Assessment of Immune Activation and Tolerance in Celiac Disease During Gluten Challenge
Phase: NA
Conditions: Celiac Disease
Sponsor: Takeda




Title: Assessment of Immune Activation and Tolerance in Celiac Disease During Gluten 
Challenge
NCT Number: NCT03409796
Protocol Approve Date: 06 October 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

TAKEDA PHARMACEUTICALS
PROTOCOL
Assessment of Immune Activation and Tolerance in Celiac Disease During Gluten Challenge
Trial Identifier:
TIMP-GLIA-5001
Compound:
Not applicable
Date:
06 October 2017
Version/Amendment 
Number:
Initial
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TABLE OF CONTENTS
1.0
TRIAL SUMMARY........................................................................................................6
2.0
TRIAL SCHEMATIC .....................................................................................................8
3.0
SCHEDULE OF TRIAL PROCEDURES........................................................................9
4.0
INTRODUCTION.........................................................................................................11
4.1
Background .............................................................................................................11
4.2
Rationale for the Proposed Trial...............................................................................12
4.3
Benefit/Risk Profile .................................................................................................12
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................13
5.1
Hypothesis...............................................................................................................13
5.2
Trial Objectives .......................................................................................................13
5.2.1
Trial Primary Objective......................................................................................13
5.2.2
Trial Secondary Objectives ................................................................................13
5.2.3
Trial Exploratory Objectives ..............................................................................13
5.3
Endpoints.................................................................................................................13
5.3.1
Primary Endpoint...............................................................................................13
5.3.2
Secondary Endpoints..........................................................................................14
5.3.3
Exploratory Endpoints .......................................................................................14
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................15
6.1
Trial Design.............................................................................................................15
6.2
Dose Escalation .......................................................................................................15
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................15
6.3.1
Rationale of Trial Design ...................................................................................15
6.3.2
Rationale for Gluten Dose..................................................................................16
6.3.3
Rationale for Endpoints......................................................................................16
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures ................19
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................19
6.5
Trial Beginning and End/Completion.......................................................................20
6.5.1
Definition of Beginning of the Trial ...................................................................20
6.5.2
Definition of End of the Trial.............................................................................20
6.5.3
Definition of Trial Completion...........................................................................20
6.5.4
Definition of Trial Discontinuation ....................................................................21
6.5.5
Criteria for Premature Termination or Suspension of a Site................................21
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............22
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7.1
Inclusion Criteria .....................................................................................................22
7.2
Exclusion Criteria ....................................................................................................23
7.3
Excluded Medications, Supplements, Dietary Products............................................24
7.4
Diet, Fluid, Activity.................................................................................................24
7.4.1
Diet and Fluid ....................................................................................................24
7.4.2
Activity..............................................................................................................24
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................24
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................25
7.7
Subject Replacement................................................................................................25
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................26
8.1
Clinical Trial Treatment...........................................................................................26
8.1.1
Clinical Trial Treatment Labeling ......................................................................26
8.1.2
Clinical Trial Treatment Inventory and Storage..................................................26
8.1.3
Clinical Trial Treatment Blinding.......................................................................26
8.1.4
Randomization Code Creation and Storage ........................................................26
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................27
8.1.6
Ancillary Supplies..............................................................................................27
9.0
TRIAL PROCEDURES.................................................................................................28
9.1
Administrative Procedures.......................................................................................28
9.1.1
Informed Consent...............................................................................................28
9.1.2
Inclusion and Exclusion Criteria.........................................................................28
9.1.3
Medical History and Demography......................................................................28
9.1.4
Prior and Concomitant Medications ...................................................................28
9.1.5
Assignment of Screening Numbers ....................................................................28
9.2
Trial Treatment Assignment and Administration......................................................29
9.2.1
Assignment to Treatment ...................................................................................29
9.2.2
Gluten Administration........................................................................................29
9.3
Clinical Procedures and Assessments.......................................................................29
9.3.1
Physical Examination.........................................................................................29
9.3.2
Vital Sign Measurements ...................................................................................29
9.3.3
CDSD ................................................................................................................30
9.3.4
Safety Monitoring ..............................................................................................30
9.3.5
Imaging..............................................................................................................30
9.3.6
Endoscopy and Duodenal Biopsy.......................................................................31
9.4
Laboratory Procedures and Assessments..................................................................31
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9.4.1
Serum Chemistry ...............................................................................................31
9.4.2
Hematology .......................................................................................................31
9.4.3
Urine..................................................................................................................32
9.4.4
Pregnancy Testing..............................................................................................32
9.5
Biomarker Samples..................................................................................................32
9.5.1
Confinement ......................................................................................................33
10.0
ADVERSE EVENTS ....................................................................................................34
10.1
Definitions and Elements of AEs .............................................................................34
10.1.1 Serious Adverse Events......................................................................................36
10.1.2 Special Interest AEs...........................................................................................36
10.1.3 Anticipated AEs.................................................................................................36
10.2
AE Procedures.........................................................................................................37
10.2.1 Assigning Severity/Intensity of AEs...................................................................37
10.2.2 Assigning Causality of AEs................................................................................37
10.2.3 Start Date...........................................................................................................38
10.2.4 End Date............................................................................................................38
10.2.5 Pattern of AEs (Frequency)................................................................................38
10.2.6 Action Taken With Trial Treatment....................................................................38
10.2.7 Outcome ............................................................................................................38
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
Liver Function Tests ..........................................................................................39
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....40
11.0
STATISTICAL METHODS..........................................................................................42
11.1
Statistical and Analytical Plans ................................................................................42
11.1.1 Analysis Sets......................................................................................................42
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................42
11.1.3 Safety Analysis ..................................................................................................42
11.1.4 Analysis of Gluten Challenge.............................................................................43
11.2
Determination of Sample Size..................................................................................44
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................45
12.1
Trial-Site Monitoring Visits.....................................................................................45
12.2
Protocol Deviations..................................................................................................45
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................45
13.0
ETHICAL ASPECTS OF THE TRIAL .........................................................................46
13.1
IRB and/or IEC Approval ........................................................................................46
13.2
Subject Information, Informed Consent, and Subject Authorization .........................47
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13.3
Subject Confidentiality ............................................................................................48
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................48
13.4.1 Publication and Disclosure.................................................................................48
13.4.2 Clinical Trial Registration..................................................................................49
13.4.3 Clinical Trial Results Disclosure ........................................................................49
13.5
Insurance and Compensation for Injury....................................................................49
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................50
14.1
Administrative Information......................................................................................50
14.1.1 Trial Contact Information...................................................................................50
14.1.2 INVESTIGATOR AGREEMENT......................................................................51
14.1.3 Trial-Related Responsibilities ............................................................................52
14.1.4 List of Abbreviations .........................................................................................53
15.0
DATA HANDLING AND RECORDKEEPING............................................................54
15.1
CRFs (Electronic and Paper)....................................................................................54
15.2
Record Retention .....................................................................................................54
16.0
REFERENCES..............................................................................................................56
17.0
APPENDICES...............................................................................................................58
LIST OF IN-TEXT TABLES
Table 3.a
Schedule of Trial Procedures................................................................................9
Table 9.a
Primary Specimen Collections ...........................................................................32
LIST OF IN-TEXT FIGURES
Figure 2.a
Trial Schematic....................................................................................................8
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................58
Appendix B
Elements of the Subject Informed Consent.........................................................60
Appendix C
Investigator Consent to the Use of Personal Information ....................................63
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1.0
TRIAL SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. 
35 Landsdowne St, Cambridge, MA 02139 
Compound:
Not applicable
Trial Identifier: TIMP-GLIA-5001
Phase: Not applicable
Protocol Title: Assessment of Immune Activation and Tolerance in Celiac Disease During Gluten Challenge
Trial Design:
This is a randomized, double-blind, 2-part gluten challenge trial in subjects with celiac disease (CeD) who are 
HLA-DQ2.5 and/or HLA-DQ8 positive and have been on a gluten-free diet (GFD) for at least 6 months. Subjects will 
be enrolled until a maximum of approximately 20 complete the gluten challenge with follow up endoscopy.
Trial Primary Objective:
To characterize changes in gluten-specific T cells and pathology in the small intestine with specific focus on 
biomarkers likely to change with therapeutic CeD treatment.
Secondary Objectives:
To assess correlation between gluten-specific blood T cells and standard CeD histological assessments.
To assess changes from Baseline in gluten-specific T cells in blood. 
Trial Subject Population: Subjects will be healthy other than having CeD, as determined by the investigator. Each 
subject in the trial will be aged 18 to 75 years, inclusive, have biopsy-confirmed disease that is clinically inactive with 
negative CeD serology, have followed a GFD for ≥6 months as reported by the subject, and be HLA-DQ2.5 and/or 
HLA-DQ8 positive.
Planned Number of Subjects:
Up to approximately 20 to complete the trial
Planned Number of Sites:
1 to 3
Dose Levels:
Gluten 3 g (Group A, n≤14)
Gluten 10 g (Group B, n≤14)
Route of Administration:
Oral
Duration of Treatment:
14 days
Planned Trial Duration:
Approximately 10 weeks
Main Criteria for Inclusion:
In order to be eligible for trial participation, subjects must: 
1.
Be a man or woman aged 18 to 75 years, inclusive, at the time of the Screening Visit. 
2.
Have a body mass index ≥18 and ≤30 kg/m2 and a body weight >50 kg at the Screening Visit.
3.
Agree to make every effort to avoid pregnancy from the time of signing the informed consent throughout the 
duration of the trial and for at least 3 months after conclusion of trial participation, if the subject is a woman of 
childbearing potential and sexually active with a nonsterilized male partner.
4.
Have well controlled biopsy-proven CeD, compliant with a GFD for ≥6 months preceding Screening, with 
resolution of CeD symptoms, normalization of CeD serology, and in the judgment of the investigator, have 
inactive or minimally-active disease. 
5.
Be HLA-DQ2.5 and/or HLA-DQ8 positive, as assessed at Screening. If subjects have already been genotyped, 
then results from previous testing may be used in lieu of genotyping at Screening.
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Main Criteria for Exclusion:
Subjects must be excluded from the trial if they have:
1.
A history of any abdominal or pelvic surgery <3 months before trial enrollment; prior surgery involving the 
luminal gastrointestinal tract (eg, cholecystectomy, appendectomy, and hysterectomy) are permitted if performed 
>3 months before trial enrollment.
2.
Positive IgA anti-tissue transglutaminase, IgA anti-deamidated gliadin peptide (DGP), and IgG DGP serologies at 
Screening.
3.
Inflammatory gastrointestinal disorders or autoimmune diseases other than CeD or autoimmune thyroid disease.
Main Criteria for Evaluation and Analyses:
The primary endpoint of the trial is change from Baseline in small intestine histology based on standard CeD 
histological assessments (intraepithelial lymphocyte counts and villus height to crypt depth ratio [Vh:Cd] measures).
Secondary endpoints will be assessed through evaluation of the following parameters: 

Correlation between gluten-specific blood T cells and standard CeD histological assessments.

Changes from Baseline in gluten-specific T cells in blood, based on functional assays and/or gluten-specific T cell 
receptor (TCR) staining.
Statistical Considerations:
Overall, a total of approximately 20 subjects will be enrolled and randomly assigned into 1 of 2 groups: 3 g gluten/day 
(Group A, n≤14), or 10 g gluten/day (Group B, n≤14). In Part 1 of the trial, 12 subjects will be randomly assigned into 
each group in a 1:1 ratio. After interim analysis, if a 2-sided paired t-test measuring change from Baseline in Vh:Cd is 
not greater in magnitude than 2.63 in the initial 12 subjects, or if a 2-sided paired t-test measuring change from 
Baseline in T cell markers as measured by tetramers or similar TCR staining reagents (if performed) is not greater than 
2.80, then additional subjects will be enrolled to enter Part 2 of the trial. A paired t-test will be performed comparing 
subjects in groups A and B, and if it is significant at a 5% level, then additional subjects will be enrolled into the group 
with the greater change in Vh:Cd. Otherwise, subjects will be enrolled equally into groups A and B.
Sample Size Justification: 
The number of subjects was selected to detect a change in Vh:Cd and T cell markers with 80% power at the interim 
analysis and with >99% by the final analysis, as well as to allow estimation of biomarker differences for secondary and 
exploratory endpoints. A single analysis with 12 subjects has 92% power to detect a change in Vh:Cd before and after 
gluten challenge, and a 99% power to detect a change in T cell markers. This was converted to a group sequential 
design such that the interim analysis with 12 subjects has 84% power to detect a change in Vh:Cd and 95% power to 
detect a change in T cell markers, for an overall power of 80% for the interim analysis.
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2.0
TRIAL SCHEMATIC
Figure 2.a
Trial Schematic
CeD=celiac disease, 
, 
.
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3.0
SCHEDULE OF TRIAL PROCEDURES
Table 3.a
Schedule of Trial Procedures
Assessment (a) 
Screening
Run-in
Gluten 
Challenge
Follow-up/Early 
Termination
Days 
-28 to -7
Days -6 
to 0
Days 1 to 14
Days 15 to 43
Day
-28 to -7
-6 to 0
1 
(Predose)
6
15
42
43
Hours postdose
4
Location
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic
Administrative Procedures
Informed consent 
X
Inclusion/exclusion criteria
X
Medical history/demographics
X
Prior and concomitant medications
-------------------------------- X ------------------------------------
Treatment Assignment and Administration
Random assignment to trial treatment
X
Gluten dosing (b)
X
X
Clinic Procedures and Assessments
Physical examination
X
X
Heart rate and blood pressure (systolic and 
diastolic)
X
X
Respiratory rate and temperature (oral at the 
floor of the mouth or tympanic)
X
X
Height
X
Weight
X
X
Body mass index
X
Adverse event assessment 
-------------------------------- X ------------------------------------
Endoscopy (d)
X
X
Laboratory Procedures and Assessments
Serum chemistry
X
Hematology
X
Serum pregnancy
X
X (e)
Urine drug screen
X
Footnotes are on last table page.
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Table 3.a
Schedule of Trial Procedures (continued)
Assessment (a) 
Screening
Run-in
Gluten 
Challenge
Follow-up/Early 
Termination
Days 
-28 to -7
Days -6 
to 0
Days 1 to 14
Days 15 to 43
Day
-28 to -7
-6 to 0
1 
(Predose)
6
15
42
43
Hours postdose
4
Location
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic
Clinic
Biomarker Evaluations
Fresh duodenum tissue biopsy (FFPE)
X
X
Frozen duodenum tissue biopsy
X
X
Blood sample for HLA typing
X
Blood sample for immunophenotyping, TCR 
staining, and ELIspot
X
X
X
X
Blood for IgA tTG, IgA DGP, and IgG DGP 
serology
X
X
X
X
Serum sample for protein (cytokines, 
chemokines, other) 
X
X (f)
X
X
X
Blood sample for RNA
X
X (f)
X
X
X
Blood sample for DNA
X
X
X
X
DGP=anti-deamidated gliadin peptide, FFPE=formalin-fixed paraffin embedded, 
 
, TCR=T cell receptor, tTG=anti-tissue transglutaminase, 
(a) Unless otherwise specified, procedures should be performed as close to the day and time indicated as possible.
(b) Gluten will be ingested daily on Days 1 to 14, inclusive, at approximately the same time each day, and without 
regard to food. On Day 1, subjects do not need to be fasting and will take their entire single dose in the clinic after 
predose blood samples have been drawn. On Days 2 through 5 and Days 7 through 14, gluten will be taken by the 
subject at home. On Day 6, gluten may be taken at home or in the clinic.
(c)
 
 
(d) The initial endoscopy can be performed at any time during Run-in before the first gluten dose. The second 
endoscopy can occur at any time on Day 15.
(e) Not needed if ≤7 days since screening pregnancy test. 
(f) Samples taken at predose and 4 hours postdose.
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4.0
INTRODUCTION
Celiac disease (CeD) is a common immunological disorder with an estimated prevalence of 
approximately 0.5% to 1% in different parts of the world [1]. Celiac disease develops in 
genetically predisposed subjects as a consequence of an abnormal T cell response to wheat 
prolamin protein, predominately gliadin, and results in diarrhea, constipation, and other 
gastrointestinal symptoms; increased intestinal permeability, malabsorption, and occult 
gastrointestinal bleeding; and systemic manifestations including secondary autoimmunity, 
infertility, dermatitis herpetiformis, and malignancy [2,3]. 
Clinical trials that include gluten challenge are used to test the effectiveness of therapies designed 
to prevent immune response to gluten in subjects with CeD [4,5]. A variety of serological and 
biopsy-based biomarkers have been used in clinical studies to characterize individual pathological 
constituents of CeD and overall disease progression. 
4.1
Background
Serological biomarkers respond slowly to ongoing changes in the intestine and are better used for 
disease diagnosis rather than as a means to monitor therapeutic changes [6]. Changes in intestinal 
tissue morphology such as measures of villus height to crypt depth ratio (Vh:Cd) and 
intraepithelial lymphocyte (IEL) counts are the standard method for diagnosing and evaluating 
progression of CeD, but require invasive biopsies and do not provide data to help understand the 
underlying mechanisms that mediate these changes. 
Patients with CeD express the major histocompatibility complex (MHC) Class II molecules, 
HLA-DQ2 or HLA-DQ8. These molecules are expressed on antigen-presenting cells (APC) and 
are capable of effectively binding and presenting deamidated gliadin peptides to T cells. Although 
all CeD patients are HLA-DQ2 and/or HLA-DQ8 positive, these proteins are required, but not 
sufficient, for development of disease [7]. In addition, patients must have CD4+ T cells that 
express a T cell receptor (TCR) that binds antigen in the context of these MHC Class II molecules. 
Highly antigenic epitopes of gliadin have been defined and the TCRs that bind these epitopes have 
been sequenced [8]. The genes that encode the TCRs differ, but TCR proteins share common 
sequences that allow them to bind specific gliadin epitopes tightly and respond to antigen 
stimulation by proliferating, producing cytokines, and starting a cascade of events leading to the 
destruction of intestinal villi [9-11]. B cells may also function in this process both as APCs and 
antibody-producing cells [12].
In this clinical trial, a number of different blood and intestinal biomarkers will be evaluated and 
how they change in subjects with CeD after gluten challenge. Included are commonly used 
serological and histological markers as well as newer, less invasive and/or more informative 
methods. The results of this trial will provide a data set that will help design future interventional 
studies in CeD.
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
the applicable regulatory requirement(s).
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4.2
Rationale for the Proposed Trial
This 14-day gluten challenge trial is being conducted to characterize and correlate the number of 
peripheral blood biomarkers, visually assessed macroscopic changes, symptoms, and small 
intestine pathology with a specific focus on markers that are likely to change with CeD treatment. 
The results of this trial will be used to select the biomarker approaches appropriate for future 
clinical development. 
4.3
Benefit/Risk Profile
As this trial does not include a therapeutic arm and will be conducted on otherwise healthy subjects 
with well-controlled CeD, there is no expected clinical benefit to the trial participants. Potential 
risks are based on symptoms related to gluten exposure and testing related to trial endpoints. These 
include the following: 
!
Phlebotomy: there is minimal risk associated with phlebotomy (limited to <500 mL) in 
otherwise healthy adults.
!
Endoscopy with duodenal biopsy: endoscopy with duodenal biopsy is a common 
gastrointestinal procedure. Risks include those related to procedural sedation, the endoscopic 
procedure, and the biopsies. Cumulatively, the risks of upper endoscopy are estimated to be 
<0.5% (Complications of diagnostic colonoscopy, upper endoscopy, and enteroscopy [13]. All
subjects enrolled in this study will have undergone at least 1 previous uncomplicated 
endoscopy with biopsy. Clinical evaluation of subjects before endoscopy will be completed 
according to established site protocols.
!
!
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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
Peripheral T cell markers can be used to accurately evaluate CeD activity after a gluten challenge 
of 3 g gluten/day for 3 days.
5.2
Trial Objectives
5.2.1
Trial Primary Objective
The primary objective of the trial is to characterize changes in gluten-specific T cells and 
pathology in the small intestine with specific focus on biomarkers likely to change with 
therapeutic CeD treatment.
5.2.2
Trial Secondary Objectives
The secondary objectives of this trial are as follows:
!
To assess correlation between gluten-specific blood T cells and standard CeD histological 
assessments.
!
To assess changes from Baseline in gluten-specific T cells in blood. 
5.2.3
Trial Exploratory Objectives
5.3
Endpoints
5.3.1
Primary Endpoint
The primary endpoint of the trial is change from Baseline in small intestine histology based on 
standard CeD histological assessments (IEL counts and Vh:Cd measures).
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5.3.2
Secondary Endpoints 
Secondary endpoints are as follows: 
!
Correlation between gluten-specific blood T cells and standard CeD histological assessments.
!
Changes from Baseline in gluten-specific T cells in blood, based on functional assays and/or 
gluten-specific TCR staining. 
5.3.3
Exploratory Endpoints
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
This is a randomized, double-blind, 2-part gluten challenge trial in subjects with CeD who are 
HLA-DQ2.5 and/or HLA-DQ8 positive and have been on a gluten-free diet (GFD) for at least 
6 months. Subjects will be enrolled until a maximum of approximately 20 subjects complete the 
gluten challenge and follow-up endoscopy. 
The trial will consist of 4 periods: Screening (Days -28 to -7), Run-in (Days -6 to 0), Gluten 
Challenge (Days 1-14, inclusive), and Follow-up (Days 15-43). 
After signing the informed consent form (ICF), subjects will be enrolled and randomly assigned to 
1 of 2 treatment groups: 3 g gluten/day or 10 g gluten/day. Both groups will be treated concurrently. 
Subjects receiving 10 g gluten/day will be able to reduce their dose to 3 g gluten/day after Day 3 if 
needed because of severity of symptoms. Dose reduction will be managed by an unblinded 
qualified staff member not directly involved in the treatment or clinical evaluation. A complete 
gluten challenge requires that at least 12 of the 14 doses of gluten are taken before the follow-up 
endoscopy.
Subjects will be genotyped at Screening. If a subject has already been genotyped, results from 
previous testing may be used in lieu of genotyping at Screening. Symptoms will be measured daily 
by subjects using the CDSD. During Run-in, each subject will undergo a single, traditional 
endoscopy, and blood sampling to establish baseline values. 
 
During Gluten Challenge, all subjects will undergo periodic blood sampling. The 
day after completion of the gluten challenge,
 
 Endoscopy will include video when 
feasible. During Follow-up, subjects will complete the CDSD, provide an additional blood sample, 
and undergo periodic
.
6.2
Dose Escalation
Not applicable.
6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale of Trial Design 
The design of this trial will allow identification of blood and tissue changes induced by gluten 
challenge that occur as a result of CeD. Expected in most subjects are changes in blood cell 
numbers and types and cytokines and proteins, intestinal changes in the types and number of 
infiltrating cells, and changes in the intestinal epithelium that are visible 
.
6.3.1.1
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6.3.1.2
Rationale for Biomarkers
The sponsor is exploring compounds for which the mechanism of action is to reduce/eliminate the 
gluten-specific effector T cell response and induce T cell tolerance. The biomarkers chosen for this 
trial will allow profiling of the inflammatory changes that occur in the small intestine as gluten 
induces an immune response, and to correlate these changes with those occurring in the blood. 
This set of markers will inform future studies in the sponsor’s CeD program. 
The sponsor will conduct future biomedical research on specimens collected during this trial. This 
research may include genetic analysis (DNA), gene expression profiling (RNA), proteomics, 
metabolomics, and/or measurements of other analytes.
6.3.2
Rationale for Gluten Dose 
The gluten doses are expected to be high enough to elicit an acute immune response in most 
subjects with tolerable symptoms [6]. The 3 g gluten/day dose level was selected based on 
published reports [5,6] that show similar dose levels are tolerable and result in histological changes 
in the small intestine; however, other studies have suggested a dose response in histological 
changes [12]. The 10 g gluten/day dose level was selected to increase the chances of seeing 
detectable levels of gluten-specific T cells in the blood. Both groups will be treated concurrently.
6.3.3
Rationale for Endpoints
6.3.3.1
Primary Endpoint: Histological Assessments
Gluten challenge followed by endoscopic biopsy of the duodenum and calculation of the Vh:Cd, 
coupled with enumeration of the number of IELs per 100 enterocytes, is a standard method for 
diagnosing CeD, especially in subjects compliant with a GFD [6]. The IELs include cytotoxic 
CD8+ T cells that increase with gluten exposure and may mediate epithelial damage [14]. Change 
in Vh:Cd is a measure of the epithelial damage, specifically of villus atrophy and compensatory 
crypt hyperplasia [15]. 
In this trial, 8 biopsies will be taken per endoscopy and used for histology and other analyses, 
which may include 12-marker IHC and transcriptional analysis. An experienced gastrointestinal 
pathologist will act as a central reader and perform all assessments, for example, Vh:Cd and 
QMarsh semiquantitative assessment. Some samples may be archived and used for future 
biomedical research.
6.3.3.2
Secondary Endpoint: T cell Markers
One approach to measuring drug response in future interventional clinical trials in subjects with 
CeD is to quantify changes in the number or function of gluten-specific T cells either directly using 
ELISpot or staining gluten-specific TCR, or alternatively indirectly using TCR sequencing 
(Section 6.3.3.3) [16]. In this trial, assay sensitivity to gluten treatment and technical feasibility of 
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each assay will be evaluated to make an informed decision on how to use these assays in future 
trials. 
Functional T Cell Marker (Blood Only)
To measure T cell function, an ELISpot assay that will evaluate gluten-specific T cell cytokine 
production (such as IL-10 and interferon-γ [INF-γ]) may be used. This assay has been used by 
others to characterize T cell responses to gluten in CeD [17]. For the purposes of this trial, this 
assay shows a functional T cell response. In comparison, fluorescently labeled TCR-staining 
reagents (such as tetramers/dextramers) show T cell binding to gluten in the context of MHC class 
II, but do not predict the results of downstream signaling; TCR profiling shows only the expansion 
of subsets of T cells with specific TCR associated with gluten binding. The ELISpot assay will be 
correlated with TCR staining and/or TCR profiling to get a clearer picture of antigen-specific T 
cell changes after gluten challenge. 
Antigen-Specific T Cells (Flow Cytometry Gluten-Specific–TCR Staining Reagents [Blood]) 
Flow cytometry may be used for identifying and quantifying gluten-specific CD4+ T cells using 
specific gluten-derived antigens bound to MHC Class II molecules. Either dextramers or tetramers 
may be used. Dextramers have a function similar to tetramers but tend to have higher affinity for 
the TCR because unlike tetramers, which are composed of 4 MHC Class II molecules, dextramers
are composed of 10 or more MHC Class II molecules on a dextran backbone.
6.3.3.3
Exploratory Endpoints (Biomarkers)
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6.3.3.4
Future Biomedical Research (Unplanned Exploratory Biomarker Research) 
Archival biopsy (FFPE and frozen tissue), blood cells, serum, RNA, and DNA may be stored and 
assessed for additional biomarkers.
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures 
For this trial, the critical procedure is endoscopy performed before and after gluten challenge. 
Endoscopy can be performed any day during Run-in before gluten challenge and anytime on 
Day 15 after gluten challenge. In addition, 4 hours after gluten dosing on Day 1, blood will be 
collected for transcriptional analysis and analysis of serum cytokines and other proteins. 
 will 
be performed as described in Section 9.3.5.1.
!
All other procedures should be completed as close as possible, either before or after the 
prescribed/scheduled time.
!
The order of priority can be changed during the trial with joint agreement of the investigator 
and the sponsor.
!
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is an assessment of gluten challenge in humans with CeD. This protocol is written with some
flexibility to accommodate the exploratory nature of this clinical trial. As such, some alterations 
from the currently outlined dose may be permitted based on newly available data, but the 
maximum daily dose detailed in Section 4.1 may not exceed those currently outlined. 
Modifications to the dose of gluten, dosing regimen, and/or clinical or laboratory procedures may 
be required to achieve the scientific goals of the trial objectives and/or to ensure appropriate safety 
monitoring of the trial subjects. Modifications may include the following:
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!
Decrease in the dose of gluten administered.
!
Additional subjects may be added after the interim analysis so that there are 20 subjects who 
complete the gluten challenge and second endoscopy.
!
Decrease in the duration of gluten administration (eg, number of days).
!
 
The sampling scheme currently outlined in the protocol may be modified during the trial based on 
newly available data. If indicated, these collected samples may also be assayed in an exploratory 
manner for additional biomarkers.
Up to an additional 50 mL of blood may be drawn for biomarker analyses. This may include repeat 
samples or modified time points based on emerging data. The total blood volume withdrawn from 
any single subject will not exceed the maximum allowable volume during his/her participation in 
the entire trial. 
The timing of planned procedures for assessment of safety procedures (eg, vital signs, safety 
laboratory tests) currently outlined in the protocol may be modified during the trial based on newly 
available safety or tolerability data. These changes will not increase the number of trial procedures 
for a given subject during his/her participation in the entire trial. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information (eg, adding creatinine kinase to serum chemistry panel that was 
already drawn). 
It is understood that the current trial may employ some or none of the alterations described above. 
Any alteration made to this protocol to meet the trial objectives must be detailed by the sponsor in 
a letter to the Trial File and forwarded to the investigator for retention. The letter may be
forwarded to the Institutional Review Board (IRB)/Institutional Ethics Committee (IEC) at the 
discretion of the investigator.
6.5
Trial Beginning and End/Completion
6.5.1
Definition of Beginning of the Trial
The overall trial begins when the first subject signs the trial ICF.
6.5.2
Definition of End of the Trial
The overall trial ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit (this can be a phone contact), discontinues from the 
trial, or is lost to follow-up (ie, the investigator is unable to contact the subject).
6.5.3
Definition of Trial Completion
The trial will be considered completed for each subject after they attend the last planned or 
follow-up visit/interaction associated with a planned visit (this can be a phone contact), 
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discontinue from the trial, or are lost to follow-up (ie, the investigator is unable to contact the 
subject).
6.5.4
Definition of Trial Discontinuation
Trial discontinuation may occur because of nonsafety reasons, such as:

A finding (eg, biologic targets) from another nonclinical or clinical trial using the trial 
treatment(s). 

Data from methodology(ies) used in this trial become available. 

Low enrollment.
Early trial termination may occur because of unanticipated concerns of safety to the trial subjects 
arising from clinical or nonclinical trials with the trial treatment(s), or methodology(ies) used in 
this trial.
6.5.5
Criteria for Premature Termination or Suspension of a Site
6.5.5.1
Criteria for Premature Termination or Suspension of a Site 
The trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the trial, or as otherwise permitted by the contractual agreement.
6.5.5.2
Procedures for Premature Termination or Suspension of a Site
In the event that the sponsor, an IRB, or regulatory authority elects to terminate or suspend the trial 
or the participation of an investigational site, a trial-specific procedure for early termination or 
suspension will be provided by the sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or trial suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must:
1. Understand the trial procedures and agree to participate by providing written informed 
consent.
2. Be willing and able to comply with all trial procedures and restrictions.
3. Be a man or woman aged 18 to 75 years, inclusive, at the Screening Visit. 
4. Have a body mass index (BMI) ≥18 and ≤30 kg/m2 and a body weight >50 kg at the Screening 
Visit.
5. Be a nonsmoker who has not used tobacco- or nicotine-containing products (eg, nicotine 
patch) for at least 6 months before Day 1 gluten administration.
6. Be judged to be in good health by the investigator, based on clinical evaluations including 
laboratory safety tests, medical history, physical examination, and vital sign measurements 
performed at the Screening Visit and before random assignment to trial treatment.
7. Agree to make every effort to avoid pregnancy from the time of signing the informed consent 
throughout the duration of the study and for at least 3 months after conclusion of study 
participation, if is a woman of childbearing potential and sexually active with a nonsterilized 
male partner.
a) A woman is considered a woman of childbearing potential if she is fertile following 
menarche until becoming postmenopausal or permanently sterile. Permanent sterilization 
methods include hysterectomy and bilateral oophorectomy. 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 (FSH >40 IU/L) 
may be used to confirm a postmenopausal state in younger women (eg, those <45 years 
old) or women who are not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient.
b) Standard methods of birth control are acceptable and may include hormonal contraceptives, 
true sexual abstinence, use of female and male condoms together, or 
cap/diaphragm/sponge without spermicide and without condom.
8. Have well-controlled biopsy-proven CeD, compliant with a GFD for ≥6 months preceding 
Screening, with resolution of CeD symptoms, normalization of CeD serology, and in the 
judgment of the investigator, have inactive or minimally-active disease. 
9. Be HLA-DQ2.5 and/or HLA-DQ8 positive, assessed at Screening. If subjects have already 
been genotyped, results from previous testing may be used in lieu of genotyping at Screening.
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10. Be willing to delay a planned procedure involving the use of powerful electromagnetic fields 
(eg, magnetic resonance imaging), 
.
11. Not undergo 
 if has an implanted electromedical device or a swallowing disorder.
12. Not undergo 
 if has a contraindication to the device or procedure as per reference 
information.
7.2
Exclusion Criteria
Subjects must be excluded from the trial if they meet any of the following criteria: 
1. Have a history of clinically significant endocrine, cardiovascular, hematological, hepatic, 
immunological (other than CeD or autoimmune thyroid disease), renal, respiratory, 
genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or 
disease.
2. Have participated in another investigational trial within 4 weeks before Screening. The 4-week 
window will be derived from the date of the last previous trial procedure and/or any adverse 
event (AE) related to the previous trial, to the Screening Visit of the current trial. 
3. Are an employee or immediate family member (eg, spouse, parent, child, or sibling) of the 
sponsor.
4. Have a history of cancer (malignancy) other than nonmelanoma skin cancer.
5. Have a history of significant multiple and/or severe allergies (eg, latex allergy).
6. Are a woman who is lactating/breastfeeding.
7. Have had major surgery and/or donated or lost 1 unit of blood (approximately 500 mL) within 
8 weeks before the first dose of gluten.
8. Are unable to refrain from or anticipate the use of any unapproved medication, including 
prescription drugs, nonprescription drugs, and herbal remedies, beginning approximately 
7 days before administration of the initial dose of gluten and continuing throughout the trial 
until the Follow-up Visit. There may be certain medications that are permitted, as described in 
Section 9.1.4.
9. Consume excessive amounts of coffee, tea, cola, energy drinks, or other caffeinated beverages 
per day. An excessive amount is defined as greater than 6 servings (1 serving is approximately 
equivalent to 120 mg of caffeine).
10. Have a positive drug screen. 
11. Have a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
consumption exceeding 2 standard drinks per day on average (1 glass is approximately
equivalent to: 354 mL/12 ounces of beer, 118 mL/4 ounces of wine, or 29.5 mL/1 ounce per 
day of distilled spirits. 
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12. Have a history of any abdominal or pelvic surgery <3 months before trial enrollment; prior 
surgery involving the luminal gastrointestinal tract (cholecystectomy, appendectomy, and 
hysterectomy) are permitted if performed >3 months before trial enrollment.
13. Have positive IgA tTG, IgA DGP, and IgG DGP serologies at Screening.
14. Have inflammatory gastrointestinal disorders or autoimmune diseases other than CeD or 
autoimmune thyroid disease.
15. Have known or suspected gastrointestinal obstructions, strictures, or fistulas based on the 
clinical picture or pre-procedure testing and profile of the 
.
16. Endoscopy and intestinal biopsy are contraindicated.
7.3
Excluded Medications, Supplements, Dietary Products
Subjects should avoid excessive use of steroids, immunosuppressants, and anticoagulants 
beginning approximately 7 days before administration of the initial dose of gluten, and continuing 
throughout the trial until the last Follow-up Visit.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
Subjects must abstain from significant alcohol use throughout the trial. Significant alcohol use is 
defined as >1 drink/day, equal to 12 oz. beer, 5 oz. wine, or 1.5 oz. liquor.
Subjects must fast for at least 8 hours before endoscopy, 
. Otherwise, subjects will 
continue their normal GFD throughout the duration of the trial, with the addition of trial gluten.
7.4.2
Activity
Subjects will be instructed to avoid unaccustomed strenuous physical activity for 24 hours after 
endoscopy.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
Subjects should be discontinued or withdrawn from the trial in the event of any of the following:
1. Any clinical features of CeD are reported to be of a serious nature (Section 10.1.1).
2. The subject experiences an AE that requires early termination because continued participation 
imposes an unacceptable risk to the subject’s health or the subject is unwilling to continue 
because of the AE. 
3. Confirmed pregnancy as evidenced by a positive pregnancy test.
4. Significant protocol deviation. The discovery that the subject failed to meet protocol entry 
criteria or did not adhere to protocol requirements, or continued participation poses an 
unacceptable risk to the subject’s health.
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5. Lost to follow-up. The subject did not return to the clinic, and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documentation.
6. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the trial. The reason for withdrawal, if provided, should be recorded in the 
electronic case report form (eCRF). 
7. Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal because of 
an AE should not be recorded in the “voluntary withdrawal” category).
8. Trial termination. The sponsor or regulatory agency terminates the trial.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s trial participation at any time during the trial when 
the subject meets the trial termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the trial. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit.
7.7
Subject Replacement
Subjects who withdraw or are withdrawn from the trial, or who have severe villus atrophy on 
initial duodenal biopsy, may be replaced in order to have 6 subjects completing each group. The 
trial site should contact the sponsor for the replacement of subject’s treatment assignment and 
allocation number.
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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
8.1
Clinical Trial Treatment 
Details regarding the composition and extemporaneous preparation of the gluten packets are found 
in trial site procedural documents and/or similar documents. Clinical trial gluten will be packaged 
to support enrollment and replacement subjects as required. When a replacement subject is 
required, the sponsor needs to be contacted before dosing.
8.1.1
Clinical Trial Treatment Labeling
Clinical trial gluten packaging will be affixed with a clinical label in accordance with regulatory 
requirements.
8.1.2
Clinical Trial Treatment Inventory and Storage
Clinical trial treatment material must be stored in a secure, limited-access location under the 
storage conditions specified on the label. Inventory (receipt and dispensing) of trial treatment must 
be recorded by an authorized person at the trial site.
8.1.3
Clinical Trial Treatment Blinding
This is a double-blind study; therefore, the subject, the trial site personnel, and the sponsor’s staff 
who are involved in the treatment or clinical evaluation are blinded to treatment or intervention. 
Certain sponsor staff not directly involved with the treatment or evaluation may be unblinded to 
the treatment or intervention.
Gluten will be prepared by the trial site. The investigator will receive blind information on the 
subject’s gluten doses in the form of sealed envelopes that will reveal the subject’s trial treatment 
if opened. The site-designated trial personnel will maintain the gluten dose blind information. 
During regularly scheduled monitoring visits, a trial monitor from the sponsor or a designee will 
perform an inventory of all trial treatment unassigned and assigned treatment packages, sealed 
envelopes, and/or tear-off labels. All treatment packages will be reconciled and returned to the 
sponsor or a designee before trial closure.
The gluten dosage level blind is maintained through a randomization schedule held by designated 
personnel.
8.1.4
Randomization Code Creation and Storage 
Subjects will be assigned a unique randomization sequence number and the appropriate amount of 
gluten for their cohort treatment group according to the randomization schedule generated by the 
sponsor’s randomization personnel or designee. Subject randomization will be in blocks and 
stratified by site. All randomization information will be stored in a secure area, accessible only by 
authorized personnel.
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8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure
A designated, unblinded qualified staff member not directly involved in the treatment or clinical 
evaluation can unblind a subject.
8.1.6
Ancillary Supplies
All ancillary supplies will be provided by the site, the sponsor, or a sponsor-designated contract 
research organization (CRO), based upon availability. If provided by the sponsor or a CRO, 
unused ancillary supplies will be accounted for and disposed of as directed by the sponsor or a 
designee.
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9.0
TRIAL PROCEDURES
The following sections describe the trial procedures and data to be collected as indicated in the 
Schedule of Trial Procedures (Section 3.0). For each procedure, subjects are to be assessed by the 
same investigator or site personnel whenever possible. Please note that it may become necessary to 
perform the following procedures at unscheduled time periods, per the discretion of the 
investigator. For information regarding procedures that are scheduled concurrently, see 
Section 6.3.4.
9.1
Administrative Procedures
9.1.1
Informed Consent 
Informed consent must be obtained before the subject enters into the trial and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in Section 13.2. 
In the case where subjects have screening assessments performed before the trial, the data from the 
general/site screening could be included/used in the trial for those who were enrolled, as long as 
the procedure was performed within the protocol screening/enrollment window. A generic site 
screening form may be used.
9.1.2
Inclusion and Exclusion Criteria
Each subject is to be assessed according to the eligibility criteria provided in Section 7.0.
9.1.3
Medical History and Demography
Qualified site personnel are to collect significant medical history and demographic information 
from each subject (past and ongoing) per the site’s standard of care and appropriate clinical 
judgment.
9.1.4
Prior and Concomitant Medications
Medications are defined as prescription and over-the-counter drugs, vitamin supplements, 
nutraceuticals, and oral herbal preparations. Qualified site personnel are to conduct ongoing 
review of medication use during the trial.
9.1.5
Assignment of Screening Numbers 
All consented participants will be given a unique screening number that will be used to identify the 
participant for all procedures that occur before allocation. Screening numbers must not be re-used 
for different subjects. Any subject who is screened multiple times will be assigned a new screening 
number for each screening event.
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9.2
Trial Treatment Assignment and Administration
9.2.1
Assignment to Treatment
Eligible subjects will be randomly assigned to treatment with high or low dose gluten in a 1:1 
fashion.
9.2.2
Gluten Administration
9.3
Clinical Procedures and Assessments
Unless otherwise specified, procedures should be performed as close to the day indicated as 
possible. 
9.3.1
Physical Examination
Qualified site personnel will conduct physical examinations.
9.3.2
Vital Sign Measurements
Subjects should rest in a semirecumbent position for at least 5 minutes before having vital sign 
measurements obtained. The same method (eg, same and appropriately sized cuff, manual, or 
automated) must be used for all measurements for each individual subject and should be the same 
for all subjects. 
9.3.2.1
Heart Rate and Blood Pressure
Heart rate and systolic and diastolic blood pressure will be assessed according to the clinical site’s 
standard procedure.
9.3.2.2
Respiratory Rate and Temperature
Respiratory rate will be assessed according to the clinical site’s standard procedure. Body 
temperature will be measured with an oral (temperature taken at floor of the mouth) or tympanic 
thermometer. The same method (eg, oral or tympanic) must be used for all subsequent 
measurements for each individual subject and should be the same for all subjects.
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9.3.2.3
Height
Height will be obtained with the subject’s shoes off and jacket or coat removed.
9.3.2.4
Weight
Body weight will be obtained with the subject’s shoes off and jacket or coat removed.
9.3.2.5
BMI
BMI equals a person’s weight in kilograms divided by height in meters squared (BMI=kg/m2). 
This measurement will be rounded to the nearest whole number according to the standard 
convention of rounding down for 0.1 to 0.4 and rounding up for 0.5 to 0.9.
9.3.3
CDSD
Subjects will use the CDSD daily throughout the trial to record any symptoms. Instructional details 
will be provided in a procedures manual.
9.3.4
Safety Monitoring
Safety will be assessed by monitoring trial related AEs and vital signs. 
AE monitoring begins after signing of informed consent. Changes in subject health status from 
baseline assessment to gluten administration should be captured in the subject’s medical history. A 
complete description of AE collections and procedures is provided in Section 10.0.
9.3.5
Imaging
Subjects must fast for at least 8 hours before 
.
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9.3.6
Endoscopy and Duodenal Biopsy
Subject preparation and preprocedure testing should be completed according to established site 
protocols. The initial endoscopy can be performed at any time during the Run-in period weeks 
before the first gluten dose. The second endoscopy can occur at any time on Day 15.
Subjects must fast for at least 8 hours before endoscopy and avoid unaccustomed strenuous 
physical activity for 24 hours afterward.
9.4
Laboratory Procedures and Assessments
Approximately 450 mL of blood will be drawn over the course of the entire trial. 
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Endoscopic procedures will be performed after a minimum 8-hour overnight fast on the days 
stipulated in Table 3.a.
9.4.1
Serum Chemistry
Serum chemistry evaluations will consist of the following:
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Blood urea nitrogen
Calcium
Bicarbonate
Chloride
Creatinine
Glucose
γ-Glutamyl transferase
Sodium
Potassium
Bilirubin (total), will be fractionated if above the upper limit of 
normal
Protein (total)
IgA tTG, IgA DGP, and IgG DGP serology
9.4.2
Hematology
Hematology assessments will consist of the following tests:
Erythrocytes (red blood cells)
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells) with absolute differential
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9.4.3
Urine
A urine drug screen will include the following tests: 
Amphetamines
3,4-methylenedioxy-methamphetamine (MDMA)
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
9.4.4
Pregnancy Testing
Women of childbearing potential will undergo pregnancy testing during Screening. An additional 
test will be conducted on Trial Day -6 if it has been more than 7 days since the last pregnancy test.
9.5
Biomarker Samples
Histological assessments will be performed on biopsied tissue. Table 9.a provides collection 
parameters for primary specimens.
Table 9.a
Primary Specimen Collections
Specimen Name in Schedule of 
Procedures
Primary 
Specimen
Primary 
Specimen 
Derivative 1
Primary 
Specimen 
Derivative 2
Description of 
Intended Use
Sample 
Collection
Fresh duodenum tissue biopsy
Fresh 
duodenum 
tissue
FFPE Block
FFPE Slides
DNA
RNA
Biomarker 
measurements
Mandatory
Frozen duodenum tissue biopsy
Frozen 
duodenum 
tissue
Biomarker 
measurements
Mandatory
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9.5.1
Confinement
Subjects will report to the trial site as specified in Table 3.a. No overnight confinement is planned.
On Day 1, subjects will need to be available for blood collection 4 hours after receiving the first 
dose of gluten. 
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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a trial; it does not necessarily have to have a causal 
relationship with the treatment (eg, gluten challenge).
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a treatment, 
whether or not it is considered related to the treatment. Anticipated symptoms related to gluten 
exposure that do not meet serious criteria are not considered to be AEs.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of trial treatment or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or electrocardiogram [ECG] findings) or symptoms should NOT 
be recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, x-ray) should NOT be recorded as an AE unless related to 
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a trial procedure. However, if the subject experiences a worsening or complication of such a 
concurrent medical history condition, the worsening or complication should be recorded 
appropriately as an AE (worsening or complication occurs after informed consent is signed). 
Investigators should ensure that the event term recorded captures the change in the condition 
(eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
trial treatment or after any change in trial treatment, the worsening or complication should be 
recorded as a new AE. Investigators should ensure that the AE term recorded captures the 
change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in trial treatment, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as 
an emergency) because of a worsening of the pre-existing condition, the worsening of the 
condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
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10.1.1 Serious Adverse Events
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.
!
The term “life threatening” refers to an event in which the subject was at risk of death at the
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
!
May require intervention to prevent items 1 through 5 above.
!
May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (Section 10.2.8.3).
10.1.2 Special Interest AEs
Not applicable.
10.1.3 Anticipated AEs
While AEs are anticipated to occur due to the underlying disease, gluten challenge, use of the 
, or use of 
 in the population studied under this protocol, this 
information does not waive the investigator’s obligation to report all SAEs (including anticipated 
SAEs) as described in Section 10.2.8.3. AEs that may be anticipated include the following:
!
Signs and/or symptoms of CeD, including gastrointestinal symptoms not described in the 
CDSD and extraintestinal manifestations such as skin rash, neurological/neurocognitive 
manifestations, elevation in liver function tests, and joint pain. Note: symptoms collected 
through the CDSD, including diarrhea, constipation, bowel movement frequency, abdominal 
pain, bloating, nausea, and fatigue should not be reported as AEs unless these events become 
serious.
!
Risks associated with the 
 retention 
and aspiration (if applicable) and any additional complications associated with medical, 
endoscopic, or surgical intervention necessary to address such complications (reference 
information provided in the study procedures manual).
CCI
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!
Complications associated with devices or procedures of endoscopy, intestinal biopsy, and 
procedural sedation. Refer to local clinical guidelines for information on these complications.
!
Risks associated with the use of the 
device or procedure of as per reference information 
(study procedures manual)
These anticipated AEs reflect the natural history of CeD, the response of patients with CeD to 
gluten challenge, and the use of devices or procedures as they are known at the time of issuance of 
this protocol and may change with accumulation of additional data. Any changes to anticipated 
AEs will be communicated to the relevant stakeholders as per regulatory requirements.
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
10.2.2 Assigning Causality of AEs
The relationship of each AE to trial treatment will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
trial treatment (including the course after withdrawal of the treatment), or for 
which a causal relationship is at least a reasonable possibility, that is, the 
relationship cannot be ruled out, although factors other than the treatment, such 
as underlying diseases, complications, concomitant drugs and concurrent 
treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a treatment and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications, and concurrent 
treatments.
CCI
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10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.4 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5 Pattern of AEs (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6 Action Taken With Trial Treatment

Treatment withdrawn: a trial treatment is stopped because of the particular AE.

Dose not changed: the particular AE did not require stopping a trial treatment.

Unknown: only to be used if it has not been possible to determine what action has been taken.

Not applicable: a trial treatment was stopped for a reason other than the particular AE eg, the 
trial has been terminated, the subject died, dosing with trial treatment had not yet started, or 
dosing with trial treatment was already stopped before the onset of the AE.

Dose reduced: the dose was reduced because of the particular AE.

Treatment interrupted: the dose was interrupted because of the particular AE.
10.2.7 Outcome 

Recovered/resolved: subject returned to first assessment status with respect to the AE.

Recovering/resolving: the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved: there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
trial period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/ Resolved with sequelae: the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal: an AE that is considered as the cause of death.
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
Unknown: the course of the AE cannot be followed up because of hospital change or residence 
change at the end of the subject’s participation in the trial.
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal Liver 
Function Tests
10.2.8.1 Collection Period
Collection of AEs (ie, AEs, SAEs, special interest AEs, and abnormal liver function tests) will 
commence at the time the subject signs the informed consent. The time of AE collection should be 
recorded. Routine collection of AEs will continue until the last follow-up visit or phone call, 
approximately 30 days after the last dose of gluten. For subjects who discontinue before the 
administration of trial treatment, AEs will be followed until the subject discontinues trial 
participation. 
10.2.8.2 Reporting AEs
At each trial visit, the investigator will assess whether any subjective AEs have occurred. A neutral 
question, such as “How have you been feeling since your last visit?” may be asked. Subjects may 
report AEs occurring at any other time during the trial. Subjects experiencing an SAE before the 
first exposure to gluten must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or there is a satisfactory explanation for the 
change. Nonserious AEs that begin before the first exposure to gluten, whether related or unrelated 
to the trial procedure, need not be followed-up for the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the trial treatment or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the trial treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/intensity.

Causality (the investigator’s opinion of the causal relationship between the event and 
administration of trial treatment).

Action taken with trial treatment.

Outcome of event.

Seriousness.
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10.2.8.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
The sponsor’s SAE form must be completed in English and signed by the investigator immediately 
or within 24 hours of first onset or notification of the event. The information should be completed 
as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the trial treatment.

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to trial participation.
Reporting of SAEs that begin before first administration of gluten will follow the same procedure 
for SAEs occurring on treatment.
SAE Follow-up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4 Reporting Special Interest AEs 
There are no specific additional reporting requirements for AEs of special interest. 
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the trial is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
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sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan will be prepared and finalized before database lock. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to 
address all trial objectives.
A targeted data review will be conducted before database lock. This review will assess the 
accuracy and completeness of the trial database, subject evaluability, or appropriateness of the 
planned statistical methods.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
The safety set will consist of all subjects who are enrolled and receive at least 1 dose of gluten. 
Subjects in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries.
11.1.1.2 Biomarker Analysis Set
All subjects who complete the gluten challenge and have all the Vh:Cd measures taken.
11.1.2 Analysis of Demography and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for all subjects. Summary statistics 
(number of subjects, mean, SD, median, minimum, and maximum) will be presented for 
continuous variables (eg, age, weight, and BMI), and the number and percentage of subjects within 
each category will be presented for categorical variables (eg, sex, ethnicity, and race). Individual 
subject demographic and baseline characteristic data will be provided in the data listings.
11.1.3 Safety Analysis
The safety set will be used for all summaries of safety parameters. These summaries will be 
presented by individual treatment group and the safety set overall.
11.1.3.1 AEs
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events (TEAEs) 
with onset occurring within 30 days (onset date minus last date of dose +1≤30) after the last dose 
of gluten treatment will be included in the summary tables. All AEs will be in the listings. TEAEs 
will be summarized by SOC and PT. The following summary tables will be included in the report: 
summary of TEAEs and trial treatment-related AEs, relationship of AEs to gluten treatment 
(related vs not related), severity of AEs, and related SAEs. Data listings will be provided for all 
AEs including TEAEs, AEs leading to discontinuation of gluten treatment, and SAEs. AE 
collection will include the time at which events were reported to clinic personnel.
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11.1.3.2 Clinical Laboratory Evaluation
Not applicable; routine laboratory evaluations will be conducted only for the purpose of screening 
and enrolling subjects.
11.1.3.3 Vital Signs
Baseline, postdose, and changes from Baseline in vital sign measurements will be summarized. All 
vital sign data will be provided in the data listings.
11.1.3.4 Other Safety Parameters
Not applicable.
11.1.4 Analysis of Gluten Challenge
The gluten challenge analysis will be performed in 2 stages. First, a 2-sided paired t-test will 
compare Vh:Cd before and after gluten challenge to confirm a response to gluten. If a histological 
difference is present, then T cell markers will be evaluated with tetramers. Previous work [6]
estimates ΔVh:Cd14 = -1.03 (0.96) (this is the change in Vh:Cd after a 14-day gluten challenge). 
Data from a recently published trial [24] estimates Δlog(Tetramer)6 = 1.87 (1.39) (this is the 
change in tetramer binding 6 days into a gluten challenge). These estimates will be used to 
calculate power and stopping thresholds.
11.1.4.1 Interim Analysis and Criteria for Early Termination
An interim analysis will be performed on 12 subjects (6 subjects at each gluten dose level). First, a 
2-sided paired t-test will compare Vh:Cd before and after gluten challenge. If the absolute value of 
the t-statistic exceeds 2.63 (nominal p-value of 2.3%, 84% power to achieve this), indicating a 
change in histology was detected, then secondary endpoint functional T-cell markers (tetramers) 
will be evaluated with a 2-sided paired t-test. If the magnitude of this t-test is greater than 2.80 
(nominal p-value of 1.7%, 95% power), then the trial will be stopped because a biomarker signal 
was detected. There is an 80% probability of stopping the trial at this interim analysis because of 
detecting a new biomarker signal.
If it is determined that more subjects are needed, a 2-sample t-test comparing the 2 dosage groups 
will be performed. 

If that test is significant at the 5% level (ie, the magnitude of the t-statistic exceeds 2.20), then 
8 additional subjects may be enrolled into the gluten treatment group with the larger change in 
Vh:Cd. 

If that test is not significant, then 4 additional subjects may be enrolled into each group. 
If the difference in Vh:Cd in the interim analysis was not significant, then a final 2-sided pairwise 
t-test will be performed, where the magnitude of the t-statistic must exceed 2.26 (nominal p-value 
of 3.4%, overall power >99%). 
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If a change in histology is detected in either the interim or final analysis, then a 2-sided paired t-test 
will be performed on the T cell markers. To achieve significance, the magnitude of the t-statistic 
must exceed 2.19 (nominal p-value of 3.9%, overall probability of tetramer significance of >99%). 
This design has an overall significance level of 5% for detecting a change in histology, and a 
separate significance level of 5% for detecting a change in T cell markers.
11.2
Determination of Sample Size
The sample size for this trial reflects several constraints. Despite having the primary analysis 
pooled across the 2 treatment arms, having the arms balanced is preferable so there must be an 
even number of subjects overall. The number of subjects was selected to detect a change in Vh:Cd
in the interim analysis with 80% probability and at the final analysis with >99% probability. 
Additionally, it was selected to allow accurate estimation of the coefficient of variation for the 
secondary and exploratory endpoints, as well as to allow for comparing the 2 dosage groups.
Using the published estimates of ΔVh:Cd14 and Δlog(Tetramer)6, a single analysis with 
12 subjects has 92% power to detect a change in Vh:Cd before and after gluten challenge, and a 
99% power to detect a change in T-cell marker tetramer binding. With the current group sequential 
design, then the interim analysis has 84% power of detecting a change in histology and an 
independent 95% power of detecting a change in T cell markers, for an overall power of 80% to 
detect both. There is 99% power to detect changes in both by the final analysis.
Uncertainty in the estimates of these 2 markers may lead to questioning the accuracy of these 
measurements. If it is assumed that the SD of ΔVh:Cd14 and Δlog(Tetramer)6 is 50% greater than 
is reported in the literature, the power of this trial would be decreased. In this scenario, the trial has 
a 47% power to detect a histological change in the interim analysis and 89% power to detect a 
histological change overall. In addition, the probability of detecting a change in T cell markers is 
63% at the interim analysis and 98% by the final analysis.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Trial-Site Monitoring Visits
Monitoring visits to the trial site will be made periodically during the trial to ensure that all aspects 
of the protocol are followed. Source documents will be reviewed for verification of data recorded 
on the eCRFs. Source documents are defined as original documents, data, and records. The 
investigator and trial site guarantee access to source documents by the sponsor or its designee and 
by the IRB or IEC.
All aspects of the trial and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, gluten, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
trial personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary trial assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The trial site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the trial. In 
addition, there is the possibility that this trial may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the trial site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator guarantees access for quality assurance auditors 
to all trial documents as described in Section 12.1.
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13.0
ETHICAL ASPECTS OF THE TRIAL
This trial will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline for 
GCP. Each investigator will conduct the trial according to applicable local or regional regulatory 
requirements and align his or her conduct in accordance with the “Responsibilities of the 
Investigator” that are listed in Appendix A. The principles of Helsinki are addressed through the
protocol and through appendices containing requirements for informed consent and investigator 
responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this trial, written notification regarding his or her abstinence from voting 
must also be obtained. Those Americas sites unwilling to provide names and titles of all members 
because of privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the ICF, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or local 
IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the trial (ie, before shipment of the sponsor-supplied treatment or trial specific 
screening activity). The IRB or IEC approval must refer to the trial by exact protocol title, number, 
and version date; identify versions of other documents (eg, ICF) reviewed; and state the approval 
date. Until the site receives notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the trial at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the trial. The ICF and the subject information sheet (if applicable) further explain the nature of the 
trial, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and, if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject authorization 
form (if applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. In the event the subject is not capable of rendering adequate written 
informed consent, then the subject’s legally acceptable representative may provide such consent 
for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the trial, and (2) decide whether or not to participate in the trial. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the trial, then the ICF and subject authorization form (if applicable) must be signed and dated by 
the subject, or the subject’s legally acceptable representative, at the time of consent and before the 
subject entering into the trial. The subject or the subject’s legally acceptable representative should 
be instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. The 
investigator must also sign and date the ICF and subject authorization (if applicable) at the time of 
consent and before the subject enters into the trial; however, the sponsor may allow a designee of 
the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
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revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
13.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this trial, a subject’s source data will only be linked to the 
sponsor’s clinical trial database or documentation via a unique identification number. As permitted 
by all applicable laws and regulations, limited subject attributes, such as sex, age, or date of birth, 
and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s trial participation, 
and autopsy reports and original images. Access to a subject’s original medical records requires 
the specific authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the trial. During and after the trial, only the sponsor may make trial 
information available to other trial investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical trial site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or trial results, other 
than trial recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the trial (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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13.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, the sponsor will, at a minimum, register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of trial, as defined in the sponsor’s policies and/or 
standards. The sponsor’s contact information, along with investigator’s city, state (for Americas 
investigators), country, and recruiting status will be registered and available for public viewing. 
For some registries, the sponsor will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Trial Results Disclosure 
The sponsor will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by the sponsor’s policy and/or standards, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the trial must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical trial insurance against the risk of injury to trial subjects. Refer to the 
trial site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Trial Contact Information 
Contact Type/Role
Contact
SAE and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
Fax: 224-554-1052 or
Email: PVSafetyAmericas@tpna.com
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14.1.2 INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this trial in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of trial subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 GCP Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.9 of this protocol.

Terms outlined in the trial site agreement.

Responsibilities of the investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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14.1.3 Trial-Related Responsibilities 
The sponsor will perform all trial-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific trial-related activities 
will perform these activities in full or in partnership with the sponsor.
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14.1.4 List of Abbreviations
AE
adverse event
APC
antigen-presenting cells
BMI
body mass index
CDSD
celiac disease symptom diary
CeD
celiac disease
CFR
Code of Federal Regulations
CRO
contract research organization
DGP
anti-deamidated gliadin peptide
ECG
electrocardiogram
eCRF
electronic case report form
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin block
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GFD
gluten-free diet
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
institutional ethics committee
IEL
intraepithelial lymphocyte
IHC
immunohistochemistry
INF-γ
interferon-γ
IRB
institutional review board
mRNA
messenger RNA
MedDRA
Medical Dictionary for Regulatory Activities
MHC
major histocompatibility complex
PT
preferred term
SAE
serious adverse event
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
TCR
T cell receptor
TEAE
treatment-emergent adverse event
tTG
anti-tissue transglutaminase
Vh:Cd
villus height to crypt depth ratio
CCI
CCI
CCI
Property of Takeda: For non-c
R
R
TEAE
TEAE
tTG
tTG
y 
CC
ommercial use only and subject to the applicable Terms of Use
Harmonis
armon
ttee
cyte
yte
mistry
istry
l review b
eview
ger RNA
er RNA
dical Dict
cal Di
major hist
ajor h
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this trial to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by sponsor 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical trial database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign and date. 
The eCRFs will be reviewed for completeness and acceptability at the trial site during periodic 
visits by trial monitors. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the trial to ensure accuracy of the eCRFs. The completed 
eCRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the trial-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of treatment disposition to enable evaluations or audits from 
regulatory authorities, the sponsor or its designees. Any source documentation printed on 
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degradable thermal sensitive paper should be photocopied by the site and filed with the original in 
the subject’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
investigator to retain essential documents specified in ICH E6 (Section 8) until at least 2 years after 
the last approval of a marketing application for a specified drug indication being investigated or, if 
an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the trial records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
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16.0
REFERENCES
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Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease. 
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6. 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 
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7. Christophersen A, Risnes LF, Bergseng E, Lundin KE, Sollid LM, Qiao SW. Healthy 
HLA-DQ2.5+ Subjects Lack Regulatory and Memory T Cells Specific for Immunodominant 
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15. Taavela J, Koskinen O, Huhtala H, Lahdeaho ML, Popp A, Laurila K, et al. Validation of 
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macrophages suppresses CD4+ T cell proliferation by augmenting IFN-gamma-induced nitric 
oxide production. J Immunol 2005;175(3):1586-92.
22. Reynoso ED, Elpek KG, Francisco L, Bronson R, Bellemare-Pelletier A, Sharpe AH, et al. 
Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade. J 
Immunol 2009;182(4):2102-12.
23. Bragde H, Jansson U, Jarlsfelt I, Soderman J. Gene expression profiling of duodenal biopsies 
discriminates celiac disease mucosa from normal mucosa. Pediatr Res 2011;69(6):530-7.
24. 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 2017.
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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this trial.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the trial in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that trial related procedures, including trial specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the trial are informed of 
these obligations.
6. Secure prior approval of the trial and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the trial to the 
IRB/IEC, and issue a final report within 3 months of trial completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the trial, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the trial. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the trial, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
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that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
trial treatment, and return all unused sponsor-supplied treatment to the sponsor. 
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the trial involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the trial.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the trial.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written ICF, the subject or the subject’s 
legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if so, 
what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the trial.
17. The anticipated expenses, if any, to the subject for participating in the trial.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
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legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial.
22. A statement that results of biomarker analysis will not be disclosed to an individual, unless 
prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the trial 
may be terminated.
24. A written subject authorization (either contained within the ICF or provided as a separate 
document) describing to the subject the contemplated and permissible uses and disclosures of 
the subject’s personal information (including personal health information) for purposes of 
conducting the trial. The subject authorization must contain the following statements regarding 
the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) the sponsor, its affiliates, and 
licensing partners; (2) business partners assisting the sponsor, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, the sponsor will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to the 
sponsor’s research databases for purposes of developing a better understanding of the 
safety of the trial treatment, studying other therapies for patients, developing a better 
understanding of disease, and improving the efficiency of future clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the trial to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that trial results are 
published.
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active with a nonsterilized male partner must use effective contraception (as 
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defined in the informed consent) from signing the informed consent and throughout the 
duration of the trial, and for 3 months after the conclusion of trial participation. 
26. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information
The sponsor will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

The sponsor, its affiliates, and licensing partners.

Business partners assisting the sponsor, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by the sponsor and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the trial and/or other clinical studies.

Management, monitoring, inspection, and audit of the trial.

Analysis, review, and verification of the trial results.

Safety reporting and pharmacovigilance relating to the trial.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the trial.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to medications used in other clinical studies.

Inspections and investigations by regulatory authorities relating to the trial.

Self-inspection and internal audit within sponsor, its affiliates, and licensing partners.

Archiving and audit of trial records.

Posting investigator site contact information, trial details, and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by the 
sponsor and other parties for the purposes described above.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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