Conditions: Atopic Dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 65
Healthy volunteers: no

Brief summary:
This study will assess the efficacy and safety of MSTT1041A (astegolimab) in participants with moderate to severe atopic dermatitis (AD). The study consists of a screening period, a 16-week treatment period, and an 8-week follow-up period.

Detailed description:

Arms:
arm 1: Participants will receive MSTT1041A arm 2: Participants will receive placebo matched to MSTT1041A

Interventions: intervention 1: MSTT1041A intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive subcutaneous (SC) MSTT1041A intervention 2: Participants will receive SC placebo

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: A Phase II, Randomized, Double-Blind, Placebo-Controlled 
Multicenter Study to Assess the Efficacy and Safety of MSTT1041A in 
Patients With Moderate to Severe Atopic Dermatitis 
NCT Number: NCT03747575 
Document Date: Protocol Version 1: 31-August-2018 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
MSTT1041A—Genentech, Inc.
Protocol GS40965, Version 1
PROTOCOL
TITLE:
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED MULTICENTER STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF MSTT1041A 
IN PATIENTS WITH MODERATE TO SEVERE ATOPIC 
DERMATITIS
PROTOCOL NUMBER:
GS40965
VERSION NUMBER:
1
EUDRACT NUMBER:
2018-003429-27
IND NUMBER:
140186
TEST PRODUCT:
MSTT1041A (RO7187807)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
See electronic date stamp below.
 
31-Aug-2018 16:41:39
Title
Approver's Name
Company Signatory
Date and Time (UTC)


MSTT1041A—Genentech, Inc.
2/Protocol GS40965, Version 1
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM................................................................................8
PROTOCOL SYNOPSIS .................................................................................................9
1.
BACKGROUND.....................................................................................................19
1.1
Background on Atopic dermatitIs....................................................19
1.2
Background on MSTT1041A ..........................................................20
1.3
Study Rationale and Benefit-Risk Assessment...............................20
2.
OBJECTIVES AND ENDPOINTS..........................................................................22
2.1
Efficacy Objectives.........................................................................22
2.1.1
Primary Efficacy Objective..............................................................22
2.1.2
Secondary Efficacy Objective.........................................................22
22
2.2
Safety Objective .............................................................................23
2.3
Pharmacokinetic Objectives ...........................................................23
2.4
Immunogenicity Objective ..............................................................23
2.5
Biomarker Objective.......................................................................23
3.
STUDY DESIGN ...................................................................................................24
3.1
Description of the Study .................................................................24
3.1.1
Internal Monitoring Committee........................................................25
3.2
End of Study and Length of Study..................................................26
3.3
Rationale for Study Design.............................................................26
26
3.3.2
Rationale for Patient Population .....................................................27
3.3.3
Rationale for Control Group............................................................27
3.3.4
Rationale for Biomarker Assessments............................................27
4.
MATERIALS AND METHODS...............................................................................27
4.1
Patients..........................................................................................27
4.1.1
Inclusion Criteria ............................................................................27
4.1.2
Exclusion Criteria ...........................................................................29
4.2
Method of Treatment Assignment and Blinding ..............................33
4.3
Study Treatment and Other Treatments Relevant to 
the Study Design............................................................................33
4.3.1
Study Treatment Formulation, Packaging, and 
Handling.........................................................................................34


MSTT1041A—Genentech, Inc.
3/Protocol GS40965, Version 1
4.3.1.1
MSTT1041A and Placebo ..............................................................34
4.3.2
Study Treatment Dosage, Administration, and 
Compliance ....................................................................................34
4.3.2.1
MSTT1041A and Placebo ..............................................................34
4.3.3
Background Treatment...................................................................35
4.3.4
Rescue Treatment..........................................................................35
4.3.5
Investigational Medicinal Product Accountability ............................36
4.3.6
Continued Access to MSTT1041A..................................................36
4.4
Concomitant Therapy, Prohibited Therapy, and 
Additional Restrictions....................................................................36
4.4.1
Cautionary Therapy........................................................................36
4.4.1.1
Herbal Therapies............................................................................36
4.4.2
Prohibited Therapy.........................................................................37
4.4.3
Additional Restrictions....................................................................37
4.5
Study Assessments........................................................................37
4.5.1
Informed Consent Forms and Screening Log .................................38
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data .........................................................................38
4.5.3
Atopy Status...................................................................................38
4.5.4
Physical Examinations ...................................................................38
4.5.5
Vital Signs ......................................................................................39
4.5.6
Laboratory, Biomarker, and Other Biological Samples ...................39
4.5.7
Electrocardiograms ........................................................................41
4.5.8
Chest X-Rays.................................................................................41
4.5.9
Clinician-Reported and Patient-Reported Outcomes ......................42
4.5.9.1
Eczema Area and Severity Index ...................................................42
4.5.9.2
SCORing Atopic Dermatitis, Clinician Reported .............................42
4.5.9.3
Investigator Global Assessment .....................................................43
43
43
 
43
43
 
44
44
44


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4/Protocol GS40965, Version 1
 
45
45
46
4.6
Treatment, Patient, Study, and Site Discontinuation.......................46
4.6.1
Study Treatment Discontinuation....................................................46
4.6.2
Patient Discontinuation from Study.................................................46
4.6.3
Study Discontinuation.....................................................................47
4.6.4
Site Discontinuation........................................................................47
5.
ASSESSMENT OF SAFETY .................................................................................47
5.1
Safety Plan.....................................................................................47
5.1.1
Risks Associated with MSTT1041A................................................48
5.1.1.1
Immunogenicity..............................................................................48
5.1.1.2
Hypersensitivity Reactions and 
Anaphylaxis/Hypersensitivity-Like Reactions..................................48
5.1.1.3
Injection-Site Reactions..................................................................49
5.1.1.4
Infection .........................................................................................49
5.1.1.5
Exacerbation of Cardiovascular Disease........................................50
5.1.2
Management of Patients Who Experience Adverse 
Events............................................................................................50
5.1.2.1
Treatment Interruption....................................................................50
5.1.2.2
Management Guidelines.................................................................51
5.1.2.3
Management of Increases in QT Interval........................................52
5.1.2.4
Anaphylaxis....................................................................................52
5.2
Safety Parameters and Definitions .................................................53
5.2.1
Adverse Events ..............................................................................53
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor)...................................................................................53
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ............................................................54
5.3
Methods and Timing for Capturing and Assessing
Safety Parameters..........................................................................55
5.3.1
Adverse Event Reporting Period ....................................................55
5.3.2
Eliciting Adverse Event Information ................................................55
5.3.3
Assessment of Severity of Adverse Events ....................................55
5.3.4
Assessment of Causality of Adverse Events...................................56
5.3.5
Procedures for Recording Adverse Events.....................................57


MSTT1041A—Genentech, Inc.
5/Protocol GS40965, Version 1
5.3.5.1
Injection Reactions.........................................................................57
5.3.5.2
Major Adverse Cardiac Events .......................................................57
5.3.5.3
Diagnosis versus Signs and Symptoms..........................................58
5.3.5.4
Adverse Events That Are Secondary to Other Events ....................58
5.3.5.5
Persistent or Recurrent Adverse Events.........................................58
5.3.5.6
Abnormal Laboratory Values ..........................................................59
5.3.5.7
Abnormal Vital Sign Values............................................................59
5.3.5.8
Abnormal Liver Function Tests.......................................................60
5.3.5.9
Deaths............................................................................................60
5.3.5.10
Preexisting Medical Conditions.......................................................61
5.3.5.11
Lack of Efficacy or Worsening of Atopic Dermatitis.........................61
5.3.5.12
Hospitalization or Prolonged Hospitalization...................................61
5.3.5.13
Safety Biomarker Data ...................................................................62
5.4
Immediate Reporting Requirements from Investigator 
to Sponsor......................................................................................62
5.4.1
Emergency Medical Contacts.........................................................62
5.4.2
Reporting Requirements for Serious Adverse Events 
and Adverse Events of Special Interest..........................................63
5.4.2.1
Events That Occur prior to Study Drug Initiation.............................63
5.4.2.2
Events That Occur after Study Drug Initiation.................................63
5.4.3
Reporting Requirements for Pregnancies.......................................63
5.4.3.1
Pregnancies in Female Patients.....................................................63
5.4.3.2
Pregnancies in Female Partners of Male Patients ..........................64
5.4.3.3
Congenital Anomalies/Birth Defects and Abortions.........................64
5.4.4
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error ........................................................65
5.5
Follow-Up of Patients after Adverse Events....................................66
5.5.1
Investigator Follow-Up....................................................................66
5.5.2
Sponsor Follow-Up.........................................................................66
5.6
Adverse Events That Occur after the Adverse Event 
Reporting Period ............................................................................66
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and Ethics 
Committees....................................................................................67
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................................67
6.1
Determination of Sample Size ........................................................67
6.2
Summaries of Conduct of Study.....................................................68


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6/Protocol GS40965, Version 1
6.3
Summaries of Treatment Group Comparability...............................68
6.4
Efficacy Analyses ...........................................................................68
6.4.1
Primary Efficacy Endpoint ..............................................................68
6.4.2
Secondary Efficacy Endpoints........................................................69
69
6.5
Safety Analyses .............................................................................69
6.6
Pharmacokinetic Analyses .............................................................69
6.7
Immunogenicity Analyses...............................................................70
6.8
Biomarker Analyses .......................................................................70
6.9
Sensitivity analysis .........................................................................71
7.
DATA COLLECTION AND MANAGEMENT ..........................................................71
7.1
Data Quality Assurance..................................................................71
7.2
Electronic Case Report Forms........................................................71
7.3
Electronic Patient- and Clinician- Reported Outcome 
Data ...............................................................................................72
7.4
Source Data Documentation ..........................................................72
7.5
Use of Computerized Systems .......................................................73
7.6
Retention of Records......................................................................73
8.
ETHICAL CONSIDERATIONS ..............................................................................73
8.1
Compliance with Laws and Regulations .........................................73
8.2
Informed Consent...........................................................................74
8.3
Institutional Review Board or Ethics Committee .............................75
8.4
Confidentiality.................................................................................75
8.5
Financial Disclosure .......................................................................76
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION................................................................................................76
9.1
Study Documentation.....................................................................76
9.2
Protocol Deviations ........................................................................76
9.3
Site Inspections..............................................................................76
9.4
Administrative Structure .................................................................77
9.5
Dissemination of Data and Protection of Trade 
Secrets...........................................................................................77
9.6
Protocol Amendments....................................................................78
10.
REFERENCES......................................................................................................79


MSTT1041A—Genentech, Inc.
7/Protocol GS40965, Version 1
LIST OF TABLES
Table 1
Guidelines for Treatment Interruption or Discontinuation for 
Patients Who Experience Hepatotoxicity .................................... 51
Table 2
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 56
Table 3
Causal Attribution Guidance ....................................................... 57
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 25
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 82
Appendix 2
WHO Classification of Topical Corticosteroids............................ 87
Appendix 3
Hepatitis B Screening Flowchart................................................. 88
Appendix 4
Eczema Area and Severity Index................................................ 89
Appendix 5
SCORing Atopic Dermatitis......................................................... 90
Appendix 6
Investigator Global Assessment.................................................. 91
92
Appendix 8
WHO Toxicity Grading Scale ...................................................... 97


MSTT1041A—Genentech, Inc.
8/Protocol GS40965, Version 1
PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED MULTICENTER STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF MSTT1041A 
IN PATIENTS WITH MODERATE TO SEVERE ATOPIC 
DERMATITIS
PROTOCOL NUMBER:
GS40965
VERSION NUMBER:
1
EUDRACT NUMBER:
2018-003429-27
IND NUMBER:
140186
TEST PRODUCT:
MSTT1041A (RO7187807)
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the CRO.






MSTT1041A—Genentech, Inc.
11/Protocol GS40965, Version 1
After providing informed consent, patients will be assessed for study eligibility during screening 
and at the randomization (Day 1) visit.  Screening will be up to 35 days.  During the screening 
period, patients must demonstrate EASI score ≥16, IGA score ≥3, pruritus NRS score for 
maximum itch intensity ≥3, and have a history of inadequate response to treatment with topical
medications.  Furthermore, patients will be required to apply moisturizers (emollients) at least 
twice daily and to refrain from topical corticosteroids (TCS) or topical calcineurin inhibitors
(TCIs) use for at least the 7 consecutive days immediately before randomization and throughout 
the study.  However, to allow adequate assessment of skin dryness, moisturizers should not be 
applied on the area(s) of non-lesional skin designated for such assessments for at least 8 hours 
before each office visit. Patients who fail to meet eligibility criteria during screening will be 
permitted to re-screen once, unless the reason for the screen failure is because of not meeting 
any of the following:

EASI score 16 at screening and the randomization visit

IGA score 3 (on the 0 to 4 IGA scale, in which 3 is moderate and 4 is severe) at screening 
and the randomization visit

10% BSA of AD involvement at screening and the randomization visit

Baseline pruritus NRS score for maximum itch intensity 3 at screening and the 
randomization visit
Patients who fail to meet eligibility requirements and are eligible to be re-screened are required 
to repeat assessments as follows:

If 35 days after Informed Consent Form completion, repeat only the assessments that 
triggered screen failure.

If > 35 days after Informed Consent Form completion, repeat the consent process and all 
screening assessments except tuberculosis (TB) screening and hepatitis serologies. 
TB screening and hepatitis serologies should be repeated if re-screening occurs 3 months 
after initial Informed Consent Form completion.
At Day 1, patients will undergo further assessments to determine eligibility for randomization to 
the double-blind treatment period. 
Approximately 90 patients will be randomized in a 1:1 ratio to receive MSTT1041A 490 mg SC
or placebo SC every 4 weeks (Q4W).  Randomization will be stratified by baseline disease 
severity IGA score (IGA 3 vs. IGA 4) and region. Patients will be given a loading dose of 
245 mg SC MSTT1041A or placebo at the Week 1 visit to reduce the time required to achieve 
steady-state exposure of MSTT1041A.
During the double-blind treatment and follow-up period, laboratory tests and clinical 
assessments will be performed at the site (office visits).  Additionally, telephone visits will be 
conducted to assess changes in health status, concomitant medications, and sleep and pruritus 
NRS score.
An Internal Monitoring Committee (IMC) will monitor data on safety and study conduct on an 
ongoing basis.  Members of the IMC will be unblinded and will include representatives from 
Clinical Science and Drug Safety who are not directly involved in the study and representatives 
from Biostatistics and Statistical Programming and Analysis.
The IMC will review cumulative data at regular intervals of approximately every 3 months from 
the time of randomization of the first patient.  Ad hoc meetings may be held at the request of the 
IMC or Sponsor at any time to address potential safety concerns.  The data to be reviewed will
include demographics, concomitant medications, study drug administration, adverse events, 
serious adverse events, adverse events of special interest, ECGs, and relevant laboratory data.
Number of Patients
Approximately 90 patients will be enrolled in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form


MSTT1041A—Genentech, Inc.
12/Protocol GS40965, Version 1

Age 18-75 years at time of signing Informed Consent Form

Body mass index of 1840 kg/m2 and weight 40 kg at screening

Ability to comply with the study protocol, in the investigator's judgment

Ability to understand and complete study-related questionnaires

Chronic AD, (according to American Academy of Dermatology Consensus Criteria), that 
has been present for at least 3 years before the screening visit

EASI score 16 at screening and the randomization (Day 1) visit

IGA score 3 (on the 0 to 4 IGA scale, in which 3 is moderate and 4 is severe) at screening 
and the randomization (Day 1) visit

10% BSA of AD involvement at screening and the randomization (Day 1) visit

Pruritus NRS score for maximum itch intensity 3 at screening and the randomization 
(Day 1) visit

Documented recent history (within 6 months before the screening visit) of inadequate 
response to treatment with topical medications or for whom topical treatments are otherwise 
medically inadvisable (e.g., because of important side effects or safety risks)
Inadequate response is defined as failure to achieve and maintain remission or a low 
disease activity state (comparable to IGA 0clear to 2 mild) despite treatment with a 
daily regimen of TCS of medium to higher potency (TCI as appropriate), applied for at 
least 4 weeks or for the maximum duration recommended by the product prescribing 
information (e.g., 2 weeks for ultra-high potent TCS), whichever is shorter.
Patients with documented systemic treatment (e.g., oral, IV) for AD at any point during 
the past 6 months are also considered as inadequate responders to topical treatments
and are potentially eligible for the study after appropriate washout.
Important side effects or safety risks are those that outweigh the potential treatment 
benefits and include intolerance to treatment, hypersensitivity reactions, significant skin 
atrophy, and systemic effects, as assessed by the investigator or by the patient’s 
treating physician.
Acceptable documentation includes contemporaneous chart notes that record topical 
medication prescription and treatment outcome, or investigator documentation based on 
communication with the patient’s treating physician.  If documentation is inadequate, 
potential patients may be re-screened after such documentation is obtained 
(e.g., patients are shown to fail a 4-week course of mid-to-higher potency TCS [TCI]).

Have applied a stable dose of topical emollient (moisturizer) twice daily for at least the 
7 consecutive days immediately before the randomization visit.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive method and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for 12 weeks after the final dose of study drug. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.


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
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for at least 12 weeks 
after the final dose of study drug to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of preventing drug exposure.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
12 weeks after the final dose of study drug
Women of childbearing potential must have a negative serum pregnancy test result 
during the screening period and a negative urine pregnancy test at the randomization 
visit

Prior treatment with MSTT1041A

Use of any of the following: 
Treatment with any investigational therapy (with the exception of biologics) within 
8 weeks or within 5 half-lives (if known), whichever is longer, before screening
Treatment with immunomodulatory, immunosuppressive (e.g., systemic corticosteroids, 
methotrexate, mycophenolate-mofetil, interferon-, Janus kinase inhibitors, cyclosporine, 
azathioprine, etc.) within 4 weeks before screening or any condition (e.g., severe 
asthma) that, in the opinion of the investigator, is likely to require such treatment during 
the course of the study
Treatment with investigational or licensed biologics as follows:
–
Any cell-depleting agents including but not limited to rituximab: within 6 months 
before screening, or until lymphocyte count returns to normal, whichever is longer
–
Other biologics:  within 3 months or 5 half-lives (if known) before screening, 
whichever is longer

Use of any of the following treatments within 2 weeks before screening, or any condition 
that, in the opinion of the investigator, is likely to require such treatment during the course of 
the study:
Regular use (more than 2 visits per week) of a tanning booth/parlor
Phototherapy

Treatment with TCS or TCIs within 1 week before the randomization (Day 1) visit

Initiation of treatment for AD with prescription moisturizers or moisturizers containing 
additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products within 
1 week before the randomization (Day 1) visit

Initiation of or change in allergen immunotherapy within 12 weeks before screening

Use of any of the following treatments within 4 weeks before screening, or any condition 
that, in the opinion of the investigator, is likely to require such treatment during the course of 
the study:
Treatment with immunoglobulin or blood products
Treatment with any live, attenuated vaccine

Acute or chronic infection requiring either surgical intervention (e.g., drainage) or medical 
therapy (e.g., antibiotics, antiviral, antiparasitics, antifungal, or antiprotozoals) within 
2 weeks before screening or superficial skin infections within 1 week before the 
randomization visit. 
Note:  Patients may be rescreened after infection resolves.


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14/Protocol GS40965, Version 1

Positive test for TB during screening, defined as either a positive purified protein derivative 
(PPD) (5 mm of induration 4872 hours after injection) or a positive QuantiFERON 
TB-Gold® (QFT) test
Patients with a history of Bacille Calmette-Guérin vaccination should be screened using the 
QFT only; the following criteria for the QFT apply:
An indeterminate QFT should be repeated
A positive QFT or two successive indeterminate QFT results should be considered a 
positive diagnostic TB test
An indeterminate QFT followed by a negative QFT test, should be considered a negative 
diagnostic TB test
Patients with a positive PPD test (without a history of Bacillus Calmette-Guérin vaccination) 
or patients with a positive QFT (see criteria above) are eligible if they meet all of the 
following criteria:
No symptoms consistent with TB (see TB worksheet provided by Genentech)
Documented history of a completed course of adequate prophylaxis (completed 
treatment for latent TB per the treatment options as stated in the WHO guideline) before
screening
No known exposure to a case of active TB after most recent prophylaxis
No evidence of active TB on chest X-ray within 3 months before screening

History of any known immunodeficiency disorder, including but not limited to HIV infection

Positive hepatitis C virus (HCV) antibody test result at screening

Ineligible test results for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody 
(HBsAb), and hepatitis B core antibody (HBcAb) total at screening as defined below:
If HBsAg testing is positive, patient is not eligible.  For patients with a negative HBsAg 
testing, following criteria apply:
If HBsAb testing is negative and HBcAb is positive, patient is not eligible.
If HBsAb testing is positive and HBcAb is negative, patient is eligible.
If HBsAb testing is negative and HBcAb is negative, patient is eligible.
If HBsAb testing is positive and HBcAb is positive, patient must undergo further testing 
for hepatitis B virus DNA (HBV DNA):
–
Patient is not eligible, if HBV DNA test value is 20 IU/mL or test cannot be 
performed.
–
Patient is eligible, if HBV DNA test value is 20 IU/mL.

Evidence of active liver disease, including jaundice or AST, ALT, total bilirubin, or ALP
2 upper limit of normal (ULN) at screening

History of anaphylaxis, hypersensitivity to a biologic agent, or known hypersensitivity to any 
component of the MSTT1041A or placebo injection

Neutrophil count 0.5 103/μL at screening

Platelet count 50 103/μL at screening

Presence of skin comorbidities that may interfere with study assessments, in the opinion of 
the investigator

Active malignancy, including cutaneous basal or squamous cell carcinoma or melanoma 

History of malignancy within 5 years before screening, except for cases of cervical 
carcinoma in situ or breast ductal carcinoma in situ that have been treated and considered 
cured

Helminthic parasitic infection diagnosed within 6 months before screening that has not been 
treated or has not responded to standard-of-care therapy or exposure to water-born 
parasites within 6 weeks before screening


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15/Protocol GS40965, Version 1

History or evidence of substance abuse that would pose a risk to patient safety, interfere 
with the conduct of the study, have an impact on the study results, or affect the patient's 
ability to participate in the study, in the opinion of the investigator

Hemoglobin A1c (HbA1c) 8.5% at screening or any other clinically significant finding that, 
in the opinion of the investigator, may define uncontrolled diabetes

History of myocardial infarction, congestive heart failure NHYA Class III and IV, unstable 
angina pectoris, or stroke within 12 months before screening

History or presence of complete left bundle branch block, second- or third-degree 
atrioventricular heart block, or evidence of prior myocardial infarction on ECG, or any 
abnormality that is clinically significant in the investigator’s opinion

QT interval corrected through use of Fridericia’s formula (QTcF) 450 ms, if patient is male, 
or QTcF 470 ms, if patient is female

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as 
diagnosed structural heart disease (e.g., left ventricular systolic dysfunction, left ventricular 
hypertrophy), coronary heart disease, clinically significant electrolyte abnormalities 
(e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden 
unexplained death or long QT syndrome

History or evidence of a medical condition or any clinically significant disorder, condition, or 
disease (e.g., psychiatric or other mental health disorder, renal failure, hypertension, liver 
disease, anemia) that is uncontrolled despite treatment or that is likely, in the opinion of the 
investigator, to require a change in therapy, pose a risk to patient safety, interfere with the 
conduct of the study, have an impact on the study results, or affect the patient's ability to 
participate in the study

Planned surgical intervention during the course of the study

Patient who is a member of the investigational team or his/her immediate family
End of Study
The end of this study is defined as the date when the last patient, last visit occurs. The end of 
the study is expected to occur approximately 6 months after the last patient is enrolled.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 17 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal products (IMPs) for this study are MSTT1041A and matching 
placebo.  Patients who meet eligibility criteria during the screening period will be randomly 
allocated to receive treatment with MSTT1041A 490 mg Q4W or placebo.  Additionally, patients 
in the active treatment arm will receive a loading dose of 245 mg at the Week 1 visit; patients in 
the placebo arm will receive placebo.  Study drug administration must occur after all other 
procedures have been completed at each office visit, unless specifically indicated otherwise.  
Study drug will be administered at the study site by trained medical personnel.  Except for the 
loading dose, each dose of study drug (MSTT1041A or placebo) will be administered as four SC 
injections (for a total of 7 mL), one in each quadrant of the abdomen.  The loading dose 
(MSTT1041A or placebo) will be administered as two SC injections (for a total of 3.5 mL).
Statistical Methods
Primary Analysis
Efficacy analyses will be based on the intent-to-treat (ITT) approach.  All patients randomized 
(ITT population) will be included in the analysis, with patients grouped according to the 
treatment assigned at randomization.  Hypothesis testing for the efficacy endpoints will be 
performed for each MSTT1041A dose level and the placebo group.
The primary efficacy endpoint for this study is percent change from baseline to Week 16 of total 
EASI score.  A mixed-effect model for repeated measures (MMRM) model will be used, with 
percent change (post baseline change divided by baseline value) as the dependent variable.  


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The model will include baseline value of the EASI score, treatment arms, visits, treatment arm 
by visit interaction, and stratification factors.  To account for repeated observations with 
patients, a random patient effect will be added to the model.  The MMRM model will provide 
adjusted least-square means of percent change from baseline at Week 16 for each of the 
treatment arms with the corresponding standard error, 95% confidence interval and p-values.
Determination of Sample Size
Approximately 90 patients in total will be randomized in a 1:1 ratio to 490 mg MSTT1041A or 
placebo Q4W.  The sample size provides at least 80% power to detect a difference of 34% in 
the percent change from baseline in EASI score at Week 16 between MSTT1041A- and 
placebo-treated patients, assuming a standard deviation of 40.6 for placebo-treated patients.  
The same number of patients can also provide at least 80% power to detect 1) a difference of 
27% between MSTT1041A- and placebo-treated patients in the proportion of patients achieving 
IGA scores of 0 or 1 at Week 16, assuming the percentage is 2% in placebo-treated patients, 
respectively, 2) a difference of 32% between MSTT1041A- and placebo-treated patients in the 
proportion of patients achieving EASI-75 at Week 16, assuming the percentage is 13% in 
placebo-treated patients, and 3) a difference of 30% between MSTT1041A- and placebo-treated 
patients in percent change from baseline to Week 16 in pruritus NRS, assuming a standard 
deviation of 37.3 for placebo-treated patients.  The sample size is calculated at a two-sided 
significance level of 0.05 and assumes 25% dropout.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AD
atopic dermatitis
ADA
anti-drug antibody
BSA
body surface area
ClinRO
clinician-reported outcome
CRO
contract research organization
EASI
Eczema Area and Severity Index
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EMA
European Medicines Agency
FDA
Food and Drug Administration
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
IFN-
interferon-
IGA
Investigator's Global Assessment
IL
interleukin
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
ITT
intent-to-treat
IxRS
web-based response system
MACE
major adverse cardiac events
MMRM
mixed model repeated measures
NRS
Numeric Rating Scale
PD
pharmacodynamic
PK
pharmacokinetic


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Abbreviation
Definition
PPD
purified protein derivative
PRO
patient-reported outcome
Q4W
every 4 weeks
QFT
QuantiFERON TB-Gold® (QFT)
QTcF
QT interval corrected through use of Fridericia's formula
SC
subcutaneous
SCORAD
SCORing Atopic Dermatitis
sST2
soluble ST2
TB
tuberculosis
TCI
topical calcineurin inhibitor
TCS
topical corticosteroids
Th1
Type 1 helper
Th2
Type 2 helper
TNF-
tumor necrosis factor-
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON ATOPIC DERMATITIS
Atopic dermatitis (AD), also known as atopic eczema, is a chronic relapsing and 
intensely pruritic inflammatory skin disease.  Clinically, AD is characterized by recurrent 
eczematous lesions (such as erythematous patches with exudation, blistering, and 
crusting at early stages and scaling fissuring and lichenification at later stages), which 
can lead to skin infections, sleep loss, and poor quality of life (Williams and Gallo 2015; 
Weidinger et al. 2018).  AD affects 15%20% of children and 1%3% of adults; recent 
data suggest that the prevalence of AD is still increasing, especially in low-income 
countries.  First manifestations of AD usually appear early in life and often precede other 
allergic diseases such as asthma or allergic rhinitis.  AD poses a significant burden on 
health care resources and the quality of life (mainly because of sleep deprivation due to 
pruritus, employment loss, time to care, and financial costs) of patients (Nutten 2015).
The therapeutic approach to AD primarily consists of trigger avoidance, skin hydration 
with bathing, and use of emollients and anti-inflammatory therapies consisting 
predominantly of topical corticosteroids (TCS).  In many patients, treatment with TCS 
provides some measure of symptomatic relief but does not adequately control their 
disease.
In those patients who have persistent moderate to severe disease not responding 
adequately to TCS, recent guidelines outline a number of step-up therapeutic options 
(Ring et al. 2012; Schneider et al. 2013, Wollenberg et al. 2016).  The step-up options 
include topical calcineurin inhibitors (TCIs), phototherapy, and immunosuppressive 
agents such as oral corticosteroids, cyclosporine, azathioprine, methotrexate, and 
mycophenolate mofetil.  Although these step-up therapies (including systemic 
immunosuppressants) used to treat patients with moderate to severe AD show evidence 
of modest to good efficacy, poor tolerability due to side effects limit their prolonged use.
In attempts to find novel therapies for moderate to severe AD with an acceptable 
benefit-risk profile, a number of biologic agents that specifically target inflammatory cells 
are being tested.  So far, only dupilumab (a fully human monoclonal antibody against 
interleukin [IL]-4Rα that blocks both IL-4 and IL-13 signaling) has been approved by the 
Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the 
treatment of moderate to severe AD.  However, on average, over half of the participants 
in the pivotal studies did not achieve Investigator's Global Assessment (IGA) 0 or 1.  
Published results suggest that dupilumab is mainly modulating the Type 2 helper (Th2)
pathway.  Yet, findings from molecular research and trials on targeted therapeutics 
demonstrate that AD is a heterogeneous disease that probably comprises many different 
endotypes with distinct pathological features and clinical implications (Weidinger et al. 
2018).  Thus, the identification and characterization of these disease subtypes as well as 
exploring novel treatment options will further help improve the efficacy of the therapy and 
quality of life of patients with AD.  IL-33/ST2 signaling has been demonstrated to 


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associate with key features of AD including decrease in filaggrin expression (Seltmann 
et al. 2015), increased itch (Liu et al. 2016), and Type 1 helper (Th1) and Th2 
inflammation (Ding et al. 2018).  Therefore, targeting ST2 with MSTT1041A has the 
potential to address the unmet need in this disease. 
1.2
BACKGROUND ON MSTT1041A
MSTT1041A is a first-in-class, fully human, IgG2 monoclonal antibody that binds to ST2, 
the receptor for IL-33, and inhibits human IL-33. Nonclinical testing confirms that the 
molecule has high receptor affinity and is non-activating.
Refer to the MSTT1041A Investigator's Brochure for details on nonclinical and clinical 
studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
MSTT1041A prevents the IL-33-induced signaling that galvanizes immune cells in 
inflammation.  IL-33 is a member of the IL-1 family of cytokines.  It is considered an 
”alarmin” or a damage-associated molecular pattern molecule, that is constitutively 
expressed on epithelial cells and released upon cell injury or stress from exposure to 
such exogenous stimuli as allergens, toxins, or infections.  IL-33 activates various 
immune cells through its receptor ST2, also known as IL-1RL1 (Nabe 2014).  Recently, 
the IL-33/ST2 pathway has been found to play an important role in allergic diseases 
such as AD, asthma, and allergic rhinitis (Ding et al. 2018).  Once released from these 
cells, typically in response to stress or damage, IL-33 signals through a receptor 
complex containing the primary binding receptor ST2 and the co-receptor IL-1RAcP.  
Intracellular signaling induced by this complex promotes the inflammatory actions of 
ST2-expressing cells.  A secreted soluble form of ST2 (sST2) arises from alternative 
splicing, is elevated in settings of inflammation, and acts as a decoy to bind and inhibit 
released IL-33 (Hayakawa et al. 2007).  Mice genetically deficient in ST2 (ST2/) are 
phenotypically normal and have been used as controls for mechanistic studies to 
demonstrate that IL-33-elicited responses in vivo are entirely dependent on ST2 (Kondo 
et al. 2008). ST2 is expressed on keratinocytes, endothelial cells, fibroblasts, and 
inflammatory cells (including Type 2 innate lymphoid cells, monocytes, natural killer 
cells, T lymphocytes, mast cells, basophils, and eosinophils) (Cevikbas and Steinhof 
2012; Liew et al. 2016).  Binding of IL-33 to ST2 can activate both Th1 and Th2 T-cell
inflammation depending on the underlying milieu.  Signaling via ST2 leads to release of 
multiple mediators including tumor necrosis factor (TNF)-, interferon (IFN)-, IL-5, IL-6, 
IL-9, amphiregulin, and IL-13 (Martin and Martin 2016; Griesenauer and Paczesny 
2017).
Du et al. (2016) showed that IL-33 is expressed in keratinocytes, endothelial cells, and 
infiltrating mononuclear cells of AD skin lesions.  ST2 is expressed in the stratum 
spinosum and was localized to the cytoplasm, cellular membrane, and intercellular 
space.  ST2 is further expressed on dermal infiltrating cells, endothelial cells, and 


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neutrophils that infiltrated the epidermis (Du et al. 2016). Triggers such as allergens, 
irritants, and staphylococcal enterotoxin B increase expression of IL-33 and ST2 
(Savinko et al. 2012).  Furthermore, IL-33 has been shown to play a crucial role in 
activating Type 2 innate lymphoid cells and by this, contributing to development of 
allergic skin inflammation (Salimi et al. 2013).  Moreover, IL-33 downregulates the 
expression of the skin barrier molecule filaggrin (Seltmann et al. 2015; Ryu et al. 2016; 
Nygaard et al. 2017) and the -defensin 2 expression in human primary keratinocytes 
(Alase et al. 2012), thereby, exacerbating the defect in the barrier against allergen 
penetration and the susceptibility to bacterial superinfection in acute AD. 
The inflammatory pathways in chronic AD are complex and involve both Th1 and Th2 
immune responses.  In vitro, IL-33 has been shown to influence both the Th1 and Th2 
pathway.  IL-33 expression is induced by TNF-and IFN-in human dermal fibroblasts, 
HaCaT keratinocytes, macrophages, and human umbilical vein endothelial cells.  
IL-33-induced dendritic cells promote the differentiation from naive Th cells into Th2 cells 
and maintain memory Th2 cells, leading to the increased production of IL-5, IL-9, and 
IL-13.  Meanwhile, Th1 cells respond to IL-33 and induce the release of IFN-, therefore 
driving skin inflammation towards chronic responses (Ding et al. 2018).
By targeting ST2, MSTT1041A has the capacity to block inflammation downstream of 
IL-33 activation.  This is expected to translate into benefit in patients with AD.  The ability 
to blunt inflammation across the broad population represents a significant therapeutic 
advance and addresses an important unmet medical need.
MSTT1041A was not associated with toxicity at doses of up to 300 mg/kg SC or IV 
(highest dose evaluated) in 28-day and 6-month cynomolgus monkey toxicology studies.  
In addition, there were no MSTT1041A-related cardiovascular findings in a single-dose 
safety pharmacology study or in repeat-dose toxicity studies.  In an ex vivo human tissue 
cross-reactivity immunohistochemistry study, no specific staining in any human tissues 
was observed.  At the no-observed-adverse-effect level (300 mg/kg SC or IV), there are 
significant exposure margins over human exposures.
As reported in the MSTT1041A Investigator's Brochure, there are no identified risks 
associated with MSTT1041A.  In three completed Phase 1 studies, there were no 
serious adverse events or adverse events that led to treatment discontinuation in healthy 
subjects who received single (n70, Study 20110235; n41, Study 20130177) or 
multiple (n41, Study 20110236) doses of MSTT1041A at SC doses ranging from 2.1 to 
560 mg and IV doses ranging from 210 to 700 mg. 
A Phase IIb study with MSTT1041A in patients with severe asthma is currently ongoing 
(502 patients were randomized into a 52-week double-blind treatment period and 
received blinded study treatment [70 mg, 210 mg, or 490 mg of MSTT1041A, or 
placebo]).  Refer to the MSTT1041A Investigator's Brochure for a complete summary of 
safety information.


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Thus, the favorable safety profile to date supports further development of MSTT1041A in 
patients with AD.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of MSTT1041A
compared with placebo in patients with moderate to severe AD.  Specific objectives and 
corresponding endpoints for the study are outlined below.
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of MSTT1041A 
compared with placebo on the basis of the following endpoint:

Percent change from baseline to Week 16 of total Eczema Area and Severity Index 
(EASI) score
2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of MSTT1041A 
compared with placebo on the basis of the following endpoints:

Proportion of patients who achieve IGA response of 0 or 1 (clear or almost clear) at 
Week 16

Proportion of patients who achieve EASI-75 (75% reduction from baseline in EASI 
score) at Week 16

Percent change in pruritus from baseline to Week 16, as assessed by a Numeric 
Rating Scale (NRS)

Percent change in body surface area (BSA) with AD involvement from baseline to 
Week 16

Percent change in disease severity from baseline to Week 16, as assessed by 
SCORing Atopic Dermatitis (SCORAD)
 
 
 


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2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety of MSTT1041A compared 
with placebo on the basis of the following endpoints:

Incidence and severity of adverse events, with severity determined according to the
WHO toxicity scale

Change from randomization visit in vital signs, ECGs, and clinical laboratory results
2.3
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objective for this study is to characterize the MSTT1041A PK 
profile on the basis of the following endpoint:

Serum concentration of MSTT1041A at specified timepoints
The exploratory PK objective is as follows:

To evaluate potential relationships between drug exposure and MSTT1041A
efficacy, safety, and biomarker endpoints
2.4
IMMUNOGENICITY OBJECTIVE
The immunogenicity objective for this study is to evaluate the immune response to 
MSTT1041A on the basis of the following endpoints:

Incidence of treatment-emergent anti-drug antibodies (ADAs) during the study 

Potential impact of ADA status on efficacy, safety, and PK endpoints
2.5
BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify biomarkers that may
provide evidence of MSTT1041A activity, or may increase the knowledge and 
understanding of disease biology, on the basis of the following endpoints:

Relative change from randomization (Day 1) visit in biomarker levels in blood 
(see Section 4.5.6) at Weeks 1, 4, 8, 16, and 24


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase II, randomized, double-blind, placebo-controlled multicenter study to 
assess the efficacy and safety of MSTT1041A in patients with moderate to severe AD.  
The study will consist of a screening period (Day 35 to 1), 16-week double-blind 
treatment period, and an 8-week follow-up period.
After providing informed consent, patients will be assessed for study eligibility during 
screening and at the randomization (Day 1) visit.  Screening will be up to 35 days.  
During the screening period, patients must demonstrate EASI score 16, IGA score 3,
pruritus NRS score for maximum itch intensity 3, and have a history of inadequate 
response to treatment with topical medications.  Furthermore, patients will be required to 
apply moisturizers (emollients) at least twice daily and to refrain from TCS or TCI use for 
at least the 7 consecutive days immediately before randomization and throughout the 
study.  However, to allow adequate assessment of skin dryness, moisturizers should not 
be applied on the area(s) of non-lesional skin designated for such assessments for at 
least 8 hours before each office visit (see Sections 4.1.1 and 4.1.2 for details). Patients 
who fail to meet eligibility criteria during screening will be permitted to re-screen once, 
unless the reason for the screen failure is because of not meeting any of the following:

EASI score 16 at screening and the randomization visit

IGA score 3 (on the 0 to 4 IGA scale, in which 3 is moderate and 4 is severe) at 
screening and the randomization visit

10% BSA of AD involvement at screening and the randomization visit

Baseline pruritus NRS score for maximum itch intensity 3 at screening and the 
randomization visit
Patients who fail to meet eligibility requirements and are eligible to be re-screened are 
required to repeat assessments as follows:

If 35 days after Informed Consent Form completion, repeat only the assessments 
that triggered screen failure.

If >35 days after Informed Consent Form completion, repeat the consent process 
and all screening assessments except tuberculosis (TB) screening and hepatitis 
serologies. TB screening and hepatitis serologies should be repeated if 
re-screening occurs 3 months after initial Informed Consent Form completion.
At Day 1, patients will undergo further assessments to determine eligibility for
randomization to the double-blind treatment period. 




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The IMC will review cumulative data at regular intervals of approximately every 3 months 
from the time of randomization of the first patient.  Ad hoc meetings may be held at the 
request of the IMC or Sponsor at any time to address potential safety concerns.  The 
data to be reviewed will include demographics, concomitant medications, study drug 
administration, adverse events, serious adverse events, adverse events of special 
interest, ECGs, and relevant laboratory data.
At the time of each review, the IMC will make one of the following recommendations:  
the trial continues as planned, the trial is stopped for safety reasons, the protocol is
amended, additional analyses need to be performed, or enrollment will be held pending 
further safety evaluations.  Decisions will be made in consideration of the totality of the 
available data.  Final decisions will rest with the Sponsor's study team.
Any outcomes of these reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Board (IRB) or Ethics Committee (EC).  
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs. The 
end of the study is expected to occur approximately 6 months after the last patient is 
enrolled.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 17 months.
In addition, the Sponsor may decide to terminate the study at any time.
3.3
RATIONALE FOR STUDY DESIGN
 
 
 
 
 
 
 
 
 
 
 


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3.3.2
Rationale for Patient Population
See Section 1 for details on the high unmet medical need for new therapies for patients 
with moderate to severe AD.
3.3.3
Rationale for Control Group
A placebo-treated control group will be used in this study to assess differences in 
efficacy and safety in patients who receive MSTT1041A compared with patients who 
receive placebo.  The use of a control group is necessary given the inherent variability in 
self-reported symptoms and investigator assessments.  All patients will continue to 
receive standard-of-care treatment in addition to study drug (MSTT1041A or placebo) 
throughout the study.
3.3.4
Rationale for Biomarker Assessments
Biomarker assessments, before and at various timepoints after treatment, will be used to 
provide evidence of the biologic activity of MSTT1041A in patients, identify biomarkers 
that may be predictive of response to MSTT1041A, define PK and/or pharmacodynamic
(PD) relationships, advance the understanding of the mechanism of action of 
MSTT1041A in patients, support selection of a recommended dose regimen, and 
increase the knowledge and understanding of disease biology.  
 
 
 
 
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 90 patients with moderate to severe AD will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 1875 years at time of signing Informed Consent Form

Body mass index of 1840 kg/m2 and weight 40 kg at screening

Ability to comply with the study protocol, in the investigator's judgment


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
Ability to understand and complete study-related questionnaires

Chronic AD, (according to American Academy of Dermatology Consensus Criteria 
[Eichenfield et al. 2014]), that has been present for at least 3 years before the 
screening visit

EASI score 16 at screening and the randomization (Day 1) visit

IGA score 3 (on the 0 to 4 IGA scale, in which 3 is moderate and 4 is severe) at 
screening and the randomization (Day 1) visit

10% BSA of AD involvement at screening and the randomization (Day 1) visit

Pruritus NRS score for maximum itch intensity 3 at screening and the 
randomization (Day 1) visit

Documented recent history (within 6 months before the screening visit) of
inadequate response to treatment with topical medications or for whom topical 
treatments are otherwise medically inadvisable (e.g., because of important side 
effects or safety risks)
Inadequate response is defined as failure to achieve and maintain remission or 
a low disease activity state (comparable to IGA 0clear to 2mild) despite 
treatment with a daily regimen of TCS of medium to higher potency (TCI as 
appropriate), applied for at least 4 weeks or for the maximum duration 
recommended by the product prescribing information (e.g., 2 weeks for 
ultra-high potent TCS; see Appendix 2), whichever is shorter.
Patients with documented systemic treatment (e.g., oral, IV) for AD at any point 
during the past 6 months are also considered as inadequate responders to 
topical treatments and are potentially eligible for the study after appropriate 
washout.
Important side effects or safety risks are those that outweigh the potential 
treatment benefits and include intolerance to treatment, hypersensitivity 
reactions, significant skin atrophy, and systemic effects, as assessed by the 
investigator or by the patient’s treating physician.
Acceptable documentation includes contemporaneous chart notes that record 
topical medication prescription and treatment outcome, or investigator 
documentation based on communication with the patient’s treating physician. 
If documentation is inadequate, potential patients may be re-screened after 
such documentation is obtained (e.g., patients are shown to fail a 4-week
course of mid-to-higher potency TCS [TCI]; see Appendix 2 for examples of 
TCS classified by potency).

Have applied a stable dose of topical emollient (moisturizer) twice daily for at least 
the 7 consecutive days immediately before the randomization visit (see 
Section 4.1.2 for limitations regarding emollients).


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
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive method and agreement to refrain 
from donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate 
of 1% per year during the treatment period and for 12 weeks after the final
dose of study drug. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for at 
least 12 weeks after the final dose of study drug to avoid exposing the embryo.  
Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 12 weeks after the final dose of study drug
Women of childbearing potential must have a negative serum pregnancy test 
result during the screening period and a negative urine pregnancy test at the 
randomization visit

Prior treatment with MSTT1041A


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
Use of any of the following: 
Treatment with any investigational therapy (with the exception of biologics) 
within 8 weeks or within 5 half-lives (if known), whichever is longer, before 
screening
Treatment with immunomodulatory, immunosuppressive (e.g., systemic 
corticosteroids, methotrexate, mycophenolate-mofetil, IFN-, Janus kinase 
inhibitors, cyclosporine, azathioprine, etc.) within 4 weeks before screening or
any condition (e.g., severe asthma) that, in the opinion of the investigator, is 
likely to require such treatment during the course of the study
Treatment with investigational or licensed biologics as follows:
–
Any cell-depleting agents including but not limited to rituximab: within 
6 months before screening, or until lymphocyte count returns to normal, 
whichever is longer
–
Other biologics: within 3 months or 5 half-lives (if known) before screening,
whichever is longer

Use of any of the following treatments within 2 weeks before screening, or any 
condition that, in the opinion of the investigator, is likely to require such treatment 
during the course of the study:
Regular use (more than 2 visits per week) of a tanning booth/parlor
Phototherapy

Treatment with TCS or TCIs within 1 week before the randomization (Day 1) visit

Initiation of treatment for AD with prescription moisturizers or moisturizers containing 
additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products 
within 1 week before the randomization (Day 1) visit

Initiation of or change in allergen immunotherapy within 12 weeks before screening

Use of any of the following treatments within 4 weeks before screening, or any 
condition that, in the opinion of the investigator, is likely to require such treatment 
during the course of the study:
Treatment with immunoglobulin or blood products
Treatment with any live, attenuated vaccine

Acute or chronic infection requiring either surgical intervention (e.g., drainage) or 
medical therapy (e.g., antibiotics, antiviral, antiparasitics, antifungal, or 
antiprotozoals) within 2 weeks before screening or superficial skin infections within 
1 week before the randomization visit. 
Note:  Patients may be rescreened after infection resolves.


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
Positive test for TB during screening, defined as either a positive purified protein 
derivative (PPD) (5 mm of induration 4872 hours after injection) or a positive 
QuantiFERON TB-Gold® (QFT) test 
Patients with a history of Bacille Calmette-Guérin vaccination should be screened 
using the QFT only; the following criteria for the QFT apply:
An indeterminate QFT should be repeated
A positive QFT or two successive indeterminate QFT results should be 
considered a positive diagnostic TB test
An indeterminate QFT followed by a negative QFT test, should be considered a 
negative diagnostic TB test
Patients with a positive PPD test (without a history of Bacillus Calmette-Guérin 
vaccination) or patients with a positive QFT (see criteria above) are eligible if they 
meet all of the following criteria:
No symptoms consistent with TB (see TB worksheet provided by Genentech)
Documented history of a completed course of adequate prophylaxis (completed 
treatment for latent TB per the treatment options as stated in the WHO 
guideline) before screening
No known exposure to a case of active TB after most recent prophylaxis
No evidence of active TB on chest X-ray within 3 months before screening

History of any known immunodeficiency disorder, including but not limited to HIV 
infection

Positive hepatitis C virus (HCV) antibody test result at screening

Ineligible test results for hepatitis B surface antigen (HBsAg), hepatitis B surface 
antibody (HBsAb), and hepatitis B core antibody (HBcAb) total at screening as 
defined below (see also Flowchart in Appendix 3):
If HBsAg testing is positive, patient is not eligible.  For patients with a negative 
HBsAg testing, following criteria apply:
If HBsAb testing is negative and HBcAb is positive, patient is not eligible.
If HBsAb testing is positive and HBcAb is negative, patient is eligible.
If HBsAb testing is negative and HBcAb is negative, patient is eligible.
If HBsAb testing is positive and HBcAb is positive, patient must undergo further 
testing for hepatitis B virus (HBV) DNA:
–
Patient is not eligible, if HBV DNA test value is 20 IU/mL or test cannot 
be performed.
–
Patient is eligible, if HBV DNA test value is 20 IU/mL.

Evidence of active liver disease, including jaundice or AST, ALT, total bilirubin, or 
ALP 2upper limit of normal (ULN) at screening


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
History of anaphylaxis, hypersensitivity to a biologic agent, or known hypersensitivity 
to any component of the MSTT1041A or placebo injection

Neutrophil count 0.5103/μL at screening

Platelet count 50103/μL at screening

Presence of skin comorbidities that may interfere with study assessments, in the 
opinion of the investigator

Active malignancy, including cutaneous basal or squamous cell carcinoma or 
melanoma 

History of malignancy within 5 years before screening, except for cases of cervical 
carcinoma in situ or breast ductal carcinoma in situ that have been treated and 
considered cured

Helminthic parasitic infection diagnosed within 6 months before screening that has 
not been treated or has not responded to standard-of-care therapy or exposure to 
water-born parasites within 6 weeks before screening

History or evidence of substance abuse that would pose a risk to patient safety, 
interfere with the conduct of the study, have an impact on the study results, or affect 
the patient's ability to participate in the study, in the opinion of the investigator

Hemoglobin A1c (HbA1c) 8.5% at screening or any other clinically significant 
finding that, in the opinion of the investigator, may define uncontrolled diabetes

History of myocardial infarction, congestive heart failure NHYA Class III and IV,
unstable angina pectoris, or stroke within 12 months before screening

History or presence of complete left bundle branch block, second- or third-degree 
atrioventricular heart block, or evidence of prior myocardial infarction on ECG, or 
any abnormality that is clinically significant in the investigator’s opinion

QT interval corrected through use of Fridericia’s formula (QTcF) 450 ms, if patient 
is male, or QTcF 470 ms, if patient is female

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such 
as diagnosed structural heart disease (e.g., left ventricular systolic dysfunction, left 
ventricular hypertrophy), coronary heart disease, clinically significant electrolyte 
abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family 
history of sudden unexplained death or long QT syndrome

History or evidence of a medical condition or any clinically significant disorder, 
condition, or disease (e.g., psychiatric or other mental health disorder, renal failure, 
hypertension, liver disease, anemia) that is uncontrolled despite treatment or that is 
likely, in the opinion of the investigator, to require a change in therapy, pose a risk to 
patient safety, interfere with the conduct of the study, have an impact on the study 
results, or affect the patient's ability to participate in the study

Planned surgical intervention during the course of the study

Patient who is a member of the investigational team or his/her immediate family


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Patients who meet all eligibility criteria will be randomized to one of the two treatment 
groups through the web-based response system (IxRS) on the first day of dosing.  
Patients will be randomized in a 1:1 ratio to receive 490 mg SC MSTT1041A Q4W or 
placebo, and stratified by baseline disease severity IGA score (IGA3 vs. IGA4) and 
region.
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of IxRS provider and prespecified personnel (e.g., IMC members).
While PK and ADA samples must be collected from patients assigned to the placebo
arm to maintain the blinding of treatment assignment, PK and ADA assay results for 
these patients are generally not needed for the safe conduct or proper interpretation of 
this study.  Laboratories responsible for performing study drug PK and ADA assays will 
be unblinded to patients' treatment assignments to identify appropriate samples to be 
analyzed.  PK samples from patients assigned to the placebo arm will not be analyzed 
for study drug PK concentration except by request (e.g., to evaluate a possible error in 
dosing).  Baseline ADA samples will be analyzed for all patients.  Postbaseline ADA 
samples from patients assigned to the placebo arm will not be analyzed for ADAs except 
by request.
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.
As per health authority reporting requirements, the Sponsor's Drug Safety representative
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are MSTT1041A and 
matching placebo.


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4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
MSTT1041A and Placebo
MSTT1041A or matching placebo will be supplied by the Sponsor as sterile, clear, and 
colorless to slightly yellow liquid in glass vials.  For information on the formulation and 
handling of MSTT1041A, see the pharmacy manual and the MSTT1041A Investigator's 
Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
No dose modifications should be performed in this study.  Any dose modification should 
be noted on the Study Drug Administration electronic Case Report Form (eCRF).  Cases 
of accidental overdose or medication error, along with any associated adverse events, 
should be reported as described in Section 5.4.4.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.2.1.
4.3.2.1
MSTT1041A and Placebo
Patients who meet eligibility criteria during the screening period will be randomly 
allocated to receive treatment with MSTT1041A 490 mg SC Q4W or placebo.  
Additionally, patients in the active treatment arm will receive a loading dose of 245 mg
SC MSTT1041A at the Week 1 visit; patients in the placebo arm will receive placebo
(see Appendix 1).
Study drug administration must occur after all other procedures have been completed at 
each office visit, unless specifically indicated otherwise.  Study drug will be administered 
at the study site by trained medical personnel.  Except for the loading dose, each dose
of study drug (MSTT1041A or placebo) will be administered as four SC injections (for a 
total of 7 mL), one in each quadrant of the abdomen.  The loading dose (MSTT1041A or 
placebo) will be administered as two SC injections (for a total of 3.5 mL).  See the 
pharmacy manual for details on study drug preparation and administration. 
All patients will be observed for at least 30 minutes after each dose and longer in the 
event of an injection-site reaction, approximately 60 minutes, as determined by the 
investigator.  If a patient develops any signs or symptoms to suggest a systemic 
hypersensitivity reaction or anaphylactic event, longer observation may be warranted in 
the opinion of the investigator. 
Patients who are unable to tolerate study drug will discontinue treatment but will be 
asked to continue with study assessments.  Study drug may be resumed after the events 
resolve, if the investigator determines that the event was not related to study drug and 
the investigator and Medical Monitor agree that it is appropriate for the patient to resume 


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study drug.  See Section 5.1.2 for specific guidelines for withholding or discontinuing 
study drug for patients who experience adverse events.
4.3.3
Background Treatment 
All patients are required to apply moisturizers (emollients) at least twice daily for at least 
the 7 consecutive days immediately before the randomization visit and to continue 
throughout the study (all 24 weeks where applicable). However, to allow adequate 
assessment of skin dryness, moisturizers should not be applied on the area(s) of 
non-lesional skin designated for such assessments for at least 8 hours before each 
office visit. All types of moisturizers are permitted, but patients may not initiate treatment 
with prescription moisturizers or moisturizers containing additives such as ceramide, 
hyaluronic acid, urea, or filaggrin degradation products within 1 week before the 
randomization visit or after enrollment into the double-blind treatment period.
If prescription moisturizers containing these additives are initiated more than 1 week 
before the randomization visit, they are permitted.  Patients should continue using stable
doses of permitted moisturizers throughout the study.
4.3.4
Rescue Treatment 
If medically necessary (i.e., to control intolerable AD symptoms), rescue treatment for 
AD may be provided to patients at the discretion of the investigator.  For the purpose of 
efficacy analysis, patients who receive rescue treatment during the study treatment 
period will be considered treatment failures, but they will continue study treatment if 
rescue consisted of topical medications (e.g., TCS). TCI may be used for rescue, but it 
should be reserved for problem areas only (e.g., face, neck, intertriginous, and genital 
areas, etc.). If possible, investigators should attempt to limit the first step of rescue 
therapy to topical medications and escalate to systemic medications only for patients 
who do not respond adequately after at least 7 days of topical treatment. If a patient 
receives rescue treatment with systemic corticosteroids or nonsteroidal systemic 
immunosuppressive drugs (e.g., cyclosporine, methotrexate, mycophenolate-mofetil, 
azathioprine), study treatment will be discontinued.
After systemic treatment with these medications is completed, study treatment may be 
resumed if deemed appropriate by the investigator and the Medical Monitor, but not 
sooner than 5 half-lives after the last dose of systemic rescue medication.
All patients will complete all study visits and assessments regardless of completion of 
study treatment and regardless of receipt of rescue treatment for AD. Investigators 
should make every attempt to conduct efficacy and safety assessments (e.g., disease 
severity scores, safety labs) immediately before administering any rescue treatment. 
An unscheduled visit may be used for this purpose if necessary.


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4.3.5
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (MSTT1041A and placebo) will be provided 
by the Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to confirm the
shipment condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.6
Continued Access to MSTT1041A
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide Genentech IMP MSTT1041A or any other study treatments or 
interventions to patients who have completed the study.  The Sponsor may evaluate 
whether to continue providing MSTT1041A in accordance with the Roche Global Policy 
on Continued Access to Investigational Medicinal Product, available at the following 
website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY, PROHIBITED THERAPY, AND 
ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements, emollients) used by a patient in addition to protocol-mandated treatment 
from 6 months before screening.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Cautionary Therapy
4.4.1.1
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies may be used during the study at the discretion of 
the investigator.


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4.4.2
Prohibited Therapy
Use of the following concomitant therapies is prohibited at any time after enrollment in 
the double-blind treatment period, unless otherwise indicated as described below
(see Sections 4.1.1 and 4.1.2 for inclusion and exclusion criteria):

Investigational therapy (other than protocol-mandated study treatment)

Treatment with TCS or TCIs

Treatment with a licensed biologic agent 

Treatment with immunomodulatory/immunosuppressive (e.g., systemic 
corticosteroids, methotrexate, mycophenolate-mofetil, IFN-, Janus kinase 
inhibitors, cyclosporine, azathioprine)

Treatment with immunoglobulin or blood products

Treatment with any live attenuated vaccines

Initiation of or change in allergen immunotherapy

Initiation of or change in treatment of AD with prescription moisturizers or 
moisturizers containing additives such as ceramide, hyaluronic acid, urea, or 
filaggrin degradation products
Note: Patients should continue using stable doses of such moisturizers if 
initiated at least 1 week before the randomization visit

Initiation of therapy with bleach baths

Regular use (more than 2 visits per week) of a tanning booth/parlor

Phototherapy
4.4.3
Additional Restrictions
Patients will have to fast for at least 8 hours prior to collection of blood samples for 
fasted glucose and lipids for select visits (see Appendix 1 for timepoints).  If patient has 
not fasted for 8 hours, the patient must return to the site for fasting blood draw. 
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and available laboratory test values are acceptable.
All assessments must be performed on the day of the specified visit unless otherwise
specified in the schedule of activities (see Appendix 1).  As much as feasible, 
the disease severity assessments (EASI, IGA, and SCORAD) for each patient should 
be administered by the same assessor throughout the study. The assessments should 


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be performed by the investigator but may be administered by other site staff who are 
qualified and trained to perform the assessment, if approved by the Sponsor.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients 
meet all eligibility criteria before enrollment.  The investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons 
for screening failure, as applicable.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history, 
reproductive status, smoking history, and use of alcohol and drugs of abuse, will be
recorded at baseline.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements, emollients) used by the patient within 6 months before screening will be 
recorded.  At the time of each follow-up physical examination, an interval medical history 
should be obtained and any changes in medications and allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Atopy Status
The patient’s atopy status (atopic or non-atopic) will be assessed during screening on 
the basis of historical documentation (e.g., patient’s medical records). A patient is 
considered atopic if he or she has a positive result to any allergen demonstrated via 
historical allergy test (e.g., skin prick [wheal diameter 3 mm and documented negative 
control]), ImmunoCAP, or other specific IgE test. Regardless of atopy status, total and 
specific IgE testing will be performed as specified in Appendix 1.
4.5.4
Physical Examinations
A complete physical examination, performed at screening and other specified visits,
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 
neurologic systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 


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should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
4.5.5
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure, ideally while the patient is in a seated position, and 
temperature.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis or analyzed at point of care:

Urine pregnancy test for all women of childbearing potential
Urine pregnancy tests will be performed at the site prior to each administration 
of study drug and at other specified visits after treatment discontinuation.  If a 
local urine pregnancy test result is positive, it must be reported immediately,
and study drug will not be administered that day. The positive urine pregnancy 
result must be confirmed by a serum pregnancy test (conducted by the central 
laboratory).  Refer to Section 5.4.3.1 for management of a patient with 
a positive pregnancy test.

TB tests:  PPD or QFT (QFT may be conducted by the central laboratory, per 
Sponsor agreement with site)
Samples for the following laboratory tests will be sent to one or several central
laboratories for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)

Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide 
(if considered standard of care for the region), sodium, potassium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total 
and direct bilirubin, ALP, ALT, AST

Fasting lipids:  total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides

Fasting glucose 

HbA1c

N-terminal pro B-type natriuretic peptide

Serum pregnancy test

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria)


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
Viral serology:  HBsAb, HBsAg, HBcAb, HCV antibody
If HBsAb testing is positive and HBcAb is positive, patient must undergo further 
testing for HBV DNA.
Blood samples will be collected to evaluate the pharmacokinetics of MSTT1041A in
serum as noted in the schedule of activities (see Appendix 1). Serum concentrations of 
MSTT1041A will be determined using validated analytical procedures.
The following samples will be sent to the Sponsor or a designee for analysis:

Serum samples for MSTT1041A PK analysis

Serum samples for immunogenicity analysis

Serum samples for specific IgE, and total IgE, and other biomarkers; mandatory 
blood
 
 
 
 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
 biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for PK 
or immunogenicity assay development and validation; therefore, these samples will 
be destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

Blood 
 research will be 
destroyed no later than 10 years after the final Clinical Study Report has been 
completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis, including data on germline mutations, will be subject 
to the confidentiality standards described in Section 8.4.


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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.7
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., blood draws).  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings will be stored at central ECG laboratory, and the
data will be sent to the Sponsor, using the Sponsor's standard procedures to handle and 
process the electronic transfer of these data.  Any clinically significant morphologic 
waveform changes or other ECG abnormalities must be documented on the appropriate 
eCRF.  If considered appropriate by the Sponsor, ECGs may be analyzed 
retrospectively at a central laboratory.
If at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms 
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs. The same procedure should be repeated approximately 30 minutes 
after QTcF has stabilized on two successive ECGs of the first measurement. The 
Medical Monitor should be notified.  Standard-of-care treatment may be instituted per the 
discretion of the investigator.  If a PK sample is not scheduled for that timepoint, an 
unscheduled PK sample should be obtained.  A decision on study drug discontinuation 
should be made, as described in Section 5.1.2.3.  The investigator should also evaluate 
the patient for potential concurrent risk factors (e.g., electrolyte abnormalities, 
co-medications known to prolong the QT interval, severe bradycardia).
4.5.8
Chest X-Rays
Patients with a positive PPD (without a history of Bacillus Calmette-Guérin vaccination) 
or a positive or indeterminate QFT will require a chest X-ray to review for evidence of 
active TB, including posteroanterior and lateral views, unless a chest X-ray has been 


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performed within 3 months before screening and the report is available for review.  
A chest computed tomography scan may substitute for a chest X-ray.  Chest X-rays 
should only be performed if patients first meet all other study eligibility criteria.  All 
imaging should be read by a radiologist or per local requirements.
4.5.9
Clinician-Reported and Patient-Reported Outcomes
Clinician-reported outcome (ClinRO) and patient-reported outcome (PRO) data will be 
collected via questionnaires to document the treatment benefit of MSTT1041A.  The 
questionnaires, translated into the local language as appropriate, will be completed in 
their entirety at specified timepoints during the study.  To ensure instrument validity and 
that data standards meet health authority requirements, questionnaires will be self- or 
interviewer-administered before the patient receives any information on disease status, 
prior to the performance of non-PRO assessments, and prior to the administration of 
study treatment, unless otherwise specified.  Adverse event reports will not be derived 
from PRO or ClinRO data by the Sponsor, and safety analyses will not be performed 
using PRO or ClinRO data.  All adverse events should be recorded as described in 
Section 5.
Patients and clinicians will use an electronic device to capture PRO and ClinRO data.  
The electronic device and/or instructions for completing the questionnaires electronically 
will be provided by site staff.  The data will be transmitted to a centralized database 
maintained by the electronic device vendor.  The data will be available for access by 
appropriate study personnel.
4.5.9.1
Eczema Area and Severity Index
EASI is a clinician-reported comprehensive measure of disease that is composed of 
individual components (i.e., body region involvement, severity) that can be separated 
and evaluated independently or in combination to provide a more complete assessment 
of the patient (see Appendix 4).  EASI evaluates four anatomical regions (head/neck,
upper limbs, trunk, lower limbs) for both the affected BSA and severity of key disease 
signs (erythema, induration, excoriation, lichenification).
4.5.9.2
SCORing Atopic Dermatitis, Clinician Reported
The SCORAD has clinician-reported and patient-reported assessments.  The 
clinician-reported assessments require physician-assessed intensity ratings for six 
signs/symptoms of AD (erythema, edema/papulation, oozing/crust, excoriation, 
lichenification, and dryness), which are each weighted by the percentage of the BSA 
affected. This clinician-rated score is augmented with patient-reported assessments 
ranging from 010 of both pruritus and sleep loss.
The patient-reported symptom components of SCORAD are single-item assessments of 
itch and sleep that use a 3-day recall period.  They can be found in Appendix 5.


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4.5.9.3
Investigator Global Assessment
The IGA is a clinician-reported assessment using a 04 point scale to capture the IGA of 
AD (see Appendix 6). The IGA severity scale will be dichotomized to success or failure, 
with success defined as a score of clear (0) or almost clear (1) with at least two grades 
reduction from baseline score.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.8)
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Every effort should be made to retain patients in the study.  All 
patients will be asked to complete all study visits and assessments regardless of 
discontinuation of study treatment.  Patients who discontinue study treatment 
prematurely will not be replaced.
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Any patient that the investigator or Sponsor considers lost to follow up


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Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  If a patient requests to be 
withdrawn from the study, this request must be documented in the source documents 
and signed by the investigator.  Patients who withdraw from the study will not be 
replaced.
If a patient is unable to complete all study visits and assessments (see Section 4.6.1), 
the patient should be asked to return to the clinic for an early termination visit.  This visit 
should occur approximately 4 weeks after the final dose of study drug (see Appendix 1, 
for study assessment details).
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
MSTT1041A is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with MSTT1041A in completed 
Phase I studies and an ongoing Phase IIb study. As reported in the MSTT1041A 
Investigator's Brochure, there are no identified risks associated with MSTT1041A and 
there were no serious adverse events or adverse events that led to treatment 
discontinuation in healthy subjects who received single (n79) or multiple (n31) SC 
doses of MSTT1041A ranging from 2.1 to 560 mg and IV doses ranging from 


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210 to 700 mg, or in patients with atopic asthma (n2) who received a single 700 mg IV 
dose of MSTT1041A. 
To date, a Phase IIb study with MSTT1041A in patients with severe asthma is currently 
ongoing.  In this study, 502 patients were randomized to a 52-week double-blind 
treatment period and received blinded study treatment (70 mg, 210 mg, 490 mg of 
MSTT1041A, or placebo).  Refer to the MSTT1041A Investigator's Brochure for a 
complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events, including criteria for treatment interruption or 
discontinuation, are provided below.
5.1.1
Risks Associated with MSTT1041A
5.1.1.1
Immunogenicity
As with administration of any exogenous protein, there is potential risk for development 
of ADAs.  Such antibodies can be neutralizing with potential for reduced therapeutic 
effect of the drug and/or sensitizing with potential for adverse events. 
Serum samples will be collected at protocol-defined intervals to monitor for the 
development of ADAs.  Patients who have clinical sequelae that are considered 
potentially related to an ADA response may also be asked to return for additional 
follow-up testing.
Refer to the MSTT1041A Investigator's Brochure for details on immunogenicity.
5.1.1.2
Hypersensitivity Reactions and
Anaphylaxis/Hypersensitivity-Like Reactions
Hypersensitivity reactions and anaphylaxis have been described with SC administration 
of monoclonal antibodies (Corominas et al. 2014).  Signs and symptoms may include 
acute onset (minutes to several hours) of one or more of the following:  respiratory 
compromise, reduced blood pressure, skin-mucosal involvement, or gastrointestinal 
symptoms (Sampson et al. 2006).
The potential for hypersensitivity to MSTT1041A in humans is unknown.  However, as 
with any large-molecule therapeutic, administration of MSTT1041A may result in 
systemic reactions.  Systemic reactions to large-molecule therapeutics can be IgE or 
non-IgE mediated or due to the release of cytokines and are generally characterized by 
signs and symptoms such as skin rash, urticaria, pruritus, local or diffuse erythema, 
angioedema, fever, chills, cough, dyspnea, wheezing, bronchospasm, nausea, vomiting, 
diaphoresis, chest pain, tachycardia or bradycardia, and/or hypotension, which can be 


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severe or life threatening.  Effects typically occur during or within several hours after 
drug administration, but they may be delayed.  Patients with a history of anaphylaxis, 
hypersensitivities to a biologic agent, or known hypersensitivity to any component of the 
MSTT1041A or placebo injection will be excluded from the study (see Section 4.1.2).
Investigators and health care professionals administering MSTT1041A should monitor 
patients after drug administration as described in Section 4.3.2.1.  Investigators and staff 
should recognize and manage the signs and symptoms of such reactions and should be 
familiar with Sampson’s criteria for defining anaphylaxis (Sampson et al. 2006).  All 
potential cases of anaphylaxis should be captured on the appropriate eCRF as 
instructed in Section 5.2 and Section 5.3.  Investigators and health care professionals 
should accurately report these events immediately to the Sponsor as serious adverse 
events if appropriate.  Health care professionals should also instruct patients on how to 
recognize the symptoms of any such events and to contact a health care provider or 
seek emergency care in case of any such symptoms. 
Refer to the MSTT1041A Investigator's Brochure for details on hypersensitivity reactions 
and anaphylaxis/hypersensitivity-like reactions.
5.1.1.3
Injection-Site Reactions
Injection-site reactions have been described with SC administration of monoclonal 
antibodies (Corominas et al. 2014).  Signs and symptoms may include pain, itching, 
erythema, and swelling at the injection site.  The reaction may be immediate, although it 
usually appears within 2448 hours with variable incidence according to the drug
administered.
No clinically significant injection-site reactions associated with MSTT1041A were 
observed following single or repeat doses in cynomolgus monkeys or healthy volunteers.  
However, as with any large-molecule therapeutic, administration of MSTT1041A may 
result in local reactions.  Local reactions may include signs and symptoms such as 
redness, tenderness or pain, bruising, warmth, swelling, pruritus, or infection.
During the study, all injection-site events should be accurately reported on the
appropriate eCRF.
Refer to the MSTT1041A Investigator's Brochure for details on injection-site reactions.
5.1.1.4
Infection
The intended mechanism of action of MSTT1041A suggests inhibitory effects on 
immune responses mediated by Th2 cells, leading to the possibility of a decrease in the 
protective response to infection, particularly helminthic infections (Molofsky et al. 2015).  
All study participants will be monitored for signs and symptoms suggestive of infection 
by collection of vital signs, clinical laboratory tests, and adverse events.
Refer to the MSTT1041A Investigator's Brochure for details on infections.


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5.1.1.5
Exacerbation of Cardiovascular Disease
Published studies involving mouse models of cardiovascular disease or in vitro culture 
systems describe potential cardioprotective and atheroprotective roles of the IL-33/ST2 
axis (Sanada et al. 2007; Miller et al. 2008; Seki et al. 2009; McLaren et al. 2010; 
Wasserman et al. 2012).  For example, after experimentally induced acute left 
ventricular pressure overload, which could be relevant to clinical scenarios involving 
increased afterload (e.g., left-sided congestive heart failure or acute hypertension), ST2
mice had more left ventricular hypertrophy, more fibrosis, and impaired survival relative
to their wild-type littermates (Sanada et al. 2007).  However, the translatability of these 
findings remains uncertain. In addition, studies with conflicting data exist (Abston et al. 
2012; Demyanets et al. 2013; Martin et al. 2015).  In nonclinical toxicology and safety 
pharmacology studies with cynomolgus monkeys, including a 28-day and 6-month,
repeat-dose toxicology study as well as a single-dose, cardiovascular safety study in 
telemetrized animals, no biologically significant changes were exhibited by MSTT1041A. 
Evidence has shown that the ST2 receptor is a prognostic biomarker of cardiovascular 
disease outcome (Sabatine et al. 2008; Shah et al. 2009; Weir et al. 2010).  Although 
published findings suggest a possible risk of exacerbation of existing cardiovascular 
disease in humans, there are no identified cardiovascular risks associated with inhibiting 
the IL-33/ST2 axis in humans.
Patients with active or unstable recent cardiovascular disease will be excluded from the 
study.  Cardiac safety will be evaluated with monitoring of vital signs, ECG assessments, 
the collection of relevant adverse events, and other assessments described in the 
protocol.  To monitor other factors that may affect cardiovascular risk, HbA1c, fasting 
glucose, and lipid panels will be monitored to observe for indication of possible 
atherogenic and metabolic effects of MSTT1041A exposure.
During the study, all major adverse cardiac events (MACE) should be accurately 
reported on the appropriate eCRF.  MACE include death due to cardiovascular causes, 
non-fatal myocardial infarction, non-fatal stroke or transient ischemic attack, unstable 
angina, or chest pain requiring hospitalization, coronary revascularization, and 
congestive heart failure requiring hospitalization.
Refer to the MSTT1041A Investigator's Brochure for details on cardiovascular disease.
5.1.2
Management of Patients Who Experience Adverse Events
5.1.2.1
Treatment Interruption
MSTT1041A treatment may be temporarily suspended in patients who experience 
toxicity considered to be related to study drug.  If MSTT1041A has been withheld for two 
or more consecutive dosing visits because of toxicity, the patient should be discontinued 
from MSTT1041A, unless resumption of treatment is approved following investigator 
discussion with the Medical Monitor.  MSTT1041A treatment may be suspended for 
reasons other than toxicity (e.g., surgical procedures) with Medical Monitor approval.  


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The investigator and the Medical Monitor will determine the acceptable length of 
treatment interruption.
Note:  For treatment interruption because of rescue treatment, see Section 4.3.4.
5.1.2.2
Management Guidelines
Table 1 provides specific guidelines for withholding or discontinuing study drug for 
patients who experience hepatotoxicity.
Table 1
Guidelines for Treatment Interruption or Discontinuation for 
Patients Who Experience Hepatotoxicity
Event
Action to Be Taken
Hepatotoxicity
ALT or AST increase that meets Hy's Law 
criteria:  ALT or AST 3ULN in combination 
with TBILI 2ULN or clinical jaundice ruling out 
other medical sequels to explain the combination 
of increased aminotransferase and serum total 
bilirubin.
Discontinue MSTT1041A.
If abnormal liver tests, but the criteria for 
Hy's Law are not met:  ALT or AST increase that 
meets at least one of the following criteria:

8ULN

5ULN for 2 weeks

3ULN with clinical signs or symptoms that 
are consistent with hepatitis (e.g., right upper 
quadrant pain or tenderness, fever, nausea, 
vomiting, jaundice)
Withhold MSTT1041A.  Treatment may be 
resumed if an alternative cause is identified 
and laboratory values have resolved to those at 
the randomization visit.  If signs or symptoms 
recur, permanently discontinue MSTT1041A.
If abnormal liver tests, but the criteria for 
Hy's Law are not met:  TBILI 3ULN
Consider withholding MSTT1041A.  Treatment 
may be resumed if an alternative cause is 
identified and laboratory values have resolved 
to those at the randomization visit.  If signs or 
symptoms recur, permanently discontinue 
MSTT1041A.
ALP 3ULN
Consider withholding MSTT1041A.  Treatment 
may be resumed if an alternative cause is 
identified and laboratory values have resolved 
to those at the randomization (Day 1) visit.  
If signs or symptoms recur, permanently 
discontinue MSTT1041A.
TBILItotal bilirubin; ULN upper limit of normal.


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5.1.2.3
Management of Increases in QT Interval
Study drug should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes:

Sustained (at least two ECG measurements 30 minutes apart) QTcF that is 
500 ms and 60 ms longer than the baseline value

Sustained absolute QTcF that is 515 ms 

An episode of torsades de pointes or a new ECG finding of clinical concern
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, because this represents an 
increase in QTcF unrelated to alterations in repolarization.  Also of note, it is not 
uncommon to record arrhythmias such as non-sustained ventricular tachycardia, 
supraventricular tachycardia, pauses, or atrial fibrillation in healthy volunteers receiving 
placebo during periods of extended ECG monitoring.  Therefore, it is critical that expert 
cardiology advice be sought to confirm any ECG changes and to ascertain the likelihood 
of a drug-induced arrhythmia versus the background occurrence of this arrhythmia.  
In such a situation, saving all available ECG data is highly suggested.
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended to help 
in the management of such patients.
In rare circumstances, it may be acceptable to resume study drug at a lower dose, 
provided that any ECG abnormalities have resolved and the patient is appropriately 
monitored.  Clinical judgment should be applied.
5.1.2.4
Anaphylaxis 
Anaphylaxis should be promptly assessed and treated per local standard of care.  For 
current guidelines, refer to Campbell et al. 2014:
https://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20and
%20Parameters/Anaphylaxis-Practice-Parameter-2014.pdf
In accordance with the current guidelines, the measurement of tryptase (serum or 
plasma) and histamine (plasma) levels should be considered to support a diagnosis of 
anaphylaxis, although clinicians should treat anaphylaxis regardless of the availability of 
the results of these tests.
During the study, all anaphylaxis events should be accurately reported on the
appropriate eCRF.


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.10
and 5.3.5.11 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.12)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, severe, or life-threatening according to 
WHO Adverse Drug Reaction Terminology; see Section 5.3.3); the event itself may be of 
relatively minor medical significance (such as severe headache without any further 
findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.8)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Anaphylaxis, anaphylactoid, and hypersensitivity reactions

MACE, including death due to cardiovascular causes, non-fatal myocardial 
infarction, non-fatal stroke or transient ischemic attack, unstable angina, or chest 
pain requiring hospitalization, coronary revascularization, and congestive heart 
failure requiring hospitalization


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 12 weeks after the 
final dose of study drug. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last office visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The WHO toxicity grading scale (see Appendix 8) will be used for assessing adverse 
event severity.  Table 2 will be used for assessing severity for adverse events that are 
not specifically listed in the WHO toxicity grading scale.


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Table 2
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in WHO Toxicity Grading Scale
Grade
Severity
1
Mild; transient or mild discomfort (48 hours); no medical intervention or 
therapy required
2
Moderate; mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention or therapy required
3
Severe; marked limitation in activity; some assistance usually required;
medical intervention or therapy required; hospitalization possible
4
Life-threatening; extreme limitation in activity; significant assistance required; 
significant medical intervention or therapy required, hospitalization or hospice 
care probable
Notes:  Developed by the Division of Microbiology and Infectious Diseases.
Regardless of severity, some events may also meet seriousness criteria.  Refer to definition of a 
serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 3):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event


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Table 3
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug injection should be captured as a diagnosis 
(e.g., "injection-site reaction" or "anaphylactic reaction") on the Adverse Event eCRF.  
If possible, avoid ambiguous terms such as "systemic reaction."  Associated signs and 
symptoms should be recorded on the dedicated eCRF.  If a patient experiences both a 
local and systemic reaction to the same dose of study drug, each reaction should be 
recorded separately on the Adverse Event eCRF, with signs and symptoms also 
recorded separately on the dedicated eCRF.  Refer to the eCRF completion guideline for 
details.
5.3.5.2
Major Adverse Cardiac Events 
MACE (including death due to cardiovascular causes, non-fatal myocardial infarction, 
non-fatal stroke or transient ischemic attack, unstable angina or chest pain requiring 
hospitalization, coronary revascularization, and congestive heart failure requiring 
hospitalization) should be recorded on the Adverse Event eCRF.  Associated details 
should be recorded on the appropriate MACE CRF. 


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5.3.5.3
Diagnosis versus Signs and Symptoms
For adverse events other than injection reactions (see Section 5.3.5.1), a diagnosis 
(if known) should be recorded on the Adverse Event eCRF rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases).  However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded on the Adverse Event eCRF.  If a 
diagnosis is subsequently established, all previously reported adverse events based on 
signs and symptoms should be nullified and replaced by one adverse event report based 
on the single diagnosis, with a starting date that corresponds to the starting date of the 
first symptom of the eventual diagnosis.
5.3.5.4
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.5
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any changes in severity, increases or decreases, will be 
captured on Adverse Event Intensity or Grade Changes eCRF.  If the event becomes 
serious, it should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning that the event became serious; see Section 5.4.2 for reporting 
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"non-serious" to "serious," providing the date that the event became serious, and 
completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.6
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., treatment interruption or treatment
discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., treatment interruption or treatment 
discontinuation)


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
Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events).
5.3.5.8
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.3) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.9
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
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Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.10
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.11
Lack of Efficacy or Worsening of Atopic Dermatitis
Medical occurrences or symptoms of deterioration that are anticipated as part of AD
should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study.  When recording an unanticipated worsening of AD on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., "accelerated worsening of atopic dermatitis”).
5.3.5.12
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary 
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
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5.3.5.13
Safety Biomarker Data
Adverse event reports will not be derived from exploratory safety biomarker data by the 
Sponsor, and exploratory safety biomarker data will not be included in the formal safety 
analyses for this study.  In addition, exploratory safety biomarker data will not inform 
decisions on patient management.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Accidental overdoses or medication errors (see Section 5.4.4 for details on reporting 
requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Contract research organization (CRO) Name Medical Monitor contact information:
Medical Monitor:
, M.D.
Telephone No.:
 (USA)


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Alternate Medical Monitor contact information for all sites:
Medical Monitor:
, M.D.
Telephone Nos.:
 (USA)
 (USA)
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 12 weeks after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Safety 
Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 12 weeks after the final 
dose of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 12 weeks after the final 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 


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should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within
12 weeks after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.4.3.3
Congenital Anomalies/Birth Defects and Abortions
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 


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elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.4
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
MSTT1041A or placebo, adverse events associated with special situations should be 
recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with MSTT1041A or placebo, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event).  Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.


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
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as
12 weeks after the final dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

MSTT1041A Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The analysis of the data from the double-blind treatment period will be performed when 
all patients have either completed the end of the treatment visit (Week 16) or 
discontinued early from the study.
The analysis of complete data for the study, including data from the double-blind
treatment period and 8-week safety follow-up period, will be performed when all patients 
have either completed the double-blind treatment period and 8-week safety follow-up 
period or discontinued early from the study, all data from the study are in the database, 
and the database is locked.
Personnel who perform the blinded-efficacy assessments will remain blinded to 
individual treatment assignment until after the study is completed (after all patients have 
either completed the double-blind treatment period and 8-week safety follow-up period or 
discontinued early from the study), all data from the study are in the database, and the 
database is locked.
6.1
DETERMINATION OF SAMPLE SIZE
Approximately 90 patients in total will be randomized in a 1:1 ratio to 490 mg SC 
MSTT1041A or placebo Q4W.  The sample size provides at least 80% power to detect a 
difference of 34% in the percent change from baseline in EASI score at Week 16
between MSTT1041A- and placebo-treated patients, assuming a standard deviation of 
40.6 for placebo-treated patients.  The same number of patients can also provide at 
least 80% power to detect 1) a difference of 27% between MSTT1041A- and 


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placebo-treated patients in the proportion of patients achieving IGA scores of 0 or 1 at 
Week 16, assuming the percentage is 2% in placebo-treated patients, respectively, 2) a 
difference of 32% between MSTT1041A- and placebo-treated patients in the proportion 
of patients achieving EASI-75 at Week 16, assuming the percentage is 13% in 
placebo-treated patients, and 3) a difference of 30% between MSTT1041A- and 
placebo-treated patients in percent change from baseline to Week 16 in pruritus NRS, 
assuming a standard deviation of 37.3 for placebo-treated patients.  The sample size is 
calculated at a two-sided significance level of 0.05 and assumes 25% dropout. 
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for treatment discontinuation and premature study withdrawal, as 
well as treatment failure, will be listed and summarized.  Enrollment and major protocol 
deviations will be listed and evaluated for their potential effects on the interpretation of 
study results.  Exposure to study treatment (number of study drug treatments and 
duration of treatment) will be summarized.  All summaries will be presented according to 
randomized treatment assignment.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (including age, sex, race/ethnicity, 
concomitant AD medication use, and comorbid illnesses) will be summarized using 
means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate.  Summaries will be presented 
overall and by treatment group.
6.4
EFFICACY ANALYSES
Efficacy analyses will be based on the intent-to-treat (ITT) approach.  All patients 
randomized (ITT population) will be included in the analysis, with patients grouped 
according to the treatment assigned at randomization.  Hypothesis testing for the 
efficacy endpoints will be performed for each MSTT1041A dose level and the placebo 
group.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint for this study is percent change from baseline to Week 16
of total EASI score.  A mixed-effect model for repeated measures (MMRM) model will be 
used, with percent change (post baseline change divided by baseline value) as the 
dependent variable.  The model will include baseline value of the EASI score, treatment 
arms, visits, treatment arm by visit interaction, and stratification factors as listed in 
Section 3.1.  To account for repeated observations with patients, a random patient effect 
will be added to the model.  The MMRM model will provide adjusted least-square means 
of percent change from baseline at Week 16 for each of the treatment arms with the 
corresponding standard error, 95% CI and p-values.


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6.4.2
Secondary Efficacy Endpoints
All secondary endpoints involving binary outcome measures will be analyzed using the 
Cochran-Mantel-Haenszel chi-square test.  Patients with missing results at Week 16 will 
be considered non-responders for the corresponding endpoint.
Percent and absolute change from baseline for (approximately) continuous endpoints 
will be analyzed using a MMRM model as described for primary endpoint in 
Section 6.4.1.  The MMRM model will provide adjusted least-square means of percent 
change from baseline at Week 16 for each of the treatment arms with the corresponding 
standard error, 95% CI and p-values.
Summary statistics of the (approximately) continuous endpoints will be calculated for 
each treatment arm in absolute changes and raw values.  Mean, standard deviations, 
medians, and lower and upper quartiles, as well as minimum and maximum will be 
reported.  For all summaries involving change from baseline, patients without baseline 
values will be excluded from the analyses.
 
 
6.5
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug, with patients grouped according to actual treatment 
received.
Safety will be assessed by adverse events, clinical laboratory evaluations, vital signs, 
and ECGs. All verbatim adverse event terms will be mapped to MedDRA thesaurus 
terms, and adverse event severity will be graded according to the WHO toxicity grading.  
The incidence of mapped adverse events will be summarized by treatment arm.  
A treatment emergent adverse event is defined as any new adverse event reported or 
any worsening of an existing condition on or after the first dose of study drug.  Treatment 
emergent adverse event will be summarized by treatment arm.  Clinical laboratory data 
(hematology and serum chemistry), vital signs, and ECGs will be summarized by 
descriptive statistics by treatment groups at each visit.  In addition, separate summaries 
will be generated for serious adverse events, adverse events of special interest, deaths,
pregnancies, malignancies, adverse events leading to discontinuation from the study, 
and adverse events leading to discontinuation of study drug.
6.6
PHARMACOKINETIC ANALYSES
Serum concentration data for MSTT1041A will be tabulated and summarized.  
Descriptive summary statistics will include the arithmetic mean, median, range, standard 


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deviation, and coefficient of variation, as appropriate. Because a sparse PK sampling 
design is being used, population (non-linear mixed-effects) modeling will be used to 
analyze the concentration-time data of MSTT1041A. Information from other clinical 
studies may be incorporated to establish the PK model. The selection of parameters 
and the derivation of individual measures of exposure, such as area under the 
concentrationtime curve, maximum concentration, and trough serum concentration, will 
depend on the final PK model used for this analysis. The results of this modeling 
analysis may be reported separately from the Clinical Study Report.  Additional analyses
such as assessment of potential relationships between drug exposure and MSTT1041A 
efficacy, safety, and biomarker endpoints, will be conducted as appropriate and may be 
reported separately from the Clinical Study Report.
6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized by treatment group.  When determining postbaseline incidence, 
patients are considered to be ADA positive if they are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more postbaseline samples is at least 0.60 titer unit greater than the titer of the 
baseline sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA negative if they are ADA negative or have missing data at baseline and all 
postbaseline samples are negative, or if they are ADA positive at baseline but do not 
have any postbaseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported via descriptive statistics.
6.8
BIOMARKER ANALYSES
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies.
 
 
 
 


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
PD biomarkers (
 
) may be assessed to determine pharmacological activity and 
mechanism of action of MSTT1041A in patients with AD.  Data will be summarized 
by absolute levels of the biomarker, as well as absolute and relative changes from 
levels at randomization visit, for each treatment group.  Additional PD analyses will 
be conducted as appropriate.
6.9
SENSITIVITY ANALYSIS
Sensitivity analyses will be performed to evaluate the robustness of primary and 
secondary analyses.  The details of the sensitivity analyses will be specified in the Data
Analysis Plan.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory and ECG data will be
sent directly to the Sponsor, using the Sponsor's standard procedures to handle and 
process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
PRO and ClinRO data will be collected through the use of an electronic device provided 
by a vendor (see Section 7.3 for details).
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.


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7.3
ELECTRONIC PATIENT- AND CLINICIAN- REPORTED 
OUTCOME DATA
An electronic device will be used to capture PRO and ClinRO data.  The device is
designed for entry of data in a way that is attributable, secure, and accurate, in 
compliance with U.S. FDA regulations for electronic records (21 CFR Part 11).  The data 
will be transmitted to a centralized database maintained by the electronic device vendor.
The electronic data will be available for view access only, via a secure method.  Only
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the trial monitoring plan.  This includes any protocol data to be entered 
directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.


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To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO and ClinRO data (if applicable), 
Informed Consent Forms, laboratory test results, and medication inventory records, must 
be retained by the Principal Investigator for 15 years after completion or discontinuation 
of the study or for the length of time required by relevant national or local health 
authorities, whichever is longer.  After that period of time, the documents may be 
destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Genentech will retain study data for 25 years after the final Clinical Study Report has 
been completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).


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8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child's Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 


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separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).


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Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data, which may include data on germline mutations, may be submitted to
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted clinical study reports 
and other summary reports will be provided upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 


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permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
Genentech, a member of the Roche group, is the Sponsor of this study. A CRO may
provide clinical operations oversight, including, but not limited to, project management, 
medical monitoring, site management, data quality support, safety reporting, and 
regulatory activities as specified in the study management plans.  Genentech will provide 
CRO oversight, develop the database and randomization scheme, and conduct 
statistical programming and analysis. An IMC will provide safety monitoring for the study 
in addition to the ongoing review of safety by the Medical Monitor and safety scientist. 
EDC will be utilized for this study. An IxRS will be used to assign patient numbers, 
randomize patients into the study through use of a dynamic hierarchical algorithm, and 
manage site drug supply. A central laboratory will be used for sample management and 
storage until shipment to specialty laboratories or Genentech for analysis. 
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries of the U.S. National Institutes of Health and the 
EMA, and in peer-reviewed journals. The Sponsor will comply with all requirements for 
publication of study results.  Study data may be shared with others who are not 
participating in this study, and redacted clinical study reports and other summary reports 
will be provided upon request (see Section 8.4 for more details).  For more information, 
refer to the Roche Global Policy on Sharing of Clinical Trials Data at the following 
website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.


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In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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     Appendix 1
Schedule of Activities
SCR
Treatment Period
FU
EOS
ET a
UV b
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Week
D 35 
to 1
D1
W1
W2
W4
W6
W8
W10
W12
W14
W16
W20
W24
Day
D8
D15
D29
D43
D57
D71
D85
D99
D113
D141 D169
(Visit window in days)
(2)
(3)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(5)
(5)
Office/Phone visit
O
O
O
O or P
O
P
O
P
O
P
O
P
O
O
O
Informed consent c
x
Demographics
x
Medical history
x
Alcohol/Smoking/Substance use history
x
Atopy status
x
Complete physical examination d
x
Limited physical examination e
x
x
x
x
x
x
Weight and height
(height at screening only)
x
x
x
x
IGA
x
x
x
x g
x
x
x
x
x
x
x
EASI 
x
x
x
x g
x
x
x
x
x
x
x
SCORAD f
x
x
x
x g
x
x
x
x
x
x
x
Pruritus and sleep NRS only f
x h
x
x
x
x
Emollient use status
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 1:
Schedule of Activities
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SCR
Treatment Period
FU
EOS
ET a
UV b
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Week
D 35 
to 1
D1
W1
W2
W4
W6
W8
W10
W12
W14
W16
W20
W24
Day
D8
D15
D29
D43
D57
D71
D85
D99
D113
D141 D169
(Visit window in days)
(2)
(3)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(5)
(5)
Office/Phone visit
O
O
O
O or P
O
P
O
P
O
P
O
P
O
O
O
Vital signs i
x
x
x
x
x
x
x
x
x
x
ECG (12-lead, single)
x
x
x
x
x
x
Serum pregnancy test j
x
x
Urine pregnancy test j
x
x
x
x
x
x
x
x
x
Hepatitis B/C serology
x
Hepatitis B DNA
x
x
x
TB test
x
Chest X-ray, TB worksheet k
x
Hematology l
x
x
x
x
x
x
x
x
x
x
Chemistry m
x
x
x
x
x
x
x
x
x
NT-proBNP
x
x n
Urinalysis o
x
x
x
x
HbA1C
x
x
x
x
x
Fasted glucose and lipids p
x
x
x
x
x
Serum PK q
x
x
x
x
x
x
x
x
x
Serum specific IgE
x


Appendix 1:
Schedule of Activities
MSTT1041A—Genentech, Inc.
84/Protocol GS40965, Version 1
SCR
Treatment Period
FU
EOS
ET a
UV b
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Week
D 35 
to 1
D1
W1
W2
W4
W6
W8
W10
W12
W14
W16
W20
W24
Day
D8
D15
D29
D43
D57
D71
D85
D99
D113
D141 D169
(Visit window in days)
(2)
(3)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(5)
(5)
Office/Phone visit
O
O
O
O or P
O
P
O
P
O
P
O
P
O
O
O
Serum for biomarker (including total IgE)
x
x
x
x
x
x
x
x
Serum ADA q
x
x
x
x
x
Randomization
x
Study drug administration s
x
x 
x
x
x
Concomitant medications t
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events u
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADatopic dermatitis; ADA anti-drug antibody;
 Dday; EASIEczema Area and Severity Index;
eCRFelectronic Case Report Form; EOSend of study visit; ET early termination visit; FUfollow up; HbA1chemoglobin A1c; 
IGAInvestigator's Global Assessment; NRSNumeric Rating Scale; NT-proBNP N-terminal pro B-type natriuretic peptide; Ooffice visit; 
Pphone visit; PKpharmacokinetic; PPDpurified protein derivative; PROpatient-reported outcome; QFTQuantiFERON TB-Gold®;
SCORADSCORing Atopic Dermatitis; SCRscreening;
TBtuberculosis; UVunscheduled visit; Vvisit; W week.
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  Visit windows should be calculated
relative to the randomization visit (Day 1).


Appendix 1:
Schedule of Activities
MSTT1041A—Genentech, Inc.
85/Protocol GS40965, Version 1
                                           
a If a patient is unable to complete all study visits and assessments, the patient should be asked to return to the clinic for an early termination visit.  
This visit should occur approximately 4 weeks after the final dose of study drug (see Section 4.6.2).
b Any of the study procedures noted may be performed at an unscheduled visit, but not all are required.
c Informed consent must be documented before any study-specific screening procedure is performed.
d Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, and neurologic systems.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions 
eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
e Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
f
Questionnaires (
, pruritus and sleep NRS) will be self- or interviewer-administered before the patient receives any information on disease 
status, prior to the performance of non-PRO assessments, and prior to the administration of study treatment.
g Assessment will be conducted only during an office visit (i.e., not at a telephone visit).
h Will only be conducted at a telephone visit.  For the Week 2 visit, if the patient does not have an office visit (chooses a telephone visit), collect 
pruritus and sleep NRS.
i
Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure, ideally while the patient is in a seated position, and temperature.  
Record abnormalities observed at baseline on the appropriate eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
j
All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed at specified 
subsequent visits. If a urine pregnancy test result is positive, it must be reported immediately, and study drug will not be administered that day.  
The positive urine pregnancy result must be confirmed by a serum pregnancy test. Refer to Section 5.4.3.1 for management of a patient with 
a positive pregnancy test.
k Patients with a positive PPD (without a history of Bacillus Calmette-Guérin vaccination) or a positive or indeterminate QFT will require a chest 
X-ray to review for evidence of active TB, including posteroanterior and lateral views, unless a chest X-ray has been performed within 3 months 
before screening and the report is available for review.  A chest computed tomography scan may substitute for a chest X-ray.  Chest X-rays 
should only be performed if patients first meet all other study eligibility criteria.
l
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
m Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST.




MSTT1041A—Genentech, Inc.
87/Protocol GS40965, Version 1
Appendix 2
WHO Classification of Topical Corticosteroids
The following table provides a non-exhaustive list of examples of topical corticosteroids 
classified by potency (Source: http://apps.who.int/medicinedocs/en/d/Jh2918e/32.html).
Potency
Class
Topical Corticosteroid
Formulation
Ultra High
I
Clobetasol propionate
Cream, 0.05%
Diflorasone diacetate
Ointment, 0.05%
High
II
Amcinonide
Ointment, 0.1%
Betamethasone dipropionate
Ointment, 0.05%
Desoximetasone
Cream or ointment, 0.025%
Fluocinonide
Cream, ointment or gel, 0.05%
Halcinonide
Cream, 0.1%
III
Betamethasone dipropionate
Cream, 0.05%
Betamethasone valerate
Ointment, 0.1%
Diflorasone diacetate
Cream, 0.05%
Triamcinolone acetonide
Ointment, 0.1%
Moderate
IV
Desoximetasone
Cream, 0.05%
Fluocinolone acetonide
Ointment, 0.025%
Fludroxycortide
Ointment, 0.05%
Hydrocortisone valerate
Ointment, 0.2%
Triamcinolone acetonide
Cream, 0.1%
V
Betamethasone dipropionate
Lotion, 0.02%
Betamethasone valerate
Cream, 0.1%
Fluocinolone acetonide
Cream, 0.025%
Fludroxycortide
Cream, 0.05%
Hydrocortisone butyrate
Cream, 0.1%
Hydrocortisone valerate
Cream, 0.2%
Triamcinolone acetonide
Lotion, 0.1%
Low
VI
Betamethasone valerate
Lotion, 0.05%
Desonide
Cream, 0.05%
Fluocinolone acetonide
Solution, 0.01%
VII
Dexamethasone sodium phosphate
Cream, 0.1%
Hydrocortisone acetate
Cream, 1%
Methylprednisolone acetate
Cream, 0.25%




MSTT1041A—Genentech, Inc.
89/Protocol GS40965, Version 1
Appendix 4
Eczema Area and Severity Index
From:  Hanifin JM, Thurston M, Omoto M, et al. The eczema area and severity index 
(EASI): assessment of reliability in atopic dermatitis. Exp Dermatol 2001;10 (1):118.
Method
Four individual body regions are assessed:  head and neck (H&N), upper limbs (UL; 
includes the external axillae and hands), trunk (includes the internal axillae and groin), 
and lower limbs (LL; includes the buttocks and feet).
For each body region 

Assess the affected body surface area (BSA):  score of 0 to 6 (see Table 1
footnote 3 below) assigned for the percentage of affected BSA (0%100%)

Individually rate the average degree of severity (03: none, mild, moderate, severe), 
with half steps allowed, for each of 4 clinical signs:  erythema, induration-papulation, 
excoriations, and lichenification.  A summed score of 0 to 12 is assigned to each 
body region

Assign a total body region score:  sum of the individual clinical signs score 
(maximum12)affected area score (maximum6)the body-region index 
(H&N0.1, UL0.2, trunk0.3, LL0.4)
Total score (072)the sum of total scores for each of the 4 body region scores.


MSTT1041A—Genentech, Inc.
90/Protocol GS40965, Version 1
Appendix 5
SCORing Atopic Dermatitis
From:  European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: 
the SCORAD Index (consensus report of the European Task Force on Atopic 
Dermatitis). Dermatology 1993;186:23–31.
Three aspects of disease severity are scored
A. Extent (A):  A sum of the affected (inflammation, not dryness) body areas as 
indicated in the figure (Total Score:  0100)
B. Intensity (B):  Six clinical signs, rated 03 for severity (absent, mild, moderate, 
severe):  erythema, edema/papulation, oozing/crusting, excoriation, lichenification, 
and dryness (Total Score:  018)
C. Subjective (C):  Two patient-reported outcomes (PRO) are assessed by numeric 
rating scale (NRS) scored 010 i) Pruritus, ii) Sleep loss (Total PRO Score 020)
The NRS is a simple assessment tool that patients will use to report the intensity of 
their pruritus (itch) and sleep loss during a recall period of 3 days. Patients will be 
asked the following questions:
For average itch intensity: “On a scale of 0 to 10, with 0 being ‘no itch’ and 
10 being the ‘worst itch imaginable,’ how would you rate your itch overall 
(on average) during the previous 3 days?”
For average sleep loss: “On a scale of 0 to 10, with 0 being ‘no sleep loss’ and 
10 being the ‘most severe loss’, how would you rate your sleep loss overall 
(on average) during the previous 3 days?”
A total score (0103) is calculated using the following formula:  A/5(7B/2)C.
No 
itch
Worst itch 
you can 
imagine
No 
sleep 
loss
Most 
severe 
sleep loss


MSTT1041A—Genentech, Inc.
91/Protocol GS40965, Version 1
Appendix 6
Investigator Global Assessment
Score
Description
0
Clear
No erythema.  No edema or induration/papulation.  No 
oozing/crusting.  Post inflammatory hyper- or 
hypopigmentation may be present.
1
Almost clear
Trace, faint pink erythema with barely perceptible edema 
and/or induration/papulation.  No oozing/crusting.
2
Mild disease
Faint pink erythema with edema and/or induration and with 
papulation perceptible upon palpitation.  No oozing/crusting.
3
Moderate disease
Pink-red with definite edema and/or induration of skin papules 
and plaques.  There may be some oozing/crusting.
4
Severe disease
Deep/bright red erythema with significant edema and/or 
induration.  Obvious raised borders with papules and plaques 
with oozing/crusting.


MSTT1041A—Genentech, Inc.
92/Protocol GS40965, Version 1


MSTT1041A—Genentech, Inc.
93/Protocol GS40965, Version 1


MSTT1041A—Genentech, Inc.
94/Protocol GS40965, Version 1


MSTT1041A—Genentech, Inc.
95/Protocol GS40965, Version 1


MSTT1041A—Genentech, Inc.
96/Protocol GS40965, Version 1


MSTT1041A—Genentech, Inc.
97/Protocol GS40965, Version 1
   Appendix 8
WHO Toxicity Grading Scale
ITEM
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
HEMATOLOGY
Hemoglobin
9.510.5 gm/Dl
8.09.4 gm/Dl
6.57.9 gm/Dl
< 6.5 gm/Dl
Absolute neutrophil count
10001500/mm3
750999/mm3
500749/mm3
<500/mm3
Platelets
7500099000/mm3
5000074999/mm3
2000049000/mm3
<20000/mm3
PT
1.011.25ULN
1.26-1.5ULN
1.51 -3.0ULN
>3ULN
aPPT
1.01 -1.66ULN
1.672.33ULN
2.343ULN
> 3ULN
Fibrinogen
0.750.99LLN
0.500.74LLN
0.250.49LLN
< 0.25LLN
Fibrin split product
2040 mcg/ml
4150 mcg/ml
5160 mcg/ml
> 60 mcg/ml
Methemoglobin
59.9 %
10.014.9 %
15.019.9%
> 20 %
LIVER ENZYMES
AST (SGOT)
1.252.5ULN
2.65ULN
5.110ULN
> 10ULN
ALT (SGPT)
1.252.5ULN
2.65ULN
5.110ULN
> 10ULN
GGT
1.252.5ULN
1.65ULN
5.110ULN
> 10ULN
ALP
1.252. 5ULN
1.65ULN
5.110ULN
> 10ULN
Amylase
1.11.5ULN
1.62.0ULN
2.15.0ULN
> 5.1ULN
CHEMISTRIES
Hyponatremia
130135 mEq/L
123129 mEq/L
116122 mEq/L
< 116 or mental status changes or 
seizures
Hypernatremia
146150 mEq/L
151157 mEq/L
158165 mEq/L
> 165 mEq/L or mental status 
changes or seizures
Hypokalemia
3.03.4 mEq/L
2.52.9 mEq/L
2.02.4 mEq/L or intensive 
replacement Rx required or 
hospitalization required.
< 2.0 mEq/L or paresis or ileus or 
life-threatening arrhythmia
Hyperkalemia
5.66.0 mEq/L
6.16.5 mEq/L
6.67.0 mEq/l
> 7.0 mEq/L or life-threatening 
arrhythmia
Hypoglycemia
5564 mg/dL
4054 mg/dL
3039 mg/dL
<30 mg/dL or mental status changes
or coma
Hyperglycemia
(note if fasting)
116160 mg/dL
161250 mg/dL
251500 mg/dL
> 500 mg/dL or ketoacidosis or 
seizures


Appendix 8:
WHO Toxicity Grading Scale
MSTT1041A—Genentech, Inc.
98/Protocol GS40965, Version 1
ITEM
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
Hypocalcemia
(corrected for albumin)
8.47.8 mg/dL
7.77.0 mg/dL
6.96.1 mg/dL
< 6.1 mg/dL or life-threatening 
arrhythmia or tetany
Hypercalcemia
(correct for albumin)
10.611.5 mg/dL
11.612.5 mg/dL
12.613.5 mg/dL
> 13.5 mg/dL life-threatening 
arrhythmia
Hypomagnesemia
1.41.2 mEq/L
1.10.9 mEq/L
0.80.6 mEq/L
< 0.6 mEq/L or life-threatening 
arrhythmia
Hypophosphatemia
2.02.4 mg/dL
1.5 1.9 mg/dL or 
replacement Rx 
required
1.0 1.4 mg/dL intensive 
Rx or hospitalization 
required
< 1.0 mg/dL or life-threatening 
arrhythmia
Hyperbilirubinemia
1.11.5ULN
1.62.5ULN
2.65ULN
> 5ULN
BUN
1.252.5ULN
2.65ULN
5.110ULN
> 10ULN
Creatinine
1.11.5ULN
1.63.0ULN
3.16ULN
> 6ULN or required dialysis
URINALYSIS
Proteinuria
1+ or 
< 0.3% or 
<3 g/L or 
200 mg-1 gm loss/day
2 3 + or 
0.3%1.0% or
310 g/L or 
12 gm loss/day
4+ or
> 1.0% or
> 10 g/L or
23.5 gm loss/day
nephrotic syndrome or 
> 3.5 gm loss/day
Hematuria
Microscopic only
Gross, no clots
Gross+ clots
Obstructive or required transfusion
CARDIAC DYSFUNCTION
Cardiac rhythm
Asymptomatic,
transient signs, no
Rx required
Recurrent/persistent;
No Rx required
Requires treatment
Hypertension
Transient inc. > 20 mm; 
no Rx
Recurrent, chronic, 
> 20 mm, Rx required
Requires acute Rx; 
no hospitalization
Requires hospitalization
Hypotension
Transient orthostatic
hypotension, no Rx
Symptoms correctable 
with oral fluids Rx
Requires IV fluids; 
no hospitalization
required
Requires hospitalization
Pericarditis
Minimal effusion
Mild/moderate
asymptomatic
effusion, no Rx
Symptomatic effusion; pain; 
EKG changes
Tamponade; pericardiocentesis or 
surgery required


Appendix 8:
WHO Toxicity Grading Scale
MSTT1041A—Genentech, Inc.
99/Protocol GS40965, Version 1
ITEM
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
Hemorrhage, blood loss
Microscopic/occult
Mild, no transfusion
Gross blood loss;
12 units transfused
Massive blood loss;
> 3 units transfused
RESPIRATORY
Cough
Transient-no Rx
Treatment associated 
cough; local Rx
Uncontrolled
Bronchospasm, acute
Transient; no Rx
< 80%70% FEV1
(or peak flow)
Requires Rx
normalizes with
bronchodilator; FEV1
50%70% (or peak 
Flow)
No normalization with 
bronchodilator; FEV1
25%50% (or peak flow
retractions)
Cyanosis: FEV1 < 25% (or peak 
flow) or Intubated
GASTROINTESTINAL
Stomatitis
Mild discomfort; 
no limits on activity
Some limits on
eating/drinking
Eating/talking very limited
Requires IV fluids
Nausea
Mild discomfort;
maintains reasonable
intake
Moderate discomfort;
intake decreased
significantly; some
activity limited
Severe discomfort; 
no significant intake;
activities limited
Minimal fluid intake
Vomiting
Transient emesis
Occasional/moderate
vomiting
Orthostatic hypotension or 
IV fluids required
Hypotensive shock or hospitalization
required for IV fluid therapy
Constipation
Mild
Moderate
Severe
Distensions w/ vomiting
Diarrhea
Transient 34 loose
stools/day
57 loose stools/day
Orthostatic hypotension or
> 7 loose stools/day or 
required IV fluids
Hypotensive shock or hospitalization 
for IV fluid therapy required
NEURO & NEUROMUSCULAR
Neurocerebellar
Slight incoordination
dysdiadochokinesis
Intention tremor,
dysmetria, slurred
speech; nystagmus
Locomotor ataxia
Incapacitated
Mood
Mild anxiety or
depression
Moderate anxiety or
depression and
therapy required
Severe anxiety or
depression or mania; needs 
assistance
Acute psychosis; incapacitated, 
requires hospitalization


Appendix 8:
WHO Toxicity Grading Scale
MSTT1041A—Genentech, Inc.
100/Protocol GS40965, Version 1
ITEM
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
Neuro control
Mild difficulty 
concentrating; 
no Rx; mild 
confusion/agitation;
ADL unaffected
Moderate
confusion/agitation
some limitation of
ADL; minimal Rx
Severe confusion/agitation
needs assistance for ADL; 
therapy required
Toxic psychosis; hospitalization
Muscle strength
Subjective weakness; 
no objective 
symptoms/signs
Mild objective 
signs/symptoms; 
no decrease in 
function
Objective weakness
function limited
Paralysis
OTHER PARAMETERS
Fever: oral, > 12 hours
37.738.5C or
100.0101.5F
38.639.5C or
101.6102.9F
39.640.5C or
103105F
> 40 C or > 105F
Headache
Mild, no Rx therapy
Transient, moderate;
Rx required
Severe; responds to initial 
narcotic therapy
Intractable; required repeated 
narcotic therapy
Fatigue
No decrease in ADL
Normal activity
decreased 25%-50%
Normal activity
decreased > 50% can’t 
work
Unable to care for self
Allergic reaction
Pruritus without rash
Localized urticaria
Generalized urticaria; 
angioedema
Anaphylaxis
Local reaction
Tenderness or 
erythema
Induration < 10 cm or 
phlebitis or 
inflammation
Induration > 10 cm or 
ulceration
Necrosis
Mucocutaneous
Erythema; pruritus
Diffuse, 
maculo-papular rash, 
dry desquamation
Vesiculation, moist
desquamation, or ulceration
Exfoliative dermatitis, mucous 
membrane involvement or erythema, 
multiforme or suspected 
Stevens-Johnson or necrosis 
requiring surgery