intervention indicated; limiting
instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Psychiatric disorders 
57
20. Psychiatric disorders
Psychiatric disorders
Grade
Adverse Event
1
2
3
4
5
Agitation
Mild mood alteration
Moderate mood alteration
Severe agitation; hospitalization
not indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a state of restlessness associated with unpleasant feelings of irritability and tension.
Anorgasmia
Inability to achieve orgasm not
adversely affecting relationship
Inability to achieve orgasm
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by an inability to achieve orgasm.
Anxiety
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization not
indicated
Life-threatening; hospitalization
indicated
Death
Definition: A disorder characterized by apprehension of danger and dread accompanied by restlessness, tension, tachycardia, and dyspnea unattached to a clearly identifiable
stimulus.
Confusion
Mild disorientation
Moderate disorientation; limiting
instrumental ADL
Severe disorientation; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a lack of clear and orderly thought and behavior.
Delayed orgasm
Delay in achieving orgasm not
adversely affecting relationship
Delay in achieving orgasm
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by sexual dysfunction characterized by a delay in climax.
Delirium
Mild acute confusional state
Moderate and acute confusional
state; limiting instrumental ADL
Severe and acute confusional
state; limiting self care ADL;
hospitalization indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by the acute and sudden development of confusion, illusions, movement changes, inattentiveness, agitation, and hallucinations. Usually, it is a
reversible condition.
Delusions
 -
Moderate delusional symptoms
Severe delusional symptoms;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by false personal beliefs held contrary to reality, despite contradictory evidence and common sense.
Depression
Mild depressive symptoms
Moderate depressive
symptoms; limiting instrumental
ADL
Severe depressive symptoms;
limiting self care ADL;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by melancholic feelings of grief or unhappiness.
Euphoria
Mild mood elevation
Moderate mood elevation
Severe mood elevation (e.g.,
hypomania)
 -
 -
Definition: A disorder characterized by an exaggerated feeling of well-being which is disproportionate to events and stimuli.
Hallucinations
Mild hallucinations (e.g.,
perceptual distortions)
Moderate hallucinations
Severe hallucinations;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by a false sensory perception in the absence of an external stimulus.
Insomnia
Mild difficulty falling asleep,
staying asleep or waking up
early
Moderate difficulty falling
asleep, staying asleep or
waking up early
Severe difficulty in falling
asleep, staying asleep or
waking up early
 -
 -
Definition: A disorder characterized by difficulty in falling asleep and/or remaining asleep.
Libido decreased
Decrease in sexual interest not
adversely affecting relationship
Decrease in sexual interest
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by a decrease in sexual desire.
Libido increased
Mild increase in sexual interest
not adversely affecting
relationship
Moderate increase in sexual
interest adversely affecting
relationship
Severe increase in sexual
interest leading to dangerous
behavior
 -
 -
Definition: A disorder characterized by an increase in sexual desire.
Mania
Mild manic symptoms (e.g.,
elevated mood, rapid thoughts,
rapid speech, decreased need
for sleep)
Moderate manic symptoms
(e.g., relationship and work
difficulties; poor hygiene)
Severe manic symptoms (e.g.,
hypomania; major sexual or
financial indiscretions);
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behavior and elevation of mood.
Personality change
Mild personality change
Moderate personality change
Severe personality change;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
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CTCAE 4.03 - June 14, 2010 : Psychiatric disorders 
58
Psychiatric disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by a conspicuous change in a person's behavior and thinking.
Psychosis
Mild psychotic symptoms
Moderate psychotic symptoms
(e.g., disorganized speech;
impaired reality testing)
Severe psychotic symptoms
(e.g., paranoid; extreme
disorganization); hospitalization
not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by personality change, impaired functioning, and loss of touch with reality. It may be a manifestation of schizophrenia, bipolar disorder or brain
tumor.
Restlessness
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an inability to rest, relax or be still.
Suicidal ideation
Increased thoughts of death but
no wish to kill oneself
Suicidal ideation with no specific
plan or intent
Specific plan to commit suicide
without serious intent to die
which may not require
hospitalization
Specific plan to commit suicide
with serious intent to die which
requires hospitalization
 -
Definition: A disorder characterized by thoughts of taking one's own life.
Suicide attempt
 -
 -
Suicide attempt or gesture
without intent to die which may
not require hospitalization
Suicide attempt with intent to
die which requires
hospitalization
Death
Definition: A disorder characterized by self-inflicted harm in an attempt to end one's own life.
Psychiatric disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; disabling;  limiting
self care ADL
Life-threatening consequences;
hospitalization or urgent
intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Renal and urinary disorders 
59
21. Renal and urinary disorders
Renal and urinary disorders
Grade
Adverse Event
1
2
3
4
5
Acute kidney injury
Creatinine level increase of >0.3
mg/dL; creatinine 1.5 - 2.0 x
above baseline
Creatinine 2 - 3 x above
baseline
Creatinine >3 x baseline or >4.0
mg/dL; hospitalization indicated
Life-threatening consequences;
dialysis indicated
Death
Definition: A disorder characterized by the acute loss of renal function and is traditionally classified as pre-renal (low blood flow into kidney), renal (kidney damage) and post-renal
causes (ureteral or bladder outflow obstruction).
Bladder perforation
 -
Extraperitoneal perforation,
indwelling catheter indicated
Intraperitoneal perforation;
elective radiologic, endoscopic
or operative intervention
indicated
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A disorder characterized by a rupture in the bladder wall.
Bladder spasm
Intervention not indicated
Antispasmodics indicated
Hospitalization indicated
 -
 -
Definition: A disorder characterized by a sudden and involuntary contraction of the bladder wall.
Chronic kidney disease
eGFR (estimated Glomerular
Filtration Rate) or CrCl
(creatinine clearance) <LLN - 60
ml/min/1.73 m2 or proteinuria
2+ present; urine
protein/creatinine >0.5
eGFR or CrCl 59 - 30
ml/min/1.73 m2
eGFR or CrCl 29 - 15
ml/min/1.73 m2
eGFR or CrCl <15 ml/min/1.73
m2; dialysis or renal transplant
indicated
Death
Definition: A disorder characterized by gradual and usually permanent loss of kidney function resulting in renal failure.
Cystitis noninfective
Microscopic hematuria; minimal
increase in frequency, urgency,
dysuria, or nocturia; new onset
of incontinence
Moderate hematuria; moderate
increase in frequency, urgency,
dysuria, nocturia or
incontinence; urinary catheter
placement or bladder irrigation
indicated; limiting instrumental
ADL
Gross hematuria; transfusion, IV
medications or hospitalization
indicated; elective endoscopic,
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by inflammation of the bladder which is not caused by an infection of the urinary tract.
Hematuria
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; urinary catheter
or bladder irrigation indicated;
limiting instrumental ADL
Gross hematuria; transfusion, IV
medications or hospitalization
indicated; elective endoscopic,
radiologic or operative
intervention indicated; limiting
self care ADL
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate blood in the urine.
Hemoglobinuria
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by laboratory test results that indicate the presence of free hemoglobin in the urine.
Proteinuria
1+ proteinuria; urinary protein
<1.0 g/24 hrs
Adults: 2+ proteinuria; urinary
protein 1.0 - 3.4 g/24 hrs;
Pediatric: urine P/C
(Protein/Creatinine) ratio 0.5 -
1.9
Adults: urinary protein >=3.5
g/24 hrs;
Pediatric: urine P/C >1.9
 -
 -
Definition: A disorder characterized by laboratory test results that indicate the presence of excessive protein in the urine. It is predominantly albumin, but also globulin.
Renal calculi
Asymptomatic or mild
symptoms; occasional use of
nonprescription analgesics
indicated
Symptomatic; oral antiemetics
indicated; around the clock
nonprescription analgesics or
any oral narcotic analgesics
indicated
Hospitalization indicated; IV
intervention (e.g., analgesics,
antiemetics); elective
endoscopic or radiologic
intervention indicated
Life-threatening consequences;
urgent radiologic, endoscopic or
operative intervention indicated
Death
Definition: A disorder characterized by the formation of crystals in the pelvis of the kidney.
Renal colic
Mild pain not interfering with
activity; nonprescription
medication indicated
Moderate pain; limiting
instrumental ADL; prescription
medication indicated
Hospitalization indicated;
limiting self care ADL
 -
 -
Definition: A disorder characterized by paroxysmal and severe flank marked discomfort radiating to the inguinal area. Often, the cause is the passage of kidney stones.
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CTCAE 4.03 - June 14, 2010 : Renal and urinary disorders 
60
Renal and urinary disorders
Grade
Adverse Event
1
2
3
4
5
Renal hemorrhage
Mild symptoms; intervention not
indicated
Analgesics and hematocrit
monitoring indicated
Transfusion, radiation, or
hospitalization indicated;
elective radiologic, endoscopic
or operative intervention
indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by bleeding from the kidney.
Urinary fistula
 -
Noninvasive intervention
indicated; urinary or suprapubic
catheter placement indicated
Limiting self care ADL; elective
radiologic, endoscopic or
operative intervention indicated;
permanent urinary diversion
indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between any part of the urinary system and another organ or anatomic site.
Urinary frequency
Present
Limiting instrumental ADL;
medical management indicated
 -
 -
 -
Definition: A disorder characterized by urination at short intervals.
Urinary incontinence
Occasional (e.g., with coughing,
sneezing, etc.), pads not
indicated
Spontaneous; pads indicated;
limiting instrumental ADL
Intervention indicated (e.g.,
clamp, collagen injections);
operative intervention indicated;
limiting self care ADL
 -
 -
Definition: A disorder characterized by inability to control the flow of urine from the bladder.
Urinary retention
Urinary, suprapubic or
intermittent catheter placement
not indicated; able to void with
some residual
Placement of urinary,
suprapubic or intermittent
catheter placement indicated;
medication indicated
Elective operative or radiologic
intervention indicated;
substantial loss of affected
kidney function or mass
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A disorder characterized by accumulation of urine within the bladder because of the inability to urinate.
Urinary tract obstruction
Asymptomatic; clinical or
diagnostic observations only
Symptomatic but no
hydronephrosis, sepsis or renal
dysfunction; urethral dilation,
urinary or suprapubic catheter
indicated
Symptomatic and altered organ
function (e.g., hydronephrosis,
or renal dysfunction); elective
radiologic, endoscopic or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the normal flow of contents of the urinary tract.
Urinary tract pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the urinary tract.
Urinary urgency
Present
Limiting instrumental ADL;
medical management indicated
 -
 -
 -
Definition: A disorder characterized by a sudden compelling urge to urinate.
Urine discoloration
Present
 -
 -
 -
 -
Definition: A disorder characterized by a change in the color of the urine.
Renal and urinary disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate, local or noninvasive
intervention indicated; limiting
instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
61
22. Reproductive system and breast disorders
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Azoospermia
 -
 -
Absence of sperm in ejaculate
 -
 -
Definition: A disorder characterized by laboratory test results that indicate complete absence of spermatozoa in the semen.
Breast atrophy
Minimal asymmetry; minimal
atrophy
Moderate asymmetry; moderate
atrophy
Asymmetry >1/3 of breast
volume; severe atrophy
 -
 -
Definition: A disorder characterized by underdevelopment of the breast.
Breast pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the breast region.
Dysmenorrhea
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by abnormally painful abdominal cramps during menses.
Dyspareunia
Mild discomfort or pain
associated with vaginal
penetration; discomfort relieved
with use of vaginal lubricants or
estrogen
Moderate discomfort or pain
associated with vaginal
penetration; discomfort or pain
partially relieved with use of
vaginal lubricants or estrogen
Severe discomfort or pain
associated with vaginal
penetration; discomfort or pain
unrelieved by vaginal lubricants
or estrogen
 -
 -
Definition: A disorder characterized by painful or difficult coitus.
Ejaculation disorder
Diminished ejaculation
Anejaculation or retrograde
ejaculation
 -
 -
 -
Definition: A disorder characterized by problems related to ejaculation. This category includes premature, delayed, retrograde and painful ejaculation.
Erectile dysfunction
Decrease in erectile function
(frequency or rigidity of
erections) but intervention not
indicated (e.g., medication or
use of mechanical device,
penile pump)
Decrease in erectile function
(frequency/rigidity of erections),
erectile intervention indicated,
(e.g., medication or mechanical
devices such as penile pump)
Decrease in erectile function
(frequency/rigidity of erections)
but erectile intervention not
helpful (e.g., medication or
mechanical devices such as
penile pump); placement of a
permanent penile prosthesis
indicated (not previously
present)
 -
 -
Definition: A disorder characterized by the persistent or recurrent inability to achieve or to maintain an erection during sexual activity.
Fallopian tube obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the normal flow of the contents in the fallopian tube.
Fallopian tube stenosis
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated (e.g., organ resection)
Death
Definition: A disorder characterized by a narrowing of the fallopian tube lumen.
Female genital tract fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between a female reproductive system organ and another organ or anatomic site.
Feminization acquired
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by the development of secondary female sex characteristics in males due to extrinsic factors.
Genital edema
Mild swelling or obscuration of
anatomic architecture on close
inspection
Readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour
Lymphorrhea; gross deviation
from normal anatomic contour;
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the genitals.
Gynecomastia
Asymptomatic breast
enlargement
Symptomatic (e.g., pain or
psychosocial impact)
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by excessive development of the breasts in males.
Hematosalpinx
Minimal bleeding identified on
imaging study or laparoscopy;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
62
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by the presence of blood in a fallopian tube.
Irregular menstruation
Intermittent menses with
skipped menses for no more
than 1 to 3 months
Intermittent menses with
skipped menses for more than 4
to 6 months
Persistent amenorrhea for more
than 6 months
 -
 -
Definition: A disorder characterized by irregular cycle or duration of menses.
Lactation disorder
Mild changes in lactation, not
significantly affecting production
or expression of breast milk
Changes in lactation,
significantly affecting breast
production or expression of
breast milk
 -
 -
 -
Definition: A disorder characterized by disturbances of milk secretion. It is not necessarily related to pregnancy that is observed in females and can be observed in males.
Menorrhagia
Mild; iron supplements indicated Moderate symptoms; medical
intervention indicated (e.g.,
hormones)
Severe; transfusion indicated;
surgical intervention indicated
(e.g., hysterectomy)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormally heavy vaginal bleeding during menses.
Nipple deformity
Asymptomatic; asymmetry with
slight retraction and/or
thickening of the nipple areolar
complex
Symptomatic; asymmetry of
nipple areolar complex with
moderate retraction and/or
thickening of the nipple areolar
complex
 -
 -
 -
Definition: A disorder characterized by a malformation of the nipple.
Oligospermia
Sperm concentration >48
million/mL or motility >68%
Sperm concentration 13 - 48
million/mL or motility 32 - 68%
Sperm concentration <13
million/mL or motility <32%
 -
 -
Definition: A disorder characterized by a decrease in the number of spermatozoa in the semen.
Ovarian hemorrhage
Minimal bleeding identified on
imaging study or laproscopy;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic  intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the ovary.
Ovarian rupture
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by tearing or disruption of the ovarian tissue.
Ovulation pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in one side of the abdomen between menstrual cycles, around the time of the discharge of the ovum from the
ovarian follicle.
Pelvic floor muscle weakness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic, not interfering
with bladder, bowel, or vaginal
function; limiting instrumental
ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a reduction in the strength of the muscles of the pelvic floor.
Pelvic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pelvis.
Penile pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the penis.
Perineal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the area between the genital organs and the anus.
Premature menopause
 -
 -
Present
 -
 -
Definition: A disorder characterized by ovarian failure before the age of 40. Symptoms include hot flashes, night sweats, mood swings and a decrease in sex drive.
Prostatic hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
63
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by bleeding from the prostate gland.
Prostatic obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by compression of the urethra secondary to enlargement of the prostate gland. This results in voiding difficulties (straining to void, slow urine
stream, and incomplete emptying of the bladder).
Prostatic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the prostate gland.
Scrotal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the scrotal area.
Spermatic cord hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the spermatic cord.
Spermatic cord obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the normal flow of the contents of the spermatic cord.
Testicular disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic but not interfering
with urination or sexual
activities; intervention not
indicated; limiting instrumental
ADL
Severe symptoms; interfering
with urination or sexual function;
limiting self care ADL;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the testis.
Testicular hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the testis.
Testicular pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the testis.
Uterine fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the uterus and another organ or anatomic site.
Uterine hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the uterus.
Uterine obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the uterine outlet.
Uterine pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the uterus.
Vaginal discharge
Mild vaginal discharge (greater
than baseline for patient)
Moderate to heavy vaginal
discharge; use of perineal pad
or tampon indicated
 -
 -
 -
Definition: A disorder characterized by vaginal secretions. Mucus produced by the cervical glands is discharged from the vagina naturally, especially during the childbearing years.
Vaginal dryness
Mild vaginal dryness not
interfering with sexual function
Moderate vaginal dryness
interfering with sexual function
or causing frequent discomfort
Severe vaginal dryness
resulting in dyspareunia or
severe discomfort
 -
 -
Definition: A disorder characterized by an uncomfortable feeling of itching and burning in the vagina.
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
64
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Vaginal fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the vagina and another organ or anatomic site.
Vaginal hemorrhage
Minimal bleeding identified on
clinical exam or imaging study;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the vagina.
Vaginal inflammation
Mild discomfort or pain, edema,
or redness
Moderate discomfort or pain,
edema, or redness; limiting
instrumental ADL
Severe discomfort or pain,
edema, or redness; limiting self
care ADL; small areas of
mucosal ulceration
Widespread areas of mucosal
ulceration; life-threatening
consequences; urgent
intervention indicated
Death
Definition: A disorder characterized by inflammation involving the vagina. Symptoms may include redness, edema, marked discomfort and an increase in vaginal discharge.
Vaginal obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of vaginal canal.
Vaginal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the vagina.
Vaginal perforation
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the vaginal wall.
Vaginal stricture
Asymptomatic; mild vaginal
shortening or narrowing
Vaginal narrowing and/or
shortening not interfering with
physical examination
Vaginal narrowing and/or
shortening interfering with the
use of tampons, sexual activity
or physical examination
 -
Death
Definition: A disorder characterized by a narrowing of the vaginal canal.
Vaginismus
Mild discomfort or pain
associated with vaginal
spasm/tightening; no impact
upon sexual function or physical
examination
Moderate discomfort or pain
associated with vaginal
spasm/tightening; disruption in
sexual function and physical
examination
Severe discomfort or pain
associated with vaginal
spasm/tightening; unable to
tolerate vaginal penetration or
physical examination
 -
 -
Definition: A disorder characterized by involuntary spasms of the pelvic floor muscles, resulting in pathologic tightness of the vaginal wall during penetration such as during sexual
intercourse.
Reproductive system and breast
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
65
23. Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Adult respiratory distress
syndrome
 -
 -
Present with radiologic findings;
intubation not indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by progressive and life-threatening pulmonary distress in the absence of an underlying pulmonary condition, usually following major trauma or
surgery.
Allergic rhinitis
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by an inflammation of the nasal mucous membranes caused by an IgE-mediated response to external allergens. The inflammation may also
involve the mucous membranes of the sinuses, eyes, middle ear, and pharynx. Symptoms include sneezing, nasal congestion, rhinorrhea and itching.
Apnea
 -
 -
Present; medical intervention
indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by cessation of breathing.
Aspiration
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Altered eating habits; coughing
or choking episodes after eating
or swallowing; medical
intervention indicated (e.g.,
suction or oxygen)
Dyspnea and pneumonia
symptoms (e.g., aspiration
pneumonia); hospitalization
indicated; unable to aliment
orally
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by inhalation of solids or liquids into the lungs.
Atelectasis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., dyspnea,
cough); medical intervention
indicated (e.g., chest
physiotherapy, suctioning);
bronchoscopic suctioning
Oxygen indicated;
hospitalization or elective
operative intervention indicated
(e.g., stent, laser)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by the collapse of part or the entire lung.
Bronchial fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
with thoracoplasty, chronic open
drainage or multiple
thoracotomies indicated
Death
Definition: A disorder characterized by an abnormal communication between the bronchus and another organ or anatomic site.
Bronchial obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., mild
wheezing); endoscopic
evaluation indicated;
radiographic evidence of
atelectasis/lobar collapse;
medical management indicated
(e.g., steroids, bronchodilators)
Shortness of breath with stridor;
endoscopic intervention
indicated (e.g., laser, stent
placement)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by blockage of a bronchus passage, most often by bronchial secretions and exudates.
Bronchial stricture
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., rhonchi or
wheezing) but without
respiratory distress; medical
intervention indicated (e.g.,
steroids, bronchodilators)
Shortness of breath with stridor;
endoscopic intervention
indicated (e.g., laser, stent
placement)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the bronchial tube.
Bronchopleural fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
with thoracoplasty, chronic open
drainage or multiple
thoracotomies indicated
Death
Definition: A disorder characterized by an abnormal communication between a bronchus and the pleural cavity.
Bronchopulmonary hemorrhage
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the bronchial wall and/or lung parenchyma.
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
66
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Bronchospasm
Mild symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Limiting self care ADL; oxygen
saturation decreased
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by a sudden contraction of the smooth muscles of the bronchial wall.
Chylothorax
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thoracentesis or
tube drainage indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by milky pleural effusion (abnormal collection of fluid) resulting from accumulation of lymph fluid in the pleural cavity.
Cough
Mild symptoms; nonprescription
intervention indicated
Moderate symptoms, medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by sudden, often repetitive, spasmodic contraction of the thoracic cavity, resulting in violent release of air from the lungs and usually accompanied
by a distinctive sound.
Dyspnea
Shortness of breath with
moderate exertion
Shortness of breath with
minimal exertion; limiting
instrumental ADL
Shortness of breath at rest;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an uncomfortable sensation of difficulty breathing.
Epistaxis
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated (e.g.,
nasal packing, cauterization;
topical vasoconstrictors)
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the nose.
Hiccups
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; interfering
with sleep; limiting self care
ADL
 -
 -
Definition: A disorder characterized by repeated gulp sounds that result from an involuntary opening and closing of the glottis. This is attributed to a spasm of the diaphragm.
Hoarseness
Mild or intermittent voice
change; fully understandable;
self-resolves
Moderate or persistent voice
changes; may require
occasional repetition but
understandable on telephone;
medical evaluation indicated
Severe voice changes including
predominantly whispered
speech
 -
 -
Definition: A disorder characterized by harsh and raspy voice arising from or spreading to the larynx.
Hypoxia
 -
Decreased oxygen saturation
with exercise (e.g., pulse
oximeter <88%); intermittent
supplemental oxygen
Decreased oxygen saturation at
rest (e.g., pulse oximeter <88%
or PaO2 <=55 mm Hg)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a decrease in the level of oxygen in the body.
Laryngeal edema
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated (e.g.,
dexamethasone, epinephrine,
antihistamines)
Stridor; respiratory distress;
hospitalization indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the larynx.
Laryngeal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
indicated (e.g., thoracoplasty,
chronic open drainage or
multiple thoracotomies)
Death
Definition: A disorder characterized by an abnormal communication between the larynx and another organ or anatomic site.
Laryngeal hemorrhage
Mild cough or trace hemoptysis;
laryngoscopic findings
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by bleeding from the larynx.
Laryngeal inflammation
Mild sore throat; raspy voice
Moderate sore throat;
analgesics indicated
Severe throat pain; endoscopic
intervention indicated
 -
 -
Definition: A disorder characterized by an inflammation involving the larynx.
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Laryngeal mucositis
Endoscopic findings only; mild
discomfort with normal intake
Moderate discomfort; altered
oral intake
Severe pain; severely altered
eating/swallowing; medical
intervention indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the larynx.
Laryngeal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids); limiting instrumental
ADL
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the laryngeal airway.
Laryngeal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids)
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a narrowing of the laryngeal airway.
Laryngopharyngeal dysesthesia
Mild symptoms; no anxiety;
intervention not indicated
Moderate symptoms; mild
anxiety, but no dyspnea; short
duration of observation and or
anxiolytic indicated; limiting
instrumental ADL
Severe symptoms; dyspnea and
swallowing difficulty; limiting self
care ADL
Life-threatening consequences
Death
Definition: A disorder characterized by an uncomfortable persistent sensation in the area of the laryngopharynx.
Laryngospasm
 -
Transient episode; intervention
not indicated
Recurrent episodes;
noninvasive intervention
indicated (e.g., breathing
technique, pressure point
massage)
Persistent or severe episodes
associated with syncope; urgent
intervention indicated (e.g.,
fiberoptic laryngoscopy,
intubation, botox injection)
Death
Definition: A disorder characterized by paroxysmal spasmodic muscular contraction of the vocal cords.
Mediastinal hemorrhage
Radiologic evidence only;
minimal symptoms; intervention
not indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
(e.g., hemostasis of bleeding
site)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the mediastinum.
Nasal congestion
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Associated with bloody nasal
discharge or epistaxis
 -
 -
Definition: A disorder characterized by obstruction of the nasal passage due to mucosal edema.
Pharyngeal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the pharynx and another organ or anatomic site.
Pharyngeal hemorrhage
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the pharynx.
Pharyngeal mucositis
Endoscopic findings only;
minimal symptoms with normal
oral intake; mild pain but
analgesics not indicated
Moderate pain and analgesics
indicated; altered oral intake;
limiting instrumental ADL
Severe pain; unable to
adequately aliment or hydrate
orally; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the pharynx.
Pharyngeal necrosis
 -
 -
Inability to aliment adequately
by GI tract; tube feeding or TPN
indicated; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
68
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by a necrotic process occurring in the pharynx.
Pharyngeal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids); limiting instrumental
ADL
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a narrowing of the pharyngeal airway.
Pharyngolaryngeal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pharyngolaryngeal region.
Pleural effusion
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; intervention
indicated (e.g., diuretics or
limited therapeutic
thoracentesis)
Symptomatic with respiratory
distress and hypoxia; surgical
intervention including chest tube
or pleurodesis indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by an increase in amounts of fluid within the pleural cavity. Symptoms include shortness of breath, cough and marked chest discomfort.
Pleural hemorrhage
Asymptomatic; mild hemorrhage
confirmed by thoracentesis
Symptomatic or associated with
pneumothorax; chest tube
drainage indicated
>1000 ml of blood evacuated;
persistent bleeding (150-200
ml/hr for 2 - 4 hr); persistent
transfusion indicated; elective
operative intervention indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the pleural cavity.
Pleuritic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pleura.
Pneumonitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; oxygen indicated
Life-threatening respiratory
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma.
Pneumothorax
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; intervention
indicated (e.g., tube placement
without sclerosis)
Sclerosis and/or operative
intervention indicated;
hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormal presence of air in the pleural cavity resulting in the collapse of the lung.
Postnasal drip
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by excessive mucous secretion in the back of the nasal cavity or throat, causing sore throat and/or coughing.
Productive cough
Occasional/minimal production
of sputum with cough
Moderate sputum production;
limiting instrumental ADL
Persistent or copious production
of sputum; limiting self care ADL
 -
 -
Definition: A disorder characterized by expectorated secretions upon coughing.
Pulmonary edema
Radiologic findings only;
minimal dyspnea on exertion
Moderate dyspnea on exertion;
medical intervention indicated;
limiting instrumental ADL
Severe dyspnea or dyspnea at
rest; oxygen indicated; limiting
self care ADL
Life-threatening respiratory
compromise; urgent intervention
or intubation with ventilatory
support indicated
Death
Definition: A disorder characterized by accumulation of fluid in the lung tissues that causes a disturbance of the gas exchange that may lead to respiratory failure.
Pulmonary fibrosis
Mild hypoxemia; radiologic
pulmonary fibrosis <25% of lung
volume
Moderate hypoxemia; evidence
of pulmonary hypertension;
radiographic pulmonary fibrosis
25 - 50%
Severe hypoxemia; evidence of
right-sided heart failure;
radiographic pulmonary fibrosis
>50 - 75%
Life-threatening consequences
(e.g., hemodynamic/pulmonary
complications); intubation with
ventilatory support indicated;
radiographic pulmonary fibrosis
>75% with severe
honeycombing
Death
Definition: A disorder characterized by the replacement of the lung tissue by connective tissue, leading to progressive dyspnea, respiratory failure or right heart failure.
Pulmonary fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Limiting self care ADL;
endoscopic stenting or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
69
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an abnormal communication between the lung and another organ or anatomic site.
Pulmonary hypertension
Minimal dyspnea; findings on
physical exam or other
evaluation
Moderate dyspnea, cough;
requiring evaluation by cardiac
catheterization and medical
intervention
Severe symptoms, associated
with hypoxemia, right heart
failure; oxygen indicated
Life-threatening airway
consequences; urgent
intervention indicated (e.g.,
tracheotomy or intubation)
Death
Definition: A disorder characterized by an increase in pressure within the pulmonary circulation due to lung or heart disorder.
Respiratory failure
 -
 -
 -
Life-threatening consequences;
urgent intervention, intubation,
or ventilatory support indicated
Death
Definition: A disorder characterized by impaired gas exchange by the respiratory system resulting in hypoxemia and a decrease in oxygenation of the tissues that may be associated
with an increase in arterial levels of carbon dioxide.
Retinoic acid syndrome
Fluid retention; <3 kg of weight
gain; intervention with fluid
restriction and/or diuretics
indicated
Moderate signs or symptoms;
steroids indicated
Severe symptoms;
hospitalization indicated
Life-threatening consequences;
ventilatory support indicated
Death
Definition: A disorder characterized by weight gain, dyspnea, pleural and pericardial effusions, leukocytosis and/or renal failure originally described in patients treated with all-trans
retinoic acid.
Sinus disorder
Asymptomatic mucosal crusting;
blood-tinged secretions
Symptomatic stenosis or
edema/narrowing interfering
with airflow; limiting instrumental
ADL
Stenosis with significant nasal
obstruction; limiting self care
ADL
Necrosis of soft tissue or bone;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by involvement of the paranasal sinuses.
Sleep apnea
Snoring and nocturnal sleep
arousal without apneic periods
Moderate apnea and oxygen
desaturation; excessive daytime
sleepiness; medical evaluation
indicated; limiting instrumental
ADL
Oxygen desaturation;
associated with hypertension;
medical intervention indicated;
limiting self care ADL
Cardiovascular or
neuropsychiatric symptoms;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by cessation of breathing for short periods during sleep.
Sneezing
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by the involuntary expulsion of air from the nose.
Sore throat
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL; limiting ability to swallow
 -
 -
Definition: A disorder characterized by of marked discomfort in the throat
Stridor
 -
 -
Respiratory distress limiting self
care ADL; medical intervention
indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a high pitched breathing sound due to laryngeal or upper airway obstruction.
Tracheal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
indicated (e.g., thoracoplasty,
chronic open drainage or
multiple thoracotomies)
Death
Definition: A disorder characterized by an abnormal communication between the trachea and another organ or anatomic site.
Tracheal mucositis
Endoscopic findings only;
minimal hemoptysis, pain, or
respiratory symptoms
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe pain; hemorrhage or
respiratory symptoms; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the trachea.
Tracheal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids)
Stridor or respiratory distress
limiting self care ADL;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a narrowing of the trachea.
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Voice alteration
Mild or intermittent change from
normal voice
Moderate or persistent change
from normal voice; still
understandable
Severe voice changes including
predominantly whispered
speech; may require frequent
repetition or face-to-face contact
for understandability; may
require assistive technology
 -
 -
Definition: A disorder characterized by a change in the sound and/or speed of the voice.
Wheezing
Detectable airway noise with
minimal symptoms
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe respiratory symptoms
limiting self care ADL; oxygen
therapy or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a high-pitched, whistling sound during breathing. It results from the narrowing or obstruction of the respiratory airways.
Respiratory, thoracic and
mediastinal disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
71
24. Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Alopecia
Hair loss of <50% of normal for
that individual that is not
obvious from a distance but only
on close inspection; a different
hair style may be required to
cover the hair loss but it does
not require a wig or hair piece to
camouflage
Hair loss of >=50% normal for
that individual that is readily
apparent to others; a wig or hair
piece is necessary if the patient
desires to completely
camouflage the hair loss;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by a decrease in density of hair compared to normal for a given individual at a given age and body location.
Body odor
Mild odor; physician intervention
not indicated; self care
interventions
Pronounced odor; psychosocial
impact; patient seeks medical
intervention
 -
 -
 -
Definition: A disorder characterized by an abnormal body smell resulting from the growth of bacteria on the body.
Bullous dermatitis
Asymptomatic; blisters covering
<10% BSA
Blisters covering 10 - 30% BSA;
painful blisters; limiting
instrumental ADL
Blisters covering >30% BSA;
limiting self care ADL
Blisters covering >30% BSA;
associated with fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by inflammation of the skin characterized by the presence of bullae which are filled with fluid.
Dry skin
Covering <10% BSA and no
associated erythema or pruritus
Covering 10 - 30% BSA and
associated with erythema or
pruritus; limiting instrumental
ADL
Covering >30% BSA and
associated with pruritus; limiting
self care ADL
 -
 -
Definition: A disorder characterized by flaky and dull skin; the pores are generally fine, the texture is a papery thin texture.
Erythema multiforme
Target lesions covering <10%
BSA and not associated with
skin tenderness
Target lesions covering 10 -
30% BSA and associated with
skin tenderness
Target lesions covering >30%
BSA and associated with oral or
genital erosions
Target lesions covering >30%
BSA; associated with fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by target lesions (a pink-red ring around a pale center).
Erythroderma
 -
Erythema covering >90% BSA
without associated symptoms;
limiting instrumental ADL
Erythema covering >90% BSA
with associated symptoms (e.g.,
pruritus or tenderness); limiting
self care ADL
Erythema covering >90% BSA
with associated fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by generalized inflammatory erythema and exfoliation. The inflammatory process involves > 90% of the body surface area.
Fat atrophy
Covering <10% BSA and
asymptomatic
Covering 10 - 30% BSA and
associated with erythema or
tenderness; limiting instrumental
ADL
Covering >30% BSA;
associated with erythema or
tenderness; limiting self-care
ADL
 -
 -
Definition: A disorder characterized by shrinking of adipose tissue.
Hirsutism
In women, increase in length,
thickness or density of hair in a
male distribution that the patient
is able to camouflage by
periodic shaving, bleaching, or
removal of hair
In women, increase in length,
thickness or density of hair in a
male distribution that requires
daily shaving or consistent
destructive means of hair
removal to camouflage;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by the presence of excess hair growth in women in anatomic sites where growth is considered to be a secondary male characteristic and under
androgen control (beard, moustache, chest, abdomen)
Hyperhidrosis
Limited to one site (palms,
soles, or axillae); self care
interventions
Involving >1 site; patient seeks
medical intervention; associated
with psychosocial impact
Generalized involving sites
other than palms, soles, or
axillae; associated with
electrolyte/hemodynamic
imbalance
 -
 -
Definition: A disorder characterized by excessive perspiration.
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
72
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Hypertrichosis
Increase in length, thickness or
density of hair that the patient is
either able to camouflage by
periodic shaving or removal of
hairs or is not concerned
enough about the overgrowth to
use any form of hair removal
Increase in length, thickness or
density of hair at least on the
usual exposed areas of the
body [face (not limited to
beard/moustache area)
plus/minus arms] that requires
frequent  shaving or use of
destructive means of hair
removal to camouflage;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by hair density or length beyond the accepted limits of normal in a particular body region, for a particular age or race.
Hypohidrosis
 -
Symptomatic; limiting
instrumental ADL
Increase in body temperature;
limiting self care ADL
Heat stroke
Death
Definition: A disorder characterized by reduced sweating.
Lipohypertrophy
Asymptomatic and covering
<10% BSA
Covering 10 - 30% BSA and
associated tenderness; limiting
instrumental ADL
Covering >30% BSA and
associated tenderness and
narcotics or NSAIDs indicated;
lipohypertrophy; limiting self
care ADL
 -
 -
Definition: A disorder characterized by hypertrophy of the subcutaneous adipose tissue at the site of multiple subcutaneous injections of insulin.
Nail discoloration
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by a change in the color of the nail plate.
Nail loss
Asymptomatic separation of the
nail bed from the nail plate or
nail loss
Symptomatic separation of the
nail bed from the nail plate or
nail loss; limiting instrumental
ADL
 -
 -
 -
Definition: A disorder characterized by loss of all or a portion of the nail.
Nail ridging
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by vertical or horizontal ridges on the nails.
Pain of skin
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the skin.
Palmar-plantar
erythrodysesthesia syndrome
Minimal skin changes or
dermatitis (e.g., erythema,
edema, or hyperkeratosis)
without pain
Skin changes (e.g., peeling,
blisters, bleeding, edema, or
hyperkeratosis) with pain;
limiting instrumental ADL
Severe skin changes (e.g.,
peeling, blisters, bleeding,
edema, or hyperkeratosis) with
pain; limiting self care ADL
 -
 -
Definition: A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet.
Periorbital edema
Soft or non-pitting
Indurated or pitting edema;
topical intervention indicated
Edema associated with visual
disturbance; increased
intraocular pressure, glaucoma
or retinal hemorrhage; optic
neuritis; diuretics indicated;
operative intervention indicated
 -
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid around the orbits of the face.
Photosensitivity
Painless erythema and
erythema covering <10% BSA
Tender erythema covering 10 -
30% BSA
Erythema covering >30% BSA
and erythema with blistering;
photosensitivity; oral
corticosteroid therapy indicated;
pain control indicated (e.g.,
narcotics or NSAIDs)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in sensitivity of the skin to light.
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
73
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Pruritus
Mild or localized; topical
intervention indicated
Intense or widespread;
intermittent; skin changes from
scratching (e.g., edema,
papulation, excoriations,
lichenification, oozing/crusts);
oral intervention indicated;
limiting instrumental ADL
Intense or widespread;
constant; limiting self care ADL
or sleep; oral corticosteroid or
immunosuppressive therapy
indicated
 -
 -
Definition: A disorder characterized by an intense itching sensation.
Purpura
Combined area of lesions
covering <10% BSA
Combined area of lesions
covering 10 - 30% BSA;
bleeding with trauma
Combined area of lesions
covering >30% BSA;
spontaneous bleeding
 -
 -
Definition: A disorder characterized by hemorrhagic areas of the skin and mucous membrane. Newer lesions appear reddish in color. Older lesions are usually a darker purple color
and eventually become a brownish-yellow color.
Rash acneiform
Papules and/or pustules
covering <10% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness
Papules and/or pustules
covering 10 - 30% BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness; associated with
psychosocial impact; limiting
instrumental ADL
Papules and/or pustules
covering >30% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness; limiting self care
ADL; associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering any % BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness and are associated
with extensive superinfection
with IV antibiotics indicated; life-
threatening consequences
Death
Definition: A disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest and back.
Rash maculo-papular
Macules/papules covering
<10% BSA with or without
symptoms (e.g., pruritus,
burning, tightness)
Macules/papules covering 10 -
30% BSA with or without
symptoms (e.g., pruritus,
burning, tightness); limiting
instrumental ADL
Macules/papules covering
>30% BSA with or without
associated symptoms; limiting
self care ADL
 -
 -
Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbillform rash, it is one of the most common cutaneous adverse
events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus.
Scalp pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the skin covering the top and the back of the head.
Skin atrophy
Covering <10% BSA;
associated with telangiectasias
or changes in skin color
Covering 10 - 30% BSA;
associated with striae or
adnexal structure loss
Covering >30% BSA;
associated with ulceration
 -
 -
Definition: A disorder characterized by the degeneration and thinning of the epidermis and dermis.
Skin hyperpigmentation
Hyperpigmentation covering
<10% BSA; no psychosocial
impact
Hyperpigmentation covering
>10% BSA; associated
psychosocial impact
 -
 -
 -
Definition: A disorder characterized by darkening of the skin due to excessive melanin deposition.
Skin hypopigmentation
Hypopigmentation or
depigmentation covering <10%
BSA; no psychosocial impact
Hypopigmentation or
depigmentation covering >10%
BSA; associated psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by loss of skin pigment.
Skin induration
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration, unable to
slide or pinch skin; limiting joint
movement or orifice (e.g.,
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by an area of hardness in the skin.
Skin ulceration
Combined area of ulcers <1 cm;
nonblanchable erythema of
intact skin with associated
warmth or edema
Combined area of ulcers 1 - 2
cm; partial thickness skin loss
involving skin or subcutaneous
fat
Combined area of ulcers >2 cm;
full-thickness skin loss involving
damage to or necrosis of
subcutaneous tissue that may
extend down to fascia
Any size ulcer with extensive
destruction, tissue necrosis, or
damage to muscle, bone, or
supporting structures with or
without full thickness skin loss
Death
Definition: A disorder characterized by circumscribed, inflammatory and necrotic erosive lesion on the skin.
Alexion Confidential
Page 767 of 979


CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
74
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Stevens-Johnson syndrome
 -
 -
Skin sloughing covering <10%
BSA with associated signs (e.g.,
erythema, purpura, epidermal
detachment and mucous
membrane detachment)
Skin sloughing covering 10 -
30% BSA with associated signs
(e.g., erythema, purpura,
epidermal detachment and
mucous membrane
detachment)
Death
Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the
mucous membranes.
Telangiectasia
Telangiectasias covering <10%
BSA
Telangiectasias covering >10%
BSA; associated with
psychosocial impact
 -
 -
 -
Definition: A disorder characterized by local dilatation of small vessels resulting in red discoloration of the skin or mucous membranes.
Toxic epidermal necrolysis
 -
 -
 -
Skin sloughing covering >=30%
BSA with associated symptoms
(e.g., erythema, purpura, or
epidermal detachment)
Death
Definition: A disorder characterized by greater than 30% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the
mucous membranes.
Urticaria
Urticarial lesions covering <10%
BSA; topical intervention
indicated
Urticarial lesions covering 10 -
30% BSA; oral intervention
indicated
Urticarial lesions covering >30%
BSA; IV intervention indicated
 -
 -
Definition: A disorder characterized by an itchy skin eruption characterized by wheals with pale interiors and well-defined red margins.
Skin and subcutaneous tissue
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 768 of 979


CTCAE 4.03 - June 14, 2010 : Social circumstances 
75
25. Social circumstances
Social circumstances
Grade
Adverse Event
1
2
3
4
5
Menopause
Menopause occurring at age 46
- 53 years of age
Menopause occurring at age 40
- 45 years of age
Menopause occurring before
age 40 years of age
 -
 -
Definition: A disorder characterized by the permanent cessation of menses, usually defined by 12 consecutive months of amenorrhea in a woman over 45 years of age.
Social circumstances - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 769 of 979


CTCAE 4.03 - June 14, 2010 : Surgical and medical procedures 
76
26. Surgical and medical procedures
Surgical and medical procedures
Grade
Adverse Event
1
2
3
4
5
Surgical and medical
procedures - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 770 of 979


CTCAE 4.03 - June 14, 2010 : Vascular disorders 
77
27. Vascular disorders
Vascular disorders
Grade
Adverse Event
1
2
3
4
5
Capillary leak syndrome
 -
Symptomatic; medical
intervention indicated
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by leakage of intravascular fluids into the extravascular space. This syndrome is observed in patients who demonstrate a state of generalized
leaky capillaries following shock syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. It can lead to generalized edema and multiple organ
failure.
Flushing
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Symptomatic, associated with
hypotension and/or tachycardia;
limiting self care ADL
 -
 -
Definition: A disorder characterized by episodic reddening of the face.
Hematoma
Mild symptoms; intervention not
indicated
Minimally invasive evacuation or
aspiration indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel.
Hot flashes
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an uncomfortable and temporary sensation of intense body warmth, flushing, sometimes accompanied by sweating upon cooling.
Hypertension
Prehypertension (systolic BP
120 - 139 mm Hg or diastolic
BP  80 - 89 mm Hg)
Stage 1 hypertension (systolic
BP 140 - 159 mm Hg or
diastolic BP 90 - 99 mm Hg);
medical intervention indicated;
recurrent or persistent (>=24
hrs); symptomatic increase by
>20 mm Hg (diastolic) or to
>140/90 mm Hg if previously
WNL; monotherapy indicated
Pediatric: recurrent or persistent
(>=24 hrs) BP >ULN;
monotherapy indicated
Stage 2 hypertension (systolic
BP >=160 mm Hg or diastolic
BP >=100 mm Hg); medical
intervention indicated; more
than one drug or more intensive
therapy than previously used
indicated
Pediatric: Same as adult
Life-threatening consequences
(e.g., malignant hypertension,
transient or permanent
neurologic deficit, hypertensive
crisis); urgent intervention
indicated
Pediatric: Same as adult
Death
Definition: A disorder characterized by a pathological increase in blood pressure; a repeatedly elevation in the blood pressure exceeding 140 over 90 mm Hg.
Hypotension
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention or
hospitalization indicated
Life-threatening and urgent
intervention indicated
Death
Definition: A disorder characterized by a blood pressure that is below the normal expected for an individual in a given environment.
Lymph leakage
 -
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the loss of lymph fluid into the surrounding tissue or body cavity.
Lymphedema
Trace thickening or faint
discoloration
Marked discoloration; leathery
skin texture; papillary formation;
limiting instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by excessive fluid collection in tissues that causes swelling.
Lymphocele
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by a cystic lesion containing lymph.
Peripheral ischemia
 -
Brief (<24 hrs) episode of
ischemia managed non-
surgically and without
permanent deficit
Recurring or prolonged (>=24
hrs) and/or invasive intervention
indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by impaired circulation to an extremity.
Phlebitis
 -
Present
 -
 -
 -
Definition: A disorder characterized by inflammation of the wall of a vein.
Superficial thrombophlebitis
 -
Present
 -
 -
 -
Definition: A disorder characterized by a blood clot and inflammation involving a superficial vein of the extremities.
Alexion Confidential
Page 771 of 979


CTCAE 4.03 - June 14, 2010 : Vascular disorders 
78
Vascular disorders
Grade
Adverse Event
1
2
3
4
5
Superior vena cava syndrome
Asymptomatic; incidental finding
of SVC thrombosis
Symptomatic; medical
intervention indicated (e.g.,
anticoagulation, radiation or
chemotherapy)
Severe symptoms; multi-
modality intervention indicated
(e.g., anticoagulation,
chemotherapy, radiation,
stenting)
Life-threatening consequences;
urgent multi-modality
intervention indicated (e.g.,
lysis, thrombectomy, surgery)
Death
Definition: A disorder characterized by obstruction of the blood flow in the superior vena cava. Signs and symptoms include swelling and cyanosis of the face, neck, and upper arms,
cough, orthopnea and headache.
Thromboembolic event
Venous thrombosis (e.g.,
superficial thrombosis)
Venous thrombosis (e.g.,
uncomplicated deep vein
thrombosis), medical
intervention indicated
Thrombosis (e.g.,
uncomplicated pulmonary
embolism [venous], non-embolic
cardiac mural [arterial]
thrombus), medical intervention
indicated
Life-threatening (e.g.,
pulmonary embolism,
cerebrovascular event, arterial
insufficiency); hemodynamic or
neurologic instability; urgent
intervention indicated
Death
Definition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via the blood stream.
Vasculitis
Asymptomatic, intervention not
indicated
Moderate symptoms, medical
intervention indicated
Severe symptoms, medical
intervention indicated (e.g.,
steroids)
Life-threatening; evidence of
peripheral or visceral ischemia;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving the wall of a vessel.
Visceral arterial ischemia
 -
Brief (<24 hrs) episode of
ischemia managed medically
and without permanent deficit
Prolonged (>=24 hrs) or
recurring symptoms and/or
invasive intervention indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a decrease in blood supply due to narrowing or blockage of a visceral (mesenteric) artery.
Vascular disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 772 of 979


28. Publication Information
NIH Publication No. 09-5410
Revised June 2010
Reprinted June 2010
J[TUTE 
Alexion Confidential
Page 773 of 979


SYNT001 
 
8 June 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 4.0 
 
Confidential 
Page 94 of 96 
Syntimmune, Inc. 
APPENDIX 2. PEMPHIGUS DISEASE AREA INDEX (PDAI) 
 
Pemphigus Disease Area Index (PDAI) 
Sk;n 
; ; 
, " 
E,OSimlBiisten or new erythema 
, 
, , 
1 
up '0 m " >2 om " any 
I 
diameter. om " > 6 em 
., 
, 2·31"';00'.0' I"",, Nlo > 2 om 
diameter. om "» 
:1-0 
. 
I 
Ii 
" , 
Scalp 
Bos;on/BIi51er. or new erythema 
, 
erythema 
, , 
, 
, in 
""a<i"ant 
, p,nent 
, Nle "".<i"ant5 
, three ""adrants 
wilde slcu' > 6 em 
" 
1 , 2_3 1" .. ms 
3 
2 I""ons >2 em 
, 
, 
, 
, , 
, 
T,,"" , 
i,.l' Score: I 
Sl'ore 
Alexion Confidential
Page 774 of 979


SYNT001 
 
8 June 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 4.0 
 
Confidential 
Page 95 of 96 
Syntimmune, Inc. 
APPENDIX 3. AUTOIMMUNE BULLOUS DISEASE QUALITY OF LIFE 
(ABQOL) QUESTIONNAIRE 
Alexion Confidential
Page 775 of 979


ABQOL Questionnaire 
 
 
Name: _______________________________________  
  Date: _________________ 
 
DOB: __________________        Sex:     M / F  
Contact Number: _______________ 
 
Pemphigus Subtype:  □  Pemphigus Vulgaris 
 
□  Epidermolysis Bullosa Aquisita 
 
 
 
                                    □  Bullous Pemphigoid 
 
□  Linear IgA Bullous Dermatoses 
 
                                    □  Pemphigus Follaceus  
□  Mucous Membrane Pemphigoid 
 
                                    □  Other  ________________________________________ 
 
The following questions ask about the ways in which blistering disease treatments affect your 
quality of life.  
 
Please choose an option from the right hand column which most closely correlates to how you 
felt within the last week. 
 
Please time your survey in minutes and seconds – start time                              AM/PM 
 
 
 
1. In regards to your blistering disease, 
does your skin burn, sting or hurt in 
any way? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
2. In regards to your blistering disease, 
does your skin itch? 
      
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
3. Have you had to change your 
clothing because of your blistering 
disease? 
    
 
 
 
◌    I have to be very careful with how tight  
      my clothing is and what materials they 
      are made of – I have had to change what 
      I wear all the time 
◌    I have had to change most of the things I  
      wear 
◌    I have had to change some of the things I 
      wear 
◌    I have never had to change what I wear 
 
4. Do you notice your skin heals slowly?  
       
 
 
 
◌    I notice this all the time 
◌    I notice this sometimes 
◌    I notice this occasionally 
◌    I have never had this problem 
 
5. Do you have difficulty bathing or 
showering because of your blistering 
disease? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
Alexion Confidential
Page 776 of 979


 
6. In regards to your blistering disease, 
does your mouth have erosions 
which are painful? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
7. In regards to your blistering disease, 
do your gums bleed easily? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
8. Does your blistering disease results 
in you having to avoid food or drinks 
that you enjoy? 
       
 
 
 
◌    I can no longer eat any of the foods I 
      used to enjoy 
◌    I can eat some of the foods I enjoy 
◌    I can eat most of the foods I enjoy 
◌    I can eat anything I like 
 
9. As a result of your blistering disease, 
are you embarrassed about your 
appearance? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
10. Do you feel depressed or angry 
because of your blistering disease? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
11. Do you feel anxious or cannot relax 
as a result of your blistering disease? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
12. Do you worry that friends and family 
find your blistering skin condition 
tiresome? 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
 
13. Is your blistering disease causing 
sexual difficulties? 
       
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
 
14. Does your blistering disease affect 
relationships with friends or loved 
ones? 
 
 
 
◌    I have had to end a relationship because 
      of my disease OR I cannot have a  
      relationship because of my disease 
◌    Relationships are very difficult 
◌    Relationships are a little difficult 
◌    This has not affected my relationships 
 
 
Alexion Confidential
Page 777 of 979


 
15. Does your blistering disease affect 
your social life? 
 
 
 
◌    I cannot go out to socialize any more 
◌    I can only go to some social events 
◌    I can go to most social events 
◌    My social life is not affected 
 
16. Does your blistering disease affect 
your work or study? 
 
 
 
◌    Yes, I can no longer work or study 
◌    Yes, I find it difficult to work or study 
◌    Yes, it is a little harder than before to 
       work or study 
◌    No, I am not affected OR not applicable 
      (N/A) 
 
17. Do employers discriminate against 
you because of your blistering 
disease? 
 
 
 
◌    I cannot find a job due to my blistering 
      disease 
◌    I have had to change jobs due to my 
      blistering disease 
◌    I still have my job but it is more difficult 
      than before 
◌    My employers are completely 
      understanding OR not applicable (N/A) 
 
 
 
 
 
 
Please indicate the time taken to finish the survery:                 minutes              seconds 
 
 
 
 
Thank you for taking the time to complete this questionnaire 
Alexion Confidential
Page 778 of 979


SYNT001 
 
8 June 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 4.0 
 
Confidential 
Page 96 of 96 
Syntimmune, Inc. 
APPENDIX 4. SKINDEX-29 
 
Alexion Confidential
Page 779 of 979


Skindex29 
MMChren,1996 
 
 
Skindex29 – United States/English – Original version 
Skindex29_AU2.0_eng-USori.doc 
 
 
 
 
 
 
 
DERMATOLOGY SURVEY 
 
 
 
 
 
This survey concerns the skin condition which has bothered you the most during the 
past four weeks.          
 
 
                                                                                                                                                                                                                   
 
 
 
 
                            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alexion Confidential
Page 780 of 979


Skindex29 
MMChren,1996 
 
 
Skindex29 – United States/English – Original version 
Skindex29_AU2.0_eng-USori.doc 
 
These questions concern your feelings over the past 4 weeks about the skin condition that has  
bothered you the most. Check the answer that comes closest to the way you have been feeling. 
 
 
HOW OFTEN DURING THE PAST FOUR WEEKS  
DO THESE STATEMENTS DESCRIBE YOU? 
___________________________________________ 
 
NEVER         RARELY      SOMETIMES       OFTEN          ALL THE   
 
TIME 
___________________________________________ 
 
  1. My skin hurts    .    .    .   .    .    .   .    .    .   .    .    .   .    .    .    . 
 
   1              2              3               4              5 
 
  2. My skin condition affects how well I sleep    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
  3. I worry that my skin condition may be serious    .    .    .    .    . 
 
   1              2              3               4              5 
 
  4. My skin condition makes it hard to work or do hobbies    .    . 
 
   1              2              3               4              5 
 
  5. My skin condition affects my social life   .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
  6. My skin condition makes me feel depressed    .    .    .    .    .   
 
   1              2              3               4              5 
 
  7. My skin condition burns or stings    .    .    .    .    .    .    .     . 
 
   1              2              3               4              5 
 
  8. I tend to stay at home because of my skin condition    .    .    . 
 
   1              2              3               4              5 
 
  9. I worry about getting scars from my skin condition    .    .    .   
 
   1              2              3               4              5 
 
10. My skin itches    .    .    .    .    .    .    .    .    .    .    .    .    .    .     
 
   1              2              3               4              5 
 
11. My skin condition affects how close I can be with those I love . 
 
   1              2              3               4              5 
 
12. I am ashamed of my skin condition    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
13. I worry that my skin condition may get worse    .    .    .    .    . 
 
   1              2              3               4              5 
 
14. I tend to do things by myself because of my skin condition    . 
 
   1              2              3               4              5 
 
15. I am angry about my skin condition    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
16. Water bothers my skin condition (bathing, washing hands)    . 
 
   1              2              3               4              5 
 
17. My skin condition makes showing affection difficult    .    .    . 
 
   1              2              3               4              5 
 
18. I worry about side-effects from skin medications / treatments  . 
 
   1              2              3               4              5 
 
19. My skin is irritated    .    .    .    .    .    .    .    .    .    .    .    .    .     
 
   1              2              3               4              5 
 
20. My skin condition affects my interactions with others    .    .     
 
   1              2              3               4              5 
 
Please turn to next page 
 
Alexion Confidential
Page 781 of 979


Skindex29 
MMChren,1996 
 
 
Skindex29 – United States/English – Original version 
Skindex29_AU2.0_eng-USori.doc 
These questions concern your feelings over the past 4 week about the skin condition that has  
bothered you the most. Check the answer that comes closest to the way you have been feeling. 
 
 
HOW OFTEN DURING THE PAST 4 WEEK  
DO THESE STATEMENTS DESCRIBE YOU? 
_____________________________________________ 
 
NEVER         RARELY      SOMETIMES       OFTEN         ALL THE  
                                                                                             TIME 
_____________________________________________ 
 
21. I am embarrassed by my skin condition    .    .    .    .    .    .    .    
 
   1              2              3               4              5 
 
22. My skin condition is a problem for the people I love    .    .    .  
 
   1              2              3               4              5 
 
23. I am frustrated by my skin condition    .    .    .    .    .    .    .    .  
 
   1              2              3               4              5 
 
24. My skin is sensitive    .    .    .    .    .    .    .    .    .    .    .    .    .   
 
   1              2              3               4              5 
 
25. My skin condition affects my desire to be with people    .    .  
 
   1              2              3               4              5 
 
26. I am humiliated by my skin condition    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
27. My skin condition bleeds    .    .    .    .    .    .    .    .    .    .    .    
 
   1              2              3               4              5 
 
28. I am annoyed by my skin condition    .    .    .    .    .    .    .    .   
 
   1              2              3               4              5 
 
29. My skin condition interferes with my sex life    .    .    .    .    .  
 
   1              2              3               4              5 
 
30. My skin condition makes me tired    .    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
 
 
 
Alexion Confidential
Page 782 of 979


SYNT001-103 
 
08 June 2018 
Protocol Amendment Summary of Changes 
 
Version 4.0 
 
Confidential 
Page 1 of 10 
Syntimmune, Inc. 
PROTOCOL AMENDMENT 
SUMMARY OF CHANGES 
 
Protocol Title: 
Phase 1b/2 Multicenter, Open-Label, Safety, and Dose-Finding Study 
of SYNT001 in Subjects with Pemphigus (Vulgaris or Foliaceus) 
 
 
Protocol Number: 
SYNT001-103 
 
 
Study Drug: 
SYNT001 
 
 
Sponsor: 
Syntimmune, Inc. 
116 Huntington Avenue 
Suite 301 
Boston, MA 02116 
 
 
Medical Monitor: 
 
Wallace House 
17-21 Maxwell Place Stirling, Scotland FK81JU 
Mobile Phone: 
 
Office Phone: 
 ext. 
 
 
 
  Original Protocol 
18 January 2017 
1.0 
21 March 2017 
2.0 
12 April 2017 
3.0 
10 October 2017 
4.0 
08 June 2018 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document is the property of Syntimmune, Inc. This document contains confidential information, which should 
not be copied, referred to, released, or published without written approval from Syntimmune. Investigators are 
cautioned that the information given in this brochure might be subject to change and revision. Any conclusion 
regarding efficacy and safety must be considered provisional. 
 
 
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SYNT001-103 
 
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Protocol Amendment Summary of Changes 
 
Version 4.0 
 
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BACKGROUND 
Protocol amendment Version 4.0 of the SYNT001-103 protocol was issued on 07 June 2018.  
Since the design of the original protocol, the Sponsor has completed longer SYNT001 
nonclinical toxicology studies (14-weeks vs 5-weeks). Additionally, the Sponsor has gained 
experience with conducting the trial and has learned about logistical issues affecting the 
successful execution of the protocol to obtain preliminary safety and effectiveness data.   
For a number of reasons, including inclusion and exclusion criteria, prohibited and permitted 
medications, and logistical burden of study conduct (eg, number and complexity of study visits), 
enrollment into study SYNT001-103 has been far slower than anticipated. Further, as currently 
designed, the study will provide only limited information on dose selection to support further 
clinical development (eg, duration of dosing and potential role of a loading dose approach cannot 
be assessed). Preliminary safety results support good safety and tolerability of SYNT001 at 10 
mg/kg for 5 weekly doses. Regarding efficacy, data thus far support proof-of-concept for 
SYNT001 in pemphigus; however, it appears that longer dosing will be needed to maintain 
response and higher doses may lead to a higher response rate and robustness of response. 
Syntimmune therefore is amending the SYNT001-103 protocol to address the above issues. The 
Study Assessments have been extensively modified to decrease the complexity of the study and 
make the execution of the study more acceptable to potential subjects and more feasible for study 
sites; changes include the removal of 7 study visits and organization of study visits into major 
and minor visits with more consistent assessments. It is anticipated that these changes should 
facilitate study enrollment, especially when combined with additional adjustments to the 
inclusion and exclusion criteria and prohibited medications, including removal of the upper limit 
on body mass index (previously was 39.9 kg/m2) and allowance for steroid tapering prior to 
screening. To better inform dose selection and pivotal trial design, dosing in Cohort 3 has been 
extended from 5 weekly doses to 14, and an optional Cohort 4 has been added to allow 
exploration of an alternate dose level (maximum of 45 mg/kg) and dosing duration (up to 14 
weekly doses) to be determined following data review by the Dose Escalation Committee (DEC). 
This option could include a loading dose followed by lower weekly doses. To gain more 
information on dose selection, endpoints regarding extent of lowering of total IgG levels and 
change in the Pemphigus Disease Area Index (PDAI) total activity score from baseline have been 
added as a primary objective in addition to safety.  
Administrative changes in the amendment include changes in the medical monitor and Sponsor 
contact information. General grammatical, typographical, and formatting updates have been 
made throughout the document to provide consistency and clarity, reduce redundancy, and 
improve readability. 
 
 
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SYNT001-103 
 
08 June 2018 
Protocol Amendment Summary of Changes 
 
Version 4.0 
 
Confidential 
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Syntimmune, Inc. 
SUMMARY OF CHANGES 
With this update, the following changes since Version 3.0 have been made: 
Table 1. 
Summary of Changes: Protocol Version 4.0 
Section 
Number and 
Title 
Description of Change 
Cover Page 
 
Protocol Title  
 Revised to indicate updated Phase 1b/2 status and dose finding intent to 
commence under Cohorts 2, 3, and optional Cohort 4.   
 Removed tolerability as a quantifiable measurement as the focus of the 
trial will be safety. 
 Medical term for primary indication revised from chronic pemphigus to 
pemphigus to more closely reflect eligibility criteria and terminology 
commonly used by treating physicians. 
Other 
 The Medical Monitor’s title and Syntimmune Inc. address have been 
updated for accuracy. 
Section 1, 
Protocol 
Synopsis  
The protocol synopsis has been modified to more closely align with 
industry standards and the National Institute of Health (NIH)/Food and 
Drug Administration (FDA) protocol template.  Below is a summary of 
changes; refer to the changes described for the individual protocol sections 
for more detail: 
 Added the sponsor, Syntimmune Inc. 
 Indicated the company’s intentions to open study sites outside the 
United States of America to support subject enrollment. 
 The study rationale is now an overview of protocol Section 2, 
Background and Rationale. 
 Study objectives have been grouped with study endpoints; study 
objectives now only appear once in the protocol synopsis. 
 The study design not only describes changes to cohorts but now 
includes the role of the Dose Escalation Committee (DEC) and 
stopping and dose escalation rules. 
 Study methodology has been separated from study design and is now in 
a stand-alone section. 
 The inclusion and exclusion criteria have been modified as described in 
Section 6 Study Population. 
 Additional detail has been added to Duration of subject participation 
and Study drug, dosage, and administration. 
 Prohibited Concomitant treatments has now been changed to Permitted 
and Prohibited Concomitant Treatments. 
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 The following sections have been removed from the synopsis, but 
content remains in the protocol text to reduce redundancy:  
o Safety assessments 
o Pharmacokinetics 
o Pharmacodynamics/Activity 
o Immunogenicity 
o Skin biopsy 
o Photography 
 In the statistical consideration section, the intent to treat (ITT) study 
population has been changed to Safety population.  Analyses have been 
updated to reflect additional detail included in the study endpoints. 
o Subheadings have been added to clearly delineated content. 
Study Diagram 
Study Diagram has been added changing the dose, number of doses and 
timing of DEC reviews for Cohorts 2 and 3 and adding optional Cohort 4 
to reflect changes to study design. 
 Cohort 1 number of subjects has been modified from 8 to up to 8. 
 Cohort 2 dose has been modified to < 30 mg/kg and the number of 
subjects reduced from 8 to 4. 
 Cohort 3 has been added with < 30 mg/kg and number of doses 
extended to 14 in 4 subjects. 
 The optional cohort has shifted from Cohort 3 to 4 with a maximum 
dose of 45 mg/kg and maximum number of doses out to 14. 
 Timing of DEC data reviews for Cohorts 2 and 3 is after 50% of 
subjects reach Day 42. 
 The DEC may now lower the dose within a cohort and add up to 4 
additional patients to Cohorts 2, 3, and optional Cohort 4. 
Schedule of 
Events 
Table 3 (Cohort 2) 
 Efforts were made to simplify the study of events to reduce subject and 
site burden and increase flexibility with visit scheduling, as described 
below: 
o A total of 7 visits have been removed (Days 1, 2, 5, 12, 19, 29, 
and 20). 
o Day 33 has been changed to Day 35 to shift to a weekly visit 
schedule out to 1 month after the final dose. 
o Visit windows have been increased as outlined below: 
 Weekly visits: ± 1 day 
 Every other week visit: ± 3 days 
 Monthly visits: ± 5 days 
 Specific changes to the Schedule of Events as compared to Cohort 1 
(Table 2) are described below. Many of the changes support 
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categorization of Treatment and Follow-up visits into major and minor 
visits.  All minor visits have the same schedule of testing. Tests 
conducted at major visits are now more consistent. 
o Pemphigus Disease Area Index (PDAI), physical examination, 
and anti-desmoglein (1 and 3) antibody titers are being done at 
every visit. 
o Tetanus and Varicella Zoster testing will now be done at set 
timepoints (Baseline, Day 56, and Day 112). 
o Pharmacokinetic (PK) sampling will only be done at Baseline 
and the day of the final SYNT001 final dose. 
o Immunogenicity is no longer done at Day 84. 
o Testing of biomarkers has been reduced [complement 
component 3 (C3), anti-epithelial cell antibody (AECA), 
RNAseq, urine immunoglobulin G (IgG), and 
immunophenotyping].  These biomarkers are now only done at 
Baseline, Day 35, and Day 56. 
o Photography is no longer done at Day 14 and Day 84. 
o Added Health-related Quality of Life (HR-QoL) questionnaires 
to Baseline, Day 35, Day 56, and Day 112. 
Table 4 (Cohort 3) 
 Assessments done at Screening, Baseline and Follow-up visits align 
with Cohort 2 (Table 3). 
 Treatment will extend from 5 to 14 doses and subjects will receive  
weekly IV infusions during this time.   
o Assessments at the mid-point of dosing and the final dose 
(major visits) align with Cohort 2 (Table 3).   
o Assessments at all other treatment visits (minor visits) also 
align with Cohort 2 (Table 3). 
Table of 
Contents 
The overall structure of the document has been modified slightly to 
improve readability and usability: 
 Study Objectives and Endpoints have been logically grouped together 
under Section 3.0. 
 Study Drug section has been moved up in the protocol due to its 
importance and now falls directly after Study Objectives and 
Endpoints.  The content has not fundamentally changed but has been 
organized into recognizable sections for easy reference. 
 The order of Study Procedures in Section 7 now more closely reflects 
the Schedule of Events. 
 A section has been added for HR-QoL questonnaires to mirror the 
updated Schedule of Events. 
 Study Assessments section now details Cohort 2 Schedule of Events 
and the extended dosing out to 14 doses for Cohort 3. 
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 Section 9 title has been changed from Removing Subjects from Study 
to Study Rules. Lost to Follow-up was added as a sub-section. 
 The Safety section has been reorganized for improved readability and 
now includes the Procedures in Case of Emergency that was previously 
at the start of the document.   
 Vaccinations, Management of Allergic or Infusion Reactions, and 
Potential Immune Effects are grouped under Warnings and Precautions 
(Section 10.3). 
 Overdose has been added to Other Safety Considerations (Section 
10.5). 
 Multiple sections were collapsed into 1 comprehensive section titled 
Study Management (Section 12).   
 Tables have been added to reflect the new study design and 
assessments by cohort. 
 Appendices have been added for the new HR-QoL questionnaires, the 
Autoimmune Bullous Disease Quality of Life (ABQoL) and Skindex-
29. 
 Figure 1 was added to illustrate the study design. 
List of 
Abbreviations 
The table was updated to include all abbreviations throughout the synopsis 
and protocol text.  Each abbreviation was defined the first time used in 
both the synopsis and protocol text. 
Section 2, 
Background and 
Rationale 
Background and Rationale 
 Text has been added to describe SYNT001’s predicted mechanism of 
action. 
 Additional indications identified as IgG-mediated autoimmune 
disorders have been added. 
Study Rationale 
 The study rationale has been updated to include dose activity criteria 
and remove tolerability criteria. 
Selection of Doses in this Study 
 Non-human primate (NHP) data is now described before the healthy 
volunteer study (Phase 1a) to follow the chronology of when the 
studies completed. Information about the completed 14-week 
toxicology study has been added. 
Section 3, Study 
Objectives and 
Endpoints 
 Study objectives and endpoints have not fundamentally changed but 
have been rewritten to more closely align with industry standards. 
 An objective and endpoint have been added for dose selection to define 
criteria to select a dose for future clinical testing. 
 Edits have been made to ensure each objective has a corresponding 
endpoint and vice versa.
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 An objective and endpoint have been added for the HR-QoL 
questionnaires; the HR-QoL will be used to better understand the 
subject experience when being dosed with SYNT001. 
Section 4, Study 
Drug 
Description of SYNT001 
 Windows for the SYNT001 infusion duration (±15 minutes) have been 
added to account for procedural and patient differences. 
Dose Requirements 
 It has been clarified that subject doses will be limited to 5000 mg.  A 
subject with a body weight that extrapolates to a dose > 5000 mg, will 
only receive 5000 mg.
Section 5, Study 
Design 
The study design has been updated to reflect changes in dose, number of 
doses and timing of DEC reviews for Cohorts 2 and 3 and adding optional 
Cohort 4. 
 Cohort 1 number of subjects modified from 8 to up to 8. 
 Cohort 2 dose modified to < 30 mg/kg and reduced the number of 
subjects from 8 to 4. 
 Cohort 3 has been added with < 30 mg/kg and number of doses to 14 in 
4 subjects. 
 The optional cohort has shifted from Cohort 3 to 4 with a maximum 
dose of 45 mg/kg and maximum doses out to 14. 
 Timing of DEC Data Reviews for Cohorts 2 and 3 is after 50% of 
subjects reach Day 42. 
 The DEC may now lower the dose within a cohort and add up to 4 
additional patients in to Cohorts 2, 3, and optional Cohort 4. 
Study Rules were not included, as done in the corresponding synopsis 
section; instead Section 9 (Study Rules) is referenced. 
Section 6, Study 
Population 
Target Population 
 Based on the new study design, the total number of subjects has been 
updated to 20 with a possible additional 12 subjects pending DEC 
evaluation.   
o Enrollment into Cohort 2 onwards revised from 8 to 4 subjects 
with an additional optional 4 subjects per cohort pending DEC 
evaluation.    
Inclusion Criteria 
 #4b. Expanded list of concomitant immunosuppressants to include 
methotrexate, dapsone, cyclosporine, tacrolimus, sirolimus, 
cyclophosphamide. Parameter of stable dose raised from <10% to 
<25% change in dose and window narrowed from 6 weeks to 4 weeks 
prior to screening. 
 #4c. Change in dose of concomitant corticosteroids considered 
acceptable during the 2 weeks prior to screening changed from a 10% 
change in dose to an increase in dose by 50%.  
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 #4d. Expanded list of allowable topical therapies for pemphigus lesions 
to include low-strength hydrocortisone (≤ 1%), tacrolimus, sirolimus, 
pimecrolimus, and dexamethasone elixir solution. 
 #4e. If not on regular corticosteroids, no pulse corticosteroids are 
allowed in the 2 weeks prior to screening. 
 #5.  Eliminated upper body mass index (BMI) limit of 39.9 kg/m2. 
 #10. Added a PDAI total severity score of >4 at screening. 
Exclusion Criteria 
 #6.  Reduced intravenous immunoglobulin (IVIG) treatment window 
prior to screening from 60 days to 30 days. 
 #9.  Reduced plasmapheresis or immunoadsorption treatment window 
prior to screening from 60 to 30 days.   
 #11. Clarified that systemic or topical immunosuppressive drugs are 
excluded unless specified in the inclusion criteria.  
Section 7, Study 
Procedures 
 Pulse oximetry has been included under vital sign measurements. 
 Table 6 with timing windows for PK/pharmacodynamic (PD) 
Sampling, electrocardiogram (ECG), and Vital Sign Measure has been 
moved to the Study Procedures Section.   
o The timing windows for Cohorts 2, 3, and optional Cohort 4 
were added.   
o Windows were separated from the pharmacokinetic sampling 
windows.  
 RR Interval as a required part of the ECG assessments has been added 
back into the protocol. 
 Blood volumes for clinical laboratory measurements have been 
recalculated to align with changes to the Schedule of Events. 
 Serum tetanus antibody and varicella-zoster virus antibody testing has 
been simplified and will be done at set timepoints. 
 For Cohorts 2, 3, and optional Cohort 4, PK parameters studied will be 
maximum plasma concentration determined directly from the 
concentration-time profile (Cmax) and observed time to reach peak 
plasma concentration (Tmax). 
 Pharmacodynamic Assessment (Table 8) has been updated to include 
timing of testing for Cohorts 2 and 3.   
 Clarified that immunogenicity testing will also include determination of 
anti-drug antibody (ADA) titer. 
 Section for HR-QoL questionnaires has been added to mirror the 
updated Schedule of Events. 
 Optional skin biopsies will not be collected after Cohort 1. 
Prior and Concomitant Medications 
 Reordered and relocated language under newly created subsection 
headers, Permitted Medications and Prohibited Medications. Key 
changes include: 
Permitted Medications 
 #5. Use of medication to treat infusion reactions. 
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 #6.  Low-strength corticosteroids applied to a single lesion. 
 #7.  Topical tacrolimus, sirolimus or pimecrolimus applied to a 
single lesion. 
 #8.  Dexamethasone elixir solution for oral lesions. 
 #9.  Stable use of immunosuppressants: tacrolimus, sirolimus, 
pimecrolimus, methotrexate, cyclophosphamide, and dapsone.  
 #10. One month after the final dose of SYNT001, corticosteroids 
may be tapered at the Investigator’s discretion.  
Prohibited Medications 
 #4. IV corticosteroids prior to infusion (except in subjects who 
received corticosteroids for treatment of a prior infusion reaction to 
SYNT001).  
 #7.  Vaccinations post treatment window reduced from 56 days to 
28 days. 
 Deleted corticosteroid taper instructions.
Section 9, Study 
Rules 
Subject Withdrawal 
 Subjects that require a significant increase in dose(s) of anti-pemphigus 
medications(s) for the management of their pemphigus will be 
encouraged to return for follow-up visits to capture safety data. 
Dose Escalation Stopping Rule 
 The description of dose escalation stopping rules now reflects the new 
study design.   
 The DEC now has the ability to reduce the dose within a cohort and 
potentially add study subjects to a given cohort.
Section 10, 
Evaluation of 
Safety 
The content of this section has not changed substantially, but text has been 
reorganized to improve flow and ability to locate critical information in the 
case of a safety event. 
Section 11, 
Statistical 
Considerations 
 General design has been updated to mirror the protocol title. 
 Dose selection data will be evaluated based on IgG response and PDAI 
score reduction. 
 Study drug serum concentrations will be calculated by Cmax and Tmax 
for Cohorts 2, 3 and optional Cohort 4.
Section 12, 
Study 
Management 
 Study Administrative Structure table has been updated with Medical 
Director and a new Sponsor Contact information.  
 Informed Consent procedures have been edited to add International 
Council on Harmonisation Good Clinical Practice (ICH GCP) 
compliance language. 
 Subject confidentiality and privacy language have been added to clarify 
Health Insurance Portability and Accountability Act (HIPPA) 
confidentiality guarantees and data protection. 
 Audits and inspections may be performed by the sponsor to ensure 
validity of study data.
Global Changes 
 Edits and formatting changes have been made throughout to improve 
clarity and readability. 
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Syntimmune, Inc. 
 Typographical and formatting corrections as well as corrections for 
consistency have been made. 
 Renamed sections and subsections to reflect content and protocol 
naming conventions. Reordered language under modified or newly 
created subsection headers.   
 Consolidated language if repeated in more than one section of protocol. 
 Naming convention for sponsor changed from Syntimmune to Sponsor. 
 Chronic pemphigus revised to pemphigus to indicate accepted medical 
terminology. 
 Nomenclature for investigational product revised to study drug for 
consistency. 
 Medical Monitoring and Sponsor contact information updated. 
 
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SYNT001 
 
18 September 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 5.0 
 
Confidential 
Page 1 of 95 
Syntimmune, Inc. 
SYNTIMMUNE, INC. 
CLINICAL STUDY PROTOCOL 
A Phase 1b/2, Multicenter, Open-Label, Safety, and Dose-Finding Study of 
SYNT001 in Subjects with Pemphigus (Vulgaris or Foliaceus) 
 
Protocol Number: 
SYNT001-103 
IND Number: 
132727 
Study Drug: 
SYNT001 
Sponsor: 
Syntimmune, Inc. 
116 Huntington Avenue 
Suite 301 
Boston, MA 02116 
 
Medical Monitor: 
 
Wallace House 
17-21 Maxwell Place 
Stirling, Scotland FK81JU 
Mobile Phone: 
 
Office Phone: 
 ext. 
 
 
Original Protocol: 
18 January 2017 
Amendment 1.1: 
21 March 2017 
Amendment 2.0 
12 April 2017 
Amendment 3.0 
10 October 2017 
Amendment 4.0 
08 June 2018 
Amendment 5.0 
18 September 2018 
 
CONFIDENTIALITY STATEMENT 
The information contained herein is confidential and the proprietary property of Syntimmune, Inc. Any unauthorized 
use or disclosure of such information without the prior written authorization of Syntimmune is expressly prohibited. 
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SYNT00I 
Protocol SYNT00I-103 for Pemphigus 
SPONSOR SIGNATURE 
18 September 2018 
Amendment 5.0 
I have read and approve this protocol. My signature, in conjunction with the signature of the 
Investigator, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) Guideline for Good Clinical Practice (GCP), the United States Code of 
Federal Regulations (CFR), and the ethical principles that have their origins in the Declaration of 
Helsinki. 
 
Syntimmune, Inc. 
Confidential 
Date of Signature 
Page 2 of97 
Syntimmune, Inc. 
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SYNT001 
 
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Syntimmune, Inc. 
INVESTIGATOR SIGNATURE 
I have read and approve this protocol. My signature, in conjunction with the signature of the 
Sponsor, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) Guideline for Good Clinical Practice (GCP), the United States Code of 
Federal Regulations (CFR), and the ethical principles that have their origins in the Declaration of 
Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations. 
 
 
 
 
Investigator Signature 
 
Date of Signature 
 
 
 
Name of Investigator (please print) 
 
 
 
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SYNT001 
 
18 September 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 5.0 
 
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Page 4 of 95 
Syntimmune, Inc. 
1. 
SYNOPSIS 
Study title 
A Phase 1b/2, Multicenter, Open-Label, Safety, and Dose-Finding Study of 
SYNT001 in Subjects with Pemphigus (Vulgaris or Foliaceus) 
Sponsor 
Syntimmune, Inc. 
Protocol number 
SYNT001-103 
Clinical phase  
Phase 1b/2 
Number of study 
centers 
Approximately 20 global study sites 
Study rationale 
Pemphigus is a potentially life-threatening group of rare blistering 
autoimmune diseases that affect the skin and mucous membranes. The exact 
cause is unknown, though autoantibodies are thought to play an important 
pathogenic role in the mucosal and cutaneous manifestations in patients with 
pemphigus. 
The prognosis of pemphigus has markedly improved over the last decades with 
steroid therapy. Nevertheless, mortality remains an issue (1.6% to 12% of 
cases) (Hsu et al., 2016; Kasperkiewicz et al., 2017; Langan et al., 2008). In 
these cases, death typically occurs as a consequence of treatment-related 
systemic infections and in a smaller proportion, as a consequence of 
superinfected lesions. While steroids have greatly improved patient outcomes, 
they are associated with serious and long-lasting side effects; therefore, their 
use should be limited as much as possible. Although other currently available 
treatments for certain autoimmune disorders, including immunosuppressants, 
intravenous immunoglobulin (IVIG), plasmapheresis, and anti-CD20 
monoclonal antibodies (mAbs), such as rituximab, can be effective, they can 
be associated with significant adverse effects and delayed or non-durable 
responses.  
SYNT001 targets key mechanisms contributing to pathology in a variety of 
immunoglobulin G (IgG)-mediated autoimmune disorders. When administered 
to healthy subjects, SYNT001 has been shown to significantly decrease total 
IgG, as well as immune complexes with which IgG is associated. Based on 
these results, it is predicted that SYNT001 will also reduce the levels of 
pathogenic autoantibodies. This could lead to a decrease in the mucosal and 
cutaneous manifestations in patients with pemphigus. Moreover, the ability of 
SYNT001 to reduce circulating immune complexes (CICs) and the associated 
innate and adaptive immune responses may allow for sustained disease 
modification. Thus, this study is being conducted to evaluate the safety and 
immunogenicity and determine a minimally effective dose (MED) of 
intravenous (IV) SYNT001 in pemphigus patients.  
 
 
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SYNT001 
 
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Amendment 5.0 
 
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Syntimmune, Inc. 
Study objectives 
and endpoints 
The study objectives and their corresponding endpoints (primary, secondary, 
and exploratory) are detailed below. 
Primary Objectives 
Primary Endpoints 
Safety: To evaluate the safety of IV 
infusions of SYNT001 at different 
dose levels and dosing regimens in 
subjects with pemphigus (vulgaris or 
foliaceus) 
Safety: The evaluation of SYNT001 
safety based on vital signs, physical 
examinations, electrocardiograms 
(ECGs), clinical safety laboratory 
tests, the incidence of adverse events 
(AEs), treatment-emergent adverse 
events (TEAEs) and serious adverse 
events (SAEs) summarized by dose 
and dosing regimen, severity, and 
relationship to study drug 
Dose Selection: To determine a 
MED of SYNT001 as assessed by (i) 
total IgG level nadir and (ii) the 
proportion of subjects that meet the 
criteria for response by Pemphigus 
Disease Area Index total activity 
score (PDAI) 
Dose Selection: The determination 
of dose and dosing regimen of 
SYNT001 that achieves (i) total IgG 
level nadir decrease by ≥60% and 
≤90% from baseline and (ii) a PDAI 
total activity score of ≥50% 
reduction from baseline to allow 
further clinical development in 
subjects with pemphigus (vulgaris or 
foliaceus) 
Secondary Objectives 
Secondary Endpoints 
To evaluate the efficacy of doses of 
SYNT001 at different dose levels 
and dosing regimens on 
pharmacodynamics (PD) biomarkers 
The evaluation of PD biomarkers 
based on absolute serum levels and 
percent change from baseline of total 
IgG, IgG subtypes (IgG1-4), 
immunoglobulin A (IgA), 
immunoglobulin M (IgM), albumin, 
and CIC summarized by dose, 
dosing regimen and visit 
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SYNT001 
 
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Amendment 5.0 
 
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Syntimmune, Inc. 
To determine the pharmacokinetics 
(PK) of SYNT001 following IV 
infusions at different dose levels and 
dosing  regimens 
The determination of PK parameters 
including half-life (t1/2), maximum 
serum concentration determined 
directly from the concentration-time 
profile (Cmax), observed time of peak 
serum concentration (Tmax), area 
under the serum concentration-time 
curve from pre-dose (time0) to 
24 hours post-dose (AUC0-24), and 
area under the serum concentration-
time curve from pre-dose (time0) to 
infinity (AUC0-∞), (Cohort 1); 
maximum serum concentration 
determined directly from the 
maximum serum concentration and 
corresponding Tmax (Cohort 2) 
summarized by dose, dosing 
regimen, visit and time point 
To assess the efficacy of doses of 
SYNT001 at different dose levels 
and dosing regimens on disease 
markers 
 
The assessment of 
pemphigus disease activity 
by responses on the PDAI 
based on absolute and 
percent change from 
baseline, summarized by 
dose, dosing regimen and 
visit 
 
The assessment of 
pemphigus disease activity 
by pathogenic antibody 
levels based on absolute and 
percent change from 
baseline of serum anti-
desmoglein 1 and 3 antibody 
(anti-Dsg 1 and anti-Dsg 3) 
levels summarized by dose, 
dosing regimen and visit 
To measure the immunogenicity of 
SYNT001 administered at different 
dose levels and dosing regimens 
The immunogenicity of SYNT001 
as determined by presence of anti-
SYNT001 binding antibodies and 
neutralizing antibodies summarized 
by dose, dosing regimen, visit and 
time point 
Exploratory Objectives 
Exploratory Endpoints 
To explore the effect of SYNT001 at 
different dose levels and dosing 
regimens on biomarkers to 
understand the pathophysiology of 
the disease and the SYNT001 
mechanisms of action  
The exploration of SYNT001 
mechanisms of action and effects of 
SYNT001 on pathophysiology 
summarized by dose, dosing 
regimen and visit as determined by:  
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 Complement component 3 levels 
by nephelometry 
 Anti-epithelial cell antibody 
(AECA) titers by indirect 
immunofluorescence 
 Fc gamma R2A receptor 
(FCGR2A) single nucleotide 
polymorphisms (SNP) by 
genotyping 
 Presence of disease and 
inflammatory markers by total 
RNA sequencing 
 Immunophenotyping including 
measurements of T cells, 
monocytes, natural killer (NK) 
cells and B cells by flow 
cytometry 
 Urine IgG levels to explore 
SYNT001 distribution and 
elimination (Cohort 1 only) 
 Exploratory biomarkers to 
investigate immune response 
associated with pemphigus 
To determine the impact of different 
SYNT001 dose levels and dosing 
regimens on the subject’s use of 
corticosteroids to treat their 
pemphigus (vulgaris or foliaceus) 
The evaluation of corticosteroid use 
during the study will be summarized 
by dose, dosing regimen and visit 
To assess the impact of SYNT001 
on the subject’s health-related 
quality of life (HR-QoL) at different 
dose levels and dosing  regimens 
The assessment of SYNT001 impact 
on subject’s health-related quality of 
life (HR-QoL) by responses to the 
Autoimmune Bullous Diseases 
Quality of Life (ABQoL) 
questionnaire and Skindex-29 scores 
summarized by dose, dosing 
regimen and visit 
To assess the effect of SYNT001 on 
the appearance of skin and mucosal 
lesions at different dose levels and 
dosing  regimens 
The qualitative assessment of 
changes in appearance of skin and 
mucosal lesions as determined by 
photography presented by dose, 
dosing regimen and visit 
To quantify the amount of 
SYNT001 in skin (skin biopsies 
optional)  
The determination of SYNT001 
levels in skin biopsies across 
timepoints (skin biopsies optional) 
(Cohort 1 only) 
 
 
 
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Study design 
This is a multicenter, open-label safety study to determine the dose regimen of 
SYNT001 administered IV in subjects with pemphigus (vulgaris or foliaceus).  
Up to 8 subjects with a diagnosis of pemphigus (vulgaris or foliaceus) will 
receive SYNT001 10 mg/kg weekly x 5 doses (Cohort 1).  
Up to 12 subjects with a diagnosis of pemphigus (vulgaris or foliaceus) will 
receive SYNT001 30 mg/kg weekly x 3 doses (Loading), followed by 
SYNT001 10 mg/kg every other week x 5 doses (Maintenance) (Cohort 2).  
Subjects in both cohorts will complete the following periods of assessment: 
Screening, Treatment, and Follow-Up. For Cohort 1 details of the dosing 
schedule and assessments, see Table 2. For Cohort 2 details, see Table 3.  
 
The Dose Escalation Committee (DEC) will consist of the Medical Monitor, 
an Independent Clinical Expert and the Sponsor Medical Lead. The DEC may 
request that Investigators, other experts, or members within their organization 
participate in the review. Additional information on the DEC’s responsibilities 
is provided in Section 9.5 and the DEC Charter. 
 
An overview of the study cohorts is provided in Table 1 and Figure 1 shows a 
schematic of the study design. 
Table 1. 
Cohort Overview 
Cohort 
No. 
No. of 
Subjects 
SYNT001 
Dose  
No. of 
Doses 
 
Frequency of Doses 
1a 
Up to 8 
10 mg/kg 
5 
Weekly 
2b 
Up to 12 
Loading: 
30 mg/kgc 
Maintenance: 
10 mg/kgc 
3c 
 
5c 
Weeklyc 
 
Every other weekc, d  
a. 
No more than 3 subjects with pemphigus foliaceus may be enrolled 
b. 
Two or fewer subjects with pemphigus foliaceus may be enrolled 
c. 
The dose, number of doses, and frequency of doses in Cohort 2 will be confirmed based 
on review of safety and PD evaluations, including but not limited to, dose-limiting 
toxicities, AEs, TEAEs, SAEs, and total IgG levels. Following Sponsor review of 
emerging safety, PD and efficacy data, the Loading dose may be reduced to 20 or 
10 mg/kg weekly and/or the Maintenance dose may be increased to 20 or 30 mg/kg 
every other week and/or dose frequency may be increased to weekly. 
d. 
Ongoing safety and PD evaluations may result in modification of the dose and dosing 
regimen in Cohort 2. See APPENDIX 5 for the corresponding visit schedule. 
 
Subjects will be enrolled at staggered intervals to facilitate adequate safety 
evaluation before dosing of subsequent subjects .  
At 24-hour and 7-day intervals described below, all available safety data 
(including but not limited to dose limiting toxicities [DLTs], AEs, TEAEs, 
SAEs and PD (including but not limited to total IgG levels), will be reviewed.  
Safety Review of 24-hour Data for Cohorts 1 and 2, Subject 1  
 
The first 2 subjects in each cohort will be dosed at least 24 hours apart. 
A DEC review of the 24-hour safety data for the first subject in Cohort 
1 will be performed to ensure that there are no overt safety concerns 
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before dosing the second subject. The Sponsor Medical Lead and 
Medical Monitor will conduct the 24-hour safety data review for the 
first subject in Cohort 2.  
 
Safety Review of 7-day Data for Cohorts 1 and 2, Subjects 1 and 2 
 
The 7-day safety data for the first 2 subjects in Cohort 1 will be 
reviewed by the DEC prior to dosing the remaining subjects in the 
cohort. The Sponsor Medical Lead and Medical Monitor will conduct 
the 7-day safety data review in Cohort 2. 
 
The 24-hour and 7-day reviews will consider seriousness and severity of 
AEs/TEAEs/SAEs and relatedness to study drug, vital sign assessments, 
physical examinations, and clinical laboratory testing. 
Safety data (including but not limited to DLTs, AEs, TEAEs, SAEs), and PD 
data (including but not limited to IgG levels) will be reviewed on an ongoing 
basis by the Medical Monitor and the Sponsor Medical Lead. In addition, at 
any point the DEC may initiate a review of all cumulative data if requested by 
a DEC member. 
 
If a DLT occurs, dosing will be halted within that cohort and dose-
escalation will not occur. NOTE: DLTs will be defined generally as 
severe (Grade 3) AEs occurring in ≥2 subjects that are determined to 
be clinically significant and considered related to study drug. 
 
If any subject at any time during the study experiences a life-
threatening AE (Grade 4) that is considered related to study drug, 
further dosing in all enrolled subjects will be suspended.  
 
At any time during the study, the study or any ongoing study cohort 
may be discontinued if the Sponsor Medical Lead determines that 
further drug exposure would pose an undue risk to subjects. 
 
Dosing for any individual subject will be discontinued (ie, no further 
administration of SYNT001) if the subject experiences any study drug-related 
SAE or any study drug-related non-serious AE that, in the judgement of the 
Investigator (following consultation with the Medical Monitor, if desired), or 
in the judgement of the Sponsor Medical Lead, suggests that it could be unsafe 
to administer further study drug to that subject. 
Number of subjects 
Up to 20 subjects are planned; up to 8 subjects in Cohort 1 and up to 
12 subjects in Cohort 2. Subjects who withdraw for any reason other than an 
AE may be replaced. 
Study population 
Male or female subjects 18 years of age and older with a confirmed diagnosis 
of pemphigus (vulgaris or foliaceus)  
Diagnosis and main 
entry criteria 
Inclusion criteria: 
Subjects must meet the following criteria to be eligible for the study: 
1. Willing and able to read, understand, and sign an informed consent form. 
2. Male or female ≥18 years of age at the time of screening. 
3. Documented diagnosis of pemphigus vulgaris or foliaceus based on all 3 
of the following criteria: 
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a. Documented clinical history consistent with pemphigus vulgaris or 
foliaceus (clinical presentation defined as mucosal and/or skin 
lesions). 
b. Presence of Anti-Dsg 1 or 3 antibodies above the upper limit of 
normal (ULN).  
c. History of at least one positive tissue-based test (eg, biopsy, direct 
immunofluorescence [DIF]). 
4. Active disease defined as lesions lasting >2 weeks, and 3 active lesions in 
skin or mucosa or 2 active lesions with at least one being a skin lesion 
>1 cm diameter: 
a. If treated with rituximab or other anti-CD20 mAb, last dose 
>9 months prior to screening. 
b. If being treated with other immunosuppressants (ie, azathioprine, 
mycophenolate mofetil, methotrexate, dapsone, cyclosporine, 
tacrolimus, sirolimus, or low-dose cyclophosphamide 
[≤100 mg/day]), dose must be stable, defined as <25% change in 
dose, for 4 weeks prior to screening. 
c. On stable dose of corticosteroids, defined as ≤1 mg/kg of 
prednisone or equivalent and may not be increased by more than 
50% in the 2 weeks prior to screening.  
d. Allowed topical therapies for pemphigus lesions upon entering the 
study include petroleum jelly or Aquaphor® for the skin or 
chlorhexidine for the mouth.  
e. Stable use of topical low strength hydrocortisone (≤1%), 
tacrolimus, sirolimus, or pimecrolimus for lesions contributing 
<10% of the PDAI total activity score for the 4 weeks prior to 
screening is allowed. Stable use of dexamethasone elixir solution 
(swish and spit only) for oral lesions for the 4 weeks prior to 
screening is allowed. 
f. If not on regular corticosteroids, no pulse corticosteroids are 
allowed in the 2 weeks prior to screening. 
5. Body mass index (BMI) >18.5 kg/m2. 
6. Has a negative pregnancy test documented prior to the first dose of study 
drug (for women of childbearing potential). 
7. Females of childbearing potential must agree to be abstinent or else use 
any two of the following medically acceptable forms of contraception 
(<1% per year failure rate) from the screening period through the final 
study visit: oral contraceptive, condom with or without spermicidal jelly, 
diaphragm or cervical cap with spermicidal jelly, or intrauterine device 
(IUD). A female whose male partner has had a vasectomy must agree to 
use one additional form of medically acceptable contraception.  
8. Females of non-childbearing potential, defined as surgically sterile (status 
post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or 
post-menopausal for at least 12 months do not require contraception 
during the study. 
9. Males with female partners of childbearing potential, including males who 
are surgically sterile (post vasectomy), must agree to be abstinent or else 
use a medically acceptable form of contraception from the screening 
period through the final study visit. 
10. A PDAI total activity score of >4 at screening. 
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Exclusion criteria:  
Subjects meeting any of the following criteria are ineligible for the study:  
1. Subject unable or unwilling to comply with the protocol. 
2. Active non-hematologic malignancy or history of non-hematologic 
malignancy in the 3 years prior to screening (exclusive of non-melanoma 
skin cancer and cervical cancer in situ). 
3. Positive for human immunodeficiency virus (HIV) or hepatitis C antibody. 
4. Positive for hepatitis B surface antigen. 
5. Active infection or history of recurrent infections. 
6. IVIG treatment within 30 days of screening. 
7. Received any cytotoxic (other than azathioprine) or any non-anti-CD20 
mAb therapy in the 3 months prior to screening. 
8. Any exposure to an investigational drug or device within the 30 days prior 
to screening. 
9. Plasmapheresis or immunoadsorption within 30 days of screening. 
10. Cellular therapy, including chimeric antigen receptor and T-cell (CAR-T), 
at any time prior to screening. 
11. Use of any systemic or topical immunosuppressive drugs within 3 months 
of screening not including those allowed by the inclusion criteria. 
12. Serum total IgG <600 mg/dL at screening. 
13. Subject has any current medical condition that, in the opinion of the 
Investigator, may compromise their safety or compliance, preclude 
successful conduct of the study, or interfere with interpretation of the 
results (eg, a significant pre-existing illness or other major comorbidity 
that the Investigator considers may confound the interpretation of the 
study results). 
14. Any vaccination within 2 weeks of screening. 
Study drug, dosage, 
and administration 
Study drug: SYNT001 
Dosages:  
Cohort 1: 10 mg/kg x 5 weekly doses 
Cohort 2: 30 mg/kg x 3 weekly doses (Loading) followed by 10 mg/kg every 
other week x 5 doses (Maintenance). 
The dose, number of doses, and frequency of doses in Cohort 2 will be 
confirmed based on ongoing review of safety and PD evaluations, including 
but not limited to, DLTs, AEs, TEAEs, SAEs, and total IgG levels. Following 
Sponsor review of emerging safety, tolerability, PD and efficacy data, the 
Loading dose may be reduced to 20 or 10 mg/kg weekly and/or the 
Maintenance dose may be increased to 20 or 30 mg/kg every other week 
and/or dose frequency may be increased to weekly. 
Product presentation and preparation: 
SYNT001 provided as a liquid at a nominal concentration of 50 mg/mL. 
SYNT001 is diluted in dextrose 5% in water (D5W) to prepare the solution for 
infusion. 
Route of administration: IV in 250 mL over 1 hour ± 15 minutes 
Investigators may adjust the duration of the infusion if needed to improve 
tolerability. 
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Control, dose, and 
route of 
administration 
Not applicable 
Duration of subject 
participation 
The duration of subject participation for each cohort is as follows: 
Cohort 
Screening 
Treatment 
Follow-up 
Maximum Total 
Days 
Weeks 
1 
≤14 days 
28 days 
84 days 
126 days 
18 weeks 
2  
≤14 days 
84 days 
56 days 
154 days 
22 weeks 
 
 
Permitted and 
prohibited 
concomitant 
treatments 
All pemphigus treatments a subject receives within at least 3 months prior to 
enrollment and all other treatments a subject receives within 14 days prior to 
enrollment through the end of the study will be documented.  
Permitted Medications 
Concomitant medication and treatment for co-existing conditions, including 
those for pemphigus, are permitted if not listed as prohibited.  
1. Topical antibiotics to treat active infections that occur during the study.  
2. Topical or systemic treatments for oral candidiasis.  
3. Topical lidocaine for transient pain relief as needed.  
4. Concomitant treatment that is medically indicated for any AEs the subject 
experiences during the study.  
5. Medication for potential infusion-related reactions (IRRs), including post-
infusion headache: the Investigator may recommend prophylactic use of 
acetaminophen, IV hydration, diphenhydramine, histamine2 (H2) blockers 
(eg, ranitidine, famotidine). 
6. Low-strength topical corticosteroids (eg, hydrocortisone ≤1%) applied to a 
single lesion contributing <10% of the PDAI total activity score. 
7. Topical tacrolimus, sirolimus or pimecrolimus applied to a single lesion 
contributing <10% of the PDAI total activity score. 
8. Dexamethasone elixir solution for oral lesions if dose remains stable 
throughout trial participation (swish and spit only). 
9. Stable regimen of the following systemic immunosuppressants: 
azathioprine, mycophenolate mofetil, low-dose methotrexate, dapsone, 
cyclosporine, tacrolimus, sirolimus, corticosteroids, or low dose oral 
cyclophosphamide (≤100 mg/day).  
Fourteen days after the final dose of SYNT001, corticosteroids may be tapered 
at the Investigator’s discretion.  
 
Prohibited Medications 
Use of the following medications will not be permitted during the study unless 
specified above as permitted: 
1. Rituximab or other anti-CD20 antibody  
2. Monoclonal antibodies other than study drug  
3. Any topical or systemic immunosuppressive drugs apart from those that 
are listed as permitted.  
4. IV corticosteroids prior to infusion (except in subjects who received 
corticosteroids for treatment of a prior infusion reaction to SYNT001) 
5. Any investigational drug or device 
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6. Vaccinations within 2 weeks of screening through 28 days following final 
dose of study drug 
 
Corticosteroids 
Before enrollment 
The dose of corticosteroids taken for pemphigus or any other condition prior to 
screening must be at a dose <1 mg/kg and the dose level must have not 
increased in dose level by more than 50% in the 2 weeks prior to screening. No 
pulse dosing of steroids is permitted in the 2 weeks prior to screening. 
From screening until 2 weeks after the last dose of SYNT001 
The dose of corticosteroids taken for pemphigus or any other condition should 
remain stable (<10% change in dose level) from screening until 2 weeks after 
the last dose of SYNT001. Corticosteroids should neither be started nor 
discontinued during this period with the exception of subjects who experience 
an IRR that requires corticosteroids as part of the management of the IRR. 
Such subjects may receive corticosteroids prophylactically prior to subsequent 
SYNT001 infusions at the discretion of the Investigator. 
 
From 2 weeks after the last dose of SYNT001 until end of study participation 
At the discretion of the Investigator, but only after at least 2 weeks beyond the 
last dose of SYNT001, a slow corticosteroid taper may be started as per the 
following suggested schedule: 
 
If on >30 mg of prednisone per day, decrease by no more than 10 mg 
every two weeks until a final dose. 
If per the Investigator’s judgement, the subject would benefit from a change to 
the pemphigus treatment beyond the allowed steroid taper, this will be 
considered on a case-by-case basis in consultation with the Sponsor. 
Statistical 
considerations 
Three populations will be employed in the analysis of study data: 
 
The Safety population will consist of all subjects who have received at 
least one dose of study drug.  
 
The PD population will consist of all subjects who receive at least one 
dose of study drug and have post-dose PD data available.  
 
The PK population will consist of all subjects who receive at least one 
dose of study drug and have post-dose PK data available. 
 
Primary safety analyses will be performed on the safety population. 
Demographics, subject disposition, screening, and baseline characteristics will 
be summarized for the Safety, PD and PK populations, where appropriate. 
 
Sample size  
Formal sample size calculations were not performed. The number of subjects 
was chosen based on feasibility and was considered sufficient to meet the 
study objectives.  
 
Criteria for evaluation 
Baseline analysis 
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Baseline characteristics to include medical history, physical examination, vital 
signs, and ECG will be summarized using descriptive statistics by dose, dose 
regimen, and visit. 
 
Safety analysis 
The evaluation of SYNT001 based on vital signs, physical examination, ECGs, 
clinical safety laboratory tests, the incidence of AEs, TEAEs, and SAEs 
summarized by dose and dose regimen, severity, and relationship to study 
drug. 
 
Dose-finding analysis 
The evaluation of SYNT001 based on total IgG levels and responses on the 
PDAI total activity score from baseline will be summarized using descriptive 
statistics by dose and dose regimen, visit and time point, as applicable.  
 
Statistical methodology 
Treatment-emergent AEs (TEAEs) will be summarized using the Medical 
Dictionary for Regulatory Activities (MedDRA®; Version 19 or higher) 
System Organ Class (SOC) and preferred term, classified from verbatim terms. 
The incidence and percentage of subjects with at least one occurrence of a 
preferred term will be included, using the most severe grade. The number of 
events per preferred term will also be summarized. Causality (relationship to 
study drug [related/not related]) will be summarized separately. 
TEAEs, SAEs, and AEs leading to withdrawal, dose modification, or treatment 
discontinuation will be listed by subject and dose using SOC and preferred 
terms. Duration of AEs will be determined and included in listings, along with 
action taken and outcome.  
Laboratory results will be summarized by time point, dose, and dose regimen. 
The incidence of laboratory abnormalities will be summarized. The worst on-
study grade after the first dose of study drug will be summarized. Results for 
variables that are not coded will be presented in the listings as below, within, 
or above the normal limits of the central laboratory. Vital sign measurements 
and change from baseline will be summarized at each scheduled time point 
using descriptive statistics. PD/PK results will be summarized by dose and 
dosing regimen. Descriptive statistics of PD/PK parameters for SYNT001 will 
include mean, standard deviation (SD), coefficient of variation (CV), median, 
minimum, and maximum.  
Immunogenicity results will be summarized by cohort, visit and time point. 
Descriptive statistics will include mean, SD, CV, median, minimum, and 
maximum. 
Disease activity marker results will be summarized by dose, dose regimen, and 
visit. Descriptive statistics will include mean, SD, median, minimum, and 
maximum. 
PDAI results will be summarized by score (total activity score, total damage 
score), cohort, and visit. Descriptive statistics will include absolute change 
from baseline and percent change from baseline. 
Additional statistical analyses may be performed. 
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Figure 1. 
Cohort Enrollment 
 
 
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Table 2. 
Study Assessments for Cohort 1 
 
Screening 
Treatment Period 
Follow-Up 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Time point (study day) 
−14 to −1 
0 
1 
(±1 h) 
2 
(±2 h) 
5p 
(±4 h) 
7 
(±6 h) 
12p 
(±6 h) 
14 
(±6 h) 
19p 
(±6 h) 
21 
(±6 h) 
28 
(±6 h) 
29 
(±1 h) 
30 
(±2 h) 
33 
(±4 h) 
42  
(±3 d) 
56  
(±5 d) 
84  
(±5 d) 
112 or 
ET 
(±5 d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationa 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryc 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Clinical safety labsd 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Hepatitis and HIV screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGf 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Tetanus and VZV antibodiesg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
PDAI 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
PK samplingh 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Immunogenicityi 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
X 
Study drug administrationj 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Immunoglobulins (IgG, IgA, 
IgM) and IgG subtypes 
(IgG1-4)k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
CIC 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Anti-Dsg (1 and 3) antibody 
titers 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
C3 and AECAl 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
FCGR2A by buccal swabm 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNAseq 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Urine IgG 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Immunophenotypingn 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Exploratory pemphigus 
immune response biomarkers 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Optional skin biopsy 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
Photographyo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Adverse events 
To be collected from the date that the ICF is signed through the last study visit 
Concomitant medications 
To be collected from within 14 days prior to Day 0 through the last study visit 
Abbreviations: CIC = circulating immune complexes; d = days; ECG = electrocardiogram; ET = early termination; h = hour(s); HIV = human immunodeficiency virus; 
ICF = informed consent form; PDAI = Pemphigus Disease Area Index; PK = pharmacokinetic; VZV = varicella zoster virus. 
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a. 
Complete physical examination, including weight, to be performed. Height and BMI will be additional assessments conducted at screening.  
b. 
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and oral temperature) to be obtained after 5 minutes of seated rest. Any abnormal 
measurements are to be repeated after 5 minutes of rest. On Days 0, 7, 14, 21, and 28, vital sign measurements will be collected immediately prior to the infusion; 15, 30, 
and 45 minutes after the start of the infusion; at completion of the infusion; and 30 minutes, 1 hour, and 2 hours following completion of the infusion.  
c. 
Pulse oximetry: On Days 0, 7, 14, 21, and 28, pulse oximetry to be measured immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at 
completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion. 
d. 
Clinical safety labs: hematology, clinical chemistry, and urinalysis (see Section 7.5 for a complete list). Full clinical safety laboratory draws will be collected at screening 
and on Days 0, 7, 14, 21, 28, 33, 42, 56, 84, and 112.  
e. 
Pregnancy test (women of childbearing potential only): To be performed at time of screening, prior to first dose of SYNT001 on Day 0, and on Days 56 and 112. Urine 
or serum test is acceptable; however, positive urine tests must be confirmed with serum testing. 
f. 
Digital 12-lead ECG to be obtained in triplicate at least 1 to 2 minutes apart and after 5 minutes of rest in a supine position. See Section 7.6 for additional information. On 
Days 0 and 28 to be obtained 5 minutes after the completion of infusion. Day 12 ECG will be collected only if the visit is conducted at the study site.  
g. 
Serology: Testing at Day 56 will not be done for any subject whose baseline titer is below the level of detection. If the Day 56 results are greater than 30% below the 
baseline value, or if the subject falls below the level of detection, the subject will be re-tested at Day 84; if still below the baseline value (or level of detection), the subject 
will be re-tested at Day 112. Any subject whose baseline value for tetanus or VZV was above the detectable level at baseline, and is not within 30% of the baseline value or 
is below the detectable level by Day 112, will be referred to their primary care physician for further management. See Section 7.5.3 for additional information. 
h. 
PK: Starting on Days 0 and 28, serum samples will be collected just prior to the start of study drug infusion (pre-dose), and at 5 minutes and 2, 4, 6, 24, and 48 hours after 
the end-of-study drug infusion. Additional samples will be collected on Days 5 and 33. See Section 7.5.4 for additional information.  
i. 
Immunogenicity: Samples will be collected pre-dose when collected on dosing days. Samples will be collected on Days 0, 14, 28, 56, 84 and 112. See Section 7.5.6 for 
additional information. 
j. 
Prior to study drug infusion, SYNT001 drug product is to be diluted in dextrose 5% in water (D5W) to a total volume of 250 mL and administered intravenously over 
1 hour using a 0.2-micron inline filter. See Section 4 and Section 7.8 for additional information.  
k. 
Immunoglobulins (IgG, IgA, IgM) and IgG subtypes (IgG1-4): Collected for measurements of IgG, IgG subtypes (IgG1-4), IgA, IgM at every visit. On Days 0, 7, 14, 
21, and 28, samples are collected prior to infusion of study drug. See Section 7.5.5 for additional information. 
l. 
Exploratory pharmacodynamic samples (C3 and AECA): Collected pre-dose when collected on dosing days. See Section 7.5.5 for complete information. 
m. Buccal samples to be collected and stored; pending review of clinical and pharmacodynamics assessments. 
n. 
Immunophenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B cells. 
o. 
Photographs of active lesions taken prior to first dose on Day 0. Follow-up photographs will be taken at Days 33, 56, 84 and 112. Subjects who begin a steroid taper will 
have additional photographs taken at the clinic visit during which the decision to begin the taper is made. 
p. 
Visit Days 5, 12, and 19 may be conducted via at-home nurse in lieu of a subject visit to the study site. 
q. 
Subjects will return to the clinic on Days 84 and 112 for follow-up visits. Subjects whose total IgG is not within 30% of their Day 0 baseline value and not above 
500 mg/dL at the Day 112 visit will be referred for further management. 
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Table 3. 
Study Assessment for Cohort 2  
 
Screening 
Loading 
Maintenance 
Follow-Up 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Time Point  
(Study Day) 
−14 to −1 
0 
Baseline 
7 
(±1 d) 
14 
(±1 d) 
28 
(±3 d) 
42 
(±3 d) 
56 
(±3 d) 
70 
(±3 d) 
84 
(±3 d) 
91 
(±5 d) or 
ET visit 
112 
(±5 d) 
140 
(±5 d) 
EOS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics/medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryc 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinical safety labsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy teste 
X 
X 
 
 
X 
 
 
 
 
X 
 
X 
Hepatitis and HIV screen 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGf 
X 
X 
 
X 
X 
 
 
 
 
X 
 
X 
Tetanus and VZV antibodiesg 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
PDAIh  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingi  
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
Immunogenicityj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administrationk 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Immunoglobulins (IgG, IgA, IgM) and 
IgG subtypes (IgG1-4)l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
CIC  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-Dsg (1 and 3) antibody titers 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C3 and AECAm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FCGR2A by buccal swabn 
 
X 
 
 
 
 
 
 
 
 
 
 
RNA sequencing  
 
X 
 
 
X 
 
 
 
 
X 
 
 
Immunophenotypingo 
 
X 
 
 
X 
 
 
 
 
X 
 
 
Exploratory pemphigus immune response 
biomarkers 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photographyp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HR-QoL assessments 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
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Abbreviations: CIC = circulating immune complexes; d = day(s); ECG = electrocardiogram; EOS = end of study; ET= early termination; FcGR2a= Fc gamma R2a receptor; HIV = 
human immunodeficiency virus; HR-QoL = health-related quality of life; ICF = informed consent form; Ig = immunoglobulin; PDAI = Pemphigus Disease Area Index; 
PK = pharmacokinetic; VZV = varicella-zoster virus  
a. 
Complete physical examination, including weight, to be performed. Height and body mass index will be additional assessments conducted at screening only. 
b. 
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and oral temperature) to be obtained after 5 minutes of seated rest. Any abnormal measurements 
are to be repeated after 5 minutes of rest. Vital sign measurements will be taken on all study visits. On dosing days, vital sign measurements will be collected immediately 
prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the 
infusion.  
c. 
Pulse oximetry: On dosing days, pulse oximetry to be measured immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at completion of the 
infusion; and 30 minutes, 1 hour, and 2 hours following completion of the infusion. 
d. 
Clinical safety labs: hematology, clinical chemistry, and urinalysis. See Section 7.5 for a complete list. Full clinical safety lab draws will be collected at screening and at all 
study visits prior to infusion if applicable.  
e. 
Pregnancy test (women of childbearing potential only): To be performed at time of screening and prior to dose on dosing days if applicable. Urine or serum test is 
acceptable; however, positive urine tests must be confirmed with serum testing. 
f. 
Digital 12-lead ECG to be obtained after 5 minutes of rest in the supine position and in triplicate approximately 1 minute apart. See Section 7.6 for additional information. On 
days of treatment, to be obtained approximately 5 minutes after the completion of infusion.  
g. 
Serology: Any subject whose baseline value for tetanus or VZV was above the protective level at baseline and is not within 30% of the baseline value or is below the 
protective level by End of Follow-up, will be referred to their primary care physician for further management. See Section 7.5.3 for additional information. 
h. 
PDAI will be administered at screening. Subject eligibility requires a PDAI total activity score >4. Thereafter, assuming eligibility, the PDAI will be administered during 
Treatment Period and Follow-up Period. See Section 7.7 for additional information. 
i. 
PK: Starting on dosing days, serum samples will be collected just prior to the start of study drug infusion (pre-dose) and at 5 minutes, 1 and 2 hours after the end of study 
drug infusion. See Section 7.5.4 for additional information. 
j. 
Immunogenicity: Samples will be collected pre-dose when collected on dosing days. See Section 7.5.6 for additional information 
k. 
Prior to study drug infusion, SYNT001 drug product is to be diluted in dextrose 5% in water to a total volume of 250 mL and administered intravenously over 1 hour 
±15 minutes using a 0.2-micron, inline filter. See Section 4 for additional information. 
l. 
Immunoglobulins (IgG, IgA, IgM) and IgG subtypes (IgG 1-4): Collected for measurements of IgG, IgG subtypes (IgG1-4), IgA, and IgM at every visit. On dosing days, 
samples are collected prior to infusion of study drug. See Section 7.5.5 for additional information. 
m. Exploratory pharmacodynamic samples (C3 and AECA): Collected pre-dose when collected on dosing days. See Section 7.5.5 for complete information. 
n. 
Buccal samples to be collected pre-dose. 
o. 
Immunophenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, natural killer (NK) cells, and B cells. Collect samples pre-dose on 
dosing days. 
p.     Photographs of all active lesions taken pre-dose on dosing days. Subjects who begin a steroid taper will have additional photographs taken at the clinic visit during which the 
decision to begin the taper is made. 
q.     Subjects whose total IgG is not within 30% of their Day 0 baseline value and not above 500 mg/dL at the Day 140 visit will be referred for further management.
Adverse events 
To be collected from the date that the ICF is signed through the last study visit 
Concomitant medications 
To be collected from within 14 days prior to Day 0 through the last study visit 
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Amendment 5.0 
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TABLE OF CONTENTS 
1.
SYNOPSIS .........................................................................................................................4
LIST OF TABLES ...................................................................................................................24 
LIST OF FIGURES .................................................................................................................24 
LIST OF APPENDICES ..........................................................................................................24 
LIST OF ABBREVIATIONS ..................................................................................................25 
2.
BACKGROUND AND RATIONALE ............................................................................28 
2.1 
Study Rationale ......................................................................................................28 
2.2 
Selection of Doses in this Study ............................................................................29 
2.3 
Compliance Statement ...........................................................................................31 
3.
STUDY OBJECTIVES AND ENDPOINTS ...................................................................32 
4.
STUDY DRUG ................................................................................................................34 
4.1 
Description of SYNT001 .......................................................................................34 
4.2 
Dose Requirements ................................................................................................34 
4.3 
Handling and Storage of SYNT001 .......................................................................34 
4.4 
Study Drug Accountability ....................................................................................34 
5.
STUDY DESIGN .............................................................................................................35 
5.1 
Study Sites .............................................................................................................35 
5.2 
Overview of Study Design .....................................................................................35 
5.3 
Randomization and Blinding .................................................................................36 
5.4 
Duration of Subject Participation...........................................................................36 
6.
STUDY POPULATION ..................................................................................................37 
6.1 
Target Population ...................................................................................................37 
6.2 
Inclusion Criteria ...................................................................................................37 
6.3 
Exclusion Criteria ..................................................................................................38 
7.
STUDY PROCEDURES .................................................................................................39 
7.1 
Informed Consent...................................................................................................39 
7.2 
Demographics and Medical History ......................................................................39 
7.3 
Physical Examination.............................................................................................39 
7.4 
Vital Sign Measurements .......................................................................................39 
7.5 
Clinical Laboratory Measurements ........................................................................41 
7.5.1 
Pregnancy Testing ........................................................................................41 
7.5.2 
Virology .......................................................................................................42 
7.5.3 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing ....42 
7.5.4 
Pharmacokinetics (PK) Sampling ................................................................42 
7.5.5 
Pharmacodynamic Sampling .......................................................................42 
7.5.6 
Immunogenicity Testing ..............................................................................43 
7.6 
12-Lead Electrocardiogram (ECG) ........................................................................44 
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7.7 
Pemphigus Disease Area Index (PDAI) ................................................................44 
7.8 
Study Drug Administration ....................................................................................44 
7.9 
Photographs............................................................................................................44 
7.10 
Health-Related Quality of Life Assessments .........................................................44 
7.11 
Adverse Event Assessments ..................................................................................45 
7.12 
Prior and Concomitant Medications ......................................................................45 
7.13 
Skin Biopsy ............................................................................................................47 
8. 
STUDY ASSESSMENTS ...............................................................................................48 
8.1 
All Cohorts: Screening Period and First Treatment (Day 0) .................................48 
8.1.1 
All Cohorts: Screening Period (Day −14 to Day −1) ..................................48 
8.1.2 
All Cohorts: Enrollment and First Treatment (Day 0) .................................49 
8.2 
Cohort 1: Day 1 to 84.............................................................................................50 
8.2.1 
Cohort 1: Follow-up Day 1 ..........................................................................50 
8.2.2 
Cohort 1: Follow-up Day 2 ..........................................................................50 
8.2.3 
Cohort 1: Follow-up Day 5 ..........................................................................50 
8.2.4 
Cohort 1: Treatment Day 7 (Dose 2) ...........................................................51 
8.2.5 
Cohort 1: Follow-up Day 12 ........................................................................52 
8.2.6 
Cohort 1: Treatment Day 14 (Dose 3) .........................................................52 
8.2.7 
Cohort 1: Follow-up Day 19 ........................................................................53 
8.2.8 
Cohort 1: Treatment Day 21 (Dose 4) .........................................................53 
8.2.9 
Cohort 1: Treatment Day 28 (Dose 5) .........................................................54 
8.2.10 
Cohort 1: Follow-up Day 29 ........................................................................55 
8.2.11 
Cohort 1: Follow-up Day 30 ........................................................................55 
8.2.12 
Cohort 1: Follow-up Day 33 ........................................................................56 
8.2.13 
Cohort 1: Follow-up Day 42 ........................................................................56 
8.2.14 
Cohort 1: Follow-up Day 56 ........................................................................57 
8.2.15 
Cohort 1: Follow-up Day 84 ........................................................................57 
8.3 
Cohort 2: Subsequent Treatments to Follow-up ....................................................58 
8.3.1 
Cohort 2: Treatment Days 7, 14, 42, 56, 70, and 84 ....................................58 
8.3.2 
Cohort 2: Treatment Day 28 ........................................................................59 
8.3.3 
Cohort 2: Follow-up Day 112 ......................................................................60 
8.4 
All Cohorts: End of Study or Early Termination Visit; Cohort 1, Day 112; Cohort 
2, Days 91 and 140.................................................................................................61 
9. 
STUDY RULES ...............................................................................................................62 
9.1 
Subject Withdrawal ................................................................................................62 
9.2 
Subject Replacement ..............................................................................................62 
9.3 
Study Discontinuation ............................................................................................63 
9.4 
Lost to Follow-up ...................................................................................................63 
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9.5 
Stopping Rules .......................................................................................................63 
9.5.1 
Dose-Escalation Stopping Rule (Cohort 1) .................................................63 
9.5.2 
Study Stopping Rule ....................................................................................63 
9.5.3 
Individual Stopping Rule .............................................................................63 
10. EVALUATION OF SAFETY .........................................................................................65 
10.1 
Safety Parameters...................................................................................................65 
10.2 
Adverse Events ......................................................................................................65 
10.2.1 
Recording an Adverse Event .......................................................................66 
10.2.2 
Assessment of Causality ..............................................................................66 
10.2.3 
Serious Adverse Events ...............................................................................66 
10.2.3.1 
Recording a Serious Adverse Event...................................................67 
10.2.3.2 
Reporting a Serious Adverse Event ...................................................68 
10.2.4 
Follow-Up of Adverse Events and Serious Adverse Events .......................69 
10.3 
Warnings and Precautions......................................................................................69 
10.3.1 
Vaccinations .................................................................................................69 
10.3.2 
Management of Allergic or Infusion-Related Reactions .............................69 
10.3.3 
Potential Immune Effects .............................................................................73 
10.4 
Events of Special Interest.......................................................................................74 
10.5 
Other Safety Considerations ..................................................................................74 
10.5.1 
Laboratory Data ...........................................................................................74 
10.5.2 
Medication Errors ........................................................................................75 
10.5.3 
Overdose ......................................................................................................75 
10.5.4 
Pregnancy .....................................................................................................75 
11. STATISTICAL CONSIDERATIONS .............................................................................76 
11.1 
General Design.......................................................................................................76 
11.2 
Study Populations ..................................................................................................76 
11.3 
Sample Size Justification .......................................................................................76 
11.4 
Statistical Analysis .................................................................................................76 
11.4.1 
Statistical Analysis Plan ...............................................................................76 
11.4.2 
Statistical Methodology ...............................................................................77 
11.4.3 
Analysis of Primary Endpoints ....................................................................77 
11.4.3.1 
Safety Analysis ..................................................................................77 
11.4.3.2 
Dose Selection Data ...........................................................................78 
11.4.4 
Analysis of Secondary Endpoints ................................................................78 
11.4.4.1 
Pharmacokinetic Analysis ..................................................................78 
11.4.4.2 
Pharmacodynamic Analysis ...............................................................78 
11.4.4.3 
Immunogenicity Analysis ..................................................................78 
11.4.4.4 
PDAI Data ..........................................................................................78 
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11.4.5 
Analysis of Exploratory Endpoints ..............................................................79 
11.4.5.1 
Corticosteroid Use .............................................................................79 
11.4.5.2 
Health-Related Quality of Life Data ..................................................79 
11.4.5.3 
Photography .......................................................................................79 
11.5 
Interim Analysis .....................................................................................................79 
12. STUDY MANAGEMENT ..............................................................................................80 
12.1 
Regulatory and Ethical Considerations ..................................................................80 
12.1.1 
Ethical Conduct ............................................................................................80 
12.1.2 
Informed Consent ........................................................................................80 
12.1.3 
Subject Confidentiality and Privacy ............................................................80 
12.1.4 
Future Use of Stored Specimens ..................................................................81 
12.2 
Study Administration .............................................................................................81 
12.2.1 
Institutional Review Board Approval ..........................................................82 
12.2.2 
Data Handling and Record Keeping ............................................................82 
12.2.3 
Data Protection ............................................................................................82 
12.2.4 
Study Site Regulatory Documentation ........................................................82 
12.2.5 
Subject Clinical Source Documents and Background Data .........................83 
12.2.6 
Electronic Case Report Forms .....................................................................84 
12.3 
Clinical Monitoring, Audits, and Inspections ........................................................84 
12.3.1 
Clinical Monitoring ......................................................................................84 
12.3.2 
Audits and Inspections .................................................................................85 
12.4 
Changes to the Protocol .........................................................................................85 
12.5 
Study Discontinuation and Closure .......................................................................85 
13. PUBLICATION AND DATA SHARING POLICY .......................................................86 
14. REFERENCES ................................................................................................................87 
 
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Amendment 5.0 
 
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LIST OF TABLES 
Table 1.Cohort Overview...........................................................................................................8 
Table 2.Study Assessments for Cohort 1 .................................................................................16 
Table 3.Study Assessment for Cohort 2 ..................................................................................18 
Table 4.Cohort Overview.........................................................................................................35 
Table 5.Timing window allowances for PK/PD sampling, ECG, and vital sign measurements 
at dosing visits..................................................................................................40 
Table 6.Clinical Safety Laboratory Panels ..............................................................................41 
Table 7.Pharmacodynamic Assessments .................................................................................43 
Table 8.Grading and Management of Allergic or Infusion-Related Reactions .......................73 
Table 9.Study Administrative Structure ..................................................................................82 
Table 10. Study Assessments for Cohort 2 (Alternate Weekly Dosing Option) .....................94 
 
LIST OF FIGURES 
Figure 1.Cohort Enrollment .....................................................................................................15 
Figure 2.Management of Moderate (Grade 2) Infusion Reactions ..........................................71 
Figure 3.Management of Severe (Grade 3 or Higher) Infusion Reactions ..............................72 
 
LIST OF APPENDICES 
APPENDIX 1.NCI CTCAE, Version 4.03 ..............................................................................89 
APPENDIX 2.Pemphigus Disease Area Index (PDAI) ...........................................................90 
APPENDIX 3.Autoimmune Bullous Disease Quality of Life (ABQoL) Questionnaire .........91 
APPENDIX 4.Skindex-29 .......................................................................................................92 
APPENDIX 5.Cohort 2 alternate schedule of events table......................................................93 
 
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Amendment 5.0 
 
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Syntimmune, Inc. 
LIST OF ABBREVIATIONS 
ABQoL 
Autoimmune Bullous Disease Quality of Life 
ADA 
anti-drug antibodies 
AE 
adverse event 
AECA 
Anti-epithelial cell antibody 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-24 
area under the serum concentration-time curve from pre-dose (time0) to 24 hours post-
dose 
AUC0-∞ 
area under the serum concentration-time curve from pre-dose (time0) to infinity 
BLQ 
below the limit of quantification  
BMI 
body mass index 
BUN 
blood urea nitrogen 
C1q 
complement component 1q 
C3 
complement component 3 
CAR-T 
chimeric antigen receptor and T-cell 
CFR 
Code of Federal Regulations 
CIC 
circulating immune complexes 
Cmax 
maximum serum concentration determined directly from the concentration-time 
profile 
CRO 
contract research organization 
CV 
coefficient of variation 
D5W 
dextrose 5% in water 
DEC 
Dose Escalation Committee 
DIF 
direct immunofluorescence 
DLT 
dose-limiting toxicity 
DNA 
dsDNA 
deoxyribonucleic acid 
double-stranded deoxyribonucleic acid 
Dsg 
desmoglein 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
eGFR 
electronic data capture 
estimated glomerular filtration rate 
ET 
early termination 
FCGR2A 
Fc gamma R2a receptor 
FcRn 
neonatal Fc receptor 
FDA 
Food and Drug Administration 
GCP 
GLP 
Good Clinical Practice 
Good Laboratory Practice 
H2 
histamine2 
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Amendment 5.0 
 
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HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR-QoL 
health-related quality of life 
IB 
Investigator’s Brochure 
IC 
immune complex 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IgG1-4 
immunoglobulin G1-G4 
IgM 
immunoglobulin M 
IND 
investigational new drug 
IRB 
IRR 
institutional review board 
infusion-related reaction 
IUD 
Intrauterine device 
IV 
intravenous 
IVIG 
LDH 
LLN 
intravenous immunoglobulin 
lactate dehydrogenase 
lower limit of normal 
mAb 
monoclonal antibody 
MED 
minimum effective dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHP 
NK 
nonhuman primate 
natural killer 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamics 
PDAI 
Pemphigus Disease Area Index 
PK 
pharmacokinetic 
QTcF 
RNA 
corrected QT interval using Fridericia's formula 
ribonucleic acid 
RNAseq 
RNA sequencing 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
SD 
standard deviation 
SNP 
single nucleotide polymorphism 
SOC 
system organ class 
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Amendment 5.0 
 
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Syntimmune, Inc. 
SYNT001 
a humanized, affinity matured IgG4-kappa monoclonal antibody 
t1/2 
Half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
observed time to reach peak plasma concentration 
ULN 
upper limit of normal 
US 
United States of America 
VZV 
varicella zoster virus 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
 
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Amendment 5.0 
 
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Syntimmune, Inc. 
2. 
BACKGROUND AND RATIONALE 
SYNT001, a humanized, affinity-matured IgG4-kappa monoclonal antibody (mAb), blocks 
immunoglobulin G (IgG) and IgG immune complex (IC) interactions with the neonatal 
crystallizable fragment receptor (FcRn), and inhibits the varied roles  of FcRn in the immune 
response.  
Through specific and high affinity blockade of FcRn, SYNT001 has been shown to increase the 
catabolism of IgG and IgG IC in healthy volunteers and is predicted to block the ability of IgG 
IC to activate intracellular signaling events associated with binding to FcRn. This predicts that 
SYNT001 will also accelerate degradation of endogenous circulating IgG autoantibodies and 
IgG-IC specifically involved in the pathogenesis of autoimmunity. Blocking FcRn interactions 
with IgG ICs further predicts that SYNT001 will have consequences for innate and adaptive 
cellular immunity. In the first instance, blocking multimeric IgG IC interactions with FcRn 
within antigen-presenting cells should result in inhibition of IC-mediated inflammatory cytokine 
production and release by these cells. In addition, as FcRn determines the intracellular itinerary 
of IgG ICs within and among compartments important in cellular immunity, it is further 
anticipated that SYNT001 will block antigen processing and presentation of antigens contained 
within ICs that would otherwise lead to CD8+ and CD4+ T cell activation. Thus, SYNT001 is 
expected to specifically target immune functions associated with IgG and IC that are involved in 
certain IgG-mediated autoimmune conditions. 
SYNT001 targets key mechanisms contributing to pathology in a variety of IgG-mediated 
autoimmune disorders.  
While current treatments for certain autoimmune disorders, including chronic steroids, 
immunosuppressants, intravenous immunoglobulin (IVIG), plasmapheresis, and anti-CD20 
mAbs, such as rituximab, can be effective, they are associated with significant adverse effects, 
and delayed or non-durable responses.  
Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous 
membranes. Autoantibodies are thought to play an important pathogenic role in the mucosal and 
cutaneous manifestations in patients with pemphigus. Administration of SYNT001 significantly 
decreases total IgG levels, including a corresponding decrease in the levels of the pathogenic 
autoantibodies. This may lead to a decrease in the mucosal and cutaneous manifestations in 
patients with pemphigus. Moreover, the ability of SYNT001 to reduce IgG ICs  and the 
associated innate and adaptive immune responses may allow for further sustained disease 
modification. 
2.1 
Study Rationale 
This study is being conducted to evaluate the safety, dose, pharmacokinetics (PK), 
pharmacodynamics (PD) and immunogenicity of intravenous (IV) SYNT001 as well as its 
effects on pemphigus disease activity markers. 
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2.2 
Selection of Doses in this Study  
The initial SYNT001 dose levels for study SYNT001-103 were selected following careful review 
of the safety, tolerability, and PD effect on total IgG levels studied in non-human primates 
(NHP) and healthy male subjects. 
Four repeat-dose toxicology studies in cynomolgus monkeys examined 2 to 14 repeat weekly IV 
doses 5 to 100 mg/kg SYNT001 with up to a 4-week follow-up.  There was one death in the 14-
week study attributed to an immune-evoked infusion reaction, which correlated with the 
development of anti-drug antibodies (ADAs), circulating immune complexes, circulating 
complement depletion, and deposition of immune complexes containing SYTN001 and 
complement in tissues. Across studies, clinical signs were limited to reports of transient 
emesis/vomitus following dosing and facial flushing and periocular swelling observed in the 5-
week study after the third dose coincident with the first appearance of ADAs. With the exception 
of emesis/vomitus, these clinical signs were effectively controlled with diphenhydramine 
pretreatment in the 5-week study and the subsequent 14-week study. There were no adverse 
SYNT001-related changes in weight gain, clinical chemistry, gross or histo-pathology. The No 
Observed Adverse Effect Level (NOAEL) was the highest dose tested in all 4 studies and the 
overall NOAEL following repeat weekly exposure to STYNT001 of up to 14 doses in 
cynomolgus monkeys was 100 mg/kg. 
The safety, tolerability, and PD effect on total IgG levels in study SYNT-101—a Phase 1a study 
that assessed single ascending doses of SYNT001 in healthy male subjects—were also reviewed. 
In study SYNT-101, the doses of SYNT001 up to and including 30 mg/kg were well tolerated. 
There were no dose-limiting toxicities, serious adverse events (SAEs), or any other safety 
concerns. No adverse events (AEs) were observed in the 1 and 3 mg/kg dose cohorts. Headache 
was the most commonly reported treatment-emergent adverse event (TEAE), occurring in 8 of 
11 subjects treated with 10 or 30 mg/kg SYNT001. One headache in the 10 mg/kg cohort was 
moderate (Grade 2) in severity; all other headaches were mild (Grade 1). One mild headache was 
treated with a single dose of acetaminophen; all other headaches resolved without treatment. 
Therefore, it is anticipated that the doses selected for this study should be well tolerated and have 
clinically relevant PD effects in patients with pemphigus.  
Further consideration was given to the desired level of FcRn blockade to achieve suppression of 
IgG to a range that has been previously correlated with disease remission induced by 
immunoadsorption in autoimmune disorders such as pemphigus vulgaris and myasthenia gravis 
(ie, >50% decrease in total IgG from baseline) (Blaha et al., 2011; Eming and Hertl, 2006; 
Kohler et al., 2011).  
The Sponsor also considered the potential effects of inhibiting FcRn function as they relate to IC 
associated innate and adaptive immunity. From the NHP studies, single doses of SYNT001 
produced a dose-dependent decrease in total IgG and a further decrease was seen with repeated 
weekly doses up to a maximum of 70% reduction at 100 mg/kg. This magnitude of total IgG 
reduction is approaching the expected maximal 90% inhibition of FcRn function based on 
murine studies performed by the Sponsor and others (Nixon et al., 2015; Roopenian et al., 2003). 
In the recently completed Phase 1a trial with SYNT001 in healthy volunteers a single dose 
caused a maximum average 50% drop in total IgG with IV dosing at 30 mg/kg. Based on the 
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NHP studies further reductions are expected following multiple dosing. A corresponding 
decrease in pathogenic autoantibodies is anticipated.  
A semi-mechanistic model of FcRn-IgG interactions and FcRn inhibition with SYNT001 was 
jointly developed by Applied BioMath and the Sponsor. The model was designed to simulate PK 
and PD responses to various dosing regimens of SYNT001 to inform clinical trial design. Initial 
simulations were able to capture both PK and PD responses to single doses of SYNT001 from a 
single-ascending dose study in healthy volunteers and predict multiple dose responses from 
ongoing studies with good fidelity. The model predicted an IgG reduction of approximately 75% 
by Day 33, which was determined to be acceptably close to the actual mean IgG reduction of 
59% by Day 30 observed in patients. Subsequent iterations of the model have used patient data 
from ongoing patient studies to further calibrate dose responses. In the most recent simulations, 
multiple dosing scenarios have been explored, including responses to weekly, bi-weekly, and 
loading doses. A simulated dosing regimen consisting of three weekly loading doses of 30 mg/kg 
SYNT001 followed by every other week maintenance doses of 10 mg/kg SYNT001 achieved a 
nadir IgG reduction of approximately 78% between Days 21 and 28 and maintained an IgG 
reduction between approximately 50% and 68%. This level of total IgG reduction has been 
associated with clinical efficacy in early studies of SYNT001-treated pemphigus subjects, and 
represents a target for future studies in other indications. This regimen of 30 mg/kg loading doses 
and 10 mg/kg maintenance doses was determined to be the optimal starting regimen to achieve 
meaningful IgG reduction while maximizing patient safety. Future cohorts may increase the 
maintenance doses to 20 mg/kg SYNT001, which the model predicts will achieve greater IgG 
reductions between approximately 55% and 72%. Given the rigorous biological approach taken 
in the development of the model, simulations of dosing schedules can be considered reliable for 
the purpose of planning clinical trials.  
Several recently completed non-clinical studies support the proposed Cohort 2 dose and dosing 
regimen. A recently completed 27-week dose-response good laboratory practice (GLP) 
toxicology study in non-human primates assessed the long-term safety, toxicology, and 
toxicokinetics of weekly doses of SYNT001. Twenty-seven (27) once weekly 10-minute 
infusions of SYNT001, at doses of 5, 30, or 100 mg/kg, to cynomolgus monkeys was associated 
with non-adverse test article-related clinical effects and clinical pathology observations at 
≥5 mg/kg. SYNT001 produced dose-dependent reduction of serum IgG levels without affecting 
IgA, IgM or albumin levels. The NOAEL of SYNT001 was 100 mg/kg following 17 infusions 
and 30 mg/kg following 27 infusions. 
As indicated above, in the recently completed Phase 1a healthy male volunteer study, single 
doses of SYNT001 up to and including 30 mg/kg have been well tolerated. There were no dose 
limiting toxicities (DLTs), serious adverse events (SAEs), or any other safety concerns 
identified. No adverse events (AEs) were observed in the 1 and 3 mg/kg dose cohorts. The only 
moderate (Grade 2) AE observed was a single instance of headache in the 10 mg/kg cohort. 
Other subjects had mild (Grade 1) AEs at 10 mg/kg. In Cohort 4 (30 mg/kg), five subjects 
received SYNT001. All five subjects experienced AEs; all were mild (Grade 1), transient and 
resolved spontaneously without intervention. The most commonly reported AEs were headache. 
A preliminary assessment of safety was conducted by SYNT001 Pemphigus Study SYNT001-
103 Dose Escalation Committee (DEC). Seven subjects with pemphigus were treated with 
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10 mg/kg IV weekly doses over a period of 5 weeks. Overall, SYNT001 10 mg/kg IV was well 
tolerated. Headache (Grade 1 or 2, self-limited) was the only drug-related AE that was reported 
in more than one subject. Total IgG and CIC biomarkers were reduced by 59% and 50% 
respectively, from baseline levels following the fifth dose, returning to baseline within 1 to 
2 months. Additionally, preliminary evidence of clinical efficacy as measured by a clinically 
validated scoring metric, the Pemphigus Disease Area Index, was observed across the 
population. The DEC approved a dose escalation of SYNT001 from 10 mg/kg IV weekly doses 
for 5 weeks to 30 mg/kg IV weekly doses for 5 weeks. 
Given these preliminary data in non-clinical toxicology species and human subjects, as well as 
supporting evidence from the computational model, it is anticipated that the doses and dose 
regimens selected for this study will be well tolerated and will demonstrate clinically relevant 
pharmacodynamic effects and efficacy in patients with pemphigus. For a summary of findings 
from the single dose clinical study in healthy subjects and further details regarding the 
nonclinical findings, please refer to the SYNT001 Investigators Brochure.  
2.3 
Compliance Statement 
This study will be conducted in compliance with Good Clinical Practice (GCP), including the 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) Guidelines and Food and Drug Administration (FDA) regulations, consistent 
with the principles outlined in the Declaration of Helsinki. In addition, the Investigator agrees to 
adhere to all applicable local laws and regulatory requirements relevant to the use of new 
therapeutic agents. 
The study will be conducted in compliance with the protocol. The appropriate Institutional 
Review Boards (IRBs) must approve the protocol, any amendments, and the subject informed 
consent form (ICF) prior to implementation.  
Freely given written informed consent must be obtained from every subject prior to participation 
in this clinical trial. As part of this procedure, the Investigator must explain orally and in writing 
the nature, duration, and purpose of the study, and the action of the drug in such a manner that 
the study subject is aware of the potential risks, inconveniences, or AEs that may occur. The 
study subject should be informed that he/she is free to withdraw from the study at any time. 
He/she will receive all information that is required by federal regulations and ICH guidelines. 
The Investigator or designee will provide the Sponsor with a copy of the IRB-approved informed 
consent form prior to the start of the study. The rights, safety, and well-being of participating 
subjects are the most important considerations and should prevail over interests of science and 
society. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct or 
fraud (eg, loss of medical licensure, debarment). 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Objectives 
Primary Endpoints 
Safety: To evaluate the safety of IV infusions of 
SYNT001 at different dose levels and dosing 
regimens in subjects with pemphigus (vulgaris or 
foliaceus) 
Safety: The evaluation of SYNT001 safety based 
on vital signs, physical examinations, 
electrocardiograms (ECGs), clinical safety 
laboratory tests, the incidence of adverse events 
(AEs), treatment-emergent adverse events 
(TEAEs) and serious adverse events (SAEs) 
summarized by dose and dosing regimen, severity, 
and relationship to study drug 
Dose Selection: To determine a MED of 
SYNT001 as assessed by (i) total IgG level nadir 
and (ii) the proportion of subjects that meet the 
criteria for response by Pemphigus Disease Area 
Index total activity score (PDAI) 
Dose Selection: The determination of dose and 
dosing regimen of SYNT001 that achieves (i) 
total IgG level nadir decrease by ≥60% and ≤90% 
from baseline and (ii) a PDAI total activity score 
of ≥50% reduction from baseline to allow further 
clinical development in subjects with pemphigus 
(vulgaris or foliaceus) 
Secondary Objectives 
Secondary Endpoints 
To evaluate the efficacy of doses of SYNT001 at 
different dose levels and dosing regimens on 
pharmacodynamics (PD) biomarkers 
The evaluation of PD biomarkers based on 
absolute serum levels and percent change from 
baseline of total IgG, IgG subtypes (IgG1-4), 
immunoglobulin A (IgA), immunoglobulin M 
(IgM), albumin, and CIC summarized by dose, 
dosing regimen and visit 
To determine the pharmacokinetics (PK) of 
SYNT001 following IV infusions at different dose 
levels and dosing regimens 
The determination of PK parameters including 
half-life (t1/2), maximum serum concentration 
determined directly from the concentration-time 
profile (Cmax), observed time of peak serum 
concentration (Tmax), area under the serum 
concentration-time curve from pre-dose (time0) to 
24 hours post-dose (AUC0-24), and area under the 
serum concentration-time curve from pre-dose 
(time0) to infinity (AUC0-∞), (Cohort 1); maximum 
serum concentration determined directly from the 
maximum serum concentration and corresponding 
Tmax (Cohort 2 onwards) summarized by dose, 
dosing regimen, visit and time point 
To assess the efficacy of doses of SYNT001 at 
different dose levels and dosing regimens on 
disease markers 
 
The assessment of pemphigus disease 
activity by responses on the PDAI based 
on absolute and percent change from 
baseline, summarized by dose, dosing 
regimen and visit 
 
The assessment of pemphigus disease 
activity by pathogenic antibody levels 
based on absolute and percent change 
from baseline of serum anti-desmoglein 1 
and 3 antibody (anti-Dsg 1 and anti-Dsg 
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3) levels summarized by dose, dosing 
regimen and visit 
To measure the immunogenicity of SYNT001 
administered at different dose levels and dosing 
regimens 
The immunogenicity of SYNT001 as determined 
by presence of anti-SYNT001 binding antibodies 
and neutralizing antibodies summarized by dose, 
dosing regimen, visit and time point 
Exploratory Objectives 
Exploratory Endpoints 
To explore the effect of SYNT001 at different 
dose levels and dosing regimens on biomarkers to 
understand the pathophysiology of the disease and 
the SYNT001 mechanisms of action  
The exploration of SYNT001 mechanisms of 
action and effects of SYNT001 on 
pathophysiology summarized by dose, dosing 
regimen and visit as determined by:  
 Complement component 3 levels by 
nephelometry 
 Anti-epithelial cell antibody (AECA) titers by 
indirect immunofluorescence 
 Fc gamma R2A receptor (FCGR2A) single 
nucleotide polymorphisms (SNP) by 
genotyping 
 Presence of disease and inflammatory markers 
by total RNA sequencing 
 Immunophenotyping including measurements 
of T cells, monocytes, natural killer (NK) cells 
and B cells by flow cytometry 
 Urine IgG levels to explore SYNT001 
distribution and elimination (Cohort 1 only) 
 Exploratory biomarkers to investigate immune 
response associated with pemphigus 
To determine the impact of different SYNT001 
dose levels and dosing regimens on the subject’s 
use of corticosteroids to treat their pemphigus 
(vulgaris or foliaceus) 
The evaluation of corticosteroid use during the 
study will be summarized by dose, dosing 
regimen and visit 
To assess the impact of SYNT001 on the subject’s 
health-related quality of life (HR-QoL) at 
different dose levels and dosing regimens 
The assessment of SYNT001 impact on subject’s 
health-related quality of life (HR-QoL) by 
responses to the Autoimmune Bullous Diseases 
Quality of Life (ABQoL) questionnaire and 
Skindex-29 scores summarized by dose, dosing 
regimen and visit 
To assess the effect of SYNT001 on the 
appearance of skin and mucosal lesions at 
different dose levels and dosing regimens 
The qualitative assessment of changes in 
appearance of skin and mucosal lesions as 
determined by photography presented by dose, 
dosing regimen and visit 
To quantify the amount of SYNT001 in skin (skin 
biopsies optional)  
The determination of SYNT001 levels in skin 
biopsies across timepoints (skin biopsies optional) 
(Cohort 1 only) 
 
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4. 
STUDY DRUG 
4.1 
Description of SYNT001 
SYNT001 is provided in vials containing 5 mL SYNT001 (extractable volume) at a nominal 
concentration of 50 mg/mL. The product is supplied as a liquid at pH 6.5 ± 0.5. SYNT001 is 
diluted in dextrose 5% in water (D5W) to prepare the solution for infusion. SYNT001 will be 
infused via IV in 250 mL over 1 hour ± 15 minutes using a 0.2-micron, inline filter.  
Investigators may adjust the duration of the infusion if needed to improve tolerability. Infusion 
of SYNT001 should be completed within 4 hours of preparation as described in the Pharmacy 
Manual. For detailed information regarding SYNT001 preparation and administration, refer to 
the Pharmacy Manual. 
4.2 
Dose Requirements 
The specification for host cell deoxyribonucleic acid (DNA) in SYNT001 is <2 pg/mg, the limit 
of quantitation of the assay. To comply with regulatory guidelines, which specify a maximum 
level of 10 ng host cell DNA per dose, dosing per subject is limited to 5000 mg SYNT001.  
For example, a subject with a body weight of 166 kg and enrolled in the ≤30 mg/kg dose cohort 
will receive ≤4960 mg SYNT001 per dose. If a subject’s body weight extrapolates to an expected 
dose ≥5000 mg SYNT001, the dose will be capped at 5000 mg to ensure the 5000 mg SYNT001 
per dose limit is not exceeded.  
4.3 
Handling and Storage of SYNT001 
All supplies of SYNT001 will be provided by the Sponsor and must be stored refrigerated 
(2ºC to 8ºC/36ºF to 46ºF) in the carton and protected from light, in a securely locked area, 
accessible to authorized persons only, until needed for dose preparation. 
4.4 
Study Drug Accountability 
The Investigator (or designee) is responsible for maintaining accurate accountability records of 
the study drug throughout the clinical study. Qualified site personnel will inventory the study 
drug received and will maintain records of disposition of the drug, including dates, quantity and 
use. All study drug received at the site must be accounted for on an accountability log provided 
by the Sponsor. All dispensing and accountability records will be available for Sponsor review. 
Study drug accountability will be verified during on-site monitoring visits. 
Upon the completion or termination of the study, and upon written authorization from the 
Sponsor, or its representative, all unused and/or partially used study drug should be returned or 
destroyed at the investigational site, as specified by Sponsor. It is the Investigator’s 
responsibility to ensure that the Sponsor, or its representative, has provided written authorization 
that procedures for proper disposal of the study drug have been established, and that appropriate 
records of the disposal are documented and maintained. No unused study drug may be disposed 
of until fully accounted for by the Sponsor monitor (or designee). 
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5. 
STUDY DESIGN 
5.1 
Study Sites 
This study will be conducted at approximately 20 global study sites. 
5.2 
Overview of Study Design 
This is a multicenter, open-label safety study to determine the dose regimen of SYNT001 
administered IV in subjects with pemphigus (vulgaris or foliaceus). Up to 8 subjects with a 
diagnosis of pemphigus (vularis or foliaceus) will receive SYNT001 10 mg/kg weekly x 5 doses 
(Cohort 1).  
Up to 12 subjects with a diagnosis of pemphigus (vulgaris or foliaceus) will receive SYNT001 
30 mg/kg weekly x 3 doses (Loading), followed by SYNT001 10 mg/kg every other week x 
5 doses (Maintenance) (Cohort 2) (Figure 1). Subjects in each cohort will complete the following 
periods of assessment: Screening, Treatment, and Follow-Up.  
For Cohort 1 details of the dosing schedule and assessments, see Table 2. For Cohort 2 details, 
see Table 3. 
The Dose Escalation Committee (DEC) will consist of the Medical Monitor, an Independent 
Clinical Expert and the Sponsor Medical Lead. The DEC may request that Investigators, other 
experts, or members within their organization participate in the review. Additional information 
on the DEC’s responsibilities is provided in Section 9.5 and the DEC Charter. 
An overview of the study cohorts is provided in Table 4 and Figure 1 shows a schematic of the 
study design. 
Table 4. 
Cohort Overview 
Cohort No. 
No. of Subjects 
SYNT001 Dose  
No. of Doses 
Frequency of Doses 
 
1a 
Up to 8 
10 mg/kg 
5 
Weekly 
2b 
Up to 12 
Loading:         
30 mg/kgc 
Maintenance: 
10 mg/kgc 
3c 
 
5c 
Weeklyc 
 
Every other weekc, d 
a. 
No more than 3 subjects with pemphigus foliaceus may be enrolled 
b. 
Two or fewer subjects with pemphigus foliaceus may be enrolled 
c. 
The dose, number of doses, and frequency of doses in Cohort 2 will be confirmed based on review of safety and PD 
evaluations, including but not limited to, dose-limiting toxicities, AEs, TEAEs, SAEs, and total IgG levels. Following 
Sponsor review of emerging safety, PD and efficacy data, the Loading dose may be reduced to 20 or 10 mg/kg weekly 
and/or the Maintenance dose may be increased to 20 or 30 mg/kg every other week and/or dose frequency may be 
increased to weekly.  
d. 
Ongoing safety and PD evaluations may result in modification of the dose and dosing regimen in Cohort 2. See 
APPENDIX 5 for the corresponding visit schedule. 
 
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Subjects will be enrolled at staggered intervals to facilitate adequate safety evaluation before 
dosing of subsequent subjects 
At 24-hour and 7-day intervals described below, all available safety data (including but not 
limited to dose-limiting toxicities [DLTs], AEs, TEAEs, SAEs, and PD (including but not 
limited to IgG levels), will be reviewed. 
Safety Review of 24-hour Data  
The first 2 subjects in each cohort will be dosed at least 24 hours apart. A DEC review of the 24-
hour safety data for the first subject in Cohort 1 will be performed to ensure that there are no 
overt safety concerns before dosing the second subject. The Sponsor Medical Lead and Medical 
Monitor will conduct the 24-hour safety data review for the first subject in Cohort 2. 
Safety Review of 7-day Data  
The 7-day safety data for the first 2 subjects in Cohort 1 will be reviewed by the DEC prior to 
dosing the remaining subjects in the cohort. The Sponsor Medical Lead and Medical Monitor 
will conduct the 7-day safety data review in Cohort 2. 
The 24-hour and 7-day reviews will consider seriousness and severity of AEs/TEAEs/SAEs and 
relatedness to study drug, vital sign assessments, physical examinations, and clinical laboratory 
testing. 
For further information about dose escalation and study stopping rules, refer to Section 9.5.1 and 
Section 9.5.2, respectively. 
5.3 
Randomization and Blinding 
This is an open-label study. 
5.4 
Duration of Subject Participation 
The duration of subject participation for each cohort is as follows: 
Cohort 
Screening 
Treatment 
Follow-up 
Maximum Total 
Days 
Weeks 
1 
≤14 days 
28 days 
84 days 
126 days 
18 weeks 
2  
≤14 days 
84 days 
56 days 
154 days 
22 weeks 
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6. 
STUDY POPULATION 
6.1 
Target Population 
This study will be conducted in male and female subjects aged 18 and older with a confirmed 
diagnosis of pemphigus (vulgaris or foliaceus). Subjects will be enrolled only once in the study 
and will not be included in subsequent dosing cohorts. Subjects who withdraw for any reason 
other than an AE may be replaced.  
Within Cohort 1, no more than 3 subjects may be enrolled with pemphigus foliaceus. Within 
Cohort 2, ≤2 subjects with pemphigus foliaceus may be enrolled.  
6.2 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for the study: 
1. Willing and able to read, understand, and sign an informed consent form. 
2. Male or female ≥18 years of age at the time of screening. 
3. Documented diagnosis of pemphigus vulgaris or foliaceus based on all 3 of the following 
criteria: 
a. Documented clinical history consistent with pemphigus vulgaris or foliaceus (clinical 
presentation defined as mucosal and/or skin lesions). 
b. Presence of Anti-Dsg 1 or 3 antibodies above the upper limit of normal (ULN).  
c. History of at least one positive tissue-based test (eg, biopsy, direct 
immunofluorescence [DIF]). 
4. Active disease defined as lesions lasting >2 weeks, and 3 active lesions in skin or mucosa or 
2 active lesions with at least one being a skin lesion >1 cm diameter: 
a. If treated with rituximab or other anti-CD20 mAb, last dose >9 months prior to 
screening. 
b. If being treated with other immunosuppressants (ie, azathioprine, mycophenolate 
mofetil, methotrexate, dapsone, cyclosporine, tacrolimus, sirolimus, or low-dose 
cyclophosphamide [≤100 mg/day]), dose must be stable, defined as <25% change in 
dose, for 4 weeks prior to screening. 
c. On stable dose of corticosteroids, defined as ≤1 mg/kg of prednisone or equivalent 
and may not be increased by more than 50% in the 2 weeks prior to screening.  
d. Allowed topical therapies for pemphigus lesions upon entering the study include 
petroleum jelly or Aquaphor® for the skin or chlorhexidine for the mouth.  
e. Stable use of topical low strength hydrocortisone (≤1%), tacrolimus, sirolimus, or 
pimecrolimus for lesions contributing <10% of the PDAI total activity score for the 4 
weeks prior to screening is allowed. Stable use of dexamethasone elixir solution 
(swish and spit only) for oral lesions for the 4 weeks prior to screening is allowed. 
f. If not on regular corticosteroids, no pulse corticosteroids are allowed in the 2 weeks 
prior to screening. 
5. Body mass index (BMI) >18.5 kg/m2. 
6. Has a negative pregnancy test documented prior to the first dose of study drug (for women of 
childbearing potential). 
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7. Females of childbearing potential must agree to be abstinent or else use any two of the 
following medically acceptable forms of contraception (<1% per year failure rate) from the 
screening period through the final study visit: oral contraceptive, condom with or without 
spermicidal jelly, diaphragm or cervical cap with spermicidal jelly, or intrauterine device 
(IUD). A female whose male partner has had a vasectomy must agree to use one additional 
form of medically acceptable contraception.  
8. Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, 
bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months 
do not require contraception during the study. 
9. Males with female partners of childbearing potential, including males who are surgically 
sterile (post vasectomy), must agree to be abstinent or else use a medically acceptable form 
of contraception from the screening period through the final study visit. 
10. A PDAI total activity score of >4 at screening. 
 
6.3 
Exclusion Criteria 
A subject who meets any of the following criteria is ineligible for the study: 
1. Subject unable or unwilling to comply with the protocol. 
2. Active non-hematologic malignancy or history of non-hematologic malignancy in the 3 years 
prior to screening (exclusive of non-melanoma skin cancer and cervical cancer in situ). 
3. Positive for human immunodeficiency virus (HIV) or hepatitis C antibody. 
4. Positive for hepatitis B surface antigen. 
5. Active infection or history of recurrent infections. 
6. IVIG treatment within 30 days of screening. 
7. Received any cytotoxic (other than azathioprine) or any non-anti-CD20 mAb therapy in the 
3 months prior to screening. 
8. Any exposure to an investigational drug or device within the 30 days prior to screening. 
9. Plasmapheresis or immunoadsorption within 30 days of screening. 
10. Cellular therapy, including chimeric antigen receptor and T-cell (CAR-T), at any time prior 
to screening. 
11. Use of any systemic or topical immunosuppressive drugs within 3 months of screening not 
including dose allowed by the inclusion criteria. 
12. Serum total IgG <600 mg/dL at screening. 
13. Subject has any current medical condition that, in the opinion of the Investigator, may 
compromise their safety or compliance, preclude successful conduct of the study, or interfere 
with interpretation of the results (eg, a significant pre-existing illness or other major 
comorbidity that the Investigator considers may confound the interpretation of the study 
results). 
14. Any vaccination within 2 weeks of screening. 
 
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7. 
STUDY PROCEDURES 
7.1 
Informed Consent 
All subjects must take part in the informed consent process. Adequate time must be allowed for 
the subject to ask questions and make a voluntary decision. No protocol-specific procedures, 
including screening procedures are to be performed until the subject has signed and dated an 
IRB-approved ICF. Subjects may withdraw consent at any time. Participation in the study may 
be terminated at any time without the subject’s consent as determined by the Investigator.  
7.2 
Demographics and Medical History 
Demographics (age, gender, race and ethnicity) and medical history will be obtained from the 
subject and recorded on the source document and electronic case report form (eCRF). Medical 
history will capture the subject’s current medical history (current disease processes), past 
medical status (past disease processes), history of surgery, concomitant treatments, and relevant 
clinical response to past disease specific treatments including duration and dosing of such 
treatments.  
7.3 
Physical Examination 
A complete physical examination will include measurements of weight (in kg) and height (in cm; 
height to be measured only at screening visit) and a review of the following body systems: 
 General appearance 
 Head, eyes, ears, nose, and throat 
 Neck 
 Respiratory 
 Cardiovascular 
 Abdomen 
 Neurologic 
 Extremities 
 Dermatologic 
 Lymphatic 
 
Any abnormal and clinically significant findings from the physical examination must be recorded 
in the appropriate eCRF. Findings at screening and Day 0 (pre-dose) will be recorded as medical 
history. 
7.4 
Vital Sign Measurements 
Vital sign assessments will include measurements of sitting blood pressure (mm Hg), heart rate 
(beats per minute), respiration rate (breaths per minute), pulse oximetry, and oral temperature 
(Celsius). Abnormal results are to be repeated after 5 minutes of rest. See Table 5 for timing 
window allowances with respect to measurement collection.  
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When vital signs are to be collected at the same time point as a blood collection, vital signs 
should be collected first. Vital sign measurements will be collected after the subject has been 
sitting for 5 minutes. Subjects should be seated quietly for at least 5 minutes in a chair with their 
backs supported, their feet flat on the floor (legs uncrossed), and their arms bared on a hard 
surface, with the arm slightly abducted and bent, with palm up and the midpoint of upper arm at 
heart level. Correct cuff and bladder size should be utilized and the same cuff and arm should be 
used per subject throughout study.  
Vital sign measurements are to be obtained immediately prior to the infusion; 15, 30, and 
45 minutes after the start of the infusion; at completion of the infusion; 30 minutes, 1 hour, and 
2 hours following completion of the infusion. Abnormalities in vital sign measurements will be 
graded in severity per the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) scale Version 4.03.  
Table 5. 
Timing window allowances for PK/PD sampling, ECG, and vital sign 
measurements at dosing visits 
Time Point 
Tolerance Window 
 
Cohort 1 
Cohort 2 
Pharmacokinetic Sampling 
 
 
0 hour 
−240 minutes to 0 hour 
−240 minutes to 0 hour 
5 minutes post end-of-infusion 
±5 minutes 
±5 minutes 
1 hour post end-of-infusion 
N/A 
±15 minutes 
2 hours post end-of-infusion 
±15 minutes 
±15 minutes 
4 and 6 hours post end-of-infusion 
±15 minutes 
N/A 
24 hours (1 day) post end-of-infusion 
±60 minutes 
N/A 
48 hours (2 days) post end-of-infusion 
±120 minutes 
N/A 
 
 
 
Pharmacodynamic Sampling 
 
 
0 hour 
−240 minutes to 0 hour 
−240 minutes to 0 hour 
24 hours (1 day) post end-of-infusion 
±60 minutes 
N/A 
48 hours (2 days) post end-of-infusion 
±120 minutes 
N/A 
 
 
 
ECG 
 
 
5 minutes post end-of-infusion 
±10 minutes 
±10 minutes 
 
 
 
Vital Signsa 
 
 
0 hour 
−240 minutes to 0 hour 
−240 minutes to 0 hour 
15, 30, and 45 minutes after start of 
infusion 
±5 minutes 
±5 minutes 
At completion of the infusion 
±10 minutes 
±10 minutes 
30 minutes, 1 and 2 hours post end-of-
infusion 
±10 minutes 
±10 minutes 
 
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7.5 
Clinical Laboratory Measurements   
Laboratory testing (hematology, urinalysis, serum chemistry, virology, serology, pregnancy tests, 
PD, PK, and ADAs) will be performed using established methods by a central laboratory. 
Clinical safety laboratory panels are listed in Table 6. Blood and urine for hematology, serum 
chemistry, and urinalysis will be prepared using standard procedures. Results will be provided to 
the Investigator. Aliquots from the PK, biomarker and ADA samples may be retained as back-up 
for additional testing as necessary. Subjects will be in a seated or supine position during blood 
collection. Collection times for all safety, PD, and exploratory labs are outlined in Table 2 and 
Table 3.  
Table 6. 
Clinical Safety Laboratory Panels 
Hematology 
Serum Chemistry 
Urinalysis 
 
CBC with differential 
and blood smear 
 
Erythrocyte 
sedimentation rate 
 
Albumin 
 
Alkaline phosphatase 
 
ALT 
 
AST 
 
BUN 
 
C-Reactive Protein  
 
Calcium 
 
Carbon dioxide 
 
Chloride 
 
Creatinine 
 
Glucose 
 
LDH 
 
Phosphorus 
 
Potassium 
 
Sodium 
 
Total and direct 
bilirubin 
 
Total protein 
 
Uric acid 
 
Appearance 
 
Color 
 
pH 
 
Specific gravity 
 
Ketones 
 
Protein 
 
Glucose 
 
Nitrite 
 
Urobilinogen 
 
Blood/hemoglobin 
 
Leukocyte esterase 
 
Bilirubin 
 
Microscopic examination 
of sediment: only if the 
results of the urinalysis 
dipstick evaluation are 
positive for 
blood/hemoglobin 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CBC = complete blood count; HIV = human immunodeficiency virus; LDH = lactate dehydrogenase; VZV = Varicella-
Zoster virus. 
 
Abnormalities in clinical laboratory tests that are considered clinically significant are to be 
recorded on the AE eCRF page. Laboratory results will be graded using the NCI CTCAE, 
Version 4.03. If laboratory values constitute part of an event that meets criteria defining it as 
serious, the event (and associated laboratory values) must be reported as an SAE (see 
Section 10.2.3). 
7.5.1 
Pregnancy Testing 
Pregnancy testing will be performed for women of childbearing potential. Urine or serum test is 
acceptable; however, positive urine tests must be confirmed with serum testing. 
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7.5.2 
Virology 
Testing for hepatitis C antibody, hepatitis B surface antigen, and HIV antibody will be performed 
at screening. 
7.5.3 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing 
Samples for serum tetanus antibody and VZV antibody testing are to be collected. Any subject 
whose baseline value for tetanus or VZV was above the protective level at baseline, and is not 
within 30% of the baseline value or is below the protective level by the end-of-study visit, will 
be referred to their primary care physician for further management. 
7.5.4 
Pharmacokinetics (PK) Sampling 
The following PK parameters will be studied in Cohort 1: t1/2, Cmax, Tmax, AUC0-24, and AUC0-∞. 
For Cohort 2, the PK parameters studied will be Cmax and Tmax. For Cohort 2, the PK parameters 
studied will be maximum serum concentration of SYNT001 and the associated Tmax. 
Specific collection times and timing window allowances are detailed in Table 5. Detailed 
instructions for sample collection and preparation will be provided in a separate laboratory 
manual. 
7.5.5 
Pharmacodynamic Sampling 
PD samples will be collected for analyses throughout the study. Measurements for albumin will 
be derived from the clinical safety laboratory results. Specific collection times are detailed in. 
Samples for each type of PD will be collected according to the schedule shown in Table 7. 
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Table 7. 
Pharmacodynamic Assessments 
Parameter 
Collection Time Points 
 
 
Cohort 1 
Cohort 2a 
Immunoglobulins: 
 
IgG 
 
IgG subtypes (IgG1-4) 
 
IgA 
 
IgM 
Screening and Days 0, 1, 2, 5, 7, 
12, 14, 19, 21, 28, 29, 30, 33, 42, 
56, 84, and 112 
Screening and Days 0, 7, 14, 28, 
42, 56, 70, 84, 91, 112, and 140 
 
Circulating immune complexes 
(CIC) 
Days 0, 5, 7, 12, 14, 19, 21, 28, 
33, 42, 56, 84, and 112 
Days 0, 7, 14, 28, 42, 56, 70, 84, 
91, 112, and 140 
 
Albumin 
Screening and Days 0, 7, 14, 21, 
28, 33, 42, 56, 84, and 112 
Screening and Days 0, 7, 14, 28, 
42, 56, 70, 84, 91, 112 and 140 
 
Anti-Dsg (1 and 3) antibody 
titers 
Screening and Days 0, 7, 14, 33, 
56, 84, and 112 
Screening and Days 0, 7, 14, 28, 
42, 56, 70, 84, 91, 112, and 140 
 
C3 and AECA levels by 
indirect immunofluorescence 
Days 0, 14, 33, 56, 84, and 112 
Screening and Days 0, 7, 14, 28, 
42, 56, 70, 84, 91, 112, and 140 
 
Exploratory biomarkers 
(RNAseq, urine IgG)b 
Days 0, 14, 33, 56, 84, and 112 
Days 0, 28, and 91 
 
Immunophenotyping by flow 
cytometry for measurement of 
T cells, monocytes, NK cells, 
and B cells 
Days 0, 28, and 56 
Days 0, 28, and 91 
 
Exploratory biomarker 
(FCGR2A SNP, via buccal 
swab) 
Day 0 
Day 0 
 
Exploratory pemphigus 
immune response biomarkers 
Days 0, 5, 7, 12, 14, 19, 21, 28, 
33, 42, 56, 84, and 112 
Days 0, 7, 14, 28, 42, 56, 70, 84, 
91, 112, and 140 
a Ongoing safety and PD evaluations may result in modification of the dosing regimen from every other week to 
weekly. See APPENDIX 5 for the corresponding visit schedule. 
b Urine IgG collected in Cohort 1 only. 
 
See Table 5 for timing window allowances with respect to measurement collection. More 
information, including detailed instructions for sample collection (including collection tubes) and 
preparation will be provided in a separate laboratory manual. 
7.5.6 
Immunogenicity Testing 
SYNT001 is being developed for the acute and chronic therapy of autoimmune disorders. 
Although SYNT001 is a humanized IgG4 mAb, exposure to SYNT001 in clinical trials could 
result in the development of ADAs, with potential consequences ranging from neutralization 
with possible lessening of drug efficacy to safety consequences such as allergic reactions. 
Testing will first detect binding ADAs. Then, for all confirmed positive samples, an ADA titer 
will be determined and there will be testing for neutralizing antibodies using a validated cell-
based assay.  
More information, including detailed instructions for sample collection and preparation will be 
provided in a separate laboratory manual. 
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7.6 
12-Lead Electrocardiogram (ECG) 
On dose administration days, digital 12-lead ECG measurements will be obtained at 5 minutes 
after the completion of the infusion. When ECGs are to be collected at the same time point as a 
blood collection, ECGs should be collected first. All ECGs are to be performed with the subject 
in a supine position having rested in this position for at least 5 minutes before each reading. 
ECGs are to be performed in triplicate, each at an interval of 1 to 2 minutes apart (Cohort 1) or 
approximately 1 minute apart (Cohort 2). See Table 5 for timing window allowances with 
respect to performing ECG. 
The following ECG parameters will be collected: PR interval, RR interval, QRS interval, and QT 
interval. The ECG findings will be evaluated by a qualified physician for the presence of 
abnormalities (qualitative assessment). The physician will assess each ECG as normal, 
abnormal/not clinically significant, or abnormal/clinically significant.  
Normal corrected QT interval using Fridericia’s formula (QTcF) is ≤450 msec.  
Abnormalities in the ECG that appear following therapy or that result in clinical signs and 
symptoms are considered clinically significant for the purposes of this study and will be recorded 
on the AE eCRF.  
7.7 
Pemphigus Disease Area Index (PDAI) 
Pemphigus severity and disease activity will be measured using the PDAI in regions where a 
validated questionnaire is available. A PDAI total activity score will be determined at screening. 
To be eligible for study participation, the patient’s grade by disease severity must be >4. 
Assuming subject eligibility, the PDAI will be administered during Treatment Period and 
Follow-up Period. Disease severity categories by PDAI are mild (0 to 8), moderate (9 to 24), and 
severe (≥25) (Shimizu et al., 2014). The Investigator will determine a PDAI score as follows: 0 
to 250 points for disease activity (≤120 for skin, ≤10 for scalp, and ≤120 for mucosa), and 0 to 
13 points for damage (≤12 for skin and ≤1 for scalp) (Rosenbach et al., 2009). See Appendix 2. 
7.8 
Study Drug Administration 
SYNT001 will be given as a 250-mL IV infusion over 1 hour ± 15 minutes using a 0.2-micron, 
inline filter.  
7.9 
Photographs 
Photographs will be taken of active lesions and follow-up photographs will be taken of the same 
areas at timepoints indicated in Table 2 and Table 3. Subjects who begin a steroid taper will have 
additional photographs taken at the clinic visit during which the decision to begin the taper is 
made. A separate manual describing the procedures for taking photographs will be provided. 
7.10 
Health-Related Quality of Life Assessments 
For Cohort 2, health-related quality of life will be assessed using ABQoL and Skindex-29 in 
regions where a validated questionnaire is available. The ABQoL questionnaire was developed 
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in Australia as a patient-based measure to quantify disease burden, monitor disease activity and 
evaluate response to therapeutic intervention in patients with autoimmune bullous disease 
(Sebaratnam et al., 2013; Sebaratnam et al., 2015) (Appendix 3). Skindex-29 was developed to 
measure the effects of skin disease on patients’ quality of life using a self-administered 
30-question dermatology survey (Chren et al., 1996) (Appendix 4). 
7.11 
Adverse Event Assessments 
Information regarding the occurrence of AEs will be collected from the time the subject signs the 
informed consent form and continuing through the last study visit. Findings at screening and 
Day 0 (pre-dose) will be recorded as medical history. Any known untoward event that occurs 
beyond the AE reporting period that the Investigator assesses as related to study drug also should 
be reported as an AE. Clinical AEs will be graded using the NCI CTCAE, Version 4.03 
(Appendix 1).  
Note: AEs resulting in a subject’s permanent discontinuation from the study, regardless of 
seriousness or relationship to study drug, MUST be promptly reported to the Sponsor. 
Additionally, subjects must be followed until return to normal and/or resolution of the AE. 
See Section 10 for more information. 
7.12 
Prior and Concomitant Medications 
All treatments a subject receives within 14 days prior to enrollment through the end of the study 
will be documented on the source document and eCRF. A history of treatments taken for the 
primary disease, even if not taken within the 14 days prior to enrollment, will be collected.  
Permitted Medications 
Concomitant medication and treatment for co-existing conditions, including those for 
pemphigus, are permitted if not listed as prohibited.  
1. Topical antibiotics to treat active infections that occur during the study.  
2. Topical or systemic treatments for oral candidiasis.  
3. Topical lidocaine for transient pain relief as needed.  
4. Concomitant treatment that is medically indicated for any AEs the subject experiences during 
the study.  
5. Medication for potential infusion-related reactions (IRRs) including post-infusion 
headache: The Investigator may recommend prophylactic use of acetaminophen, IV 
hydration, diphenhydramine, histamine2 (H2) blockers (eg, ranitidine, famotidine), etc to 
manage potential IRRs. 
6. Low-strength corticosteroids (eg, hydrocortisone ≤1%) applied to a single lesion contributing 
<10% of the PDAI total activity score. 
7. Topical tacrolimus, sirolimus or pimecrolimus applied to a single lesion contributing <10% 
of the PDAI total activity score. 
8. Dexamethasone elixir solution for oral lesions if dose remains stable throughout trial 
participation (swish and spit only). 
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9. Stable regimen of the following systemic immunosuppressants: azathioprine, mycophenolate 
mofetil, methotrexate, dapsone, cyclosporine, tacrolimus, sirolimus, corticosteroids, or low 
dose oral cyclophosphamide (≤100 mg/day).  
Fourteen days after the final dose of SYNT001, corticosteroids may be tapered at the 
Investigator’s discretion.  
Prohibited Medications 
Use of the following medications will not be permitted during the study unless specified above 
as permitted: 
1. Rituximab or other anti-CD20 antibody  
2. Monoclonal antibodies other than study drug  
3. Any topical or systemic immunosuppressive drugs apart from those that are listed as 
permitted.  
4. IV corticosteroids prior to infusion (except in subjects who received corticosteroids for 
treatment of a prior IRR to SYNT001) 
5. Any investigational drug or device 
6. Vaccinations within 2 weeks of screening through 28 days following final dose of study drug 
 
Corticosteroids 
Before enrollment 
The dose of corticosteroids taken for pemphigus or any other condition prior to screening must 
be at a dose <1 mg/kg and the dose level must have not increased in dose level by more than 
50% in the 2 weeks prior to screening. No pulse dosing of steroids is permitted in the 2 weeks 
prior to screening. 
 
From screening until 2 weeks after the last dose of SYNT001 
The dose of corticosteroids taken for pemphigus or any other condition should remain stable 
(<10% change in dose level) from screening until 2 weeks after the last dose of SYNT001. 
Corticosteroids should neither be started nor discontinued during this period with the exception 
of subjects who experience an IRR that requires corticosteroids as part of the management of the 
IRR. Such subjects may receive corticosteroids prophylactically prior to subsequent SYNT001 
infusions at the discretion of the Investigator. 
 
From 2 weeks after the last dose of SYNT001 until end of study participation 
At the discretion of the Investigator, but only after at least 2 weeks beyond the last dose of 
SYNT001, a slow corticosteroid taper may be started as per the following suggested schedule: 
 
If on >30 mg of prednisone per day, decrease by no more than 10 mg every two weeks until a 
final dose. 
If per the Investigator’s judgement, the subject would benefit from a change to the pemphigus 
treatment beyond the allowed steroid taper, this will be considered on a case-by-case basis in 
consultation with the Sponsor. 
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7.13 
Skin Biopsy 
In Cohort 1, optional skin biopsy samples from lesional or non-lesional skin will be collected to 
analyze SYNT001 levels. 
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8. 
STUDY ASSESSMENTS 
Study assessments are performed on a weekly basis and will be comprised of the following 
periods: Screening, Treatment (including Baseline [Day 0]), and Follow-Up (including End-Of 
Study). For those subjects that complete all periods in Cohort 1, maximum study duration is 
126 days. For those subjects that complete all periods in Cohort 2, maximum study duration is 
154 days.  
Further detail on specific study assessments is provided in Section 7. 
8.1 
All Cohorts: Screening Period and First Treatment (Day 0) 
8.1.1 
All Cohorts: Screening Period (Day −14 to Day −1) 
For all cohorts, informed consent must be obtained before any study-specific samples are taken 
or study-specific tests or evaluations are conducted. The following assessments at the screening 
visit are to occur within 14 days before dosing. Study eligibility will be based on satisfying all 
the study inclusion and exclusion criteria (see Section 6).  
At the screening visit, information will be collected and subjects will have clinical evaluations as 
follows: 
 Informed consent 
 Medical history and demographic data 
 Review inclusion and exclusion criteria 
 Complete physical examination, including height and weight 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature); abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis)  
 PDAI (Cohort 2 only) 
 Pregnancy test 
 Hepatitis and HIV screen 
 12-lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position) 
 Immunogenicity sample collection (Cohort 2 only) 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 Anti-Dsg1 and Dsg3 antibody titers 
 C3 (Cohort 2 only) 
 AECA (Cohort 2 only) 
 Concomitant medication assessment 
 AE assessment 
 
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8.1.2 
All Cohorts: Enrollment and First Treatment (Day 0)  
For all cohorts, study Day 0 is defined as the date the subject is administered their first dose of 
study drug. On Day 0, subjects will be asked to come to the clinic and the following procedures 
will be performed prior to the first dose of study drug: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 Pregnancy test 
 12-lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position) 
(Cohort 2 only) 
 Serum tetanus antibody and VZV antibody 
 PDAI 
 PK baseline sample collection (collected just prior to the start of the study drug infusion) 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3 
 AECA 
 FCGR2A SNP via buccal swab  
 RNAseq 
 Urine IgG (Cohort 1 only) 
 Immunophenotyping  
 Exploratory pemphigus immune response biomarkers 
 Skin biopsy (optional) (Cohort 1 only) 
 Photography 
 HR-QoL assessments (ABQoL, Skindex-29) (Cohort 2 only) 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry will be performed at 15, 30, and 45 minutes after the 
start of the infusion and at completion of the infusion 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion 
of the infusion; abnormal results to be repeated after 5 minutes of rest  
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 PK sample collection at 5 minutes. Thereafter at 2, 4, 6 hours (Cohort 1) or 1 and 2 hours 
(Cohort 2) after the completion of study drug infusion; record collection date and time for 
each PK sample 
 12-lead ECG (to be obtained in triplicate approximately 5 minutes after the completion of 
study drug infusion 
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
8.2 
Cohort 1: Day 1 to 84 
8.2.1 
Cohort 1: Follow-up Day 1  
On Day 1 (24 hours ± 1 hour from end-of-infusion time on Day 0), the subject will return to the 
clinic and the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PK sample collection (record collection date and time) 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 Skin biopsy (optional) 
 Concomitant medication assessment 
 AE assessment 
 
8.2.2 
Cohort 1: Follow-up Day 2  
On Day 2 (48 hours ± 2 hours from end-of-infusion time on Day 0), the subject will return to the 
clinic and the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PK sample collection (record collection date and time) 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 Skin biopsy (optional) 
 Concomitant medication assessment 
 AE assessment 
 
8.2.3 
Cohort 1: Follow-up Day 5  
On Day 5 (120 hours ± 4 hours from end-of-infusion time on Day 0), subjects may return to the 
clinic or be visited by an at-home nurse, and the following procedures are to be performed: 
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 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PK sample collection (record collection date and time 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 CIC 
 Exploratory pemphigus immune response biomarkers 
 Concomitant medication assessment 
 AE assessment 
 
8.2.4 
Cohort 1: Treatment Day 7 (Dose 2) 
On Day 7 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 Exploratory pemphigus immune response biomarkers 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry will be performed at 15, 30, and 45 minutes after the 
start of the infusion and at completion of the infusion 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion 
of the infusion; abnormal results to be repeated after 5 minutes of rest  
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
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8.2.5 
Cohort 1: Follow-up Day 12  
On Day 12 (± 6 hours), subjects may return to the clinic or be visited by an at-home nurse, and 
the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 CIC 
 Exploratory pemphigus immune response biomarkers 
 If visit performed at the study site: 12-lead ECG to be obtained in triplicate 
 Concomitant medication assessment 
 AE assessment 
 
8.2.6 
Cohort 1: Treatment Day 14 (Dose 3) 
On Day 14 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3 
 AECA 
 RNAseq 
 Urine IgG 
 Exploratory pemphigus immune response biomarkers 
 Skin biopsy (optional) 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry will be performed at 15, 30, and 45 minutes after the 
start of the infusion and at completion of the infusion 
 
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After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion 
of the infusion; abnormal results to be repeated after 5 minutes of rest  
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
8.2.7 
Cohort 1: Follow-up Day 19  
On Day 19 (± 6 hours), subjects may return to the clinic or be visited by an at-home nurse, and 
the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 CIC 
 Exploratory pemphigus immune response biomarkers 
 Concomitant medication assessment 
 AE assessment 
 
8.2.8 
Cohort 1: Treatment Day 21 (Dose 4) 
On Day 21 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Exploratory pemphigus immune response biomarkers 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
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 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry will be performed at 15, 30, and 45 minutes after the 
start of the infusion and at completion of the infusion 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion 
of the infusion; abnormal results to be repeated after 5 minutes of rest  
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
8.2.9 
Cohort 1: Treatment Day 28 (Dose 5) 
On Day 28 (± 6 hours) subjects will return to the clinic and the following procedures are to be 
performed prior to study drug infusion: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 PK sample collection (collected just prior to the start of the study drug infusion) 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Immunophenotyping  
 Exploratory pemphigus immune response biomarkers 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry will be performed at 15, 30, and 45 minutes after the 
start of the infusion and at completion of the infusion 
 
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After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion 
of the infusion; abnormal results to be repeated after 5 minutes of rest  
 PK sample collection at 5 minutes and 2, 4, and 6 hours after the completion of study 
drug infusion; record collection date and time for each PK sample 
 12-lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion 
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
8.2.10 
Cohort 1: Follow-up Day 29  
On Day 29 (24 hours ± 1 hour from end-of-infusion time on Day 28), the subject will return to 
the clinic and the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PK sample collection (record collection date and time) 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 Concomitant medication assessment 
 AE assessment 
 
8.2.11 
Cohort 1: Follow-up Day 30 
On Day 30 (48 hours ± 2 hours from end-of-infusion time on Day 28), the subject will return to 
the clinic and the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 PK sample collection (record collection date and time) 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM 
 Concomitant medication assessment 
 AE assessment 
 
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8.2.12 
Cohort 1: Follow-up Day 33  
On Day 33 (120 hours ± 4 hours from end-of-infusion time on Day 28), subjects will return to 
the clinic and the following procedures are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 PK sample collection (record collection date and time) 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3 
 AECA 
 RNAseq 
 Urine IgG 
 Exploratory pemphigus immune response biomarkers 
 Skin biopsy (optional) 
 Photography 
 Concomitant medication assessment 
 AE assessment 
 
8.2.13 
Cohort 1: Follow-up Day 42 
On Day 42 (± 3 days), subjects will return to the clinic and the following procedures are to be 
performed: 
 Complete physical exam 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Exploratory pemphigus immune response biomarkers 
 Concomitant medication assessment 
 AE assessment 
 
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8.2.14 
Cohort 1: Follow-up Day 56  
On Day 56 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed: 
 Complete physical exam 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 Pregnancy test 
 12-lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position) 
 Serum tetanus antibody and VZV antibody 
 PDAI 
 Immunogenicity sample collection 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3 
 AECA 
 RNAseq 
 Urine IgG 
 Immunophenotyping  
 Exploratory pemphigus immune response biomarkers 
 Skin biopsy (optional) 
 Photography 
 Concomitant medication assessment 
 AE assessment 
 
8.2.15 
Cohort 1: Follow-up Day 84  
On Day 84 (± 5 days), subjects are to return to the clinic and the following procedures are to be 
performed: 
 Complete physical exam 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 Serum tetanus antibody and VZV antibody 
 PDAI 
 Immunogenicity sample collection 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
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 C3 
 AECA 
 RNAseq 
 Urine IgG 
 Exploratory pemphigus immune response biomarkers 
 Skin biopsy (optional) 
 Photography 
 Concomitant medication assessment 
 AE assessment 
 
Note: Cohort 1 End-of-Study visit is detailed in Section 8.4. 
8.3 
Cohort 2: Subsequent Treatments to Follow-up 
8.3.1 
Cohort 2: Treatment Days 7, 14, 42, 56, 70, and 84 
For Cohort 2 Days 7, 14 (all ± 1 day), 42, 56, 70, and 84 (all ± 3 days), subjects will return to the 
clinic and the following procedures are to be performed prior to study drug infusion: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 PDAI 
 PK sample collection (collected just prior to the start of the study drug infusion) 
(Cohort 2, Days 7, 14, and 84 only) 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion)  
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3  
 AECA  
 Exploratory pemphigus immune response biomarkers 
 Photography 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry will be performed at 15, 30, and 45 minutes after the 
start of the infusion and at completion of the infusion 
 
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After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion 
of the infusion; abnormal results to be repeated after 5 minutes of rest  
 12-lead ECG (to be obtained in triplicate approximately 5 minutes after the completion of 
study drug infusion (Cohort 2, Day 14 only) 
 PK sample collection at 5 minutes and 1 and 2 hours after the completion of study drug 
infusion; record collection date and time for each PK sample (Cohort 2, Days 7, 14, and 
84 only) 
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
8.3.2 
Cohort 2: Treatment Day 28 
For Cohort 2 Day 28 (± 3 days), subjects will return to the clinic and the following procedures 
are to be performed prior to study drug infusion: 
 Complete physical exam 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry; to be measured immediately prior to the infusion 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 Pregnancy test  
 12-lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position)  
 Serum tetanus antibody and VZV antibody  
 PDAI 
 PK sample collection (collected just prior to the start of the study drug infusion)  
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3  
 AECA  
 RNAseq  
 Immunophenotyping  
 Exploratory pemphigus immune response biomarkers 
 Photography  
 HR-Qol (ABQoL, Skindex-29)  
 
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After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry will be performed at 15, 30, and 45 minutes after the 
start of the infusion and at completion of the infusion 
 
After administration of study drug, the following post treatment procedures and 
assessments will be performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, oral 
temperature) and pulse oximetry: 30 minutes, 1 hour, and 2 hours following completion 
of the infusion; abnormal results to be repeated after 5 minutes of rest 
 PK sample collection at 5 minutes and 1 and 2 hours after the completion of study drug 
infusion; record collection date and time for each PK sample  
 12-lead ECG (to be obtained in triplicate approximately 5 minutes after the completion of 
study drug infusion 
 
Throughout the study visit, the following assessments will be performed: 
 Concomitant medication assessment 
 AE assessment 
 
8.3.3 
Cohort 2: Follow-up Day 112  
For Cohort 2 Day 112 (± 5 days), subjects are to return to the clinic and the following procedures 
are to be performed: 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis)  
 PDAI  
 Immunogenicity sample collection  
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3 
 AECA 
 Exploratory pemphigus immune response biomarkers 
 Photography 
 Concomitant medication assessment  
 AE assessment 
 
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8.4 
All Cohorts: End of Study or Early Termination Visit; Cohort 1, Day 112; 
Cohort 2, Days 91 and 140  
For Cohort 1 Day 112 (± 5 days) and Cohort 2 Days 91 and 140 (± 5 days), subjects are to return 
to the clinic and the following procedures are to be performed: 
 Complete physical exam 
 Vital sign measurements (after 5 minutes of rest; sitting blood pressure, heart rate, 
respiratory rate, oral temperature): abnormal results to be repeated after 5 minutes of rest 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
 Pregnancy test  
 12-lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position) 
(Cohort 2, Days 91 and 140 only) 
 Serum tetanus antibody and VZV antibody 
 PDAI 
 Immunogenicity sample collection 
 PD sample collection 
 IgG, IgG subtypes (IgG1-4), IgA, IgM  
 CIC 
 Anti-Dsg (1 and 3) antibody titers 
 C3  
 AECA  
 RNAseq (Cohort 1 Day 112; Cohort 2, Day 91 only) 
 Urine IgG (Cohort 1 only) 
 Immunophenotyping (Cohort 2, Day 91 only) 
 Exploratory pemphigus immune response biomarkers 
 Photography 
 HR-Qol (ABQoL, Skindex-29) (Cohort 2 only) 
 Concomitant medication assessment 
 AE assessment 
 
Note: a subject may choose to terminate participation in the study at any time. Under this 
circumstance, the subject will be encouraged to return as soon as possible for an early 
termination visit and to receive assessments otherwise scheduled on Day 112 (Cohort 1) or Day 
91 (Cohort 2). 
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9. 
STUDY RULES 
9.1 
Subject Withdrawal  
Every reasonable effort will be made to keep the subject in the study; however, if a subject 
withdraws from the study, the Investigator should complete and report the reasons for 
withdrawal as thoroughly as possible. The reason(s) for termination must be clearly documented 
on the appropriate page of the eCRF.  
Subjects who have received at least one SYNT001 dose and withdraw or prematurely 
discontinue study drug should be encouraged to attend, at a minimum, the early termination (ET) 
visit Day 112 (Cohort 1) or Day 91 (Cohort 2). Subjects in Cohort 2 will also be encouraged to 
attend the remaining follow up visits on Days 112 and 140. 
If the subject fails to return for these assessments for unknown reasons, every effort (eg, 
telephone, email, and letter) should be made to contact them.  
The reason(s) for a subject’s participation in the study may be prematurely discontinued will be 
documented and include:  
1. The subject wishes to withdraw from the study. 
2. Request by a regulatory agency or Institutional Review Board). 
3. The subject experiences a significant or intolerable AE.  
4. The subject experiences a significant adverse change in vital signs, physical examination 
findings, or clinical laboratory parameter. 
5. The subject has a need for a concomitant medication that is not permitted by the study 
protocol. 
6. The subject experiences generalized impairment or mental incompetence that would result in 
the subject being unable to understand his or her participation in the study. 
7. If, in the Investigator’s medical judgment, further participation would be injurious to the 
health and well-being of the subject, or is not in the best interest of the subject.  
8. Administrative reasons, such as subject non-compliance or a major protocol violation. 
 
If at the discretion of the Investigator with consultation with the Medical Monitor, a subject 
requires a significant increase in dose(s) of anti-pemphigus medication(s) for the management of 
pemphigus, the subject should be encouraged to attend, at a minimum, the ET visit Day 112 
(Cohort 1) or Day 91 (Cohort 2). Subjects in Cohort 2 will also be encouraged to attend the 
remaining follow up visits on Days 112 and 140. 
9.2 
Subject Replacement 
Enrolled subjects withdrawn for a reason other than an AE may be replaced.  
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9.3 
Study Discontinuation 
The Sponsor has the right to terminate or to stop the study at any time. Reasons for study 
discontinuation may include, but are not limited to, the following:  
 The incidence or severity of AEs in this or other related studies indicates a potential 
health hazard to subjects  
 Subject enrollment is unsatisfactory 
 Drug supply issues 
 Excessive subject self-withdrawal 
 Significant protocol violations (eg, violation of eligibility criteria, dosing errors, missing 
data for study endpoint analysis) 
 
9.4 
Lost to Follow-up 
All reasonable efforts should be made to contact any subject lost to follow-up during the study to 
complete assessments and retrieve any outstanding data. If the subject is unreachable after three 
good faith attempts, at a minimum, the Investigator should follow up with a registered letter 
requesting contact so safety data may be collected, recorded, and reported (if necessary).  
9.5 
Stopping Rules 
9.5.1 
Dose-Escalation Stopping Rule (Cohort 1) 
Dose recommendations will be made by a DEC and will be based on safety and PD evaluations 
including but not limited to, DLTs, AEs, SAEs, and total IgG levels. 
Dose-limiting toxicity (DLT) will be defined generally as severe (Grade 3) AEs occurring in 
≥2 subjects that are determined to be clinically significant and considered related to study drug. 
If 2 or more subjects at any time in any cohort have Grade 3 AEs that are determined to be 
clinically significant and considered to be related to study drug, dosing will be halted within that 
cohort and dose-escalation to a higher dose will not occur. Upon review of the available 
information, the DEC may reduce the dose by at least 50% prior to enrolling additional subjects.  
9.5.2 
Study Stopping Rule 
If any subject at any time experiences a life-threatening AE (Grade 4) that is considered to be 
related to study drug, any further dosing in all enrolled subjects will be suspended until the 
Sponsor Medical Lead has evaluated the event and determined the next appropriate course of 
action. At any time during the study, the study may be discontinued if the Sponsor Medical Lead 
determines that further drug exposure would pose an undue risk to subjects. 
9.5.3 
Individual Stopping Rule 
Dosing for any individual subject will be discontinued (ie, no further study drug will be given to 
that subject) if the subject experiences any study drug-related SAE or any study drug-related 
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non-serious AE that, in the judgement of the Investigator (following consultation with the 
Medical Monitor, if desired) or in the judgement of the Sponsor Medical Lead, suggest that it 
could be unsafe to administer further study drug to that subject. 
Subjects who withdraw from this study due to an AE determined to be related to study drug are 
to be followed until there is: 
 Resolution or stabilization of the AE determined to be related 
 The subject is lost to follow-up 
 The event is otherwise explained 
 
If there is a persistent AE contributing to discontinuation that is determined to be related to 
SYNT001, subjects must be followed with appropriate medical management until resolution or 
stabilization. Refer to Section 10 for more information.  
Additionally, a subject will be discontinued from further treatment with study drug, at the 
discretion of the Investigator with consultation with the Medical Monitor, if they require a 
significant increase in doses of anti-pemphigus medications for the management of pemphigus. 
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10. 
EVALUATION OF SAFETY 
10.1 
Safety Parameters 
Subjects will be monitored continuously throughout the treatment and follow-up period for AEs 
(acute, delayed, and/or cumulative), as well as for changes in clinical status. Parameters 
measure/assess safety include physical examinations, vital sign measurements (including pulse 
oximetry), clinical (safety) laboratory tests (hematology, serum chemistries, urinalysis), 
concomitant medication assessments, and ECG. Clinical and laboratory AEs will be graded using 
the NCI CTCAE; Version 4.03 (see Appendix 1).  
10.2 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical trial subject associated with 
the use of a drug, whether considered drug related or not. An AE can be an unfavorable and 
unintended sign (eg, an abnormal laboratory value finding), a symptom, or a disease temporally 
associated with the use of a drug, without judgment as to causality. An AE can arise from use of 
the drug (eg, use in combination with another drug) and from any route of administration, 
formulation or dose, including an overdose. An AE also includes, but is not limited to, any 
clinically significant worsening of a pre-existing condition. Examples include: 
 Any sign, symptom, physical finding, or laboratory result that has worsened in nature, 
severity or frequency compared to baseline 
 Reactions from an investigational drug, including those occurring because of an 
overdose, abuse of the study drug, withdrawal phenomena, sensitivity or toxicity 
 Concurrent illness that was not present or worsens in nature, severity, or frequency 
compared to baseline  
 Injury or accident 
 Exacerbation of a pre-existing condition 
 
Pregnancy is not considered an AE or SAE; however, any pregnancy complication(s) should be 
recorded as an AE(s) or SAE(s) (if applicable). Elective abortions without complications should 
not be regarded as AEs, unless they were therapeutic abortions. Hospitalization for normal 
delivery of a healthy newborn should not be considered an SAE. If a female subject becomes 
pregnant during the conduct of the study, the Investigator must notify the Sponsor according to 
the procedures provided in Section 10.5.4. 
Planned hospitalization admissions or surgical procedures for a condition known to exist before 
the subject signed the informed consent are not an AE and should be recorded as medical history. 
If the planned hospitalization or procedure is executed as planned and without complication, the 
record in the subject’s medical history is considered complete. However, if the event/condition 
deteriorates in an unexpected manner during the study or following surgery, it must be reported 
as an AE according to the procedures provided in Section 10.2.1. 
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10.2.1 
Recording an Adverse Event 
For data collection, all untoward events that occur after informed consent through the last study 
visit are to be recorded on eCRFs by the investigational site. All AEs are to be accurately 
recorded on the Adverse Event page of the subject’s eCRF. The severity of each AE will be 
graded using the NCI CTCAE, Version 4.03 (see Appendix 1). The date of onset as well as the 
end date of the event should be recorded or the event should be entered as “ongoing”. In 
addition, the method used to treat the AE and the outcome of the AE will be noted. The 
Investigator will assess the relationship of the event to study drug.  
10.2.2 
Assessment of Causality 
A medically qualified Investigator must assess the relationship of any AE (including SAEs) to 
the use of the study drug, as related or not related, based on clinical judgment and using all 
available information. The causal relationship between the study medication and the AE will be 
assessed using one of the following categories: 
Not Related: Factors consistent with an assessment of Not Related include: 
 Temporal relationship is lacking (eg, the event did not occur within a reasonable time 
frame following administration of the study medication); or 
 Other causative factors more likely explain the event (eg, a pre-existing condition, other 
concomitant treatments). 
 
Related: Factors consistent with an assessment of Related include: 
 There is a positive temporal relationship (eg, the event occurred within a reasonable time 
frame following administration of study medication); or 
 The AE is more likely explained by the investigational product than by another cause (ie, 
the AE shows a pattern consistent with previous knowledge of the investigational product 
or the class of the investigational product) 
 
10.2.3 
Serious Adverse Events 
(Notify Medpace Safety within 24 hours; document on eCRF) 
The SAE definition and reporting requirements are in accordance with Title 21 Part Code of 
Federal Regulations (CFR) 312.32 and the Guidance for Industry and Investigators Safety 
Reporting Requirements for Investigational New Drug (INDs) and Bioavailability 
/Bioequivalence Studies. 
An AE is considered "serious" if, in the view of either the Investigator or sponsor, it results in 
any of the following outcomes: 
 Death: This includes any death that occurs while the subject is “on study” through the 
last study visit.  
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Note: Death is an outcome of an AE and not an AE. The event(s) that caused death (eg, 
illness, accident) is the SAE. Death due to any other cause(s) must also be reported as an 
outcome of the reportable SAE. 
 Life-threatening adverse drug event: An AE or suspected adverse reaction is 
considered “life threatening” if, in the view of either the Investigator or Sponsor, its 
occurrence places the patient or subject at immediate risk of death. It does not include an 
AE or suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death.  
 Inpatient hospitalization or prolongation of existing hospitalization: an AE that 
requires admission to a hospital for medical and/or surgical intervention. 
 In the absence of an AE, the Investigator should not report hospitalization or prolongation 
of hospitalization as an SAE, as detailed in the following examples: 
o An elective or previously scheduled surgery for a pre-existing condition that has not 
deteriorated unexpectedly after initiation of treatment (eg, a previously scheduled 
ventral hernia repair) 
o Hospitalization or prolongation of hospitalization is needed for a procedure required 
by the protocol 
o Hospitalization or prolongation of hospitalization is part of routine procedure 
followed by study center 
o Hospitalization for survey visits, annual physicals, or planned observation 
o Hospitalization for observation with release within 24 hours (eg, an emergency room 
visit for hematuria that results in a diagnosis of cystitis and discharge to home on oral 
antibiotics 
 Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 Congenital anomaly/birth defect 
 Important medical event: An event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, it may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. 
 
10.2.3.1 
Recording a Serious Adverse Event 
When the diagnosis of an SAE is known or suspected, the Investigator should record the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms. Signs and 
symptoms may then be described in the event description. For example, dyspnea should not be 
used as an SAE term if the diagnosis, which caused the dyspnea, is known to be malignant 
pleural effusion.  
Death should not be recorded as an SAE, but as an outcome of a specific SAE, unless the event 
preceding the death is unknown. In the exceptional case where the events leading to death are 
unknown, then death may be used as an event term. If an autopsy was performed, the autopsy the 
autopsy report should be provided. 
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10.2.3.2 
Reporting a Serious Adverse Event 
RESPONSIBILITIES OF THE INVESTIGATOR 
Any death, SAE, or pregnancy, experienced by the subject after informed consent through the 
last study visit, regardless of relationship to study drug, must be promptly reported (within 
24 hours of the Investigator becoming aware of the event) by telephone or electronic 
transmission to the Sponsor (or designee). 
Contact information for SAE reporting: 
Medpace Clinical Safety 
Medpace SAE hotline: 
Telephone: 
 dial  or 
 dial  
Facsimile: 
 or 
 
e-mail:
 
 
Additionally, the Investigator will be able to contact the Medical Monitor: 
Medical Safety Contact 
 
 
Phone (EU): 
 extension 
 
Mobile phone: 
 
Email: 
 
 
The Investigator will report the SAE to his or her IRB in accordance with IRB’s standard 
operating procedures and policies. Adequate documentation must be maintained showing that the 
IRB was properly notified. 
SAEs must be recorded on the SAE form in the electronic data capture (EDC) system. This 
requirement includes all SAEs that occur after informed consent through the last study visit. The 
minimum information required for SAE reporting includes identity of investigator, site number, 
subject number, an event description, SAE term(s), onset date, the reason why the event is 
serious (ie, the seriousness criteria), and the Investigator’s assessment of the relationship of the 
event to study treatment. Additional SAE information including medications or other therapeutic 
measures used to treat the event, action taken with the study treatment due to the event, and the 
outcome/resolution of the event will be recorded. Paper forms for reporting SAEs will be 
provided to the study sites as back-up in case the EDC system is not accessible. 
In all cases, the Investigator should continue to monitor the clinical situation and report all 
material facts relating to the progression or outcome of the SAE. Furthermore, the Investigator 
may be required to provide supplementary information as requested by the Sponsor (or 
designee). 
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RESPONSIBILITIES OF THE SPONSOR (OR DESIGNEE) 
The Sponsor (or designee) will process and evaluate all SAE as soon as the reports are received. 
For each SAE received, the Sponsor will decide as to whether the criteria for expedited reporting 
have been met. 
The Sponsor (or designee) is responsible for promptly informing the FDA and other regulatory 
authorities as well as other participating Investigators of the event. Written submission must be 
made by the Sponsor to the FDA as soon as possible and in no event later than 15 calendar days 
after the Sponsor’s initial notification of the event, or for an event that is fatal or life-threatening 
no later than 7 calendar days after the Sponsor’s initial notification.  
EXPEDITED REPORTING  
Under FDA ruling (US Code of Federal Regulations, Title 21 CFR Part 312.32) and the ICH 
Guideline “Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting E2A,” the Sponsor is required to submit written documentation, in the form of a safety 
report, detailing: 
 Any event associated with the use of the drug, that is both serious and unexpected, or  
 Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.  
 
The Sponsor will submit SAEs that meet the criteria for expedited reporting to the regulatory 
authorities in accordance with local regulations governing safety reporting. 
10.2.4 
Follow-Up of Adverse Events and Serious Adverse Events 
Any SAE or AE must be followed until either resolution of the event or determination by the 
Investigator that the event has become stable or irreversible. Appropriate diagnostic tests should 
be performed and therapeutic measures, if indicated, should be instituted until the event has 
returned to baseline or until a clinically satisfactory resolution has been achieved. The 
appropriate follow-up visits must be scheduled and the specific tests repeated or performed as 
necessary. The status of all AEs will be documented as of the last study visit. If all required 
information is not available at the time of the initial report, follow-up information will be 
completed in the EDC system.  
10.3 
Warnings and Precautions 
10.3.1 
Vaccinations 
Subjects must not receive any vaccinations from within 2 weeks of screening until 28 days 
following final dose of study drug. 
10.3.2 
Management of Allergic or Infusion-Related Reactions 
As observed with all mAbs administered by IV infusion, infusion-related reactions to SYNT001 
are possible. In general, infusion reactions to mAbs observed in human studies typically develop 
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within 30 minutes to 2 hours after the initiation of drug infusion, although symptoms may be 
delayed for up to 24 hours. These infusion reactions can occur with the first dose of a mAb and 
are generally mild in severity, although severe and even fatal reactions can occur.  
Allergic and/or infusion-related reactions include hypersensitivity reactions and cytokine release 
syndromes. These reactions are experienced by subjects during or within hours of the infusion of 
mAb therapy. Symptoms can include flushing, alterations in heart rate and blood pressure, 
dyspnea, bronchospasm, back pain, fever, urticaria, edema, nausea, and all types of rashes. 
Anaphylaxis is recognized as a severe, life-threatening, generalized, or systemic reaction. This is 
a medical emergency characterized by rapidly developing life-threatening airway and/or 
breathing and/or circulation problems usually associated with skin or mucosal changes.  
Management of Grade 1 infusion reactions include interrupting the infusion or decreasing the 
rate of infusion by 50% and observing. Symptoms may also be treated as needed with 
medications such as diphenhydramine, hydrocortisone, or acetaminophen, either alone or in 
combination, depending on the subject’s signs and symptoms. If the infusion is interrupted or the 
infusion rate is decreased, it is important to note that all study drug infusions must be completed 
within 4 hours of SYNT001 preparation. 
Management of Grade 2 and higher infusion reactions should include stopping the infusion of 
study drug. Continued treatment with SYNT001 is prohibited following Grade 2 or higher 
infusion reactions. See Figure 2 and Figure 3 for details on the management of Grade 2 and 
Grade 3 infusion reactions. Allergic or IRRs will be graded in severity and managed based on 
NCI CTCAE Version 4.03 (see Table 8). 
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Figure 2. 
Management of Moderate (Grade 2) Infusion Reactions 
 
Stop  
Infusion 
Assess airway, breathing, circulation, and consciousness, and 
recline subject 
Start high flow oxygen 
Insert large bore IV and start IV fluids 
Initiate vital sign assessments at least every 15 minutes 
Any problem with airway, 
breathing circulation, or 
consciousness? 
NO: 
Initiate medical 
review 
YES:  
Initiate treatment per 
the Severe Infusion 
Reaction Flow Chart 
Monitor for symptom resolution 
If symptoms persist, proceed with medications as needed. For 
example: diphenhydramine 25-50 mg IV and/ or 
hydrocortisone 200 mg IV 
Note: If desaturation, 
hypotension, or urticaria 
present, refer to Severe 
Infusion Reaction Flow 
Chart. 
Subject presents with any of the below: 

Impending 
feeling of 
doom 

Flushing 

Pyrexia 

GI symptoms 

Altered vision 

Pain: back, 
abdomen, 
chest 

Wheezing 
without 
desaturation 

Peripheral 
edema 
If ongoing symptoms, consider 
ongoing observation or hospital 
admission 
If symptoms and signs resolve completely either spontaneously or after administration of diphenhydramine 
with or without hydrocortisone, consider rechallenge:  
Wait at least 20 minutes following medication administration before commencing rechallenge at an infusion 
rate of 50% or less of the initial infusion rate or 
Consider pre-medicating the subject with the same medication(s) 20-30 minutes in advance of subsequent 
administrations of SYNT001 and starting infusion at 50% of the planned infusion rate for the first 30 minutes, 
then returning to the intended infusion rate in the absence of any infusion reaction. If the infusion is interrupted 
or the infusion rate is decreased, it is important to note that all study drug infusions must be completed within 4 
hours of SYNT001 adminstration. 
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Figure 3. 
Management of Severe (Grade 3 or Higher) Infusion Reactions 
 
 
Subject presents with any of the below: 

Urticaria 

Airway threatened by angioedema 

Angioedema: Lip, mouth, facial swelling 

Respiratory compromise - wheezing, dyspnea, stridor or hypoxia 
(O2 saturation <90%) 

BP <90 mmHg SBP or >30% decrease from patient baseline 
Stop  
Infusion 
Consider (under medial direction): 
Epinephrine 1:1000 

0.3 mg (0.3 mL) IM into lateral thigh 
Transfer to Emergency Room/ICU 
Observe until all symptoms resolved. 
Start basic life support: 

High oxygen flow 

On bed, head down, legs up 

Large bore IV cannula, 1 L normal saline STAT 

Initiate vital signs at least every 15 minutes 
Airway Threatened:  
Bronchospasm: 
(Wheeze or Hypoxia) 
 
Hypotension: 
(Systolic BP <100 mmHg) 
Nebulized epinephrine 1:1000, 3–5 mL (3–5 mg) 
Nebulized salbutamol 5 mg 
Consider: Intubation / nebulized epinephrine 
 
Place on cardiac monitor 
Further epinephrine 1:1000, 0.3 mg IM and  
IV normal saline bolus 20 mL/kg STAT as needed 
Have vasopressin on hand 
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Table 8. 
Grading and Management of Allergic or Infusion-Related Reactions 
Adverse 
Event 
Grade 
1 
2 
3 
4 
5 
Infusion-
related 
reaction 
Mild transient 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, non-
steroidal anti-
inflammatory drugs 
[NSAIDS], narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤24 hours 
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated 
for clinical sequelae 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Allergic 
reaction 
Transient 
flushing or 
rash, drug 
fever 
<38.0°C. 
Intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤24 hours 
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Anaphylaxis 
– 
– 
Symptomatic 
bronchospasm, with or 
without urticarial; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-
threatening 
consequences; 
urgent 
intervention 
required 
Death 
Cytokine 
release 
syndrome 
Mild reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, IV 
fluids): prophylactic 
medications indicated for 
≤24 hours 
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement, 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
Life-
threatening 
consequences; 
pressor or 
ventilator 
support 
indicated 
Death 
Abstracted from NCI CTCAE Version 4.03. 
 
10.3.3 
Potential Immune Effects 
An antibody blocking FcRn is anticipated to have several effects. These include acceleration of 
catabolism of IgG, but not other immunoglobulin isotypes such as IgA and IgM, leading to dose-
dependent decreases in circulating IgG levels by up to an estimated 50% from the baseline levels 
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after a single dose and further decreases after multiple doses up to a 70% to 80% reduction. 
Based on studies in humans, it is expected that with a single dose, the nadir of this effect will 
occur approximately 5 days after dosing. The time course of recovery of IgG following dosing in 
the Phase 1a study suggests that a return to within 30% of baseline levels observed at 
pretreatment occurs within 4 weeks after a single dose and within 4 weeks after multiple doses as 
shown in NHPs.  
Given the normal adult range of total IgG of 500 to 1600 mg/dL (Agarwal and Cunningham-
Rundles, 2007; Furst, 2009; Gonzalez-Quintela et al., 2008; Jolliff et al., 1982; Keystone et al., 
2007; McMillan et al., 1997; van Vollenhoven et al., 2013), with a mean of 1150 mg/dL, a 50% 
decrease in mean total IgG would translate to 575 mg/dL and a 50% decrease from the low end 
of the normal range used for the inclusion criteria of 600 mg/dL in this study would be to 300 
mg/dL. An 80% decrease from baseline after multiple doses would result in IgG levels of 230 
mg/dL and 120 mg/dL, respectively. While these levels are in the range found in patients with 
primary humoral immunodeficiency (Ameratunga et al., 2013), the levels will be transient. 
Further, as reported for other therapies used for pemphigus, the temporary (ie, less than 4 
months) depletion of IgG (up to 95% reduction of total IgG as seen with immunoadsorption) 
does not appear to impart an increased risk of infection (Eming and Hertl, 2006; Furst, 2009; 
Keystone et al., 2007; Schmaldienst et al., 2001; van Vollenhoven et al., 2013). Study subjects 
will be monitored clinically for any infection. Further, commercial IVIG can be given to 
immediately restore IgG levels in case of a bacterial infection occurring while their IgG levels 
are decreased. 
An antibody that blocks FcRn is expected to also down-modulate innate and adaptive immunity 
and the catabolism of IgG-containing ICs. Specifically, it is expected that anti-FcRn will 
promote the clearance of IgG-containing ICs and the effects of these ICs on stimulating innate 
immune cell production of inflammatory cytokines (eg, interleukin 12 [IL-12], interferon-γ, and 
tumor necrosis factor) and inhibit the processing and presentation of antigens contained within 
ICs and thus the antigen-specific activation of CD4+ and CD8+ T-cells. Therefore, subjects with 
pre-existing conditions that are dependent upon IgG antibodies, such as chronic infections (eg, 
HIV, hepatitis B virus [HBV] or hepatitis C virus [HCV]), will be excluded from this study, as 
will subjects with active infection, in general. 
10.4 
Events of Special Interest 
Not applicable. 
10.5 
Other Safety Considerations 
10.5.1 
Laboratory Data 
All laboratory data obtained during the study should be reviewed. Any abnormal value that leads 
to a change in subject management (eg, requirement for additional medication or monitoring) or 
is determined to be of clinical significance by the Investigator should be reported as an AE 
and/or SAE as appropriate, unless this value is consistent with values obtained before entry into 
the study.  
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10.5.2 
Medication Errors 
Any medication error that results in an AE, even if it does not meet the definition of serious, 
requires reporting within 24 hours to the safety Medical Monitor. Refer to Section 10.2.3.2 for 
more information. 
10.5.3 
Overdose 
For the purposes of this study, an overdose of SYNT001 is defined as a dose that is two-fold 
higher than the intended dose for the subject. As all dosing for this study will be conducted in a 
controlled clinical setting, an overdose is not anticipated. In the unlikely event an overdose 
should occur, it should be reported as an AE.  
10.5.4 
Pregnancy 
If a female subject or the female partner of a male subject becomes pregnant during the course of 
the study, the Investigator must report the pregnancy to Medpace Safety using the Pregnancy 
Reporting Form within 24 hours of becoming aware of the event. The Investigator must obtain 
consent to collect pregnancy information (including the status of the newborn, if applicable). 
If some of the information required for completion of the Pregnancy Reporting Form is 
unavailable at the time of the initial report, follow-up reports will be completed and submitted 
within 24 hours of becoming aware of the new information. Any pregnancy will be followed 
through delivery for the observation of any SAEs. Any SAE that occurs during pregnancy must 
be recorded on the SAE report form in the EDC system (eg, maternal serious complications, 
therapeutic or spontaneous abortion, ectopic pregnancy, stillbirth, neonatal death, congenital 
abnormality, birth defect) and reported within 24 hours in accordance with the procedure for 
reporting SAEs (see Section 10.2.3.2).  
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11. 
STATISTICAL CONSIDERATIONS  
11.1 
General Design  
This study is being conducted to evaluate the safety, tolerability, PK, PD, activity, and 
immunogenicity of SYNT001 in pemphigus patients. 
11.2 
Study Populations  
Three populations will be employed in the analysis of study data: 
 The Safety population will consist of all subjects who have received at least one dose of 
study drug.  
 The PD population will consist of all subjects who receive at least one dose of study drug 
and have post-dose PD data available. 
 The PK population will consist of all subjects who receive at least one dose of study drug 
and have post-dose PK data available. 
 
Primary safety analyses will be performed on the Safety population. Demographics, subject 
disposition, screening, and baseline characteristics will be summarized for the Safety, PK, and 
PD populations, where appropriate. 
11.3 
Sample Size Justification  
Formal sample size calculations were not performed. The number of subjects was chosen based 
on feasibility and was considered sufficient to meet the study objectives. 
11.4 
Statistical Analysis  
11.4.1 
Statistical Analysis Plan 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP). The SAP may modify the plans outlined in 
the protocol; however, any deviations from the previously approved statistical plan will be 
described and justified in a SAP amendment. Additional statistical analyses other than those 
described in this section may be performed if deemed appropriate and will be described in the 
SAP. The SAP will be finalized prior to database lock. 
Statistical analyses will be performed using Statistical Analysis System (SAS) software version 
9.4 or later (Cary, NC). All clinical data captured will be provided in data listings.  
Methods of handling of missing data for different endpoints will be further specified in the SAP. 
In general, where individual data points are missing because of insufficient samples, dropouts, or 
other reasons, the data will be analyzed based on reduced denominators unless specified 
otherwise in the SAP.  
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11.4.2 
Statistical Methodology 
All clinical data captured will be provided in data listings. Subject disposition, demographic 
information, and baseline characteristics will be presented. Baseline will be defined at the last 
value obtained prior to the first dose of study drug. Results will be summarized by dose level and 
cohort. Any discrepancy between treatment to be given and treatment received will be accounted 
for in these displays.  
Continuous data will be summarized using descriptive statistics: number of subjects (N), number 
of observations (n), mean, median, standard deviation (SD), minimum, and maximum.  
Categorical data will be summarized using frequencies and percentages. When categorical data 
will be presented, the percent will be suppressed when the count is zero to draw attention to the 
non-zero counts. The denominator for all percentages, unless otherwise specified, will be the 
number of subjects in the specified analysis population. 
11.4.3 
Analysis of Primary Endpoints 
11.4.3.1 
Safety Analysis  
All statistical analysis of safety outcomes will be descriptive. The evaluation of SYNT001 based 
on vital signs, physical examination, ECGs, clinical safety laboratory tests, the incidence of AEs, 
TEAEs, and SAEs will be summarized by dose and dose regimen, severity, and relationship to 
study drug. 
TEAEs will be summarized using the Medical Dictionary for Regulatory Activities (MedDRA®; 
Version 19 or higher) System Organ Class (SOC) and preferred term, classified from verbatim 
terms. The incidence and percentage of subjects with at least one occurrence of a preferred term 
will be included, using the most severe grade. The number of events per preferred term will also 
be summarized. Causality (relationship to study drug [related/not related]) will be summarized 
separately.  
TEAEs, SAEs, and AEs leading to withdrawal, dose modification, or treatment discontinuation 
will be listed by subject per SOC and preferred terms. Duration of AEs will be determined and 
included in listings, along with action taken and outcome.  
Laboratory results will be summarized by visit, time point, dose, and dose regimen. The 
incidence of laboratory abnormalities will be summarized. The worst on-study grade after the 
first dose of study drug will be summarized. Results for variables that are not coded will be 
presented in the listings as below, within, and above the normal limits of the central laboratory. 
Vital sign measurements and change from baseline will be summarized at each scheduled time 
point by cohort using descriptive statistics.  
Arithmetic mean of parameters from triplicate ECG will be calculated first for each subject at 
each planned time point. Then summary statistics of ECG test parameters (mean of triplicate) 
and change from baseline to each post-dose time point will be calculated. Shift tables for ECG 
test result category change (normal, abnormal, clinically abnormal) from pre-dose to each post-
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dose time point showing number and percentage of subjects with movement between categories 
will be presented by treatment group. Frequency and percentage of subjects experiencing 
potential QTc prolongation (QTcF > 450) will be summarized at each time point by cohort. 
Concomitant medications will be coded using WHO Drug Dictionary (WHO-DD March 2013, 
Type B2 or later) and the data will be summarized and presented in tables and listings.  
11.4.3.2 
Dose Selection Data 
The evaluation of SYNT001 based on total IgG levels and responses on the PDAI total activity 
score from baseline will be summarized using descriptive statistics. Descriptive statistics will 
include mean, SD, coefficient of variation (CV), median, minimum, and maximum. The 
determination of dose and dosing duration of SYNT001 that achieves (i) total IgG level nadir 
decrease by ≥60% and ≤90% from baseline and (ii) a PDAI total activity score of ≥50% 
reduction from baseline to allow further clinical development in subject with pemphigus 
(vulgaris or foliaceus). 
11.4.4 
Analysis of Secondary Endpoints 
11.4.4.1 
Pharmacokinetic Analysis 
PK results for SYNT001 will be summarized by dose and dose regimen, visit and time point. 
Descriptive statistics will be provided for the PK parameters including mean, SD, CV, median, 
minimum, and maximum.  
For calculation of mean concentrations and generation of mean concentration-time profiles, all 
below the limit of quantification (BLQ) values will be set to zero except when an individual 
BLQ falls between 2 quantifiable values, in which case it will be omitted. 
If there are values above the BLQ, but too sparse to allow full analysis, descriptive statistics will 
be performed on available values. 
11.4.4.2 
Pharmacodynamic Analysis  
Disease activity marker results will be summarized by dose, dose regimen and visit. Descriptive 
statistics of PD will include mean, SD, median, minimum, and maximum. 
11.4.4.3 
Immunogenicity Analysis 
Immunogenicity results will be summarized by cohort, visit and time point. Descriptive statistics 
will include mean, SD, CV, median, minimum, and maximum.  
11.4.4.4 
PDAI Data 
PDAI results will be summarized by score (total activity score, total damage score), cohort, and 
visit. Descriptive statistics will include absolute change from baseline, and percent change from 
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baseline. PDAI will also be summarized by disease severity category, mild (0 to 8), moderate (9 
to 24), and severe (≥25). 
11.4.5 
Analysis of Exploratory Endpoints 
11.4.5.1 
Corticosteroid Use 
The evaluation of corticosteroid use during the study will be summarized by dose, dose regimen 
and visit. 
11.4.5.2 
Health-Related Quality of Life Data 
HR-QoL results from the ABQoL and Skindex-29 assessments will be summarized by dose, dose 
regimen, and visit. 
11.4.5.3 
Photography 
The qualitative assessment of changes in appearance of skin and mucosal lesions as determined 
by photography presented by dose, dose regimen, and visit. 
11.5 
Interim Analysis 
No interim analysis is planned. 
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12. 
STUDY MANAGEMENT 
12.1 
Regulatory and Ethical Considerations 
12.1.1 
Ethical Conduct 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
ICH E6 Tripartite Guideline (January 1997), and in general, be conducted in a manner consistent 
with the principles described in the Declaration of Helsinki. The Investigator will ensure that the 
conduct of the study complies with the basic principles of GCP as outlined in the current version 
of 21 CFR, subpart D, Part 312, “Responsibilities of Sponsors and Investigators”, Part 50, 
“Protection of Human Subjects”, and Part 56, “Institutional Review Boards”. 
12.1.2 
Informed Consent  
A signed informed consent form (ICF) in compliance with 21 CFR, Part 50.25(a) and Part 
50.25(b) and the ICH guidelines, will be obtained from each subject before the subject is entered 
into the study and before any study screening procedure is performed that involves risk. The 
method of obtaining and documenting the informed consent will comply with ICH GCP and all 
applicable laws and regulations and will be subject to approval by the Sponsor. 
The Investigator, or designee, is responsible for obtaining written informed consent from each 
subject (or the subject’s legally authorized representative) participating in this study after a 
thorough and clear explanation of the objectives, procedures, anticipated benefits, and potential 
hazards of the study. In the case where the subject is unable to read, an impartial witness should 
be present during the entire informed consent discussion. After the subject has orally consented 
to participation in the trial, the witness’ signature on the form will attest that the information in 
the consent form was accurately explained and understood. The study site must retain the 
original ICF and a copy must be provided to the subject or to the subject’s legally authorized 
representative. If applicable, it will be provided in a certified translation of the local language. 
The Sponsor, or designee, must review the signed ICF against any proposed deviations from a 
sample ICF the Sponsor has supplied to each site. The final IRB-approved document must be 
provided to the Sponsor for regulatory purposes. 
The eCRF for this study contains a section for documenting informed subject consent, and this 
must be completed appropriately. Signed ICFs must remain in each subject’s study file and must 
be available for verification by site monitors at any time. If new safety information results in 
significant changes in the risk/benefit assessment, the consent form should be reviewed and 
updated as necessary. All subjects (including those already being treated) should be informed of 
the new information, should be given a copy of the revised form, and should give their consent to 
continue in the study. 
12.1.3 
Subject Confidentiality and Privacy 
As applicable, in accordance with the Health Insurance Portability and Accountability Act 
(HIPAA), and associated privacy regulations, a patient authorization to use personally 
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identifiable health information may be required from each patient before research activities 
begin.  
The Investigator must ensure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On eCRFs or other documents submitted to the Sponsor, 
subjects should be identified by an identification code and not by their names. The Investigator 
should keep a subject enrollment log showing codes, names, and addresses. The Investigator 
should maintain documents intended for storing onsite (eg, subjects’ written consent forms) in 
strict confidence. 
All study drugs, subject bodily fluids and tissue, and/or other materials collected shall be used 
solely in accordance with this protocol, unless otherwise agreed to in writing by the Sponsor. 
12.1.4 
Future Use of Stored Specimens 
Not all the tissue and blood components obtained during this study may be required for the tests 
that are part of the clinical trial. Available samples may be used for additional analyses and 
research. This research will help to understand disease subtypes, drug response, and AEs, and 
possibly identify new drug targets or biomarkers that predict subject response to treatment. The 
use of the samples for internal research will adhere to the guidelines defined by the FDA in 
“Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human 
Specimens that are Not Individual Identifiable” (issued 25 April 2006) and the European 
Medicines Agency “Reflection Paper on Pharmacogenetic Samples, Testing and Data Handling” 
(Doc. Ref. EMEA/CHMP/PGxWP/201914/2006; 15 November 2007). If a subject requests 
destruction of their tissue and blood samples and the samples have not yet been de-identified, the 
Sponsor will destroy the samples as described in the FDA guidance. The Sponsor will notify the 
Investigator in writing that the samples have been destroyed. 
12.2 
Study Administration 
The study administration structure is provided in Table 9. 
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Table 9. 
Study Administrative Structure 
Sponsor Contact and Medical Director: 
 
 
Phone: 
 
Email: 
 
Medical Monitor: 
 
Medpace 
Wallace House 
Stirling, Scotland FK81JU 
Phone: 
 extension 
 
Email: 
 
Study Monitoring: 
Medpace 
5375 Medpace Way 
Cincinnati, OH 45227 USA 
Phone (Main): 
 
Email: 
 
 
12.2.1 
Institutional Review Board Approval 
This study is being conducted under US IND 132727. This protocol (and any modifications) and 
appropriate consent procedures must be reviewed and approved by the site-specific IRB before 
the study is initiated. The IRB must operate in accordance with the current federal or local 
regulations. The Investigator will send a letter or certificate of IRB approval to the Sponsor (or 
designee) before subject enrollment and whenever subsequent modifications to the protocol are 
made. 
12.2.2 
Data Handling and Record Keeping 
All data will be entered in a validated electronic data capture system using single data entry. 
Standard procedures (including following data review guidelines, manual clinical review based 
on subject profiles, computerized validation to produce queries, and maintenance of an audit file, 
which includes all database modifications) will be followed to ensure accurate data. Clinical 
personnel will review all data listings for outliers, data inconsistencies, and spelling errors. 
12.2.3 
Data Protection 
The Investigator agrees that all information received from the Sponsor, including but not limited 
to the IB, this protocol, eCRFs, the INDs, and any other study information remain the sole and 
exclusive property of the Sponsor during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) or otherwise into the public domain 
without prior written consent from the Sponsor. 
12.2.4 
Study Site Regulatory Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
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be classified into 2 separate categories as follows: (1) Investigator’s study file and (2) subject 
clinical source documents (see Section 12.2.5). 
The Investigator’s study file will contain the protocol and protocol amendments, eCRFs, query 
forms, IRB and governmental approval with correspondence, sample informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
Subject clinical source documents (usually predefined by the project to record key efficacy and 
safety parameters independent of the eCRFs) may include subject hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, 
electroencephalogram, X-ray, pathology and special assessment reports, signed ICFs, consultant 
letters, and subject screening and enrollment logs. The Investigator must keep these two 
categories of documents on file for at least 2 years following the marketing application approval 
date for the study treatment and for the indication being investigated or for 2 years after the 
development program is discontinued and the FDA notified. After that period, the documents 
may be destroyed subject to local regulations with prior written permission from the Sponsor. If 
the Investigator wants to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee the archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and the Sponsor to 
store these in a sealed container outside of the study site so that they can be returned sealed to the 
Investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside of the study site. 
12.2.5 
Subject Clinical Source Documents and Background Data 
Investigators must maintain adequate and accurate source documents on which the eCRFs for 
each subject are based. They are separate and distinct from the eCRFs. 
These records include detailed notes on the following: 
 Medical history 
 Informed consent 
 HIPAA authorization, if applicable (either contained in the ICF or presented to the 
subject candidate as a standalone document) 
 Description of the complete consenting process 
 The basic identifying information that linked the subject’s medical record with the eCRFs 
 The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject 
 The medical condition of the subject during their involvement in the study 
 All AEs 
 The subject’s exposure to the study medication 
 The subject’s exposure to any concomitant therapy 
 All relevant observations and data on the condition of the subject throughout the trial 
 Justification for all entries in the subject’s eCRF 
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A subject log of all potentially eligible subjects considered, but not consented, for obvious 
deviations from the entry criteria, will be kept at each site. The log will contain subjects’ initials, 
diagnosis, eligibility, or, if not eligible, reason for not consenting. All consented subjects will be 
logged, regardless of whether they ultimately enroll.  
Upon request, the Investigator will supply the Sponsor with any required background data from 
the study documentation or clinic records. This is particularly important when eCRFs are 
illegible or when errors in data transcription are suspected. In case of special problems or 
governmental queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected. 
12.2.6 
Electronic Case Report Forms 
Clinical trial data for this study will be captured on eCRF designed for computer processing and 
analysis. This computerized system will be validated and compliant with 21 CFR Part 11, as 
described in the FDA guidance “Use of Electronic Records and Electronic Signatures in Clinical 
Investigations Under 21 CFR Part 11 – Questions and Answers.” If corrections are made after 
review and sign-off by the Investigator, he/she must be aware of the changes and provide written 
acknowledgement. There will also be an electronic audit trail. Corrections on paper CRFs must 
be initialed and dated by the person making the change. The Investigator agrees to provide all 
information requested on the eCRF in an accurate manner using instructions provided. The 
Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the Sponsor in the eCRF and in all required reports. 
An eCRF is required to be submitted for every subject who receives any amount of study drug. 
This includes submission of retrievable data on subjects who withdraw before completion of the 
study. Prior to submission, eCRFs must be reviewed for completeness and accuracy, and signed 
and dated where indicated, by the Investigator or designee. If a subject stops treatment or 
terminates from the study, the dates and reasons must be noted on the eCRF. 
12.3 
Clinical Monitoring, Audits, and Inspections 
The Investigator and study staff are responsible for maintaining a comprehensive and accurate 
filing system of all study-related documentation that will be suitable for inspection for routine 
monitoring, audit, or inspection at any time by the Sponsor (or designee) and/or a regulatory 
authority. 
12.3.1 
Clinical Monitoring 
During the clinical study, it is understood that the responsible Sponsor site monitor or designee 
(eg, contract research organization [CRO]) will contact and visit the study site at regular 
intervals for routine monitoring of various records. Routine monitoring activities will be 
conducted to verify adherence to the protocol, completeness, consistency and accuracy of the 
data, and to review study source documents and drug accountability records. Regular review of 
the eCRFs for completeness, clarity, and to cross-check against source documents is required to 
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monitor the progress of the study. Data will be reviewed and verified against the source 
documents (eg, original medical records and laboratory results) to ensure validity. 
The Investigator will provide the Sponsor or designee with full access to all source data 
(including laboratory tests) and provide administrative support if requested. The Investigator (or 
designee) must agree to cooperate with the site monitor to ensure that any problems detected 
during these monitoring visits are resolved. 
Site-specific study procedures, such data-recording and handling of the data, may be assessed 
during the study by a Clinical Quality Assurance representative(s) authorized by the Sponsor. 
Further, this designee, as well as the site monitor, will be permitted to inspect the study 
documents (study protocol, eCRFs, study drug accountability, original study-relevant medical 
records) to ensure that the study is conducted in compliance with the protocol.  
During these visits, all representatives of the Sponsor will be responsible for ensuring data 
integrity and subject confidentiality is protected. 
12.3.2 
Audits and Inspections 
Clinical site and study audits will be conducted as necessary to assure the validity of the study 
data. The Sponsor (or designee) may perform a quality assurance audit to ensure compliance 
with GCP, this protocol, and all applicable regulatory requirements. The Investigator should 
ensure that study documents (protocol, eCRFs, study drug record-keeping, original study-
relevant medical records) are made available to the Sponsor (or designee) for examination. All 
subject data will be treated as confidential. 
A regulatory authority, after appropriate notification, may also wish to conduct an inspection 
during the study or even after its completion. If a regulatory authority requests an inspection, the 
Investigator must immediately inform the Sponsor. 
12.4 
Changes to the Protocol 
Protocol modifications to ongoing studies must be made only after consultation between a 
Sponsor representative and the Investigator. Protocol modifications will be prepared, reviewed, 
and approved by Sponsor representatives. 
All protocol modifications must be submitted to the IRB for information and approval in 
accordance with local requirements, and to regulatory agencies, if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects, or when the change involves only logistical or administrative 
aspects of the trial (eg, change in site monitor, change of telephone number). 
12.5 
Study Discontinuation and Closure 
The Sponsor has the right to terminate the study at any time. In terminating the study, the 
Sponsor and the Investigator will ensure that adequate consideration is given to the protection of 
the subjects’ interests. 
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13. 
PUBLICATION AND DATA SHARING POLICY 
The results of this study may be published or presented at scientific meetings. The Investigator 
agrees that any manuscript or abstract they author may be published only after receiving written 
permission from the Sponsor. 
If the Sponsor coordinates a publication or presentation of study results from all study sites, the 
participation of Investigator or other representatives of study site as a named author shall be 
determined in accordance with the Sponsor’s policy and generally accepted standards for 
authorship as developed by the International Committee of Medical Journal Editors (ICMJE) and 
in accordance with Good Publication Practices. 
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14. 
REFERENCES 
Agarwal S, Cunningham-Rundles C. Assessment and clinical interpretation of reduced IgG 
values. Ann Allergy Asthma Immunol. 2007;99(3):281-3. 
Ameratunga R, Woon ST, Gillis D, Koopmans W, Steele R. New diagnostic criteria for common 
variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or 
subcutaneous immunoglobulin. Clin Exp Immunol. 2013;174(2):203-11. 
Blaha M, Pitha J, Blaha V, Lanska M, Maly J, Filip S, et al. Experience with extracorporeal 
elimination therapy in myasthenia gravis. Transfus Apher Sci. 2011;45(3):251-6. 
Chren MM, Lasek RJ, Quinn LM, Mostow EN, Zyzanski SJ. Skindex, a quality-of-life measure 
for patients with skin disease: reliability, validity, and responsiveness. J Invest Dermatol. 
1996;107(5):707-13. 
Eming R, Hertl M. Immunoadsorption in pemphigus. Autoimmunity. 2006;39(7):609-16. 
Furst DE. Serum immunoglobulins and risk of infection: how low can you go?  Semin Arthritis 
Rheum. 2009;39(1):18-29. 
Gonzalez-Quintela A, Alende R, Gude F, Campos J, Rey J, Meijide LM, et al. Serum levels of 
immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with 
alcohol consumption, smoking and common metabolic abnormalities. Clin Exp Immunol. 
2008;151(1):42-50. 
Hsu DY, Brieva J, Sinha AA, Langan SM, Silverberg JI. Comorbidities and inpatient mortality 
for pemphigus in the U.S.A. Br J Dermatol. 2016;174(6):1290-8. 
Jolliff CR, Cost KM, Stivrins PC, Grossman PP, Nolte CR, Franco SM, et al. Reference intervals 
for serum IgG, IgA, IgM, C3, and C4 as determined by rate nephelometry. Clin Chem. 
1982;28(1):126-8. 
Kasperkiewicz M, Ellebrecht CT, Takahashi H, Yamagami J, Zillikens D, Payne AS, et al. 
Pemphigus. Nat Rev Dis Primers. 2017;3:17026. 
Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, et al. Safety and 
efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-
label extension analysis. Arthritis Rheum. 2007;56(12):3896-908. 
Kohler W, Bucka C, Klingel R. A randomized and controlled study comparing 
immunoadsorption and plasma exchange in myasthenic crisis. J Clin Apher. 2011;26(6):347-55. 
Langan SM, Smeeth L, Hubbard R, Fleming KM, Smith CJ, West J. Bullous pemphigoid and 
pemphigus vulgaris--incidence and mortality in the UK: population based cohort study. BMJ. 
2008;337:a180. 
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McMillan SA, Douglas JP, Archbold GP, McCrum EE, Evans AE. Effect of low to moderate 
levels of smoking and alcohol consumption on serum immunoglobulin concentrations. J Clin 
Pathol. 1997;50(10):819-22. 
Nixon AE, Chen J, Sexton DJ, Muruganandam A, Bitonti AJ, Dumont J, et al. Fully human 
monoclonal antibody inhibitors of the neonatal fc receptor reduce circulating IgG in non-human 
primates. Front Immunol. 2015;6:176. 
Roopenian DC, Christianson GJ, Sproule TJ, Brown AC, Akilesh S, Jung N, et al. The MHC 
class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-
coupled drugs. J Immunol. 2003;170(7):3528-33. 
Rosenbach M, Murrell DF, Bystryn JC, Dulay S, Dick S, Fakharzadeh S, et al. Reliability and 
convergent validity of two outcome instruments for pemphigus. J Invest Dermatol. 
2009;129(10):2404-10. 
Schmaldienst S, Mullner M, Goldammer A, Spitzauer S, Banyai S, Horl WH, et al. Intravenous 
immunoglobulin application following immunoadsorption: benefit or risk in patients with 
autoimmune diseases?  Rheumatology. 2001;40(5):513-21. 
Sebaratnam DF, Hanna AM, Chee SN, Frew JW, Venugopal SS, Daniel BS, et al. Development 
of a quality-of-life instrument for autoimmune bullous disease: the Autoimmune Bullous Disease 
Quality of Life questionnaire. JAMA Dermatol. 2013;149(10):1186-91. 
Sebaratnam DF, Okawa J, Payne A, Murrell DF, Werth VP. Reliability of the autoimmune 
bullous disease quality of life (ABQOL) questionnaire in the USA. Qual Life Res. 
2015;24(9):2257-60. 
Shimizu T, Takebayashi T, Sato Y, Niizeki H, Aoyama Y, Kitajima Y, et al. Grading criteria for 
disease severity by pemphigus disease area index. J Dermatol. 2014;41(11):969-73. 
van Vollenhoven RF, Emery P, Bingham CO, 3rd, Keystone EC, Fleischmann RM, Furst DE, et 
al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global 
clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum 
Dis. 2013;72(9):1496-502. 
 
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APPENDIX 1. NCI CTCAE, VERSION 4.03 
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1. CTCAE 4.03
 
 
Common Terminology Criteria for
Adverse Events (CTCAE)
Version 4.0
Published: May 28, 2009 (v4.03: June 14, 2010)
U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Cancer Institute
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C o m m o n  T er mi n ol o g y  Crit eri a  f or A d v ers e  E v e nts  v 4. 0  ( C T C A E) 
P u blis h D at e: M a y 2 8, 2 0 0 9  
Q uic k R ef er e nc e  
T h e  N CI  C o m m o n  T er mi n ol o g y  Crit eri a f or 
A d v ers e  E v e nts  is a  d escri pti v e  t er mi n ol o g y w hic h 
c a n b e utiliz e d f or A d v ers e E v e nt ( A E) r e p orti n g. 
A gr a di n g (s e v erit y) sc al e is pr o vi d e d f or e ac h A E 
t er m. 
C o m p o n e nts a n d Or g a niz ati o n 
S O C  
S yst e m  Or g a n Cl ass, t h e hi g h est l e v el of t h e 
M e d D R A hi er arc h y, is i d e ntifi e d b y a n at o mic al or 
p h ysi ol o gic al sys t e m, eti ol o g y, or p ur p os e ( e. g., 
S O C I n v esti g ati o ns f or l a b or at or y t est r es ults). 
C T C A E t er ms ar e gr o u p e d b y  M e d D R A Pri m ar y 
S O Cs.  Wit hi n e ac h S O C,  A Es ar e list e d a n d 
acc o m p a ni e d by d escri pti o ns of s e v erit y ( Gr a d e).  
C T C A E T er ms  
A n A d v ers e E v e nt ( A E) is a n y u nf a v or a bl e a n d 
u ni nt e n d e d   si g n   (i ncl u di n g   a n   a b n or m al 
l a b or at or y  fi n di n g),  s y m pt o m,   or   dis e as e 
t e m p or all y ass oci at e d wit h t h e us e of a m e dic al 
tr e at m e nt or pr oc e d ur e t h at m a y or m a y n ot b e 
c o nsi d er e d r el at e d t o t h e m e dic al tr e at m e nt or 
pr oc e d ur e. A n A E is  a t er m t h at is a u ni q u e 
r e pr es e nt ati o n  of a s p ecific e v e nt  us e d f or 
m e dic al d oc u m e nt ati o n a n d sci e ntific a n al ys es. 
E ac h C T C A E v 4. 0 t er m is a M e d D R A LL T (L o w est 
L e v el T er m).  
D efi niti o ns  
A bri ef d efi niti o n is pr o vi d e d 
m e a ni n g of e ac h A E t er m.  
Gr a d es  
N ot all  Gr a d es ar e a p pr o pri at e f or all  A Es. 
T h er ef or e, s o m e A Es ar e list e d wit h f e w er t h a n 
fi v e o pti o ns f or Gr a d e s el ecti o n. 
Gr a d e 5  
Gr a d e 5 ( D e at h) is n ot a p pr o pri at e f or s o m e A Es 
a n d t h er ef or e is n ot a n  o pti o n.  
Acti viti es  of  D ail y  Li vi n g ( A DL) 
*I nstr u m e n t al  A DL r ef er t o pr e p ari n g  m e als, 
s h o p pi n g f or gr oc eri es or cl ot h es, usi n g t h e 
t el e p h o n e, m a n a gi n g m o n e y, etc. 
* * S elf c ar e A DL r ef er t o b at hi n g, dr essi n g a n d 
u n dr essi n g, f e e di n g s elf, usi n g t h e t oil et, t a ki n g 
m e dic ati o ns, a n d n ot b e dri d d e n.  
t o cl arify  t h e 
Gr a d e r ef ers t o t h e s e v erit y of t h e A E. T h e  C T C A E 
dis pl a ys Gr a d es 1 t hr o u g h 5 wit h u ni q u e cli nic al 
d escri pti o ns of s e v erit y f or e ac h A E b as e d o n t his 
g e n er al  g ui d eli n e:  
Gr a d e 1  
Mil d;   as y m pt o m atic   or   
mil d 
s y m pt o ms; cli nic al  or  di a g n ostic 
o bs er v ati o ns o nl y; i nt er v e nti o n  n ot 
i n dic at e d. 
M o d er at e;   mi ni m al,   l oc al   or 
n o ni nv asi v e i nt er v e nti o n  i n dic at e d; 
Gr a d e 2  
li miti n g 
i nstr u m e nt al A DL *.  
a g e -a p pr o pri at e  
Gr a d e 3  
S e v er e or m e dic all y si g nific a nt b ut  
n ot i m m e di at el y lif e -t hr e at e ni n g; 
h os pit aliz ati o n or pr ol o n g ati o n of 
h os pit aliz ati o n i n dic at e d;  dis a bli n g; 
li miti n g s elf c ar e A DL * *.  
Gr a d e 4   Lif e-t hr e at e ni n g  
c o ns e q u e nc es; 
ur g e nt  i nt er v e nti o n i n dic at e d. 
D e at h r el at e d t o A E.  
Gr a d e 5  
A S e mi -c ol o n i n dic at es ‘ or’ wit hi n t h e d escri pti o n 
of t h e gr a d e.  
A  si n gl e d as h  (-) i n dic at es a  gr a d e  is n ot  a v ail a bl e.  
†  C T C A E  v 4. 0 i nc or p or at es c ert ai n el e m e nts  of  t h e M e d D R A  t er mi n ol o g y. F or  f urt h er d et ails  o n  M e d D R A  r ef er t o t h e M e d D R A  M S S O  W e b  sit e (htt p:// w w w. m e d dr a mss o.c o m ).  
Pa ge 8 8 3 of 9 7 9  
Ale xi o n C o nfi de ntial  
 
 


C O N T E N T S
S O C
P a g e
Bl o o d  a n d l y m p h ati c s yst e m  dis or d ers
3
C ar di a c  dis or d ers
4
C o n g e nit al, f a mili al  a n d  g e n eti c  dis or d ers
7
E ar  a n d l a b yri nt h  dis or d ers
8
E n d o cri n e  dis or d ers
9
E y e  dis or d ers
1 0
G astr oi nt esti n al  dis or d ers
1 2
G e n er al  dis or d ers  a n d  a d mi nistr ati o n sit e  c o n diti o ns
2 2
H e p at o bili ar y  dis or d ers
2 4
I m m u n e s yst e m  dis or d ers
2 6
I nf e cti o ns  a n d i nf est ati o ns
2 7
I nj ur y,  p ois o ni n g  a n d  pr o c e d ur al  c o m pli c ati o ns
3 4
I n v esti g ati o ns
4 1
M et a b olis m  a n d  n utriti o n  dis or d ers
4 4
M us c ul os k el et al  a n d  c o n n e cti v e tiss u e  dis or d ers
4 6
N e o pl as ms  b e ni g n,  m ali g n a nt  a n d  u ns p e cifi e d (i n cl  c ysts  a n d  p ol y ps)
5 0
N er v o us s yst e m  dis or d ers
5 1
Pr e g n a n c y,  p u er p eri u m  a n d  p eri n at al  c o n diti o ns
5 6
Ps y c hi atri c  dis or d ers
5 7
R e n al  a n d  uri n ar y  dis or d ers
5 9
R e pr o d u cti v e s yst e m  a n d  br e ast  dis or d ers
6 1
R es pir at or y, t h or a ci c  a n d  m e di asti n al  dis or d ers
6 5
S ki n  a n d s u b c ut a n e o us tiss u e  dis or d ers
7 1
S o ci al  cir c u mst a n c es
7 5
S ur gi c al  a n d  m e di c al  pr o c e d ur es
7 6
V as c ul ar  dis or d ers
7 7
Al e xi o n  C o nfi d e nti al
P a g e  8 8 4  of  9 7 9


CTCAE 4.03 - June 14, 2010 : Blood and lymphatic system disorders 
3
2. Blood and lymphatic system disorders
Blood and lymphatic system disorders
Grade
Adverse Event
1
2
3
4
5
Anemia
Hemoglobin (Hgb) <LLN - 10.0
g/dL; <LLN - 6.2 mmol/L; <LLN -
100 g/L
Hgb <10.0 - 8.0 g/dL; <6.2 - 4.9
mmol/L;  <100 - 80g/L
Hgb <8.0 g/dL; <4.9 mmol/L;
<80 g/L; transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an reduction in the amount of hemoglobin in 100 ml of blood. Signs and symptoms of anemia may include pallor of the skin and mucous
membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.
Bone marrow hypocellular
Mildly hypocellular or <=25%
reduction from normal cellularity
for age
Moderately hypocellular or >25 -
<50% reduction from normal
cellularity for age
Severely hypocellular or >50 -
<=75% reduction cellularity from
normal for age
Aplastic persistent for longer
than 2 weeks
Death
Definition: A disorder characterized by the inability of the bone marrow to produce hematopoietic elements.
Disseminated intravascular
coagulation
 -
Laboratory findings with no
bleeding
Laboratory findings and
bleeding
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by systemic pathological activation of blood clotting mechanisms which results in clot formation throughout the body. There is an increase in the
risk of hemorrhage as the body is depleted of platelets and coagulation factors.
Febrile neutropenia
 -
 -
ANC <1000/mm3 with a single
temperature of >38.3 degrees C
(101 degrees F) or a sustained
temperature of >=38 degrees C
(100.4 degrees F) for more than
one hour.
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an ANC <1000/mm3 and a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >=38 degrees C (100.4
degrees F) for more than one hour.
Hemolysis
Laboratory evidence of
hemolysis only (e.g., direct
antiglobulin test; DAT; Coombs';
schistocytes; decreased
haptoglobin)
Evidence of hemolysis and >=2
gm decrease in hemoglobin.
Transfusion or medical
intervention indicated (e.g.,
steroids)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate widespread erythrocyte cell membrane destruction.
Hemolytic uremic syndrome
Evidence of RBC destruction
(schistocytosis) without clinical
consequences
 -
Laboratory findings with clinical
consequences (e.g., renal
insufficiency, petechiae)
Life-threatening consequences,
(e.g., CNS hemorrhage or
thrombosis/embolism or renal
failure)
Death
Definition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, hemolytic anemia, and severe thrombocytopenia.
Leukocytosis
 -
 -
>100,000/mm3
Clinical manifestations of
leucostasis; urgent intervention
indicated
Death
Definition: A disorder characterized by laboratory test results that indicate an increased number of white blood cells in the blood.
Lymph node pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in a lymph node.
Spleen disorder
Incidental findings (e.g., Howell-
Jolly bodies); mild degree of
thrombocytosis and
leukocytosis
Prophylactic antibiotics
indicated
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder of the spleen.
Thrombotic thrombocytopenic
purpura
Evidence of RBC destruction
(schistocytosis) without clinical
consequences
 -
Laboratory findings with clinical
consequences (e.g., renal
insufficiency, petechiae)
Life-threatening consequences,
(e.g., CNS hemorrhage or
thrombosis/embolism or renal
failure)
Death
Definition: A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic purpura, fever, renal abnormalities and neurological abnormalities such
as seizures, hemiplegia, and visual disturbances. It is an acute or subacute condition.
Blood and lymphatic system
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 885 of 979


CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
4
3. Cardiac disorders
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Acute coronary syndrome
 -
Symptomatic, progressive
angina; cardiac enzymes
normal; hemodynamically stable
Symptomatic, unstable angina
and/or acute myocardial
infarction, cardiac enzymes
abnormal, hemodynamically
stable
Symptomatic, unstable angina
and/or acute myocardial
infarction, cardiac enzymes
abnormal, hemodynamically
unstable
Death
Definition: A disorder characterized by signs and symptoms related to acute ischemia of the myocardium secondary to coronary artery disease. The clinical presentation covers a
spectrum of heart diseases from unstable angina to myocardial infarction.
Aortic valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in aortic valve function or structure.
Asystole
Periods of asystole; non-urgent
medical management indicated
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without cardiac electrical activity. Typically, this is accompanied by cessation of the pumping function of the heart.
Atrial fibrillation
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker), or ablation
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without discernible P waves and an irregular ventricular response due to multiple reentry circuits. The rhythm disturbance
originates above the ventricles.
Atrial flutter
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker), or ablation
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with organized rhythmic atrial contractions with a rate of 200-300 beats per minute. The rhythm disturbance originates in the
atria.
Atrioventricular block complete
 -
Non-urgent intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with complete failure of atrial electrical impulse conduction through the AV node to the ventricles.
Atrioventricular block first
degree
Asymptomatic, intervention not
indicated
Non-urgent intervention
indicated
 -
 -
 -
Definition: A disorder characterized by a dysrhythmia with a delay in the time required for the conduction of an electrical impulse through the atrioventricular (AV) node beyond 0.2
seconds; prolongation of the PR interval greater than 200 milliseconds.
Cardiac arrest
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by cessation of the pumping function of the heart.
Chest pain - cardiac
Mild pain
Moderate pain; limiting
instrumental ADL
Pain at rest; limiting self care
ADL
 -
 -
Definition: A disorder characterized by substernal discomfort due to insufficient myocardial oxygenation.
Conduction disorder
Mild symptoms; intervention not
indicated
Moderate symptoms
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by pathological irregularities in the cardiac conduction system.
Constrictive pericarditis
 -
 -
Symptomatic heart failure or
other cardiac symptoms,
responsive to intervention
Refractory heart failure or other
poorly controlled cardiac
symptoms
Death
Definition: A disorder characterized by a thickened and fibrotic pericardial sac; these fibrotic changes impede normal myocardial function by restricting myocardial muscle action.
Heart failure
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe with symptoms at rest or
with minimal activity or exertion;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., continuous IV therapy or
mechanical hemodynamic
support)
Death
Definition: A disorder characterized by the inability of the heart to pump blood at an adequate volume to meet tissue metabolic requirements, or, the ability to do so only at an elevation
in the filling pressure.
Alexion Confidential
Page 886 of 979


CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
5
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Left ventricular systolic
dysfunction
 -
 -
Symptomatic due to drop in
ejection fraction responsive to
intervention
Refractory or poorly controlled
heart failure due to drop in
ejection fraction; intervention
such as ventricular assist
device, intravenous vasopressor
support, or heart transplant
indicated
Death
Definition: A disorder characterized by failure of the left ventricle to produce adequate output despite an increase in distending pressure and in end-diastolic volume. Clinical
manifestations mayinclude dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema.
Mitral valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in mitral valve function or structure.
Mobitz (type) II atrioventricular
block
Asymptomatic, intervention not
indicated
Symptomatic; medical
intervention indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with relatively constant PR interval prior to the block of an atrial impulse. This is the result of intermittent failure of atrial electrical
impulse conduction through the atrioventricular (AV) node to the ventricles.
Mobitz type I
Asymptomatic, intervention not
indicated
Symptomatic; medical
intervention indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a progressively lengthening PR interval prior to the blocking of an atrial impulse. This is the result of intermittent failure of
atrial electrical impulse conduction through the atrioventricular (AV) node to the ventricles.
Myocardial infarction
 -
Asymptomatic and cardiac
enzymes minimally abnormal
and no evidence of ischemic
ECG changes
Severe symptoms; cardiac
enzymes abnormal;
hemodynamically stable; ECG
changes consistent with
infarction
Life-threatening consequences;
hemodynamically unstable
Death
Definition: A disorder characterized by gross necrosis of the myocardium; this is due to an interruption of blood supply to the area.
Myocarditis
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe with symptoms at rest or
with minimal activity or exertion;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., continuous IV therapy or
mechanical hemodynamic
support)
Death
Definition: A disorder characterized by inflammation of the muscle tissue of the heart.
Palpitations
Mild symptoms; intervention not
indicated
Intervention indicated
 -
 -
 -
Definition: A disorder characterized by an unpleasant sensation of irregular and/or forceful beating of the heart.
Paroxysmal atrial tachycardia
Asymptomatic, intervention not
indicated
Symptomatic; medical
management indicated
IV medication indicated
Life-threatening consequences;
incompletely controlled
medically; cardioversion
indicated
Death
Definition: A disorder characterized by a dysrhythmia with abrupt onset and sudden termination of atrial contractions with a rate of 150-250 beats per minute. The rhythm disturbance
originates in the atria.
Pericardial effusion
 -
Asymptomatic effusion size
small to moderate
Effusion with physiologic
consequences
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by fluid collection within the pericardial sac, usually due to inflammation.
Pericardial tamponade
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in intrapericardial pressure due to the collection of blood or fluid in the pericardium.
Pericarditis
Asymptomatic, ECG or physical
findings (e.g., rub) consistent
with pericarditis
Symptomatic pericarditis (e.g.,
chest pain)
Pericarditis with physiologic
consequences (e.g., pericardial
constriction)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by irritation to the layers of the pericardium (the protective sac around the heart).
Alexion Confidential
Page 887 of 979


CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
6
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Pulmonary valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in pulmonary valve function or structure.
Restrictive cardiomyopathy
 -
 -
Symptomatic heart failure or
other cardiac symptoms,
responsive to intervention
Refractory heart failure or other
poorly controlled cardiac
symptoms
Death
Definition: A disorder characterized by an inability of the ventricles to fill with blood because the myocardium (heart muscle) stiffens and loses its flexibility.
Right ventricular dysfunction
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe symptoms, associated
with hypoxemia, right heart
failure; oxygen indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., ventricular assist device);
heart transplant indicated
Death
Definition: A disorder characterized by impairment of right ventricular function associated with low ejection fraction and a decrease in motility of the right ventricular wall.
Sick sinus syndrome
Asymptomatic, intervention not
indicated
Non-urgent intervention
indicated
Severe, medically significant;
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with alternating periods of bradycardia and atrial tachycardia accompanied by syncope, fatigue and dizziness.
Sinus bradycardia
Asymptomatic, intervention not
indicated
Symptomatic, medical
intervention indicated
Severe, medically significant,
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate less than 60 beats per minute that originates in the sinus node.
Sinus tachycardia
Asymptomatic, intervention not
indicated
Symptomatic; non-urgent
medical intervention indicated
Urgent medical intervention
indicated
 -
 -
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates in the sinus node.
Supraventricular tachycardia
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates above the ventricles.
Tricuspid valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis;
symptoms controlled with
medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in tricuspid valve function or structure.
Ventricular arrhythmia
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia that originates in the ventricles.
Ventricular fibrillation
 -
 -
 -
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without discernible QRS complexes due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the
ventricles.
Ventricular tachycardia
 -
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates distal to the bundle of His.
Wolff-Parkinson-White
syndrome
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically or
controlled with procedure
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the presence of an accessory conductive pathway between the atria and the ventricles that causes premature ventricular activation.
Cardiac disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 888 of 979


CTCAE 4.03 - June 14, 2010 : Congenital, familial and genetic disorders 
7
4. Congenital, familial and genetic disorders
Congenital, familial and genetic disorders
Grade
Adverse Event
1
2
3
4
5
Congenital, familial and genetic
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 889 of 979


CTCAE 4.03 - June 14, 2010 : Ear and labyrinth disorders 
8
5. Ear and labyrinth disorders
Ear and labyrinth disorders
Grade
Adverse Event
1
2
3
4
5
Ear pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the ear.
External ear inflammation
External otitis with erythema or
dry desquamation
External otitis with moist
desquamation, edema,
enhanced cerumen or
discharge; tympanic membrane
perforation; tympanostomy
External otitis with mastoiditis;
stenosis or osteomyelitis;
necrosis of soft tissue or bone
Urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation, swelling and redness to the outer ear and ear canal.
External ear pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the external ear region.
Hearing impaired
Adults enrolled on a Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift of 15 - 25 dB averaged at 2
contiguous test frequencies in at
least one ear.
Adults not enrolled in Monitoring
Program: subjective change in
hearing in the absence of
documented hearing loss.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift >20 dB at 8 kHz in at least
one ear.
Adults enrolled in Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz  audiogram):  Threshold
shift of >25 dB averaged at 2
contiguous test frequencies in at
least one ear.
Adults not enrolled in Monitoring
Program: hearing loss but
hearing aid or intervention not
indicated; limiting instrumental
ADL.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift >20 dB at 4 kHz and above
in at least one ear.
Adults enrolled in Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift of >25 dB averaged at 3
contiguous test frequencies in at
least one ear; therapeutic
intervention indicated.
Adults not enrolled in Monitoring
Program:  hearing loss with
hearing aid or intervention
indicated; limiting self care ADL.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): hearing loss
sufficient to indicate therapeutic
intervention, including hearing
aids; threshold shift >20 dB at 3
kHz and above in at least one
ear; additional speech-language
related services indicated.
Adults: Decrease in hearing to
profound bilateral loss (absolute
threshold >80 dB HL  at 2 kHz
and above); non-servicable
hearing.
Pediatric: Audiologic indication
for cochlear implant and
additional speech-language
related services indicated.
 -
Definition: A disorder characterized by partial or complete loss of the ability to detect or understand sounds resulting from damage to ear structures.
Middle ear inflammation
Serous otitis
Serous otitis, medical
intervention indicated
Mastoiditis; necrosis of canal
soft tissue or bone
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation (physiologic response to irritation), swelling and redness to the middle ear.
Tinnitus
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by noise in the ears, such as ringing, buzzing, roaring or clicking.
Vertigo
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective
vertigo).
Vestibular disorder
 -
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by dizziness, imbalance, nausea, and vision problems.
Ear and labyrinth disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 890 of 979


CTCAE 4.03 - June 14, 2010 : Endocrine disorders 
9
6. Endocrine disorders
Endocrine disorders
Grade
Adverse Event
1
2
3
4
5
Adrenal insufficiency
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms;
hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder that occurs when the adrenal cortex does not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. It may be due to a disorder
of the adrenal cortex as in Addison's disease or primary adrenal insufficiency.
Cushingoid
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms, medical
intervention or hospitalization
indicated
 -
 -
Definition: A disorder characterized by signs and symptoms that resemble Cushing's disease or syndrome: buffalo hump obesity, striations, adiposity, hypertension, diabetes, and
osteoporosis, usually due to exogenous corticosteroids.
Delayed puberty
 -
No breast development by age
13 yrs for females; testes
volume of <3 cc or no Tanner
Stage 2 development by age
14.5 yrs for males
No breast development by age
14 yrs for females; no increase
in testes volume or no Tanner
Stage 2 by age 16 yrs for
males; hormone replacement
indicated
 -
 -
Definition: A disorder characterized by unusually late sexual maturity.
Growth accelerated
 -
>= +2 SD (standard deviation)
above mid parental height or
target height
 -
 -
 -
Definition: A disorder characterized by greater growth than expected for age.
Hyperparathyroidism
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by an increase in production of parathyroid hormone by the parathyroid glands. This results in hypercalcemia (abnormally high levels of calcium in
the blood).
Hyperthyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thyroid
suppression therapy indicated;
limiting instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by excessive levels of thyroid hormone in the body. Common causes include an overactive thyroid gland or thyroid hormone overdose.
Hypoparathyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; medical
intervention or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a decrease in production of parathyroid hormone by the parathyroid glands.
Hypothyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thyroid
replacement indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a decrease in production of thyroid hormone by the thyroid gland.
Precocious puberty
Physical signs of puberty with
no biochemical markers for
females <8 years and males <9
years
Physical signs and biochemical
markers of puberty for females
<8 years and males <9 years
 -
 -
 -
Definition: A disorder characterized by unusually early development of secondary sexual features; the onset of sexual maturation begins usually before age 8 for girls and before age
9 for boys.
Virilization
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by inappropriate masculinization occurring in a female or prepubertal male.
Endocrine disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Eye disorders 
10
7. Eye disorders
Eye disorders
Grade
Adverse Event
1
2
3
4
5
Blurred vision
Intervention not indicated
Symptomatic; limiting
instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by visual perception of unclear or fuzzy images.
Cataract
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; moderate
decrease in visual acuity
(20/40 or better)
Symptomatic with marked
decrease in visual acuity
(worse than 20/40 but better
than 20/200); operative
intervention indicated (e.g.,
cataract surgery)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by partial or complete opacity of the crystalline lens of one or both eyes. This results in a decrease in visual acuity and eventual blindness if
untreated.
Conjunctivitis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; topical
intervention indicated (e.g.,
antibiotics); limiting
instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by inflammation, swelling and redness to the conjunctiva of the eye.
Corneal ulcer
 -
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Limiting self care ADL;
declining vision (worse than
20/40 but better than 20/200)
Perforation or blindness
(20/200 or worse) in the
affected eye
 -
Definition: A disorder characterized by an area of epithelial tissue loss on the surface of the cornea. It is associated with inflammatory cells in the cornea and anterior chamber.
Dry eye
Asymptomatic; clinical or
diagnostic observations only;
mild symptoms relieved by
lubricants
Symptomatic; multiple
agents indicated; limiting
instrumental ADL
Decrease in visual acuity
(<20/40); limiting self care
ADL
 -
 -
Definition: A disorder characterized by dryness of the cornea and conjunctiva.
Extraocular muscle paresis
Asymptomatic; clinical or
diagnostic observations only
Symptomatic; limiting
instrumental ADL
Limiting self care ADL;
disabling
 -
 -
Definition: A disorder characterized by incomplete paralysis of an extraocular muscle.
Eye pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the eye.
Eyelid function disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; nonoperative
intervention indicated;
limiting instrumental ADL
Limiting self care ADL;
operative intervention
indicated
 -
 -
Definition: A disorder characterized by impaired eyelid function.
Flashing lights
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by a sudden or brief burst of light.
Floaters
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by an individual seeing spots before their eyes. The spots are shadows of opaque cell fragments in the vitreous humor or lens.
Glaucoma
Elevated intraocular
pressure (EIOP) with single
topical agent for intervention;
no visual field deficit
EIOP causing early visual
field deficits; multiple topical
or oral agents indicated;
limiting instrumental ADL
EIOP causing marked visual
field deficits (e.g., involving
both superior and inferior
visual fields); operative
intervention indicated;
limiting self care ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by an increase in pressure in the eyeball due to obstruction of the aqueous humor outflow.
Keratitis
 -
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Decline in vision (worse than
20/40 but better than
20/200); limiting self care
ADL
Perforation or blindness
(20/200 or worse) in the
affected eye
 -
Definition: A disorder characterized by inflammation to the cornea of the eye.
Night blindness
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by an inability to see clearly in dim light.
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CTCAE 4.03 - June 14, 2010 : Eye disorders 
11
Eye disorders
Grade
Adverse Event
1
2
3
4
5
Optic nerve disorder
Asymptomatic; clinical or
diagnostic observations only
Limiting vision of the affected
eye (20/40 or better)
Limiting vision in the affected
eye (worse than 20/40 but
better than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by involvement of the optic nerve (second cranial nerve).
Papilledema
Asymptomatic; no visual field
defects
Symptomatic decline in
vision; visual field defect
present sparing the central
20 degrees
Marked visual field defect
(worse than 20/40 but better
than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by swelling around the optic disc.
Photophobia
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by fear and avoidance of light.
Retinal detachment
Asymptomatic
Exudative and visual acuity
20/40 or better
Rhegmatogenous or
exudative detachment;
operative intervention
indicated; decline in vision
(worse than 20/40 but better
than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by the separation of the inner retina layers from the underlying pigment epithelium.
Retinal tear
 -
Laser therapy or
pneumopexy indicated
Vitroretinal surgical repair
indicated
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by a small laceration of the retina, this occurs when the vitreous separates from the retina. Symptoms include flashes and floaters.
Retinal vascular disorder
 -
Topical medication indicated
Intravitreal medication;
operative intervention
indicated
 -
 -
Definition: A disorder characterized by pathological retinal blood vessels that adversely affects vision.
Retinopathy
Asymptomatic; clinical or
diagnostic observations only
Symptomatic with moderate
decrease in visual acuity
(20/40 or better); limiting
instrumental ADL
Symptomatic with marked
decrease in visual acuity
(worse than 20/40);
disabling; limiting self care
ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder involving the retina.
Scleral disorder
Asymptomatic; clinical or
diagnostic observations only
Symptomatic, limiting
instrumental ADL; moderate
decrease in visual acuity
(20/40 or better)
Symptomatic, limiting self
care ADL; marked decrease
in visual acuity (worse than
20/40)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by involvement of the sclera of the eye.
Uveitis
Asymptomatic; clinical or
diagnostic observations only
Anterior uveitis; medical
intervention indicated
Posterior or pan-uveitis
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by inflammation to the uvea of the eye.
Vitreous hemorrhage
Asymptomatic or mild
symptoms; clinical or
diagnostic observations only
Symptomatic; limiting
instrumental ADL
Limiting self care ADL;
vitrectomy indicated
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by blood extravasation into the vitreous humor.
Watering eyes
Intervention not indicated
Intervention indicated
Operative intervention
indicated
 -
 -
Definition: A disorder of excessive tearing in the eyes; it can be caused by overproduction of tears or impaired drainage of the tear duct.
Eye disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or
diagnostic observations only;
intervention not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental
ADL
Severe or medically
significant but not
immediately sight-
threatening; hospitalization
or prolongation of existing
hospitalization indicated;
disabling;  limiting self care
ADL
Sight-threatening
consequences; urgent
intervention indicated;
blindness (20/200 or worse)
in the affected eye
 -
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
12
8. Gastrointestinal disorders
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Abdominal distension
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe discomfort; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling of the abdomen.
Abdominal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the abdominal region.
Anal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the opening in the anal canal to the perianal skin.
Anal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the anal region.
Anal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the anus.
Anal necrosis
 -
 -
TPN or hospitalization indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the anal region.
Anal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the anal region.
Anal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Symptomatic and severely
altered GI function; non-
emergent operative intervention
indicated; TPN or hospitalization
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the anal canal.
Anal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the anal canal.
Ascites
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; invasive
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by accumulation of serous or hemorrhagic fluid in the peritoneal cavity.
Bloating
No change in bowel function or
oral intake
Symptomatic, decreased oral
intake; change in bowel function
 -
 -
 -
Definition: A disorder characterized by subject-reported feeling of uncomfortable fullness of the abdomen.
Cecal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the cecum.
Cheilitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; intervention indicated
 -
 -
Definition: A disorder characterized by inflammation of the lip.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
13
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Colitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Abdominal pain; mucus or blood
in stool
Severe abdominal pain; change
in bowel habits; medical
intervention indicated;
peritoneal signs
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the colon.
Colonic fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
bowel rest, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the large intestine and another organ or anatomic site.
Colonic hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the colon.
Colonic obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Hospitalization indicated;
elective operative intervention
indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the colon.
Colonic perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the colonic wall.
Colonic stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the colon.
Colonic ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the colon.
Constipation
Occasional or intermittent
symptoms; occasional use of
stool softeners, laxatives,
dietary modification, or enema
Persistent symptoms with
regular use of laxatives or
enemas; limiting instrumental
ADL
Obstipation with manual
evacuation indicated; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by irregular and infrequent or difficult evacuation of the bowels.
Dental caries
One or more dental caries, not
involving the root
Dental caries involving the root
Dental caries resulting in pulpitis
or periapical abscess or
resulting in tooth loss
 -
 -
Definition: A disorder characterized by the decay of a tooth, in which it becomes softened, discolored and/or porous.
Diarrhea
Increase of <4 stools per day
over baseline; mild increase in
ostomy output compared to
baseline
Increase of 4 - 6 stools per day
over baseline; moderate
increase in ostomy output
compared to baseline
Increase of >=7 stools per day
over baseline; incontinence;
hospitalization indicated; severe
increase in ostomy output
compared to baseline; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by frequent and watery bowel movements.
Dry mouth
Symptomatic (e.g., dry or thick
saliva) without significant dietary
alteration; unstimulated saliva
flow >0.2 ml/min
Moderate symptoms; oral intake
alterations (e.g., copious water,
other lubricants, diet limited to
purees and/or soft, moist foods);
unstimulated saliva 0.1 to 0.2
ml/min
Inability to adequately aliment
orally; tube feeding or TPN
indicated; unstimulated saliva
<0.1 ml/min
 -
 -
Definition: A disorder characterized by reduced salivary flow in the oral cavity.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
14
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Duodenal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the duodenum and another organ or anatomic site.
Duodenal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the duodenum.
Duodenal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Hospitalization or elective
operative intervention indicated;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of stomach contents through the duodenum.
Duodenal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the duodenal wall.
Duodenal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the duodenum.
Duodenal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the duodenal wall.
Dyspepsia
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; surgical
intervention indicated
 -
 -
Definition: A disorder characterized by an uncomfortable, often painful feeling in the stomach, resulting from impaired digestion. Symptoms include burning stomach, bloating,
heartburn, nausea and vomiting.
Dysphagia
Symptomatic, able to eat
regular diet
Symptomatic and altered
eating/swallowing
Severely altered
eating/swallowing; tube feeding
or TPN or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by difficulty in swallowing.
Enterocolitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Abdominal pain; mucus or blood
in stool
Severe or persistent abdominal
pain; fever; ileus; peritoneal
signs
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the small and large intestines.
Enterovesical fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; noninvasive
intervention indicated
Severe, medically significant;
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the urinary bladder and the intestine.
Esophageal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the esophagus and another organ or anatomic site.
Esophageal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the esophagus.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
15
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Esophageal necrosis
 -
 -
Inability to aliment adequately
by GI tract; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the esophageal wall.
Esophageal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents in the esophagus.
Esophageal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the esophageal region.
Esophageal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the wall of the esophagus.
Esophageal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the esophagus.
Esophageal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the esophageal wall.
Esophageal varices
hemorrhage
 -
Self-limited; intervention not
indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from esophageal varices.
Esophagitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered
eating/swallowing;  oral
supplements indicated
Severely altered
eating/swallowing; tube feeding,
TPN or hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the esophageal wall.
Fecal incontinence
Occasional use of pads required Daily use of pads required
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by inability to control the escape of stool from the rectum.
Flatulence
Mild symptoms; intervention not
indicated
Moderate; persistent;
psychosocial sequelae
 -
 -
 -
Definition: A disorder characterized by a state of excessive gas in the alimentary canal.
Gastric fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
bowel rest; tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the stomach and another organ or anatomic site.
Gastric hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the gastric wall.
Gastric necrosis
 -
 -
Inability to aliment adequately
by GI tract; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the gastric wall.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
16
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Gastric perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the stomach wall.
Gastric stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the stomach.
Gastric ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; medical intervention
indicated; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the stomach.
Gastritis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; medical intervention
indicated
Severely altered eating or
gastric function; TPN or
hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the stomach.
Gastroesophageal reflux
disease
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; surgical
intervention indicated
 -
 -
Definition: A disorder characterized by reflux of the gastric and/or duodenal contents into the distal esophagus. It is chronic in nature and usually caused by incompetence of the lower
esophageal sphincter, and may result in injury to the esophageal mucosal. Symptoms include heartburn and acid indigestion.
Gastrointestinal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between any part of the gastrointestinal system and another organ or anatomic site.
Gastrointestinal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gastrointestinal region.
Gastroparesis
Mild nausea, early satiety and
bloating, able to maintain caloric
intake on regular diet
Moderate symptoms; able to
maintain nutrition with dietary
and lifestyle modifications; may
need pharmacologic
intervention
Weight loss; refractory to
medical intervention; unable to
maintain nutrition orally
 -
 -
Definition: A disorder characterized by an incomplete paralysis of the muscles of the stomach wall resulting in delayed emptying of the gastric contents into the small intestine.
Gingival pain
Mild pain
Moderate pain interfering with
oral intake
Severe pain; inability to aliment
orally
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gingival region.
Hemorrhoidal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the hemorrhoids.
Hemorrhoids
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; banding or
medical intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by the presence of dilated veins in the rectum and surrounding area.
Ileal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the ileum and another organ or anatomic site.
Ileal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the ileal wall.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
17
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Ileal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the ileum.
Ileal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the ileal wall.
Ileal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the ileum.
Ileal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the ileum.
Ileus
 -
Symptomatic; altered GI
function; bowel rest indicated
Severely altered GI function;
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by failure of the ileum to transport intestinal contents.
Intra-abdominal hemorrhage
 -
Medical intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding in the abdominal cavity.
Jejunal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the jejunum and another organ or anatomic site.
Jejunal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the jejunal wall.
Jejunal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the jejunum.
Jejunal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the jejunal wall.
Jejunal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the jejunum.
Jejunal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the jejunum.
Lip pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort of the lip.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
18
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Lower gastrointestinal
hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the lower gastrointestinal tract (small intestine, large intestine, and anus).
Malabsorption
 -
Altered diet; oral intervention
indicated
Inability to aliment adequately;
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inadequate absorption of nutrients in the small intestine. Symptoms include abdominal marked discomfort, bloating and diarrhea.
Mucositis oral
Asymptomatic or mild
symptoms; intervention not
indicated
Moderate pain; not interfering
with oral intake; modified diet
indicated
Severe pain; interfering with oral
intake
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the oral mucosal.
Nausea
Loss of appetite without
alteration in eating habits
Oral intake decreased without
significant weight loss,
dehydration or malnutrition
Inadequate oral caloric or fluid
intake; tube feeding, TPN, or
hospitalization indicated
 -
 -
Definition: A disorder characterized by a queasy sensation and/or the urge to vomit.
Obstruction gastric
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents in the stomach.
Oral cavity fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the oral cavity and another organ or anatomic site.
Oral dysesthesia
Mild discomfort; not interfering
with oral intake
Moderate pain; interfering with
oral intake
Disabling pain; tube feeding or
TPN indicated
 -
 -
Definition: A disorder characterized by a burning or tingling sensation on the lips, tongue or entire mouth.
Oral hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the mouth.
Oral pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the mouth, tongue or lips.
Pancreatic duct stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the pancreatic duct.
Pancreatic fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the pancreas and another organ or anatomic site.
Pancreatic hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the pancreas.
Pancreatic necrosis
 -
 -
Tube feeding or TPN indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the pancreas.
Pancreatitis
 -
Enzyme elevation or radiologic
findings only
Severe pain; vomiting; medical
intervention indicated (e.g.,
analgesia, nutritional support)
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
19
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by inflammation of the pancreas.
Periodontal disease
Gingival recession or gingivitis;
limited bleeding on probing; mild
local bone loss
Moderate gingival recession or
gingivitis; multiple sites of
bleeding on probing; moderate
bone loss
Spontaneous bleeding; severe
bone loss with or without tooth
loss; osteonecrosis of maxilla or
mandible
 -
 -
Definition: A disorder in the gingival tissue around the teeth.
Peritoneal necrosis
 -
 -
Tube feeding or TPN  indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the peritoneum.
Proctitis
Rectal discomfort, intervention
not indicated
Symptoms (e.g., rectal
discomfort, passing blood or
mucus); medical intervention
indicated; limiting instrumental
ADL
Severe symptoms; fecal
urgency or stool incontinence;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the rectum.
Rectal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the rectum and another organ or anatomic site.
Rectal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the rectal wall and discharged from the anus.
Rectal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the rectum.
Rectal necrosis
 -
 -
Tube feeding or TPN indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the rectal wall.
Rectal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the rectum.
Rectal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the rectal region.
Rectal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the rectal wall.
Rectal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the rectum.
Rectal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function (e.g. altered dietary
habits, vomiting, diarrhea)
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the rectum.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
20
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Retroperitoneal hemorrhage
 -
Self-limited; intervention
indicated
Transfusion, medical, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the retroperitoneal area.
Salivary duct inflammation
Slightly thickened saliva; slightly
altered taste (e.g., metallic)
Thick, ropy, sticky saliva;
markedly altered taste;
alteration in diet indicated;
secretion-induced symptoms;
limiting instrumental ADL
Acute salivary gland necrosis;
severe secretion-induced
symptoms (e.g., thick saliva/oral
secretions or gagging);  tube
feeding or TPN indicated;
limiting self care ADL; disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the salivary duct.
Salivary gland fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; tube feeding indicated
Severely altered GI function;
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between a salivary gland and another organ or anatomic site.
Small intestinal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe pain; interfering with oral
intake; tube feeding, TPN or
hospitalization indicated; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the small intestine.
Small intestinal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents.
Small intestinal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the small intestine wall.
Small intestinal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Symptomatic and severely
altered GI function; tube
feeding, TPN or hospitalization
indicated; non-emergent
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the small intestine.
Small intestine ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the small intestine.
Stomach pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the stomach.
Tooth development disorder
Asymptomatic; hypoplasia of
tooth or enamel
Impairment correctable with oral
surgery
Maldevelopment with
impairment not surgically
correctable; disabling
 -
 -
Definition: A disorder characterized by a pathological process of the teeth occurring during tooth development.
Tooth discoloration
Surface stains
 -
 -
 -
 -
Definition: A disorder characterized by a change in tooth hue or tint.
Toothache
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the tooth.
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CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
21
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Typhlitis
 -
 -
Symptomatic (e.g., abdominal
pain, fever, change in bowel
habits with ileus); peritoneal
signs
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the cecum.
Upper gastrointestinal
hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the upper gastrointestinal tract (oral cavity, pharynx, esophagus, and stomach).
Vomiting
1 - 2 episodes (separated by 5
minutes) in 24 hrs
3 - 5 episodes (separated by 5
minutes) in 24 hrs
>=6 episodes (separated by 5
minutes) in 24 hrs; tube feeding,
TPN or hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
Gastrointestinal disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : General disorders and administration site conditions 
22
9. General disorders and administration site conditions
General disorders and administration site conditions
Grade
Adverse Event
1
2
3
4
5
Chills
Mild sensation of cold;
shivering; chattering of teeth
Moderate tremor of the entire
body; narcotics indicated
Severe or prolonged, not
responsive to narcotics
 -
 -
Definition: A disorder characterized by a sensation of cold that often marks a physiologic response to sweating after a fever.
Death neonatal
 -
 -
 -
 -
Death
Definition: A disorder characterized by cessation of life occurring during the first 28 days of life.
Death NOS
 -
 -
 -
 -
Death
Definition: A cessation of life that cannot be attributed to a CTCAE term associated with Grade 5.
Edema face
Localized facial edema
Moderate localized facial
edema; limiting instrumental
ADL
Severe swelling; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in facial tissues.
Edema limbs
5 - 10% inter-limb discrepancy
in volume or circumference at
point of greatest visible
difference; swelling or
obscuration of anatomic
architecture on close inspection
>10 - 30% inter-limb
discrepancy in volume or
circumference at point of
greatest visible difference;
readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour; limiting
instrumental ADL
>30% inter-limb discrepancy in
volume; gross deviation from
normal anatomic contour;
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the upper or lower extremities.
Edema trunk
Swelling or obscuration of
anatomic architecture on close
inspection
Readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour; limiting
instrumental ADL
Gross deviation from normal
anatomic contour; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the trunk area.
Facial pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the face.
Fatigue
Fatigue relieved by rest
Fatigue not relieved by rest;
limiting instrumental ADL
Fatigue not relieved by rest,
limiting self care ADL
 -
 -
Definition: A disorder characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities.
Fever
38.0 - 39.0 degrees C  (100.4 -
102.2 degrees F)
>39.0 - 40.0 degrees C (102.3 -
104.0 degrees F)
>40.0 degrees C (>104.0
degrees F) for <=24 hrs
>40.0 degrees C (>104.0
degrees F) for >24 hrs
Death
Definition: A disorder characterized by elevation of the body's temperature above the upper limit of normal.
Flu like symptoms
Mild flu-like symptoms present
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a group of symptoms similar to those observed in patients with the flu. It includes fever, chills, body aches, malaise, loss of appetite and dry
cough.
Gait disturbance
Mild change in gait (e.g., wide-
based, limping or hobbling)
Moderate change in gait (e.g.,
wide-based, limping or
hobbling); assistive device
indicated; limiting instrumental
ADL
Disabling; limiting self care ADL
 -
 -
Definition: A disorder characterized by walking difficulties.
Hypothermia
 -
35 - >32 degrees C;  95 - >89.6
degrees F
32 - >28 degrees C;  89.6 -
>82.4 degrees F
<=28 degrees C; 82.4 degrees
F; life-threatening
consequences (e.g., coma,
hypotension, pulmonary edema,
acidemia, ventricular fibrillation)
Death
Definition: A disorder characterized by an abnormally low body temperature. Treatment is required when the body temperature is 35C (95F) or below.
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CTCAE 4.03 - June 14, 2010 : General disorders and administration site conditions 
23
General disorders and administration site conditions
Grade
Adverse Event
1
2
3
4
5
Infusion related reaction
Mild transient reaction; infusion
interruption not indicated;
intervention not indicated
Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.,
antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic
medications indicated for <=24
hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by adverse reaction to the infusion of pharmacological or biological substances.
Infusion site extravasation
 -
Erythema with associated
symptoms (e.g., edema, pain,
induration, phlebitis)
Ulceration or necrosis; severe
tissue damage; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by leakage of a pharmacologic or a biologic substance from the infusion site into the surrounding tissue. Signs and symptoms include induration,
erythema, swelling, burning sensation and marked discomfort at the infusion site.
Injection site reaction
Tenderness with or without
associated symptoms (e.g.,
warmth, erythema, itching)
Pain; lipodystrophy; edema;
phlebitis
Ulceration or necrosis; severe
tissue damage; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an intense adverse reaction (usually immunologic) developing at the site of an injection.
Irritability
Mild; easily consolable
Moderate; limiting instrumental
ADL; increased attention
indicated
Severe abnormal or excessive
response; limiting self care ADL;
inconsolable
 -
 -
Definition: A disorder characterized by an abnormal responsiveness to stimuli or physiological arousal; may be in response to pain, fright, a drug, an emotional situation or a medical
condition.
Localized edema
Localized to dependent areas,
no disability or functional
impairment
Moderate localized edema and
intervention indicated; limiting
instrumental ADL
Severe localized edema and
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation at a specific anatomic site.
Malaise
Uneasiness or lack of well being Uneasiness or lack of well
being; limiting instrumental ADL
 -
 -
 -
Definition: A disorder characterized by a feeling of general discomfort or uneasiness, an out-of-sorts feeling.
Multi-organ failure
 -
 -
Shock with azotemia and acid-
base disturbances; significant
coagulation abnormalities
Life-threatening consequences
(e.g., vasopressor dependent
and oliguric or anuric or
ischemic colitis or lactic
acidosis)
Death
Definition: A disorder characterized by progressive deterioration of the lungs, liver, kidney and clotting mechanisms.
Neck edema
Asymptomatic localized neck
edema
Moderate neck edema; slight
obliteration of anatomic
landmarks; limiting instrumental
ADL
Generalized neck edema (e.g.,
difficulty in turning neck);
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to an accumulation of excessive fluid in the neck.
Non-cardiac chest pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by discomfort in the chest unrelated to a heart disorder.
Pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by the sensation of marked discomfort, distress or agony.
Sudden death NOS
 -
 -
 -
 -
Death
Definition: An unexpected cessation of life that cannot be attributed to a CTCAE term associated with Grade 5.
General disorders and
administration site conditions -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
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CTCAE 4.03 - June 14, 2010 : Hepatobiliary disorders 
24
10. Hepatobiliary disorders
Hepatobiliary disorders
Grade
Adverse Event
1
2
3
4
5
Bile duct stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; IV fluids indicated <24
hrs
Severely altered GI function;
radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the bile duct.
Biliary fistula
 -
Symptomatic and intervention
not indicated
Severely altered GI function;
TPN indicated; endoscopic
intervention indicated; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the bile ducts and another organ or anatomic site.
Cholecystitis
 -
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation involving the gallbladder. It may be associated with the presence of gallstones.
Gallbladder fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Symptomatic or severely altered
GI function; TPN indicated;
radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the gallbladder and another organ or anatomic site.
Gallbladder necrosis
 -
 -
 -
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the gallbladder.
Gallbladder obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; IV fluids indicated  <24
hrs
Symptomatic and severely
altered GI function; tube
feeding, TPN or hospitalization
indicated; non-emergent
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents of the gallbladder.
Gallbladder pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gallbladder region.
Gallbladder perforation
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the gallbladder wall.
Hepatic failure
 -
 -
Asterixis; mild encephalopathy;
limiting self care ADL
Moderate to severe
encephalopathy; coma; life-
threatening consequences
Death
Definition: A disorder characterized by the inability of the liver to metabolize chemicals in the body. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic
dehydrogenase, and alkaline phosphatase.
Hepatic hemorrhage
Mild; intervention not indicated
Symptomatic; medical
intervention indicated
Transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the liver.
Hepatic necrosis
 -
 -
 -
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the hepatic parenchyma.
Hepatic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the liver region.
Perforation bile duct
 -
 -
Radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the wall of the extrahepatic or intrahepatic bile duct.
Alexion Confidential
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CTCAE 4.03 - June 14, 2010 : Hepatobiliary disorders 
25
Hepatobiliary disorders
Grade
Adverse Event
1
2
3
4
5
Portal hypertension
 -
Decreased portal vein flow
Reversal/retrograde portal vein
flow; associated with varices
and/or ascites
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in blood pressure in the portal venous system.
Portal vein thrombosis
 -
Intervention not indicated
Medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the formation of a thrombus (blood clot) in the portal vein.
Hepatobiliary disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 907 of 979


CTCAE 4.03 - June 14, 2010 : Immune system disorders 
26
11. Immune system disorders
Immune system disorders
Grade
Adverse Event
1
2
3
4
5
Allergic reaction
Transient flushing or rash, drug
fever <38 degrees C (<100.4
degrees F); intervention not
indicated
Intervention or infusion
interruption indicated; responds
promptly to symptomatic
treatment (e.g., antihistamines,
NSAIDS, narcotics);
prophylactic medications
indicated for <=24 hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae (e.g., renal
impairment, pulmonary
infiltrates)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
 -
 -
Symptomatic bronchospasm,
with or without urticaria;
parenteral intervention
indicated; allergy-related
edema/angioedema;
hypotension
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivity
immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death.
Autoimmune disorder
Asymptomatic; serologic or
other evidence of autoimmune
reaction, with normal organ
function;  intervention not
indicated
Evidence of autoimmune
reaction involving a non-
essential organ or function (e.g.,
hypothyroidism)
Autoimmune reactions involving
major organ (e.g., colitis,
anemia, myocarditis, kidney)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder resulting from loss of function or tissue destruction of an organ or multiple organs, arising from humoral or cellular immune responses of the individual to his own
tissue constituents.
Cytokine release syndrome
Mild reaction; infusion
interruption not indicated;
intervention not indicated
Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.,
antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic
medications indicated for <=24
hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae (e.g., renal
impairment, pulmonary
infiltrates)
Life-threatening consequences;
pressor or ventilatory support
indicated
Death
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused by the release of cytokines from the cells.
Serum sickness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate arthralgia; fever, rash,
urticaria, antihistamines
indicated
Severe arthralgia or arthritis;
extensive rash; steroids or IV
fluids indicated
Life-threatening consequences;
pressor or ventilatory support
indicated
Death
Definition: A disorder characterized by a delayed-type hypersensitivity reaction to foreign proteins derived from an animal serum. It occurs approximately six to twenty-one days
following the administration of the foreign antigen. Symptoms include fever, arthralgias, myalgias, skin eruptions, lymphadenopathy, chest marked discomfort and dyspnea.
Immune system disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
27
12. Infections and infestations
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Abdominal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the abdominal cavity.
Anorectal infection
Localized; local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the anal area and the rectum.
Appendicitis
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent.
Appendicitis perforated
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent with gangrenous changes resulting in the rupture of the
appendiceal wall. The appendiceal wall rupture causes the release of inflammatory and bacterial contents from the appendiceal lumen into the abdominal cavity.
Arteritis infective
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving an artery.
Biliary tract infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the biliary tract.
Bladder infection
 -
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bladder.
Bone infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bones.
Breast infection
 -
Local infection with moderate
symptoms; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral)
Severe infection; axillary
adenitis;  IV antibacterial,
antifungal, or antiviral
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the breast.
Bronchial infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bronchi.
Catheter related infection
 -
Localized; local intervention
indicated; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process that arises secondary to catheter use.
Cecal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
28
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the cecum.
Cervicitis infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the uterine cervix.
Conjunctivitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the conjunctiva. Clinical manifestations include pink or red color in the eyes.
Corneal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the cornea.
Cranial nerve infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a cranial nerve.
Device related infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the use of a medical device.
Duodenal infection
 -
Moderate symptoms; medical
intervention indicated (e.g., oral
antibiotics)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the duodenum.
Encephalitis infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
severe changes in mental
status; self-limited seizure
activity; focal neurologic
abnormalities
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the brain tissue.
Encephalomyelitis infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the brain and spinal cord tissues.
Endocarditis infective
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the endocardial layer of the heart.
Endophthalmitis
 -
Local intervention indicated
Systemic intervention or
hospitalization indicated
Blindness (20/200 or worse)
 -
Definition: A disorder characterized by an infectious process involving the internal structures of the eye.
Alexion Confidential
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
29
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Enterocolitis infectious
 -
Passage of >3 unformed stools
per 24 hrs or duration of illness
>48 hrs; moderate abdominal
pain
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated;
profuse watery diarrhea with
signs of hypovolemia;  bloody
diarrhea; fever; severe
abdominal pain; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the small and large intestines.
Esophageal infection
 -
Local intervention indicated
(e.g., oral antibiotic, antifungal,
antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the esophagus.
Eye infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated;
enucleation
Death
Definition: A disorder characterized by an infectious process involving the eye.
Gallbladder infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the gallbladder.
Gum infection
Local therapy indicated (swish
and swallow)
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the gums.
Hepatic infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the liver.
Hepatitis viral
Asymptomatic, treatment not
indicated
 -
Symptomatic liver dysfunction;
fibrosis by biopsy; compensated
cirrhosis; reactivation of chronic
hepatitis
Decompensated liver function
(e.g., ascites, coagulopathy,
encephalopathy, coma)
Death
Definition: A disorder characterized by a viral pathologic process involving the liver parenchyma.
Infective myositis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the skeletal muscles.
Joint infection
 -
Localized; local intervention
indicated; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral); needle
aspiration indicated (single or
multiple)
Arthroscopic intervention
indicated (e.g., drainage) or
arthrotomy (e.g., open surgical
drainage)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a joint.
Kidney infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the kidney.
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
30
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Laryngitis
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammatory process involving the larynx.
Lip infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by an infectious process involving the lips.
Lung infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the lungs.
Lymph gland infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the lymph nodes.
Mediastinal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the mediastinum.
Meningitis
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated; focal
neurologic deficit
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation of the meninges of the brain and/or spinal cord.
Mucosal infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a mucosal surface.
Nail infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by an infectious process involving the nail.
Otitis externa
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the outer ear and ear canal. Contributory factors include excessive water exposure (swimmer's ear infection)
and cuts in the ear canal. Symptoms include fullness, itching, swelling and marked discomfort in the ear and ear drainage.
Otitis media
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the middle ear.
Ovarian infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the ovary.
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
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Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Pancreas infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pancreas.
Papulopustular rash
Papules and/or pustules
covering <10% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness
Papules and/or pustules
covering 10-30% BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness; associated with
psychosocial impact; limiting
instrumental ADL
Papules and/or pustules
covering >30% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness; limiting self-care
ADL; associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering  any % BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness and are associated
with extensive superinfection
with IV antibiotics indicated; life-
threatening consequences
Death
Definition: A disorder characterized by an eruption consisting of papules (a small, raised pimple) and pustules (a small pus filled blister), typically appearing in face, scalp, and upper
chest and back Unlike acne, this rash does not present with whiteheads or blackheads, and can be symptomatic, with itchy or tender lesions.
Paronychia
Nail fold edema or erythema;
disruption of the cuticle
Localized intervention indicated;
oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral);
nail fold edema or erythema
with pain; associated with
discharge or nail plate
separation; limiting instrumental
ADL
Surgical intervention or IV
antibiotics indicated; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an infectious process involving the soft tissues around the nail.
Pelvic infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pelvic cavity.
Penile infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the penis.
Periorbital infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the orbit of the eye.
Peripheral nerve infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the peripheral nerves.
Peritoneal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the peritoneum.
Pharyngitis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the throat.
Phlebitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
32
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the vein. Clinical manifestations include erythema, marked discomfort, swelling, and induration along the course
of the infected vein.
Pleural infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pleura.
Prostate infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the prostate gland.
Rash pustular
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by a circumscribed and elevated skin lesion filled with pus.
Rhinitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
 -
 -
 -
Definition: A disorder characterized by an infectious process involving the nasal mucosal.
Salivary gland infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the salivary gland.
Scrotal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the scrotum.
Sepsis
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the presence of pathogenic microorganisms in the blood stream that cause a rapidly progressing systemic reaction that may lead to shock.
Sinusitis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the mucous membranes of the paranasal sinuses.
Skin infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the skin.
Small intestine infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the small intestine.
Soft tissue infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving soft tissues.
Splenic infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Infections and infestations 
33
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the spleen.
Stoma site infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a stoma (surgically created opening on the surface of the body).
Tooth infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a tooth.
Tracheitis
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the trachea.
Upper respiratory infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the upper respiratory tract (nose, paranasal sinuses, pharynx, larynx, or trachea).
Urethral infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the urethra.
Urinary tract infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the urinary tract, most commonly the bladder and the urethra.
Uterine infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the endometrium. It may extend to the myometrium and parametrial tissues.
Vaginal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the vagina.
Vulval infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the vulva.
Wound infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the wound.
Infections and infestations -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
34
13. Injury, poisoning and procedural complications
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Ankle fracture
Mild; non-surgical intervention
indicated
Limiting instrumental ADL;
operative intervention indicated
Limiting self care ADL; elective
surgery indicated
 -
 -
Definition: A finding of damage to the ankle joint characterized by a break in the continuity of the ankle bone. Symptoms include marked discomfort, swelling and difficulty moving the
affected leg and foot.
Aortic injury
 -
 -
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to the aorta.
Arterial injury
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic (e.g.,
claudication); repair or revision
not indicated
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to an artery.
Biliary anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of bile due to breakdown of a biliary anastomosis (surgical connection of two separate anatomic structures).
Bladder anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of urine due to breakdown of a bladder anastomosis (surgical connection of two separate anatomic structures).
Bruising
Localized or in a dependent
area
Generalized
 -
 -
 -
Definition: A finding of injury of the soft tissues or bone characterized by leakage of blood into surrounding tissues.
Burn
Minimal symptoms; intervention
not indicated
Medical intervention; minimal
debridement indicated
Moderate to major debridement
or reconstruction indicated
Life-threatening consequences
Death
Definition: A finding of impaired integrity to the anatomic site of an adverse thermal reaction. Burns can be caused by exposure to chemicals, direct heat, electricity, flames and
radiation. The extent of damage depends on the length and intensity of exposure and time until provision of treatment.
Dermatitis radiation
Faint erythema or dry
desquamation
Moderate to brisk erythema;
patchy moist desquamation,
mostly confined to skin folds
and creases; moderate edema
Moist desquamation in areas
other than skin folds and
creases; bleeding induced by
minor trauma or abrasion
Life-threatening consequences;
skin necrosis or ulceration of full
thickness dermis; spontaneous
bleeding from involved site; skin
graft indicated
Death
Definition: A finding of cutaneous inflammatory reaction occurring as a result of exposure to biologically effective levels of ionizing radiation.
Esophageal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an esophageal anastomosis (surgical connection of two separate anatomic structures).
Fall
Minor with no resultant injuries;
intervention not indicated
Symptomatic; noninvasive
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding of sudden movement downward, usually resulting in injury.
Fallopian tube anastomotic leak
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a fallopian tube anastomosis (surgical connection of two separate anatomic structures).
Fallopian tube perforation
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated (e.g., organ resection)
Death
Definition: A finding of rupture of the fallopian tube wall.
Fracture
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic but non-displaced;
immobilization indicated
Severe symptoms; displaced or
open wound with bone
exposure; disabling; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of traumatic injury to the bone in which the continuity of the bone is broken.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
35
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Gastric anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a gastric anastomosis (surgical connection of two separate anatomic structures).
Gastrointestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a gastrointestinal anastomosis (surgical connection of two separate anatomic structures).
Gastrointestinal stoma necrosis
 -
Superficial necrosis;
intervention not indicated
Severe symptoms;
hospitalization or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of a necrotic process occurring in the gastrointestinal tract stoma.
Hip fracture
 -
Hairline fracture; mild pain;
limiting instrumental ADL; non-
surgical intervention indicated
Severe pain; hospitalization or
intervention indicated for pain
control (e.g., traction); operative
intervention indicated
Life-threatening consequences;
symptoms associated with
neurovascular compromise
 -
Definition: A finding of traumatic injury to the hip in which the continuity of either the femoral head, femoral neck, intertrochanteric or subtrochanteric regions is broken.
Injury to carotid artery
 -
 -
Severe symptoms; limiting self
care ADL (e.g., transient
cerebral ischemia); repair or
revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the carotid artery.
Injury to inferior vena cava
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the inferior vena cava.
Injury to jugular vein
 -
 -
Symptomatic limiting self care
ADL; disabling; repair or
revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the jugular vein.
Injury to superior vena cava
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic; repair or revision
not indicated
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to the superior vena cava.
Intestinal stoma leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of contents from an intestinal stoma (surgically created opening on the surface of the body).
Intestinal stoma obstruction
 -
Self-limited; intervention not
indicated
Severe symptoms; IV fluids,
tube feeding, or TPN indicated
>=24 hrs; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of blockage of the normal flow of the contents of the intestinal stoma.
Intestinal stoma site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of blood leakage from the intestinal stoma.
Intraoperative arterial injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to an artery during a surgical procedure.
Intraoperative breast injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
36
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of damage to the breast parenchyma during a surgical procedure.
Intraoperative cardiac injury
 -
 -
Primary repair of injured
organ/structure indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the heart during a surgical procedure.
Intraoperative ear injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection of injured
organ/structure indicated;
disabling (e.g., impaired
hearing; impaired balance)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the ear during a surgical procedure.
Intraoperative endocrine injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the endocrine gland during a surgical procedure.
Intraoperative gastrointestinal
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the gastrointestinal system during a surgical procedure.
Intraoperative head and neck
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the head and neck during a surgical procedure.
Intraoperative hemorrhage
 -
 -
Postoperative radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of uncontrolled bleeding during a surgical procedure.
Intraoperative hepatobiliary
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the hepatic parenchyma and/or biliary tract during a surgical procedure.
Intraoperative musculoskeletal
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the musculoskeletal system during a surgical procedure.
Intraoperative neurological
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the nervous system during a surgical procedure.
Intraoperative ocular injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the eye during a surgical procedure.
Intraoperative renal injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the kidney during a surgical procedure.
Intraoperative reproductive tract
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
37
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of damage to the reproductive organs during a surgical procedure.
Intraoperative respiratory injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the respiratory system during a surgical procedure.
Intraoperative skin injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the skin during a surgical procedure.
Intraoperative splenic injury
 -
Primary repair of injured
organ/structure indicated
Resection or reconstruction of
injured organ/structure
indicated; disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the spleen during a surgical procedure.
Intraoperative urinary injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the urinary system during a surgical procedure.
Intraoperative venous injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to a vein during a surgical procedure.
Kidney anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of urine due to breakdown of a kidney anastomosis (surgical connection of two separate anatomic structures).
Large intestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the large intestine.
Pancreatic anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a pancreatic anastomosis (surgical connection of two separate anatomic structures).
Pharyngeal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a pharyngeal anastomosis (surgical connection of two separate anatomic structures).
Postoperative hemorrhage
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; radiologic,
endoscopic, or operative
intervention indicated
Transfusion indicated of >=2
units (10 cc/kg for pediatrics)
pRBCs beyond protocol
specification; urgent radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding occurring after a surgical procedure.
Postoperative thoracic
procedure complication
 -
Extubated within 24 - 72 hrs
postoperatively
Extubated >72 hrs
postoperatively, but before
tracheostomy indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A finding of a previously undocumented problem that occurs after a thoracic procedure.
Prolapse of intestinal stoma
Asymptomatic; reducible
Recurrent after manual
reduction; local irritation or stool
leakage; difficulty to fit
appliance; limiting instrumental
ADL
Severe symptoms; elective
operative intervention indicated;
limiting self care ADL
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
38
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of protrusion of the intestinal stoma (surgically created opening on the surface of the body) above the abdominal surface.
Prolapse of urostomy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Local care or maintenance;
minor revision indicated
Dysfunctional stoma; elective
operative intervention or major
stomal revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of displacement of the urostomy.
Radiation recall reaction
(dermatologic)
Faint erythema or dry
desquamation
Moderate to brisk erythema;
patchy moist desquamation,
mostly confined to skin folds
and creases; moderate edema
Moist desquamation in areas
other than skin folds and
creases; bleeding induced by
minor trauma or abrasion
Life-threatening consequences;
skin necrosis or ulceration of full
thickness dermis; spontaneous
bleeding from involved site; skin
graft indicated
Death
Definition: A finding of acute skin inflammatory reaction caused by drugs, especially chemotherapeutic agents, for weeks or months following radiotherapy. The inflammatory reaction
is confined to the previously irradiated skin and the symptoms disappear after the removal of the pharmaceutical agent.
Rectal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a rectal anastomosis (surgical connection of two separate anatomic structures).
Seroma
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; simple aspiration
indicated
Symptomatic, elective radiologic
or operative intervention
indicated
 -
 -
Definition: A finding of tumor-like collection of serum in the tissues.
Small intestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the small bowel.
Spermatic cord anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a spermatic cord anastomosis (surgical connection of two separate anatomic structures).
Spinal fracture
Mild back pain; nonprescription
analgesics indicated
Moderate back pain;
prescription analgesics
indicated; limiting instrumental
ADL
Severe back pain;
hospitalization or intervention
indicated for pain control (e.g.,
vertebroplasty); limiting self care
ADL; disability
Life-threatening consequences;
symptoms associated with
neurovascular compromise
Death
Definition: A finding of traumatic injury to the spine in which the continuity of a vertebral bone is broken.
Stenosis of gastrointestinal
stoma
 -
Symptomatic; IV fluids indicated
<24 hrs; manual dilation at
bedside
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of narrowing of the gastrointestinal stoma (surgically created opening on the surface of the body).
Stomal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the jejunal mucosal surface close to the anastomosis site following a
gastroenterostomy procedure.
Tracheal hemorrhage
Minimal bleeding identified on
clinical or diagnostic exam;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding from the trachea.
Tracheal obstruction
Partial asymptomatic
obstruction on examination
(e.g., visual, radiologic or
endoscopic)
Symptomatic (e.g., noisy airway
breathing), no respiratory
distress; medical intervention
indicated (e.g., steroids); limiting
instrumental ADL
Stridor; radiologic or endoscopic
intervention indicated (e.g.,
stent, laser); limiting self care
ADL
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A finding of blockage of the lumen of the trachea.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
39
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Tracheostomy site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of blood leakage from the tracheostomy site.
Ureteric anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a ureteral anastomosis (surgical connection of two separate anatomic structures).
Urethral anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a urethral anastomosis (surgical connection of two separate anatomic structures).
Urostomy leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of contents from a urostomy.
Urostomy obstruction
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; dilation or
endoscopic repair or stent
placement indicated
Altered organ function (e.g.,
sepsis or hydronephrosis, or
renal dysfunction); elective
operative intervention indicated
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A finding of blockage of the urostomy.
Urostomy site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding from the urostomy site.
Urostomy stenosis
 -
Symptomatic but no
hydronephrosis, no sepsis or no
renal dysfunction; dilation or
endoscopic repair or stent
placement indicated
Symptomatic (e.g.,
hydronephrosis, or renal
dysfunction); elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of narrowing of the opening of a urostomy.
Uterine anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a uterine anastomosis (surgical connection of two separate anatomic structures).
Uterine perforation
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the uterine wall.
Vaginal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a vaginal anastomosis (surgical connection of two separate anatomic structures).
Vas deferens anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a vas deferens anastomosis (surgical connection of two separate anatomic structures).
Vascular access complication
 -
Device dislodgement, blockage,
leak, or malposition; device
replacement indicated
Deep vein or cardiac
thrombosis; intervention
indicated (e.g., anticoagulation,
lysis, filter, invasive procedure)
Embolic event including
pulmonary embolism or life-
threatening thrombus
Death
Definition: A finding of a previously undocumented problem related to the vascular access site.
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CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
40
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Venous injury
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic (e.g.,
claudication); repair or revision
not indicated
Severe symptoms; limiting self
care ADL; repair or revision
indicated; disabling
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to a vein.
Wound complication
Incisional separation of <=25%
of wound, no deeper than
superficial fascia
Incisional separation >25% of
wound; local care indicated
Hernia without evidence of
strangulation; fascial
disruption/dehiscence; primary
wound closure or revision by
operative intervention indicated
Hernia with evidence of
strangulation; major
reconstruction flap, grafting,
resection, or amputation
indicated
Death
Definition: A finding of development of a new problem at the site of an existing wound.
Wound dehiscence
Incisional separation of <=25%
of wound, no deeper than
superficial fascia
Incisional separation >25% of
wound with local care;
asymptomatic hernia or
symptomatic hernia without
evidence of strangulation
Fascial disruption or dehiscence
without evisceration; primary
wound closure or revision by
operative intervention indicated
Life-threatening consequences;
symptomatic hernia with
evidence of strangulation;
fascial disruption with
evisceration; major
reconstruction flap, grafting,
resection, or amputation
indicated
Death
Definition: A finding of separation of the approximated margins of a surgical wound.
Wrist fracture
Mild; non-surgical intervention
indicated
Limiting instrumental ADL;
operative intervention indicated
Limiting self care ADL; elective
surgery indicated
 -
 -
Definition: A finding of traumatic injury to the wrist joint in which the continuity of a wrist bone is broken.
Injury, poisoning and procedural
complications - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Investigations 
41
14. Investigations
Investigations
Grade
Adverse Event
1
2
3
4
5
Activated partial thromboplastin
time prolonged
>ULN - 1.5 x ULN
>1.5 - 2.5 x ULN
>2.5 x ULN; hemorrhage
 -
 -
Definition: An abnormal laboratory test result in which the partial thromboplastin time is found to be greater than the control value. As a possible indicator of coagulopathy, a prolonged
partial thromboplastin time (PTT) may occur in a variety of diseases and disorders, both primary and related to treatment.
Alanine aminotransferase
increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT or SGPT) in the blood specimen.
Alkaline phosphatase increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of alkaline phosphatase in a blood specimen.
Aspartate aminotransferase
increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of aspartate aminotransferase (AST or SGOT) in a blood specimen.
Blood antidiuretic hormone
abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of antidiuretic hormone in the blood specimen.
Blood bilirubin increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an abnormally high level of bilirubin in the blood. Excess bilirubin is associated with jaundice.
Blood corticotrophin decreased
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of corticotrophin in a blood specimen.
Blood gonadotrophin abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of gonadotrophin hormone in a blood specimen.
Blood prolactin abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
 -
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of prolactin hormone in a blood specimen.
Carbon monoxide diffusing
capacity decreased
3 - 5 units below LLN; for follow-
up, a decrease of 3 - 5 units
(ml/min/mm Hg) below the
baseline value
6 - 8 units below LLN; for follow-
up, an asymptomatic decrease
of >5 - 8 units (ml/min/mm Hg)
below the baseline value
Asymptomatic decrease  of >8
units drop;  >5 units drop along
with the presence of pulmonary
symptoms (e.g. , >Grade 2
hypoxia or >Grade 2 or higher
dyspnea)
 -
 -
Definition: A finding based on lung function test results that indicate  a decrease in the lung capacity to absorb carbon monoxide.
Cardiac troponin I increased
Levels above the upper limit of
normal and below the level of
myocardial infarction as defined
by the manufacturer
 -
Levels consistent with
myocardial infarction as defined
by the manufacturer
 -
 -
Definition: A laboratory test result which indicates increased levels of cardiac troponin I in a biological specimen.
Cardiac troponin T increased
Levels above the upper limit of
normal and below the level of
myocardial infarction as defined
by the manufacturer
 -
Levels consistent with
myocardial infarction as defined
by the manufacturer
 -
 -
Definition: A laboratory test result which indicates increased levels of cardiac troponin T in a biological specimen.
CD4 lymphocytes decreased
<LLN - 500/mm3;  <LLN - 0.5 x
10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x
10e9 /L
<200 - 50/mm3; <0.2 x 0.05 -
10e9 /L
<50/mm3; <0.05 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of CD4 lymphocytes in a blood specimen.
Cholesterol high
>ULN - 300 mg/dL; >ULN - 7.75
mmol/L
>300 - 400 mg/dL; >7.75 - 10.34
mmol/L
>400 - 500 mg/dL; >10.34 -
12.92 mmol/L
>500 mg/dL; >12.92 mmol/L
 -
Definition: A finding based on laboratory test results that indicate higher than normal levels of cholesterol in a blood specimen.
CPK increased
>ULN - 2.5 x ULN
>2.5 x ULN - 5 x ULN
>5 x ULN - 10 x ULN
>10 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in levels of creatine phosphokinase in a blood specimen.
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CTCAE 4.03 - June 14, 2010 : Investigations 
42
Investigations
Grade
Adverse Event
1
2
3
4
5
Creatinine increased
>1 - 1.5 x baseline; >ULN - 1.5
x ULN
>1.5 - 3.0 x baseline; >1.5 - 3.0
x ULN
>3.0 baseline; >3.0 - 6.0 x ULN
>6.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate increased levels of creatinine in a biological specimen.
Ejection fraction decreased
 -
Resting ejection fraction (EF) 50
- 40%; 10 - 19% drop from
baseline
Resting ejection fraction (EF) 39
- 20%; >20% drop from baseline
Resting ejection fraction (EF)
<20%
 -
Definition: The percentage computed when the amount of blood ejected during a ventricular contraction of the heart is compared to the amount that was present prior to the
contraction.
Electrocardiogram QT corrected
interval prolonged
QTc 450 - 480 ms
QTc 481 - 500 ms
QTc >= 501 ms on at least two
separate ECGs
QTc >= 501 or >60 ms change
from baseline and Torsade de
pointes or polymorphic
ventricular tachycardia or
signs/symptoms of serious
arrhythmia
 -
Definition: A finding of a cardiac dysrhythmia characterized by an abnormally long corrected QT interval.
Fibrinogen decreased
<1.0 - 0.75 x LLN  or <25%
decrease from baseline
<0.75 - 0.5 x LLN or 25 - <50%
decrease from baseline
<0.5 - 0.25 x LLN or 50 - <75%
decrease from baseline
<0.25 x LLN  or 75% decrease
from baseline or absolute value
<50 mg/dL
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of fibrinogen in a blood specimen.
Forced expiratory volume
decreased
FEV1% (percentages of
observed FEV1 and FVC
related to their respective
predicted values)  99 - 70%
predicted
FEV1 60 - 69%
50 - 59%
<= 49%
 -
Definition: A finding based on test results that indicate a relative decrease in the fraction of the forced vital capacity that is exhaled in a specific number of seconds.
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate higher than normal levels of the enzyme gamma-glutamyltransferase in the blood specimen. GGT (gamma-
glutamyltransferase ) catalyzes the transfer of a gamma glutamyl group from a gamma glutamyl peptide to another peptide, amino acids or water.
Growth hormone abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
 -
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of growth hormone in a biological specimen.
Haptoglobin decreased
<LLN
 -
 -
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of haptoglobin in a blood specimen.
Hemoglobin increased
Increase in >0 - 2 gm/dL above
ULN or above baseline if
baseline is above ULN
Increase in >2 - 4 gm/dL above
ULN or above baseline if
baseline is above ULN
Increase in >4 gm/dL above
ULN or above baseline if
baseline is above ULN
 -
 -
Definition: A finding based on laboratory test results that indicate increased levels of hemoglobin in a biological specimen.
INR increased
>1 - 1.5 x ULN; >1 - 1.5 times
above baseline if on
anticoagulation
>1.5 - 2.5 x ULN; >1.5 - 2.5
times above baseline if on
anticoagulation
>2.5 x ULN; >2.5 times above
baseline if on anticoagulation
 -
 -
Definition: A finding based on laboratory test results that indicate an increase in the ratio of the patient's prothrombin time to a control sample in the blood.
Lipase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of lipase in a biological specimen.
Lymphocyte count decreased
 <LLN - 800/mm3; <LLN - 0.8 x
10e9 /L
<800 - 500/mm3; <0.8 - 0.5 x
10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x
10e9 /L
<200/mm3; <0.2 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of lymphocytes in a blood specimen.
Lymphocyte count increased
 -
>4000/mm3 - 20,000/mm3
>20,000/mm3
 -
 -
Definition: A finding based on laboratory test results that indicate an abnormal increase in the number of lymphocytes in the blood, effusions or bone marrow.
Neutrophil count decreased
<LLN - 1500/mm3; <LLN - 1.5 x
10e9 /L
<1500 - 1000/mm3; <1.5 - 1.0 x
10e9 /L
<1000 - 500/mm3; <1.0 - 0.5 x
10e9 /L
<500/mm3; <0.5 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of neutrophils in a blood specimen.
Pancreatic enzymes decreased
<LLN and asymptomatic
Increase in stool frequency,
bulk, or odor; steatorrhea
Sequelae of absorption
deficiency
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of pancreatic enzymes in a biological specimen.
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CTCAE 4.03 - June 14, 2010 : Investigations 
43
Investigations
Grade
Adverse Event
1
2
3
4
5
Platelet count decreased
<LLN - 75,000/mm3; <LLN -
75.0 x 10e9 /L
<75,000 - 50,000/mm3; <75.0 -
50.0 x 10e9 /L
<50,000 - 25,000/mm3; <50.0 -
25.0 x 10e9 /L
<25,000/mm3; <25.0 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.
Serum amylase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the levels of amylase in a serum specimen.
Urine output decreased
 -
 -
Oliguria (<80 ml in 8 hr)
Anuria (<240 ml in 24 hr)
 -
Definition: A finding based on test results that indicate urine production is less relative to previous output.
Vital capacity abnormal
90 - 75% of predicted value
<75 - 50% of predicted value;
limiting instrumental ADL
<50% of predicted value;
limiting self care ADL
 -
 -
Definition: A finding based on pulmonary function test results that indicate an abnormal vital capacity (amount of exhaled after a maximum inhalation) when compared to the predicted
value.
Weight gain
5 - <10% from baseline
10 - <20% from baseline
>=20% from baseline
 -
 -
Definition: A finding characterized by an increase in overall body weight; for pediatrics, greater than the baseline growth curve.
Weight loss
5 to <10% from baseline;
intervention not indicated
10 - <20% from baseline;
nutritional support indicated
>=20% from baseline; tube
feeding or TPN indicated
 -
 -
Definition: A finding characterized by a decrease in overall body weight; for pediatrics, less than the baseline growth curve.
White blood cell decreased
<LLN - 3000/mm3; <LLN - 3.0 x
10e9 /L
<3000 - 2000/mm3; <3.0 - 2.0 x
10e9 /L
<2000 - 1000/mm3; <2.0 - 1.0 x
10e9 /L
<1000/mm3; <1.0 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate an decrease in number of white blood cells in a blood specimen.
Investigations - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Metabolism and nutrition disorders 
44
15. Metabolism and nutrition disorders
Metabolism and nutrition disorders
Grade
Adverse Event
1
2
3
4
5
Acidosis
pH <normal, but >=7.3
 -
pH <7.3
Life-threatening consequences
Death
Definition: A disorder characterized by abnormally high acidity (high hydrogen-ion concentration) of the blood and other body tissues.
Alcohol intolerance
 -
Present
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in sensitivity to the adverse effects of alcohol, which can include nasal congestion, skin flushes, heart dysrhythmias, nausea,
vomiting, indigestion and headaches.
Alkalosis
pH >normal, but <=7.5
 -
pH >7.5
Life-threatening consequences
Death
Definition: A disorder characterized by abnormally high alkalinity (low hydrogen-ion concentration) of the blood and other body tissues.
Anorexia
Loss of appetite without
alteration in eating habits
Oral intake altered without
significant weight loss or
malnutrition; oral nutritional
supplements indicated
Associated with significant
weight loss or malnutrition (e.g.,
inadequate oral caloric and/or
fluid intake); tube feeding or
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a loss of appetite.
Dehydration
Increased oral fluids indicated;
dry mucous membranes;
diminished skin turgor
IV fluids indicated <24 hrs
IV fluids or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Glucose intolerance
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; dietary
modification or oral agent
indicated
Severe symptoms; insulin
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inability to properly metabolize glucose.
Hypercalcemia
Corrected serum calcium of
>ULN - 11.5 mg/dL; >ULN - 2.9
mmol/L;  Ionized calcium  >ULN
- 1.5 mmol/L
Corrected serum calcium of
>11.5 - 12.5 mg/dL; >2.9 - 3.1
mmol/L;  Ionized calcium >1.5 -
1.6 mmol/L; symptomatic
Corrected serum calcium of
>12.5 - 13.5 mg/dL; >3.1 - 3.4
mmol/L;  Ionized calcium  >1.6 -
1.8 mmol/L; hospitalization
indicated
Corrected serum calcium of
>13.5 mg/dL; >3.4 mmol/L;
Ionized calcium  >1.8 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of calcium (corrected for albumin) in blood.
Hyperglycemia
Fasting glucose value >ULN -
160 mg/dL; Fasting glucose
value >ULN - 8.9 mmol/L
Fasting glucose value >160 -
250 mg/dL; Fasting glucose
value >8.9 - 13.9 mmol/L
>250 - 500 mg/dL; >13.9 - 27.8
mmol/L; hospitalization
indicated
>500 mg/dL; >27.8 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of blood sugar. It is usually an indication of diabetes mellitus or glucose
intolerance.
Hyperkalemia
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L
>6.0 - 7.0 mmol/L;
hospitalization indicated
>7.0 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of potassium in the blood; associated with kidney failure or sometimes with
the use of diuretic drugs.
Hypermagnesemia
>ULN - 3.0 mg/dL; >ULN - 1.23
mmol/L
 -
>3.0 - 8.0 mg/dL; >1.23 - 3.30
mmol/L
>8.0 mg/dL; >3.30 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of magnesium in the  blood.
Hypernatremia
>ULN - 150 mmol/L
>150 - 155 mmol/L
>155 - 160 mmol/L;
hospitalization indicated
>160 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of sodium in the  blood.
Hypertriglyceridemia
150 mg/dL - 300 mg/dL; 1.71
mmol/L - 3.42 mmol/L
>300 mg/dL - 500 mg/dL;  >3.42
mmol/L - 5.7 mmol/L
>500 mg/dL - 1000 mg/dL;  >5.7
mmol/L - 11.4 mmol/L
>1000 mg/dL; >11.4 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of triglyceride concentration in the blood.
Hyperuricemia
>ULN - 10 mg/dL (0.59 mmol/L)
without physiologic
consequences
 -
>ULN - 10 mg/dL (0.59 mmol/L)
with physiologic consequences
>10 mg/dL; >0.59 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of uric acid.
Hypoalbuminemia
<LLN - 3 g/dL; <LLN - 30 g/L
<3 - 2 g/dL; <30 - 20 g/L
<2 g/dL; <20 g/L
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of albumin in the blood.
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CTCAE 4.03 - June 14, 2010 : Metabolism and nutrition disorders 
45
Metabolism and nutrition disorders
Grade
Adverse Event
1
2
3
4
5
Hypocalcemia
Corrected serum calcium of
<LLN - 8.0 mg/dL; <LLN - 2.0
mmol/L; Ionized calcium  <LLN -
1.0 mmol/L
Corrected serum calcium of
<8.0 - 7.0 mg/dL; <2.0 - 1.75
mmol/L; Ionized calcium  <1.0 -
0.9 mmol/L; symptomatic
Corrected serum calcium of
<7.0 - 6.0 mg/dL; <1.75 - 1.5
mmol/L;  Ionized calcium  <0.9 -
0.8 mmol/L; hospitalization
indicated
Corrected serum calcium of
<6.0 mg/dL; <1.5 mmol/L;
Ionized calcium  <0.8 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of calcium (corrected for albumin) in the  blood.
Hypoglycemia
<LLN - 55 mg/dL; <LLN - 3.0
mmol/L
<55 - 40 mg/dL; <3.0 - 2.2
mmol/L
<40 - 30 mg/dL; <2.2 - 1.7
mmol/L
<30 mg/dL; <1.7 mmol/L; life-
threatening consequences;
seizures
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of glucose in the blood.
Hypokalemia
<LLN - 3.0 mmol/L
<LLN - 3.0 mmol/L;
symptomatic; intervention
indicated
<3.0 - 2.5 mmol/L;
hospitalization indicated
<2.5 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of potassium in the  blood.
Hypomagnesemia
<LLN - 1.2 mg/dL; <LLN - 0.5
mmol/L
<1.2 - 0.9 mg/dL; <0.5 - 0.4
mmol/L
<0.9 - 0.7 mg/dL; <0.4 - 0.3
mmol/L
<0.7 mg/dL; <0.3 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of magnesium in the  blood.
Hyponatremia
<LLN - 130 mmol/L
 -
<130 - 120 mmol/L
<120 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of sodium in the blood.
Hypophosphatemia
<LLN - 2.5 mg/dL; <LLN - 0.8
mmol/L
<2.5 - 2.0 mg/dL; <0.8 - 0.6
mmol/L
<2.0 - 1.0 mg/dL; <0.6 - 0.3
mmol/L
<1.0 mg/dL; <0.3 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of phosphates in the  blood.
Iron overload
 -
Moderate symptoms;
intervention not indicated
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by accumulation of iron in the tissues.
Obesity
 -
BMI 25 - 29.9 kg/m2
BMI 30 - 39.9 kg/m2
BMI >=40 kg/m2
 -
Definition: A disorder characterized by having a high amount of body fat.
Tumor lysis syndrome
 -
 -
Present
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by metabolic abnormalities that result from a spontaneous or therapy-related cytolysis of tumor cells.
Metabolism and nutrition
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
46
16. Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Abdominal soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g. tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the abdominal wall.
Arthralgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in a joint.
Arthritis
Mild pain with inflammation,
erythema, or joint swelling
Moderate pain associated with
signs of inflammation,
erythema, or joint swelling;
limiting instrumental ADL
Severe pain associated with
signs of inflammation,
erythema, or joint swelling;
irreversible joint damage;
disabling; limiting self care ADL
 -
 -
Definition: A disorder characterized by inflammation involving a joint.
Avascular necrosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by necrotic changes in the bone tissue due to interruption of blood supply. Most often affecting the epiphysis of the long bones, the necrotic
changes result in the collapse and the destruction of the bone structure.
Back pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the back region.
Bone pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the bones.
Buttock pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the buttocks.
Chest wall pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the chest wall region.
Exostosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by non-neoplastic overgrowth of bone.
Fibrosis deep connective tissue
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration; unable to
slide or pinch skin; limiting joint
or orifice movement (e.g.
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by fibrotic degeneration of the deep connective tissues.
Flank pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation on the lateral side of the body in the region below the ribs and above the hip.
Generalized muscle weakness
Symptomatic; weakness
perceived by patient but not
evident on physical exam
Symptomatic; weakness evident
on physical exam; weakness
limiting instrumental ADL
Weakness limiting self care
ADL; disabling
 -
 -
Definition: A disorder characterized by a reduction in the strength of muscles in multiple anatomic sites.
Growth suppression
Reduction in growth velocity by
10 - 29% ideally measured over
the period of a year
Reduction in growth velocity by
30 - 49% ideally measured over
the period of a year or 0 - 49%
reduction in growth from the
baseline growth curve
Reduction in growth velocity of
>=50% ideally measured over
the period of a year
 -
 -
Definition: A disorder characterized by of stature that is smaller than normal as expected for age.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
47
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Head soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the head.
Joint effusion
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated; disabling
 -
 -
Definition: A disorder characterized by excessive fluid in a joint, usually as a result of joint inflammation.
Joint range of motion decreased <=25% loss of ROM (range of
motion); decreased ROM
limiting athletic activity
>25 - 50% decrease in ROM;
limiting instrumental ADL
>50% decrease in ROM; limiting
self care ADL; disabling
 -
 -
Definition: A disorder characterized by a decrease in joint flexibility of any joint.
Joint range of motion decreased
cervical spine
Mild restriction of rotation or
flexion between 60 - 70 degrees
Rotation <60 degrees to right or
left; <60 degrees of flexion
Ankylosed/fused over multiple
segments with no C-spine
rotation
 -
 -
Definition: A disorder characterized by a decrease in flexibility of a cervical spine joint.
Joint range of motion decreased
lumbar spine
Stiffness; difficulty bending to
the floor to pick up a very light
object but able to do athletic
activity
Pain with range of motion
(ROM) in lumbar spine; requires
a reaching aid to pick up a very
light object from the floor
<50% lumbar spine flexion;
associated with symptoms of
ankylosis or fused over multiple
segments with no L-spine
flexion (e.g., unable to reach to
floor to pick up a very light
object)
 -
 -
Definition: A disorder characterized by a decrease in flexibility of a lumbar spine joint.
Kyphosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate accentuation; limiting
instrumental ADL
Severe accentuation; operative
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an abnormal increase in the curvature of the thoracic portion of the spine.
Lordosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate accentuation; limiting
instrumental ADL
Severe accentuation; operative
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an abnormal increase in the curvature of the lumbar portion of the spine.
Muscle weakness left-sided
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the muscles on the left side of the body.
Muscle weakness lower limb
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the lower limb muscles.
Muscle weakness right-sided
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the muscles on the right side of the body.
Muscle weakness trunk
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the trunk muscles.
Muscle weakness upper limb
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the upper limb muscles.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
48
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Musculoskeletal deformity
Cosmetically and functionally
insignificant hypoplasia
Deformity, hypoplasia, or
asymmetry able to be
remediated by prosthesis (e.g.,
shoe insert) or covered by
clothing
Significant deformity,
hypoplasia, or asymmetry,
unable to be remediated by
prosthesis or covered by
clothing; disabling
 -
 -
Definition: A disorder characterized by of a malformation of the musculoskeletal system.
Myalgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation originating from a muscle or group of muscles.
Myositis
Mild pain
Moderate pain associated with
weakness; pain limiting
instrumental ADL
Pain associated with severe
weakness; limiting self care
ADL
 -
 -
Definition: A disorder characterized by inflammation involving the skeletal muscles.
Neck pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the neck area.
Neck soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the neck.
Osteonecrosis of jaw
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the bone of the mandible.
Osteoporosis
Radiologic evidence of
osteoporosis or Bone Mineral
Density (BMD) t-score -1 to -2.5
(osteopenia); no loss of height
or intervention indicated
BMD t-score <-2.5; loss of
height <2 cm; anti-osteoporotic
therapy indicated; limiting
instrumental ADL
Loss of height >=2 cm;
hospitalization indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by reduced bone mass, with a decrease in cortical thickness and in the number and size of the trabeculae of cancellous bone (but normal chemical
composition), resulting in increased fracture incidence.
Pain in extremity
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the upper or lower extremities.
Pelvic soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the pelvis.
Scoliosis
<20 degrees; clinically
undetectable
>20 - 45 degrees; visible by
forward flexion; limiting
instrumental ADL
>45 degrees; scapular
prominence in forward flexion;
operative intervention indicated;
limiting self care ADL; disabling
 -
 -
Definition: A disorder characterized by a malformed, lateral curvature of the spine.
Soft tissue necrosis lower limb
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the lower extremity.
Soft tissue necrosis upper limb
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the upper extremity.
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CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
49
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Superficial soft tissue fibrosis
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration; unable to
slide or pinch skin; limiting joint
or orifice movement (e.g.,
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by fibrotic degeneration of the superficial soft tissues.
Trismus
Decreased ROM (range of
motion) without impaired eating
Decreased ROM requiring small
bites, soft foods or purees
Decreased ROM with inability to
adequately aliment or hydrate
orally
 -
 -
Definition: A disorder characterized by lack of ability to open the mouth fully due to a decrease in the range of motion of the muscles of mastication.
Unequal limb length
Mild length discrepancy <2 cm
Moderate length discrepancy 2 -
5 cm; shoe lift indicated; limiting
instrumental ADL
Severe length discrepancy >5
cm; limiting self care ADL;
disabling; operative intervention
indicated
 -
 -
Definition: A disorder characterized by of a discrepancy between the lengths of the lower or upper extremities.
Musculoskeletal and connective
tissue disorder -  Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
50
17. Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Grade
Adverse Event
1
2
3
4
5
Leukemia secondary to
oncology chemotherapy
 -
 -
 -
Present
Death
Definition: A disorder characterized by leukemia arising as a result of the mutagenic effect of chemotherapy agents.
Myelodysplastic syndrome
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by insufficiently healthy hematapoietic cell production by the bone marrow.
Treatment related secondary
malignancy
 -
 -
Non life-threatening secondary
malignancy
Acute life-threatening secondary
malignancy; blast crisis in
leukemia
Death
Definition: A disorder characterized by development of a malignancy most probably as a result of treatment for a previously existing malignancy.
Tumor pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort from a neoplasm that may be pressing on a nerve, blocking blood vessels, inflamed or fractured from metastasis.
Neoplasms benign, malignant
and unspecified (incl cysts and
polyps) - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
51
18. Nervous system disorders
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Abducens nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the abducens nerve (sixth cranial nerve).
Accessory nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the accessory nerve (eleventh cranial nerve).
Acoustic nerve disorder NOS
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the acoustic nerve (eighth cranial nerve).
Akathisia
Mild restlessness or increased
motor activity
Moderate restlessness or
increased motor activity; limiting
instrumental ADL
Severe restlessness or
increased motor activity; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an uncomfortable feeling of inner restlessness and inability to stay still; this is a side effect of some psychotropic drugs.
Amnesia
Mild; transient memory loss
Moderate; short term memory
loss; limiting instrumental ADL
Severe; long term memory loss;
limiting self care ADL
 -
 -
Definition: A disorder characterized by systematic and extensive loss of memory.
Aphonia
 -
 -
Voicelessness; unable to speak
 -
 -
Definition: A disorder characterized by the inability to speak. It may result from injuries to the vocal cords or may be functional (psychogenic).
Arachnoiditis
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the arachnoid membrane and adjacent subarachnoid space.
Ataxia
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; mechanical
assistance indicated
 -
 -
Definition: A disorder characterized by lack of coordination of muscle movements resulting in the impairment or inability to perform voluntary activities.
Brachial plexopathy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by regional paresthesia of the brachial plexus, marked discomfort and muscle weakness, and limited movement in the arm or hand.
Central nervous system
necrosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms;
corticosteroids indicated
Severe symptoms; medical
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the brain and/or spinal cord.
Cerebrospinal fluid leakage
Post-craniotomy: asymptomatic;
Post-lumbar puncture: transient
headache; postural care
indicated
Post-craniotomy: moderate
symptoms; medical intervention
indicated; Post-lumbar
puncture: persistent moderate
symptoms; blood patch
indicated
Severe symptoms; medical
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by loss of cerebrospinal fluid into the surrounding tissues.
Cognitive disturbance
Mild cognitive disability; not
interfering with work/school/life
performance; specialized
educational services/devices
not indicated
Moderate cognitive disability;
interfering with work/school/life
performance but capable of
independent living; specialized
resources on part time basis
indicated
Severe cognitive disability;
significant impairment of
work/school/life performance
 -
 -
Definition: A disorder characterized by a conspicuous change in cognitive function.
Concentration impairment
Mild inattention or decreased
level of concentration
Moderate impairment in
attention or decreased level of
concentration; limiting
instrumental ADL
Severe impairment in attention
or decreased level of
concentration; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a deterioration in the ability to concentrate.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
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Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Depressed level of
consciousness
Decreased level of alertness
Sedation; slow response to
stimuli; limiting instrumental
ADL
Difficult to arouse
Life-threatening consequences
Death
Definition: A disorder characterized by a decrease in ability to perceive and respond.
Dizziness
Mild unsteadiness or sensation
of movement
Moderate unsteadiness or
sensation of movement; limiting
instrumental ADL
Severe unsteadiness or
sensation of movement; limiting
self care ADL
 -
 -
Definition: A disorder characterized by a disturbing sensation of lightheadedness, unsteadiness, giddiness, spinning or rocking.
Dysarthria
Mild slurred speech
Moderate impairment of
articulation or slurred speech
Severe impairment of
articulation or slurred speech
 -
 -
Definition: A disorder characterized by slow and slurred speech resulting from an inability to coordinate the muscles used in speech.
Dysesthesia
Mild sensory alteration
Moderate sensory alteration;
limiting instrumental ADL
Severe sensory alteration;
limiting self care ADL
 -
 -
Definition: A disorder characterized by distortion of sensory perception, resulting in an abnormal and unpleasant sensation.
Dysgeusia
Altered taste but no change in
diet
Altered taste with change in diet
(e.g., oral supplements);
noxious or unpleasant taste;
loss of taste
 -
 -
 -
Definition: A disorder characterized by abnormal sensual experience with the taste of foodstuffs; it can be related to a decrease in the sense of smell.
Dysphasia
Awareness of receptive or
expressive characteristics; not
impairing ability to communicate
Moderate receptive or
expressive characteristics;
impairing ability to communicate
spontaneously
Severe receptive or expressive
characteristics; impairing ability
to read, write or communicate
intelligibly
 -
 -
Definition: A disorder characterized by impairment of verbal communication skills, often resulting from brain damage.
Edema cerebral
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the brain.
Encephalopathy
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a pathologic process involving the brain.
Extrapyramidal disorder
Mild involuntary movements
Moderate involuntary
movements; limiting
instrumental ADL
Severe involuntary movements
or torticollis; limiting self care
ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormal, repetitive, involuntary muscle movements, frenzied speech and extreme restlessness.
Facial muscle weakness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a reduction in the strength of the facial muscles.
Facial nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the facial nerve (seventh cranial nerve).
Glossopharyngeal nerve
disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the glossopharyngeal nerve (ninth cranial nerve).
Headache
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in various parts of the head, not confined to the area of distribution of any nerve.
Hydrocephalus
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms;
intervention not indicated
Severe symptoms or
neurological deficit; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal increase of cerebrospinal fluid in the ventricles of the brain.
Hypersomnia
Mild increased need for sleep
Moderate increased need for
sleep
Severe increased need for
sleep
 -
 -
Definition: A disorder characterized by characterized by excessive sleepiness during the daytime.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
53
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Hypoglossal nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the hypoglossal nerve (twelfth cranial nerve).
Intracranial hemorrhage
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Ventriculostomy, ICP
monitoring, intraventricular
thrombolysis, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the cranium.
Ischemia cerebrovascular
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms
 -
 -
 -
Definition: A disorder characterized by a decrease or absence of blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurological
damage.
IVth nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the trochlear nerve (fourth cranial nerve).
Lethargy
Mild symptoms; reduced
alertness and awareness
Moderate symptoms; limiting
instrumental ADL
 -
 -
 -
Definition: A disorder characterized by a decrease in consciousness characterized by mental and physical inertness.
Leukoencephalopathy
Asymptomatic; small focal
T2/FLAIR hyperintensities;
involving periventricular white
matter or <1/3 of susceptible
areas of cerebrum +/- mild
increase in subarachnoid space
(SAS) and/or mild
ventriculomegaly
Moderate symptoms; focal
T2/FLAIR hyperintensities,
involving periventricular white
matter extending into centrum
semiovale or involving 1/3 to 2/3
of susceptible areas of
cerebrum +/- moderate increase
in SAS and/or moderate
ventriculomegaly
Severe symptoms; extensive
T2/FLAIR hyperintensities,
involving periventricular white
matter involving 2/3 or more of
susceptible areas of cerebrum
+/- moderate to severe increase
in SAS and/or moderate to
severe ventriculomegaly
Life-threatening consequences;
extensive T2/FLAIR
hyperintensities, involving
periventricular white matter
involving most of susceptible
areas of cerebrum +/- moderate
to severe increase in SAS
and/or moderate to severe
ventriculomegaly
Death
Definition: A disorder characterized by diffuse reactive astrocytosis with multiple areas of necrotic foci without inflammation.
Memory impairment
Mild memory impairment
Moderate memory impairment;
limiting instrumental ADL
Severe memory impairment;
limiting self care ADL
 -
 -
Definition: A disorder characterized by a deterioration in memory function.
Meningismus
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by neck stiffness, headache, and photophobia resulting from irritation of the cerebral meninges.
Movements involuntary
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by uncontrolled and purposeless movements.
Myelitis
Asymptomatic; mild signs (e.g.,
Babinski's reflex or Lhermitte's
sign)
Moderate weakness or sensory
loss; limiting instrumental ADL
Severe weakness or sensory
loss; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving the spinal cord. Symptoms include weakness, paresthesia, sensory loss, marked discomfort and incontinence.
Neuralgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by intense painful sensation along a nerve or group of nerves.
Nystagmus
 -
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involuntary movements of the eyeballs.
Oculomotor nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the oculomotor nerve (third cranial nerve).
Olfactory nerve disorder
 -
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the olfactory nerve (first cranial nerve).
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
54
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Paresthesia
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by functional disturbances of sensory neurons resulting in abnormal cutaneous sensations of tingling, numbness, pressure, cold, and warmth that
are experienced in the absence of a stimulus.
Peripheral motor neuropathy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; assistive device
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation or degeneration of the peripheral motor nerves.
Peripheral sensory neuropathy
Asymptomatic; loss of deep
tendon reflexes or paresthesia
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation or degeneration of the peripheral sensory nerves.
Phantom pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort related to a limb or an organ that is removed from or is not physically part of the body.
Presyncope
 -
Present (e.g., near fainting)
 -
 -
 -
Definition: A disorder characterized by an episode of lightheadedness and dizziness which may precede an episode of syncope.
Pyramidal tract syndrome
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by dysfunction of the corticospinal (pyramidal) tracts of the spinal cord. Symptoms include  an increase in the muscle tone in the lower extremities,
hyperreflexia, positive Babinski and a decrease in fine motor coordination.
Radiculitis
Mild symptoms
Moderate symptoms; limiting
instrumental ADL; medical
intervention indicated
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving a nerve root. Patients experience marked discomfort radiating along a nerve path because of spinal pressure on the
connecting nerve root.
Recurrent laryngeal nerve palsy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms
Severe symptoms; medical
intervention indicated (e.g.,
thyroplasty, vocal cord injection)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by paralysis of the recurrent laryngeal nerve.
Reversible posterior
leukoencephalopathy syndrome
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; abnormal
imaging studies; limiting
instrumental ADL
Severe symptoms; very
abnormal imaging studies;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by headaches, mental status changes, visual disturbances, and seizures associated with imaging findings of posterior leukoencephalopathy. It has
been observed in association with hypertensive encephalopathy, eclampsia, and immunosuppressive and cytotoxic drug treatment. It is an acute or subacute reversible condition.
Seizure
Brief partial seizure; no loss of
consciousness
Brief generalized seizure
Multiple seizures despite
medical intervention
Life-threatening; prolonged
repetitive seizures
Death
Definition: A disorder characterized by a sudden, involuntary skeletal muscular contractions of cerebral or brain stem origin.
Sinus pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort in the face, between the eyes, or upper teeth originating from the sinuses.
Somnolence
Mild but more than usual
drowsiness or sleepiness
Moderate sedation; limiting
instrumental ADL
Obtundation or stupor
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by characterized by excessive sleepiness and drowsiness.
Spasticity
Mild or slight increase in muscle
tone
Moderate increase in muscle
tone and increase in resistance
through range of motion
Severe increase in muscle tone
and increase in resistance
through range of motion
Life-threatening; unable to move
active or passive range of
motion
Death
Definition: A disorder characterized by increased involuntary muscle tone that affects the regions interfering with voluntary movement. It results in gait, movement, and speech
disturbances.
Stroke
Asymptomatic or mild
neurologic deficit; radiographic
findings only
Moderate neurologic deficit
Severe neurologic deficit
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a sudden loss of sensory function due to an intracranial vascular event.
Syncope
 -
 -
Fainting; orthostatic collapse
 -
 -
Definition: A disorder characterized by spontaneous loss of consciousness caused by insufficient blood supply to the brain.
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CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
55
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Transient ischemic attacks
Mild neurologic deficit with or
without imaging confirmation
Moderate neurologic deficit with
or without imaging confirmation
 -
 -
 -
Definition: A disorder characterized by a brief attack (less than 24 hours) of cerebral dysfunction of vascular origin, with no persistent neurological deficit.
Tremor
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by the uncontrolled shaking movement of the whole body or individual parts.
Trigeminal nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the trigeminal nerve (fifth cranial nerve).
Vagus nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the vagus nerve (tenth cranial nerve).
Vasovagal reaction
 -
 -
Present
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a sudden drop of the blood pressure, bradycardia, and peripheral vasodilation that may lead to loss of consciousness. It results from an
increase in the stimulation of the vagus nerve.
Nervous system disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Pregnancy, puerperium and perinatal conditions 
56
19. Pregnancy, puerperium and perinatal conditions
Pregnancy, puerperium and perinatal conditions
Grade
Adverse Event
1
2
3
4
5
Fetal death
 -
 -
 -
 -
Fetal loss at
any
gestational
age
Definition: A disorder characterized by death in utero; failure of the product of conception to show evidence of respiration, heartbeat, or definite movement of a voluntary muscle after
expulsion from the uterus, without possibility of resuscitation.
Fetal growth retardation
 -
<10% percentile of weight for
gestational age
<5% percentile of weight for
gestational age
<1% percentile of weight for
gestational age
 -
Definition: A disorder characterized by inhibition of fetal growth resulting in the inability of the fetus to achieve its potential weight.
Premature delivery
Delivery of a liveborn infant at
>34 to 37 weeks gestation
Delivery of a liveborn infant at
>28 to 34 weeks gestation
Delivery of a liveborn infant at
24 to 28 weeks gestation
Delivery of a liveborn infant at
24 weeks of gestation or less
 -
Definition: A disorder characterized by delivery of a viable infant before the normal end of gestation. Typically, viability is achievable between the twentieth and thirty-seventh week of
gestation.
Unintended pregnancy
 -
 -
Unintended pregnancy
 -
 -
Definition: A disorder characterized by an unexpected pregnancy at the time of conception.
Pregnancy, puerperium and
perinatal conditions - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate, local or noninvasive
intervention indicated; limiting
instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Psychiatric disorders 
57
20. Psychiatric disorders
Psychiatric disorders
Grade
Adverse Event
1
2
3
4
5
Agitation
Mild mood alteration
Moderate mood alteration
Severe agitation; hospitalization
not indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a state of restlessness associated with unpleasant feelings of irritability and tension.
Anorgasmia
Inability to achieve orgasm not
adversely affecting relationship
Inability to achieve orgasm
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by an inability to achieve orgasm.
Anxiety
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization not
indicated
Life-threatening; hospitalization
indicated
Death
Definition: A disorder characterized by apprehension of danger and dread accompanied by restlessness, tension, tachycardia, and dyspnea unattached to a clearly identifiable
stimulus.
Confusion
Mild disorientation
Moderate disorientation; limiting
instrumental ADL
Severe disorientation; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a lack of clear and orderly thought and behavior.
Delayed orgasm
Delay in achieving orgasm not
adversely affecting relationship
Delay in achieving orgasm
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by sexual dysfunction characterized by a delay in climax.
Delirium
Mild acute confusional state
Moderate and acute confusional
state; limiting instrumental ADL
Severe and acute confusional
state; limiting self care ADL;
hospitalization indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by the acute and sudden development of confusion, illusions, movement changes, inattentiveness, agitation, and hallucinations. Usually, it is a
reversible condition.
Delusions
 -
Moderate delusional symptoms
Severe delusional symptoms;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by false personal beliefs held contrary to reality, despite contradictory evidence and common sense.
Depression
Mild depressive symptoms
Moderate depressive
symptoms; limiting instrumental
ADL
Severe depressive symptoms;
limiting self care ADL;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by melancholic feelings of grief or unhappiness.
Euphoria
Mild mood elevation
Moderate mood elevation
Severe mood elevation (e.g.,
hypomania)
 -
 -
Definition: A disorder characterized by an exaggerated feeling of well-being which is disproportionate to events and stimuli.
Hallucinations
Mild hallucinations (e.g.,
perceptual distortions)
Moderate hallucinations
Severe hallucinations;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by a false sensory perception in the absence of an external stimulus.
Insomnia
Mild difficulty falling asleep,
staying asleep or waking up
early
Moderate difficulty falling
asleep, staying asleep or
waking up early
Severe difficulty in falling
asleep, staying asleep or
waking up early
 -
 -
Definition: A disorder characterized by difficulty in falling asleep and/or remaining asleep.
Libido decreased
Decrease in sexual interest not
adversely affecting relationship
Decrease in sexual interest
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by a decrease in sexual desire.
Libido increased
Mild increase in sexual interest
not adversely affecting
relationship
Moderate increase in sexual
interest adversely affecting
relationship
Severe increase in sexual
interest leading to dangerous
behavior
 -
 -
Definition: A disorder characterized by an increase in sexual desire.
Mania
Mild manic symptoms (e.g.,
elevated mood, rapid thoughts,
rapid speech, decreased need
for sleep)
Moderate manic symptoms
(e.g., relationship and work
difficulties; poor hygiene)
Severe manic symptoms (e.g.,
hypomania; major sexual or
financial indiscretions);
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behavior and elevation of mood.
Personality change
Mild personality change
Moderate personality change
Severe personality change;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
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CTCAE 4.03 - June 14, 2010 : Psychiatric disorders 
58
Psychiatric disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by a conspicuous change in a person's behavior and thinking.
Psychosis
Mild psychotic symptoms
Moderate psychotic symptoms
(e.g., disorganized speech;
impaired reality testing)
Severe psychotic symptoms
(e.g., paranoid; extreme
disorganization); hospitalization
not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by personality change, impaired functioning, and loss of touch with reality. It may be a manifestation of schizophrenia, bipolar disorder or brain
tumor.
Restlessness
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an inability to rest, relax or be still.
Suicidal ideation
Increased thoughts of death but
no wish to kill oneself
Suicidal ideation with no specific
plan or intent
Specific plan to commit suicide
without serious intent to die
which may not require
hospitalization
Specific plan to commit suicide
with serious intent to die which
requires hospitalization
 -
Definition: A disorder characterized by thoughts of taking one's own life.
Suicide attempt
 -
 -
Suicide attempt or gesture
without intent to die which may
not require hospitalization
Suicide attempt with intent to
die which requires
hospitalization
Death
Definition: A disorder characterized by self-inflicted harm in an attempt to end one's own life.
Psychiatric disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; disabling;  limiting
self care ADL
Life-threatening consequences;
hospitalization or urgent
intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Renal and urinary disorders 
59
21. Renal and urinary disorders
Renal and urinary disorders
Grade
Adverse Event
1
2
3
4
5
Acute kidney injury
Creatinine level increase of >0.3
mg/dL; creatinine 1.5 - 2.0 x
above baseline
Creatinine 2 - 3 x above
baseline
Creatinine >3 x baseline or >4.0
mg/dL; hospitalization indicated
Life-threatening consequences;
dialysis indicated
Death
Definition: A disorder characterized by the acute loss of renal function and is traditionally classified as pre-renal (low blood flow into kidney), renal (kidney damage) and post-renal
causes (ureteral or bladder outflow obstruction).
Bladder perforation
 -
Extraperitoneal perforation,
indwelling catheter indicated
Intraperitoneal perforation;
elective radiologic, endoscopic
or operative intervention
indicated
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A disorder characterized by a rupture in the bladder wall.
Bladder spasm
Intervention not indicated
Antispasmodics indicated
Hospitalization indicated
 -
 -
Definition: A disorder characterized by a sudden and involuntary contraction of the bladder wall.
Chronic kidney disease
eGFR (estimated Glomerular
Filtration Rate) or CrCl
(creatinine clearance) <LLN - 60
ml/min/1.73 m2 or proteinuria
2+ present; urine
protein/creatinine >0.5
eGFR or CrCl 59 - 30
ml/min/1.73 m2
eGFR or CrCl 29 - 15
ml/min/1.73 m2
eGFR or CrCl <15 ml/min/1.73
m2; dialysis or renal transplant
indicated
Death
Definition: A disorder characterized by gradual and usually permanent loss of kidney function resulting in renal failure.
Cystitis noninfective
Microscopic hematuria; minimal
increase in frequency, urgency,
dysuria, or nocturia; new onset
of incontinence
Moderate hematuria; moderate
increase in frequency, urgency,
dysuria, nocturia or
incontinence; urinary catheter
placement or bladder irrigation
indicated; limiting instrumental
ADL
Gross hematuria; transfusion, IV
medications or hospitalization
indicated; elective endoscopic,
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by inflammation of the bladder which is not caused by an infection of the urinary tract.
Hematuria
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; urinary catheter
or bladder irrigation indicated;
limiting instrumental ADL
Gross hematuria; transfusion, IV
medications or hospitalization
indicated; elective endoscopic,
radiologic or operative
intervention indicated; limiting
self care ADL
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate blood in the urine.
Hemoglobinuria
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by laboratory test results that indicate the presence of free hemoglobin in the urine.
Proteinuria
1+ proteinuria; urinary protein
<1.0 g/24 hrs
Adults: 2+ proteinuria; urinary
protein 1.0 - 3.4 g/24 hrs;
Pediatric: urine P/C
(Protein/Creatinine) ratio 0.5 -
1.9
Adults: urinary protein >=3.5
g/24 hrs;
Pediatric: urine P/C >1.9
 -
 -
Definition: A disorder characterized by laboratory test results that indicate the presence of excessive protein in the urine. It is predominantly albumin, but also globulin.
Renal calculi
Asymptomatic or mild
symptoms; occasional use of
nonprescription analgesics
indicated
Symptomatic; oral antiemetics
indicated; around the clock
nonprescription analgesics or
any oral narcotic analgesics
indicated
Hospitalization indicated; IV
intervention (e.g., analgesics,
antiemetics); elective
endoscopic or radiologic
intervention indicated
Life-threatening consequences;
urgent radiologic, endoscopic or
operative intervention indicated
Death
Definition: A disorder characterized by the formation of crystals in the pelvis of the kidney.
Renal colic
Mild pain not interfering with
activity; nonprescription
medication indicated
Moderate pain; limiting
instrumental ADL; prescription
medication indicated
Hospitalization indicated;
limiting self care ADL
 -
 -
Definition: A disorder characterized by paroxysmal and severe flank marked discomfort radiating to the inguinal area. Often, the cause is the passage of kidney stones.
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CTCAE 4.03 - June 14, 2010 : Renal and urinary disorders 
60
Renal and urinary disorders
Grade
Adverse Event
1
2
3
4
5
Renal hemorrhage
Mild symptoms; intervention not
indicated
Analgesics and hematocrit
monitoring indicated
Transfusion, radiation, or
hospitalization indicated;
elective radiologic, endoscopic
or operative intervention
indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by bleeding from the kidney.
Urinary fistula
 -
Noninvasive intervention
indicated; urinary or suprapubic
catheter placement indicated
Limiting self care ADL; elective
radiologic, endoscopic or
operative intervention indicated;
permanent urinary diversion
indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between any part of the urinary system and another organ or anatomic site.
Urinary frequency
Present
Limiting instrumental ADL;
medical management indicated
 -
 -
 -
Definition: A disorder characterized by urination at short intervals.
Urinary incontinence
Occasional (e.g., with coughing,
sneezing, etc.), pads not
indicated
Spontaneous; pads indicated;
limiting instrumental ADL
Intervention indicated (e.g.,
clamp, collagen injections);
operative intervention indicated;
limiting self care ADL
 -
 -
Definition: A disorder characterized by inability to control the flow of urine from the bladder.
Urinary retention
Urinary, suprapubic or
intermittent catheter placement
not indicated; able to void with
some residual
Placement of urinary,
suprapubic or intermittent
catheter placement indicated;
medication indicated
Elective operative or radiologic
intervention indicated;
substantial loss of affected
kidney function or mass
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A disorder characterized by accumulation of urine within the bladder because of the inability to urinate.
Urinary tract obstruction
Asymptomatic; clinical or
diagnostic observations only
Symptomatic but no
hydronephrosis, sepsis or renal
dysfunction; urethral dilation,
urinary or suprapubic catheter
indicated
Symptomatic and altered organ
function (e.g., hydronephrosis,
or renal dysfunction); elective
radiologic, endoscopic or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the normal flow of contents of the urinary tract.
Urinary tract pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the urinary tract.
Urinary urgency
Present
Limiting instrumental ADL;
medical management indicated
 -
 -
 -
Definition: A disorder characterized by a sudden compelling urge to urinate.
Urine discoloration
Present
 -
 -
 -
 -
Definition: A disorder characterized by a change in the color of the urine.
Renal and urinary disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate, local or noninvasive
intervention indicated; limiting
instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
61
22. Reproductive system and breast disorders
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Azoospermia
 -
 -
Absence of sperm in ejaculate
 -
 -
Definition: A disorder characterized by laboratory test results that indicate complete absence of spermatozoa in the semen.
Breast atrophy
Minimal asymmetry; minimal
atrophy
Moderate asymmetry; moderate
atrophy
Asymmetry >1/3 of breast
volume; severe atrophy
 -
 -
Definition: A disorder characterized by underdevelopment of the breast.
Breast pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the breast region.
Dysmenorrhea
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by abnormally painful abdominal cramps during menses.
Dyspareunia
Mild discomfort or pain
associated with vaginal
penetration; discomfort relieved
with use of vaginal lubricants or
estrogen
Moderate discomfort or pain
associated with vaginal
penetration; discomfort or pain
partially relieved with use of
vaginal lubricants or estrogen
Severe discomfort or pain
associated with vaginal
penetration; discomfort or pain
unrelieved by vaginal lubricants
or estrogen
 -
 -
Definition: A disorder characterized by painful or difficult coitus.
Ejaculation disorder
Diminished ejaculation
Anejaculation or retrograde
ejaculation
 -
 -
 -
Definition: A disorder characterized by problems related to ejaculation. This category includes premature, delayed, retrograde and painful ejaculation.
Erectile dysfunction
Decrease in erectile function
(frequency or rigidity of
erections) but intervention not
indicated (e.g., medication or
use of mechanical device,
penile pump)
Decrease in erectile function
(frequency/rigidity of erections),
erectile intervention indicated,
(e.g., medication or mechanical
devices such as penile pump)
Decrease in erectile function
(frequency/rigidity of erections)
but erectile intervention not
helpful (e.g., medication or
mechanical devices such as
penile pump); placement of a
permanent penile prosthesis
indicated (not previously
present)
 -
 -
Definition: A disorder characterized by the persistent or recurrent inability to achieve or to maintain an erection during sexual activity.
Fallopian tube obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the normal flow of the contents in the fallopian tube.
Fallopian tube stenosis
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated (e.g., organ resection)
Death
Definition: A disorder characterized by a narrowing of the fallopian tube lumen.
Female genital tract fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between a female reproductive system organ and another organ or anatomic site.
Feminization acquired
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by the development of secondary female sex characteristics in males due to extrinsic factors.
Genital edema
Mild swelling or obscuration of
anatomic architecture on close
inspection
Readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour
Lymphorrhea; gross deviation
from normal anatomic contour;
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the genitals.
Gynecomastia
Asymptomatic breast
enlargement
Symptomatic (e.g., pain or
psychosocial impact)
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by excessive development of the breasts in males.
Hematosalpinx
Minimal bleeding identified on
imaging study or laparoscopy;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by the presence of blood in a fallopian tube.
Irregular menstruation
Intermittent menses with
skipped menses for no more
than 1 to 3 months
Intermittent menses with
skipped menses for more than 4
to 6 months
Persistent amenorrhea for more
than 6 months
 -
 -
Definition: A disorder characterized by irregular cycle or duration of menses.
Lactation disorder
Mild changes in lactation, not
significantly affecting production
or expression of breast milk
Changes in lactation,
significantly affecting breast
production or expression of
breast milk
 -
 -
 -
Definition: A disorder characterized by disturbances of milk secretion. It is not necessarily related to pregnancy that is observed in females and can be observed in males.
Menorrhagia
Mild; iron supplements indicated Moderate symptoms; medical
intervention indicated (e.g.,
hormones)
Severe; transfusion indicated;
surgical intervention indicated
(e.g., hysterectomy)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormally heavy vaginal bleeding during menses.
Nipple deformity
Asymptomatic; asymmetry with
slight retraction and/or
thickening of the nipple areolar
complex
Symptomatic; asymmetry of
nipple areolar complex with
moderate retraction and/or
thickening of the nipple areolar
complex
 -
 -
 -
Definition: A disorder characterized by a malformation of the nipple.
Oligospermia
Sperm concentration >48
million/mL or motility >68%
Sperm concentration 13 - 48
million/mL or motility 32 - 68%
Sperm concentration <13
million/mL or motility <32%
 -
 -
Definition: A disorder characterized by a decrease in the number of spermatozoa in the semen.
Ovarian hemorrhage
Minimal bleeding identified on
imaging study or laproscopy;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic  intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the ovary.
Ovarian rupture
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by tearing or disruption of the ovarian tissue.
Ovulation pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in one side of the abdomen between menstrual cycles, around the time of the discharge of the ovum from the
ovarian follicle.
Pelvic floor muscle weakness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic, not interfering
with bladder, bowel, or vaginal
function; limiting instrumental
ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a reduction in the strength of the muscles of the pelvic floor.
Pelvic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pelvis.
Penile pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the penis.
Perineal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the area between the genital organs and the anus.
Premature menopause
 -
 -
Present
 -
 -
Definition: A disorder characterized by ovarian failure before the age of 40. Symptoms include hot flashes, night sweats, mood swings and a decrease in sex drive.
Prostatic hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
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Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by bleeding from the prostate gland.
Prostatic obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by compression of the urethra secondary to enlargement of the prostate gland. This results in voiding difficulties (straining to void, slow urine
stream, and incomplete emptying of the bladder).
Prostatic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the prostate gland.
Scrotal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the scrotal area.
Spermatic cord hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the spermatic cord.
Spermatic cord obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the normal flow of the contents of the spermatic cord.
Testicular disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic but not interfering
with urination or sexual
activities; intervention not
indicated; limiting instrumental
ADL
Severe symptoms; interfering
with urination or sexual function;
limiting self care ADL;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the testis.
Testicular hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the testis.
Testicular pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the testis.
Uterine fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the uterus and another organ or anatomic site.
Uterine hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the uterus.
Uterine obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the uterine outlet.
Uterine pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the uterus.
Vaginal discharge
Mild vaginal discharge (greater
than baseline for patient)
Moderate to heavy vaginal
discharge; use of perineal pad
or tampon indicated
 -
 -
 -
Definition: A disorder characterized by vaginal secretions. Mucus produced by the cervical glands is discharged from the vagina naturally, especially during the childbearing years.
Vaginal dryness
Mild vaginal dryness not
interfering with sexual function
Moderate vaginal dryness
interfering with sexual function
or causing frequent discomfort
Severe vaginal dryness
resulting in dyspareunia or
severe discomfort
 -
 -
Definition: A disorder characterized by an uncomfortable feeling of itching and burning in the vagina.
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CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
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Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Vaginal fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the vagina and another organ or anatomic site.
Vaginal hemorrhage
Minimal bleeding identified on
clinical exam or imaging study;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the vagina.
Vaginal inflammation
Mild discomfort or pain, edema,
or redness
Moderate discomfort or pain,
edema, or redness; limiting
instrumental ADL
Severe discomfort or pain,
edema, or redness; limiting self
care ADL; small areas of
mucosal ulceration
Widespread areas of mucosal
ulceration; life-threatening
consequences; urgent
intervention indicated
Death
Definition: A disorder characterized by inflammation involving the vagina. Symptoms may include redness, edema, marked discomfort and an increase in vaginal discharge.
Vaginal obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of vaginal canal.
Vaginal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the vagina.
Vaginal perforation
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the vaginal wall.
Vaginal stricture
Asymptomatic; mild vaginal
shortening or narrowing
Vaginal narrowing and/or
shortening not interfering with
physical examination
Vaginal narrowing and/or
shortening interfering with the
use of tampons, sexual activity
or physical examination
 -
Death
Definition: A disorder characterized by a narrowing of the vaginal canal.
Vaginismus
Mild discomfort or pain
associated with vaginal
spasm/tightening; no impact
upon sexual function or physical
examination
Moderate discomfort or pain
associated with vaginal
spasm/tightening; disruption in
sexual function and physical
examination
Severe discomfort or pain
associated with vaginal
spasm/tightening; unable to
tolerate vaginal penetration or
physical examination
 -
 -
Definition: A disorder characterized by involuntary spasms of the pelvic floor muscles, resulting in pathologic tightness of the vaginal wall during penetration such as during sexual
intercourse.
Reproductive system and breast
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
65
23. Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Adult respiratory distress
syndrome
 -
 -
Present with radiologic findings;
intubation not indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by progressive and life-threatening pulmonary distress in the absence of an underlying pulmonary condition, usually following major trauma or
surgery.
Allergic rhinitis
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by an inflammation of the nasal mucous membranes caused by an IgE-mediated response to external allergens. The inflammation may also
involve the mucous membranes of the sinuses, eyes, middle ear, and pharynx. Symptoms include sneezing, nasal congestion, rhinorrhea and itching.
Apnea
 -
 -
Present; medical intervention
indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by cessation of breathing.
Aspiration
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Altered eating habits; coughing
or choking episodes after eating
or swallowing; medical
intervention indicated (e.g.,
suction or oxygen)
Dyspnea and pneumonia
symptoms (e.g., aspiration
pneumonia); hospitalization
indicated; unable to aliment
orally
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by inhalation of solids or liquids into the lungs.
Atelectasis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., dyspnea,
cough); medical intervention
indicated (e.g., chest
physiotherapy, suctioning);
bronchoscopic suctioning
Oxygen indicated;
hospitalization or elective
operative intervention indicated
(e.g., stent, laser)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by the collapse of part or the entire lung.
Bronchial fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
with thoracoplasty, chronic open
drainage or multiple
thoracotomies indicated
Death
Definition: A disorder characterized by an abnormal communication between the bronchus and another organ or anatomic site.
Bronchial obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., mild
wheezing); endoscopic
evaluation indicated;
radiographic evidence of
atelectasis/lobar collapse;
medical management indicated
(e.g., steroids, bronchodilators)
Shortness of breath with stridor;
endoscopic intervention
indicated (e.g., laser, stent
placement)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by blockage of a bronchus passage, most often by bronchial secretions and exudates.
Bronchial stricture
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., rhonchi or
wheezing) but without
respiratory distress; medical
intervention indicated (e.g.,
steroids, bronchodilators)
Shortness of breath with stridor;
endoscopic intervention
indicated (e.g., laser, stent
placement)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the bronchial tube.
Bronchopleural fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
with thoracoplasty, chronic open
drainage or multiple
thoracotomies indicated
Death
Definition: A disorder characterized by an abnormal communication between a bronchus and the pleural cavity.
Bronchopulmonary hemorrhage
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the bronchial wall and/or lung parenchyma.
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Bronchospasm
Mild symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Limiting self care ADL; oxygen
saturation decreased
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by a sudden contraction of the smooth muscles of the bronchial wall.
Chylothorax
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thoracentesis or
tube drainage indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by milky pleural effusion (abnormal collection of fluid) resulting from accumulation of lymph fluid in the pleural cavity.
Cough
Mild symptoms; nonprescription
intervention indicated
Moderate symptoms, medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by sudden, often repetitive, spasmodic contraction of the thoracic cavity, resulting in violent release of air from the lungs and usually accompanied
by a distinctive sound.
Dyspnea
Shortness of breath with
moderate exertion
Shortness of breath with
minimal exertion; limiting
instrumental ADL
Shortness of breath at rest;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an uncomfortable sensation of difficulty breathing.
Epistaxis
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated (e.g.,
nasal packing, cauterization;
topical vasoconstrictors)
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the nose.
Hiccups
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; interfering
with sleep; limiting self care
ADL
 -
 -
Definition: A disorder characterized by repeated gulp sounds that result from an involuntary opening and closing of the glottis. This is attributed to a spasm of the diaphragm.
Hoarseness
Mild or intermittent voice
change; fully understandable;
self-resolves
Moderate or persistent voice
changes; may require
occasional repetition but
understandable on telephone;
medical evaluation indicated
Severe voice changes including
predominantly whispered
speech
 -
 -
Definition: A disorder characterized by harsh and raspy voice arising from or spreading to the larynx.
Hypoxia
 -
Decreased oxygen saturation
with exercise (e.g., pulse
oximeter <88%); intermittent
supplemental oxygen
Decreased oxygen saturation at
rest (e.g., pulse oximeter <88%
or PaO2 <=55 mm Hg)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a decrease in the level of oxygen in the body.
Laryngeal edema
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated (e.g.,
dexamethasone, epinephrine,
antihistamines)
Stridor; respiratory distress;
hospitalization indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the larynx.
Laryngeal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
indicated (e.g., thoracoplasty,
chronic open drainage or
multiple thoracotomies)
Death
Definition: A disorder characterized by an abnormal communication between the larynx and another organ or anatomic site.
Laryngeal hemorrhage
Mild cough or trace hemoptysis;
laryngoscopic findings
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by bleeding from the larynx.
Laryngeal inflammation
Mild sore throat; raspy voice
Moderate sore throat;
analgesics indicated
Severe throat pain; endoscopic
intervention indicated
 -
 -
Definition: A disorder characterized by an inflammation involving the larynx.
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67
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Laryngeal mucositis
Endoscopic findings only; mild
discomfort with normal intake
Moderate discomfort; altered
oral intake
Severe pain; severely altered
eating/swallowing; medical
intervention indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the larynx.
Laryngeal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids); limiting instrumental
ADL
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the laryngeal airway.
Laryngeal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids)
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a narrowing of the laryngeal airway.
Laryngopharyngeal dysesthesia
Mild symptoms; no anxiety;
intervention not indicated
Moderate symptoms; mild
anxiety, but no dyspnea; short
duration of observation and or
anxiolytic indicated; limiting
instrumental ADL
Severe symptoms; dyspnea and
swallowing difficulty; limiting self
care ADL
Life-threatening consequences
Death
Definition: A disorder characterized by an uncomfortable persistent sensation in the area of the laryngopharynx.
Laryngospasm
 -
Transient episode; intervention
not indicated
Recurrent episodes;
noninvasive intervention
indicated (e.g., breathing
technique, pressure point
massage)
Persistent or severe episodes
associated with syncope; urgent
intervention indicated (e.g.,
fiberoptic laryngoscopy,
intubation, botox injection)
Death
Definition: A disorder characterized by paroxysmal spasmodic muscular contraction of the vocal cords.
Mediastinal hemorrhage
Radiologic evidence only;
minimal symptoms; intervention
not indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
(e.g., hemostasis of bleeding
site)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the mediastinum.
Nasal congestion
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Associated with bloody nasal
discharge or epistaxis
 -
 -
Definition: A disorder characterized by obstruction of the nasal passage due to mucosal edema.
Pharyngeal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the pharynx and another organ or anatomic site.
Pharyngeal hemorrhage
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the pharynx.
Pharyngeal mucositis
Endoscopic findings only;
minimal symptoms with normal
oral intake; mild pain but
analgesics not indicated
Moderate pain and analgesics
indicated; altered oral intake;
limiting instrumental ADL
Severe pain; unable to
adequately aliment or hydrate
orally; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the pharynx.
Pharyngeal necrosis
 -
 -
Inability to aliment adequately
by GI tract; tube feeding or TPN
indicated; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by a necrotic process occurring in the pharynx.
Pharyngeal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids); limiting instrumental
ADL
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a narrowing of the pharyngeal airway.
Pharyngolaryngeal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pharyngolaryngeal region.
Pleural effusion
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; intervention
indicated (e.g., diuretics or
limited therapeutic
thoracentesis)
Symptomatic with respiratory
distress and hypoxia; surgical
intervention including chest tube
or pleurodesis indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by an increase in amounts of fluid within the pleural cavity. Symptoms include shortness of breath, cough and marked chest discomfort.
Pleural hemorrhage
Asymptomatic; mild hemorrhage
confirmed by thoracentesis
Symptomatic or associated with
pneumothorax; chest tube
drainage indicated
>1000 ml of blood evacuated;
persistent bleeding (150-200
ml/hr for 2 - 4 hr); persistent
transfusion indicated; elective
operative intervention indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the pleural cavity.
Pleuritic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pleura.
Pneumonitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; oxygen indicated
Life-threatening respiratory
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma.
Pneumothorax
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; intervention
indicated (e.g., tube placement
without sclerosis)
Sclerosis and/or operative
intervention indicated;
hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormal presence of air in the pleural cavity resulting in the collapse of the lung.
Postnasal drip
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by excessive mucous secretion in the back of the nasal cavity or throat, causing sore throat and/or coughing.
Productive cough
Occasional/minimal production
of sputum with cough
Moderate sputum production;
limiting instrumental ADL
Persistent or copious production
of sputum; limiting self care ADL
 -
 -
Definition: A disorder characterized by expectorated secretions upon coughing.
Pulmonary edema
Radiologic findings only;
minimal dyspnea on exertion
Moderate dyspnea on exertion;
medical intervention indicated;
limiting instrumental ADL
Severe dyspnea or dyspnea at
rest; oxygen indicated; limiting
self care ADL
Life-threatening respiratory
compromise; urgent intervention
or intubation with ventilatory
support indicated
Death
Definition: A disorder characterized by accumulation of fluid in the lung tissues that causes a disturbance of the gas exchange that may lead to respiratory failure.
Pulmonary fibrosis
Mild hypoxemia; radiologic
pulmonary fibrosis <25% of lung
volume
Moderate hypoxemia; evidence
of pulmonary hypertension;
radiographic pulmonary fibrosis
25 - 50%
Severe hypoxemia; evidence of
right-sided heart failure;
radiographic pulmonary fibrosis
>50 - 75%
Life-threatening consequences
(e.g., hemodynamic/pulmonary
complications); intubation with
ventilatory support indicated;
radiographic pulmonary fibrosis
>75% with severe
honeycombing
Death
Definition: A disorder characterized by the replacement of the lung tissue by connective tissue, leading to progressive dyspnea, respiratory failure or right heart failure.
Pulmonary fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Limiting self care ADL;
endoscopic stenting or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
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CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an abnormal communication between the lung and another organ or anatomic site.
Pulmonary hypertension
Minimal dyspnea; findings on
physical exam or other
evaluation
Moderate dyspnea, cough;
requiring evaluation by cardiac
catheterization and medical
intervention
Severe symptoms, associated
with hypoxemia, right heart
failure; oxygen indicated
Life-threatening airway
consequences; urgent
intervention indicated (e.g.,
tracheotomy or intubation)
Death
Definition: A disorder characterized by an increase in pressure within the pulmonary circulation due to lung or heart disorder.
Respiratory failure
 -
 -
 -
Life-threatening consequences;
urgent intervention, intubation,
or ventilatory support indicated
Death
Definition: A disorder characterized by impaired gas exchange by the respiratory system resulting in hypoxemia and a decrease in oxygenation of the tissues that may be associated
with an increase in arterial levels of carbon dioxide.
Retinoic acid syndrome
Fluid retention; <3 kg of weight
gain; intervention with fluid
restriction and/or diuretics
indicated
Moderate signs or symptoms;
steroids indicated
Severe symptoms;
hospitalization indicated
Life-threatening consequences;
ventilatory support indicated
Death
Definition: A disorder characterized by weight gain, dyspnea, pleural and pericardial effusions, leukocytosis and/or renal failure originally described in patients treated with all-trans
retinoic acid.
Sinus disorder
Asymptomatic mucosal crusting;
blood-tinged secretions
Symptomatic stenosis or
edema/narrowing interfering
with airflow; limiting instrumental
ADL
Stenosis with significant nasal
obstruction; limiting self care
ADL
Necrosis of soft tissue or bone;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by involvement of the paranasal sinuses.
Sleep apnea
Snoring and nocturnal sleep
arousal without apneic periods
Moderate apnea and oxygen
desaturation; excessive daytime
sleepiness; medical evaluation
indicated; limiting instrumental
ADL
Oxygen desaturation;
associated with hypertension;
medical intervention indicated;
limiting self care ADL
Cardiovascular or
neuropsychiatric symptoms;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by cessation of breathing for short periods during sleep.
Sneezing
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by the involuntary expulsion of air from the nose.
Sore throat
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL; limiting ability to swallow
 -
 -
Definition: A disorder characterized by of marked discomfort in the throat
Stridor
 -
 -
Respiratory distress limiting self
care ADL; medical intervention
indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a high pitched breathing sound due to laryngeal or upper airway obstruction.
Tracheal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
indicated (e.g., thoracoplasty,
chronic open drainage or
multiple thoracotomies)
Death
Definition: A disorder characterized by an abnormal communication between the trachea and another organ or anatomic site.
Tracheal mucositis
Endoscopic findings only;
minimal hemoptysis, pain, or
respiratory symptoms
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe pain; hemorrhage or
respiratory symptoms; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the trachea.
Tracheal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids)
Stridor or respiratory distress
limiting self care ADL;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a narrowing of the trachea.
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Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Voice alteration
Mild or intermittent change from
normal voice
Moderate or persistent change
from normal voice; still
understandable
Severe voice changes including
predominantly whispered
speech; may require frequent
repetition or face-to-face contact
for understandability; may
require assistive technology
 -
 -
Definition: A disorder characterized by a change in the sound and/or speed of the voice.
Wheezing
Detectable airway noise with
minimal symptoms
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe respiratory symptoms
limiting self care ADL; oxygen
therapy or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a high-pitched, whistling sound during breathing. It results from the narrowing or obstruction of the respiratory airways.
Respiratory, thoracic and
mediastinal disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
71
24. Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Alopecia
Hair loss of <50% of normal for
that individual that is not
obvious from a distance but only
on close inspection; a different
hair style may be required to
cover the hair loss but it does
not require a wig or hair piece to
camouflage
Hair loss of >=50% normal for
that individual that is readily
apparent to others; a wig or hair
piece is necessary if the patient
desires to completely
camouflage the hair loss;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by a decrease in density of hair compared to normal for a given individual at a given age and body location.
Body odor
Mild odor; physician intervention
not indicated; self care
interventions
Pronounced odor; psychosocial
impact; patient seeks medical
intervention
 -
 -
 -
Definition: A disorder characterized by an abnormal body smell resulting from the growth of bacteria on the body.
Bullous dermatitis
Asymptomatic; blisters covering
<10% BSA
Blisters covering 10 - 30% BSA;
painful blisters; limiting
instrumental ADL
Blisters covering >30% BSA;
limiting self care ADL
Blisters covering >30% BSA;
associated with fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by inflammation of the skin characterized by the presence of bullae which are filled with fluid.
Dry skin
Covering <10% BSA and no
associated erythema or pruritus
Covering 10 - 30% BSA and
associated with erythema or
pruritus; limiting instrumental
ADL
Covering >30% BSA and
associated with pruritus; limiting
self care ADL
 -
 -
Definition: A disorder characterized by flaky and dull skin; the pores are generally fine, the texture is a papery thin texture.
Erythema multiforme
Target lesions covering <10%
BSA and not associated with
skin tenderness
Target lesions covering 10 -
30% BSA and associated with
skin tenderness
Target lesions covering >30%
BSA and associated with oral or
genital erosions
Target lesions covering >30%
BSA; associated with fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by target lesions (a pink-red ring around a pale center).
Erythroderma
 -
Erythema covering >90% BSA
without associated symptoms;
limiting instrumental ADL
Erythema covering >90% BSA
with associated symptoms (e.g.,
pruritus or tenderness); limiting
self care ADL
Erythema covering >90% BSA
with associated fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by generalized inflammatory erythema and exfoliation. The inflammatory process involves > 90% of the body surface area.
Fat atrophy
Covering <10% BSA and
asymptomatic
Covering 10 - 30% BSA and
associated with erythema or
tenderness; limiting instrumental
ADL
Covering >30% BSA;
associated with erythema or
tenderness; limiting self-care
ADL
 -
 -
Definition: A disorder characterized by shrinking of adipose tissue.
Hirsutism
In women, increase in length,
thickness or density of hair in a
male distribution that the patient
is able to camouflage by
periodic shaving, bleaching, or
removal of hair
In women, increase in length,
thickness or density of hair in a
male distribution that requires
daily shaving or consistent
destructive means of hair
removal to camouflage;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by the presence of excess hair growth in women in anatomic sites where growth is considered to be a secondary male characteristic and under
androgen control (beard, moustache, chest, abdomen)
Hyperhidrosis
Limited to one site (palms,
soles, or axillae); self care
interventions
Involving >1 site; patient seeks
medical intervention; associated
with psychosocial impact
Generalized involving sites
other than palms, soles, or
axillae; associated with
electrolyte/hemodynamic
imbalance
 -
 -
Definition: A disorder characterized by excessive perspiration.
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
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Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Hypertrichosis
Increase in length, thickness or
density of hair that the patient is
either able to camouflage by
periodic shaving or removal of
hairs or is not concerned
enough about the overgrowth to
use any form of hair removal
Increase in length, thickness or
density of hair at least on the
usual exposed areas of the
body [face (not limited to
beard/moustache area)
plus/minus arms] that requires
frequent  shaving or use of
destructive means of hair
removal to camouflage;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by hair density or length beyond the accepted limits of normal in a particular body region, for a particular age or race.
Hypohidrosis
 -
Symptomatic; limiting
instrumental ADL
Increase in body temperature;
limiting self care ADL
Heat stroke
Death
Definition: A disorder characterized by reduced sweating.
Lipohypertrophy
Asymptomatic and covering
<10% BSA
Covering 10 - 30% BSA and
associated tenderness; limiting
instrumental ADL
Covering >30% BSA and
associated tenderness and
narcotics or NSAIDs indicated;
lipohypertrophy; limiting self
care ADL
 -
 -
Definition: A disorder characterized by hypertrophy of the subcutaneous adipose tissue at the site of multiple subcutaneous injections of insulin.
Nail discoloration
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by a change in the color of the nail plate.
Nail loss
Asymptomatic separation of the
nail bed from the nail plate or
nail loss
Symptomatic separation of the
nail bed from the nail plate or
nail loss; limiting instrumental
ADL
 -
 -
 -
Definition: A disorder characterized by loss of all or a portion of the nail.
Nail ridging
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by vertical or horizontal ridges on the nails.
Pain of skin
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the skin.
Palmar-plantar
erythrodysesthesia syndrome
Minimal skin changes or
dermatitis (e.g., erythema,
edema, or hyperkeratosis)
without pain
Skin changes (e.g., peeling,
blisters, bleeding, edema, or
hyperkeratosis) with pain;
limiting instrumental ADL
Severe skin changes (e.g.,
peeling, blisters, bleeding,
edema, or hyperkeratosis) with
pain; limiting self care ADL
 -
 -
Definition: A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet.
Periorbital edema
Soft or non-pitting
Indurated or pitting edema;
topical intervention indicated
Edema associated with visual
disturbance; increased
intraocular pressure, glaucoma
or retinal hemorrhage; optic
neuritis; diuretics indicated;
operative intervention indicated
 -
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid around the orbits of the face.
Photosensitivity
Painless erythema and
erythema covering <10% BSA
Tender erythema covering 10 -
30% BSA
Erythema covering >30% BSA
and erythema with blistering;
photosensitivity; oral
corticosteroid therapy indicated;
pain control indicated (e.g.,
narcotics or NSAIDs)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in sensitivity of the skin to light.
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CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
73
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Pruritus
Mild or localized; topical
intervention indicated
Intense or widespread;
intermittent; skin changes from
scratching (e.g., edema,
papulation, excoriations,
lichenification, oozing/crusts);
oral intervention indicated;
limiting instrumental ADL
Intense or widespread;
constant; limiting self care ADL
or sleep; oral corticosteroid or
immunosuppressive therapy
indicated
 -
 -
Definition: A disorder characterized by an intense itching sensation.
Purpura
Combined area of lesions
covering <10% BSA
Combined area of lesions
covering 10 - 30% BSA;
bleeding with trauma
Combined area of lesions
covering >30% BSA;
spontaneous bleeding
 -
 -
Definition: A disorder characterized by hemorrhagic areas of the skin and mucous membrane. Newer lesions appear reddish in color. Older lesions are usually a darker purple color
and eventually become a brownish-yellow color.
Rash acneiform
Papules and/or pustules
covering <10% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness
Papules and/or pustules
covering 10 - 30% BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness; associated with
psychosocial impact; limiting
instrumental ADL
Papules and/or pustules
covering >30% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness; limiting self care
ADL; associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering any % BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness and are associated
with extensive superinfection
with IV antibiotics indicated; life-
threatening consequences
Death
Definition: A disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest and back.
Rash maculo-papular
Macules/papules covering
<10% BSA with or without
symptoms (e.g., pruritus,
burning, tightness)
Macules/papules covering 10 -
30% BSA with or without
symptoms (e.g., pruritus,
burning, tightness); limiting
instrumental ADL
Macules/papules covering
>30% BSA with or without
associated symptoms; limiting
self care ADL
 -
 -
Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbillform rash, it is one of the most common cutaneous adverse
events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus.
Scalp pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the skin covering the top and the back of the head.
Skin atrophy
Covering <10% BSA;
associated with telangiectasias
or changes in skin color
Covering 10 - 30% BSA;
associated with striae or
adnexal structure loss
Covering >30% BSA;
associated with ulceration
 -
 -
Definition: A disorder characterized by the degeneration and thinning of the epidermis and dermis.
Skin hyperpigmentation
Hyperpigmentation covering
<10% BSA; no psychosocial
impact
Hyperpigmentation covering
>10% BSA; associated
psychosocial impact
 -
 -
 -
Definition: A disorder characterized by darkening of the skin due to excessive melanin deposition.
Skin hypopigmentation
Hypopigmentation or
depigmentation covering <10%
BSA; no psychosocial impact
Hypopigmentation or
depigmentation covering >10%
BSA; associated psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by loss of skin pigment.
Skin induration
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration, unable to
slide or pinch skin; limiting joint
movement or orifice (e.g.,
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by an area of hardness in the skin.
Skin ulceration
Combined area of ulcers <1 cm;
nonblanchable erythema of
intact skin with associated
warmth or edema
Combined area of ulcers 1 - 2
cm; partial thickness skin loss
involving skin or subcutaneous
fat
Combined area of ulcers >2 cm;
full-thickness skin loss involving
damage to or necrosis of
subcutaneous tissue that may
extend down to fascia
Any size ulcer with extensive
destruction, tissue necrosis, or
damage to muscle, bone, or
supporting structures with or
without full thickness skin loss
Death
Definition: A disorder characterized by circumscribed, inflammatory and necrotic erosive lesion on the skin.
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Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Stevens-Johnson syndrome
 -
 -
Skin sloughing covering <10%
BSA with associated signs (e.g.,
erythema, purpura, epidermal
detachment and mucous
membrane detachment)
Skin sloughing covering 10 -
30% BSA with associated signs
(e.g., erythema, purpura,
epidermal detachment and
mucous membrane
detachment)
Death
Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the
mucous membranes.
Telangiectasia
Telangiectasias covering <10%
BSA
Telangiectasias covering >10%
BSA; associated with
psychosocial impact
 -
 -
 -
Definition: A disorder characterized by local dilatation of small vessels resulting in red discoloration of the skin or mucous membranes.
Toxic epidermal necrolysis
 -
 -
 -
Skin sloughing covering >=30%
BSA with associated symptoms
(e.g., erythema, purpura, or
epidermal detachment)
Death
Definition: A disorder characterized by greater than 30% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the
mucous membranes.
Urticaria
Urticarial lesions covering <10%
BSA; topical intervention
indicated
Urticarial lesions covering 10 -
30% BSA; oral intervention
indicated
Urticarial lesions covering >30%
BSA; IV intervention indicated
 -
 -
Definition: A disorder characterized by an itchy skin eruption characterized by wheals with pale interiors and well-defined red margins.
Skin and subcutaneous tissue
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 956 of 979


CTCAE 4.03 - June 14, 2010 : Social circumstances 
75
25. Social circumstances
Social circumstances
Grade
Adverse Event
1
2
3
4
5
Menopause
Menopause occurring at age 46
- 53 years of age
Menopause occurring at age 40
- 45 years of age
Menopause occurring before
age 40 years of age
 -
 -
Definition: A disorder characterized by the permanent cessation of menses, usually defined by 12 consecutive months of amenorrhea in a woman over 45 years of age.
Social circumstances - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 957 of 979


CTCAE 4.03 - June 14, 2010 : Surgical and medical procedures 
76
26. Surgical and medical procedures
Surgical and medical procedures
Grade
Adverse Event
1
2
3
4
5
Surgical and medical
procedures - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 958 of 979


CTCAE 4.03 - June 14, 2010 : Vascular disorders 
77
27. Vascular disorders
Vascular disorders
Grade
Adverse Event
1
2
3
4
5
Capillary leak syndrome
 -
Symptomatic; medical
intervention indicated
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by leakage of intravascular fluids into the extravascular space. This syndrome is observed in patients who demonstrate a state of generalized
leaky capillaries following shock syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. It can lead to generalized edema and multiple organ
failure.
Flushing
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Symptomatic, associated with
hypotension and/or tachycardia;
limiting self care ADL
 -
 -
Definition: A disorder characterized by episodic reddening of the face.
Hematoma
Mild symptoms; intervention not
indicated
Minimally invasive evacuation or
aspiration indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel.
Hot flashes
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an uncomfortable and temporary sensation of intense body warmth, flushing, sometimes accompanied by sweating upon cooling.
Hypertension
Prehypertension (systolic BP
120 - 139 mm Hg or diastolic
BP  80 - 89 mm Hg)
Stage 1 hypertension (systolic
BP 140 - 159 mm Hg or
diastolic BP 90 - 99 mm Hg);
medical intervention indicated;
recurrent or persistent (>=24
hrs); symptomatic increase by
>20 mm Hg (diastolic) or to
>140/90 mm Hg if previously
WNL; monotherapy indicated
Pediatric: recurrent or persistent
(>=24 hrs) BP >ULN;
monotherapy indicated
Stage 2 hypertension (systolic
BP >=160 mm Hg or diastolic
BP >=100 mm Hg); medical
intervention indicated; more
than one drug or more intensive
therapy than previously used
indicated
Pediatric: Same as adult
Life-threatening consequences
(e.g., malignant hypertension,
transient or permanent
neurologic deficit, hypertensive
crisis); urgent intervention
indicated
Pediatric: Same as adult
Death
Definition: A disorder characterized by a pathological increase in blood pressure; a repeatedly elevation in the blood pressure exceeding 140 over 90 mm Hg.
Hypotension
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention or
hospitalization indicated
Life-threatening and urgent
intervention indicated
Death
Definition: A disorder characterized by a blood pressure that is below the normal expected for an individual in a given environment.
Lymph leakage
 -
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the loss of lymph fluid into the surrounding tissue or body cavity.
Lymphedema
Trace thickening or faint
discoloration
Marked discoloration; leathery
skin texture; papillary formation;
limiting instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by excessive fluid collection in tissues that causes swelling.
Lymphocele
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by a cystic lesion containing lymph.
Peripheral ischemia
 -
Brief (<24 hrs) episode of
ischemia managed non-
surgically and without
permanent deficit
Recurring or prolonged (>=24
hrs) and/or invasive intervention
indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by impaired circulation to an extremity.
Phlebitis
 -
Present
 -
 -
 -
Definition: A disorder characterized by inflammation of the wall of a vein.
Superficial thrombophlebitis
 -
Present
 -
 -
 -
Definition: A disorder characterized by a blood clot and inflammation involving a superficial vein of the extremities.
Alexion Confidential
Page 959 of 979


CTCAE 4.03 - June 14, 2010 : Vascular disorders 
78
Vascular disorders
Grade
Adverse Event
1
2
3
4
5
Superior vena cava syndrome
Asymptomatic; incidental finding
of SVC thrombosis
Symptomatic; medical
intervention indicated (e.g.,
anticoagulation, radiation or
chemotherapy)
Severe symptoms; multi-
modality intervention indicated
(e.g., anticoagulation,
chemotherapy, radiation,
stenting)
Life-threatening consequences;
urgent multi-modality
intervention indicated (e.g.,
lysis, thrombectomy, surgery)
Death
Definition: A disorder characterized by obstruction of the blood flow in the superior vena cava. Signs and symptoms include swelling and cyanosis of the face, neck, and upper arms,
cough, orthopnea and headache.
Thromboembolic event
Venous thrombosis (e.g.,
superficial thrombosis)
Venous thrombosis (e.g.,
uncomplicated deep vein
thrombosis), medical
intervention indicated
Thrombosis (e.g.,
uncomplicated pulmonary
embolism [venous], non-embolic
cardiac mural [arterial]
thrombus), medical intervention
indicated
Life-threatening (e.g.,
pulmonary embolism,
cerebrovascular event, arterial
insufficiency); hemodynamic or
neurologic instability; urgent
intervention indicated
Death
Definition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via the blood stream.
Vasculitis
Asymptomatic, intervention not
indicated
Moderate symptoms, medical
intervention indicated
Severe symptoms, medical
intervention indicated (e.g.,
steroids)
Life-threatening; evidence of
peripheral or visceral ischemia;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving the wall of a vessel.
Visceral arterial ischemia
 -
Brief (<24 hrs) episode of
ischemia managed medically
and without permanent deficit
Prolonged (>=24 hrs) or
recurring symptoms and/or
invasive intervention indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a decrease in blood supply due to narrowing or blockage of a visceral (mesenteric) artery.
Vascular disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Alexion Confidential
Page 960 of 979


28. Publication Information
NIH Publication No. 09-5410
Revised June 2010
Reprinted June 2010
J[TUTE 
Alexion Confidential
Page 961 of 979


SYNT001 
 
18 September 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 5.0 
 
Confidential 
Page 90 of 95 
Syntimmune, Inc. 
APPENDIX 2. PEMPHIGUS DISEASE AREA INDEX (PDAI) 
 
Alexion Confidential
Page 962 of 979


SYNT001 
 
18 September 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 5.0 
 
Confidential 
Page 91 of 95 
Syntimmune, Inc. 
APPENDIX 3. AUTOIMMUNE BULLOUS DISEASE QUALITY OF LIFE 
(ABQOL) QUESTIONNAIRE 
Alexion Confidential
Page 963 of 979


ABQOL Questionnaire 
 
 
Name: _______________________________________  
  Date: _________________ 
 
DOB: __________________        Sex:     M / F  
Contact Number: _______________ 
 
Pemphigus Subtype:  □  Pemphigus Vulgaris 
 
□  Epidermolysis Bullosa Aquisita 
 
 
 
                                    □  Bullous Pemphigoid 
 
□  Linear IgA Bullous Dermatoses 
 
                                    □  Pemphigus Follaceus  
□  Mucous Membrane Pemphigoid 
 
                                    □  Other  ________________________________________ 
 
The following questions ask about the ways in which blistering disease treatments affect your 
quality of life.  
 
Please choose an option from the right hand column which most closely correlates to how you 
felt within the last week. 
 
Please time your survey in minutes and seconds – start time                              AM/PM 
 
 
 
1. In regards to your blistering disease, 
does your skin burn, sting or hurt in 
any way? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
2. In regards to your blistering disease, 
does your skin itch? 
      
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
3. Have you had to change your 
clothing because of your blistering 
disease? 
    
 
 
 
◌    I have to be very careful with how tight  
      my clothing is and what materials they 
      are made of – I have had to change what 
      I wear all the time 
◌    I have had to change most of the things I  
      wear 
◌    I have had to change some of the things I 
      wear 
◌    I have never had to change what I wear 
 
4. Do you notice your skin heals slowly?  
       
 
 
 
◌    I notice this all the time 
◌    I notice this sometimes 
◌    I notice this occasionally 
◌    I have never had this problem 
 
5. Do you have difficulty bathing or 
showering because of your blistering 
disease? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
Alexion Confidential
Page 964 of 979


 
6. In regards to your blistering disease, 
does your mouth have erosions 
which are painful? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
7. In regards to your blistering disease, 
do your gums bleed easily? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
8. Does your blistering disease results 
in you having to avoid food or drinks 
that you enjoy? 
       
 
 
 
◌    I can no longer eat any of the foods I 
      used to enjoy 
◌    I can eat some of the foods I enjoy 
◌    I can eat most of the foods I enjoy 
◌    I can eat anything I like 
 
9. As a result of your blistering disease, 
are you embarrassed about your 
appearance? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
10. Do you feel depressed or angry 
because of your blistering disease? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
11. Do you feel anxious or cannot relax 
as a result of your blistering disease? 
       
 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
12. Do you worry that friends and family 
find your blistering skin condition 
tiresome? 
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
 
13. Is your blistering disease causing 
sexual difficulties? 
       
 
 
◌    All the time 
◌    Sometimes 
◌    Occasionally 
◌    Not at all 
 
 
14. Does your blistering disease affect 
relationships with friends or loved 
ones? 
 
 
 
◌    I have had to end a relationship because 
      of my disease OR I cannot have a  
      relationship because of my disease 
◌    Relationships are very difficult 
◌    Relationships are a little difficult 
◌    This has not affected my relationships 
 
 
Alexion Confidential
Page 965 of 979


 
15. Does your blistering disease affect 
your social life? 
 
 
 
◌    I cannot go out to socialize any more 
◌    I can only go to some social events 
◌    I can go to most social events 
◌    My social life is not affected 
 
16. Does your blistering disease affect 
your work or study? 
 
 
 
◌    Yes, I can no longer work or study 
◌    Yes, I find it difficult to work or study 
◌    Yes, it is a little harder than before to 
       work or study 
◌    No, I am not affected OR not applicable 
      (N/A) 
 
17. Do employers discriminate against 
you because of your blistering 
disease? 
 
 
 
◌    I cannot find a job due to my blistering 
      disease 
◌    I have had to change jobs due to my 
      blistering disease 
◌    I still have my job but it is more difficult 
      than before 
◌    My employers are completely 
      understanding OR not applicable (N/A) 
 
 
 
 
 
 
Please indicate the time taken to finish the survery:                 minutes              seconds 
 
 
 
 
Thank you for taking the time to complete this questionnaire 
Alexion Confidential
Page 966 of 979


SYNT001 
 
18 September 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 5.0 
 
Confidential 
Page 92 of 95 
Syntimmune, Inc. 
APPENDIX 4. SKINDEX-29 
 
Alexion Confidential
Page 967 of 979


Skindex29 
MMChren,1996 
 
 
Skindex29 – United States/English – Original version 
Skindex29_AU2.0_eng-USori.doc 
 
 
 
 
 
 
 
DERMATOLOGY SURVEY 
 
 
 
 
 
This survey concerns the skin condition which has bothered you the most during the 
past four weeks.          
 
 
                                                                                                                                                                                                                   
 
 
 
 
                            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alexion Confidential
Page 968 of 979


Skindex29 
MMChren,1996 
 
 
Skindex29 – United States/English – Original version 
Skindex29_AU2.0_eng-USori.doc 
 
These questions concern your feelings over the past 4 weeks about the skin condition that has  
bothered you the most. Check the answer that comes closest to the way you have been feeling. 
 
 
HOW OFTEN DURING THE PAST FOUR WEEKS  
DO THESE STATEMENTS DESCRIBE YOU? 
___________________________________________ 
 
NEVER         RARELY      SOMETIMES       OFTEN          ALL THE   
 
TIME 
___________________________________________ 
 
  1. My skin hurts    .    .    .   .    .    .   .    .    .   .    .    .   .    .    .    . 
 
   1              2              3               4              5 
 
  2. My skin condition affects how well I sleep    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
  3. I worry that my skin condition may be serious    .    .    .    .    . 
 
   1              2              3               4              5 
 
  4. My skin condition makes it hard to work or do hobbies    .    . 
 
   1              2              3               4              5 
 
  5. My skin condition affects my social life   .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
  6. My skin condition makes me feel depressed    .    .    .    .    .   
 
   1              2              3               4              5 
 
  7. My skin condition burns or stings    .    .    .    .    .    .    .     . 
 
   1              2              3               4              5 
 
  8. I tend to stay at home because of my skin condition    .    .    . 
 
   1              2              3               4              5 
 
  9. I worry about getting scars from my skin condition    .    .    .   
 
   1              2              3               4              5 
 
10. My skin itches    .    .    .    .    .    .    .    .    .    .    .    .    .    .     
 
   1              2              3               4              5 
 
11. My skin condition affects how close I can be with those I love . 
 
   1              2              3               4              5 
 
12. I am ashamed of my skin condition    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
13. I worry that my skin condition may get worse    .    .    .    .    . 
 
   1              2              3               4              5 
 
14. I tend to do things by myself because of my skin condition    . 
 
   1              2              3               4              5 
 
15. I am angry about my skin condition    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
16. Water bothers my skin condition (bathing, washing hands)    . 
 
   1              2              3               4              5 
 
17. My skin condition makes showing affection difficult    .    .    . 
 
   1              2              3               4              5 
 
18. I worry about side-effects from skin medications / treatments  . 
 
   1              2              3               4              5 
 
19. My skin is irritated    .    .    .    .    .    .    .    .    .    .    .    .    .     
 
   1              2              3               4              5 
 
20. My skin condition affects my interactions with others    .    .     
 
   1              2              3               4              5 
 
Please turn to next page 
 
Alexion Confidential
Page 969 of 979


Skindex29 
MMChren,1996 
 
 
Skindex29 – United States/English – Original version 
Skindex29_AU2.0_eng-USori.doc 
These questions concern your feelings over the past 4 week about the skin condition that has  
bothered you the most. Check the answer that comes closest to the way you have been feeling. 
 
 
HOW OFTEN DURING THE PAST 4 WEEK  
DO THESE STATEMENTS DESCRIBE YOU? 
_____________________________________________ 
 
NEVER         RARELY      SOMETIMES       OFTEN         ALL THE  
                                                                                             TIME 
_____________________________________________ 
 
21. I am embarrassed by my skin condition    .    .    .    .    .    .    .    
 
   1              2              3               4              5 
 
22. My skin condition is a problem for the people I love    .    .    .  
 
   1              2              3               4              5 
 
23. I am frustrated by my skin condition    .    .    .    .    .    .    .    .  
 
   1              2              3               4              5 
 
24. My skin is sensitive    .    .    .    .    .    .    .    .    .    .    .    .    .   
 
   1              2              3               4              5 
 
25. My skin condition affects my desire to be with people    .    .  
 
   1              2              3               4              5 
 
26. I am humiliated by my skin condition    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
27. My skin condition bleeds    .    .    .    .    .    .    .    .    .    .    .    
 
   1              2              3               4              5 
 
28. I am annoyed by my skin condition    .    .    .    .    .    .    .    .   
 
   1              2              3               4              5 
 
29. My skin condition interferes with my sex life    .    .    .    .    .  
 
   1              2              3               4              5 
 
30. My skin condition makes me tired    .    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
 
 
 
Alexion Confidential
Page 970 of 979


SYNT001 
 
18 September 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 5.0 
 
Confidential 
Page 93 of 95 
Syntimmune, Inc. 
APPENDIX 5. COHORT 2 ALTERNATE SCHEDULE OF EVENTS TABLE 
Alexion Confidential
Page 971 of 979


SYNT001 
 
18 September 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 5.0 
 
Confidential 
Page 94 of 95 
Syntimmune, Inc. 
Table 10.  
Study Assessments for Cohort 2 (Alternate Weekly Dosing Option) 
 
Screening 
Loading 
Maintenance 
Follow-Up 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Time Point  
(Study Day) 
−14 to −1 
0 
Baseline 
7 
(±1 d) 
14 
(±1 d) 
21 
(±3 d) 
28 
(±3 d) 
35 
(±3 d) 
42 
(±3 d) 
49 
(±3 d) 
56 
(±3 d) 
63 
(±3 d) 
70 
(±3 d) 
77 
(±3 d) 
84 
(±3 d) 
91 
(±5 d) 
or ET 
Visit 
112 
(±5 d) 
140 
(±5 d) 
EOS 
Visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryc 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinical safety labsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy teste 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Hepatitis and HIV screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGf 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Tetanus and VZV antibodiesg 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
PDAIh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingi 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
Immunogenicityj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administrationk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Immunoglobulins (IgG, IgA, 
IgM) and IgG subtypes  
(IgG1-4)l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
CIC  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-Dsg (1 and 3) antibody 
titers 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C3 and AECAm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FCGR2A by buccal swabn 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNA sequencing  
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Immunophenotypingo 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Exploratory pemphigus 
immune response biomarkers 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alexion Confidential
Page 972 of 979


SYNT001 
 
18 September 2018 
Protocol SYNT001-103 for Pemphigus 
 
Amendment 5.0 
 
Confidential 
Page 95 of 95 
Syntimmune, Inc. 
CIC = circulating immune complexes; d = day(s); ECG = electrocardiogram; EOS = end of study; ET= early termination; FCGR2A = Fc gamma R2a receptor; HIV = human 
immunodeficiency virus; HR-QoL = health-related quality of life; ICF = informed consent form; Ig = immunoglobulin; PDAI = Pemphigus Disease Area Index; 
PK = pharmacokinetic; VZV = varicella-zoster virus 
a. 
Complete physical examination, including weight, to be performed. Height and body mass index will be additional assessments conducted at screening only. 
b. 
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and oral temperature) to be obtained after 5 minutes of seated rest. Any abnormal measurements 
are to be repeated after 5 minutes of rest. Vital sign measurements will be taken on all study visits. On dosing days, vital sign measurements will be collected immediately 
prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the 
infusion.  
c. 
Pulse oximetry: On dosing days, pulse oximetry to be measured immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at completion of the 
infusion; and 30 minutes, 1 hour, and 2 hours following completion of the infusion. 
d. 
Clinical safety labs: hematology, clinical chemistry, and urinalysis. See Section 7.5 for a complete list. Full clinical safety lab draws will be collected at screening and at all 
study visits prior to infusion if applicable. 
e. 
Pregnancy test (women of childbearing potential only): To be performed at time of screening and prior to dose on dosing days if applicable. Urine or serum test is 
acceptable; however, positive urine tests must be confirmed with serum testing. 
f. 
Digital 12-lead ECG to be obtained after 5 minutes of rest in the supine position and in triplicate approximately 1 minute apart. See Section 7.6 for additional information. On 
dosing days, to be obtained approximately 5 minutes after the completion of infusion.  
g. 
Serology: Any subject whose baseline value for tetanus or VZV was above the protective level at baseline and is not within 30% of the baseline value or is below the 
protective level by End of Follow-up, will be referred to their primary care physician for further management. See Section 7.5.3 for additional information. 
h. 
PDAI will be administered at screening. Subject eligibility requires a PDAI total activity score >4. Thereafter, assuming eligibility, the PDAI will be administered during 
Treatment Period and Follow-up Period. See Section 7.7 for additional information. 
i. 
PK: On dosing days if applicable, serum samples will be collected just prior to the start of study drug infusion (pre-dose) and at 5 minutes, 1 and 2 hours after the end of 
study drug infusion. See Section 7.5.4 for additional information. 
j. 
Immunogenicity: Samples will be collected pre-dose when collected on dosing days. See Section 7.5.6 for additional information.  
k. 
Prior to study drug infusion, SYNT001 drug product is to be diluted in dextrose 5% in water to a total volume of 250 mL and administered intravenously over 1 hour 
±15 minutes using a 0.2-micron, inline filter. See Section 4 for additional information.  
l. 
Immunoglobulins (IgG, IgA, IgM) and IgG subtypes (IgG 1-4): Collected for measurements of IgG, IgG subtypes (IgG1-4), IgA, and IgM at every visit. On dosing days, 
samples are collected prior to infusion of study drug. See Section 7.5.5 for additional information.  
m. Exploratory pharmacodynamic samples (C3 and AECA): Collected pre-dose when collected on dosing days. See Section 7.5.5 for complete information.  
n. 
Buccal samples to be collected pre-dose. 
o. 
Immunophenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, natural killer (NK) cells, and B cells. Collect samples pre-dose on 
dosing days. 
p 
Photographs of all active lesions taken pre-dose on dosing days. Subjects who begin a steroid taper will have additional photographs taken at the clinic visit during which the 
decision to begin the taper is made. 
q 
Subjects whose total IgG is not within 30% of their Day 0 baseline value and not above 500 mg/dL at Day 140 will be referred for further management. 
Photographyp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HR-QoL assessments 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Adverse events 
To be collected from the date that the ICF is signed through the last study visit 
Concomitant medications 
To be collected from within 14 days prior to Day 0 through the last study visit 
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SYNT001-103 
 
18 September 2018 
Protocol Amendment Summary of Changes 
 
Amendment 5.0 
 
Confidential 
Page 1 of 6 
Syntimmune, Inc. 
PROTOCOL AMENDMENT 
SUMMARY OF CHANGES 
 
Protocol Title: 
A Phase 1b/2, Multicenter, Open-Label, Safety, and Dose-Finding Study of 
SYNT001 in Subjects with Pemphigus (Vulgaris or Foliaceus) 
 
 
Protocol Number: 
SYNT001-103 
 
 
Study Drug: 
SYNT001 
 
 
Sponsor: 
Syntimmune, Inc. 
116 Huntington Avenue 
Suite 301 
Boston, MA 02116 
 
 
Medical Monitor: 
 
Wallace House 
17-21 Maxwell Place Stirling, Scotland FK81JU 
Mobile Phone: 
 
Office Phone: 
 ext. 
 
 
 
Original Protocol: 
18 January 2017 
Amendment 1.0: 
21 March 2017 
Amendment 2.0 
12 April 2017 
Amendment 3.0 
10 October 2017 
Amendment 4.0 
08 June 2018 
Amendment 5.0 
18 September 2018 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document is the property of Syntimmune, Inc. This document contains confidential information, which should 
not be copied, referred to, released, or published without written approval from Syntimmune. Investigators are 
cautioned that the information given in this brochure might be subject to change and revision. Any conclusion 
regarding efficacy and safety must be considered provisional. 
 
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SYNT001-103 
 
18 September 2018 
Protocol Amendment Summary of Changes 
 
Amendment 5.0 
 
Confidential 
Page 2 of 6 
Syntimmune, Inc. 
BACKGROUND 
Protocol amendment Version 5.0 of the SYNT001-103 protocol was issued on 18 September 
2018.  
Syntimmune is amending the SYNT001-103 protocol to adjust the dosing schedule and cohort 
options. Because enrollment in Cohort 1 is complete, subjects will be enrolled in Cohort 2 which 
will now evaluate 3 weekly loading doses followed by 5 every other week maintenance doses, 
with the option to adjust to weekly dosing, if needed. Most updates in the amendment were 
incorporated to reflect this change, as well as refine how the ongoing safety of subjects in Cohort 
2 would be monitored. The number of sites was increased to aid in enrollment and PDAI and 
photography assessments are now included at every post-treatment visit for Cohort 2 to better 
assess efficacy. PDAI also assessment added at screening for Cohort 2. 
General grammatical, typographical, and formatting updates have been made throughout the 
document to provide consistency and clarity, reduce redundancy, and improve readability. These 
changes are not detailed in the summary below. Please see Amendment 5 for details. 
 
 
Alexion Confidential
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SYNT001-103 
 
18 September 2018 
Protocol Amendment Summary of Changes 
 
Amendment 5.0 
 
Confidential 
Page 3 of 6 
Syntimmune, Inc. 
SUMMARY OF CHANGES 
With this update, the following changes since Version 4.0 have been made: 
Table 1. 
Summary of Changes: Protocol Version 5.0 
Section Number 
and Title 
Description of Change 
Sponsor 
Signature 
The name of the Sponsor Representative has been updated. 
Section 1, 
Protocol Synopsis  
Below is a summary of changes to the protocol synopsis; refer to the 
changes described for the individual protocol sections for more detail: 
 Increased the number of study sites from 10 to 20 global sites to 
support subject enrollment. 
 Study objectives and endpoints were updated to reflect changes to the 
dosing regimen (every other week in maintenance phase), to clarify 
that serum is used for pharmacokinetic analyses, and to update how 
analysis summaries will be presented. 
 The Study design and Methodology sections have been merged. 
 The Study design not only describes changes to cohorts but also 
includes the role of the Dose Escalation Committee (DEC), Sponsor 
Medical Lead, and stopping and dose escalation rules. 
 The Number of subjects section has been updated to reflect the 
changes in the number of subjects and that Cohort 1 may enroll “up 
to” 8 subjects and Cohort 2 may enroll “up to” 12 subjects. 
 The Study population section was modified to better define the 
population.  
 Inclusion criterion #4a was updated to reduce the last previous dose of 
rituximab or other anti-CD20 monoclonal antibodies from >12 months 
to >9 months prior to screening. 
 Inclusion criterion #9 was updated to reflect that male subjects are 
only required to use contraception through the final study visit.  
 Exclusion criterion #12 was updated to specify “at screening.” 
 Additional detail regarding dose/cohort changes has been added to 
Study drug, dosage, and administration and Duration of subject 
participation sections. 
 More detail was added for clarity regarding corticosteroids. 
 In the statistical consideration section, analyses have been updated to 
reflect changes to the dosing regimen (every other week in 
maintenance phase) and to update how analysis summaries will be 
presented. 
Study Diagram 
Study Diagram has been added for clarity around the changes to study 
design and the reduction in the number of cohorts to 2. 
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SYNT001-103 
 
18 September 2018 
Protocol Amendment Summary of Changes 
 
Amendment 5.0 
 
Confidential 
Page 4 of 6 
Syntimmune, Inc. 
 Cohort 2 has been modified to 3 weekly loading doses of 30 mg/kg 
followed by 5 every other week doses of 10 mg/kg and the number of 
subjects enrolled will be up to 12. 
 The original Cohort 2 and optional Cohort 4 were removed. 
 The Sponsor Medical Team will conduct the 24-hour and 7-day safety 
reviews for subjects in Cohort 2. 
 Ongoing safety review may result in may modified dosing regimen 
(e.g. 10 weekly maintenance doses at 10-30 mg/kg). 
Schedule of 
Events 
Tables 3 and 4 (original Cohort 2 and Cohort 3) were deleted. 
 
Table 3 (Cohort 2): This table reflects a new dosing schedule with loading 
and maintenance doses, as well as the increase of PDAI and photography 
assessments to every post-treatment visit. PDAI also added at screening. 
See Table 3 for details. 
List of 
Abbreviations 
The table was updated to include all abbreviations throughout the synopsis 
and protocol text. Each abbreviation was defined the first time used in 
both the synopsis and protocol text. 
Section 2, 
Background and 
Rationale 
Background and Rationale 
 Text has been added to describe SYNT001’s predicted mechanism of 
action  
 Additional indications identified as IgG-mediated autoimmune 
disorders have been removed  
Selection of Doses in this Study 
 Details of mathematical modeling of study dose selection were added. 
 Details of non-clinical and clinical studies supporting the proposed 
Cohort 2 dose and dosing regimen were added. 
Section 3, Study 
Objectives and 
Endpoints 
 Study objectives and endpoints were updated to reflect changes to the 
dosing regimen (every other week in maintenance phase), to clarify 
that serum is used for pharmacokinetic analyses, and to update how 
analysis summaries will be presented. 
 The secondary objectives were reordered to reflect their importance. 
Section 4, Study 
Drug 
Description of SYNT001 
 Added that Investigators are allowed to adjust the duration of the 
infusion to increase tolerability up to 4 hours, if needed. 
Dose Requirements 
 It has been clarified that subject doses will be limited to 5000 mg. A 
subject with a body weight that extrapolates to a dose > 5000 mg, will 
only receive 5000 mg. 
Section 5, Study 
Design 
The number of study sites was increased from 10 to 20. 
The study design has been updated to reflect changes in dosing regimen 
for Cohort 2. 
 Cohort 1 number of subjects has been modified from 8 to up to 8. 
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SYNT001-103 
 
18 September 2018 
Protocol Amendment Summary of Changes 
 
Amendment 5.0 
 
Confidential 
Page 5 of 6 
Syntimmune, Inc. 
 Cohort 2 has been modified to 3 weekly loading doses of 30 mg/kg 
followed by 5 every other week doses of 10 mg/kg and the number of 
subjects enrolled will be up to 12. 
 Original Cohort 2 and optional Cohort 3 were removed. 
 The Sponsor Medical Team will conduct the 24-hour and 7-day safety 
reviews for Cohort 2. 
 Ongoing safety review may result in may modified dosing regimen 
(e.g. 10 weekly maintenance doses at 10-30 mg/kg). 
 Duration of Subject Participation was added to the body of the 
protocol for consistency with the synopsis. 
Section 6, Study 
Population 
Target Population 
 Based on the new study design, the total number of subjects has been 
changed to a maximum of 20 subjects, but the number is not included 
in this section, just a description of the study population.  
Inclusion Criteria 
 Inclusion criterion #4a was updated to reduce the last previous dose of 
rituximab or other anti-CD20 monoclonal antibodies from >12 months 
to >9 months prior to screening. 
 Inclusion criterion #9 was updated to reflect that male subjects are 
only required to use contraception through the final study visit.  
Exclusion Criteria 
 Exclusion criterion #12 was updated to specify “at screening.” 
Section 7, Study 
Procedures 
 References to specific days have been removed because of the 
addition of the separate Cohort 2 table and possibility of following the 
optional weekly schedule in Appendix 3. 
 Virology assessments were removed from Table 6 because they are 
not included with clinical laboratory panels. 
 PK parameters studied in Cohort 1 differ from (the) successive 
cohort(s) and which include maximum serum concentration of 
SYNT001 and the associated Tmax. 
 Pharmacodynamic Assessment (Table 7) has been updated to include 
timing of testing for Cohort 2  
 A subsection re: corticosteroid use was added for clarity. 
Section 8, Study 
Assessments 
Sections were edited to reflect the updates to assessments performed in 
the new schedule of events for Cohort 2. See Section 8 for details. 
Section 9, Study 
Rules 
Subject Withdrawal 
 Details were added to distinguish between follow up assessments for 
subjects who prematurely discontinue study drug versus subjects who 
prematurely discontinue from the study. 
 Details were added to specify which study visits the subject should be 
encouraged to attend in each case above. 
Stopping Rules 
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SYNT001-103 
 
18 September 2018 
Protocol Amendment Summary of Changes 
 
Amendment 5.0 
 
Confidential 
Page 6 of 6 
Syntimmune, Inc. 
 The description of dose escalation stopping rules now reflects that 
Cohort 2 will not be a dose escalation cohort.  
 Decisions regarding study stopping rules originally to be made by the 
DEC were updated to be decided by the Sponsor Medical Lead. 
Section 10, 
Evaluation of 
Safety 
No substantial changes were made to this section; only updates to 
abbreviations and minor corrections for consistency. 
Warnings and Precautions 
 Allowed vaccinations were updated to 28 days after the final dose of 
study drug rather than discretion of investigator. 
Section 11, 
Statistical 
Considerations 
“Data” was updated to “analysis” in headings. 
Details of analyses have been updated to reflect changes to the dosing 
regimen (every other week in maintenance phase) and to update how 
analysis summaries will be presented. 
Safety Analysis 
 More detail was added to the safety analyses to be performed. 
 Relationship of adverse events (AEs) to study drug was defined as in 
the AE section (related/not related). 
 The lab analyses were updated to be formed by a central laboratory. 
Pharmacokinetic Analysis 
 PK and PD analyses were moved to separate sections. 
 Details were made more general to cover different analyses performed 
in the 2 cohorts.  
Pharmacodynamic (PD) Analysis 
 Details of the presentation of disease activity marker results were 
added. 
Sections 12-14 
No edits other than global changes mentioned below. 
Appendix 5 
Appendix was added to include an alternate schedule of events for 
Cohort 2 (weekly dosing) 
Global Changes 
 Edits and formatting changes have been made throughout to improve 
clarity and readability. 
 Typographical and formatting corrections as well as corrections for 
consistency have been made. 
 
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SAP_000.pdf: 
A Phase 1b/2, Multicenter, Open-Label, Safety, and 
Dose-Finding Study of SYNT001 in Subjects with 
Pemphigus (Vulgaris or Foliaceus) 
 
 
Unique Protocol ID: 
SYNT001-103 
NCT Number: 
NCT03075904 
Date of SAP:  
25 March 2019 
 


Clinical Study Report 
 
SYNT001-103 
16.1 Study Information 
 
 
 
 
 
Alexion Confidential 
 
9. 
DOCUMENTATION OF STATISTICAL METHODS 
• Statistical Analysis Plan Version 1.0, 25 March 2019 


Alexion Pharmaceuticals Inc. 
Protocol SYNT001-103 
CONFIDENTIAL 
V1.0 
 
 
 March 25, 2019 
 
 
 
Page 1 of 30 
 
 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL SYNT001-003 
 
A Phase 1b/2, Multicenter, Open-Label, Safety, and Dose-Finding Study of 
SYNT001 in Subjects with Pemphigus (Vulgaris or Foliaceus) 
 
 
 
 
Investigational Product: 
SYNT001 
Protocol Number: 
SYNT001-103 
Development Phase: 
Phase 1b/2 
Sponsor: 
Alexion Pharmaceuticals Inc. 
121 Seaport Blvd 
Boston, MA 02210 
 
 
 
 
 
Original Protocol: January 18, 2017 
Amendment 1.1: March 21, 2017 
Amendment 2.0: April 12, 2017 
Amendment 3.0: October 19, 2017 
Amendment 4.0: June 8, 2018 
Amendment 5.0: Sep 18, 2018 
 
SAP Version V1.0 
SAP Date: March 25, 2019 
 
 
 
Alexion Confidential
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Alexion Pharmaceuticals Inc. 
Protocol SYNTOOl-103 
SIGNATURE PAGE 
CONFIDENTIAL 
VJ.O 
March 25, 2019 
STUDY TITLE: A Phase 1 b/2, Multicenter, Open-Label, Safety, and Dose-Finding Study of 
SYNTOOl in Subjects with Pemphigus (Vulgaris or Foliaceus) 
Prepared by: 
 
 
Medpace 
We, the undersigned, have reviewed and approved this statistical analysis plan. 
Signature 
Medpace 
Medpace 
Alexion Pharmaceuticals Inc. 
Alexion Pharmaceuticals Inc. 
Date 
:; 3 /Zfcud &(5 
' 
25/I)(A:R 2D lj 
Page 2 of30 
Alexion Confidential
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Alexion Pharmaceuticals Inc. 
Protocol SYNT001-103 
CONFIDENTIAL 
V1.0 
 
 
 March 25, 2019 
 
 
 
Page 3 of 30 
 
Document History 
Version 
Date 
Comments 
1.0 
March 25, 2019 
Original version 
 
 
Alexion Confidential
Page 4 of 31


Alexion Pharmaceuticals Inc. 
Protocol SYNT001-103 
CONFIDENTIAL 
V1.0 
 
 
 March 25, 2019 
 
 
 
Page 4 of 30 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 6 
1. 
INTRODUCTION ..................................................................................................... 8 
2. 
STUDY OBJECTIVES AND ENDPOINTS............................................................. 8 
2.1 
Primary Objective and Endpoint ............................................................................... 8 
2.2 
Secondary Objective and Endpoint ........................................................................... 8 
2.3 
Exploratory Objective and Endpoint ......................................................................... 9 
3. 
STUDY OVERVIEW .............................................................................................. 10 
3.1 
Overall Study Design and Treatment Assignment .................................................. 10 
3.1.1 
Informed Consent .............................................................................................. 12 
3.1.2 
Demographics and Medical History ................................................................. 12 
3.1.3 
Physical Examination ........................................................................................ 12 
3.1.4 
Vital Sign Measurements .................................................................................. 12 
3.1.5 
Clinical Laboratory Measurements ................................................................... 13 
3.1.6 
Pregnancy Testing ............................................................................................. 13 
3.1.7 
Virology ............................................................................................................ 13 
3.1.8 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing ......... 13 
3.1.9 
Pharmacokinetics (PK) Sampling ..................................................................... 13 
3.1.10 Pharmacodynamic Sampling............................................................................. 13 
3.1.11 Immunogenicity Testing ................................................................................... 14 
3.1.12 12-Lead Electrocardiogram (ECG) ................................................................... 14 
3.1.13 Pemphigus Disease Area Index (PDAI)............................................................ 14 
3.1.14 Study Drug Administration ............................................................................... 14 
3.1.15 Photographs ....................................................................................................... 15 
3.1.16 Health-Related Quality of Life Assessments .................................................... 15 
3.1.17 Adverse Event Assessments.............................................................................. 15 
3.1.18 Prior and Concomitant Medications ................................................................. 15 
3.1.19 Skin Biopsy ....................................................................................................... 15 
4. 
STATISTICAL METHODOLOGY ........................................................................ 15 
4.1 
General Design ........................................................................................................ 16 
4.2 
Study Populations .................................................................................................... 16 
4.3 
Subject Disposition .................................................................................................. 16 
4.4 
Demographics and Baseline Characteristics ............................................................ 16 
4.5 
Prior and Concomitant Medications ........................................................................ 17 
4.6 
Study Medication Administration ........................................................................... 17 
4.7 
Safety Analyses ....................................................................................................... 18 
4.7.1 
Adverse Events ................................................................................................. 18 
4.7.2 
Clinical Laboratory Tests .................................................................................. 19 
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CONFIDENTIAL 
V1.0 
 
 
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Page 5 of 30 
 
4.7.3 
Physical Examination, Vital Signs, and Electrocardiogram Findings .............. 19 
4.8 
Dose Selection Analyses.......................................................................................... 20 
4.9 
Analysis of Secondary Endpoints ............................................................................ 20 
4.9.1 
Pharmacokinetic Analysis ................................................................................. 20 
4.9.2 
Pharmacodynamic/ Disease Activity Analysis ................................................. 21 
4.9.3 
Immunogenicity Analysis ................................................................................. 21 
4.9.4 
PDAI data .......................................................................................................... 21 
4.10 
Analysis of Exploratory Endpoints .......................................................................... 22 
4.10.1 Exploratory Pharmacodynamic/ Activity Analysis........................................... 22 
4.10.2 Corticosteroid Use............................................................................................. 22 
4.10.3 Health-Related Quality of Life Data ................................................................. 22 
4.10.4 Photography ...................................................................................................... 23 
4.10.5 Skin Biopsy ....................................................................................................... 23 
5. 
SAMPLE SIZE DETERMINATION ...................................................................... 23 
6. 
PROGRAMMING SPECIFICATIONS .................................................................. 23 
7. 
INTERIM ANALYSIS ............................................................................................ 23 
8. 
APPENDICES ......................................................................................................... 24 
 
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Protocol SYNT001-103 
CONFIDENTIAL 
V1.0 
 
 
 March 25, 2019 
 
 
 
Page 6 of 30 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ABQoL 
Autoimmune bullous diseases quality of life 
AE 
Adverse event 
AECA 
Anti-epithelial cell antibody 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under curve 
BLQ 
Below the limit of quantification 
BMI 
Body mass index 
C3 
Complement component 3 
CIC 
Circulating Immune Complexes 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DEC 
Dose Escalation Committee  
DLT 
Dose-limiting toxicities 
ECG 
Electrocardiogram 
FCGR2A 
Fc gamma R2A receptor 
GM 
Geometric mean 
HR-QoL 
Health-related quality of life 
IGA 
Immunoglobulin A 
IGG 
Immunoglobulin G 
IGM 
Immunoglobulin M 
IV 
Intravenous  
MED 
Minimum Effective Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
PD 
Pharmacodynamic 
PDAI 
Pemphigus Disease Area Index 
PE 
Physical Exam 
PK 
Pharmacokinetics  
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval Fridericia's formula 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
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Page 7 of 30 
 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SNP 
Single nucleotide polymorphisms 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
 
 
 
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Page 8 of 30 
 
1. 
INTRODUCTION 
This study is being conducted to evaluate the safety, dose, pharmacokinetics (PK), 
pharmacodynamics (PD) and immunogenicity of intravenous (IV) SYNT001 as well as its 
effects on pemphigus disease activity markers. 
Results obtained from the analysis outlined in this document will become the basis for the 
final Clinical Study Report (CSR) for this protocol.  This SAP supersedes the statistical 
considerations identified in the protocol; where considerations are substantially different, 
they will be so identified.  If additional analyses are required to supplement the planned 
analyses described in this SAP, they may be performed and will be identified in the CSR. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective and Endpoint 
Primary Objectives 
Primary Endpoints 
Safety: To evaluate the safety of IV 
infusions of SYNT001 at different dose 
levels and dosing regimens in subjects with 
pemphigus (vulgaris or foliaceus) 
Safety: The evaluation of SYNT001 safety 
based on vital signs, physical examinations, 
electrocardiograms (ECGs), clinical safety 
laboratory tests, the incidence of adverse 
events (AEs), treatment-emergent adverse 
events (TEAEs) and serious adverse events 
(SAEs) summarized by dose and dosing 
regimen, severity, and relationship to study 
drug 
Dose Selection: To determine a Minimum 
Effective Dose (MED) of SYNT001 as 
assessed by (i) total IgG level nadir and (ii) 
the proportion of subjects that meet the 
criteria for response by Pemphigus Disease 
Area Index total activity score (PDAI) 
Dose Selection: The determination of dose 
and dosing regimen of SYNT001 that 
achieves (i) total IgG level nadir decrease 
by ≥60% and ≤90% from baseline and (ii) a 
PDAI total activity score of ≥50% reduction 
from baseline to allow further clinical 
development in subjects with pemphigus 
(vulgaris or foliaceus) 
 
2.2 
Secondary Objective and Endpoint 
Secondary Objectives 
Secondary Endpoints 
To evaluate the efficacy of doses of 
SYNT001 at different dose levels and 
dosing regimens on pharmacodynamics 
(PD) biomarkers 
The evaluation of PD biomarkers based on 
absolute serum levels and percent change 
from baseline of total IgG, IgG subtypes 
(IgG1-4), immunoglobulin A (IgA), 
immunoglobulin M (IgM), albumin, and 
CIC summarized by dose, dosing regimen 
and visit 
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Page 9 of 30 
 
Secondary Objectives 
Secondary Endpoints 
To determine the pharmacokinetics (PK) of 
SYNT001 following IV infusions at 
different dose levels and dosing regimen 
The determination of PK parameters 
including half-life (t1/2), maximum serum 
concentration determined directly from the 
concentration-time profile (Cmax), observed 
time of peak serum concentration (Tmax), 
area under the serum concentration-time 
curve from pre-dose (time0) to 24 hours 
post-dose (AUC0-24), and area under the 
serum concentration-time curve from pre-
dose (time0) to infinity (AUC0-∞), (Cohort 
1); maximum serum concentration 
determined directly from the maximum 
serum concentration and corresponding Tmax 
(Cohort 2) summarized by dose, dosing 
regimen, visit and time point 
To assess the efficacy of doses of SYNT001 
at different dose levels and dosing regimens 
on disease markers 
• 
The assessment of pemphigus 
disease activity by responses on the PDAI 
based on absolute and percent change from 
baseline, summarized by dose, dosing 
regimen and visit. 
• 
The assessment of pemphigus 
disease activity by pathogenic antibody 
levels based on absolute and percent change 
from baseline of serum anti-desmoglein 1 
and 3 antibody (anti-Dsg 1 and anti-Dsg 3) 
levels summarized by dose, dosing regimen 
and visit 
To measure the immunogenicity of 
SYNT001 administered at different dose 
levels and dosing regimens 
The immunogenicity of SYNT001 as 
determined by presence of anti-SYNT001 
binding antibodies and neutralizing 
antibodies summarized by dose, dosing 
regimen, visit and time point 
 
2.3 
Exploratory Objective and Endpoint 
Exploratory Objectives 
Exploratory Endpoints 
To explore the effect of SYNT001 at 
different dose levels and dosing regimens 
on biomarkers to understand the 
pathophysiology of the disease and the 
SYNT001 mechanisms of action 
The exploration of SYNT001 mechanisms 
of action and effects of SYNT001 on 
pathophysiology summarized by dose, 
dosing regimen and visit as determined by: 
 
Complement component 3 levels by 
nephelometry 
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Exploratory Objectives 
Exploratory Endpoints 
 
Anti-epithelial cell antibody 
(AECA) titers by indirect 
immunofluorescence 
 
Fc gamma R2A receptor (FCGR2A) 
single nucleotide polymorphisms 
(SNP) by genotyping 
 
Presence of disease and 
inflammatory markers by total RNA 
sequencing 
 
Immunophenotyping including 
measurements of T cells, monocytes, 
natural killer (NK) cells and B cells 
by flow cytometry 
 
Urine IgG levels to explore 
SYNT001 distribution and 
elimination (Cohort 1 only) 
 
Exploratory biomarkers to 
investigate immune response 
associated with pemphigus 
To determine the impact of different 
SYNT001 dose levels and dosing regimens 
on the subject’s use of corticosteroids to 
treat their pemphigus (vulgaris or foliaceus) 
The evaluation of corticosteroid use during 
the study will be summarized by dose, 
dosing regimen and visit 
To assess the impact of SYNT001 on the 
subject’s health-related quality of life (HR-
QoL) at different dose levels and dosing 
regimens 
The assessment of SYNT001 impact on 
subject’s health-related quality of life (HR-
QoL) by responses to the Autoimmune 
Bullous Diseases Quality of Life (ABQoL) 
questionnaire and Skindex-29 scores 
summarized by dose, dosing regimen and 
visit 
To assess the effect of SYNT001 on the 
appearance of skin and mucosal lesions at 
different dose levels and dosing regimen 
The qualitative assessment of changes in 
appearance of skin and mucosal lesions as 
determined by photography presented by 
dose, dosing regimen and visit 
To quantify the amount of SYNT001 in skin 
(skin biopsies optional) 
The determination of SYNT001 levels in 
skin biopsies across time points (skin 
biopsies optional) (Cohort 1 only) 
 
3. 
STUDY OVERVIEW 
3.1 
Overall Study Design and Treatment Assignment 
This is a multicenter, open-label safety study to determine the dose regimen of SYNT001 
administered IV in subjects with pemphigus (vulgaris or foliaceus). Up to 8 subjects with a 
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diagnosis of pemphigus (vulgaris or foliaceus) will receive SYNT001 10 mg/kg weekly x 5 
doses (Cohort 1). Up to 12 subjects with a diagnosis of pemphigus (vulgaris or foliaceus) will 
receive SYNT001 30 mg/kg weekly x 3 doses (Loading), followed by SYNT001 10 mg/kg 
every other week x 5 doses (Maintenance) (Cohort 2). 
Subjects in both cohorts will complete the following periods of assessment: Screening, 
Treatment, and Follow-Up. 
The Dose Escalation Committee (DEC) will consist of the Medical Monitor, an Independent 
Clinical Expert and the Sponsor Medical Lead. The DEC may request that Investigators, 
other experts, or members within their organization participate in the review. Additional 
information on the DEC’s responsibilities is provided in Protocol Section 9.5 and the DEC 
Charter. 
An overview of the study cohorts is provided in Table 1. 
Table 1. Cohort Overview 
Cohort No. 
No. of 
subjects 
SYNT001 Dose No. of Doses 
 Frequency of Doses 
1a 
Up to 8 
10 mg/kg 
5 
NA 
2b 
Up to 12 
Loading: 30 
mg/kgc 
Maintenance: 
10 mg/kgc 
3c 
 
5c 
 Weeklyc 
 
Every other weekc, d   
a. No more than 3 subjects with pemphigus foliaceus may be enrolled 
b. Two or fewer subjects with pemphigus foliaceus may be enrolled 
c. The dose, number of doses, and frequency of doses in Cohort 2 will be confirmed based on 
review of safety and PD evaluations, including but not limited to, dose-limiting toxicities, 
AEs, TEAEs, SAEs, and total IgG levels. Following Sponsor review of emerging safety, PD 
and efficacy data, the Loading dose may be reduced to 20 or 10 mg/kg weekly and/or the 
Maintenance dose may be increased to 20 or 30 mg/kg every other week and/or dose 
frequency may be increased to weekly.  
d. Ongoing safety and PD evaluations may result in modification of the dose and dosing 
regimen in Cohort 2. See Protocol APPENDIX 5 for the corresponding visit schedule.  
 
The duration of subject participation for each cohort is as follows: 
Cohort 
Screening 
Treatment 
Follow-up 
Maximum Total 
Days 
Weeks 
1 
≤14 days 
28 days 
84 days 
126 days 
18 weeks 
2 
≤14 days 
84 days 
56 days 
154 days 
22 weeks 
Subjects will be enrolled at staggered intervals to facilitate adequate safety evaluation before 
dosing of subsequent subjects.  
Refer to Table 2 and Table 3 for detail study assessments and Table 4 for Timing Windows 
for PK/PD Sampling, ECG, and Vital Sign Measurements.  
 
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3.1.1 
Informed Consent 
All subjects must take part in the informed consent process. Adequate time must be allowed 
for the subject to ask questions and make a voluntary decision. No protocol-specific 
procedures, including screening procedures are to be performed until the subject has signed 
and dated an IRB-approved ICF. Subjects may withdraw consent at any time. Participation in 
the study may be terminated at any time without the subject’s consent as determined by the 
Investigator. 
3.1.2 
Demographics and Medical History 
Demographics (age, gender, race and ethnicity) and medical history will be obtained from the 
subject and recorded on the source document and electronic case report form (eCRF). 
Medical history will capture the subject’s current medical history (current disease processes), 
past medical status (past disease processes), history of surgery, concomitant treatments, and 
relevant clinical response to past disease specific treatments including duration and dosing of 
such treatments. 
3.1.3 
Physical Examination 
A complete physical examination will include measurements of weight (in kg) and height (in 
cm; height to be measured only at screening visit) and a review of the following body 
systems: 
 
General appearance 
 
Head, eyes, ears, nose, and throat 
 
Neck 
 
Respiratory 
 
Cardiovascular 
 
Abdomen 
 
Neurologic 
 
Extremities 
 
Dermatologic 
 
Lymphatic 
Any abnormal and clinically significant findings from the physical examination must be 
recorded in the appropriate eCRF. All clinically significant findings at screening and Day 0 
(pre-dose) will be recorded as medical history. All clinically significant findings after the first 
dose will be reported as adverse events. 
3.1.4 
Vital Sign Measurements 
Vital sign assessments will include measurements of sitting blood pressure (mm Hg), heart 
rate (beats per minute), respiration rate (breaths per minute), pulse oximetry, and oral 
temperature (Celsius). Abnormal results are to be repeated after 5 minutes of rest. See Table 
4 for timing window allowances with respect to measurement collection. 
When vital signs are to be collected at the same time point as a blood collection, vital signs 
should be collected first. Vital sign measurements will be collected after the subject has been 
sitting for 5 minutes. Subjects should be seated quietly for at least 5 minutes in a chair with 
their backs supported, their feet flat on the floor (legs uncrossed), and their arms bared on a 
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hard surface, with the arm slightly abducted and bent, with palm up and the midpoint of 
upper arm at heart level. Correct cuff and bladder size should be utilized and the same cuff 
and arm should be used per subject throughout study. 
Vital sign measurements are to be obtained immediately prior to the infusion; 15, 30, and 45 
minutes after the start of the infusion; at completion of the infusion; 30 minutes, 1 hour, and 2 
hours following completion of the infusion. Abnormalities in vital sign measurements will be 
graded in severity per the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) scale Version 4.03. 
3.1.5 
Clinical Laboratory Measurements 
Laboratory testing (hematology, urinalysis, serum chemistry, virology, serology, pregnancy 
tests, PD, PK, and ADA) will be performed using established methods by a central 
laboratory. 
Abnormalities in clinical laboratory tests that are considered clinically significant are to be 
recorded on the AE eCRF page. Laboratory results will be graded using the NCI CTCAE, 
Version 4.03. 
3.1.6 
Pregnancy Testing 
Pregnancy testing will be performed for women of childbearing potential. Urine or serum test 
is acceptable; however, positive urine tests must be confirmed with serum testing. 
3.1.7 
Virology 
Testing for hepatitis C antibody, hepatitis B surface antigen, and HIV antibody will be 
performed at screening. 
3.1.8 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing 
Samples for serum tetanus antibody and VZV antibody testing are to be collected. Any 
subject whose baseline value for tetanus or VZV was above the protective level at baseline, 
and is not within 30% of the baseline value or is below the protective level by the end-of-
study visit, will be referred to their primary care physician for further management. 
3.1.9 
Pharmacokinetics (PK) Sampling 
The following PK parameters will be studied in Cohort 1: t1/2, Cmax, Tmax, AUC0-24, and 
AUC0-∞.  
For Cohort 2, the PK parameters studied will be maximum serum concentration of SYNT001 
and the associated Tmax. Specific collection times are detailed in Table 4.  
3.1.10 
Pharmacodynamic Sampling 
PD samples will be collected for analyses throughout the study. Measurements for albumin 
will be derived from the clinical safety laboratory results. Specific collection times are 
detailed in Table 5. 
Samples for each type of PD will be collected according to the schedule shown in Table 5. 
 
 
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3.1.11 
Immunogenicity Testing 
SYNT001 is being developed for the acute and chronic therapy of autoimmune disorders. 
Although SYNT001 is a humanized IgG4 mAb, exposure to SYNT001 in clinical trials could 
result in the development of ADAs, with potential consequences ranging from neutralization 
with possible lessening of drug efficacy to safety consequences such as allergic reactions. 
Testing will first detect binding ADAs. Then, for all confirmed positive samples, an ADA 
titer will be determined and there will be testing for neutralizing antibodies using a validated 
cell-based assay. 
3.1.12 
12-Lead Electrocardiogram (ECG) 
On dose administration days, digital 12-lead ECG measurements will be obtained at 5 
minutes after the completion of the infusion. When ECGs are to be collected at the same time 
point as a blood collection, ECGs should be collected first. All ECGs are to be performed 
with the subject in a supine position having rested in this position for at least 5 minutes 
before each reading. ECGs are to be performed in triplicate, each at an interval of 1 to 2 
minutes apart (Cohort 1) or approximately 1 minute apart (Cohort 2). See Table 4 for timing 
window allowances with respect to performing ECG. 
The following ECG parameters will be collected: PR interval, RR interval, QRS interval, and 
QT interval. The ECG findings will be evaluated by a qualified physician for the presence of 
abnormalities (qualitative assessment). The physician will assess each ECG as normal, 
abnormal/not clinically significant, or abnormal/clinically significant. 
Normal corrected QT interval using Fridericia’s formula (QTcF) is ≤450 msec. 
Abnormalities in the ECG that appear following therapy or that result in clinical signs and 
symptoms are considered clinically significant for the purposes of this study and will be 
recorded on the AE eCRF. 
3.1.13 
Pemphigus Disease Area Index (PDAI) 
Pemphigus severity and disease activity will be measured using the PDAI in regions where a 
validated questionnaire is available. A PDAI total activity score will be determined at 
screening. 
To be eligible for study participation, the patient’s grade by disease severity must be >4. 
Assuming subject eligibility, the PDAI will be administered during Treatment Period and 
Follow-up Period. Disease severity categories by PDAI are mild (0 to 8), moderate (9 to 24), 
and severe (≥25) (Shimizu et al., 2014). The Investigator will determine a PDAI score as 
follows: 0 to 250 points for disease activity (≤120 for skin, ≤10 for scalp, and ≤120 for 
mucosa), and 0 to 13 points for damage (≤12 for skin and ≤1 for scalp) (Rosenbach et al., 
2009). 
3.1.14 
Study Drug Administration 
SYNT001 will be given as a 250-mL IV infusion over 1 hour ± 15 minutes using a 0.2-
micron, inline filter. 
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3.1.15 
Photographs 
Photographs will be taken of active lesions and follow-up photographs will be taken of the 
same areas at timepoints indicated in Table 2 and Table 3. Subjects who begin a steroid taper 
will have additional photographs taken at the clinic visit during which the decision to begin 
the taper is made. 
3.1.16 
Health-Related Quality of Life Assessments 
For Cohort 2, health-related quality of life will be assessed using ABQoL and Skindex-29 in 
regions where a validated questionnaire is available. The ABQoL questionnaire was 
developed in Australia as a patient-based measure to quantify disease burden, monitor disease 
activity and evaluate response to therapeutic intervention in patients with autoimmune 
bullous disease (Sebaratnam et al., 2013; Sebaratnam et al., 2015). Skindex-29 was 
developed to measure the effects of skin disease on patients’quality of life using a self-
administered 30-question dermatology survey (Chren et al., 1996). 
3.1.17 
Adverse Event Assessments 
Information regarding the occurrence of AEs will be collected from the time the subject signs 
the informed consent form and continuing through the last study visit. Findings at screening 
and Day 0 (pre-dose) will be recorded as medical history. Any known untoward event that 
occurs beyond the AE reporting period that the Investigator assesses as related to study drug 
also should be reported as an AE. Clinical AEs will be graded using the NCI CTCAE, 
Version 4.03. 
3.1.18 
Prior and Concomitant Medications 
All non-pemphigus treatments a subject receives within 14 days prior to enrollment (Day 0) 
through the last study visit will be collected. All immunosuppressants, corticosteroids or 
blood transfusions a subject has received in 3 months (90 days) prior to enrollment and all 
rituxan cycles a subject has received in 5 years prior to enrollment will also be documented. 
3.1.19 
Skin Biopsy 
In Cohort 1, optional skin biopsy samples from lesional or non-lesional skin will be collected 
to analyze SYNT001 levels. 
4. 
STATISTICAL METHODOLOGY 
All descriptive and inferential statistical analyses will be performed using Statistical Analysis 
System (SAS®) software Version 9.4 or higher.  
Phoenix WinNonlin Version 6.4 or higher will be used in the determination of the PK 
terminal phase and the calculation of PK parameters. PK parameters will be calculated via 
SAS and verified with the Phoenix WinNonlin results. 
Missing data will not be imputed unless otherwise stated. All clinical data captured will be 
provided in data listings. 
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4.1 
General Design 
All clinical data captured will be provided in data listings. Subject disposition, demographic 
information, and baseline characteristics will be presented. Baseline will be defined at the last 
value obtained prior to the first dose of study drug. Results will be summarized by dose and 
dosing regimen (cohort), and in total. Any discrepancy between treatment to be given and 
treatment received will be accounted for in these displays. 
Continuous data will be summarized using descriptive statistics: number of subjects (N), 
number of observations (n), mean, median, standard deviation (SD), minimum, and 
maximum. 
Categorical data will be summarized using frequencies and percentages. When categorical 
data will be presented, the percent will be suppressed when the count is zero to draw attention 
to the non-zero counts. The denominator for all percentages, unless otherwise specified, will 
be the number of subjects in the specified analysis population. 
4.2 
Study Populations 
Three sub-populations will be employed in the analysis of study data: 
 The Safety population will consist of all subjects who received at least one dose of 
study drug. 
 
 The PD population will consist of all subjects who received at least one dose of study 
drug and have post-dose PD data available. 
 
 The PK population will consist of all subjects who received at least one dose of 
study drug and have post-dose PK data available. 
Primary safety analyses will be performed on the Safety population. Demographics, subject 
disposition, screening, and baseline characteristics will be summarized for the Safety, PK and 
PD populations, where appropriate. 
4.3 
Subject Disposition 
Counts and percentage of subjects who are in each study population (Safety, PK and PD 
populations), who complete the study, and who withdraw early from the study will be 
presented by cohort and in total. The primary reasons for early withdrawals will also be 
tabulated.  
Subject disposition, inclusion / exclusion criteria and comments will be listed. 
A listing of all screen failures (i.e., subjects who were screened but not enrolled) will be 
presented along with reasons for screen failure. 
4.4 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized descriptively by cohort and in 
total for the Safety population and repeated for PK and PD populations if they are different 
from the Safety population.   
Demographic and baseline characteristics include, but are not limited to, age at informed 
consent, gender, race, ethnicity, body weight, body mass index (BMI), age at diagnosis of 
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pemphigus, pemphigus disease duration at Day 0, type of pemphigus, type of tissue-based 
test positive for pemphigus, tissue-based test positive for pemphigus duration at Day 0, 
current exacerbation duration at Day 0.   
Continuous variables (e.g., age, weight, and BMI) will be summarized by descriptive 
statistics. Categorical variables (e.g., gender, race, and ethnicity) will be summarized by the 
number and percentage of patients in corresponding categories.  
Baseline is defined as the Day 0 (pre-dose) measurement. If missing, the last measurement 
prior to the first study drug administration will be used as the baseline value. 
Medical/surgical history will be will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA 19.1) and summarized for the number and percentage for each System 
Organ Class (SOC) and preferred term by cohort and in total for the Safety population. 
A summary table for categories of protocol deviations will be produced for major protocol 
deviations. Protocol deviations will also be listed for the Safety population. 
4.5 
Prior and Concomitant Medications 
All medications administered during the study will be listed and coded using the most current 
version of WHO Drug Dictionary (WHO Drug Sept 2016E B2).   
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or 
stop date will be imputed. When the start date and the stop date are both incomplete for a 
subject, impute the start date first. See Appendix B for details on imputation rules.  
A listing of all prior and concomitant medications including the reported term, preferred 
term, and anatomical therapeutic chemical (ATC) class, start and stop dates, and other 
relevant data will be provided.   
The number and percentage of patients taking, prior medications, concomitant medications, 
and medication for potential infusion-related reactions (IRRs) will be summarized by cohort, 
ATC class, and preferred term. Concomitant medications include all medications taken on or 
after the first dose of the study drug. Prior medications include all medications taken before 
the first dose of study drug. 
4.6 
Study Medication Administration 
SYNT001 is provided in vials containing 5 mL SYNT001 (extractable volume) at a nominal 
concentration of 50 mg/mL. The product is supplied as a liquid at pH 6.5 ± 0.5. SYNT001 is 
diluted in dextrose 5% in water (D5W) to prepare the solution for infusion. SYNT001 will be 
infused via IV in 250 mL over 1 hour ± 15 minutes using a 0.2-micron, inline filter. 
Dose administered (mg/kg), percentage of total dose administered (%), total administration 
time (minutes), volume administered (mL) and number of vials used will be summarized at 
each scheduled visits by cohort.  
Percentage of total dose administered (%) = total dose administered / planned total dose * 
100%. 
Study medication administration data will be listed. 
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4.7 
Safety Analyses 
All statistical analysis of safety outcomes will be descriptive. Safety observations and 
measurements include AEs, treatment-emergent AEs (TEAEs), SAEs, clinical safety 
laboratory tests, vital sign measurements, physical examinations, and ECGs. The incidence of 
AEs, TEAEs and SAEs will be summarized by cohort, severity and relationship to study 
product. Baseline for safety parameters is defined as Day 0 (pre-dose) measurement. If 
missing, the last measurement prior to the first study drug administration will be used as the 
baseline value. 
4.7.1 
Adverse Events 
Adverse events data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA 19.1). Adverse events will be graded using the NCI CTCAE, Version 4.03. 
A treatment-emergent adverse event (TEAE) is defined as any AE that starts on or after the 
first dose of study drug or occurs prior to the first dose and worsens in severity on or after the 
first dose of study drug, during the treatment period and follow-up period.  
For AEs with partial start dates, non-missing date parts will be used to determine if the AE is 
treatment-emergent or not.  If a determination cannot be made using the non-missing date 
parts as to when the AE occurred relative to study drug administration, e.g. AE start year and 
month are the same as the year and month of the first dose of investigational product, then the 
AE will be classified as treatment-emergent. See Appendix B for details on imputation rules. 
An overview of TEAEs will be provided. The overview will summarize the subject incidence 
of the following information: 
 Any TEAEs 
 Worst NCI CTCAE grade of TEAEs  
 Drug-related TEAEs 
 Worst NCI CTCAE grade of drug-related TEAEs  
 Any study drug-related Grade 3 or greater TEAEs 
 TE-SAEs 
 Drug-related TE-SAEs 
 TEAE leading to discontinuation of study drug 
 Drug-related TEAE leading to discontinuation of study drug 
 TEAE leading to study drug interruption 
 Drug-related TEAE leading to study drug interruption 
 TEAE leading to study drug dose reduction 
 Drug-related TEAE leading to study drug dose reduction 
 Death 
TEAEs will also be summarized using SOC, preferred term and severity grade based on NCI 
CTCAE (Version 4.03). Drug-related TEAEs will be summarized by the same manner. 
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The incidence and percentage of subjects with at least 1 occurrence of a preferred term will 
be included, using the most severe grade. The number of events per preferred term will also 
be summarized.  
TEAEs, SAEs, and TEAEs leading to discontinuation of study drug, dose reduction or 
interruption will be listed. Duration of AEs will be determined and included in listings, along 
with action taken and outcome.  
4.7.2 
Clinical Laboratory Tests 
Laboratory results, percentage change and absolute change from baseline will be summarized 
by cohort, visit and time point using descriptive statistics. Incidence of laboratory 
abnormalities and laboratory NCI CTCAE (Version 4.03) will be summarized. Shift tables of 
CTCAE Grade for chemistry parameters (Normal, Grade 1, Grade 2, Grade 3, Grade 4, Grade 
3/4, Total, Missing) from baseline to each post-baseline time point showing number and 
percentage of subjects with movement between categories will be presented. The worst on-
study grade after the first study drug administration will be summarized.  
Baseline is defined as the Day 0 (pre-dose) measurement. If the baseline measurement is 
missing, the last measurement prior to the first study drug administration. 
Results for variables that are not coded will be presented in the listings as below, within, and 
above the normal limits of the local laboratory. 
4.7.3 
Physical Examination, Vital Signs, and Electrocardiogram Findings 
The number and percentage of subjects with normal, abnormal and clinical significant , 
abnormal but not clinically significant physical exam findings will be summarized by visit 
and dose. 
Vital sign measurements and change from baseline will be summarized at each scheduled 
time point by cohort using descriptive statistics. Baseline is defined as the Day 0 (pre-dose) 
measurement. If the baseline measurement is missing, the last measurement prior to the first 
study drug administration. 
Arithmetic mean of parameters from triplicate ECG will be calculated first for each subject at 
each planned time point. Then summary statistics of ECG test parameters (mean of triplicate) 
and change from baseline to each post-dose time point will be calculated. Shift tables for 
ECG test result category change (normal, abnormal not clinically significant, abnormal 
clinically significant) from baseline to each post-baseline time point showing number and 
percentage of subjects with movement between categories will be presented by treatment 
group. The worst overall interpretation at each visit from the three triplicate readings are 
summarized. 
The number and percentage of subjects with elevated QTcF during the post baseline period 
will be presented for the following categories: QTcF worsening to >450 msec, >480 msec, 
and >500 msec from baseline, and increase in QTcF from baseline >30 msec and >60 msec.   
Actual sampling times that are outside the scheduled sampling times window described in 
Table 5 will be excluded from summary statistics. 
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4.8 
Dose Selection Analyses 
The evaluation of SYNT001 based on total IgG levels and responses on the PDAI total 
activity score from baseline will be summarized using descriptive statistics. The number and 
proportion of patients that achieve the following criteria will be summarized (i) total IgG 
level nadir decrease by ≥60% and ≤90% from baseline and (ii) a PDAI total activity score of 
≥50% reduction from baseline to allow further clinical development in subject with 
pemphigus (vulgaris or foliaceus). 
4.9 
Analysis of Secondary Endpoints 
4.9.1 
Pharmacokinetic Analysis 
PK results for SYNT001 will be summarized by cohort, visit and time point. 
Descriptive statistics will be provided for the PK parameters including mean, SD, CV, 
median, minimum, and maximum.  
For calculation of mean concentrations and generation of mean concentration-time profiles, 
all below the limit of quantification (BLQ) values will be set to zero except when an 
individual BLQ falls between 2 quantifiable values, in which case it will be omitted. 
If there are values above the BLQ, but too sparse to allow full analysis, descriptive statistics 
will be performed on available values. 
PK concentrations will be summarized descriptively at each nominal time point by cohort 
using n, mean, SD, percent coefficient of variation (CV%), standard error, median, minimum, 
maximum, geometric mean, geometric CV%. 
Mean concentrations (±SD) of SYNT001 will be plotted on a linear and semi-logarithmic 
scale against nominal time points, by cohort.  Individual concentration for each subject will 
be plotted using original scale and semi-log scale.  
Study drug concentrations will be used to calculate the following PK parameters, if feasible: 
Parameters 
Description 
Cmax 
Maximum observed plasma concentration observed directly from 
data 
Tmax 
Time to reach maximum observed concentration directly from data  
λz 
Apparent first-order terminal elimination rate constant calculated 
by linear regression of the terminal linear portion of the log 
concentration vs. time curve 
t½ 
Terminal elimination half-life, calculated as ln(2)/ λz 
AUC0-24 
AUC from time zero to 24 hours post-dose administration 
AUC0-∞ 
AUC from time zero to infinity time (as AUC0-t + Clast/ λz, where 
Clast is the last quantifiable concentration) 
Actual sampling time will be used for PK calculations. Actual sampling times that are outside 
the scheduled sampling times window described in Table 4 will be excluded from summary 
statistics of PK concentrations but will still be used in the calculations of PK parameters.   
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The Linear Up Log Down method will be used in the computation of AUCs.  The PK 
parameters λz and t1/2 will not be presented for subjects who do not exhibit a terminal 
elimination phase in their concentration-time profiles.  
The constant λz will not be assigned if one of the following happens: 
1. Tmax is or is equal to one of the 3 last data points, 
2. The adjusted regression coefficient is less than 0.8, 
3. The percent of AUC0-∞ extrapolated exceeds 20%, 
4. The estimated elimination rate indicates a positive slope, or 
5. The terminal elimination phase is not linear (as appears in a semi-logarithmic scale) 
based on visual inspection. 
In cases where the constant λz is not assigned, the values of associated parameters (e.g., t1/2 
and AUC0-∞) will not be calculated. 
4.9.2 
Pharmacodynamic/ Disease Activity Analysis 
PD samples will be collected for analyses throughout the study. Samples for each type of PD 
will be collected according to the schedule shown in Table 5.  
PD and disease activity markers will include but not limited to following information: 
 Serum levels of total IgG, 
 IgG subtypes (IgG1-4),  
 Immunoglobulin A (IgA),  
 Immunoglobulin M (IgM),  
 Albumin,  
 CIC  
 Anti-Dsg 1 and 3 antibodies 
All PD/disease activity data will be summarized by cohort and visit. Descriptive statistics of 
PD will include mean, SD, median, minimum, and maximum. Mean (±SD) of values and 
percentage change and absolute change from baseline will also be plotted. 
4.9.3 
Immunogenicity Analysis 
Immunogenicity results including anti-SYNT001 antibody, anti-SYNT001 neutralizing 
antibodies and anti-SYNT001 antibodies titer available at the time of the database lock will 
be summarized by cohort, visit and time point. Descriptive statistics will include mean, SD, 
CV, median, minimum, and maximum. 
4.9.4 
PDAI data 
PDAI skin activity score (0-120), mucous membrane activity score (0-120), scalp activity 
score (0-10), skin damage score (0-12), scalp damage score (0-1), total activity score (0-250), 
and total damage score (0-13) will be summarized by cohort and visit. Higher score indicates 
higher impact of skin disease. Descriptive statistics will include absolute change from 
baseline, and percentage change from baseline.  
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PDAI total activity score ranges from 0 to 250. The number and percentage of subject will be 
summarized by disease severity category based on PDAI total activity score, such as 
mild (0-8), moderate (9-24), and severe (≥25).  
4.10 
Analysis of Exploratory Endpoints 
4.10.1 
Exploratory Pharmacodynamic/ Activity Analysis 
Exploratory PD and disease activity markers will include: 
 Complement component 3  
 AECA 
 FCGR2A 
 RNAseq 
 Immunophenotyping 
 Urine IgG levels to explore SYNT001 distribution and elimination (Cohort 1 only)  
 Exploratory Pemphigus Immune Response Biomarkers 
All exploratory PD/disease activity data will be summarized by cohort and visit. Descriptive 
statistics will include mean, SD, median, minimum, and maximum. Mean (±SD) of values 
and percentage change and absolute change from baseline will also be plotted. 
4.10.2 
Corticosteroid Use 
The number and percent of subjects who use corticosteroid will be summarized by cohort and 
visit. 
4.10.3 
Health-Related Quality of Life Data 
For Cohort 2, Autoimmune Bullous Disease Quality of Life (ABQOL) questionnaire total 
score will be calculated and summarized by visit.  
SKINDEX-29 is a three-dimensional, dermatology-specific HRQL questionnaire. Twenty-
nine items are combined to form three domains: symptoms, emotions, and functioning. The 
domain scores and an overall score are expressed on a 100-point scale, with higher scores 
indicating lower levels of quality of life.  
Domains/Scales 
Number of 
Items 
Cluster of Items 
Item 
reversion 
Direction of 
Domains 
Emotions 
10 
3; 6; 9; 12; 13; 15; 21; 
23; 26; 28 
No 
Higher score = 
higher impact 
of skin disease 
Symptoms 
7 
1; 7; 10; 16; 19; 24; 27 
Functioning 
12 
2; 4; 5; 8; 11; 14; 17; 
20; 22; 25; 29; 30 
Note: Item 18 is a single item, not included in scoring. 
All responses are transformed to a linear scale of 100. Transformed item scores: never = 0, 
rarely = 25, sometimes = 50, often = 75, and all the time = 100. A scale score is the mean of a 
patient’s responses to the items in a given scale. If responses to more than 25% of items are 
missing overall, the questionnaire is eliminated. If any scale has more than 25% of the 
responses missing, the scale is missing.  Scale scores are the average of non-missing items in 
a given scale. An item with multiple answers is considered missing. 
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For Cohort 2, three domain scores and the overall score from SKINDEX-29 will be 
summarized by visit.  
 
4.10.4 
Photography 
The quantitative photography data will not be part of the database. Only visit and date of 
collection will be listed in data listing. No summary table will be presented. 
4.10.5 
Skin Biopsy  
The quantitative skin biopsy data will not be part of the database. Only visit, date of 
collection and type of skin will be listed in data listing. No summary table will be presented. 
5. 
SAMPLE SIZE DETERMINATION 
Formal sample size calculations were not performed. The number of subjects was chosen 
based on feasibility and was considered sufficient to meet the study objectives.     
6. 
PROGRAMMING SPECIFICATIONS 
The programming specifications, including the mock-up validity listings, analysis tables, 
figures, and data listings, as well as the derived database specifications, will be prepared in 
stand-alone documents. The programming specification documents will be finalized prior to 
database lock. 
7. 
INTERIM ANALYSIS 
No interim analysis is planned. 
 
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8. 
APPENDICES 
Appendix A: Study Assessments and Timing Window 
Table 2. 
Study Assessments for Cohort 1 
 
Screening 
Treatment Period 
Follow-Up 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Time point (study day) 
−14 to −1 
0 
1 
(±1 h) 
2 
(±2 h) 
5p 
(±4 h) 
7 
(±6 h) 
12p 
(±6 h) 
14 
(±6 h) 
19p 
(±6 h) 
21 
(±6 h) 
28 
(±6 h) 
29 
(±1 h) 
30 
(±2 h) 
33 
(±4 h) 
42 
(±3 d) 
56 
(±5 d) 
84 
(±5 d) 
112 or 
ET (±5 
d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics/medical 
history 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
Physical examinationa 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryc 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Clinical safety labsd 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
X 
 
X 
Hepatitis and HIV screen 
X 
 
 
 
 
 
 
 
 
 
12-lead ECGf 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
Tetanus and VZV antibodiesg 
X 
 
 
 
 
 
 
X 
X 
X 
PDAI 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
PK samplingh 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
Immunogenicityi 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
Study drug administrationj 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Immunoglobulins (IgG, IgA, 
IgM) and IgG subtypes 
(IgG1-4)k 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Xq 
CIC 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-Dsg (1 and 3) antibody 
titers 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
C3 and AECAl 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
FCGR2A by buccal swabm 
X 
 
 
 
 
 
 
 
 
 
RNAseq 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
Urine IgG 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
Immunophenotypingn 
X 
 
 
 
 
 
 
X 
X 
 
 
Exploratory pemphigus 
immune response biomarkers 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Optional skin biopsy 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
Photographyo 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Adverse events 
To be collected from the date that the ICF is signed through the last study visit 
Concomitant medications 
To be collected from within 14 days prior to Day 0 through the last study visit 
Abbreviations: CIC = circulating immune complexes; d = days; ECG = electrocardiogram; ET = early termination; h = hour(s); HIV = human immunodeficiency virus; 
ICF = informed consent form; PDAI = Pemphigus Disease Area Index; PK = pharmacokinetic; VZV = varicella zoster virus. 
a. Complete physical examination, including weight, to be performed. Height and BMI will be additional assessments conducted at screening. 
b. Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and oral temperature) to be obtained after 5 minutes of seated rest. Any abnormal measurements are to 
be repeated after 5 minutes of rest. On Days 0, 7, 14, 21, and 28, vital sign measurements will be collected immediately prior to the infusion; 15, 30, and 45 minutes after the start of 
the infusion; at completion of the infusion; and 30 minutes, 1 hour, and 2 hours following completion of the infusion. 
c. Pulse oximetry: On Days 0, 7, 14, 21, and 28, pulse oximetry to be measured immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at completion 
of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion. 
d. Clinical safety labs: hematology, clinical chemistry, and urinalysis (See Protocol Section 7.5 for a complete list). Full clinical safety laboratory draws will be collected at screening 
and on Days 0, 7, 14, 21, 28, 33, 42, 56, 84, and 112. 
e. Pregnancy test (women of childbearing potential only): To be performed at time of screening, prior to first dose of SYNT001 on Day 0, and on Days 56 and 112. Urine or serum 
test is acceptable; however, positive urine tests must be confirmed with serum testing. 
f. Digital 12-lead ECG to be obtained in triplicate at least 1 to 2 minutes apart and after 5 minutes of rest in a supine position. See Protocol Section 7.6 for additional information. On 
Days 0 and 28 to be obtained 5 minutes after the completion of infusion. Day 12 ECG will be collected only if the visit is conducted at the study site. 
g. Serology: Testing at Day 56 will not be done for any subject whose baseline titer is below the level of detection. If the Day 56 results are greater than 30% below the baseline value, 
or if the subject falls below the level of detection, the subject will be re-tested at Day 84; if still below the baseline value (or level of detection), the subject will be re-tested at Day 
112. Any subject whose baseline value for tetanus or VZV was above the detectable level at baseline, and is not within 30% of the baseline value or is below the detectable level by 
Day 112, will be referred to their primary care physician for further management. See Protocol Section 7.5.3 for additional information. 
h. PK: Starting on Days 0 and 28, serum samples will be collected just prior to the start of study drug infusion (pre-dose), and at 5 minutes and 2, 4, 6, 24, and 48 hours after the end-
of-study drug infusion. Additional samples will be collected on Days 5 and 33. See Protocol Section 7.5.4 for additional information. 
i. Immunogenicity: Samples will be collected pre-dose when collected on dosing days. Samples will be collected on Days 0, 14, 28, 56, 84 and 112. See Protocol Section 7.5.6 for 
additional information. 
j. Prior to study drug infusion, SYNT001 drug product is to be diluted in dextrose 5% in water (D5W) to a total volume of 250 mL and administered intravenously over 1 hour using a 
0.2-micron inline filter. See Protocol Section 4 and Section 7.8 for additional information. 
k. Immunoglobulins (IgG, IgA, IgM) and IgG subtypes (IgG1-4): Collected for measurements of IgG, IgG subtypes (IgG1-4), IgA, IgM at every visit. On Days 0, 7, 14, 21, and 28, 
samples are collected prior to infusion of study drug. See Protocol Section 7.5.5 for additional information. 
l. Exploratory pharmacodynamic samples (C3 and AECA): Collected pre-dose when collected on dosing days. See Protocol Section 7.5.5 for complete information. 
m. Buccal samples to be collected and stored; pending review of clinical and pharmacodynamics assessments. 
n. Immunophenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B cells. 
o. Photographs of active lesions taken prior to first dose on Day 0. Follow-up photographs will be taken at Days 33, 56, 84 and 112. Subjects who begin a steroid taper will have 
additional photographs taken at the clinic visit during which the decision to begin the taper is made. 
p. Visit Days 5, 12, and 19 may be conducted via at-home nurse in lieu of a subject visit to the study site. 
q. Subjects will return to the clinic on Days 84 and 112 for follow-up visits. Subjects whose total IgG is not within 30% of their Day 0 baseline value and not above 500 mg/dL at the 
Day 112 visit will be referred for further management. 
 
 
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Table 3. 
Study Assessment for Cohort 2 
 
Visit Number 
Screening 
Loading 
Maintenance 
Follow-Up 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Time Point 
(Study Day) 
−14 to −1 
 
0 
Baseline 
 
7 
(±1 d) 
 
14 
(±1 d) 
 
28 
(±3 d) 
 
42 
(±3 d) 
56 
(±3 d) 
70 
(±3 d) 
84 
(±3 d) 
91 
(±5 d) or 
ET visit 
 
112 
(±5 d) 
140 
(±5 d) 
EOS 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics/medical history 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
Physical examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetryc 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical safety labsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy teste 
X 
X 
 
 
X 
 
X 
 
X 
Hepatitis and HIV screen 
X 
 
 
 
 
 
 
 
12-lead ECGf 
X 
X 
 
X 
X 
 
X 
 
X 
Tetanus and VZV antibodiesg 
X 
 
 
X 
 
X 
 
X 
PDAIh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplingi 
X 
X 
X 
X 
 
X 
 
 
Immunogenicityj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administrationk 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Immunoglobulins (IgG, IgA, IgM) and 
IgG subtypes (IgG1-4)l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
CIC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-Dsg (1 and 3) antibody titers 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C3 and AECAm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FCGR2A by buccal swabn 
X 
 
 
 
 
 
 
RNA sequencing 
X 
 
 
X 
 
X 
 
 
Immunophenotypingo 
X 
 
 
X 
 
X 
 
 
Exploratory pemphigus immune response 
biomarkers 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photographyp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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HR-QoL assessments 
X 
 
 
X 
 
X 
 
X 
Adverse events 
To be collected from the date that the ICF is signed through the last study visit 
Concomitant medications 
To be collected from within 14 days prior to Day 0 through the last study visit 
Abbreviations: CIC = circulating immune complexes; d = day(s); ECG = electrocardiogram; EOS = end of study; ET= early termination; FcGR2a= Fc gamma R2a receptor; HIV = 
human immunodeficiency virus; HR-QoL = health-related quality of life; ICF = informed consent form; Ig = immunoglobulin; PDAI = Pemphigus Disease Area Index; PK = 
pharmacokinetic; VZV = varicella-zoster virus 
a. Complete physical examination, including weight, to be performed. Height and body mass index will be additional assessments conducted at screening only.  
b. Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and oral temperature) to be obtained after 5 minutes of seated rest. Any abnormal measurements are to 
be repeated after 5 minutes of rest. Vital sign measurements will be taken on all study visits. On dosing days, vital sign measurements will be collected immediately prior to the 
infusion; 15, 30, and 45 minutes after the start of the infusion; at completion of the infusion; and 30 minutes, 1 hour and 2 hours following completion of the infusion.   
c. Pulse oximetry: On dosing days, pulse oximetry to be measured immediately prior to the infusion; 15, 30, and 45 minutes after the start of the infusion; at completion of the 
infusion; and 30 minutes, 1 hour, and 2 hours following completion of the infusion.  
d. Clinical safety labs: hematology, clinical chemistry, and urinalysis. See Protocol Section 7.5 for a complete list. Full clinical safety lab draws will be collected at screening and at 
all study visits prior to infusion if applicable.   
e. Pregnancy test (women of childbearing potential only): To be performed at time of screening and prior to dose on dosing days if applicable. Urine or serum test is acceptable; 
however, positive urine tests must be confirmed with serum testing.  
f. Digital 12-lead ECG to be obtained after 5 minutes of rest in the supine position and in triplicate approximately 1 minute apart. See Protocol Section 7.6 for additional information. 
On days of treatment, to be obtained approximately 5 minutes after the completion of infusion.   
g. Serology: Any subject whose baseline value for tetanus or VZV was above the protective level at baseline and is not within 30% of the baseline value or is below the protective 
level by End of Follow-up, will be referred to their primary care physician for further management. See Protocol Section 7.5.3 for additional information.  
h. PDAI will be administered at screening. Subject eligibility requires a PDAI total activity score >4. Thereafter, assuming eligibility, the PDAI will be administered during Treatment 
Period and Follow-up Period. See Protocol Section 7.7 for additional information.  
i. PK: Starting on dosing days, serum samples will be collected just prior to the start of study drug infusion (pre-dose) and at 5 minutes, 1 and 2 hours after the end of study drug 
infusion. See Protocol Section 7.5.4 for additional information.  
j. Immunogenicity: Samples will be collected pre-dose when collected on dosing days. See Protocol Section 7.5.6 for additional information.  
k. Prior to study drug infusion, SYNT001 drug product is to be diluted in dextrose 5% in water to a total volume of 250 mL and administered intravenously over 1 hour ±15 minutes 
using a 0.2-micron, inline filter. See Protocol Section 4 for additional information.  
l. Immunoglobulins (IgG, IgA, IgM) and IgG subtypes (IgG 1-4): Collected for measurements of IgG, IgG subtypes (IgG1-4), IgA, and IgM at every visit. On dosing days, samples 
are collected prior to infusion of study drug. See Protocol Section 7.5.5 for additional information.  
m. Exploratory pharmacodynamic samples (C3 and AECA): Collected pre-dose when collected on dosing days. See Protocol Section 7.5.5 for complete information.  
n. Buccal samples to be collected pre-dose.  
o. Immunophenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, natural killer (NK) cells, and B cells. Collect samples pre-dose on dosing 
days.  
p. Photographs of all active lesions taken pre-dose on dosing days. Subjects who begin a steroid taper will have additional photographs taken at the clinic visit during which the 
decision to begin the taper is made.  
q. Subjects whose total IgG is not within 30% of their Day 0 baseline value and not above 500 mg/dL at the Day 140 visit will be referred for further management. 
 
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Table 4. 
Timing Window Allowances for PK/PD Sampling, ECG, and Vital Sign 
Measurements at Dosing Visits 
Time Point 
Tolerance Window 
 
Cohort 1 
Cohort 2 
Pharmacokinetic Sampling 
 
 
0 hour 
−240 minutes to 0 hour 
−240 minutes to 0 hour 
5 minutes post end-of-infusion 
±5 minutes 
±5 minutes 
1 hour post end-of-infusion 
N/A 
±15 minutes 
2 hour post end-of-infusion 
±15 minutes 
±15 minutes 
4 and 6 hours post end-of-infusion 
±15 minutes 
N/A 
24 hours (1 day) post end-of-infusion 
±60 minutes 
N/A 
48 hours (2 days) post end-of-infusion 
±120 minutes 
N/A 
 
 
 
Pharmacodynamic Sampling 
 
 
0 hour 
−240 minutes to 0 hour 
−240 minutes to 0 hour 
24 hours (1 day) post end-of-infusion 
±60 minutes 
N/A 
48 hours (2 days) post end-of-infusion 
±120 minutes 
N/A 
 
 
 
ECG 
 
 
5 minutes post end-of-infusion 
±10 minutes 
±10 minutes 
 
 
 
Vital Signsa 
 
 
0 hour 
−240 minutes to 0 hour 
−240 minutes to 0 hour 
15, 30, and 45 minutes after start of 
infusion 
±5 minutes 
±5 minutes 
At completion of the infusion 
±10 minutes 
±10 minutes 
30 minutes, 1 and 2 hours post end-of- 
infusion 
±10 minutes 
±10 minutes 
 
Abbreviations: ECG = electrocardiogram; N/A = not applicable; PD = pharmacodynamics; PK = pharmacokinetic. 
a. Vital signs to include blood pressure, pulse rate, respiratory rate, oral temperature, and pulse oximetry. 
 
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Table 5. 
Pharmacodynamic Assessments 
Parameter 
Collection Time Points 
Cohort 1 
Cohort 2a 
Immunoglobulins: 
 
IgG 
 
IgG subtypes (IgG1-4) 
 
IgA 
 
IgM 
Screening and Days 0, 1, 2, 5, 7, 
12, 14, 19, 21, 28, 29, 30, 33, 42, 
56, 84, and 112 
Screening and Days 0, 7, 14, 28, 
42, 56, 70, 84, 91, 112, and 140 
 
Circulating immune complexes 
(CIC) 
Days 0, 5, 7, 12, 14, 19, 21, 28, 
33, 42, 56, 84, and 112 
Days 0, 7, 14, 28, 42, 56, 70, 84, 
91, 112, and 140 
 
Albumin 
Screening and Days 0, 7, 14, 21, 
28, 33, 42, 56, 84, and 112 
Screening and Days 0, 7, 14, 28, 
42, 56, 70, 84, 91, 112 and 140 
 
Anti-Dsg (1 and 3) antibody 
titers 
Screening and Days 0, 7, 14, 33, 
56, 84, and 112 
Screening and Days 0, 7, 14, 28, 
42, 56, 70, 84, 91, 112, and 140 
 
C3 and AECA levels by 
indirect immunofluorescence 
Days 0, 14, 33, 56, 84, and 112 
Screening and Days 0, 7, 14, 28, 
42, 56, 70, 84, 91, 112, and 140 
 
Exploratory biomarkers 
(RNAseq, urine IgG)b 
Days 0, 14, 33, 56, 84, and 112 
Days 0, 28, and 91 
 
Immunophenotyping by flow 
cytometry for measurement of 
T cells, monocytes, NK cells, 
and B cells 
Days 0, 28, and 56 
Days 0, 28, and 91 
 
Exploratory biomarker 
(FCGR2A SNP, via buccal 
swab) 
Day 0 
Day 0 
 
Exploratory pemphigus 
immune response biomarkers 
Days 0, 5, 7, 12, 14, 19, 21, 28, 
33, 42, 56, 84, and 112 
Days 0, 7, 14, 28, 42, 56, 70, 84, 
91, 112, and 140 
 
a Ongoing safety and PD evaluations may result in modification of the dosing regimen from every other week to weekly. See 
Protocol APPENDIX 5 for the corresponding visit schedule.  
b Urine IgG collected in Cohort 1 only. 
 
 
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Appendix B: Imputation Rules for Missing Dates 
Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1.     Missing or partial medication start date: 
 If only DAY is missing, use the first day of the month. 
 If DAY and Month are both missing, use the first day of the year. 
 If DAY, Month and Year are all missing, use a date before the first dose date (in 
practical, use Jan. 01, 2000 to impute). 
2.     Missing or partial medication stop date: 
 If only DAY is missing, use the last day of the month. 
 If DAY and Month are both missing, use the last day of the year. 
 If DAY, Month and year are all missing, assign ‘continuing’ status to stop date (in 
practical, use Dec. 31, 2050 to impute). 
 
Imputation rules for missing or partial AE start date are defined below: 
If only Day of AE start date is missing: 
If the AE start year and month are the same as that for the first dose date, then: 
 If the full (or  partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start day as the day of first dose date; otherwise, impute 
the AE start day as 1. 
 Otherwise, impute the AE start day as 1. 
Compare the imputed AE start date with Treatment-Emergent period to determine whether the 
AE is pretreatment AE, TEAE or post-treatment AE. 
If Day and Month of AE start date are missing: 
If AE start year = first dose year, then: 
 If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start Month and Day as the Month and Day of first dose 
date; otherwise, impute the AE start Month as January and the Day as 1. 
 Otherwise, impute the AE start MONTH as January and the DAY as 1. 
Compare the imputed AE start date with Treatment-Emergent period to determine whether the 
AE is pretreatment AE, TEAE or post-treatment AE. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site with no 
imputation. Also compare the full (or partial) AE end date to the first dose date. If the AE end 
date is before the first dose date then the AE should be considered as a pretreatment AE. 
Otherwise, the AE will be considered as TEAE. 
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