A Gluten Challenge Study to Characterize Peripheral Blood and Intestinal Gluten-specific CD4+ T Cell Subsets in Patients With Celiac Disease
Phase: EARLY_PHASE1
Conditions: Celiac Disease
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04054544 
Document Date: 
17-Jul-2020
A Gluten Challenge Study to Characterize Peripheral Blood and 
Intestinal Gluten-specific CD4+ T cell Subsets in Patients With 
Celiac Disease

PRODUCT:  MK-0000  
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PROTOCOL/AMENDMENT NO.:  402-05 
MK-0000-402-05 FINAL PROTOCOL
17-JUL-2020
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Gluten Challenge Study to Characterize Peripheral Blood and Intestinal 
Gluten-specific CD4+ T cell Subsets in Patients With Celiac Disease
Protocol Number: 402-05
Compound Number: MK-0000
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
Approval Date: 17 July 2020
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment -05
17-Jul-2020
To ensure participant safety, COVID-19 testing was added to the screening 
visit and prior to the duodenal biopsy procedure.
Amendment -04
18-Jun-2020
The main rationale for Amendment 04 is to remove the restriction that 
leftover PBMC samples will only be retained if initial samples for ELISPOT 
analysis have insufficient signal for assay development.
Amendment -03
13-Apr-2020
To ensure participant safety, Exclusion Criterion #9 was revised to exclude 
participants on Coumadin™or any anticoagulants.
Amendment -02
25-Oct-2019
The Secondary Objective was moved to be an Exploratory Objective.
Amendment -01
16-Aug-2019
The main rationale for Amendment 01 is reprioritization of study objectives 
and some changes in participant entry criteria.
Original Protocol
30-Apr-2019
Not applicable
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
To ensure participant safety, COVID-19 testing was added to the screening visit and prior to the duodenal biopsy procedure.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities
10.2 Appendix 2: Clinical 
Laboratory Tests
Added COVID-19 testing.
Due to global COVID-19 restrictions, COVID-19 testing 
was added to the screening visit and prior to the duodenal 
biopsy procedure to ensure participant safety.
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................14
1.3
Schedule of Activities (SoA)................................................................................16
2
INTRODUCTION..........................................................................................................19
2.1
Study Rationale....................................................................................................19
2.2
Background ..........................................................................................................19
2.3
Benefit/Risk Assessment......................................................................................20
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................20
4
STUDY DESIGN............................................................................................................22
4.1
Overall Design......................................................................................................22
4.2
Scientific Rationale for Study Design.................................................................22
4.2.1
Rationale for Endpoints ...............................................................................23
4.2.1.1
Safety Endpoints................................................................................23
4.2.1.2
Pharmacodynamic Endpoints.............................................................23
4.2.1.3
Planned Exploratory Biomarker Research.........................................23
4.2.1.3.1
Planned Genetic Analysis ........................................................23
4.2.1.4
Future Biomedical Research..............................................................23
4.3
Justification for Dose...........................................................................................24
4.4
Beginning and End of Study Definition .............................................................24
4.4.1
Clinical Criteria for Early Study Termination .............................................24
5
STUDY POPULATION ................................................................................................25
5.1
Inclusion Criteria.................................................................................................25
5.2
Exclusion Criteria................................................................................................26
5.3
Lifestyle Considerations......................................................................................28
5.3.1
Diet Restrictions...........................................................................................28
5.3.2
Alcohol Restrictions.....................................................................................29
5.3.3
Activity Restrictions ....................................................................................29
5.4
Screen Failures.....................................................................................................29
5.5
Participant Replacement Strategy......................................................................29
6
STUDY INTERVENTION............................................................................................29
6.1
Study Intervention(s) Administered...................................................................29
6.2
Preparation/Handling/Storage/Accountability .................................................31
 
 
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6.2.1
Dose Preparation..........................................................................................31
6.2.2
Handling, Storage, and Accountability........................................................31
6.3
Measures to Minimize Bias: Randomization and Blinding..............................32
6.3.1
Intervention Assignment..............................................................................32
6.3.2
Stratification.................................................................................................32
6.3.3
Blinding........................................................................................................32
6.4
Study Intervention Compliance..........................................................................32
6.5
Concomitant Therapy..........................................................................................32
6.5.1
Rescue Medications and Supportive Care ...................................................33
6.6
Dose Modification (Escalation/Titration/Other)...............................................33
6.7
Intervention After the End of the Study............................................................33
6.8
Clinical Supplies Disclosure................................................................................33
6.9
Standard Policies..................................................................................................33
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................33
7.1
Discontinuation of Study Intervention...............................................................33
7.2
Participant Withdrawal From the Study...........................................................34
7.3
Lost to Follow-up .................................................................................................34
8
STUDY ASSESSMENTS AND PROCEDURES........................................................35
8.1
Administrative and General Procedures ...........................................................35
8.1.1
Informed Consent.........................................................................................35
8.1.1.1
General Informed Consent.................................................................36
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................36
8.1.2
Inclusion/Exclusion Criteria ........................................................................36
8.1.3
Participant Identification Card.....................................................................36
8.1.4
Medical History ...........................................................................................37
8.1.5
Prior and Concomitant Medications Review...............................................37
8.1.5.1
Prior Medications...............................................................................37
8.1.5.2
Concomitant Medications..................................................................37
8.1.6
Assignment of Screening Number...............................................................37
8.1.7
Assignment of Treatment/Randomization Number.....................................37
8.1.8
Study Intervention Administration ..............................................................37
8.1.8.1
Timing of Dose Administration.........................................................38
8.1.9
Blood Collection..........................................................................................38
8.1.10
Duodenal Biopsy Procedure ........................................................................38
8.1.11
Discontinuation and Withdrawal .................................................................38
8.1.11.1
Withdrawal From Future Biomedical Research ................................39
 
 
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8.1.12
Participant Blinding/Unblinding..................................................................39
8.1.13
Domiciling ...................................................................................................39
8.1.14
Calibration of Equipment.............................................................................39
8.2
Efficacy/Immunogenicity Assessments ..............................................................39
8.3
Safety Assessments...............................................................................................39
8.3.1
Physical Examinations.................................................................................40
8.3.2
Vital Signs....................................................................................................40
8.3.3
Electrocardiograms ......................................................................................40
8.3.4
Clinical Safety Laboratory Assessments .....................................................41
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................41
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................42
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......44
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...44
8.4.4
Regulatory Reporting Requirements for SAE .............................................44
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................44
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................45
8.4.7
Events of Clinical Interest (ECIs)................................................................45
8.5
Treatment of Overdose........................................................................................45
8.6
Pharmacokinetics.................................................................................................45
8.7
Pharmacodynamics..............................................................................................46
8.7.1
Blood and Tissue Samples...........................................................................46
8.7.2
Duodenal Biopsy Pathology ........................................................................46
8.7.3
Celiac Disease Symptom Diary ...................................................................46
8.8
Biomarkers ...........................................................................................................46
8.8.1
Planned Genetic Analysis Sample Collection..............................................46
8.9
Future Biomedical Research Sample Collection...............................................47
8.10
Health Economics Medical Resource Utilization and Health Economics.......47
8.11
Visit Requirements...............................................................................................47
8.11.1
Screening......................................................................................................47
8.11.2
Treatment Period Visits ...............................................................................47
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........47
8.11.4
Poststudy......................................................................................................47
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......48
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................48
9
STATISTICAL ANALYSIS PLAN .............................................................................49
 
 
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9.1
Statistical Analysis Plan Summary.....................................................................49
9.2
Responsibility for Analyses.................................................................................49
9.3
Hypotheses/Estimation ........................................................................................49
9.4
Analysis Endpoints...............................................................................................49
9.5
Analysis Populations............................................................................................49
9.6
Statistical Methods...............................................................................................50
9.7
Interim Analyses ..................................................................................................50
9.8
Multiplicity ...........................................................................................................50
9.9
Sample Size and Power Calculations .................................................................50
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................52
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........52
10.1.1
Code of Conduct for Clinical Trials.............................................................52
10.1.2
Financial Disclosure.....................................................................................54
10.1.3
Data Protection.............................................................................................54
10.1.3.1
Confidentiality of Data ......................................................................55
10.1.3.2
Confidentiality of Participant Records...............................................55
10.1.3.3
Confidentiality of IRB/IEC Information............................................55
10.1.4
Publication Policy........................................................................................55
10.1.5
Compliance with Study Registration and Results Posting Requirements ...56
10.1.6
Compliance with Law, Audit, and Debarment ............................................56
10.1.7
Data Quality Assurance ...............................................................................57
10.1.8
Source Documents .......................................................................................57
10.1.9
Study and Site Closure.................................................................................58
10.2
Appendix 2: Clinical Laboratory Tests..............................................................59
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................60
10.3.1
Definition of AE ..........................................................................................60
10.3.2
Definition of SAE ........................................................................................61
10.3.3
Additional Events Reported in the Same Manner as SAE...........................62
10.3.4
Recording AE and SAE ...............................................................................62
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................66
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................67
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................68
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................69
10.7
Appendix 7: Country-specific Requirements....................................................74
 
 
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10.8
Appendix 8: Blood Volume and Tissue Collection Tables ...............................75
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ....................76
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values .....77
10.11 Appendix 11: Abbreviations ...............................................................................78
11
REFERENCES...............................................................................................................79
 
 
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LIST OF TABLES
Table 1
Study Interventions....................................................................................30
Table 2
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................43
Table 3
Half width of the 95% confidence interval (CI) ........................................51
Table 4
Protocol-required Safety Laboratory Assessments....................................59
 
 
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LIST OF FIGURES
Figure 1
Study Diagram ...........................................................................................15
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Gluten Challenge Study to Characterize Peripheral Blood and Intestinal Gluten-
specific CD4+ T cell Subsets in Patients With Celiac Disease
Short Title: Gluten Challenge Study in Celiac Disease Patients
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
This study is to be conducted in male and female participants with celiac disease.
Primary Objectives
Primary Endpoints
- To determine the phenotypes of gliadin 
peptide/HLA-DQ2 multimer-positive CD4+ 
T cell subsets in the peripheral blood before 
and after gluten challenge and from duodenal 
biopsies after gluten challenge. Estimation: 
The percentages of α-gliadin and ω-gliadin-
reactive CD4+ T cells expressing known 
activation and inhibitory receptors (including 
but not limited to: CD25 (IL-2R), CD95 
(Fas), CD279 (PD-1), TGFβ1R, and IL-27R) 
will be estimated.
- α-gliadin and ω-gliadin-reactive CD4+ T 
cells
 
 
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Overall Design:
Study Phase
Early Phase 1
Primary Purpose
Basic Science
Indication
Celiac Disease
Population
Participants with celiac disease
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
No Treatment Control
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 12 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 15 participants will be allocated/randomized such that 15 evaluable 
participants complete the study as described in Section 9.9.
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Intervention
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period
Use
All participants
Gluten
4 g
Twice daily
Oral
Daily for 13 
days
Challenge 
agent
Total 
Number
1
Duration of 
Participation
Each participant will participate in the study for approximately 8 weeks from 
the time the participant signs the Informed Consent Form through the final 
contact. After a screening period of up to 28 days, each participant will be 
receiving assigned intervention for 13 days. After the end of treatment each 
participant will be followed for 14 days.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 11.
1.2
Schema
The study design is depicted in Figure 1.
 
 
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Figure 1
Study Diagram
 
 
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1.3
Schedule of Activities (SoA)
All Panels/Periods
Study Period
Screening
Pre-dose
Intervention
Post-study
Notes
Scheduled Day
Screening
(up to -28 
days)
Day 1
Pre-dose Day 1 Day 6 Day 13
Day 14
(+/- 1 
day)
Post-study
(14 days after last 
gluten administration)
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Assignment of Screening Number
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
X
Recheck clinical status before start of 
gluten challenge
Medical History
X
Includes usage of drugs, alcohol, and 
tobacco
Prior/Concomitant Medication Review
X
X
X
X
X
X
Assignment of 
Treatment/Randomization Number
X
Gluten Administration/Dispensing
X-----------------------X
Gluten will be administered daily  
from Day 1 to Day 13. In the event 
that Day 14 procedures are conducted 
on Day 13, gluten  intended for Day 
13 will not be consumed. 
Participant Gluten Consumption Log
X-----------------------X
Participants will complete this log
daily.
Safety Procedures
Full physical examination
X
X
X
Pre-dose will be targeted PE
Height
X
Weight
X
X
X
X
Vital Signs (BP, HR, RR)
X
X
X
X
 
 
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All Panels/Periods
Study Period
Screening
Pre-dose
Intervention
Post-study
Notes
Scheduled Day
Screening
(up to -28 
days)
Day 1
Pre-dose Day 1 Day 6 Day 13
Day 14
(+/- 1 
day)
Post-study
(14 days after last 
gluten administration)
Body Temperature
X
X
X
X
12-lead ECG
X
Serum β-Human Chorionic 
Gonadotropin
(β-hCG; WOCBP only)
X
Urine β-Human Chorionic 
Gonadotropin
(β-hCG; WOCBP only)
X
X
Serum FSH - (postmenopausal women
only)
X
Blood for HLA Genotyping for Celiac 
Disease
X
Results from previous testing may be 
used in lieu of genotyping at 
screening
Anti-tTg, HIV, hepatitis B and C screen
X
UDS
X
Screening UDS is mandatory, any 
additional UDS are conducted per site 
SOP
COVID-19 Testing
X
X
COVID-19 nasal swab test or blood 
test, per local practice, if deemed 
possible/allowed based on test 
capacity, and according to local 
health practice. Testing prior to the
Day 14 duodenal biopsy may be done 
within 2 to 3 days prior to the 
procedure per the investigator’s 
discretion. Result must be negative 
for duodenal biopsy to be performed.
Hematology
X
X
Urinalysis
X
X
 
 
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All Panels/Periods
Study Period
Screening
Pre-dose
Intervention
Post-study
Notes
Scheduled Day
Screening
(up to -28 
days)
Day 1
Pre-dose Day 1 Day 6 Day 13
Day 14
(+/- 1 
day)
Post-study
(14 days after last 
gluten administration)
Chemistry
X
X
CDSD
X
X-------------------------------------------X
Participants will complete the CDSD 
daily.
AE/SAE review
X
X
X
X
X
X
X
Pharmacodynamics
Blood for Serum Cytokine/Chemokine
Assay 
X
X
X
Blood for PBMC
X
X
X
Duodenal Biopsy
X
Biomarkers
Blood for Genetic Analysis
X
Collect predose from enrolled 
participants only – See Section 8.8
AE=adverse event; BP=blood pressure; CDSD=Celiac Disease Symptom Diary; ECG=electrocardiogram; FSH=follicle-stimulating hormone; hCG=human 
chorionic gonadotropin; HLA=human lymphocyte antigen; HR=heart rate; PBMC=peripheral blood mononuclear cells; PE=physical examination; 
RR=respiratory rate; SAE=serious adverse event; UDS=urine drug screen; WOCBP=women of childbearing potential
 
 
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2
INTRODUCTION
2.1
Study Rationale
The objective of this experimental medicine study is to profile cell surface receptors on blood 
and intestinal gluten-specific CD4+ cells from patients with CeD to inform the development 
of novel therapies for celiac disease. 
2.2
Background
Celiac disease is an enteropathy of the small intestine triggered by ingestion of gluten present 
in wheat (gliadin), rye (secalin), and barley (hordein). It is one of the most common immune-
mediated diseases, affecting an estimated 10 million people globally, with a prevalence of 
0.5-1% which is predicted to increase over time. It is a malabsorptive disease characterized 
by GI symptoms (diarrhea, weight loss) and vitamin deficiencies (iron, vitamin D), leading to 
anemia and osteoporosis. CeD is diagnosed by the presence of antibodies to tTG and 
characteristic pathologic changes on duodenal biopsies. The only current management option
for CeD is strict, lifelong adherence to a GFD; however, unintentional exposure to gluten 
through food contamination is common, which may lead to persistent disease over time. In 
addition, gluten-free food options can be scarce, expensive, and low in key nutrients, and
patient anxiety in social situations involving food is common. There is a high unmet need for 
CeD treatments beyond GFD, and multiple agents are being studied for the treatment of CeD
in Phase 2 clinical trials, targeting both immune- and non-immune mediated mechanisms 
[Wungjiranirun, M., et al 2016].
Proline-rich gliadin peptides derived from gluten are deamidated in intestinal submucosa by 
type 2 tTG, which then bind with high affinity to HLA-DQ2.5/DQ8 (~90%/~10% CeD 
patients, respectively) on antigen presenting cells. These HLA-gliadin complexes bind to 
specific gluten-specific T cell receptors expressed by CD4+ T cells in the lamina propria, 
differentiating them towards a pro-inflammatory Th1 phenotype, producing cytokines such 
as IFN-γ, IL-21, and TNF. Within the inflammatory lesion, B cells act as antigen presenting 
cells (APCs) for gliadin-specific T cells and differentiate into plasma cells producing high 
affinity anti-TTG Abs, whose pathogenic significance are not clear, but function as a 
biomarker for disease diagnosis and recent gluten exposure. Activated intraepithelial CD8 
T cells induce further mucosal damage [Jabri, B. 2017].
The HLA-DQ2.5 restricted, gluten-specific Th1 response in CeD is largely driven by a few 
overlapping immunodominant gliadin peptides. Multiple studies have confirmed α-gliadin 
57-73 (Q65E) as a dominant T cell epitope in CeD [Anderson, R. P., et al 2000]. A follow up 
epitope mapping study systematically profiled gliadin peptide libraries consisting of over 
2500 20-aa oligopeptides and identified ω-gliadin W03-E7 as an additional immunodominant 
peptide [Tye-Din, J. A., et al 2010]. Regulatory T cells (Tregs) play an important role in 
maintaining immune tolerance. Treg subsets, including FOXP3+ Tregs (CD4+CD25+IL-
127low) and IL-10 producing Tr1 T cells (CD4+CD49b+LAG3+), can be generated in vitro 
and are being studied in cellular therapy clinical trials for organ transplantation and T1DM.
 
 
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2.3
Benefit/Risk Assessment
Participants in this clinical study will not receive direct benefit from participation.
Risks anticipated for participants in this trial are those related to the gluten challenge, 
venipuncture and biopsy procedures. 
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
This study is to be conducted in male and female participants with celiac disease.
Objectives
Endpoints
Primary
•
To determine the phenotypes of gliadin 
peptide/HLA-DQ2 multimer-positive 
CD4+ T cell subsets in the peripheral 
blood before and after gluten challenge 
and from duodenal biopsies after gluten 
challenge. Estimation: The percentages of 
α-gliadin and ω-gliadin-reactive CD4+ T 
cells expressing known activation and 
inhibitory receptors (including but not 
limited to: CD25 (IL-2R), CD95 (Fas), 
CD279 (PD-1), TGFβ1R, and IL-27R) 
will be estimated.
•
α-gliadin and ω-gliadin-reactive CD4+ T 
cells
Secondary
•
None
Exploratory
•
To estimate the frequency, phenotype, 
and function of effector IFN-γ-producing 
gluten-specific CD4+ T cells (Teff) in the 
peripheral blood before and after gluten 
challenge.
•
effector IFN-γ-producing gluten-specific 
CD4+ T cells (Teff)
 
 
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Objectives
Endpoints
•
To characterize individual single-cell 
gene expression to define T cell receptor 
sequences as well as novel activation and 
inhibitory receptors in blood (pre- and 
post-gluten challenge) and post-gluten 
challenge duodenal biopsies using single 
cell RNA sequencing (scRNA-Seq).
•
single cell RNA sequencing (scRNA-
Seq).
•
To determine the relationship between 
severity of histologic damage on 
duodenal biopsy, celiac disease 
symptoms, and the quantity and quality of 
gluten-specific CD4+ T cell responses 
after gluten challenge.
•
Histology, CDSD, gluten-specific CD4+ 
T cells
•
To estimate the frequency, phenotype, 
and function of blood and duodenal 
gluten-specific CD4+ regulatory T cells 
(Treg) induced after in vitro treatment 
with experimental compounds.
•
gluten-specific CD4+ regulatory T cells 
(Treg)
•
To estimate the frequency, phenotype, 
and function of effector IFN-γ-producing 
gluten-specific CD4+ T cells (Teff) after 
in vitro treatment with experimental 
compounds.
•
effector IFN-γ-producing gluten-specific 
CD4+ T cells (Teff)
•
To estimate the levels of cytokines and 
chemokines in serum before and after 
gluten challenge
•
Serum cytokines and chemokines
•
To explore the relationship between 
genetic variation and response to the 
treatment(s) administered, and 
mechanisms of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected in 
this study.
•
Germline genetic variation
 
 
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4
STUDY DESIGN
4.1
Overall Design
This is a multi-site, open-label gluten challenge study to characterize peripheral blood and 
intestinal gluten-specific CD4+ T cell subsets in patients with CeD. Participants will receive 
8 g gluten daily for 13 consecutive days. Blood samples will be taken at pre-dose, Day 6, and 
Day 14. Duodenal biopsy samples will also be collected on Day 14. Participants will 
complete a symptom diary as described in the SoA.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
Because it is a Phase 1 assessment of a gluten challenge in humans, and the 
pharmacodynamic and safety profiles of a gluten challenge are being evaluated, this protocol 
is written with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical 
studies. Refer to Section 8.11.6 for examples of modification permitted within the protocol 
parameters.
4.2
Scientific Rationale for Study Design
Gliadin-specific CD4+ T cells are infrequent in the blood above background staining by flow 
cytometry in patients with CeD on a GFD [Raki, M., et al 2007]. Gliadin-specific CD4+ T 
cells may be identified by flow cytometry using MHC-gliadin tetramers. After the first three
days of a gluten challenge, gliadin-specific T cells are detectable in the blood on day 6 after 
initial challenge and can therefore be readily identified [Raki, M., et al 2007]. Gliadin peptide 
mixtures can stimulate an IFN-γ enzyme-linked immunospot (ELISPOT) response from 
peripheral blood T cells after gluten challenge [Tye-Din, J. A., et al 2010].  Gliadin-specific 
T cells may also be isolated at ~10-100x higher frequencies from duodenal biopsies after 
gluten challenge [Bodd, M., et al 2013]. A traditional gluten challenge used in clinical 
practice for the diagnosis of CeD may last from 2 to 8 weeks. A biomarker study assessing 
histologic responses at 3 and 14 days after gluten challenge determined that histologic 
changes were more pronounced at 14 days at both dosage levels [Leffler, D., et al 2013]; 
therefore, a 13 day gluten challenge is proposed in order to maximize the feasibility of 
obtaining immune cells in the blood and duodenum on Day 14, as well as to adequately 
replicate the inflammatory milieu for scRNA-Seq analysis. Polyclonal gliadin-specific T cell 
cultures and monoclonal gliadin-specific T cell lines from patients will also be generated for 
long-term use in the laboratory using established protocols.  These assays will be utilized to 
analyze gliadin-specific T cells from patients after gluten challenge.
 
 
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4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
The safety and tolerability of gluten administration and procedures during this study will be 
evaluated by clinical assessment of adverse experiences and other safety measurements. 
Summary statistics for laboratory safety tests and/or vital signs may also be computed, as 
deemed clinically appropriate.
4.2.1.2
Pharmacodynamic Endpoints
Patient responses to gluten challenge will be monitored by symptom assessment using the 
CDSD and by histologic scoring of duodenal biopsies.
4.2.1.3
Planned Exploratory Biomarker Research
4.2.1.3.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.4
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
 
 
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such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research are presented in Appendix 6.
4.3
Justification for Dose
A biomarker study assessing histologic responses at 3 and 14 days after both low-dose 
(3 g/day) and high-dose (7.5 g/day) gluten challenges determined that histologic changes 
were more pronounced at 14 days at both dosage levels [Leffler, D., et al 2013]. Another 
biomarker study determined that a 5.7 g/day gluten challenge administered over 14 days 
resulted in significant increases in circulating gluten-specific T cells and intraepithelial 
lymphocytes on duodenal biopsy, but did not fully establish significant mucosal architectural 
changes in the majority of patients [Sarna, V. K., et al 2018]. An 8 g/day, 13-day gluten 
challenge is proposed in order to maximize the feasibility of obtaining immune cells in the 
blood and duodenum and to replicate the inflammatory milieu for scRNA-Seq analysis. 
As this is a Phase 1 assessment of a gluten challenge in humans, and the pharmacodynamic 
and safety profiles of a gluten challenge are being evaluated, modifications to the dosing 
regimen or study procedures may be required to achieve the scientific goals of the study 
objectives and/or to ensure appropriate safety monitoring of the study participants. Details of 
allowed modifications are provided in Section 8.11.6.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. The overall study end will then not be 
identified until the Sponsor has made the decision to end the study following this review 
period. The Competent Authority(ies) and Institutional Review Board(s)/Independent Ethics 
Committee(s) [IRB(s)/IEC(s)] will be apprised of the maximum duration of the study beyond 
the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
 
 
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5
STUDY POPULATION
Male/Female participants with biopsy-proven CeD between the ages of 18 and 70 years
(inclusive) will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
1. Participant must have documented diagnosis with CeD by duodenal/jejunal biopsy at 
least 6 months prior to entrance into the study.
2. Participant must be on a GFD for at least the past 12 months.
Demographics
3. Participant is male or female.
4. Participant is from 18 years to 70 years of age inclusive, at the time of signing the 
informed consent.
Female Participants
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
-
Is not a WOCBP
OR
-
Is a WOCBP and using an acceptable contraceptive method, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long 
term and persistent basis), as described in Appendix 5 during the intervention period 
and for at least 14 days after the last dose of study intervention. The investigator 
should evaluate the potential for contraceptive method failure (ie, noncompliance, 
recently initiated) in relationship to the first dose of study intervention.
-
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
-
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
 
 
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Informed Consent
6. The participant (or legally acceptable representative if applicable) provides written 
informed consent/assent for the study. The participant may also provide consent/assent 
for future biomedical research. However, the participant may participate in the main 
study without participating in future biomedical research.
Diagnostic Assessments
7. Must be HLA-DQ2.5 positive, assessed at screening. If participants have already been 
genotyped, results from previous testing may be used in lieu of genotyping at screening.
8. Has anti-tTG <2x ULN as measured by serology.
Medical Condition
9.
Be judged to be in good health based on medical history, physical examination (including 
a targeted neurological exam), VS measurements and ECG performed prior to treatment 
allocation. 
10. Have a BMI 18-35 kg/m2, inclusive. See Section 8.3.1 for criteria on rounding to the 
nearest whole number. BMI = weight (kg)/height (m)2.
Other Inclusions
11. Have a negative urinary screen for illicit drugs at screening.
12. Understands study procedures and is willing to comply with trial restrictions (see 
Section 5.3 for a summary of trial restrictions).
13. Be judged to be in good health based on laboratory safety tests obtained at screening. 
Appendix 2 provides a table of laboratory safety tests to be performed, and Appendix 10 
provides an algorithm for the assessment of out of range laboratory values.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has any chronic active GI disease (eg, clinically active CeD despite being on GFD for 
past 12 months, Crohn's disease, ulcerative colitis, lymphocytic colitis). Inactive, 
stable/well-treated lactose intolerance, FODMAP intolerance, GERD, and IBS are 
allowed.
 
 
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2. Has clinically active endocrine, gastrointestinal (other than CeD), cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary, or major 
neurological (including stroke and chronic seizures) abnormalities or diseases. 
Participants with a remote history of uncomplicated medical events or stable medical 
diseases with no symptoms and stable treatment for the past >3 months may be enrolled
in the study at the discretion of the investigator.
3. Is mentally or legally incapacitated, has significant emotional problems at the time of 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder within the last 5 years. Participants who have 
had situational depression may be enrolled in the study at the discretion of the 
investigator.
4. Participant has an eGFR ≤80 mL/min/1.73 m2 at the screening visit based on the 
Cockcroft-Gault (CG) equation below:
Cockcroft-Gault Equation: 
ClCr = (140-age[yr])(body wt [kg])
(72)(serum creat [mg/dL])
When creatinine is measured in micromole/litre, use this formula:
ClCr = (140-age[yr])(body wt[kg])
(72)(serum creatinine [micromol/L] x 0.0113)
For females, multiple the result by 0.85.
At the discretion of the investigator a measured creatinine clearance, as determined by a 
24-hour urine collection, may be used in place of, or in conjunction with, the estimate of 
the creatinine clearance.
Participants who have a measured creatinine clearance of up to 10% below 80 mL/min 
may be enrolled in the study at the discretion of the investigator.
5. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), 
or has had an anaphylactic reaction or systemic allergic reaction to prescription or non-
prescription drugs or food.
6. Subject has a history of severe acute symptomatic reactions to sporadic gluten ingestion.
7. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
8. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
 
 
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Prior/Concomitant Therapy
9. Is on Coumadin™or other anticoagulants. 
10. Is unable to refrain from or anticipates the use of systemic anti-inflammatory, 
immunosuppressive, or immunomodulatory medications, which may include 
ibuprofen > 2400 mg/day, naproxen >750 mg/day, prednisone >10 mg/day, or 
methylprednisolone > 8 mg/day, within 48 hours prior to the start of and throughout the 
entire gluten challenge.
Prior/Concurrent Clinical Study Experience
11. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the prestudy (screening) visit. The window will be derived 
from the date of the last visit in the previous study.
Diagnostic Assessments
12. Has a QTc interval ≥470 msec (for males) or ≥480 msec (for females).
Other Exclusions
13. Is under the age of legal consent.
14. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day. Participants who consume 4 glasses of alcoholic beverages 
per day may be enrolled at the discretion of the investigator. All alcoholic beverages must 
be gluten free.
15. Is a regular user of any illicit drugs or has a history of drug (including alcohol) abuse 
within approximately 6 months. Participants must have a negative UDS at screening.
16. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
17. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Diet Restrictions
Participants will be required to fast at least 8 hours (may be longer if required per site SOP) 
prior to the duodenal biopsy procedure.
The gluten may be consumed with or without a meal.
 
 
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5.3.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours prior to the prestudy and 
poststudy visits. On blood sampling days (ie, Days 1, 6, and 14) participants will refrain from 
consumption of alcohol 24 hours prior to reporting to the CRU and after departing the CRU.
On intermediate days and at all other times, alcohol consumption is limited to no more than 
approximately 3 gluten-free alcoholic beverages or equivalent (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weight lifting, running, 
bicycling, etc.) from the prestudy (screening) visit, throughout the study, and until the 
poststudy visit.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information may be 
included, as outlined in the electronic case report forms (eCRF) entry guidelines. Minimal 
information may include demography, screen failure details, eligibility criteria, and any AEs 
or SAEs meeting reporting requirements.
5.5
Participant Replacement Strategy
If a participant discontinues from study intervention or withdraws from the study a 
replacement participant may be enrolled if deemed appropriate by the investigator and 
Sponsor. The replacement participant will generally receive the same intervention or 
intervention sequence (as appropriate) as the participant being replaced. The replacement 
participant will be assigned a unique treatment/randomization number. The study site should 
contact the Sponsor for the replacement participant’s treatment/randomization number.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Each participant will receive study intervention (gluten) at Visit 2 and is to take the first dose 
that same day. The participant should consume the intervention (gluten) daily for 13 days.
6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in [Table 1].
 
 
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Table 1
Study Interventions
Intervention 
Name
Type
Dose 
Formulation
Dosage 
Level
Route of 
Administration
Regimen/Treatment 
Period
Use
IMP/NIMP
Sourcing
Gluten 
Challenge
Dietary 
substance
Powder
4 g
Oral
BID for 13 consecutive 
days
Challenge 
agent
NIMP
Locally
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
 
 
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All supplies indicated in [Table 1] will be provided per the "Sourcing" column depending 
upon local country operational requirements. If local sourcing, every attempt should be made 
to source these supplies from a single lot/batch number where possible (eg, not applicable in 
the case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
 
 
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management. See Section 7.1 for the compliance threshold requiring 
discontinuation.
Study participants will complete a gluten consumption log to record daily intake of gluten
during the challenge. Sites may also institute a phone or mobile texting plan to remind 
participants to comply with challenge agent intake and return for follow up visits.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study. If there is a clinical indication for any medications or vaccinations
specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy rests with the investigator and/or the 
participant’s primary physician. However, the decision to continue the participant on study 
intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
At the investigator’s discretion, participants may self-administer anti-nausea or anti-diarrheal 
medications (over the counter or prescribed by their own physician) according to the product 
label as needed. These medications will be recorded.
Listed below are specific restrictions for concomitant therapy:
Systemic anti-inflammatory, immunosuppressive, or immunomodulatory medications, which 
may include ibuprofen > 2400 mg/day, naproxen >750 mg/day, prednisone >10 mg/day, or 
methylprednisolone > 8 mg/day.
 
 
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6.5.1
Rescue Medications and Supportive Care
No rescue medications or supportive care are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
At the discretion of the investigator, the dose of gluten may be decreased to 4 g/day for 
participants experiencing severe gastrointestinal symptoms (eg, nausea, vomiting, or diarrhea 
interfering with the participant’s daily activities).
In the event that Day 14 procedures are conducted on Day 13, gluten intended for Day 13 
will not be consumed. 
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. 
6.9
Standard Policies
Not applicable
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment
regimen will still continue to participate in the study as specified in Section 1.3 and Section 
8.1.9, or if available, a protocol clarification letter.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Sections 8.1.9 and 8.11.3.
 
 
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A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.

The participant interrupts study intervention administration during Days 1 through 3 of 
the gluten challenge, or for more than 1 day between Day 4 through Day 13 (or Day 12 if 
endoscopy performed on Day 13) of the gluten challenge.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.

The participant has a confirmed positive serum pregnancy test.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.11. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
 
 
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician .
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 376 mL for males and 384.5 mL for females (Appendix 8).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research.If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate consent is in place.
 
 
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8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to future biomedical research. A copy of the 
informed consent will be given to the participant.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
 
 
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The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 3 months before starting the study.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Participant will consume the gluten challenge agent daily for 13 days at a total daily dose of 
8 g gluten.
 
 
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At Visit 2, participants will consume 4 g of gluten while at the CRU. The participant will be 
provided with the remaining amount of gluten for Day 1 of the challenge as well as the 
gluten for Days 2 to 6 for at home administration. When returning to the CRU on Day 6, 
participants should bring with them their completed gluten consumption log. The participant 
will be provided with gluten for Days 7 to 13 for at home administration. When returning to 
the CRU for Day 14 procedures, participants should bring with them their completed gluten 
consumption log and any gluten that has not been consumed.
8.1.8.1
Timing of Dose Administration
Participants will be encouraged, but not required, to consume the two gluten doses (total 
8 g/day) approximately 6 hours apart, if feasible. Ultimately the timing does not matter to 
achieve the objectives of the study, but consuming the two doses at different times may limit 
undesirable gastrointestinal effects for the participant.
8.1.9
Blood Collection
Blood will be collected at Screening, Predose, Day 6, and Day 14 for safety, 
pharmacodynamic, and biomarker assessments. See Section 1.3 for detailed timing.
8.1.10
Duodenal Biopsy Procedure
After completing the gluten challenge (Day 14), participants will undergo an upper 
endoscopy (esophagogastroduodenoscopy) with biopsies from the duodenal bulb and distal 
duodenum. The clinical evaluation of the participants before the procedure will be according 
to site standard practice. Participants will receive either conscious sedation or medically 
assisted anesthesia according to PI judgement. Participants will fast for at least 8 hours prior 
to the procedure.  Up to 12 duodenal biopsies, including at least 2 from the duodenal bulb,
will be collected using regular biopsy forceps.  Four (4) biopsies, including at least one from 
the duodenal bulb, will be used for histopathological assessment, and the remainder of the 
biopsies will be used for additional pharmacodynamic and biomarker assessments.
8.1.11
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, the participant may 
be asked to return to the clinic (or be contacted) for a poststudy visit as per the number of 
days described in Section 8.11.4 ) to have the applicable procedures conducted. However, the 
investigator may decide to perform the poststudy procedures at the time of discontinuation or 
as soon as possible after discontinuation. If the poststudy visit occurs prior to the safety 
follow-up time frame as specified in Section 8.4.1, the investigator should perform a follow-
up telephone call at the end of the follow-up period (Section 8.4.1) to if any AEs have 
occurred since the poststudy clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
 
 
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8.1.11.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
8.1.12
Participant Blinding/Unblinding
Not applicable
8.1.13
Domiciling
Not applicable
8.1.14
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
Not applicable
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood to be drawn over the course of the study (from 
prestudy to poststudy visits), including approximate blood volumes drawn by visit and by 
sample type per participant, can be found in Appendix 8. The total amount of tissue to be 
collected during the post-challenge duodenal biopsy study, can be found in Appendix 8.
Planned time points for all safety assessments are provided in the SoA.
 
 
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8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. Height and weight 
will also be measured and recorded.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Body Mass Index (BMI)
Body Mass Index equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). Body Mass Index will be rounded to the nearest whole number according to 
the standard convention of 0.1-0.4 round down and 0.5-0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Vital Signs
•
Participants should be resting in a quiet setting without distractions in a semi-recumbent
position for at least 5 minutes prior to having VS measurements obtained.
•
Semi-recumbent VS assessments will include systolic and diastolic BP, HR, RR, and 
temperature.
•
Oral or  tympanic temperature will be assessed.  The same method for measuring body 
temperature should be used throughout the study for each individual participant.
•
BP and HR measurements will be assessed with a completely automated device. Manual 
techniques will be used only if an automated device is not available.
8.3.3
Electrocardiograms
Single 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA. 
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry prior to lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove interfering garments.
Participants should be resting in the semi-recumbent for at least 10 minutes prior to the ECG 
measurement during screening.
The correction formula to be used for QTc is Fredericia.
 
 
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8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
 
 
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
AEs, SAEs, and other reportable safety events that occur after the consent form is signed but 
before intervention allocation/randomization, must be reported by the investigator for 
randomized participants only if the event is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment, or a procedure.
From the time of intervention allocation/randomization through 14 days following cessation 
of intervention, all AEs, SAEs and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the Sponsor 
if the event is considered drug-related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in [Table 2].
 
 
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Table 2
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time Period:
After the Protocol-
specified Follow-up Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
Sponsor:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours of 
learning of event
Pregnancy/
Lactation Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours of 
learning of event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential drug-
induced liver injury 
(DILI)
- require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
Event of Clinical 
Interest (do not require 
regulatory reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 calendar 
days of learning of 
event
Cancer
Report if: 
- due to intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning of 
event
Overdose
Report if: 
- receiving placebo 
run-in or other run-
in medication
Report all
Not required
Within 24 hours of 
learning of event
 
 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply wth country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
 
 
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include: 
1
An overdose of Sponsor's product, as defined in Section 8.5.
2
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must 
trigger an additional evaluation for an underlying etiology. The study site guidance
for assessment and follow up of these criteria can be found in the Investigator Study 
File Binder (or equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug/challenge 
agent administered as part of the trial exceeding the dose prescribed by the protocol. It is up 
to the investigator or the reporting physician to decide whether a dose is to be considered an 
overdose, in consultation with the Sponsor.
8.6
Pharmacokinetics
Not applicable
 
 
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8.7
Pharmacodynamics
8.7.1
Blood and Tissue Samples
Sample collection, storage, and shipment instructions for pharmacodynamic blood (for 
PBMC and cytokine/chemokine assays) and tissue samples (duodenal biopsy) will be 
provided in the operations/laboratory manual.
8.7.2
Duodenal Biopsy Pathology
Biopsy sample slides will be sent to a pathologist for review. The pathology report will 
provide assessments of villus height, crypt depth, villus height/crypt depth ratio, and IEL, 
which are altered as a result of the pathological effects of gluten on the small intestine.  
8.7.3
Celiac Disease Symptom Diary
The CDSD assesses for the presence of symptoms common to CeD over a 24-hour period. 
See the SoA for the timing of assessments. Symptoms assessed in the diary are diarrhea, 
abdominal pain, bloating, nausea, and fatigue. Patients who report a symptom are further 
prompted with 1 to 4 questions to assess severity, duration, frequency, or interference with 
daily activities. [Canestaro, W. J., et al 2016]  
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for genetic analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant signs 
the future biomedical research consent. If the planned genetic analysis is not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for 
the purpose of future biomedical research.
Sample collection, storage, and shipment instructon for planned genetic analysis samples will 
be provided in the operations/laboratory manual.
 
 
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8.9
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
Leftover DNA for future research 
•
Leftover PBMC samples
8.10
Health Economics Medical Resource Utilization and Health Economics
Not applicable
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Up to approximately 4 weeks prior to intervention allocation, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention allocation.
8.11.2
Treatment Period Visits
Participants will be administered the challenge agent on Day 1 and every day for 13 days. In-
clinic visits will occur on Days 1, 6, and 14.
8.11.3
Discontinued Participants Continuing to be Monitored in the Study 
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, a subset of study procedures specified in the SoA may be completed at the discretion 
of the investigator and with Sponsor agreement. The subset of study procedures completed 
will be communicated in a PCL.
8.11.4
Poststudy
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
14 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
 
 
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8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the blood samples for PBMCs and cytokines/chemokines are the critical 
procedure.
All procedures should be completed on the scheduled day per the SoA with the exception of 
the procedures on Day 14 which may be conducted on Day 13 or 15 if needed for scheduling 
purposes. If Day 14 procedures will be conducted on Day 13, gluten intended for Day 13 will 
not be consumed.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This protocol is written with some flexibility to accommodate the inherent dynamic nature of 
Phase 1 clinical studies. Modifications to the dose and laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.
The pharmacodynamic sampling scheme currently outlined in the protocol may be modified 
during the study based on newly available pharmacodynamic data. If indicated, these 
collected samples may also be assayed in an exploratory manner for additional 
pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety and/or pharmacodynamic analyses. 
The total blood volume withdrawn from any single participant will not exceed the maximum 
allowable volume during his/her participation in the entire study (Appendix 8).
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc.) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may employ some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
 
 
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9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 9.2 - 9.9)
9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with Discovery Biology, Translational Biomarkers, and Translational Pharmacology 
Departments of the Sponsor.
If, after the study has begun, changes are made to the statistical analysis plan stated below, 
then these deviations to the plan will be listed, along with an explanation as to why they 
occurred, in the Clinical Study Report.
9.3
Hypotheses/Estimation
This is an estimation study and no formal hypothesis will be tested. Objectives of the study 
are stated in Section 3.
9.4
Analysis Endpoints
Primary Endpoints

Percentage of α-gliadin and ω-gliadin-reactive CD4+ T cells expressing known 
activation and inhibitory receptors (including but not limited to: CD25 (IL-2R), CD95 
(FasR), CD279 (PD-1), TGF1R, and IL-27R)) in the peripheral blood before and 
after gluten challenge and from duodenal biopsies after gluten challenge.
9.5
Analysis Populations
The following population is defined for the analysis and reporting of data. All participants
will be reported, and their data analyzed, according to the intervention(s) they actually 
received. 
All Participants as Treated (APT): The All Participants as Treated Population consists of all
participants who received low-dose gluten challenge at least for one day. This population will 
be used for assessments of safety and tolerability.
Per-Protocol (PP): The Per-Protocol Population consists of the set of data generated by the 
subset of participants who comply with the protocol sufficiently to ensure that these data will 
be likely to exhibit the effects of intervention, according to the underlying scientific model.
Compliance covers such considerations as exposure to intervention (Gluten challenge for 
Day 1 to 13), availability of measurements and absence of important protocol deviations. 
Important protocol deviations will be identified by individuals responsible for data 
 
 
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collection/compliance, and its analysis and interpretation. Any participants or data values
excluded from analysis will be identified, along with their reason for exclusion, in the CSR. 
At the end of the study, all participants who are compliant with the study procedure as 
aforementioned and have available data from at least one intervention will be included in the 
Per-Protocol dataset. This population will be used for all primary and secondary sensitivity 
analyses.
9.6
Statistical Methods
To conduct initial data exploration, summary statistics and plots will be generated as deemed 
clinically appropriate. For primary endpoint, i.e., the percentages of α-gliadin and ω-gliadin-
reactive CD4+ T cells, descriptive summary (mean, standard deviation, median, min, max) 
will be provided.  
In order to assess the association between the primary endpoints and histology (villus height, 
crypt depth, villus height/crypt depth ratio) with a continuous variable (i.e., CDSD 14-days 
mean symptoms, CD4+ cell count, etc.),  appropriate display such as scatter plot will be 
provided and correlation coefficient will be reported.
For CDSD, weekly average will be calculated for each patient for both frequency and 
severity scores of stool (diarrhea and complete spontaneous bowel movement) and non-stool 
symptoms (abdominal pain, bloating, nausea, tiredness). Then data will be summarized 
(mean, standard deviation, median, min, max) at the end of each week. In addition, count and
proportion of patients who did not indicate diarrhea or constipation (i.e., less than 3 complete 
spontaneous bowel movements within a 1-week timeframe) will be provided at each time 
point of interest (Day 7 and Day 14).  
9.7
Interim Analyses
No interim analysis is planned for this study.
9.8
Multiplicity
In this estimation study no multiplicity adjustment is planned.
9.9
Sample Size and Power Calculations
Approximately 15 patients will be enrolled in this study. [Table 3] below provides half-width 
of the 95% CI using t-distribution for selected standard deviation assuming sample size of 
n=15.
 
 
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Table 3
Half width of the 95% confidence interval (CI)
n
Standard Deviation
Half width of the 95% CI
15
5
2.7689
15
6
3.3227
15
7
3.8765
15
8
4.4303
15
9
4.9840
15
10
5.5378
15
11
6.0916
15
12
6.6454
15
13
7.1992
15
14
7.7529
15
15
8.3067
15
16
8.8605
15
17
9.4143
15
18
9.9681
15
19
10.5218
15
20
11.0756
15
21
11.6294
15
22
12.1832
15
23
12.7370
15
24
13.2908
15
25
13.8445
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
 
 
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
 
 
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10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
 
 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
 
 
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contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in [Table 4] will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 4
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with 
Differential (absolute 
values):
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/ SGPT
Total Protein
Glucose fasting
Calcium
Alkaline phosphatase
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
•
HLA Genotyping for Celiac Disease
•
UDS (to include at minimum: amphetamines, barbiturates, cocaine, opiates) 
•
Serology (anti-tTG antibody, HIV antibody, HBsAg, and hepatitis C virus antibody)
•
Serum/urine β hCG pregnancy test (WOCBP only)
•
FSH (as needed for women of nonchildbearing potential only)
•
COVID-19 test
ALT=alanine aminotransferase; AST= aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle 
stimulating hormone; HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; HLA: 
human lymphocyte antigen; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; 
RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase ; SGPT=serum glutamic-pyruvic 
transaminase; UDS=urine drug screen; WBC=white blood cell; WOCBP=women of childbearing potential
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
 
 
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•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
 
 
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f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
 
 
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Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
 
 
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-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
-
If yes, did the AE resolve or improve?
-
If yes, this is a positive dechallenge.
-
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
 
 
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
 
 
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10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
This appendix is not applicable for this study.
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.
Definitions
a Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d DNA: Deoxyribonucleic acid.
e RNA: Ribonucleic acid.
2.
Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways drugs/vaccines may interact with
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.
Summary of Procedures for Future Biomedical Research.
a
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research.
 
 
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b
Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d
Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.
Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
 
 
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5.
Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in outlined in the future biomedical research protocol 
and consent. Future biomedical research specimens remaining with the third party after 
specific analysis is performed will be reported to the Sponsor.
6.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7.
Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
 
 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.
Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.
Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10.
Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11.
Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12.
Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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13.
References
1.
National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.
International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3.
Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4.
Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
This appendix is not applicable for this study.
 
 
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10.8
Appendix 8: Blood Volume and Tissue Collection Tables
Blood Volume
Sample Types Collected
Pre-study
Treatment 
Period
Total 
Collections
mL Per 
Collection
Total mL Per
Test
Laboratory Safety Tests 
1
1
2
10
20
Anti-tTG/ HIV/ Hepatitis 
Screen  
1
--
1
17
17
Serum β-hCG or serum 
FSH (females only)
1
--
1
8.5
8.5
Blood for HLA 
Genotyping for CeD
1
--
1
10
10
Blood for Planned 
Genetic Analysis 
1
--
1
8.5
8.5
Blood for Serum 
Cytokine/Chemokine 
Assay
1
2
3
8.5
25.5
Blood for PBMC
1a
(75 mL 
total)
2a
(110 mL
total)
3
75 & 110
295
Total Blood Volume per Participantb
376 mL for males
384.5 mL for 
females
hCG=human chorionic gonadotropin ; CeD=celiac disease; FSH=follicle stimulating hormone; HLA=human leukocyte 
antigen; PBMC=peripheral blood mononuclear cell
a
Prestudy (Day 1 Predose) sample collection will be 75 mL. Subsequent timepoints (Day 6 and Day 14) will collect 
110 mL.
b
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (not to exceed 
50 mL) may be obtained.
Tissue Collection
Sample Types Collected
Pre-study
Treatment 
Period
Total Collections
Amount Per Collection
Duodenal biopsya
--
1
1
12 samples
a
See Operations Manual for details on biopsy collection amounts.
 
 
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
This appendix is not applicable for this study.
 
 
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1.
The participant may be excluded from the study;
2.
The participant may be included in the study if the abnormal value(s) is not 
clinically significant (NCS) (the investigator must annotate the laboratory value 
“NCS” on the laboratory safety test source document).
3.
The participant may be included in the study if the abnormality is consistent with a 
pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical 
condition should be annotated on the laboratory report.
OR
4.
The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.
If the repeat test value is within the normal range, the participant may enter 
the study.
b.
If the repeat test value is still abnormal, the study investigator will evaluate 
the potential participant with a complete history and physical examination, 
looking especially for diseases that could result in the abnormal laboratory 
value in question. If such diseases can be ruled out, and if the abnormal 
laboratory value is not clinically relevant, then the participant may enter the 
study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
 
 
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
anti-tTG
Anti-Tissue Transglutaminase  
APC
antigen presenting cell
APT
All Participants as Treated
BP
blood pressure
CDSD
Celiac Disease Symptom Diary
CeD
Celiac Disease
CI
confidence interval
CRF
Case Report Form 
CRU
clinical research unit
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EMA
European Medicines Agency
FDAAA
Food and Drug Administration Amendments Act
FODMAP
Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice 
GERD
gastroesophageal reflux disease
GFD
gluten-free diet
HLA
Human leukocyte antigen
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
IBS
Irritable bowel syndrome
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IEL
Intraepithelial lymphocytes (per 100 enterocytes)
IFN
Interferon
IRB
Institutional Review Board 
PP
per-protocol
RNA
ribonucleic acid
RR
respiratory rate
SAE
serious adverse event
scRNA-Seq
single cell RNA sequencing
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
Teff
effector T cells
Tr1
Type 1 regulatory
Treg
regulatory T cells 
tTG
tissue transglutaminase
UDS
urine drug screen
WOCBP
woman/women of childbearing potential 
 
 
05JSX0
07Y6Z6

PRODUCT:  MK-0000  
79
PROTOCOL/AMENDMENT NO.:  402-05  
MK-0000-402-05 FINAL PROTOCOL
17-JUL-2020
11
REFERENCES
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DP, Hill AVS. In vivo antigen challenge in 
celiac disease identifies a single 
transglutaminase-modified peptide as the 
dominant A-gliadin T-cell epitope. Nat Med. 
2000 Mar;6(3):337-42.
056BMX
[Bodd, M., et al 2013]
Bodd M, Raki M, Bergseng E, Jahnsen J, 
Lundin KEA, Sollid LM. Direct cloning and 
tetramer staining to measure the frequency 
of intestinal gluten-reactive T cells in celiac 
disease. Eur J Immunol. 2013;43:2605-12.
056BMZ
[Canestaro, W. J., et al 2016]
Canestaro WJ, Edwards TC, Patrick DL. 
Systematic review: patient-reported outcome 
measures in coeliac disease for regulatory 
submissions. Aliment Pharmacol Ther. 
2016;44:313-31.
056V6L
[Jabri, B. 2017]
Jabri B, Sollid LM. T cells in celiac disease. 
J Immunol. 2017;198:3005-14.
056BN0
[Leffler, D., et al 2013]
Leffler D, Schuppan D, Pallav K, Najarian 
R, Goldsmith JD, Hansen J, et al. Kinetics of 
the histological, serological and 
symptomatic responses to gluten challenge 
in adults with coeliac disease. Gut. 
2013;62:996-1004.
056BN2
[Raki, M., et al 2007]
Raki M, Fallang LE, Brottveit M, Bergseng 
E, Quarsten H, Lundin KEA, et al. Tetramer 
visualization of gut-homing gluten-specific 
T cells in the peripheral blood of celiac 
disease patients. Proc Natl Acad Sci USA. 
2007 Feb 20;104(8):2831-6.
056BN3
[Sarna, V. K., et al 2018]
Sarna VK, Skodje GI, Reims HM, Risnes 
LF, Dahal-Koirala S, Sollid LM, et al. HLA-
DQ:gluten tetramer test in blood gives better 
detection of coeliac patients than biopsy 
after 14-day gluten challenge. Gut. 
2018;67:1606-13.
056BN4
 
 
05JSX0
07Y6Z6

PRODUCT:  MK-0000  
80
PROTOCOL/AMENDMENT NO.:  402-05  
MK-0000-402-05 FINAL PROTOCOL
17-JUL-2020
[Tye-Din, J. A., et al 2010]
Tye-Din JA, Stewart JA, Dromey JA, 
Beissbarth T, van Heel DA, Tatham A, et al. 
Comprehensive, quantitative mapping of T 
cell epitopes in gluten in celiac disease. Sci 
Transl Med. 2010 Jul 21;2(41):41ra51.
056CVW
[Wungjiranirun, M., et al 
2016]
Wungjiranirun M, Kelly CP, Leffler DA. 
Current status of celiac disease drug 
development. Am J Gastroenterol. 2016 
Jun;111:779-86.
056BN5
 
 
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