Clinical trial NCT03075878
Conditions: Warm Autoimmune Hemolytic Anemia
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2018-01-10; Completion date: 2019-08-06
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This main study objective was to evaluate the safety and tolerability of intravenous (IV) SYNT001 (ALXN1830) in participants with WAIHA.

Detailed description:
This study planned to evaluate 2 cohorts: Cohort 1, up to 8 participants to receive IV doses of ALXN1830 (SYNT001 Dose 1); Cohort 2, up to 12 participants to receive IV doses of ALXN1830 (SYNT001 Dose 2).

This study was terminated after the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy were characterized in participants with WAIHA in Cohort 1 (SYNT001 Dose 1), before any participants were enrolled in Cohort 2.

Arms: arm 1: SYNT001 Dose 1 arm 2: SYNT001 Dose 2
Interventions: intervention 1: ALXN1830
Intervention descriptions: intervention 1: Administered via IV infusion.

Protocol documents:
Prot_001.pdf: 
 
A Phase 1b/2, Multicenter, Open-Label, Safety, Tolerability, 
and Activity Study of SYNT001 in Subjects with Warm 
Autoimmune Hemolytic Anemia (WAIHA) 
 
 
 
Unique Protocol ID:  
SYNT001-102  
NCT Number:  
NCT03075878 
Date of Protocol:  
23 October 2018 
 


SYNT001 
 
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Protocol SYNT001-102 for WAIHA 
 
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Syntimmune, Inc. 
SYNTIMMUNE, INC. 
CLINICAL STUDY PROTOCOL 
A Phase 1b/2, Multicenter, Open-Label, Safety, Tolerability, and Activity 
Study of SYNT001 in Subjects with Warm Autoimmune Hemolytic Anemia 
(WAIHA) 
 
Protocol Number: 
SYNT001-102 
IND Number: 
128152 
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: 
19 December 2016 
Amendment 1.1: 
18 January 2017 
Amendment 2.0 
12 April 2017 
Amendment 3.0 
10 October 2017 
Amendment 4.0 
21 December 2017 
Amendment 5.0 
23 October 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. 
PPD
PPD
PPD
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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 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. 
 
 
Date of Signature 
 
PPD
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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 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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1. 
SYNOPSIS 
Study title 
A Phase 1b/2, Multicenter, Open-Label, Safety, Tolerability, and Activity 
Study of SYNT001 in Subjects with Warm Autoimmune Hemolytic 
Anemia (WAIHA) 
Protocol number 
SYNT001-102 
Number of study 
centers 
Approximately 15 global study sites 
Clinical phase  
Phase 1b/2 
Study background 
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 
thereby inhibits the varied roles of FcRn in 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’s 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 (IV) 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. 
IgG autoantibodies directed against red blood cells (RBCs) are considered 
to play a central role in the hemolysis and anemia observed in patients with 
warm autoimmune hemolytic anemia (WAIHA). SYNT001 is a humanized 
IgG4 mAb that blocks IgG interactions with FcRn that would be anticipated 
to affect pathogenic behavior of IgG autoantibodies. 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 IgG coating of RBCs and the interaction of 
IgG-coated RBCs with FcRn in phagocytic cells, leading to decreased 
hemolysis in WAIHA patients with active hemolysis. Moreover, the ability 
of SYNT001 to reduce circulating immune complexes (CICs) and the 
associated innate and adaptive immune responses may allow for sustained 


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disease modification. 
Study rationale 
This study is being conducted to evaluate the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and 
effects of IV SYNT001 in subjects with WAIHA. 
Study objectives and 
endpoints 
The study objectives and their corresponding endpoints (primary, 
secondary, and exploratory) are detailed below. 
Primary Objective 
Primary Endpoint 
Safety: To evaluate the safety and 
tolerability of IV infusions of 
SYNT001 at different dose levels 
and dosing regimens in subjects 
with WAIHA 
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 
Secondary Objective 
Secondary Endpoint 
To evaluate the efficacy of doses 
of SYNT001 at different dose 
levels and dosing regimens on 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 time point 
To determine the 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 and time 
point 


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To assess the efficacy of doses of 
SYNT001 at different dose levels 
and dosing regimens on disease 
markers 
The assessment of WAIHA disease 
activity by absolute changes in the 
disease activity markers of 
hematocrit, hemoglobin, platelet 
count, reticulocyte count, lactate 
dehydrogenase (LDH), haptoglobin, 
and total and indirect bilirubin will 
be summarized by dose, dosing 
regimen and time point 
The direct Coombs test result 
(positive or negative) will be 
summarized by dose, dosing 
regimen and time point 
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 and time point 
Exploratory Objectives 
Exploratory Endpoint 
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 time point, as 
determined by:  
 
D-dimer 
 
Antiphospholipid antibodies 
(lupus anticoagulant, 
anti-cardiolipin antibody, 
anti-beta-2-GP1 antibody) 
 
Antinuclear antibody titer 
 
Anti-dsDNA antibody titer 
 
Quantitative Coombs assay 
 
Cold agglutinins (titer and 
thermal amplitude) 
 
Fc gamma R2A receptor 
(FCGR2A) single nucleotide 
polymorphisms (SNP) by 
genotyping 
 
Complement component 3 
levels by nephelometry 
 
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 


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cytometry 
To characterize blood transfusions 
during the study 
The number of units of packed red 
blood cells received by subjects 
will be summarized by dose and 
dosing regimen 
To determine the impact of 
different SYNT001 dose levels 
and dosing regimens on the 
subject’s use of corticosteroids to 
treat their WAIHA 
The evaluation of corticosteroid use 
during the study will be 
summarized by dose, dosing 
regimen and time point 
Study design 
This is a multicenter, open-label study to assess the safety, tolerability, 
efficacy, PK, PD, and immunogenicity of SYNT001 IV administered to 
subjects with WAIHA.  
Up to 8 subjects with a diagnosis of WAIHA will receive SYNT001 10 
mg/kg weekly x 5 doses (Cohort 1).  
Up to 12 subjects with a diagnosis of WAIHA will receive SYNT001 (10, 
20 or 30 mg/kg) weekly x 3 doses (Loading), followed by SYNT001 (10, 
20 or 30 mg/kg) every other week x 5 doses (Maintenance) (Cohort 2). For 
Cohort 1 details of the dosing schedule and assessments, see Table 2. For 
Cohort 2 details, see Table 3. An alternative weekly maintenance schedule 
of assessment for Cohort 2 is presented in APPENDIX 3, Table 10. 
Subjects in both cohorts will complete the following periods of assessment: 
Screening, Treatment, and Follow-Up. 
Up to 8 subjects may be enrolled in Cohort 1. After 4 subjects reach 
Day 42, the Sponsor Medical Team will review available safety and PD 
data and will decide the dosing regimen for Cohort 2. The maintenance 
dose frequency may be increased to weekly (Cohort 2 alternative weekly 
maintenance schedule). Dosing regimen decisions for Cohort 2 will be 
communicated to the sites prior to Day 0 dosing. 
The Sponsor Medical Team will consist of at least the Medical Monitor and 
the Sponsor Medical Lead. The Sponsor Medical Team may request that 
Investigators, other experts, or members within their organization 
participate in the review. 
An overview of the study cohorts is provided in Table 1. 
 
Table 1. 
Cohort Overview 
 
Cohort 
No. of 
subjects 
SYNT001 Dose 
No. of 
Doses 
Frequency 
of Doses 
1 
Up to 8 
10 mg/kg 
5 
Weekly 
2 
Up to 12 
Loading: 
10, 20 or 30 mg/kg 
Maintenance:  
10, 20 or 30 mg/kg 
3 
 
5 
Weekly 
 
Every other 
week 


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2 
Alternative 
weekly 
schedule 
Up to 12 
Loading:  
10, 20 or 30 mg/kg 
Maintenance:  
10, 20 or 30 mg/kg 
3 
 
10 
Weekly 
 
Weekly 
 
Subjects in Cohorts 1 and 2 will be enrolled at staggered intervals to 
facilitate adequate safety evaluation before dosing of subsequent subjects 
may proceed.  
At 24-hour and 7-day intervals described below, 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 will be dosed at least 24 hours apart. A Dose 
Escalation Committee (DEC) 24-hour safety data review 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 Team 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 
performed by the DEC prior to dosing the remaining subjects in the 
cohort.  
 
The 7-day safety data for the first 2 subjects in Cohort 2 will be 
performed by the Sponsor Medical Team 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.  
 
Safety (including but not limited to DLTs, AEs, TEAEs, and SAEs), and 
PD (including but not limited to IgG levels) data will be reviewed on an 
ongoing basis by the Sponsor Medical Team. In addition, at any point a 
review of all cumulative data may be performed. 
 
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 Team determines that 
further drug exposure would pose an undue risk to subjects. 
Dosing for any individual subject will be discontinued (ie, no further 


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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 Team, 
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 or older with a confirmed diagnosis 
of WAIHA 
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. Confirmed diagnosis by enrolling physician of WAIHA, including 
positive direct Coombs test. 
4. Hemoglobin <11 g/dL 
5. Evidence of active hemolysis, including any one of the below: 
a. LDH >upper limit of normal (ULN) or  
b. Haptoglobin <lower limit of normal (LLN) or 
c. Indirect bilirubin >ULN.  
6. Other treatments for WAIHA: 
a. If treated with rituximab or other anti-CD20 mAb, last dose 
>3 months prior to screening (a dose is defined as ≥10% of the 
intended dose). 
b. If being treated with other immunosuppressants (ie, azathioprine, 
mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, 
sirolimus, or low-dose oral cyclophosphamide [≤100 mg/day]), 
dose must be stable (<25% change in dose) for 4 weeks prior to 
screening. 
c. If being treated with corticosteroids, dose must be ≤1 mg/kg/day of 
prednisone or equivalent, and the dose may not be increased by 
more than 50% in the 2 weeks prior to screening. 
d. No pulse corticosteroids are allowed in the 2 weeks prior to 
screening. 
7. Treatment of chronic lymphocytic leukemia (CLL) or non-Hodgkin 
lymphoma (NHL) must be: 
a. Food and Drug Administration (FDA)-approved for oral treatment,  
and 
b. Stable (<10% change in dose) for 6 weeks prior to screening; 
Bruton’s tyrosine kinase inhibitor dose must be stable (<10% 
change in dose) for 8 weeks prior to screening.  
8. Body mass index (BMI) >18.5 kg/m2. 
9. Has a negative pregnancy test (for women of childbearing potential) 
documented prior to the first dose of study drug. 
10. Females of childbearing potential must agree to be abstinent or else use 
any two of the following medically acceptable forms of contraception 


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(<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.  
11. 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. 
12. 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 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. Karnofsky Performance Scale ≤50. 
4. Estimated glomerular filtration rate (eGFR) <45 mL/minute/1.73 m2. 
5. Platelet count <30 ×109/L. 
6. Corrected reticulocyte count <2% (using the following calculation; 
(% reticulocyte x % hematocrit) / normal hematocrit [45%]). 
7. Positive for human immunodeficiency virus (HIV) or hepatitis C 
antibody. 
8. Positive for hepatitis B surface antigen. 
9. Splenectomy within 3 months of screening. 
10. Any T-cell or NK-cell NHL, and any moderate- or high-grade B-cell 
lymphoma, including Burkitt lymphoma, lymphoblastic B-cell 
lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, or 
small non-cleaved cell non-Burkitt lymphoma. 
11. Received any cytotoxic (other than azathioprine, chlorambucil, low-
dose methotrexate, or low-dose oral cyclophosphamide [≤100 mg/day]) 
or any non-anti-CD20 mAb therapy in the 3 months prior to screening. 
12. Any exposure to an investigational drug or device within the 30 days 
prior to screening. 
13. IVIG treatment within 30 days of screening. 
14. Plasmapheresis or immunoadsorption within 30 days of screening. 
15. Cellular therapy, including chimeric antigen receptor T-cell (CAR-T), 
at any time prior to screening. 
16. Use of any immunosuppressive drugs within 3 months of screening, not 
including those allowed by the inclusion criteria. 
17. Active infection or history of recurrent infections. 
18. Serum total IgG <600 mg/dL. 
19. 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 


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study results). 
20. Any vaccination within 2 weeks of screening. 
Study drug, dosage, 
and administration 
Study drug: SYNT001 
Dosage:  
Cohort 1: 10 mg/kg weekly x 5 doses  
Cohort 2: 10, 20 or 30 mg/kg weekly x 3 doses (Loading) followed by 10, 
20 or 30 mg/kg every other week x 5 doses (Maintenance). 
Up to 8 subjects may be enrolled in Cohort 1.  After 4 subjects reach 
Day 42, the Sponsor Medical Team will review available safety and PD 
data and will decide the dosing regimen for Cohort 2. The Maintenance 
dose frequency may be increased to weekly (Cohort 2 alternative weekly 
maintenance schedule).   
Product presentation and preparation: 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 ±15 minutes. 
Investigators may adjust the duration of the infusion if needed to increase 
tolerability. 
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 
≤28 days 
84 days 
56 days 
154 days 
22 weeks 
Permitted and 
prohibited concomitant 
treatments 
All WAIHA treatments and all other treatments a subject receives within at 
least 3 months prior to screening through the end of the study will be 
documented.  
Permitted medications: 
Concomitant medication and treatment for co-existing conditions, including 
those for WAIHA, are permitted if not listed as prohibited.  
1. Concomitant treatment that is medically indicated for any AEs the 
subject experiences during the study. 
2. Medication for potential infusion-related reactions (IRRs), including 
post-infusion headache: the Investigator may recommend prophylactic 
use of acetaminophen, IV hydration, diphenhydramine, or histamine2 
blockers (eg, ranitidine, famotidine). 
3. Stable regimen of the following systemic immunosuppressants: 
azathioprine, mycophenolate mofetil, low-dose methotrexate, 
cyclosporine, tacrolimus, sirolimus, corticosteroids, or low-dose oral 
cyclophosphamide (≤100 mg/day). 
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  


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3. Any immunosuppressive drugs apart from those that are listed as 
permitted 
4. Any cytotoxic agent other than azathioprine, chlorambucil, low-dose 
methotrexate, or low-dose oral cyclophosphamide (≤100 mg/day) 
5. IV corticosteroids prior to infusion of study drug (except in subjects 
who received corticosteroids for treatment of a prior infusion reaction 
to SYNT001). 
6. Any investigational drug or device 
7. Vaccinations within 2 weeks of screening through 28 days following 
the final dose of study drug. 
 
WAIHA Co-medication: 
Subjects receiving WAIHA treatment at enrollment, should remain on a 
stable treatment regimen throughout dosing and for the 14 days after the 
last dose of SYNT001.  
 
Corticosteroids 
Before enrollment 
The dose of corticosteroids taken for WAIHA 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 WAIHA 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 WAIHA 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 PK population will consist of all subjects who receive at least 
one dose of study drug and have post-dose PK data available. 
 
The PD population will consist of all subjects who receive at least 


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one dose of study drug and have post-dose PD data available.  
 
Primary safety analyses will be performed on the Safety population. 
Demographics, subject disposition, and screening and baseline 
characteristics will be summarized for the Safety, PK and PD 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.  
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 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 by using descriptive statistics. 
PD/PK results will be summarized by dose and dose 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 and time point. 
Descriptive statistics will include mean, SD, CV, median, minimum, and 
maximum. 
Disease activity marker results (hematocrit, hemoglobin, platelet count, 
reticulocyte count, LDH, haptoglobin, total and indirect bilirubin, and direct 
Coombs test) will be summarized by dose and dose regimen. Descriptive 
statistics will include mean, SD, median, minimum, and maximum. 
 
Final statistical analyses details will be documented in the statistical 
analysis plan. 


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Figure 1. 
Cohort Enrollment 
 
WAIHA = warm autoimmune hemolytic anemia 
 
 
 
 
 


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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 (or 
ET) 
Time Point (Study Day) 
−14 to −1 
0 
1 
(±1 h) 
2 
(±2 h) 
5a 
(±4 h) 
7 
(±6 h) 
12a 
(±6 h) 
14 
(±6 h) 
19a 
(±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 (±5 
d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky Performance Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse oximetryd 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Clinical safety labse 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
Pregnancy testf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Hepatitis and HIV antibody 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGg 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Tetanus and VZV antibodiesh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Cold agglutinins (titer and 
thermal amplitude) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
PK samplingi 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Immunogenicityj 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
X 
Study drug administrationk 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Immunoglobulinsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xm 
CIC 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Haptoglobin 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
Direct Coombs test 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Additional PD sample 
collectionn 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
FCGR2A by buccal swabo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNA sequencing 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Urine IgG 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Immunophenotypingp 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Quantitative Coombs assay 
 
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 at least 3 months prior to screening through the last study visit 


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Protocol SYNT001-102 for WAIHA 
 
Amendment 5.0 
 
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CIC = circulating immune complexes; d = day(s); ECG = electrocardiogram; ET = early termination; h = hour(s); FCGR2A = Fc gamma R2a receptor; HIV = human 
immunodeficiency virus; ICF = informed consent form; Ig = immunoglobulin; PD = pharmacodynamic; PK = pharmacokinetic; VZV = varicella-zoster virus. 
a. 
Visit Days 5, 12, and 19 may be conducted via at-home nurse in lieu of a subject visit to the study site. 
b. 
Complete physical examination, including weight, to be performed. Height and body mass index will be additional assessments conducted at screening.  
c. 
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.  
d. 
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. 
e. 
Clinical safety labs: hematology, clinical chemistry, and urinalysis. See Section 6.7 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. PD markers (albumin levels, hematocrit, hemoglobin, platelet count, reticulocyte count, lactate dehydrogenase, and total and 
indirect bilirubin) will be derived from the clinical safety laboratory results. 
f. 
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. 
g. 
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 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.  
h. 
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. 
i. 
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.  
j. 
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. 
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 9 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. 
m. 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. 
n. 
Additional PD samples to be collected for measurements of biomarkers, including D-dimer; antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and anti-beta-
2-GP1 antibodies); antinuclear antibody titer; anti-double-stranded DNA antibody titer; complement component 3. See Section 6.7.5 for complete information. 
o. 
Buccal samples to be collected and stored. 
p. 
Immunophenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, natural killer (NK) cells, and B cells 
 
 


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Amendment 5.0 
 
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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) 
−28 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 
Karnofsky Performance Scale 
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 
Pregnancy teste 
X 
X 
 
 
X 
 
 
 
 
X 
 
X 
Hepatitis and HIV antibody screen 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGf 
X 
X 
 
X 
X 
 
 
 
 
X 
 
X 
Tetanus and VZV antibodiesg 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
Cold agglutinins (titer and thermal 
amplitude)  
 
X 
 
 
X 
 
 
 
 
X 
 
X 
PK samplingh 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
Immunogenicityi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administrationj 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Immunoglobulinsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
Xl 
Xl 
CIC  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haptoglobin  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Direct Coombs test 
X 
X 
 
X 
X 
 
 
 
 
X 
 
X 
Additional PD sample collectionm  
 
X 
 
 
X 
 
 
 
 
X 
 
 
FCGR2A by buccal swabn 
 
X 
 
 
 
 
 
 
 
 
 
 
RNA sequencing  
 
X 
 
 
X 
 
 
 
 
X 
 
 
Immunophenotypingo 
 
X 
 
 
X 
 
 
 
 
X 
 
 
Quantitative Coombs assay  
 
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 at least 3 months prior to screening through the last study visit 
CIC = circulating immune complexes; d = day(s); ECG = electrocardiogram; EOS = end of study; ET= early termination; FCGR2A = Fc gamma R2a receptor; HIV = human 


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Protocol SYNT001-102 for WAIHA 
 
Amendment 5.0 
 
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immunodeficiency virus; ICF = informed consent form; Ig = immunoglobulin; PD = pharmacodynamic; 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 day, 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 at all 
study visits prior to infusion if applicable. PD markers (albumin levels, hematocrit, hemoglobin, platelet count, reticulocyte count, lactate dehydrogenase, and total and 
indirect bilirubin) will be derived from the clinical safety laboratory results. 
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 6.6 for additional information. On 
days of treatment, to be obtained 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 6.7.3 for additional information. 
h. 
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 6.7.4 for additional information. 
i. 
Immunogenicity: 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 to a total volume of 250 mL and administered intravenously over 1 hour 
±15 minutes 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 dosing days, 
samples are collected prior to infusion of study drug. See Section 6.7.5 for additional information. 
l. 
Subjects will return to the clinic on Days 91, 112, and 140 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 Day 140 will be referred for further management. 
m. Additional PD samples to be collected for measurements of biomarkers, including D-dimer; antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and anti-beta-
2-GP1 antibodies); antinuclear antibody titer; anti-double-stranded DNA antibody titer; complement component 3. Collect samples pre-dose on dosing days. See Section 6.7.5 
for additional information.  
n. 
Buccal samples to be collected and stored. 
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. 


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TABLE OF CONTENTS 
1. 
SYNOPSIS .........................................................................................................................4 
LIST OF TABLES ...................................................................................................................23 
LIST OF FIGURES .................................................................................................................23 
LIST OF APPENDICES ..........................................................................................................23 
LIST OF ABBREVIATIONS ..................................................................................................24 
2. 
BACKGROUND AND RATIONALE ............................................................................27 
2.1 
Study Rationale ......................................................................................................27 
2.2 
Selection of Doses in this Study ............................................................................28 
2.3 
Compliance Statement ...........................................................................................29 
3. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................31 
4. 
STUDY DESIGN .............................................................................................................33 
4.1 
Study Sites .............................................................................................................33 
4.2 
Overview of Study Design .....................................................................................33 
4.3 
Randomization and Blinding .................................................................................34 
4.4 
Duration of Subject Participation...........................................................................34 
5. 
STUDY POPULATION ..................................................................................................35 
5.1 
Target Population ...................................................................................................35 
5.2 
Inclusion Criteria ...................................................................................................35 
5.3 
Exclusion Criteria ..................................................................................................36 
6. 
STUDY PROCEDURES .................................................................................................37 
6.1 
Informed Consent...................................................................................................37 
6.2 
Demographics and Medical History ......................................................................37 
6.3 
Physical Examination.............................................................................................37 
6.4 
Karnofsky Performance Scale................................................................................37 
6.5 
Vital Sign Measurements .......................................................................................38 
6.6 
12-Lead Electrocardiogram (ECG) ........................................................................39 
6.7 
Clinical Laboratory Measurements ........................................................................39 
6.7.1 
Pregnancy Testing ........................................................................................40 
6.7.2 
Virology .......................................................................................................40 
6.7.3 
Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing ....40 
6.7.4 
Pharmacokinetics (PK) Sampling ................................................................40 
6.7.5 
Pharmacodynamic Sampling .......................................................................41 
6.7.6 
Immunogenicity Testing ..............................................................................43 
6.7.7 
Circulating Immune Complexes ..................................................................43 
6.7.8 
Direct Antiglobulin (Coombs) Test (DAT) .................................................43 
6.7.9 
Quantitative Coombs Assay .........................................................................43 
6.8 
Study Drug Administration ....................................................................................44 


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6.9 
Adverse Event Assessments ..................................................................................44 
6.10 
Prior and Concomitant Medications ......................................................................44 
7. 
STUDY ASSESSMENTS ...............................................................................................47 
7.1 
Cohort 1 Assessments ............................................................................................47 
7.1.1 
Screening Period: Day −14 to Day −1 .........................................................47 
7.1.2 
Enrollment and First Treatment: Day 0 .......................................................47 
7.1.3 
Follow-up: Day 1 .........................................................................................49 
7.1.4 
Follow-up: Day 2 .........................................................................................49 
7.1.5 
Follow-up: Day 5 .........................................................................................49 
7.1.6 
Treatment Day 7 (Dose 2) ...........................................................................50 
7.1.7 
Dose 2 Follow-up: Day 12 ...........................................................................51 
7.1.8 
Treatment Day 14 (Dose 3) .........................................................................51 
7.1.9 
Dose 3 Follow-up: Day 19 ...........................................................................52 
7.1.10 
Treatment Day 21 (Dose 4) .........................................................................52 
7.1.11 
Treatment Day 28 (Dose 5) .........................................................................53 
7.1.12 
Follow-up: Day 29 .......................................................................................54 
7.1.13 
Follow-up: Day 30 .......................................................................................55 
7.1.14 
Follow-up: Day 33 .......................................................................................55 
7.1.15 
Follow-up: Day 42 .......................................................................................55 
7.1.16 
Follow-up: Day 56 .......................................................................................56 
7.1.17 
Follow-up: Day 84 .......................................................................................57 
7.1.18 
Follow-up: Day 112 (End of Study) or Early Termination Visit .................57 
7.2 
Cohort 2 Assessments ............................................................................................58 
7.2.1 
Screening Period: Day −28 to Day −1 .........................................................58 
7.2.2 
Enrollment and First Treatment: Day 0 .......................................................59 
7.2.3 
Loading Doses 2 and 3 (Cohort 2 weekly Day 7 and 14 [±1 day]) .............60 
7.2.4 
Maintenance Doses (Cohort 2 every other Week Day 28, 42, 56, and 70 
[± 3 days]) ....................................................................................................61 
7.2.5 
Final Maintenance Dose Visit (Cohort 2 Day 84) .......................................62 
7.2.6 
Follow-up: Day 91, 112, and 140 (± 5 days) (Day 91 is Early Termination 
[ET] Visit and Day 140 is End of Study [EOS] Visit) .................................63 
8. 
STUDY RULES ...............................................................................................................65 
8.1 
Subject Withdrawal ................................................................................................65 
8.2 
Subject Replacement ..............................................................................................65 
8.3 
Study Discontinuation ............................................................................................65 
8.4 
Lost to Follow up ...................................................................................................66 
8.5 
Stopping Rule.........................................................................................................66 
8.5.1 
Dose-Escalation Stopping Rule ...................................................................66 
8.5.2 
Study Stopping Rule ....................................................................................66 


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8.5.3 
Individual Stopping Rule .............................................................................66 
9. 
STUDY DRUG ................................................................................................................68 
9.1 
SYNT001 ...............................................................................................................68 
9.2 
Dose Requirements ................................................................................................68 
9.3 
Cohort Dosing ........................................................................................................68 
9.4 
Handling and Storage of SYNT001 .......................................................................68 
9.5 
Study Drug Accountability ....................................................................................69 
9.6 
Warnings and Precautions......................................................................................69 
9.6.1 
Infusion-Related Reaction ...........................................................................69 
9.6.2 
Guidelines for Grading and Management of Allergic or Infusion-Related 
Reactions ......................................................................................................70 
9.6.3 
Potential Immune Effects .............................................................................73 
10. SAFETY ..........................................................................................................................75 
10.1 
Safety Parameters...................................................................................................75 
10.2 
Adverse Event Definition ......................................................................................75 
10.3 
Evaluating Adverse Events ....................................................................................75 
10.3.1 
Serious Adverse Events ...............................................................................76 
10.3.2 
Overdose ......................................................................................................77 
10.3.3 
Non-Serious Adverse Events .......................................................................77 
10.3.4 
Protocol-Related Adverse Events ................................................................77 
10.3.5 
Assessment of Causality ..............................................................................77 
10.3.6 
Recording Adverse Events ...........................................................................78 
10.3.7 
Planned Hospitalization ...............................................................................78 
10.3.8 
Reporting Pregnancies .................................................................................78 
10.3.9 
Serious Adverse Event Reporting ................................................................79 
10.3.9.1 
Governing Regulatory Requirements ................................................79 
10.3.9.2 
Time Frame for Reporting .................................................................79 
10.3.9.3 
Information to be Provided by the Investigator .................................80 
10.3.10 
Regulatory Reporting ...................................................................................80 
10.3.11 
Follow-up Information on a Serious Adverse Event (SAE) ........................81 
10.4 
Other Safety Considerations ..................................................................................81 
10.4.1 
Laboratory Data ...........................................................................................81 
10.4.2 
Medication Errors ........................................................................................81 
10.4.3 
Follow-Up of Adverse Events .....................................................................81 
10.5 
Safety Monitoring for Dose Escalation..................................................................81 
11. STATISTICAL CONSIDERATIONS .............................................................................82 
11.1 
General Design.......................................................................................................82 
11.2 
Sample Size Justification .......................................................................................82 


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11.3 
Statistical Considerations .......................................................................................82 
11.3.1 
Study Populations ........................................................................................82 
11.3.2 
Subject Accountability, Demographics, and Baseline Characteristics ........83 
11.3.2.1 
Baseline Analysis ...............................................................................83 
11.3.3 
Concomitant Medications ............................................................................83 
11.4 
Planned PK Analysis..............................................................................................83 
11.5 
Safety Analysis ......................................................................................................83 
11.6 
Pharmacodynamic Analysis ...................................................................................84 
11.7 
Immunogenicity Analysis ......................................................................................84 
11.8 
Interim Analysis .....................................................................................................84 
12. DATA QUALITY ASSURANCE ...................................................................................85 
13. STUDY ADMINISTRATION .........................................................................................86 
13.1 
Study Administrative Structure..............................................................................86 
13.2 
Ethical Conduct of the Study .................................................................................86 
13.3 
Informed Consent (ICF) .........................................................................................86 
13.4 
Institutional Review Board ....................................................................................87 
13.5 
Dose Escalation Committee ...................................................................................87 
13.6 
Sponsor Medical Team ..........................................................................................87 
13.7 
Future Use of Subject Samples ..............................................................................88 
14. CONDITIONS FOR MODIFYING THE PROTOCOL ..................................................89 
15. CONDITIONS FOR TERMINATING THE STUDY ....................................................90 
16. STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING ..............................91 
16.1 
Investigator’s Files and Retention of Documents ..................................................91 
16.2 
Source Documents and Background Data .............................................................91 
16.3 
Audits and Inspections ...........................................................................................92 
16.4 
Electronic Case Report Forms ...............................................................................92 
17. MONITORING THE STUDY .........................................................................................93 
18. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS ..........94 
19. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ...................95 
20. REFERENCES ................................................................................................................96 
 


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LIST OF TABLES 
Table 1.Cohort Overview...........................................................................................................7 
Table 2.Study Assessments for Cohort 1 .................................................................................15 
Table 3. Study Assessment for Cohort 2 .................................................................................17 
Table 4.Cohort Overview.........................................................................................................33 
Table 5.Timing window allowances for PK/PD sampling, ECG, and vital sign measurements 
at dosing visits..................................................................................................38 
Table 6.Clinical Safety Laboratory Panels ..............................................................................39 
Table 7.Pharmacodynamic Assessments .................................................................................42 
Table 8.Grading and Management of Allergic or Infusion-Related Reactions .......................73 
Table 9.Study Administrative Structure ..................................................................................86 
Table 10. Study Assessments for Cohort 2; Alternative Weekly Maintenance Schedule .....101 
 
LIST OF FIGURES 
Figure 1.Cohort Enrollment .....................................................................................................14 
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 ..............................................................................98 
APPENDIX 2.Karnofsky Performance Scale ..........................................................................99 
APPENDIX 3.Cohort 2 alternative weekly maintenanceSchedule of Events Table .............100 
 


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LIST OF ABBREVIATIONS 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibody 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC0-24 
area under the serum concentration-time curve from pre-dose (time 0) to 24 hours 
post-dose 
AUC0-∞ 
area under the serum 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 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum serum concentration determined directly from the concentration-time 
profile 
CRO 
contract research organization 
CV 
coefficient of variation 
D5W 
dextrose 5% in water 
DAT 
direct antiglobulin test 
DEC 
Dose Escalation Committee 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
dsDNA 
double-stranded deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ET 
early termination 
FCGR2A 
Fc gamma R2a receptor 
FcRn 
neonatal Fc receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 


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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 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IND 
investigational new drug 
IRB 
institutional review board 
IRR 
infusion-related reaction 
IUD 
intrauterine device 
IV 
intravenous 
IVIG 
intravenous immunoglobulin 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin lymphoma 
NHP 
non-human primate 
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
NSAID 
non-steroidal anti-inflammatory drug 
PD 
pharmacodynamics 
PK 
pharmacokinetic 
RBC 
red blood cells 
RNA 
ribonucleic acid 
RNAseq 
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 


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SYNT001 
a humanized, affinity matured IgG4-kappa monoclonal antibody 
t1/2 
Half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
observed time to reach peak serum concentration 
ULN 
upper limit of normal 
UNS 
unscheduled 
US 
United States 
VZV 
Varicella-Zoster virus 
WAIHA 
warm 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 
immunoglobulin G (IgG) and IgG immune complex (IC) interactions with the neonatal 
crystallizable fragment receptor (FcRn) and thereby inhibits the varied roles of FcRn in 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’s 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 (IV) 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.  
IgG autoantibodies directed against red blood cells (RBCs) are considered to play a central role 
in the hemolysis and anemia observed in patients with warm autoimmune hemolytic anemia 
(WAIHA). SYNT001 is a humanized IgG4 mAb that blocks IgG interactions with FcRn that 
would be anticipated to affect the pathogenic behavior of IgG autoantibodies. 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 IgG coating of RBCs 
and the interaction of IgG-coated RBCs with FcRn in phagocytic cells, leading to decreased 
hemolysis in WAIHA patients with active hemolysis. 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. 
2.1 
Study Rationale 
This study is being conducted to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD), immunogenicity, and effects of IV SYNT001 in subjects with 
WAIHA. 


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2.2 
Selection of Doses in this Study  
The initial dose levels of SYNT001 for this Phase 1b/2 proof-of-concept study of 10 mg/kg and 
up to 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 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 also 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 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 


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toxicokinetics of weekly IV 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 No-Observed Adverse-Effect Level (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.  
A preliminary assessment of safety was conducted by SYNT001 Pemphigus Study SYNT001-
103 Dose Escalation Committee (DEC). Seven subjects with pemphigus were treated with 
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 
1-2 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 (Cohort 1) to 30 mg/kg IV weekly doses for 5 weeks (Cohort 2). 
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 WAIHA. 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.  


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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 Objective 
Primary Endpoint 
Safety: To evaluate the safety and tolerability of 
IV infusions of SYNT001 at different dose levels 
and dosing regimens in subjects with WAIHA 
Safety: The evaluation of SYNT001 safety based 
on vital signs, physical examinations, 
electrocardiograms (ECGs), clinical safety 
laboratory tests, the incidence of AEs, treatment-
emergent adverse events (TEAEs), and SAEs 
summarized by dose and dosing regimen, severity, 
and relationship to study drug 
Secondary Objective 
Secondary Endpoint 
To evaluate the efficacy of doses of SYNT001 at 
different dose levels and dosing regimens on 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 time point 
To determine the 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 and time point 
To assess the efficacy of doses of SYNT001 at 
different dose levels and dosing regimens on 
disease markers 
The assessment of WAIHA disease activity by 
absolute changes in the disease activity markers of 
hematocrit, hemoglobin, platelet count, 
reticulocyte count, lactate dehydrogenase (LDH), 
haptoglobin, and total and indirect bilirubin will be 
summarized by dose, dosing regimen and time 
point 
The direct Coombs test result (positive or negative) 
will be summarized by dose, dosing regimen and 
time point 
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 and time point 
Exploratory Objectives 
Exploratory Endpoint 
To explore the effect of SYNT001 at different 
dose levels and dosing regimens on biomarkers to 
understand the pathophysiology of the disease 
The exploration of SYNT001 mechanisms of 
action and effects of SYNT001 on 
pathophysiology summarized by dose, dosing 


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and the SYNT001 mechanisms of action  
regimen and time point, as determined by:  
 
D-dimer 
 
Antiphospholipid antibodies (lupus 
anticoagulant, anti-cardiolipin antibody, 
anti-beta-2-GP1 antibody) 
 
Antinuclear antibody titer 
 
Anti-double-stranded deoxyribonucleic acid 
(dsDNA) antibody titer 
 
Quantitative Coombs assay 
 
Cold agglutinins (titer and thermal amplitude) 
 
Fc gamma R2A receptor (FCGR2A) single 
nucleotide polymorphisms (SNP) by 
genotyping 
 
Complement component 3 levels 
by nephelometry 
 
Presence of disease and inflammatory markers 
by total ribonucleic acid (RNA) sequencing 
 
Immunophenotyping including measurements 
of T cells, monocytes, natural killer (NK) cells, 
and B cells by flow cytometry 
 
To characterize blood transfusions during the 
study 
The number of units of packed red blood cells 
received by subjects will be summarized by dose 
and dosing regimen 
To determine the impact of different SYNT001 
dose levels and dosing regimens on the subject’s 
use of corticosteroids to treat their WAIHA 
The evaluation of corticosteroid use during the 
study will be summarized by dose, dosing regimen 
and time point 
 
 


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4. 
STUDY DESIGN 
4.1 
Study Sites 
This study will be conducted at approximately 15 sites globally. 
4.2 
Overview of Study Design 
This is a multicenter, open-label study to assess the safety, tolerability, efficacy, PK, PD, and 
immunogenicity of IV infusions of SYNT001 administered to subjects with WAIHA. 
Up to 8 subjects with a diagnosis of WAIHA will receive SYNT001 10 mg/kg weekly x 5 doses 
(Cohort 1). Up to 12 subjects with a diagnosis of WAIHA will receive SYNT001 (10, 20 or 30 
mg/kg) weekly x 3 doses (Loading), followed by SYNT001 (10, 20 or 30 mg/kg) every other 
week x 5 doses (Maintenance) (Cohort 2) (Figure 1). 
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. An alternative weekly maintenance schedule of 
assessment for Cohort 2 is presented in APPENDIX 3, Table 10. 
An overview of the study cohorts is provided in Table 4. 
 
Table 4. 
Cohort Overview 
Cohort 
No. of 
subjects 
SYNT001 Dose 
No. of 
Doses 
Frequency of Doses 
1 
Up to 8 
10 mg/kg 
5 
Weekly 
2 
Up to 12 
Loading: 10, 20 or 30 mg/kg 
Maintenance: 10, 20 or 30 mg/kg 
3 
5 
Weekly 
Every other week 
2 Alternative 
weekly schedule 
Up to 12 
Loading: 10, 20 or 30 mg/kg 
Maintenance: 10, 20 or 30 mg/kg 
3 
10 
Weekly 
Weekly 
 
Up to 8 subjects may be enrolled in Cohort 1. After 4 subjects reach Day 42, the Sponsor 
Medical Team will review available safety and PD data and decide the dosing regimen for 
Cohort 2. The maintenance dose frequency may be increased to weekly (Cohort 2 alternative 
weekly maintenance schedule).  Dosing regimen decisions for Cohort 2 will be communicated to 
the sites prior to Day 0 dosing. 
The Sponsor Medical Team will consist of at least the Medical Monitor and the Sponsor Medical 
Lead. The Sponsor Medical Team may request that Investigators, other experts, or members 
within their organization participate in the review.  
Subjects in Cohorts 1 and 2 will be enrolled at staggered intervals to facilitate adequate safety 
evaluation before dosing of subsequent subjects may proceed.  


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At 24-hour and 7-day intervals described below, available safety data (including, but not limited 
to, 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 will be dosed at least 24 hours apart. A DEC 24-hour safety data 
review 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 Team 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 performed by the DEC 
prior to dosing the remaining subjects in the cohort. 
 The 7-day safety data for the first 2 subjects in Cohort 2 will be performed by the 
Sponsor Medical Team 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.  
4.3 
Randomization and Blinding 
This is an open-label study. 
4.4 
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 
≤28 days 
84 days 
56 days 
154 days 22 weeks 
 


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5. 
STUDY POPULATION 
5.1 
Target Population 
This study will be conducted in male and female subjects with a confirmed diagnosis of 
WAIHA. 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. 
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 at the time of screening.  
3. Confirmed diagnosis by enrolling physician of WAIHA, including positive direct Coombs 
test. 
4. Hemoglobin <11 g/dL. 
5. Evidence of active hemolysis including any one of the below: 
a. LDH >upper limit of normal (ULN) or 
b. Haptoglobin <lower limit of normal (LLN) or  
c. Indirect bilirubin >ULN. 
6. Other treatments for WAIHA: 
a. If treated with rituximab or other anti-CD20 mAb, last dose >3 months prior to screening 
(a dose is defined as ≥10% of the intended dose). 
b. If being treated with other immunosuppressants (ie, azathioprine, mycophenolate mofetil, 
methotrexate, cyclosporine, tacrolimus, sirolimus, or low-dose oral cyclophosphamide 
[≤100 mg/day]), dose must be stable (<25% change in dose) for the 4 weeks prior to 
screening. 
c. If being treated with corticosteroids, dose must be ≤1mg/kg/day of prednisone or 
equivalent, and the dose may not be increased by more than 50% in the 2 weeks prior to 
screening. 
d. No pulse corticosteroids are allowed in the 2 weeks prior to screening. 
7. Treatment of chronic lymphocyte leukemia (CLL) or non-Hodgkin lymphoma (NHL) must 
be: 
a. FDA-approved for oral treatment, 
and 
b. Stable (<10% change in dose) for 6 weeks prior to screening; Bruton’s tyrosine kinase 
inhibitor dose must be stable (<10% change in dose) for 8 weeks prior to screening. 
8. Body mass index (BMI) >18.5 kg/m2. 
9. Has a negative pregnancy test (for women of childbearing potential) documented prior to the 
first dose of study drug. 
10. 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.  


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11. 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. 
12. 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. 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. Karnofsky Performance Scale ≤50. 
4. Estimated glomerular filtration rate (eGFR) <45 mL/minute/1.73m2.  
5. Platelet count <30 ×109/L.  
6. Corrected reticulocyte count <2% (using the following calculation; (% reticulocyte x % 
hematocrit) / normal hematocrit [45%]). 
7. Positive for human immunodeficiency virus (HIV) or hepatitis C antibody.  
8. Positive for hepatitis B surface antigen. 
9. Splenectomy within 3 months of screening. 
10. Any T-cell or NK-cell NHL, and any moderate- or high-grade B-cell lymphoma, including 
Burkitt lymphoma, lymphoblastic B-cell lymphoma, diffuse large B-cell lymphoma, mantle 
cell lymphoma, or small non-cleaved cell non-Burkitt lymphoma. 
11. Received any cytotoxic (other than azathioprine, chlorambucil, low-dose methotrexate, or 
low-dose oral cyclophosphamide [≤100 mg/day]), or any non-anti-CD20 mAb therapy in the 
3 months prior to screening. 
12. Any exposure to an investigational drug or device within 30 days prior to screening. 
13. IVIG treatment within 30 days of screening. 
14. Plasmapheresis or immunoadsorption within 30 days of screening. 
15. Cellular therapy, including chimeric antigen receptor and T-cell (CAR-T), at any time prior 
to screening. 
16. Use of any immunosuppressive drugs within 3 months of screening, not including those 
allowed by the inclusion criteria. 
17. Active infection or history of recurrent infections. 
18. Serum total IgG <600 mg/dL. 
19. 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). 
20. 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 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, transfusions, concomitant treatments, 
and relevant clinical response to past disease specific treatments including duration and dosing of 
such treatments.  
6.3 
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. 
6.4 
Karnofsky Performance Scale 
A Karnofsky performance scale evaluation will be conducted at screening. Subjects who score 
less than or equal to 50 are excluded from the study. See Appendix 2. 


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6.5 
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. 
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; and 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 post end-of-infusion 
±60 minutes 
N/A 
48 hours post end-of-infusion 
±120 minutes 
N/A 
Pharmacodynamic (Immunoglobulins) Sampling 
0 hour 
−240 minutes to 0 hour
−240 minutes to 0 hour
24 hours post end-of-infusion 
±60 minutes 
N/A 
48 hours 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


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15, 30, and 45 minutes after start of 
infusion 
±5 minutes 
±5 minutes 
At completion of the infusion 
±10 minutes 
±10 minutes 
30, 60, and 120 minutes post end-of-
infusion 
±10 minutes 
±10 minutes 
Abbreviations: ECG = electrocardiogram; PD = pharmacodynamic; PK = pharmacokinetic. 
aVital signs to include blood pressure, pulse rate, respiratory rate, oral temperature, and pulse oximetry (Cohort 1 only). 
6.6 
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. 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 at least 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.  
6.7 
Clinical Laboratory Measurements 
Laboratory testing (hematology, urinalysis, serum chemistry, virology, serology, pregnancy tests, 
PD, PK, and anti-drug antibodies [ADA]) will be performed using established methods by a 
central laboratory (for screening purposes, retest can be performed using established methods by 
the local 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.  
Table 6. 
Clinical Safety Laboratory Panels 
Hematology 
Serum Chemistry 
Urinalysis 

CBC with differential and
blood smear

Albumin

Alkaline phosphatase

ALT

Appearance

Color

pH


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Table 6. 
Clinical Safety Laboratory Panels 
Hematology 
Serum Chemistry 
Urinalysis 

AST

BUN

C-Reactive Protein

Calcium

Carbon dioxide

Chloride

Creatinine

Creatine Phosphokinase

Glucose

LDH

Phosphorus

Potassium

Sodium

Total and direct bilirubin

Total protein

Uric acid

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
Abnormalities in clinical safety 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 10.3.1). 
6.7.1 
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. 
6.7.2 
Virology 
Testing for hepatitis C 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. 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. 
6.7.4 
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 maximum serum concentration of 
SYNT001 and the associated Tmax. 


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See Table 5 for timing window allowances with respect to PK samples. 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. Measurements for PD 
biomarkers (albumin levels, hematocrit, hemoglobin, platelet count, reticulocyte count, LDH, 
and total and indirect bilirubin) 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 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, 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, 
140 
Albumin 
Hematocrit 
Hemoglobin 
Haptoglobin 
Platelet count 
Reticulocyte count 
Lactate dehydrogenase (LDH) 
Total and indirect bilirubin 
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, 140 
Direct Coombs test  
(also known as direct 
antiglobulin test [DAT]) 
Screening and Days 0, 14, 33, 
56, 84, and 112 
Screening and Days 0, 14, 28, 91, 140 
D-dimer
Antiphospholipid antibodies
Lupus anticoagulant
Anti-cardiolipin antibody
Anti-beta-2-GP1 antibody
Antinuclear antibody (ANA)
titer
Anti-dsDNA antibody titer
Complement component 3 (C3)
Days 0, 14, 33, 56, 84, and 
112 
Days 0, 28, 91 
RNA sequencing 
Days 0, 14, 33, 56, 84, and 
112 
Days 0, 28, 91 
Urine IgG 
Days 0, 14, 33, 56, 84, and 
112 
NA 
Quantitative Coombs assay 
Days 0, 14, 33, and 56 
Days 0, 14, 28, 91 
Immunophenotyping by flow 
cytometry for measurement of; 

CD3+CD4+ T

CD3+CD8+ T

monocytes

NK cells

B cells
Days 0, 28, and 56 
Days 0, 28, 91 
Cold agglutinins (titer and 
thermal amplitude) 
Days 0, 33, 56, 84, and 112 
Days 0, 28, 91, 140 
FCGR2A SNP by buccal swab 
Day 0 
Day 0 
a Ongoing safety and PD evaluations may result in modification of the dosing regimen from every other week 
to weekly. See Appendix 3 for the corresponding visit schedule.  
See Table 5 for timing window allowances with respect to measurement collection 
Immunoglobulins. 


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Detailed instructions for sample collection (including collection tubes) and preparation will be 
provided in a separate laboratory manual. 
6.7.6 
Immunogenicity Testing 
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 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, a titer 
will be determined and there will be testing for neutralizing antibodies using a validated cell-
based assay.  
Detailed instructions for sample collection and preparation will be provided in a separate 
laboratory manual. 
6.7.7 
Circulating Immune Complexes 
Patients with autoimmune diseases such as WAIHA frequently have elevated levels of CICs as 
part of their autoimmune disease process. In these patients the degree of elevation may correlate 
with disease activity. In the SYNT001 phase 1a single dose escalation healthy volunteer study, 
almost all baseline CIC results were within the normal range. Treatment with a single IV dose of 
SYNT001 resulted in a dose-dependent decrease of up to 50% in CICs. CICs are most frequently 
assessed using either a C1q-based binding assay (ELISA), or less frequently by binding to Raji 
Cells via their complement receptor (Flow Cytometry). 
6.7.8 
Direct Antiglobulin (Coombs) Test (DAT) 
WAIHA is caused by autoantibodies (usually IgG) that bind to RBC antigens. This results to the 
activation of the complement system and deposition of complement protein C3 on the RBCs. 
Red blood cells coated with IgG with or without complement disposition are removed from the 
circulation by the reticuloendothelial system in the spleen and liver leading to anemia via a 
process known as extravascular hemolysis. The direct antiglobulin, or Coombs, test is used to 
determine whether a patient’s RBCs are coated with IgG and/or complement proteins. Anti-IgG 
and anti-C3 antisera are added to a patient’s red cells, and if IgG or C3 are present the RBCs 
clump or agglutinate, which is detected visually. 
6.7.9 
Quantitative Coombs Assay 
Subject and control RBC-bound IgG, IgM and C3 will be measured by flow cytometry. RBCs 
coated with serial dilutions of monoclonal anti-Rh(D) IgG and IgM serve as positive controls. 
Quantum™ MESF (Molecules of Equivalent Soluble Fluorochrome) microsphere beads coated 
with known numbers of fluorescent dye molecules are used as internal validation markers prior 
to analysis. Dynabeads® Protein G are used to quantify binding of mouse anti-human IgG, IgM 
and C3 antibodies. Binding of IgG is expressed as the geometric mean of the fluorescence 
intensity.  


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6.8 
Study Drug Administration 
Up to 20 subjects are planned; up to 8 subjects in Cohort 1 and up to 12 subjects in Cohort 2. 
Subject in Cohort 1 will receive SYNT001 10 mg/kg weekly x 5 doses. 
Subjects in Cohort 2 will receive SYNT001 10, 20 or 30 mg/kg weekly x 3 doses (Loading), 
followed by SYNT001 10, 20 or 30 mg/kg every other week x 5 doses (Maintenance). The 
Maintenance dose frequency may be increased to weekly (Cohort 2 alternative weekly 
maintenance schedule).   
SYNT001 will be given as a 250-mL IV infusion over 1 hour ±15 minutes using a 0.2-micron, 
inline filter. 
Investigators may adjust the duration of the infusion if needed to increase tolerability. Prepared 
SYNT001 should be used within 4 hours as described in the pharmacy manual. Full information 
on infusion preparation and administration refer to pharmacy manual. 
See Section 9 for details of study drug.  
6.9 
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. 
6.10 
Prior and Concomitant Medications 
All WAIHA treatments and all other treatments a subject receives within at least 3 months prior 
to screening through the end of study will be documented.  
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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Permitted Medications 
The following concomitant medications and treatment for co-existing conditions, including those 
for WAIHA, are permitted if not listed as prohibited:  
1. Concomitant treatment that is medically indicated for any AEs the subject experiences 
during the study. 
2. Medication for potential infusion-related reactions (IRRs), including post-infusion 
headache: The Investigator may recommend prophylactic use of acetaminophen, IV 
hydration, diphenhydramine, or histamine2 blockers (eg, ranitidine, famotidine). 
3. Stable regimen of the following systemic immunosuppressants: azathioprine, 
mycophenolate mofetil, low-dose methotrexate, cyclosporine, tacrolimus, sirolimus, 
corticosteroids, or low-dose oral cyclophosphamide (≤100 mg/day). 
Prohibited Medications 
The following treatments are prohibited during the study unless specified above as permitted: 
1. Rituximab or other anti-CD20 antibody  
2. Monoclonal antibodies other than study drug. 
3. Any immunosuppressive drugs apart from those that are listed as permitted. 
4. Any cytotoxic agent other than azathioprine, chlorambucil, low-dose methotrexate, or 
low-dose oral cyclophosphamide (≤100 mg/day).  
5. IV corticosteroids prior to infusion of study drug (except in subjects who received 
corticosteroids for treatment of a prior infusion reaction to SYNT001).  
6. Any investigational drug or device. 
7. Vaccinations within 2 weeks of screening through 28 days following final dose of study 
drug. 
WAIHA Co-medication 
Subjects receiving WAIHA treatment at enrollment, should remain on a stable treatment regimen 
throughout dosing and for the 14 days after the last dose of SYNT001.  
 
Corticosteroids 
Before enrollment 
The dose of corticosteroids taken for WAIHA 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 WAIHA 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 


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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 WAIHA 
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. 
STUDY ASSESSMENTS 
7.1 
Cohort 1 Assessments 
7.1.1 
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 physical examination, 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) 
 Karnofsky Performance Scale (Section 6.4) 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
(Section 6.7) 
 Pregnancy test (Section 6.7) 
 Hepatitis and HIV antibody screen (Section 6.7) 
 12-lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position) 
(Section 6.6) 
 PD sample collection (Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM 
o Haptoglobin 
o Direct Coombs test 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
7.1.2 
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 examination (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) 
 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) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 
o Direct Coombs test 
o D-dimer 
o Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and anti-beta-
2-GP1 antibodies) 
o ANA and anti-dsDNA antibody titers  
o C3 
o Cold agglutinins (titer and thermal amplitude) 
o Quantitative Coombs assay 
o Exploratory biomarkers (FCGR2A SNP via buccal swab, RNA sequencing 
[RNAseq], urine IgG) 
o Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, 
CD3+CD8+ T, monocytes, NK cells and B cells 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
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 6.10) 
 AE assessment (Section 6.9) 
 
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) 


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 PK sample collection at 5 minutes and 2, 4, 6 hours after the completion 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 6.10) 
 AE assessment (Section 6.9) 
 
7.1.3 
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) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM 
 PK sampling (record collection date and time) (Section 6.7) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
7.1.4 
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) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM 
 PK sampling (record collection date and time) (Section 6.7) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
7.1.5 
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 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) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM, and CIC 


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 PK sampling (record collection date and time) (Section 6.7) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
7.1.6 
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 examination (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) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
(Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
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 6.10) 
 AE assessment (Section 6.9) 
 
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 6.10) 
 AE assessment (Section 6.9) 
 


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7.1.7 
Dose 2 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 
(Section 6.5) 
 PD sample collection (Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM, and CIC 
 If visit is performed at the study site: 12-lead ECG to be obtained in triplicate 
(Section 6.6) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
7.1.8 
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 examination (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) 
 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) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 
o Direct Coombs test 
o D-dimer 
o Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and anti-beta-
2-GP1 antibodies) 
o ANA and anti-dsDNA antibody titers  
o C3 
o Quantitative Coombs assay 
o Exploratory biomarkers (RNAseq, urine IgG) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) (Section 9) 


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 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 6.10) 
 AE assessment (Section 6.9) 
 
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 6.10) 
 AE assessment (Section 6.9) 
 
7.1.9 
Dose 3 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 
(Section 6.5) 
 PD sample collection (Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM, and CIC 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
7.1.10 
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 examination (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) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
(Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 


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o Haptoglobin 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
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 6.10) 
 AE assessment (Section 6.9) 
 
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 6.10) 
 AE assessment (Section 6.9) 
 
7.1.11 
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 examination (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) 
 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) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 


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o Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, 
CD3+CD8+ T, monocytes, NK cells and B cells 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
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 6.10) 
 AE assessment (Section 6.9) 
 
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) 
 12-Lead ECG (to be obtained in triplicate at 5 minutes after the completion of study drug 
infusion (Section 6.6) 
 PK sample collection at 5 minutes and 2, 4, 6 hours after the completion of study drug 
infusion; record collection date and time for each PK sample (Section 6.7) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
7.1.12 
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) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM 
 PK sampling (record collection date and time) (Section 6.7) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 


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7.1.13 
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) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM 
 PK sampling (record collection date and time) (Section 6.7) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
7.1.14 
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) 
 PD sample collection (Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 
o Direct Coombs test 
o D-dimer 
o Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and anti-beta-
2-GP1 antibodies) 
o ANA and anti-dsDNA antibody titers  
o C3 
o Cold agglutinins (titer and thermal amplitude) 
o Quantitative Coombs assay 
o Exploratory biomarkers (RNAseq, urine IgG) 
 PK sampling (record collection date and time) (Section 6.7) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
7.1.15 
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) 


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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 
(Section 6.5) 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
(Section 6.7) 
 PD sample collection (Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
7.1.16 
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 examination (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 at 5 minutes after the completion of study drug 
infusion (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) 
 PD sample collection (Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 
o Direct Coombs test 
o D-dimer 
o Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and anti-beta-
2-GP1 antibodies) 
o ANA and anti-dsDNA antibody titers  
o C3 
o Cold agglutinins (titer and thermal amplitude) 
o Quantitative Coombs assay 
o Exploratory biomarkers (RNAseq, urine IgG) 
o Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, 
CD3+CD8+ T, monocytes, NK cells and B cells 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 


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7.1.17 
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 examination (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 if required. See Section 6.7.3 for additional 
information. 
 Immunogenicity sample collection (Section 6.7) 
 PD sample collection (Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 
o Direct Coombs test 
o D-dimer 
o Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and anti-beta-
2-GP1 antibodies) 
o ANA and anti-dsDNA antibody titers  
o C3 
o Cold agglutinins (titer and thermal amplitude) 
o Exploratory biomarkers (RNAseq, urine IgG) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
7.1.18 
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 examination (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) 
 PD sample collection (Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 


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o Direct Coombs test 
o D-dimer 
o Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and anti-beta-
2-GP1 antibodies) 
o ANA and anti-dsDNA antibody titers  
o C3 
o Cold agglutinins (titer and thermal amplitude) 
o Exploratory biomarkers (RNAseq, urine IgG) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
7.2 
Cohort 2 Assessments 
7.2.1 
Screening Period: Day −28 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 28 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 physical examination, 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) 
 Karnofsky Performance Scale (Section 6.4) 
 Clinical safety laboratory tests (hematology, serum chemistry panel, urinalysis) 
(Section 6.7) 
 Pregnancy test (Section 6.7) 
 Hepatitis and HIV antibody screen (Section 6.7) 
 12-lead ECG (to be obtained in triplicate after 5 minutes of rest in the supine position) 
(Section 6.6) 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
(Section 6.7) 
 PD sample collection (Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM 
o Haptoglobin 
o Direct Coombs test 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 


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7.2.2 
Enrollment and First Treatment: Day 0 
Study Day 0 is defined as the date the subject is administered their first dose of study drug. 
Subjects should be encouraged drink two 8-ounce glasses of water prior to dosing. 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 examination (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) 
 Pregnancy test (Section 6.7) 
 Serum tetanus antibody and VZV antibody (Section 6.7) 
 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) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 
o Direct Coombs test 
o D-dimer, antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and 
anti-beta-2-GP1 antibodies); antinuclear antibody titer; anti-double-stranded DNA 
antibody titer; complement component 3.  
o Cold agglutinins (titer and thermal amplitude) 
o Quantitative Coombs assay 
o Exploratory biomarkers (FCGR2A SNP via buccal swab, RNAseq) 
o Immune phenotyping by flow cytometry for measurement of CD3+CD4+ T, 
CD3+CD8+ T, monocytes, NK cells and B cells 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
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 6.10) 
 AE assessment (Section 6.9) 


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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): 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, 1 and 2 hours after the completion 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 6.10) 
 AE assessment (Section 6.9) 
 
7.2.3 
Loading Doses 2 and 3 (Cohort 2 weekly Day 7 and 14 [±1 day])  
Subjects will return to the clinic for loading doses 2 and 3. Subjects should be encouraged to 
drink two 8-ounce glasses of water prior to dosing. The following procedures are to be 
performed prior to study drug infusion: 
 Complete physical examination (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) 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
(Section 6.7) 
 PK sample collection (collected just prior to the start of the study drug infusion) 
(Section 6.7) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
(Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 
o Day 14 ONLY: Direct Coombs test 
o Day 14 ONLY: Quantitative Coombs assay 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
After the preceding procedures and assessments are completed: 
 Study drug administration (record date and time of dose of study drug) (Section 9) 


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 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 6.10) 
 AE assessment (Section 6.9) 
 
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) 
 Day 14 ONLY: 12 Lead ECG (to be obtained in triplicate at 5 minutes after the 
completion of study drug infusion (Section 6.6) 
 PK sample collection at 5 minutes, 1 and 2 hours after the completion of study drug 
infusion; record collection date and time for each PK sample (Section 6.7) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
7.2.4 
Maintenance Doses (Cohort 2 every other Week Day 28, 42, 56, and 70 
[± 3 days])  
Subjects will return to the clinic for maintenance doses in Cohort 2 every other week dosing on 
Day 28, 42, 56, and 70. Subjects should be encouraged drink two 8-ounce glasses of water prior 
to dosing. The following procedures are to be performed prior to study drug infusion: 
 Complete physical examination (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) 
 Day 28 ONLY: Pregnancy test (Section 6.7) 
 Day 28 ONLY: Serum tetanus antibody and VZV antibody (Section 6.7) 
 Immunogenicity sample collection (collected just prior to the start of study drug infusion) 
(Section 6.7) 
 Day 28 ONLY: PK sample collection (collected just prior to the start of the study drug 
infusion) (Section 6.7) 
 PD sample collection (collected just prior to the start of the study drug infusion) 
(Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 


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o Haptoglobin 
o Day 28 ONLY: Direct Coombs test 
o Day 28 ONLY: D-dimer, antiphospholipid antibodies (lupus anticoagulant, anti-
cardiolipin, and anti-beta-2-GP1 antibodies); antinuclear antibody titer; anti-
double-stranded DNA antibody titer; complement component 3.  
o Day 28 ONLY: Cold agglutinins (titer and thermal amplitude) 
o Day 28 ONLY: Exploratory biomarkers (RNA seq) 
o Day 28 ONLY: Quantitative Coombs assay 
o Day 28 ONLY: Immune phenotyping by flow cytometry for measurement of 
CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B cells 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
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 6.10) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
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) 
 Day 28 ONLY: PK sample collection at 5 minutes, 1 and 2 hours after the completion of 
study drug infusion; record collection date and time for each PK sample (Section 6.7) 
 Day 28 ONLY: 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 6.10) 
 AE assessment (Section 6.9) 
 
7.2.5 
Final Maintenance Dose Visit (Cohort 2 Day 84) 
Subjects will return to the clinic for the final maintenance dose on Day 84 ±3 days. Subjects 
should be encouraged drink two 8-ounce glasses of water prior to dosing. The following 
procedures are to be performed prior to study drug infusion: 


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 Complete physical examination (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) 
 PK 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) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 
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 6.10) 
 AE assessment (Section 6.9) 
 
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, 1 and 2 hours after the completion of study drug 
infusion; record collection date and time for each PK sample (Section 6.7) 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
7.2.6 
Follow-up: Day 91, 112, and 140 (± 5 days) (Day 91 is Early Termination 
[ET] Visit and Day 140 is End of Study [EOS] Visit)  
On Day 91, 112, and Day 140, subjects are to return to the clinic and the following procedures 
are to be performed.  


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Note: If a subject prematurely discontinues study drug, the subject should be encouraged to 
attend, at a minimum, the early termination (ET) visit (Day 91), and subjects will also be 
encouraged to attend the remaining study visits (Days 112, and 140). 
Subjects who prematurely discontinue from the study during follow up should attend the end of 
study (EOS) visit on Day 140. 
 Day 91 and 140 ONLY: Complete physical examination (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) 
 Day 91 and 140 ONLY: Clinical safety laboratory tests (hematology, serum chemistry 
panel, urinalysis) (Section 6.7) 
 Day 91 and 140 ONLY: Pregnancy test (Section 6.7) 
 Day 91 and 140 ONLY: 12 Lead ECG (Section 6.6) 
 Day 91 and 140 ONLY: Serum tetanus antibody and VZV antibody See Section 6.7.3 for 
additional information. 
 Immunogenicity sample collection (Section 6.7) 
 PD sample collection (Section 6.7) 
o IgG, IgG subtypes (IgG1-4), IgA, IgM and CIC 
o Haptoglobin 
o Day 91 and 140 ONLY: Direct Coombs test 
o Day 91 ONLY: D-dimer, antiphospholipid antibodies (lupus anticoagulant, anti-
cardiolipin, and anti-beta-2-GP1 antibodies); antinuclear antibody titer; anti-
double-stranded DNA antibody titer; complement component 3.  
o Day 91 and 140 ONLY: Cold agglutinins (titer and thermal amplitude) 
o Day 91 ONLY: Exploratory biomarkers (RNAseq) 
o Day 91 ONLY: Immune phenotyping by flow cytometry for measurement of 
CD3+CD4+ T, CD3+CD8+ T, monocytes, NK cells and B cells 
o Day 91 ONLY: Quantitative Coombs assay 
 Concomitant medication assessment (Section 6.10) 
 AE assessment (Section 6.9) 
 


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8. 
STUDY RULES 
8.1 
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 withdraws or prematurely 
discontinue study drug should be encouraged to attend, at a minimum, the early termination (ET) 
visit (Day 112 for Cohort 1 or Day 91 for 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. 
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 or IRB. 
3. 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. 
 
8.2 
Subject Replacement 
Enrolled subjects withdrawn for a reason other than an AE may be replaced.  
8.3 
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 


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 Excessive subject self-withdrawal 
 Significant protocol violations (eg, violation of eligibility criteria, dosing errors, missing 
data for study endpoint analysis) 
 
8.4 
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).  
8.5 
Stopping Rule 
8.5.1 
Dose-Escalation Stopping Rule  
Up to 8 subjects may be enrolled in Cohort 1.  After 4 subjects reach Day 42, the Sponsor 
Medical Team will review available safety and PD data and will decide the dosing regimen for 
Cohort 2. 
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. If the dose-escalation stopping rule is 
met during Cohort 1 (10 mg/kg) all safety data and all available PD 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.  
8.5.2 
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 Sponsor 
Medical Team 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 Team 
determines that further drug exposure would pose an undue risk to subjects. 
8.5.3 
Individual Stopping Rule 
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 AE that, in the judgement of the Investigator (following consultation with 
Medical Monitor, if desired) suggests that it could be unsafe to administer further study drug to 
that subject.  


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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. 
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-WAIHA medications for the management of WAIHA.  
If dosing with study drug is stopped because of an AE/SAE, or because of significant increase in 
doses of anti-WAIHA medications, or any other reason for prematurely discontinuation of study 
drug during the treatment period, the subject should be encouraged to attend, at a minimum, the 
ET visit (Day 112 for Cohort 1 or Day 91 for Cohort 2). Subjects in Cohort 2 will also be 
encouraged to attend the remaining follow up visits on Days 112, and 140.  


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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 ±15 minutes using a 0.2-micron, inline filter.  
Investigators may adjust the duration of the infusion if needed to increase tolerability. Prepared 
SYNT001 should be used within 4 hours as described in the pharmacy manual. For detailed 
information regarding SYNT001 preparation and administration, refer to the Pharmacy Manual. 
9.2 
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. 
9.3 
Cohort Dosing 
Enrolled subjects will receive SYNT001 according to their dose-cohort assignment: 
Cohort 1: 10 mg/kg weekly x 5 doses 
Cohort 2: 10, 20 or 30 mg/kg weekly x 3 doses (Loading), followed by 10, 20 or 30 mg/kg 
every other week x 5 doses (Maintenance).  The Maintenance dose frequency may be 
increased to weekly (Cohort 2 alternative weekly maintenance schedule). 
 
Up to 8 subjects may be enrolled in Cohort 1.  After 4 subjects reach Day 42, the Sponsor 
Medical Team will review available safety and PD data and will decide the dosing regimen for 
Cohort 2. 
9.4 
Handling and Storage of SYNT001 
SYNT001 will be supplied 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.  


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9.5 
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 
investigational product 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). 
9.6 
Warnings and Precautions  
Note: Subjects must not receive any vaccinations from within 2 weeks of screening until 28 days 
after the final dose of study drug. 
9.6.1 
Infusion-Related Reaction 
SYNT001 will be administered as an IV infusion over 1 hour ±15 minutes. Investigators may 
adjust the duration of the infusion if needed to increase tolerability. As with all mAbs 
administered by IV infusion, IRR are possible. In nonclinical testing of SYNT001 in NHPs, 
clinical observations were limited to IRRs due to the immunogenicity of SYNT001 in NHPs. 
These reactions included transient emesis/vomitus which typically occurred within one 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. Since xenobiotic hypersensitivity reactions commonly occur in NHPs following 
administration of humanized proteins, neither infusion reactions nor ADAs are considered 
predictive of immunogenicity or toxicity in humans (Bugelski and Treacy, 2004; ICH S6(R1), 
2011; Ponce et al., 2009).  
In general, infusion reactions to monoclonal antibodies observed in human studies typically 
develop within 30 minutes to 2 hours after the initiation of drug infusion, although symptoms 


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may be delayed for up to 24 hours. Most are mild in severity, although severe and even fatal 
reactions can occur. 
9.6.2 
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 2 and Figure 3 for 
details on the management of Grade 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 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 administration. 


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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. 
 
9.6.3 
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, 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 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 IC on stimulating innate 
immune cell production of inflammatory cytokines (eg, 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. 
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. 
SAFETY 
10.1 
Safety Parameters 
Clinical and laboratory AEs will be graded using the NCI CTCAE; Version 4.03 (see  
Appendix 1).  
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 physical examinations, vital sign measurements, hematology, serum chemistries, 
urinalysis, and ECG. 
10.2 
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 (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; 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 10.3.8). 
10.3 
Evaluating Adverse Events 
The Investigator will determine the seriousness, intensity, and causality of an AE associated with 
the use of the study drug (ie, events where there is a reasonable possibility that the event may 
have been caused by the study drug) based on the definitions that follow. 


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10.3.1 
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 (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: 
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 
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.  
 


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10.3.2 
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. 
10.3.3 
Non-Serious Adverse Events  
(Document on eCRF) 
All other AEs, not fulfilling the previous definitions, are classified as non-serious. 
10.3.4 
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. 
10.3.5 
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: 
 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 (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). 
 


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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) 
 
10.3.6 
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.  
10.3.7 
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 
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. 
10.3.8 
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 electronic data capture (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 10.3.9).  


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10.3.9 
Serious Adverse Event Reporting 
10.3.9.1 
Governing Regulatory Requirements 
Compliance with this request for prompt reporting is essential in that the sponsor is responsible 
for informing the United States (US) 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.  
 
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. 
10.3.9.2 
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). 
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 
 
 
Medical Monitor 
Mobile phone: 
 
Phone (EU): 
 extension 
 
Email: 
 
 
PPD
P
PPD
P
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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10.3.9.3 
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 (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. 
When reporting 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:  
o Elective or previously scheduled surgery, eg, a previously scheduled ventral hernia 
repair 
o Procedures for pre-existing conditions that have not worsened after initiation of 
treatment 
o Pre-specified study hospitalizations for observation 
o Events that result in hospital stays of less than 24 hours and that do not require 
admission, eg, 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. 
 
10.3.10 
Regulatory Reporting 
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. 


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The Sponsor (or designee) will submit SAE that meet the criteria for expedited reporting to the 
regulatory authorities in accordance with local regulations governing safety reporting. Reporting 
of SAE 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. 
10.3.11 
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.  
10.4 
Other Safety Considerations 
10.4.1 
Laboratory Data 
All laboratory data obtained during the study should be reviewed. Any abnormal value that leads 
to a change in subject management (eg, 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.  
10.4.2 
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. 
10.4.3 
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. 
10.5 
Safety Monitoring for Dose Escalation 
Up to 8 subjects may be enrolled in Cohort 1.  After 4 subjects reach Day 42, the Sponsor 
Medical Team will review available safety and PD data and will decide the dosing regimen for 
Cohort 2. 


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11. 
STATISTICAL CONSIDERATIONS  
Statistical analyses will be performed using Statistical Analysis System (SAS) software (Cary, 
NC).  All clinical data captured will be provided in data listings.  A Statistical Analysis Plan 
(SAP) will be finalized prior to database lock.  
11.1 
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. 
11.2 
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. 
11.3 
Statistical Considerations  
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a 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. 
11.3.1 
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 PK population will consist of all subjects who receive at least one dose of study drug 
and have post-dose PK data available. 
 The PD population will consist of all subjects who receive at least one dose of study drug 
and have post-dose PD data available. 
 


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Primary safety analyses will be performed on the Safety population. Demographics, subject 
disposition, and screening and baseline characteristics will be summarized for the Safety, PK and 
PD populations, where appropriate. 
11.3.2 
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.  
11.3.2.1 
Baseline Analysis 
Baseline characteristics to include medical history, physical examination, vital signs, and ECG 
will be summarized using descriptive statistics by dose and dose regimen. 
11.3.3 
Concomitant Medications  
Concomitant medications will be coded using WHO-DD (March 2013, Type B2 or later) and the 
data will be summarized and presented in tables and listings.  
11.4 
Planned PK Analysis 
PK results will be summarized by dose regimen. Descriptive statistics of PK parameters for 
SYNT001 will include mean, SD, coefficient of variation (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. 
11.5 
Safety Analysis 
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. 
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 drug 
[related/not related]) will be summarized separately.  


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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 time point, dose, and dose regimen. 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 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. 
11.6 
Pharmacodynamic Analysis 
Disease activity marker results (hematocrit, hemoglobin, platelet count, reticulocyte count, LDH, 
haptoglobin, total and indirect bilirubin, and direct Coombs test) will be summarized by dose and 
dose regimen. Descriptive statistics of PD will include mean, SD, median, minimum, and 
maximum. 
11.7 
Immunogenicity Analysis  
Immunogenicity results will be summarized by cohort and time point. Descriptive statistics will 
include mean, SD, CV, median, minimum, and maximum. 
11.8 
Interim Analysis 
No formal interim analysis is planned. Safety and PD results will be examined on an ongoing 
basis for making dose-escalation decisions; no statistical analyses are planned for aiding these 
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12. 
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 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 the Sponsor 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 the Sponsor 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 the Sponsor or 
their designee (eg, 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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13. 
STUDY ADMINISTRATION 
13.1 
Study Administrative Structure 
The study administration structure is provided in Table 9. 
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: 
 
 
13.2 
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”. 
13.3 
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. 
Sample ICFs will be supplied to each site. The Sponsor or its designee must review any proposed 
deviations from the sample ICF. The final IRB -approved document must be provided to the 
Sponsor for regulatory purposes. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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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. 
13.4 
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 the Sponsor (or designee) before subject enrollment and 
whenever subsequent modifications to the protocol are made. 
13.5 
Dose Escalation Committee 
The DEC will perform the 24-hour safety data review for the first subject in Cohort 1 to ensure 
that there are no overt safety concerns before dosing the second subject.  The DEC will also 
review the 7-day safety data for the first 2 subjects in Cohort 1 prior to dosing the remaining 
subjects in the cohort.  
13.6 
Sponsor Medical Team 
The Sponsor Medical Team will consist of at least the Medical Monitor and the Sponsor Medical 
Lead.  
After 4 subjects in Cohort 1 reach Day 42, the Sponsor Medical team will review available safety 
and PD data and will decide the dosing regimen for Cohort 2. The Sponsor Medical Team will 
also perform the 24-hour safety data review for the first subject in Cohort 2 to ensure that there 
are no overt safety concerns before dosing the second subject in Cohort 2, The Sponsor Medical 
Team will review the 7-day safety data for the first 2 subjects in Cohort 2 prior to dosing the 
remaining subjects in the cohort. In addition, the Sponsor Medical Team will, on an ongoing 
basis, review Safety and PD data. 
 


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13.7 
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 analyses and 
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 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 this FDA guidance. The Sponsor will notify the Investigator 
in writing that the samples have been destroyed. 


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14. 
CONDITIONS FOR MODIFYING 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). 


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15. 
CONDITIONS FOR TERMINATING THE STUDY 
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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16. 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
16.1 
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 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. 
16.2 
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: 
 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 


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 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 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. 
16.3 
Audits and Inspections 
The Investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the Sponsor (or designee), or to health 
authority inspectors after appropriate notification. The verification of the eCRF data must be by 
direct inspection of source documents. 
16.4 
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 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 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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17. 
MONITORING THE STUDY 
It is understood that the responsible Sponsor 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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18. 
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 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 not for submission to the Sponsor (eg, subjects’ written consent 
forms) in strict confidence. 
Authorized regulatory officials and Sponsor 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 the Sponsor. 
The Principal Investigator also agrees that all information received from the Sponsor, including 
but not limited to the Investigator’s Brochure (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) 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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19. 
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 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 Sponsor policy and generally accepted standards for authorship. 


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20. 
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. 
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):10-6. 
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. 
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, 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. 
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. 
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. 
Ponce R, Abad L, Amaravadi L, Gelzleichter T, Gore E, Green J, et al. Immunogenicity of 
biologically-derived therapeutics: assessment and interpretation of nonclinical safety studies. 
Regul Toxicol Pharmacol. 2009;54(2):164-82. 


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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. 
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. 
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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APPENDIX 2. KARNOFSKY PERFORMANCE SCALE 
General Category 
Index 
Specific Criteria 
Able to carry on normal 
activity; no special care 
needed. 
100% 
Normal, no complaints, no 
evidence of disease. 
90% 
Able to carry on normal 
activity, minor signs or 
symptoms of disease. 
80% 
Normal activity with effort, 
some signs or symptoms of 
disease. 
Unable to work, able to live 
at home and care for most 
personal needs, varying 
amount of assistance needed. 
70% 
Cares for self, unable to carry 
on normal activity or to do 
work. 
60% 
Requires occasional 
assistance from others but 
able to care for most needs. 
50% 
Requires considerable 
assistance from others and 
frequent medical care. 
Unable to care for self, 
requires institutional or 
hospital care or equivalent, 
disease may be rapidly 
progressing. 
40% 
Disabled, requires special 
care and assistance. 
30% 
Severely disabled, 
hospitalization indicated, 
death not imminent. 
20% 
Very sick, hospitalization 
necessary, active supportive 
treatment necessary. 
10% 
Moribund. 
0% 
Dead. 
Source: Mor V, Laliberte L, Morris JN, Wiemann M. The Karnofsky Performance Status Scale. An examination 
of its reliability and validity in a research setting. Cancer. 1984;53(9):2002-2007. 


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APPENDIX 3. COHORT 2 ALTERNATIVE WEEKLY MAINTENANCE SCHEDULE OF EVENTS TABLE 


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Table 10.  
Study Assessments for Cohort 2; Alternative Weekly Maintenance Schedule 
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) 
−28 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 
Visitq 
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 
Karnofsky Performance Scale 
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 
Pregnancy teste 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Hepatitis and HIV antibody 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGf 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Tetanus and VZV antibodiesg 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Cold agglutinins (titer and 
thermal amplitude)  
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
PK samplingh 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Immunogenicityi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administrationj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Immunoglobulinsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
Xl 
Xl 
CIC 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haptoglobin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Direct Coombs test 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Additional PD sample 
collectionsm  
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
FCGR2A by buccal swabn 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNA sequencing  
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Immunophenotypingo 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 


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Quantitative Coombs assay 
 
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 at least 3 months prior to screening through the last study visit 
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; ICF = informed consent form; Ig = immunoglobulin; PD = pharmacodynamic; 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 6.7 for a complete list. Full clinical safety lab draws will be collected at screening and at all 
study visits prior to infusion. PD markers (albumin levels, hematocrit, hemoglobin, platelet count, reticulocyte count, lactate dehydrogenase, and total and indirect bilirubin) 
will be derived from the clinical safety laboratory results. 
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 6.6 for additional information. On 
dosing 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 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 6.7.3 for additional information. 
h. 
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 6.7.4 for additional information. 
i. 
Immunogenicity: 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 to a total volume of 250 mL and administered intravenously over 1 hour 
±15 minutes 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 dosing days, 
samples are collected prior to infusion of study drug. See Section 6.7.5 for additional information. 
l. 
Subjects will return to the clinic on Days 91, 112, and 140 or ET 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 Day 140 will be referred for further management. 
m. Additional PD samples to be collected for measurements of biomarkers, including D-dimer; antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and anti-beta-
2-GP1 antibodies); antinuclear antibody titer; anti-double-stranded DNA antibody titer; complement component 3. Collect samples pre-dose on dosing days. See Section 6.7.5 
for additional information.  
n. 
Buccal samples to be collected and stored. 
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. 

SAP_000.pdf: 
 
A Phase 1b/2, Multicenter, Open-Label, Safety, Tolerability, 
and Activity Study of SYNT001 in Subjects with Warm 
Autoimmune Hemolytic Anemia (WAIHA) 
 
 
 
Unique Protocol ID:  
SYNT001-102  
NCT Number:  
NCT03075878 
Date of SAP:  
09 April 2019 
 


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Protocol SYNT001-102 
CONFIDENTIAL 
V1.0 
 
 
 
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Page 1 of 31 
 
 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL SYNT001-102 
 
A Phase 1b/2, Multicenter, Open-Label, Safety, Tolerability, and Activity 
Study of SYNT001 in Subjects with Warm Autoimmune Hemolytic Anemia 
(WAIHA) 
 
 
 
Investigational Product: 
SYNT001 
Protocol Number: 
SYNT001-102 
Development Phase: 
Phase 1b/2 
Sponsor: 
Alexion Pharmaceuticals Inc.  
121 Seaport Blvd  
Boston, MA 02210  
 
 
 
 
 
Original Protocol: December 19, 2016 
Amendment 1.1: January 18, 2017 
Amendment 2.0: April 12, 2017 
Amendment 3.0: October 10, 2017 
Amendment 4.0: December 21, 2017 
Amendment 5.0: October 23, 2018 
 
SAP Version V1.0 
SAP Date: April 09, 2019 
 


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Page 2 of 31 
 
 
 
SIGNATURE PAGE 
STUDY TITLE: A Phase 1b/2, Multicenter, Open-Label, Safety, Tolerability, and Activity 
Study of SYNT001 in Subjects with Warm Autoimmune Hemolytic Anemia (WAIHA) 
 
Prepared by: 
 
 
Medpace 
 
We, the undersigned, have reviewed and approved this statistical analysis plan. 
 
 
Signature 
      Date 
 
 
  
 
____________________________________________       _____________________ 
 
 
Medpace 
 
 
 
____________________________________________       _____________________ 
  
 
Medpace 
 
 
____________________________________________       _____________________ 
 
   
Alexion Pharmaceuticals Inc. 
 
 
 
____________________________________________       _____________________ 
 
   
Alexion Pharmaceuticals Inc. 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Document History 
Version 
Date 
Comments 
1.0 
April 09, 2019 
Original version 


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Page 4 of 31 
 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 6 
1. 
INTRODUCTION ..................................................................................................... 8 
2. 
STUDY OBJECTIVES AND ENDPOINTS............................................................. 8 
2.1.1 
Primary Objective and Endpoint ......................................................................... 8 
2.1.2 
Secondary Objectives and Endpoints .................................................................. 8 
2.1.3 
Exploratory Objectives and Endpoints ............................................................... 9 
3. 
STUDY OVERVIEW .............................................................................................. 10 
3.1 
Overview of Study Design....................................................................................... 10 
3.2 
Study Assessments .................................................................................................. 12 
3.2.1 
Informed Consent .............................................................................................. 12 
3.2.2 
Demographics and Medical History ................................................................. 12 
3.2.3 
Physical Examination ........................................................................................ 12 
3.2.4 
Karnofsky Performance Scale ........................................................................... 12 
3.2.5 
Vital Sign Measurements .................................................................................. 12 
3.2.6 
12-Lead Electrocardiogram (ECG) ................................................................... 13 
3.2.7 
Clinical Laboratory Measurements ................................................................... 13 
3.2.8 
Pregnancy Testing ............................................................................................. 13 
3.2.9 
Virology ............................................................................................................ 13 
3.2.10 Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing ......... 13 
3.2.11 Pharmacokinetics (PK) Sampling ..................................................................... 14 
3.2.12 Pharmacodynamic Sampling............................................................................. 14 
3.2.13 Immunogenicity Testing ................................................................................... 14 
3.2.14 Circulating Immune Complexes ....................................................................... 14 
3.2.15 Direct Antiglobulin (Coombs) Test .................................................................. 14 
3.2.16 Quantitative Coombs Assay .............................................................................. 14 
3.2.17 Study Drug Administration ............................................................................... 15 
3.2.18 Adverse Event Assessments.............................................................................. 15 
3.2.19 Prior and Concomitant Medications ................................................................. 15 
4. 
STATISTICAL METHODOLOGY ........................................................................ 15 
4.1 
General Design ........................................................................................................ 15 
4.2 
Analysis 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 ....................................................................................................... 17 


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4.7.1 
Adverse Events ................................................................................................. 18 
4.7.2 
Clinical Laboratory Tests .................................................................................. 19 
4.7.3 
Physical Examination, Vital Signs, and Electrocardiogram Findings .............. 19 
4.8 
Analysis of Secondary Endpoints ............................................................................ 19 
4.8.1 
Pharmacokinetic Analysis ................................................................................. 19 
4.8.2 
Pharmacodynamic / Disease Activity Analysis ................................................ 21 
4.8.3 
Immunogenicity Analysis ................................................................................. 21 
4.9 
Analysis of Exploratory Endpoints .......................................................................... 21 
4.9.1 
Exploratory Pharmacodynamic / Disease Activity Analysis ............................ 21 
4.9.2 
Blood Transfusions ........................................................................................... 22 
4.9.3 
Corticosteroid Use............................................................................................. 22 
5. 
SAMPLE SIZE DETERMINATION ...................................................................... 22 
6. 
PROGRAMMING SPECIFICATIONS .................................................................. 22 
7. 
INTERIM ANALYSIS ............................................................................................ 22 
8. 
APPENDICES ......................................................................................................... 23 
 


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Page 6 of 31 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
anti-drug antibodies 
AE 
adverse event 
ANA 
antinuclear antibody 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the curve 
BLQ 
below the limit of quantification 
BMI 
body mass index 
C3 
complement component 3 
CIC 
circulating immune complexes 
Cmax 
maximum observed plasma concentration observed directly from data 
Cmin 
minimum observed plasma concentration observed directly from data 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
percent coefficient of variation 
dsDNA 
double-stranded deoxyribonucleic acid 
ECG 
electrocardiograms 
ELISA 
C1q-based binding assay 
FCGR2A 
Fc gamma R2A receptor 
HIV 
human immunodeficiency virus 
IgA 
immunoglobulin A 
IgG 
Immunoglobulin G 
IgG1-4 
IgG subtypes 
IgM 
immunoglobulin M 
IRR 
infusion-related reaction 
IV 
intravenous 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NK 
natural killer 
PD 
pharmacodynamics 
PE 
physical examinations 
PK 
pharmacokinetics 
QTcF 
corrected QT interval using Fridericia's formula 


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RBC 
red blood cells 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
SD 
standard deviation 
SNP 
single nucleotide polymorphisms 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
t½ 
terminal elimination half-life 
Tmax 
observed time to reach peak plasma concentration 
Tmin 
time to reach minimum observed concentration directly from data 
VZV 
Varicella-Zoster virus 
WAIHA 
warm autoimmune hemolytic anemia 
WHO 
World Health Organization 
λz 
apparent first-order terminal elimination rate constant 


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1. 
INTRODUCTION 
This study is being conducted to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD), immunogenicity, and effects of intravenous (IV) SYNT001 in 
subjects with warm autoimmune hemolytic anemia (WAIHA). 
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 
2.1.1 
Primary Objective and Endpoint 
Primary Objectives 
Primary Endpoints 
Safety: To evaluate the safety and 
tolerability of IV infusions of SYNT001 at 
different dose levels and dosing regimens in 
subjects with WAIHA 
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 
2.1.2 
Secondary Objectives and Endpoints 
Secondary Objectives 
Secondary Endpoints 
To evaluate the efficacy of doses of 
SYNT001 at different dose levels and 
dosing regimens on 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 time point 
To determine the 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 


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Secondary Objectives 
Secondary Endpoints 
1); maximum serum concentration 
determined directly from the maximum 
serum concentration and corresponding Tmax 
(Cohort 2) summarized by dose, dosing 
regimen and time point 
To assess the efficacy of doses of SYNT001 
at different dose levels and dosing regimens 
on disease markers 
The assessment of WAIHA disease activity 
by absolute changes in the disease activity 
markers of hematocrit, hemoglobin, platelet 
count, reticulocyte count, lactate 
dehydrogenase (LDH), haptoglobin, and 
total and indirect bilirubin will be 
summarized by dose, dosing regimen and 
time point The direct Coombs test result 
(positive or negative) will be summarized 
by dose, dosing regimen and time point 
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 and time point 
2.1.3 
Exploratory Objectives and Endpoints 
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 time point, as 
determined by:   
 D-dimer  
 Antiphospholipid antibodies (lupus 
anticoagulant, anti-cardiolipin 
antibody, anti-beta-2-GP1 antibody)  
 Antinuclear antibody titer  
 Anti-dsDNA antibody titer  
 Quantitative Coombs assay  
 Cold agglutinins (titer and thermal 
amplitude)  
 Fc gamma R2A receptor (FCGR2A) 
single nucleotide polymorphisms 
(SNP) by genotyping  
 Complement component 3 levels by 


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Exploratory Objectives 
Exploratory Endpoints 
nephelometry  
 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 
To characterize blood transfusions during 
the study 
The number of units of packed red blood 
cells received by subjects will be 
summarized by dose and dosing regimen 
To determine the impact of different 
SYNT001 dose levels and dosing regimens 
on the subject’s use of corticosteroids to 
treat their WAIHA 
The evaluation of corticosteroid use during 
the study will be summarized by dose, 
dosing regimen and time point 
3. 
STUDY OVERVIEW 
3.1 
Overview of Study Design  
This is a multicenter, open-label study to assess the safety, tolerability, efficacy, PK, PD, and 
immunogenicity of SYNT001 IV administered to subjects with WAIHA. 
Up to 8 subjects with a diagnosis of WAIHA will receive SYNT001 10 mg/kg weekly x 5 
doses (Cohort 1). Up to 12 subjects with a diagnosis of WAIHA will receive SYNT001 (10, 
20 or 30 mg/kg) weekly x 3 doses (Loading), followed by SYNT001 (10, 20 or 30 mg/kg) 
every other week x 5 doses (Maintenance) or SYNT001 (10, 20 or 30 mg/kg) weekly x 10 
doses (alternative weekly maintenance schedule) (Cohort 2). An overview of the study 
cohorts is provided in Table 1. 
Table 1. 
Cohort Overview 
Cohort 
No. of 
subjects 
SYNT001 Dose 
No. of 
Doses 
Frequency of 
Doses 
1 
Up to 8 
10 mg/kg 
5 
Weekly  
2 
Up to 12 
Loading: 10, 20 or 30 mg/kg 
Maintenance: 10, 20 or 30 mg/kg  
3  
5 
Weekly   
Every other 
week 
2 Alternative 
weekly 
schedule 
Up to 12 
Loading: 10, 20 or 30 mg/kg 
Maintenance: 10, 20 or 30 mg/kg 
3  
10 
Weekly  
Weekly 


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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 
Appendix Table 2. For Cohort 2 details, see Appendix Table 3. An alternative weekly 
maintenance schedule of assessment for Cohort 2 is presented in Appendix Table 4. 
 


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3.2 
Study Assessments 
3.2.1 
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. 
3.2.2 
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, transfusions, concomitant 
treatments, and relevant clinical response to past disease specific treatments including 
duration and dosing of such treatments. 
3.2.3 
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. 
3.2.4 Karnofsky Performance Scale 
A Karnofsky performance scale evaluation will be conducted at screening. Subjects who 
score less than or equal to 50 are excluded from the study. 
3.2.5 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 


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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. 
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.  
3.2.6 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. ECGs are to be performed in 
triplicate at least 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. 
3.2.7 Clinical Laboratory Measurements 
Laboratory testing (hematology, urinalysis, serum chemistry, virology, serology, pregnancy 
tests, PD, PK, and anti-drug antibodies [ADA]) will be performed using established methods 
by a central laboratory. 
Abnormalities in clinical safety 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. 
3.2.8 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.  
3.2.9 Virology  
Testing for hepatitis C antibody, hepatitis B surface antigen, and HIV antibody will be 
performed at screening. 
3.2.10 Serum Tetanus Antibody and Varicella-Zoster Virus Antibody Testing 
Samples for serum tetanus antibody and Varicella-Zoster virus antibody testing are to be 
collected. 


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3.2.11 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 maximum serum 
concentration of SYNT001 and the associated Tmax. Specific collection times are detailed in 
Table 5. 
3.2.12 Pharmacodynamic Sampling 
PD samples will be collected for analyses throughout the study. Measurements for PD 
biomarkers (albumin levels, hematocrit, hemoglobin, platelet count, reticulocyte count, LDH, 
and total and indirect bilirubin) 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 6. 
3.2.13 Immunogenicity Testing 
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 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, a titer will be 
determined and there will be testing for neutralizing antibodies using a validated cell based 
assay.  
3.2.14 Circulating Immune Complexes 
Patients with autoimmune diseases such as WAIHA frequently have elevated levels of CICs 
as part of their autoimmune disease process. In these patients the degree of elevation may 
correlate with disease activity. In the SYNT001 phase 1a single dose escalation healthy 
volunteer study, almost all baseline CIC results were within the normal range. Treatment with 
a single IV dose of SYNT001 resulted in a dose-dependent decrease of up to 50% in CICs. 
CICs are most frequently assessed using either a C1q-based binding assay (ELISA), or less 
frequently by binding to Raji Cells via their complement receptor (Flow Cytometry).  
3.2.15 Direct Antiglobulin (Coombs) Test 
WAIHA is caused by autoantibodies (usually IgG) that bind to RBC antigens. This results to 
the activation of the complement system and deposition of complement protein C3 on the 
RBCs. Red blood cells coated with IgG with or without complement disposition are removed 
from the circulation by the reticuloendothelial system in the spleen and liver leading to 
anemia via a process known as extravascular hemolysis. The direct antiglobulin, or Coombs, 
test is used to determine whether a patient’s RBCs are coated with IgG and/or complement 
proteins. Anti-IgG and anti-C3 antisera are added to a patient’s red cells, and if IgG or C3 are 
present the RBCs clump or agglutinate, which is detected visually.  
3.2.16 Quantitative Coombs Assay 
Subject and control RBC-bound IgG, IgM and C3 will be measured by flow cytometry. RBCs 
coated with serial dilutions of monoclonal anti-Rh(D) IgG and IgM serve as positive controls. 
Quantum™ MESF (Molecules of Equivalent Soluble Fluorochrome) microsphere beads 


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coated with known numbers of fluorescent dye molecules are used as internal validation 
markers prior to analysis. Dynabeads® Protein G are used to quantify binding of mouse anti-
human IgG, IgM and C3 antibodies. Binding of IgG is expressed as the geometric mean of 
the fluorescence intensity.  
3.2.17 Study Drug Administration 
Subject in Cohort 1 will receive SYNT001 10 mg/kg weekly x 5 doses.  
Subjects in Cohort 2 will receive SYNT001 10, 20 or 30 mg/kg weekly x 3 doses (Loading), 
followed by SYNT001 10, 20 or 30 mg/kg every other week x 5 doses (Maintenance). The 
Maintenance dose frequency may be increased to weekly (Cohort 2 alternative weekly 
maintenance schedule).  
SYNT001 will be given as a 250-mL IV infusion over 1 hour ±15 minutes using a 0.2-
micron, inline filter. 
3.2.18 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. 
3.2.19 Prior and Concomitant Medications 
Prior to protocol amendment 5, all medications a subject received within 14 days prior to 
enrollment through the end of the study were documented. A history of treatments taken for 
primary disease, even if not taken within the 14 days prior to enrollment, were collected.  
After protocol amendment 5, all WAIHA treatments and all other treatments a subject receives 
within at least 3 months prior to screening through the end of study will be documented.  
4. 
STATISTICAL METHODOLOGY 
All descriptive and inferential statistical analyses will be performed using Statistical Analysis 
System (SAS®) software Version 9.3 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. 
4.1 
General Design 
All clinical data captured will be provided in data listings. Subject disposition, demographic 
information, and baseline characteristics will be presented. 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. 


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Continuous data will be described using descriptive statistics: number of observations (n), 
mean, standard deviation (SD), median, Q1 (25th percentile), Q3 (75th percentile), minimum, 
and maximum. Geometric mean (GM) and GM CV will be provided for PK parameters. 
Categorical data will be summarized using frequencies and percentages. 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. 
4.2 
Analysis Populations 
Three sub-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 PK population will consist of all subjects who receive at least one dose of study 
drug and have post-dose PK data available. PK concentrations and parameters will be 
summarized based on the PK population. 
 
 The PD population will consist of all subjects who receive at least one dose of study 
drug and have post-dose PD data available. PD data will be summarized based on the 
PD population. 
Primary safety analyses will be performed on the Safety population. Demographics, subject 
disposition, and 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, and body mass index (BMI), age at diagnosis of 
WAIHA, WAIHA disease duration, and Karnofsky Performance Scale score (%). 
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 subjects in corresponding categories.  


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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 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. Hematologic 
variables history will also be summarized. All medical/surgical history and hematologic 
variables history will also be listed. 
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 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 
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 visit by cohort. 
Percentage of total dose administered (%) = total dose administered / planned total dose * 
100%. 
Study medication administration data will be listed. 
4.7 
Safety Analyses 
All statistical analysis of safety outcomes will be descriptive. Safety observations and 
measurements include AEs, treatment-emergent AEs (TEAEs), SAEs, safety laboratory tests, 
vital sign measurements, PEs, 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. 


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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 
 TEAEs leading to discontinuation of study drug 
 Drug-related TEAEs leading to discontinuation of study drug 
 TEAEs leading to study drug interruption 
 Drug-related TEAEs leading to study drug interruption 
 TEAEs leading to study drug dose reduction 
 Drug-related TEAEs leading to study drug reduction 
 Death 
TEAEs will also be summarized using SOC, preferred term and SOC, preferred term and 
severity grade based on NCI CTCAE (Version 4.03). Drug-related TEAEs will be 
summarized in the same manner. IRR related AEs will be summarized separately. 
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 drug) will be summarized separately.  
TEAEs, SAEs, deaths and AEs leading to withdrawal, dose reduction, dose interruption, or 
treatment discontinuation will be listed. Duration of AEs will be determined and included in 
listings, along with action taken and outcome.  


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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 also 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 will be used. 
Results, normal limits of the local laboratory, and abnormality flags will be listed. 
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 will be used. 
The arithmetic mean of parameters from triplicate ECGs will be calculated first for each 
participant at each planned time point. Then summary statistics for 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 changes (normal, abnormal not clinically significant, 
abnormal clinically significant) from pre-dose to each post-dose time point showing number 
and percentage of subjects with changes between categories will be presented by cohort.  
The number and percentage of subjects experiencing potential QTcF prolongation (QTcF > 
450, >480 and >500 msec, and change from baseline in QTcF >30 and >60 msec) will be 
summarized at each time point by cohort. 
Actual sampling times that are outside the scheduled sampling times window described in 
Table 5 will be excluded from summary statistics. 
4.8 
Analysis of Secondary Endpoints 
4.8.1 
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. 


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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 serum concentration data will be used to calculate the following PK parameters, if 
feasible: 
Parameters 
Description 
Cmax 
Maximum observed plasma concentration observed directly from 
data at Day 0 and Day 28 
Tmax 
Time to reach maximum observed concentration directly from data 
at Day 0 and Day 28 
λz 
Apparent first-order terminal elimination rate constant calculated 
by linear regression of the terminal linear portion of the log 
concentration vs. time curve at Day 0 and Day 28 
t½ 
Terminal elimination half-life, calculated as ln(2)/ λz at Day 0 and 
Day 28 
AUC0-24 
AUC from time zero to 24 hours post-dose administration at Day 0 
and Day 28 
AUC∞ 
AUC from time zero to infinity time (as AUC0-t + Clast/ λz, where 
Clast is the last quantifiable concentration) at Day 0 and Day 28 
Actual sampling time will be used for PK calculations. Actual sampling times that are outside 
the scheduled sampling times window described in Table 5 will be excluded from summary 
statistics of average PK SYNT001 serum concentrations but will still be used in the 
calculation of PK parameters.   
PK parameters will be determined using non-compartmental method. 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 AUC∞ 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 AUC∞) will not be calculated.  


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4.8.2 
Pharmacodynamic / Disease Activity Analysis 
PD samples will be collected for analyses throughout the study. PD samples will be collected 
according to the schedule shown in Table 5. 
Measurements for PD and disease activity biomarkers include:  
 Total IgG assessments 
 IgG subtypes (IgG1-4) 
 Immunoglobulin A (IgA) 
 Immunoglobulin M (IgM) 
 Albumin levels 
 CIC 
 Hematocrit 
 Hemoglobin 
 Platelet count 
 Reticulocyte count 
 LDH 
 Haptoglobin 
 Direct Coombs tests  
 Total and indirect bilirubin  
PD/disease activity values, percentage change and absolute change from baseline will be 
summarized by cohort using descriptive statistics if result type is numerical. Mean (±SD) of 
values and percentage change and absolute change from baseline will be plotted by cohort. 
PD/disease activity result categories will be summarized if result type is categorical. 
4.8.3 
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 
Analysis of Exploratory Endpoints 
4.9.1 
Exploratory Pharmacodynamic / Disease Activity Analysis 
Exploratory PD and disease activity markers may include: 
 D-dimer  
 Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin antibody, anti-beta-
2-GP1 antibody)  
 Antinuclear antibody titer  
 Anti-dsDNA antibody titer  
 Quantitative Coombs assay  
 Cold agglutinins 
 Fc gamma R2A receptor (FCGR2A) 
 Complement component 3 
 RNA sequencing  
 Immunophenotyping including measurements of T cells, monocytes, natural killer 
(NK) cells, and B cells 


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All exploratory PD/disease activity data available at the time of the database lock 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. 
4.9.2 
Blood Transfusions 
The number of units of packed red blood cells received by subjects will be summarized by 
cohort. 
4.9.3 
Corticosteroid Use 
The number and percent of subjects who use corticosteroid, and corticosteroid dose will be 
summarized by cohort and visit. 
5. 
SAMPLE SIZE DETERMINATION 
This study will be conducted in male and female subjects with a confirmed diagnosis of 
WAIHA. 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.  
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 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. Footnotes in listings will reference datasets used in the listing.  Footnotes in tables and 
figures will reference the appurtenant listings. 
7. 
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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8. 
APPENDICES 
Appendix A:  Study Assessment 
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 (or 
ET) 
Time Point (Study Day) 
−14 to −1 
0 
1 
(±1 h) 
2 
(±2 h) 
5a 
(±4 h) 
7 
(±6 h) 
12a 
(±6 h) 
14 
(±6 h) 
19a 
(±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 
(±5 d) 
Informed consent 
X 
Demographics/medical history 
X 
Inclusion/exclusion 
X 
Physical examinationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky Performance Scale 
X 
Pulse oximetryd 
X 
X 
X 
X 
X 
Clinical safety labse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testf 
X 
X 
X 
X 
Hepatitis and HIV antibody screen 
X 
12-lead ECGg 
X 
X 
X 
X 
X 
Tetanus and VZV antibodiesh 
X 
X 
X 
X 
Cold agglutinins (titer and thermal 
amplitude) 
X 
X 
X 
X 
X 
PK samplingi 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicityj 
X 
X 
X 
X 
X 
X 
Study drug administrationk 
X 
X 
X 
X 
X 
Immunoglobulinsl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xm 
CIC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haptoglobin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Direct Coombs test 
X 
X 
X 
X 
X 
X 
X 
Additional PD sample collectionn 
X 
X 
X 
X 
X 
X 
FCGR2A by buccal swabo 
X 
RNA sequencing 
X 
X 
X 
X 
X 
X 
Urine IgG 
X 
X 
X 
X 
X 
X 


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Immunophenotypingp 
X 
X 
X 
Quantitative Coombs assay 
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 at least 3 months prior to screening through the last study visit 
CIC = circulating immune complexes; d = day(s); ECG = electrocardiogram; ET = early termination; h = hour(s); FCGR2A = Fc gamma R2a receptor; HIV = human immunodeficiency virus; 
ICF = informed consent form; Ig = immunoglobulin; PD = pharmacodynamic; PK = pharmacokinetic; VZV = varicella-zoster virus. 
a. 
Visit Days 5, 12, and 19 may be conducted via at-home nurse in lieu of a subject visit to the study site. 
b. 
Complete physical examination, including weight, to be performed. Height and body mass index will be additional assessments conducted at screening. 
c. 
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. 
d. 
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. 
e. 
Clinical safety labs: hematology, clinical chemistry, and urinalysis. See Protocol Section 6.7 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. PD markers (albumin levels, hematocrit, hemoglobin, platelet count, reticulocyte count, lactate dehydrogenase, and total and 
indirect bilirubin) will be derived from the clinical safety laboratory results. 
f. 
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. 
g. 
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 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. 
h. 
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 6.7.3 for additional information. 
i. 
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 6.7.4 for additional information. 
j. 
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 Protocol Section 6.7.6 
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 9 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. 
m. 
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. 
n. 
Additional PD samples to be collected for measurements of biomarkers, including D-dimer; antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and 
anti-beta-2-GP1 antibodies); antinuclear antibody titer; anti-double-stranded DNA antibody titer; complement component 3. See Protocol Section 6.7.5 for complete information. 
o. 
Buccal samples to be collected and stored. 
p. 
Immunophenotyping by flow cytometry for measurement of CD3+CD4+ T, CD3+CD8+ T, monocytes, natural killer (NK) cells, and B cells. 


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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) 
−28 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 
Karnofsky Performance Scale 
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 
Pregnancy teste 
X 
X 
X 
X 
X 
Hepatitis and HIV antibody screen 
X 
12-lead ECGf 
X 
X 
X 
X 
X 
X 
Tetanus and VZV antibodiesg 
X 
X 
X 
X 
Cold agglutinins (titer and thermal 
amplitude) 
X 
X 
X 
X 
PK samplingh 
X 
X 
X 
X 
X 
Immunogenicityi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administrationj 
X 
X 
X 
X 
X 
X 
X 
X 
Immunoglobulinsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
Xl 
Xl 
CIC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haptoglobin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Direct Coombs test 
X 
X 
X 
X 
X 
X 
Additional PD sample collectionm 
X 
X 
X 
FCGR2A by buccal swabn 
X 
RNA sequencing 
X 
X 
X 


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Immunophenotypingo 
X 
X 
X 
Quantitative Coombs assay 
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 at least 3 months prior to screening through the last study visit 
 
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; ICF = informed consent form; Ig = immunoglobulin; PD = pharmacodynamic; 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 day, 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 6.7 for a complete list. Full clinical safety lab draws will be collected at screening and at all 
study visits prior to infusion if applicable. PD markers (albumin levels, hematocrit, hemoglobin, platelet count, reticulocyte count, lactate dehydrogenase, and total and indirect 
bilirubin) will be derived from the clinical safety laboratory results. 
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 6.6 for additional information. On 
days of treatment, to be obtained 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 6.7.3 for additional information. 
h. 
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 6.7.4 for additional information. 
i. 
Immunogenicity: Samples will be collected pre-dose when collected on dosing days. See Protocol 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 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 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 dosing days, samples are 
collected prior to infusion of study drug. See Protocol Section 6.7.5 for additional information. 
l. 
Subjects will return to the clinic on Days 91, 112, and 140 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 Day 140 will be referred for further management. 
m. Additional PD samples to be collected for measurements of biomarkers, including D-dimer; antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and anti-beta- 2-GP1 
antibodies); antinuclear antibody titer; anti-double-stranded DNA antibody titer; complement component 3. Collect samples pre-dose on dosing days. See Protocol Section 6.7.5 for 
additional information. 
n. 
Buccal samples to be collected and stored. 
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. 


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Table 4. 
Study Assessments for Cohort 2; Alternative Weekly Maintenance Schedule 
Visit Number 
Screening 
Loading 
Maintenance 
Follow-Up 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Time Point 
(Study Day) 
−28 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 
Visitq 
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 
Karnofsky Performance Scale 
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 
Pregnancy teste 
X 
X 
X 
X 
X 
Hepatitis and HIV antibody 
screen 
X 
12-lead ECGf 
X 
X 
X 
X 
X 
X 
Tetanus and VZV antibodiesg 
X 
X 
X 
X 
Cold agglutinins (titer and 
thermal amplitude) 
X 
X 
X 
X 
PK samplingh 
X 
X 
X 
X 
X 
Immunogenicityi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administrationj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunoglobulinsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
Xl 
Xl 
CIC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haptoglobin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Direct Coombs test 
X 
X 
X 
X 
X 
X 
Additional PD sample 
collectionsm 
X 
X 
X 


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FCGR2A by buccal swabn 
X 
RNA sequencing 
X 
X 
X 
Immunophenotypingo 
X 
X 
X 
Quantitative Coombs assay 
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 at least 3 months prior to screening through the last study visit 
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; ICF = informed consent form; Ig = immunoglobulin; PD = pharmacodynamic; 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 6.7 for a complete list. Full clinical safety lab draws will be collected at screening and at all 
study visits prior to infusion. PD markers (albumin levels, hematocrit, hemoglobin, platelet count, reticulocyte count, lactate dehydrogenase, and total and indirect bilirubin) will be 
derived from the clinical safety laboratory results. 
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 6.6 for additional information. On 
dosing 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 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 6.7.3 for additional information. 
h. 
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 Protocol Section 6.7.4 for additional information. 
i. 
Immunogenicity: Samples will be collected pre-dose when collected on dosing days. See Protocol 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 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 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 dosing days, samples are 
collected prior to infusion of study drug. See Protocol Section 6.7.5 for additional information. 
l. 
Subjects will return to the clinic on Days 91, 112, and 140 or ET 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 Day 140 will be referred for further management. 
m. Additional PD samples to be collected for measurements of biomarkers, including D-dimer; antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and anti-beta- 2-GP1 
antibodies); antinuclear antibody titer; anti-double-stranded DNA antibody titer; complement component 3. Collect samples pre-dose on dosing days. See Protocol Section 6.7.5 for 
additional information. 
n. 
Buccal samples to be collected and stored. 
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 
 


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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 post end-of-infusion 
±60 minutes 
N/A 
48 hours post end-of-infusion 
±120 minutes 
N/A 
Pharmacodynamic (Immunoglobulins) Sampling 
0 hour 
−240 minutes to 0 hour 
−240 minutes to 0 hour 
24 hours post end-of-infusion 
±60 minutes 
N/A 
48 hours 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, 60, and 120 minutes post end-of- 
infusion 
±10 minutes 
±10 minutes 
Abbreviations: ECG = electrocardiogram; PD = pharmacodynamic; PK = pharmacokinetic. 
aVital signs to include blood pressure, pulse rate, respiratory rate, oral temperature, and pulse oximetry (Cohort 1 only).


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Table 6. 
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, 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, 
140 
Albumin 
Hematocrit 
Hemoglobin 
Haptoglobin 
Platelet count 
Reticulocyte count 
Lactate dehydrogenase (LDH) 
Total and indirect bilirubin 
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, 140 
Direct Coombs test 
(also known as direct 
antiglobulin test [DAT]) 
Screening and Days 0, 14, 33, 
56, 84, and 112 
Screening and Days 0, 14, 28, 91, 140 
D-dimer 
Antiphospholipid antibodies 
Lupus anticoagulant 
Anti-cardiolipin antibody 
Anti-beta-2-GP1 antibody 
Antinuclear antibody (ANA) 
titer 
Anti-dsDNA antibody titer 
Complement component 3 (C3) 
Days 0, 14, 33, 56, 84, and 
112 
Days 0, 28, 91 
RNA sequencing 
Days 0, 14, 33, 56, 84, and 
112 
Days 0, 28, 91 
Urine IgG 
Days 0, 14, 33, 56, 84, and 
112 
NA 
Quantitative Coombs assay 
Days 0, 14, 33, and 56 
Days 0, 14, 28, 91 
Immunophenotyping by flow 
cytometry for measurement of; 
 
CD3+CD4+ T 
 
CD3+CD8+ T 
 
monocytes 
 
NK cells 
 
B cells 
Days 0, 28, and 56 
Days 0, 28, 91 
Cold agglutinins (titer and 
thermal amplitude) 
Days 0, 33, 56, 84, and 112 
Days 0, 28, 91, 140 
FCGR2A SNP by buccal swab 
Day 0 
Day 0 
a Ongoing safety and PD evaluations may result in modification of the dosing regimen from every other 
week to weekly. 
 


Alexion Pharmaceuticals, Inc. 
Protocol SYNT001-102 
CONFIDENTIAL 
V1.0 
 
 
APR 09, 2019 
 
 
Page 31 of 31 
 
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.