Clinical trial NCT05353985
Conditions: Celiac Disease
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2022-06-30; Completion date: 2024-11-06
Enrollment: 153 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main aim is to see how TAK-062 works to reduce celiac-related symptoms and improve small intestinal damage due to gluten exposure, in participants with celiac disease (CeD) attempting to maintain a gluten-free diet (GFD) in treated participants versus placebo controls.

Detailed description:
The drug being tested in this study is called TAK-062. TAK-062 is designed to break down gluten in the stomach and is being tested to treat people who have active CeD, attempting to maintain a GFD.

The study will enroll approximately 357 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups in Cohort 1:

1. Cohort 1 (Age 18 and older): TAK-062 Placebo + SIGE Gluten-Bar
2. Cohort 1 (Age 18 and older): TAK-062 Dose 1 + SIGE Gluten-Bar

After the interim analysis (IA), Cohort 1 data will be reviewed by an external independent data monitoring committee (DMC), and based on the Sponsor's decision, adolescent participants will be enrolled in Cohort 2. Adult participants, 18 years and older will be enrolled into Cohort 2 once Cohort 1 has completed enrolment. Adult participants will be randomly assigned to one of the five study drug and SIGE treatment groups (Groups a-e), and approximately 21 adolescent participants will be enrolled and randomly assigned to Groups d, e, and f (adolescents only). Adolescents in Cohort 2 will receive only gluten-free SIGE bars.

1. Cohort 2 (Age 18 and older): TAK-062 Placebo + SIGE Gluten-Bar
2. Cohort 2 (Age 18 and older): TAK-062 Dose 2 + SIGE Gluten-Bar
3. Cohort 2 (Age 18 and older): TAK-062 Dose 3 + SIGE Gluten-Bar
4. Cohort 2 (Age 12 and older): TAK-062 Placebo + Gluten-free SIGE Bar
5. Cohort 2 (Age 12 and older): TAK-062 Dose 1 + Gluten-free SIGE Bar
6. Cohort 2 (Age 12-17): TAK-062 Dose 2 + Gluten-free SIGE Bar

This multi-center trial will be conducted in the United States (US), Canada, United Kingdom and the European Union. The overall time to participate in this study is approximately 36 weeks.

Arms: arm 1: TAK-062 placebo-matching 4 tablets, orally, taken within pre-determined time before the start of a meal and SIGE gluten bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. arm 2: TAK-062 Dose 1, 4 tablets, orally, taken within pre-determined time before the start of a meal and SIGE gluten bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. arm 3: TAK-062 placebo-matching 4 tablets, orally, taken within pre-determined time before the start of a meal and SIGE gluten bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. arm 4: TAK-062 Dose 2, 4 tablets, orally, taken within pre-determined time before the start of a meal and SIGE gluten bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. arm 5: TAK-062 Dose 3, 4 tablets, orally, taken within pre-determined time before the start of a meal and SIGE gluten bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. arm 6: TAK-062 placebo-matching 4 tablets, orally, taken within pre-determined time before the start of a meal and gluten-free SIGE bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. arm 7: TAK-062 Dose 1, 4 tablets, orally, taken within pre-determined time before the start of a meal and gluten-free SIGE bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. arm 8: TAK-062 4 tablets, orally, taken within pre-determined time before the start of a meal and gluten-free SIGE bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks.
Interventions: intervention 1: TAK-062 intervention 2: Simulated Inadvertent Gluten Exposure (SIGE) Gluten-Bar intervention 3: TAK-062 Placebo intervention 4: Simulated Inadvertent Gluten Exposure (SIGE) Gluten-free Bar
Intervention descriptions: intervention 1: TAK-062 tablets. intervention 2: SIGE gluten bars. intervention 3: TAK-062 placebo-matching tablets. intervention 4: SIGE gluten-free bars.

Protocol documents:
Prot_000.pdf: 
For non-commercial use only


TAKEDA PHARMACEUTICALS 
PROTOCOL 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to 
Evaluate the Efficacy and Safety of TAK-062 for the Treatment of Active Celiac Disease in 
Subjects Attempting a Gluten-Free Diet 
Sponsor: 
Takeda Development Center Americas, Inc. 
95 Hayden Avenue 
Lexington, MA 02421, USA 
Study Number: 
TAK-062-2001 
IND Number: 
137372 
EudraCT Number: 
2020-005438-14 
Compound: 
TAK-062 
Date: 
16 November 2023 
Amendment Number: 
5 
Amendment History: 
Date 
Amendment Number 
Amendment Type 
Region 
16 November 2023 
5 
Substantial 
Global 
02 June 2023 
4 
Substantial (not submitted to 
European Health Authorities) 
Global 
26 October 2022 
3 
Substantial 
Global 
22 July 2022 
2 
Substantial 
Global 
23 June 2022 
1 
Substantial 
Global 
18 January 2022 
Initial protocol 
Not applicable 
Global 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study. 
For non-commercial use only


TAK-062 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
A separate contact information list will be provided to each site. 
Takeda Development Center sponsored investigators per individual country requirements will be 
provided with emergency medical contact information cards to be carried by each subject. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site. 
Contact Type/Role 
United States, Canada, and the Rest of the World 
Serious adverse event and pregnancy 
reporting 
Fax: +1-224-554-1052 
Email: PVSafetyAmericas@tpna.com 
Medical Monitor 
(medical advice on protocol and study 
drug) 
, Clinical Science 
Responsible Medical Officer  
(carries overall responsibility for the 
conduct of the study) 
, Clinical Science 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
1.2 
Approval  
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this study protocol and also in accordance with the 
following: 
•
The ethical principles that have their origin in the Declaration of Helsinki.
•
International Conference on Harmonisation (ICH) E6 Good Clinical Practice (GCP):
Consolidated Guideline.
•
All applicable laws and regulations, including, without limitation, data privacy laws, clinical
trial disclosure laws, and regulations.
SIGNATURES 
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page. 
Electronic signatures are provided on the last page of this document. 
, MD, MS 
, Clinical Science 
Date 
, PhD 
, Statistical and Quantitative Sciences 
Date 
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CONFIDENTIAL 
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the investigator’s brochure (IB), 
package insert and any other product information provided by the sponsor. I agree to conduct this 
study in accordance with the requirements of this protocol and also to protect the rights, safety, 
privacy, and well-being of study subjects in accordance with the following: 
•
The ethical principles that have their origin in the Declaration of Helsinki.
•
International Conference on Harmonisation, E6 GCP: Consolidated Guideline.
•
All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.
•
Regulatory requirements for reporting serious adverse events (SAEs) defined in Section 10.2
of this protocol.
•
Terms outlined in the study site agreement.
•
Responsibilities of the investigator (Appendix C).
•
I further authorize that my personal information may be processed and transferred in
accordance with the uses contemplated in Appendix E 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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CONFIDENTIAL 
1.3 
Protocol Amendment 5 Summary of Changes 
Protocol Amendment 5 Summary and Rationale: 
This document describes the changes to the protocol incorporating Amendment 5. The primary 
reason for this amendment is to update approximate subject numbers per cohort and treatment 
arms and to clarify combining of placebo groups of Cohort 1 and Cohort 2 for analyses, 
exclusion criteria, strategies for reduction of potential protocol deviations, handling of 
intercurrent events, and withdrawal-from-treatment criteria. 
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only. 
Protocol Amendment 5 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1.  
Section 2.0 STUDY SUMMARY 
Section 9.3.6.1 CDSD v2.1 
Table 13.a 
 
 
 
Appendix A Schedule of Study 
Procedures 
Clarified that Version 2.1 of the 
Celiac Disease Symptom Diary 
(CDSD) will be used. 
Clarification. 
2.  
Section 2.0 STUDY SUMMARY 
Section 6.1 Study Design 
Figure 6.a Schematic of Study 
Design 
Table 8.b Dose and Regimen 
Section 13.3 Determination of 
Sample Size 
 
Updated the planned 
approximate sample size from 
377 to 357 to account for the 
combining of subjects within the 
placebo gluten-containing 
simulated inadvertent gluten 
exposure (SIGE) arms from 
Cohorts 1 and 2 for analysis. 
Updated the approximate 
number of subjects to be 
enrolled in Cohort 2 from 257 to 
237. 
Updated the approximate 
number of subjects to be 
enrolled to Cohort 2 Group 1 
(TAK-062 placebo
 
 + SIGE bar 
 
 from 50 to 30.  
Added the number of adults and 
adolescent subjects per cohort. 
 
Update. There will be no 
pause between the end of 
Cohort 1 enrollment and 
the beginning of Cohort 2 
enrollment, and no 
difference is expected for 
the 2 placebo-SIGE arms 
under the same eligibility 
criteria. For these reasons, 
the decision was made to 
reduce the size of the 
placebo gluten-containing 
SIGE arm in Cohort 2 
from 50 to 30 subjects, as 
all subjects from the 
Cohort 1 placebo gluten-
containing SIGE arm will 
be combined with the 
placebo gluten-containing 
SIGE arm from Cohort 2 
in the analyses. 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
Protocol Amendment 5 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
3.  
Section 2.0 STUDY SUMMARY 
Section 4.1 Background 
Section 6.1 Study Design 
Section 6.2.1 Rationale for Study 
Design 
Section 13.1.1 Analysis Sets 
Section 13.1.3.1 Primary Efficacy 
Endpoint Analysis: Change From 
Baseline in Weekly CDSD GI 
Symptom Severity Score at Week 
12 
Section 13.3 Determination of 
Sample Size 
Updated wording for inadvertent 
gluten exposure (ie, SIGE) to 
“gluten-containing SIGE.” 
Clarification of 
terminology. 
4.  
Section 2.0 STUDY SUMMARY 
Section 6.1 Study Design 
Clarified wording for when 
subjects will receive simulated 
SIGE bars with or without gluten 
 
Clarification. 
5.  
Section 2.0 STUDY SUMMARY 
Section 7.1 Inclusion Criteria 
Clarified the process for 
inclusion of subjects older than 
75 years, which will require 
discussion with the medical 
monitor. 
Clarification. 
6.  
Section 2.0 STUDY SUMMARY 
Section 6.1 Study Design 
 
Clarified wording of gluten-free 
SIGE bars 
 
 
and 
 
from Week -2 to Day -1. 
Correction. 
7.  
Section 2.0 STUDY SUMMARY 
Added clarification that subjects 
will be excluded upon 
development of symptoms that 
suggest a confounding nongluten 
food intolerance. 
Clarification. 
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CONFIDENTIAL 
Protocol Amendment 5 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
8. 
Section 2.0 STUDY SUMMARY 
Section 5.2.1 Primary Endpoint 
Section 5.2.4 
Exploratory/Additional Endpoints 
Section 6.2.3.1 Efficacy 
Section 13.1.3.1 Primary Efficacy 
Endpoint Analysis: Change From 
Baseline in Weekly CDSD GI 
Symptom Severity Score at Week 
12 
Updated wording for the primary 
endpoint from change in once- 
per-week average CDSD 
gastrointestinal (GI) symptom 
severity to change in “weekly 
CDSD GI symptom severity 
score” to clarify main criteria for 
evaluation and updated primary 
estimand attributes and text. 
Updated phrasing from “once 
per week” to “weekly” for 
consistency in discussing the 
primary endpoint. 
Clarification. 
9. 
Section 2.0 STUDY SUMMARY 
Appendix A Schedule of Study 
Procedures 
Updated the number of subjects 
in the subset to receive second 
 
before SIGE for a test/retest 
assessment from approximately 
30 to approximately 40. 
Correction. 
10. 
Section 2.0 STUDY SUMMARY 
Section 6.1 Study Design 
Section 6.2.3.4 Urine-Based 
Biomarker: GIP 
Appendix A Schedule of Study 
Procedures 
Added clarification that missed 
gluten immunogenic peptide 
(GIP) samples will not be 
considered a protocol deviation. 
Clarification of 
expectations. 
11. 
Section 2.0 STUDY SUMMARY 
Section 7.4 Rescue Medications 
Section 13.1.3.1 Primary Efficacy 
Endpoint Analysis: Change From 
Baseline in Weekly CDSD GI 
Symptom Severity Score at Week 
12 
Clarified that rescue medications 
will be administered only for 
symptoms considered related to 
celiac disease (CeD). 
Clarification. 
12. 
Section 2.0 STUDY SUMMARY 
Section 6.1 Study Design 
Section 7.1 Inclusion Criteria 
Clarified that adolescent subjects 
will be enrolled into Cohort 2 
only after review by the 
independent data monitoring 
committee (IDMC) at interim 
analysis (IA). 
Clarification. 
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CONFIDENTIAL 
Protocol Amendment 5 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
13. 
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
Updated exclusion criteria text 
to allow subjects with systemic 
autoimmune disease who do not 
have GI symptoms and are stable 
and to allow subjects with proton 
pump inhibitor–responsive 
eosinophilic esophagitis to be 
discussed with the study medical 
monitor to determine eligibility. 
Update. 
14. 
Section 9.3.7.4 Research Subject 
Responsibilities Training 
Clarified that subjects may 
receive training once training is 
available. 
Clarification. 
15. 
Section 2.0 STUDY SUMMARY 
Section 13.1.3.1 Primary Efficacy 
Endpoint Analysis: Change From 
Baseline in Weekly CDSD GI 
Symptom Severity Score at Week 
12 
 
 
 
 
 
 
 
 
 
 
 
16. 
Section 2.0 STUDY SUMMARY 
Section 13.3 Determination of 
Sample Size 
Added sample-size reevaluation 
for power and dropout rate for 
the combined placebo groups in 
Cohort 1 and Cohort 2. 
Clarified that higher analytical 
power should be expected due to 
the combining of placebo subject 
groups. 
Addition of sample-size 
reevaluation for the 
combining of placebo 
cohorts. 
17. 
Section 4.1 Background 
Section 6.2.1 Rationale for Study 
Design 
Updated instances of “without 
SIGE” to “gluten-free SIGE” for 
consistency across all sections. 
Clarification. 
18. 
Section 4.1 Background 
Removed “and regulatory 
authority feedback has been 
incorporated” from the 
description of CDSD and 
clarified that patient-reported 
outcomes “may” (changed from 
“will”) enable CDSD to be used 
as a primary endpoint. 
Clarification. 
19. 
Section 6.1 Study Design 
Clarified that on-study gluten 
intake will be assessed by 
measuring GIP in urine. 
Clarification. 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
Protocol Amendment 5 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
20. 
Section 6.1 Study Design 
Corrected improvement in PGIS 
(Patient Global Impression of 
Severity) during 
 run-in 
period from “Week -2 through 
Day 0” to “Week -2 to Day -1.” 
Correction. 
21. 
Section 6.1 Study Design 
Section 6.2.3.2 Tissue-Based 
Biomarkers: Vh:Cd and IELs 
Section 9.3.12.2 Biomarker 
Collection 
Appendix A Schedule of Study 
Procedures 
Added clarification that predose 
plasma and serum collections for 
exploratory analysis will be 
performed at the same visits as 
pharmacokinetic (PK) collection. 
Clarification of timing of 
biomarker collection to 
minimize confusion with 
PK collections. 
22. 
Figure 6.a Schematic of Study 
Design 
Updated presentation of the 
duration of treatment for  
Week 12 and Week 24 for 
clarity.  
Added 
 test/retest subset. 
Updated “Gluten-containing 
SIGE” and “Gluten-Free SIGE” 
for consistency with body text. 
Clarification. 
23. 
Section 6.2.1 Rationale for Study 
Design 
Updated wording to clarify that 
adult subjects in Cohort 2 will 
receive gluten-containing or 
gluten-free SIGE bars. 
Clarification. 
24. 
Section 6.2.2 Rationale for Dose 
Section 7.6 Criteria for 
Discontinuation or Withdrawal of a 
Subject  
Clarified that a break in gluten-
containing SIGE bars due to 
worsened CeD symptoms for 
more than 2 weeks will result in 
a subject’s withdrawal from 
treatment, but the subject will 
remain in the study for safety 
monitoring. 
Clarification. 
25. 
Section 6.2.3.1 Efficacy 
Added that the CDSD is not yet 
validated “for the intended 
context of use.” 
Clarification of regulatory 
language. 
26. 
Section 6.2.3.2 Tissue-Based 
Biomarkers: Vh:Cd and IELs 
Appendix A Schedule of Study 
Procedures 
Updated subheading to “Other 
Exploratory Biomarkers.”  
Added examples of exploratory 
biomarkers from plasma and 
serum collections for improved 
noninvasive patient selection or 
disease monitoring. 
Correction. 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
Protocol Amendment 5 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
27.  
Section 7.1 Inclusion Criteria 
Corrected the upper age limit for 
adolescents in criterion 10. 
Correction. 
28.  
Section 7.2 Exclusion Criteria 
Section 7.3 Excluded Medications 
Updated reporting for prior and 
concomitant medication from 
“6 months” to “90 days” for 
consistency throughout the 
protocol. 
Clarification. 
29.  
Section 7.2 Exclusion Criteria 
Added “eg,” to the list of food 
allergies in criterion 18 to 
indicate nonexhaustive 
examples. 
Added criterion 29 to exclude 
subjects with active malignancy 
or malignancies diagnosed 
within 5 years prior to screening. 
Subjects with Stage 0 or 
nonrecurrent Stage 1 disease will 
not be excluded. 
Clarification of eligibility 
criteria. 
30.  
Section 9.3.6 PRO Assessments 
Section 9.3.6.1 CDSD v2.1 
Section 13.1.3.3 Other Efficacy 
Endpoint Analyses 
Appendix A Schedule of Study 
Procedures 
Clarified that the CDSD and 
supplementary frequency 
questionnaire are separate 
measures competed at the same 
time points. 
Updated the text to describe 
CDSD from a “8-item” to “5-
item” questionnaire to clarify 
that CDSD is a separate measure 
from the frequency of CeD 
symptoms, which is captured by 
the supplemental frequency 
questionnaire. 
Clarification of 2 different 
measures used for 
symptom severity and 
symptom frequency. 
31.  
Section 9.3.9 Endoscopy and Biopsy 
Collection 
Removed a statement that 
subjects, site staff, and study 
team members will remain 
blinded to postrandomization 
histopathological findings 
throughout the study. 
Correction to align with 
blinding procedures. 
32.  
Section 13.1.3 Efficacy Analysis 
Clarified that full analysis set–
SIGE analysis will include all 
subjects randomized to receive 
placebo 
 and gluten-
containing SIGE bars 
 from 
Cohorts 1 and 2. 
Update to align with the 
combining of placebo 
groups from Cohorts 1 
and 2. 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
Protocol Amendment 5 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
33.  
Section 13.1.3.1 Primary Efficacy 
Endpoint Analysis: Change From 
Baseline in Weekly CDSD GI 
Symptom Severity Score at Week 
12 
Updated the definition of AUC 
from “area under the 
concentration-time curve” to 
“area under the curve.” 
Clarified estimands using AUC 
from Day 1 to Week 12 for GI 
severity will use daily scores.  
Clarified that severity scores 
range from 0 (no symptoms) to 4 
(very severe). 
Clarification.  
34.  
Section 13.1.3.2 Secondary Efficacy 
Endpoint Analysis  
Included “other reasons for 
discontinuations” that are not 
otherwise listed. 
Correction. 
35.  
Section 13.2 IA and Criteria for 
Early Termination 
Table 13.a 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
36.  
Appendix A Schedule of Study 
Procedures 
Added “Section” to clarify a link 
to the text for pregnancy testing 
(in Footnote g). 
Clarification. 
 
 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment 5 Summary of Changes...............................................................5 
2.0 
STUDY SUMMARY.........................................................................................................18 
3.0 
STUDY REFERENCE INFORMATION .........................................................................25 
3.1 
Study-Related Responsibilities ....................................................................................25 
3.2 
Coordinating Investigator ............................................................................................25 
3.3 
List of Abbreviations ...................................................................................................26 
3.4 
Corporate Identification ...............................................................................................27 
4.0 
INTRODUCTION .............................................................................................................28 
4.1 
Background ..................................................................................................................28 
4.1.1 
Disease State Background ...................................................................................29 
4.2 
Rationale for the Proposed Study ................................................................................30 
4.3 
Benefit-Risk Profile .....................................................................................................30 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................32 
5.1 
Objectives ....................................................................................................................32 
5.1.1 
Primary Objective ................................................................................................32 
5.1.2 
Secondary Objectives ..........................................................................................32 
5.1.3 
Exploratory/Additional Objectives ......................................................................32 
5.2 
Endpoints .....................................................................................................................33 
5.2.1 
Primary Endpoint .................................................................................................33 
5.2.2 
Secondary Endpoint .............................................................................................33 
5.2.3 
Safety Endpoints ..................................................................................................33 
5.2.4 
Exploratory/Additional Endpoints .......................................................................33 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................35 
6.1 
Study Design ................................................................................................................35 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................39 
6.2.1 
Rationale for Study Design .................................................................................39 
6.2.2 
Rationale for Dose ...............................................................................................40 
6.2.3 
Rationale for Endpoints .......................................................................................41 
6.2.3.1 
Efficacy .......................................................................................................41 
6.2.3.2 
Tissue-Based Biomarkers: Vh:Cd and IELs ...............................................42 
6.2.3.3 
 .............................................................................................................42 
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CONFIDENTIAL 
6.2.3.4 
Urine-Based Biomarker: GIP ......................................................................42 
6.2.3.5 
Safety...........................................................................................................43 
6.3 
Premature Termination or Suspension of Study or Study Site ....................................43 
6.3.1 
Criteria for Premature Termination or Suspension of the Study .........................43 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites ......................43 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) ...............................................................................43 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............43 
7.1 
Inclusion Criteria .........................................................................................................44 
7.2 
Exclusion Criteria ........................................................................................................45 
7.3 
Excluded Medications ..................................................................................................48 
7.4 
Rescue Medications .....................................................................................................49 
7.5 
Diet ...............................................................................................................................50 
7.6 
Criteria for Discontinuation or Withdrawal of a Subject .............................................50 
7.7 
Procedures for Discontinuation or Withdrawal of a Subject .......................................51 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT .......................................................51 
8.1 
Study Drug and Materials ............................................................................................51 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ....................................51 
8.1.1.1 
TAK-062 .....................................................................................................51 
8.1.1.2 
Placebo ........................................................................................................52 
8.1.1.3 
SIGE Bars ...................................................................................................52 
8.1.2 
Storage .................................................................................................................52 
8.1.3 
Dose and Regimen ...............................................................................................52 
8.1.4 
Overdose ..............................................................................................................53 
8.2 
Study Drug and SIGE Assignment and Dispensing Procedures ..................................54 
8.3 
Randomization Code Creation and Storage .................................................................54 
8.4 
Study Drug and SIGE Blind Maintenance ...................................................................54 
8.5 
Unblinding Procedure ..................................................................................................54 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs and SIGE Bars..............55 
9.0 
STUDY PLAN ...................................................................................................................56 
9.1 
Study Procedures .........................................................................................................56 
9.2 
Administrative Procedures ...........................................................................................56 
9.2.1 
Informed Consent/Pediatric Assent Procedure ....................................................56 
9.2.2 
Demographics, Medical History, and Medication History Procedure ................56 
9.3 
Clinical Procedures and Assessments ..........................................................................57 
9.3.1 
Physical Examination Procedure .........................................................................57 
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9.3.2 
Weight, Height, and BMI ....................................................................................57 
9.3.3 
Vital Sign Procedure ............................................................................................57 
9.3.4 
ECG Procedure ....................................................................................................57 
9.3.5 
GFD Knowledge Quiz .........................................................................................57 
9.3.6 
PRO Assessments ................................................................................................58 
9.3.6.1 
CDSD v2.1 ..................................................................................................58 
9.3.6.2 
EQ-5D-5L ...................................................................................................58 
9.3.6.3 
PGIS ............................................................................................................59 
9.3.6.4 
PGIC ............................................................................................................59 
9.3.6.5 
CeD Most Bothersome Symptom ...............................................................59 
9.3.6.6 
PROMIS—Fatigue Instrument ...................................................................59 
9.3.6.7 
CeD-GSRS ..................................................................................................59 
9.3.6.8 
PROMIS—Cognitive Function Instrument.................................................60 
9.3.6.9 
WPAI+CIQ:CeD .........................................................................................60 
9.3.6.10 SF-12 v2 ......................................................................................................60 
9.3.6.11 ICDSQ .........................................................................................................60 
9.3.6.12 CDAQ .........................................................................................................60 
9.3.6.13 CD-QoL ......................................................................................................61 
9.3.7 
Placebo Reduction Plan .......................................................................................61 
9.3.7.1 
Accurate Symptom Reporting Training ......................................................61 
9.3.7.2 
Placebo Response Reduction Training........................................................61 
9.3.7.3 
Participant Scorecard ..................................................................................61 
9.3.7.4 
Research Subject Responsibilities Training ................................................61 
9.3.8 
Exit Interview – United States Only ....................................................................61 
9.3.9 
Endoscopy and Biopsy Collection .......................................................................62 
9.3.10 
 ....................................................................................................63 
9.3.11 
Procedures for Clinical Laboratory Samples .......................................................63 
9.3.12 
PK and Biomarker Sample Collection and Analysis ...........................................65 
9.3.12.1 Collection of Blood and Plasma for PK Sampling .....................................65 
9.3.12.2 Biomarker Collection ..................................................................................65 
9.3.13 
Contraception and Pregnancy Avoidance Procedure ..........................................66 
9.3.13.1 Male Subjects and Their Female Partners ...................................................66 
9.3.13.2 Female Subjects and Their Male Partners ...................................................66 
9.3.13.3 Definitions and Procedures for Contraception and Pregnancy 
Avoidance ...................................................................................................66 
9.3.14 
Pregnancy ............................................................................................................69 
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9.3.15 
Documentation of Concomitant Medications ......................................................69 
9.3.16 
Documentation of Screen Failure ........................................................................69 
9.3.17 
Documentation of Randomization .......................................................................70 
9.4 
Monitoring Subject Treatment Compliance.................................................................70 
9.5 
Schedule of Observations and Procedures ...................................................................70 
9.6 
Biological Sample Retention and Destruction .............................................................71 
9.6.1 
Flexible Options for Study Procedures in Response to Pandemic ......................71 
10.0 
PTES AND AES ................................................................................................................72 
10.1 
Definitions....................................................................................................................72 
10.1.1 
PTEs ....................................................................................................................72 
10.1.2 
AEs ......................................................................................................................72 
10.1.3 
Additional Points to Consider for PTEs and AEs ...............................................73 
10.1.4 
SAEs ....................................................................................................................75 
10.1.5 
AEs of Special Interest ........................................................................................76 
10.1.6 
Intensity of PTEs and AEs ..................................................................................76 
10.1.7 
Causality of AEs ..................................................................................................76 
10.1.8 
Relationship to Study Procedures ........................................................................76 
10.1.9 
Start Date .............................................................................................................76 
10.1.10 Stop Date .............................................................................................................77 
10.1.11 Pattern ..................................................................................................................77 
10.1.12 Action Concerning Study Drug ...........................................................................77 
10.1.13 Outcome ..............................................................................................................77 
10.2 
Procedures ....................................................................................................................78 
10.2.1 
Collection and Reporting of AEs ........................................................................78 
10.2.1.1 PTE and AE Collection Period ...................................................................78 
10.2.1.2 PTE and AE Reporting................................................................................78 
10.2.2 
Collection and Reporting of SAEs ......................................................................79 
10.2.3 
Reporting of Abnormal Liver Enzymes and Bilirubin ........................................79 
10.3 
Follow-up of SAEs ......................................................................................................79 
10.3.1 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ...........................................................................................................80 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................80 
11.1 
IDMC ...........................................................................................................................80 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................81 
12.1 
eCRFs ...........................................................................................................................81 
12.2 
Record Retention .........................................................................................................82 
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13.0 
STATISTICAL METHODS ..............................................................................................82 
13.1 
Statistical and Analytical Plans ....................................................................................82 
13.1.1 
Analysis Sets .......................................................................................................82 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ..........................83 
13.1.3 
Efficacy Analysis .................................................................................................83 
13.1.3.1 Primary Efficacy Endpoint Analysis: Change From Baseline in 
Weekly CDSD GI Symptom Severity Score at Week 12 ...........................83 
13.1.3.2 Secondary Efficacy Endpoint Analysis .......................................................85 
13.1.3.3 Other Efficacy Endpoint Analyses ..............................................................86 
13.1.4 
PK Analysis .........................................................................................................87 
13.1.5 
 ................................................................................87 
13.1.6 
Pharmacodynamic Analysis ................................................................................87 
13.1.7 
Psychometric Analyses for CDSD ......................................................................88 
13.1.8 
Exit Interview Analysis .......................................................................................88 
13.1.9 
Safety Analysis ....................................................................................................88 
13.1.10 Immunogenicity Analysis ....................................................................................88 
13.2 
IA and Criteria for Early Termination .........................................................................89 
13.3 
Determination of Sample Size .....................................................................................90 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................90 
14.1 
Study Site Monitoring Visits .......................................................................................90 
14.2 
Protocol Deviations ......................................................................................................91 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................91 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................91 
15.1 
Subject Confidentiality ................................................................................................92 
15.2 
IRB and/or IEC Approval ............................................................................................92 
15.3 
Subject Information, Informed Consent/Pediatric Assent, and Subject 
Authorization ...............................................................................................................93 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................95 
15.4.1 
Publication and Disclosure ..................................................................................95 
15.4.2 
Clinical Trial Registration ...................................................................................95 
15.4.3 
Clinical Trial Results Disclosure .........................................................................95 
15.5 
Insurance and Compensation for Injury .......................................................................95 
16.0 
REFERENCES ..................................................................................................................96 
 
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LIST OF IN-TEXT TABLES 
Table 8.a 
Dose and Regimen .................................................................................................53 
Table 8.b 
Dose and Regimen .................................................................................................53 
Table 9.a 
Clinical Laboratory Tests .......................................................................................64 
Table 9.b 
Acceptable Contraception Methods and Lactation Guidance for This Study ........67 
Table 9.c 
Unacceptable Contraception Methods ...................................................................68 
Table 13.a 
 ..............................89 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................38 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ...............................................................................98 
Appendix B 
Schedule of PK Samples ......................................................................................103 
Appendix C 
Responsibilities of the Investigator ......................................................................104 
Appendix D 
Elements of the Subject Informed Consent .........................................................106 
Appendix E 
Investigator Consent to Use of Personal Information ..........................................109 
Appendix F 
Guidance on Liver Test Abnormality Monitoring, Evaluation, and Follow-up ..110 
Appendix G 
Rescue Medications .............................................................................................114 
Appendix H 
Protocol History ...................................................................................................115 
 
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2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Development Center Americas, Inc. 
Compound: 
TAK-062 
Title of Protocol: A Phase 2, Randomized, Double-blind, 
Placebo-Controlled, Dose-Ranging Study to Evaluate the 
Efficacy and Safety of TAK-062 for the Treatment of Active 
Celiac Disease in Subjects Attempting a Gluten-Free Diet 
IND No.: 137372 
EudraCT No.: 
2020-005438-14 
Study Number: TAK-062-2001 
Phase: 2 
Study Design: 
Despite attempts to maintain a gluten-free diet (GFD), many individuals with celiac disease (CeD) continue to 
have symptoms and/or intestinal damage due to inadvertent gluten exposure. TAK-062 is a computationally 
designed enzyme intended to reduce or prevent symptoms and intestinal damage related to gluten exposure. This 
is a 2-cohort phase 2, multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy 
and safety of TAK-062 for treatment of ongoing symptoms and small intestinal mucosal injury due to gluten 
exposure in subjects with CeD attempting to maintain a GFD. In addition, this study is designed to further 
evaluate the psychometric properties of the Celiac Disease Symptom Diary (CDSD) Version (v)2.1, 
 
, and to 
provide data on the optimal histologic measure for assessment of response to treatment in CeD.  
Approximately 357 subjects with CeD and both ongoing symptoms and small intestine villous atrophy on 
duodenal biopsy, despite attempting to maintain a GFD for at least 12 months, will be enrolled and randomly 
assigned into 1 of 2 treatment groups in the Cohort 1 proof of concept study and 1 of 6 treatment groups in the 
Cohort 2 dose-ranging study (see the Number of Subjects section below):  
The interim analysis (IA) will be initiated when at least 75% of the subjects in Cohort 1 have either completed 
12 weeks of treatment or have dropped out to determine inclusion of adolescents in Cohort 2. Cohort 1 data will 
be reviewed by an external independent data monitoring committee (IDMC) and shared with health authorities 
and independent ethics committees (IECs)/institutional review boards (IRBs) as required by region, before 
enrollment of adolescents in Cohort 2. If efficacy and safety data from Cohort 1 is considered acceptable, Cohort 
2 will also include adolescents aged 12 to 17 years. Adolescents will receive only gluten-free simulated 
inadvertent gluten exposure (SIGE) bars. 
This study will consist of 4 periods in each cohort: a 2- to 4-week screening period (Week -8 to Week -4), a 
4-week single-blind placebo run-in (Week -4 to Day -1), a 24-week double-blind treatment period (Week 0 to
Week 24), and a 4-week safety follow-up period. At the first visit (Week -8), subjects will consume 1 gluten-free
SIGE bar to ensure no intolerance to any of the nongluten components of the bar. During the screening period
(between Week -8 visit to Week -4 visit), subjects will complete the CDSD daily to confirm they have at least
1 ongoing CeD-related gastrointestinal (GI) symptom of moderate or greater severity on at least 3 days out of
any consecutive 7-day period. The CeD-related symptom(s) may vary day by day as long as the severity of at
least 1 symptom is moderate or greater. Eligible subjects will undergo an esophagogastroduodenoscopy (EGD)
with duodenal biopsy 
. In addition, a subset of
approximately 40 subjects in total will have a 
 and
before SIGE for a test/re-test assessment. During the screening period, urine samples will be collected once per
week for gluten immunogenic peptide (GIP) to assess systemic exposure to gluten.
During the single-blind run-in period (Week -4 through Day -1), subjects will receive TAK-062 placebo 
 
 
 
 
 
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. Beginning Week -8, urine samples (first morning void) will be collected once per week 
for GIP throughout the study. 
 
 
 
 While all efforts should be made to obtain weekly urine 
samples, missed urine GIP samples will not be considered a protocol deviation. 
Eligible subjects with villous atrophy on duodenal biopsy (defined as villous height–to–crypt depth ratio [Vh:Cd] 
<2.5 by central pathology assessment) will be randomly assigned to 1 of 2 treatment groups in Cohort 1 or 1 of 
6 treatment groups in Cohort 2 to receive double-blind treatment and gluten-containing SIGE or gluten-free 
SIGE (Cohort 2) for 24 weeks (Day 1 through Week 24). Initially, all subjects who meet symptom criteria and 
histologic criteria will be randomized. If more than 10% of planned enrollment in a cohort report a greater than 
1 point improvement in Patient Global Impression of Severity during 
 run-in period (Week -2 through 
Day -1), further subjects showing this degree of improvement will be excluded from the cohort. 
Randomization will be stratified by celiac serologic status at Visit 1, defined as normal or elevated celiac 
serology (1 or more of the following: IgA-tissue transglutaminase (tTg) >1 time the upper limit of normal 
[ULN], IgA–deaminated gliadin peptide [DGP] >2 × ULN, or IgG-DGP >2 × ULN), mild to moderate (Vh:Cd 
1.5 to <2.5) versus moderate to severe (Vh:Cd <1.5) histologic injury at baseline, and by use of proton pump 
inhibitors (PPIs) or histamine type 2 receptor antagonists (yes or no) at Visit 1. 
In Cohort 1, all subjects will consume gluten-containing SIGE bars 
 
with a meal 
 
In Cohort 2, adult subjects will receive either gluten-containing or gluten-free SIGE bars with a meal 
 
 throughout the treatment period. 
 
 
 It is expected that SIGE will 
result in stable, rather than worsening, symptoms and enteropathy in the TAK-062 placebo groups. If a subject 
has severe symptoms of diarrhea, nausea, vomiting, or abdominal spasm, that are related to their CeD symptoms, 
the use of the medications to treat these severe symptoms will be considered as rescue medications. 
Subjects will report symptoms daily using the CDSD from Week -8 through Week 24.  
EGD with biopsy will again be performed at the end of the 24-week treatment period (Week 24). 
 
  
Sparse blood samples to evaluate the pharmacokinetics (PK) of TAK-062 in plasma will be collected in all 
subjects at Weeks -4, 0, 3, 12, 24, and 28. Approximately 10 adult subjects enrolled in Cohort 1 and 30 adult 
subjects enrolled in Cohort 2 will participate in the PK subgroup for slightly more intensive collections at 
Week 0 (randomization) and Week 3 visits. 
There is a safety follow-up visit at Week 28, 4 weeks after the last date of treatment.  
A diagram of the study design for Cohorts 1 and 2 is located below. 
 
EGD: esophagogastroduodenoscopy; EOT: end of treatment; SIGE: simulated inadvertent gluten exposure; 
 
 
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 1
Screening
Visit
Symptom 
Screening
Week -8
Week -4
Week 0
Week 3
Week 12
Week 24
Week 28
Randomization
EOT Visit
Follow-up Visit
Screening
Run-in
Study Drug Treatment
(TAK-062 or Placebo + SIGE Bar)
Follow-up
EGD & 
EGD & 
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Primary Objective: 
The primary objective of this study is: 
• 
To evaluate the efficacy of TAK-062, as measured by the CDSD, for reducing celiac-related symptoms due 
to gluten exposure in subjects with CeD attempting to maintain a GFD in treated subjects versus placebo 
controls. 
Secondary Objectives: 
The secondary objectives of this study are: 
• 
To evaluate the efficacy of TAK-062 for improvement of small intestine mucosal injury due to gluten 
exposure in subjects with CeD attempting to maintain a GFD in treated subjects versus placebo controls. 
• 
To evaluate the safety and tolerability of TAK-062. 
Subject Population: All subjects will be human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8 positive, have 
biopsy-confirmed disease that is clinically active with ongoing GI symptoms as measured by the CDSD and 
small intestinal villous atrophy on duodenal biopsy, and have been attempting to maintain GFD for ≥12 months. 
Adolescents and a maximum of 20% of adult subjects without a producible initial biopsy report confirming CeD 
may be enrolled if they meet the following inclusion criteria: 
a) Serology (IgA-tTg) at diagnosis or subsequent visit is at least 2 times the ULN. 
b) Histology at screening biopsy at Week -4 must be consistent with Marsh-Oberhuber score of 2 or 
greater as read by a central pathologist.  
Subjects aged 18 and older will be included in Cohort 1. Cohort 1 data will be reviewed by an external IDMC 
and shared with health authorities and IECs/IRBs as required by region, before enrollment of adolescents in 
Cohort 2. If data suggests an appropriate benefit-risk profile, Cohort 2 will also include adolescents aged 12 to 
17 years, inclusive following IDMC review at IA. Adolescents will receive only gluten-free SIGE bars. Inclusion 
of subjects older than 75 years of age will require discussion with the study medical monitor prior to enrollment. 
Number of Subjects: 
Approximate total: 357 randomized subjects 
Cohort 1 (120 adults): 
1. TAK-062 placebo 
 before 
the start of a meal + gluten-containing SIGE bar with a 
meal 
: 60 subjects.  
2. TAK-062 
 before 
the start of a meal + gluten-containing SIGE bar with a 
meal 
: 60 subjects. 
Cohort 2 (216 adults and 21 adolescents): 
1. TAK-062 placebo 
 before 
the start of a meal + gluten-containing SIGE bar with a 
meal 
: 30 subjects (adults only). 
2. TAK-062 
 before 
the start of a meal + gluten-containing SIGE bar with a 
meal 
: 50 subjects (adults only).  
3. TAK-062 
 before 
the start of a meal + gluten-containing SIGE bar with a 
meal 
: 50 subjects (adults only). 
4. TAK-062 placebo
 before 
the start of a meal + gluten-free SIGE bar with a meal 
: 50 subjects (43 adults, 7 adolescents). 
5. TAK-062 
 before 
the start of a meal + gluten-free SIGE bar with a meal 
: 50 subjects (43 adults, 7 adolescents). 
Number of Sites:  
Approximate total: 110 sites in the United States, 
Canada, United Kingdom, and the European 
Union 
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6. TAK-062 
 + gluten-free SIGE bar 
: 7 
subjects (adolescents only). 
Dose Levels: 
TAK-062 
. 
TAK-062 
. 
TAK-062 
. 
Placebo 
  
Route of Administration: 
TAK-062 tablets orally.  
Duration of Treatment: 
24 weeks. 
Period of Evaluation: 
Approximately 36 weeks. 
Main Criteria for Inclusion: 
• 
Biopsy-confirmed CeD. 
• 
Attempting to maintain GFD for at least 12 months as self-reported by the subject. 
• 
Adequate comprehension of a GFD assessed by the site investigator after completion of a knowledge test. 
• 
Small intestinal villous atrophy on duodenal biopsy defined as Vh:Cd <2.5 at Week -4. 
• 
At least 1 CeD-related GI symptom of moderate or greater severity, as measured by the CDSD, on at least 3 
days out of any consecutive 7-day period during the screening period (Week -8 visit until Week -4 visit) felt 
by the investigator to be related to gluten exposure. The CeD-related symptom(s) may vary day by day as 
long as the severity of at least 1 symptom is moderate or greater. Subjects must meet symptom criteria to 
undergo EGD/VCE. 
• 
HLA-DQ2 and/or HLA-DQ8 positive. 
• 
For Cohort 1, subjects aged 18 years and older at the time of signing the informed consent form; for 
Cohort 2, subjects aged 12 years and older, at the time of signing the informed consent form/pediatric assent 
form. Inclusion of subjects older than 75 years of age will require discussion with the study medical monitor 
prior to enrollment. Subjects 12 to 17 years of age, inclusive, will only be included in Cohort 2 after IDMC 
review at the IA. 
• 
Good general state of health according to clinical history and physical examination, in the opinion of the 
investigator. 
Main Criteria for Exclusion: 
Subjects with: 
1. Presence of other inflammatory GI disorders or systemic autoimmune diseases that either have the potential 
to cause persistent GI symptoms similar to CeD or are not well controlled without the use of excluded 
medications.  
• 
Examples of conditions that are exclusionary include inflammatory bowel disease, eosinophilic 
gastroenteritis or colitis, and microscopic colitis requiring treatment in the 6 months before screening. 
• 
Examples of conditions that may be permissible after discussion with the medical monitor include 
systemic autoimmune disease such as scleroderma, psoriatic or rheumatoid arthritis, or lupus that is 
stable and without GI involvement; well-controlled autoimmune thyroid disease; well-controlled type 1 
diabetes; or PPI-responsive eosinophilic esophagitis in symptomatic and histologically confirmed 
remission.  
2. Renal or hepatic disease before randomization based on the following laboratory parameters:  
• 
Total bilirubin ≥1.5 × ULN unless subject has known Gilbert’s syndrome that can explain the elevation 
of bilirubin, or 
• 
Serum alanine aminotransferase ≥3 × ULN, or serum aspartate aminotransferase ≥3 × ULN. 
• 
Glomerular filtration rate (GFR) <49 mL/min. For subjects with GFR 49 to 59 mL/min, inclusion 
determination should be discussed with the sponsor. 
Note: Subjects may be retested to meet eligibility criteria at the discretion of the investigator. 
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3. Ongoing systemic immunosuppressant, systemic corticosteroid treatment excluding medication given for 
endoscopies, or treatment with systemic immunosuppressants or corticosteroids in the 12 weeks before 
screening. 
• 
Receiving immunosuppressive doses of corticosteroids: 3 mg per day or more of budesonide for more 
than 3 consecutive days within 3 months before screening, more than 20 mg of prednisone given daily 
or on alternative days for 2 weeks or more within 6 months before the first dose, any dose of oral or IV 
corticosteroids within 30 days of the first dose, or high-dose inhaled corticosteroids (>960 µg/day of 
beclomethasone dipropionate or equivalent), or other systemic immunosuppressive agents. 
4. Ongoing use of over-the-counter digestive enzymes or digestive supplements, other than lactase, including 
those for gluten digestion. Probiotics are allowable if they were started before screening and not 
discontinued or changed in dose or type during the study. 
5. Ongoing symptoms that are considered by the investigator to be due to other GI conditions, including 
irritable bowel syndrome, small intestinal bacterial overgrowth, and eosinophilic disorders. 
6. Known or suspected type 2 refractory CeD or ulcerative jejunitis. 
7. Completed the CDSD on ≤75% of evaluable days during the run-in period until randomization. 
Main Criteria for Evaluation and Analyses: 
The primary endpoint is: 
• 
Change in weekly CDSD GI symptom severity score from baseline (Week -1) to Week 12. 
The secondary endpoints are: 
• 
Change in Vh:Cd from baseline (measured at Week -4) to Week 24. 
The safety endpoints are: 
• 
Treatment-emergent adverse events (TEAE), serious adverse events (SAEs), treatment-related TEAEs, 
electrocardiographic findings (electrocardiogram), vital signs, laboratory parameters, and immunogenicity 
(posttreatment, positive antidrug antibodies [ADAs] in serum for TAK-062). 
Statistical Considerations: 
Analysis Sets: 
Full analysis set (FAS)–SIGE: All randomized subjects who are randomized to receive gluten-containing SIGE 
bar.  
FAS–no SIGE: All randomized subjects who are randomized to gluten-free SIGE bar.  
Safety analysis set (SAF): All randomized subjects who received at least 1 dose of study drug.  
SAF–SIGE: All randomized subjects who received at least 1 dose of study drug and gluten-containing SIGE bar.  
SAF–no SIGE: All randomized subjects who received at least 1 dose of study drug and gluten-free SIGE bar.  
Per-protocol set (PPS)–SIGE: All subjects in FAS-SIGE who do not violate the terms of the protocol in a way 
that would impact the study outcome. All decisions to exclude subjects for the PPS-SIGE will be made before 
the unblinding of the study.  
The PK analysis set: All randomized subjects who received at least 1 dose of study drug with at least 1 measured 
PK concentration.  
Immunogenicity analysis set: All randomized subjects who received any TAK-062 and have the baseline and at 
least 1 postbaseline immunogenicity sample assessment.  
Efficacy Analysis: 
Primary Efficacy Analysis: The primary efficacy analysis will be based on FAS-SIGE. The weekly CDSD GI 
symptom severity score is an average of the daily GI symptom severity scores during the week. The daily GI 
symptom severity score is the average of the severity score for diarrhea, abdominal pain, bloating and nausea, 
ranging from 0 (no symptoms) to 4 (very severe). Weekly CDSD GI symptom severity scores will be calculated 
where the CDSD is completed on at least 4 of the 7 days. When the daily diary is completed on less than 4 of the 
7 days, the weekly CDSD GI symptom severity score will be considered missing. The attributes of the primary 
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estimand are: 
• 
Population: Subjects with clinically active CeD and small intestinal villous atrophy who are experiencing 
inadvertent gluten exposure and meet all eligibility criteria. 
• 
Variable/endpoint: Change in weekly CDSD GI symptom severity score from baseline to Week 12 
• 
Treatments: TAK-062 (
) versus placebo. 
• 
Intercurrent events (ICEs): Treatment discontinuation (due to adverse events [AEs] or other reasons), SIGE 
discontinuations, and use of rescue medications for CeD symptoms. 
Strategy for addressing ICEs: A composite strategy will be used to address rescue medication use and 
treatment discontinuation due to lack of efficacy or treatment-related AEs. For subjects who use rescue 
medications for CeD-related symptoms, the severity of the treated GI symptom(s) in CDSD on the days 
when the rescue medications are used will be set to very severe. For subjects who discontinue treatment due 
to lack of efficacy or treatment-related AEs, the Week 12 CDSD GI symptom severity score will be set to 
the baseline (Week -1) weekly CDSD GI symptom severity score. A treatment policy strategy will be used 
to address SIGE discontinuation (ie, the recorded weekly CDSD GI symptom severity scores will be used 
regardless of whether a subject has discontinued SIGE) and treatment discontinuation due to reasons other 
than lack of efficacy or treatment-related AEs. 
• 
Population-level summary: Treatment difference (TAK-062 – placebo) in the mean change from baseline to 
Week 12 in weekly CDSD GI symptom severity score, for each dose level. 
The primary endpoint will be analyzed with a mixed model for repeated measures (MMRM) approach using the 
appropriate contrast at Week 12. The model will be based on all available weekly CDSD GI symptom severity 
scores from Week -1 through Week 12. The model will include treatment group, week, treatment-by-week 
interaction, and the randomization stratification factors as fixed effects and baseline CDSD GI symptom severity 
score as covariates. An unstructured covariance structure will be used to model the within-subject errors. If the 
model does not converge, additional covariance structure will be used with the order specified in the statistical 
analysis plan (SAP). Two-sided tests comparing each of the TAK-062 dose groups with placebo at Week 12 will 
be conducted. The corresponding p-values, LS means of treatment differences and 2-sided 95% CI will be 
reported. The MMRM assumes data is missing at random. Sensitivity analysis will be performed with an 
alternative assumption that data is missing not at random. Supplementary analyses will be performed for the 
overall CDSD symptom severity score using the same approach as in the primary analysis. 
Secondary Efficacy Analysis: The secondary efficacy analysis will be based on FAS-SIGE. The estimand 
framework corresponding to each secondary efficacy analysis has the same attributes in population, treatments, 
and ICEs as for the primary estimand. The variable/endpoint attributes for the secondary analysis are: 
• 
Change in Vh:Cd from baseline (measured at Week -4) to Week 24. 
The corresponding population-level summaries are: 
• 
Treatment difference (TAK-062 – placebo) in the mean change from baseline (measured at Week -4) to 
Week 24 in Vh:Cd for each dose level. 
The analysis will be conducted using analysis of covariance. The model will include treatment group and the 
randomization stratification factors as fixed effects and baseline values as covariate. Missing values will be 
regarded as missing at random. Missing data will be handled using multiple imputation (details will be provided 
in the SAP). The LS means and 2-sided 95% CI will be provided for the Week 24 treatment difference between 
the 
 TAK-062 dose groups versus placebo, respectively. Nominal 2-sided p-values will be 
provided for the comparison of 
 TAK-062 versus placebo, 
 TAK-062 versus placebo, and 
 
TAK-062 versus placebo, respectively. 
The placebo group includes all subjects randomized to receive placebo 
 and gluten-containing SIGE bar 
 
in Cohorts 1 and 2 in all analyses unless specified otherwise. 
Multiplicity Control: To control the overall Type I error rate for the primary efficacy endpoint, a fixed-sequence 
testing procedure will be used for the comparison of 3 doses of TAK-062 versus placebo. Specifically, the 
primary endpoint tested will be conducted in the following order:  
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i. 
First, 
 TAK-062 versus placebo for subjects taking gluten-containing SIGE. 
ii. 
If the test in Step 1 is statistically significant, then perform the test comparing 
 TAK-062 versus 
placebo for subjects taking gluten-containing SIGE. 
iii. 
If the test in Step 2 is statistically significant, then perform the test comparing 
 TAK-062 versus 
placebo for subjects taking gluten-containing SIGE. 
Sample Size Justification:  
The planned sample size is approximately 357 subjects. For a 2-sample comparison of means, 0.5 standardized 
mean difference is regarded as a medium effect size. A sample size of 53 subjects per treatment group will 
provide 80% power to detect a standardized mean difference (mean difference/SD) of 0.55 between 
 
TAK-062 and placebo in the change from baseline in weekly CDSD GI symptom severity score (assuming a 
common SD) for a 2-sided statistical hypothesis test, using a 2-sample t-test and a 5% significance level. 
Assuming a dropout rate of approximately 12%, a sample size of 60 subjects per treatment group for the 
 
and placebo arms in the gluten-containing SIGE group (Cohort 1) will be the planned enrollment.  
The planned enrollment for Cohort 2 is 30 and 50 subjects per treatment arm in the placebo and active (
 
 TAK-062) respectively, in the gluten-containing SIGE arms; 50 subjects (43 adults and 7 adolescents) 
per arm in the 
 and placebo gluten-free SIGE bar arms; and 7 subjects (adolescents only) in the 
 
gluten-free SIGE bar arm. The analysis to detect the difference between the combined placebo gluten-containing 
SIGE group and the active group would yield a higher power.  
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3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities 
The sponsor will perform oversight of all study-related activities. Qualified vendors will be 
identified to perform study-related activities in full or in partnership with the sponsor. 
3.2 
Coordinating Investigator 
Takeda may select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study drug, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The signatory coordinating investigator will be required 
to review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study. 
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3.3 
List of Abbreviations 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
Cd 
crypt depth 
CDAQ 
Coeliac Disease Assessment Questionnaire 
CD-QoL 
celiac disease quality of life 
CDSD 
Celiac Disease Symptom Diary 
CeD 
celiac disease 
CeD-GSRS 
Celiac Disease Gastrointestinal Symptom Rating Scale 
CFR 
Code of Federal Regulations 
 
 
COVID-19 
coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
DGP 
deaminated gliadin peptide 
ECG 
Electrocardiogram, electrocardiographic 
eCRF 
electronic case report form 
EGD 
esophagogastroduodenoscopy 
EQ-5D-5L 
EuroQol-5 Dimensions-5 Levels 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GFD 
gluten-free diet 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
GIP 
gluten immunogenic peptide 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HLA 
human leukocyte antigen 
HRQOL 
health-related quality of life 
IA 
interim analysis 
IB 
investigator’s brochure 
ICDSQ 
Impact of Celiac Disease Symptoms Questionnaire 
ICE 
intercurrent event 
ICH 
International Conference on Harmonisation 
ID 
identification (number) 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IEL 
intraepithelial lymphocyte 
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INR 
international normalized ratio 
IRB 
institutional review board 
IRT 
interactive response technology 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
NAb 
neutralizing antibody 
NOAEL 
no-observed-adverse-effect level 
PAP 
psychometric analysis plan 
PCR 
polymerase chain reaction 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity  
PK 
pharmacokinetic(s) 
PPI 
proton pump inhibitor 
PPS 
per-protocol set 
PRO 
patient-reported outcome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PTE 
pretreatment event 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SF-12 
Short Form 12-Item 
SIGE 
simulated inadvertent gluten exposure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
 
 
 
 
tTg 
tissue transglutaminase 
ULN 
upper limit of normal 
US 
United States 
v 
Version 
VCE 
video capsule endoscopy 
Vh 
villous height 
Vh:Cd 
villous height–to–crypt depth ratio 
WOCBP 
woman of childbearing potential 
WPAI+CIQ:CeD 
Work Productivity and Activity Impairment Plus Classroom Impairment Questionnaire: Celiac 
Disease 
3.4 
Corporate Identification 
TDC Americas 
Takeda Development Center Americas, Inc. 
 
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4.0 
INTRODUCTION 
4.1 
Background 
Despite attempts to maintain a gluten-free diet (GFD), many individuals with celiac disease 
(CeD) continue to have symptoms and/or intestinal damage due to gluten exposure. TAK-062 is 
a computationally designed enzyme intended to reduce or prevent symptoms and intestinal 
damage related to gluten exposure (Pultz et al. 2021). TAK-062 is being investigated as an 
adjunct to a GFD for the treatment of moderate to severe symptomatic CeD in patients with 
inadequate response to dietary modifications and signs of small intestine mucosal injury. The 
primary goal of this study is to assess the efficacy and safety of TAK-062 for treatment of 
symptoms and intestinal damage related to inadvertent gluten exposure in subjects with CeD. To 
robustly assess protection from real-world gluten exposure, the study will use food bars 
containing a small amount of gluten, referred to as simulated inadvertent gluten exposure 
(SIGE).  
The study will have 2 cohorts; in Cohort 1, safety and efficacy of TAK-062 will be evaluated in 
adult subjects at the highest dose (
) in the presence of SIGE; in Cohort 2, safety and 
efficacy of TAK-062 will be evaluated at 3 doses (
) in adults with gluten-
containing and gluten-free SIGE and at 2 doses (
) in adolescent subjects with 
gluten-free SIGE. The interim analysis (IA) will be initiated when at least 75% of the subjects in 
Cohort 1 have either completed 12 weeks of treatment or have dropped out, to determine 
inclusion of adolescents in Cohort 2. Cohort 1 data will be reviewed by an external independent 
data monitoring committee (IDMC) and shared with health authorities and independent ethics 
committees (IECs)/institutional review boards (IRBs) as required by region, before enrollment of 
adolescents in Cohort 2. If efficacy and safety data from Cohort 1 is considered acceptable, 
Cohort 2 will also include adolescents aged 12 to 17 years, inclusive. Adolescents will receive 
only gluten-free SIGE bars. 
In addition, this study has 3 other important goals:  
1. Evaluation of the psychometric properties of the Celiac Disease Symptom Diary (CDSD) 
Version (v)2.1. The CDSD has been developed specifically for CeD. This study will include 
additional patient-reported outcomes (PROs) such as the Patient Global Impression of 
Severity (PGIS), Patient Global Impression of Change (PGIC), and Celiac Disease 
Gastrointestinal Symptom Rating Scale (CeD-GSRS) to facilitate psychometric evaluation of 
the CDSD, which may enable the CDSD to be used as a primary endpoint in future studies. 
Results from CDSD psychometric assessment will be reported in a separate psychometric 
report. 
2. To provide data on the optimal histologic measure for assessment of response to treatment in 
CeD. While there is consensus that assessment of change in small intestinal mucosal injury 
and intraepithelial lymphocyte (IEL) infiltration is important in studies of CeD treatment, the 
optimal histologic endpoint for use in clinical studies is unclear. This study will assess the 
utility of quantitative and qualitative histologic endpoints (eg, IEL counts, villous height 
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[Vh], crypt depth [Cd], villous height–to–crypt depth ratio [Vh:Cd], Marsh-Oberhuber score) 
to inform future studies. 
 
 
 
 
 
 
 
 
 
4.1.1 
Disease State Background 
CeD is a multisystem autoimmune disease triggered by ingestion of dietary gluten in genetically 
susceptible individuals (Ludvigsson et al. 2013). Deamidated gluten peptides can bind with high 
affinity to human leukocyte antigen (HLA)-DQ2/DQ8 on antigen-presenting cells, which elicits 
T cell-driven cytotoxic and antibody-mediated immune responses. Intestinal injury is 
predominantly cell-mediated and characterized by villous atrophy, crypt hyperplasia, and 
infiltration of lymphoid cells into both the epithelium and lamina propria. CeD is one of the most 
common immune-mediated gastrointestinal (GI) diseases and can affect individuals at any age, 
although most diagnoses occur in late adolescence and early adulthood.  
Currently, there are no approved therapies for CeD and the only option for patients is a GFD that 
involves strict lifelong avoidance of exposure to >20 ppm of gluten proteins from wheat, barley, 
and rye as stipulated by The Codex Standard for Foods for Special Dietary Use for Persons 
Intolerant to Gluten (Codex Alimentarius 2015). The threshold of daily gluten that will cause 
mucosal injury in both adults and children is thought to be 10 to 50 mg/day, or about one-
hundredth of a slice of bread (Catassi et al. 2007; Gibert et al. 2013). However, there are reports 
of patients where even a single milligram of gluten, an amount impossible to avoid in daily life, 
can prevent adequate clinical disease control (Biagi et al. 2004). 
The majority of patients report frequent symptoms related to gluten exposure despite attempts at 
gluten avoidance (Hall et al. 2013). More than 70% of patients with CeD are not satisfied with 
the GFD due to the combination of ongoing symptoms and/or high burden of maintenance of 
lifelong strict dietary restriction (Barratt et al. 2011).  
Disease control attained with the GFD has traditionally been grouped into 3 categories. The first 
category is responsive disease whereby dietary modification results in resolution of small 
intestine mucosal injury and infrequent or minor ongoing symptoms and represents 70% of the 
CeD population. The majority of the remaining 30% of the CeD population fall into the second 
category and have what is known as persistently active CeD, which is defined by ongoing 
symptoms and/or small intestine mucosal injury despite dietary modification (Leonard et al. 
2017). The most common reason for persistently active CeD is inadvertent gluten exposure. It is 
these patients, with ongoing symptoms and intestinal damage felt to be related to gluten 
exposure, who are the intended subjects in this study. Less than 1% of patients have refractory 
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CeD, the third category, in which there are ongoing severe symptoms and small intestine 
mucosal injury despite demonstrated gluten avoidance. 
4.2 
Rationale for the Proposed Study 
Phase 1 studies have demonstrated robust gluten digestion, acceptable pharmacokinetic (PK) 
characteristics and no safety concerns to date. This study will be the first phase 2 study to test the 
efficacy and safety of TAK-062 in subjects with CeD on a GFD. 
4.3 
Benefit-Risk Profile 
Oral enzyme supplementation with a highly effective glutenase has the potential to meet a 
significant unmet medical need for a pharmacologic intervention used as an adjunct to a GFD. In 
particular, given its ability to effectively and rapidly degrade gluten in vitro and in vivo, as well 
as its favorable safety profile in clinical and nonclinical studies to date, further development of 
TAK-062 for subjects with CeD is warranted. 
Repeat-dose nonclinical studies have shown no TAK-062–related toxicity up to the highest 
evaluated dose of 2000 mg/kg/day (limit dose) in both rats (up to 6 months) and monkeys (up to 
13 weeks), and no effects on embryofetal development in the rat or rabbit (see IB for further 
detail). Based on the human equivalent dose the no-observed-adverse-effect level (NOAEL) of 
1000 mg/kg administered orally twice per day (2000 mg/kg/day) in the 6 month general toxicity 
study in the rat and the 13-week general toxicity studies in the cynomolgus monkey, this 
provides a margin of 10.8 and 21.5 relative to the proposed high dose of 
 
 in humans, respectively. 
Antidrug antibodies (ADAs) were seen in nonclinical studies but are not considered predictive 
for the development of ADAs in humans. Clinical ADAs were nonneutralizing, not associated 
with adverse event (AE), and had no measurable impact on gluten degradation. Development of 
ADA to TAK-062 liquid and capsule formulations was evaluated in Parts 1 and 2, and 
development of ADA to TAK-062 tablet formulation was evaluated in Parts 3 and 4 of the 
phase 1 clinical study (PvP-102-01). 
Currently, there are no important identified or important potential risks associated with TAK-062 
treatment based on the evidence from phase 1 clinical studies and nonclinical toxicology studies. 
However, ADA is considered a potential risk with the administration of TAK-062 based on 
limited data in the phase 1 clinical trial, and this will be monitored in this study and future 
studies. Cohort 1 data will be reviewed by an external IDMC and shared with health authorities 
and IECs/IRBs as required by region, before enrollment of adolescents. If efficacy and safety 
data from Cohort 1 is considered acceptable, Cohort 2 also will include adolescents aged 12 to 
17 years, inclusive. Adolescent subjects will be randomized into the gluten-free SIGE groups 
only. 
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Potential risks are based on symptoms related to gluten exposure and testing related to study 
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 GI 
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% (Levy 
and Gralnek 2016). Clinical evaluation of subjects before endoscopy will be completed 
according to established site protocols. 
 
 
 
 
 
 
 
 
 
  
In summary, there have been no safety signals and no important identified or important potential 
risks associated with TAK-062 treatment based on the data from phase 1 clinical studies and 
toxicology studies to date. 
• The development of ADA is a potential risk. 
• There has been 1 unrelated serious adverse event (SAE) reported across the clinical program 
to date. 
• There was no evidence of systemic exposure to TAK-062 liquid and capsule formulations 
after treatment with any dose administered in phase 1 studies. 
• There are no AE designated as AEs of special interest for TAK-062.  
• AEs and SAEs will continue to be routinely monitored in ongoing studies and future studies.  
Overall, the phase 1 and nonclinical study results are not suggestive of any safety risks related to 
TAK-062 for the ongoing development program; the benefit-risk profile is, therefore, considered 
appropriate to support the continuation of the clinical development program for TAK-062 for 
CeD indication as planned.  
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective 
The primary objective of this study is: 
• To evaluate the efficacy of TAK-062, as measured by the CDSD, for reducing celiac-related 
symptoms due to gluten exposure in subjects with CeD attempting to maintain a GFD in 
treated subjects versus placebo controls. 
5.1.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To evaluate the efficacy of TAK-062 for improvement of small intestine mucosal injury due 
to gluten exposure in subjects with CeD attempting to maintain a GFD in treated subjects 
versus placebo controls. 
• To evaluate the safety and tolerability of TAK-062. 
5.1.3 
Exploratory/Additional Objectives 
The exploratory/additional objectives of this study are: 
• To further evaluate the psychometric properties of the CDSD in symptomatic subjects with 
CeD. 
• To evaluate the efficacy of TAK-062 on reducing their most bothersome symptom. 
• To evaluate the treatment effect of TAK-062 on IEL counts and quantitative and qualitative 
histological measures of disease severity.  
• To evaluate immunogenicity to TAK-062. 
• To evaluate the effect of TAK-062 on quality of life and additional PROs. 
• To evaluate the effect of TAK-062 on celiac serology titers. 
• To evaluate the relationship between PROs and histological measures of intestinal injury. 
• To evaluate the effect of SIGE on response to therapy with TAK-062. 
• To evaluate urine gluten immunogenic peptide (GIP) detection as a means of monitoring 
gluten exposure and response to therapy. 
 
 
 
 
 
• To characterize the PK of TAK-062 in subjects with CeD attempting to maintain a GFD. 
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5.2 
Endpoints 
5.2.1 
Primary Endpoint 
The primary endpoint is: 
• Change in weekly CDSD GI symptom severity score from baseline (Week -1) to Week 12. 
5.2.2 
Secondary Endpoint 
The secondary endpoint is: 
• Change in Vh:Cd from baseline (measured at Week -4) to Week 24. 
5.2.3 
Safety Endpoints 
Treatment-emergent adverse events (TEAEs), SAEs, treatment-related TEAEs, 
electrocardiographic (ECG) findings, vital signs, laboratory parameters, and immunogenicity 
(posttreatment, positive ADA in serum for TAK-062). 
5.2.4 
Exploratory/Additional Endpoints 
Exploratory/additional endpoints (baseline assessments made 
 unless 
specified otherwise) are: 
Impact of SIGE: 
• Differences in responses in CeD endpoints including PROs, celiac serology, histology 
 
 will be assessed between SIGE and gluten-free SIGE bar arms. 
PRO Outcomes: 
• Change in CDSD GI symptom severity score from Week -8 and Week -1 to Week 24. 
• Change in CDSD GI symptom severity score from Week -8 to Week 12. 
• PGIC at Weeks 0, 12, and 24. 
• Percent of subjects reporting each symptom on the CeD Most Bothersome Symptom 
Questionnaire at each time point measured.  
• Change from Week -8 and Week -1 to Week 12 and Week 24 in the following PROs:  
– Weekly score of the most bothersome symptom as reported by the CDSD. 
– Severity rating or frequency of each item (symptom) of the CDSD. 
– Frequency of constipation based on the CDSD. 
– Proportion of minimal symptom days per week (defined as days with none or no more 
than 1 mild score of either bloating, abdominal pain, nausea, or diarrhea) as reported on 
the CDSD. 
– Proportion of symptom-free days per week as reported on the CDSD. 
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– Impact of Celiac Disease Symptoms Questionnaire (ICDSQ).  
– PGIS.  
– Patient-Reported Outcomes Measurement Information System (PROMIS)—Cognitive 
Function Instrument. 
– PROMIS—Fatigue Instrument. 
– Short Form 12-Item (SF-12) Health Survey. 
– EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) health survey.  
– Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire: 
Celiac Disease (WPAI+CIQ: CeD).  
– CeD-GSRS. 
– Coeliac Disease Assessment Questionnaire (CDAQ). 
– Celiac disease quality of life (CD-QoL) questionnaire. 
Serology titers: 
• Change from baseline (Week -8) to Week 24 in celiac serology titers.  
Histological endpoints: 
• Proportion of subjects achieving mucosal remission (Vh:Cd ≥3) at Week 24. 
• Change from baseline (Week -4) to Week 24 in IEL counts. 
• Change from baseline (Week -4) to Week 24 in Marsh-Oberhuber scores, both qualitatively 
assessed and calculated from IEL and Vh:Cd results. 
• Change from baseline (Week -4) to Week 24 in individual Vh and Cd measurements. 
• Proportion of subjects with an increase of ≥0.5, ≥0.75, and ≥1 in Vh:Cd from baseline 
(Week -4) to Week 24. 
  
 
 
 
 
 
 
 
 
 
GIP endpoints: 
• Frequency of positive urine GIP tests in subjects across the different treatment groups. 
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PK 
• Plasma concentration of TAK-062. 
6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a 2-cohort phase 2, multicenter, double-blind, randomized, placebo-controlled, dose-
ranging study to evaluate the efficacy and safety of multiple dose levels of TAK-062 for the 
treatment of ongoing symptoms and small intestinal mucosal injury due to gluten exposure in 
subjects with CeD attempting to maintain a GFD. In addition, this study is designed to further 
evaluate the psychometric properties of the CDSD 
 
 
Cohort 1 will have approximately 120 adult subjects. After the IA, a decision will be made by 
the sponsor on whether to begin enrollment of adolescents in Cohort 2. Cohort 1 data will be 
reviewed by an external IDMC and shared with health authorities and IECs/IRBs as required by 
region, before enrollment of adolescents in Cohort 2. If efficacy and safety data from Cohort 1 is 
considered acceptable, Cohort 2 will also include adolescents aged 12 to 17 years, inclusive after 
IDMC review at IA. If initiated, Cohort 2 will include approximately 216 adults and 
21 adolescents aged 12 to 17 years, inclusive. 
In Cohort 1, all subjects will consume gluten-containing SIGE bars 
 
 with a meal 
). In Cohort 2, adult subjects 
will receive either gluten-containing or gluten-free SIGE bars, 
 with a 
meal throughout the treatment period. 
 
 
. On-study gluten intake will be assessed by 
measuring GIP in urine. It is expected that SIGE will result in stable, rather than worsening, 
symptoms 
 and in the placebo groups. Adolescents in Cohort 2 will 
receive only gluten-free SIGE bars. 
Cohort 1 (120 adults) 
Cohort 1 will consist of 120 adult subjects randomly assigned to receive 1 of 2 treatments: 
1. TAK-062 placebo 
 + gluten-containing SIGE bar 
: 60 subjects. 
2. TAK-062 
 + gluten-containing SIGE bar 
: 60 subjects. 
Cohort 2 (216 adults and 21 adolescents) 
Cohort 2 will consist of approximately 237 subjects overall. Approximately, 216 adult subjects 
to be enrolled and randomly assigned into 1 of 5 study drug and SIGE treatment groups 
(Groups 1-5), and approximately 21 adolescent subjects to be enrolled and randomly assigned 
into Groups 4, 5, and 6 (adolescents only). 
1. TAK-062 placebo 
 + gluten-containing SIGE bar 
: 30 subjects (adults only).  
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2. TAK-062 
 + gluten-containing SIGE bar 
: 50 subjects (adults only). 
3. TAK-062 
 + gluten-containing SIGE bar 
: 50 subjects (adults only). 
4. TAK-062 placebo 
 + gluten-free SIGE bar 
: 50 subjects (43 adults, 7 adolescents). 
5. TAK-062 
 + gluten-free SIGE bar 
: 50 subjects (43 adults, 7 adolescents). 
6. TAK-062 
 + gluten-free SIGE bar 
: 7 subjects (adolescents only). 
The study period will consist of 4 periods in each cohort: a 2- to 4-week screening period, a 
4-week single-blind placebo run-in, a 24-week double-blind treatment period, and a 4-week 
safety follow-up period. At the first visit (Week -8), the subject will consume 1 gluten-free SIGE 
bar, and will be excluded if they develop significant symptoms suggesting a confounding 
nongluten food intolerance. During the screening period (between Week -8 visit to Week -4 
visit), subjects will complete the CDSD daily to confirm they have at least 1 ongoing CeD-
related GI symptom of moderate or greater severity on at least 3 days out of any consecutive 
7-day period. The CeD-related symptom(s) may vary day by day as long as the severity of at 
least 1 symptom is moderate or greater. Eligible subjects will undergo an 
esophagogastroduodenoscopy (EGD) with duodenal biopsy 
 for the 
assessment of villous atrophy.  
In addition, a subset of approximately 40 subjects in total that provide a wide range of villous 
injury 
 
 
 
 
 
During the single-blind run-in period (Week -4 through Day -1), subjects will receive TAK-062 
placebo 
 and complete the CDSD daily. 
 
 
 
 
 
 
 
 
 
 
 
 While all efforts should be made to obtain weekly urine 
samples, missed urine GIP samples will not be considered a protocol deviation. 
Eligible subjects with villous atrophy on duodenal biopsy (defined as Vh:Cd <2.5 by central 
pathology assessment) will be randomly assigned to 1 of 2 (Cohort 1) or 1 of 6 (Cohort 2) 
treatment groups described above to receive double-blind treatment and SIGE or gluten-free 
SIGE (Cohort 2) treatment for 24 weeks (Day 1 through Week 24). Initially, all subjects who 
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meet symptom criteria and histologic criteria will be randomized. If more than 10% of planned 
enrollment in a cohort report a greater than 1 point improvement in PGIS during 
 run-in 
period (Week -2 through Day -1), further subjects showing this degree of improvement will be 
excluded from the cohort. 
Randomization will be stratified by celiac serologic status at Visit 1, defined as normal or 
elevated celiac serology (1 or more of the following: IgA-tissue transglutaminase (tTg) >1 × the 
upper limit of normal [ULN], IgA–deaminated gliadin peptide [DGP] >2 × ULN, or IgG-
DGP >2 × ULN), mild to moderate (Vh:Cd 1.5 to <2.5) versus moderate to severe (Vh:Cd <1.5) 
histologic injury at baseline, and by use of proton pump inhibitors (PPIs) or histamine 
2 antagonists (yes or no) at Visit 1. 
Subjects will report symptoms daily using the CDSD from Week -8 through Week 24.  
EGD with biopsy will again be performed at the end of the 24-week treatment period (Week 24). 
 
 
Sparse blood samples to evaluate the PK of TAK-062 in plasma will be collected in all subjects 
at Weeks -4, 0, 3, 12, 24, and 28. Approximately 10 adult subjects enrolled in Cohort 1, and 
30 adult subjects enrolled in Cohort 2 will participate in the PK subgroup for slightly more 
intensive collections at the Week 0 (randomization) and Week 3 visits. Predose plasma and 
serum collections will be done at these same clinic visits for exploratory analysis of circulating 
biomarkers. There is a safety follow-up visit at Week 28, 4 weeks after the last date of treatment.  
Diagrams of the study design are included as Figure 6.a and a Schedule of Study Procedures is 
listed in Appendix A. 
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6.2 
Justification for Study Design, Dose, and Endpoints 
6.2.1 
Rationale for Study Design 
Three TAK-062 doses versus placebo will be evaluated in this study with a primary outcome of 
improvement in symptoms as measured by the CDSD along with secondary outcomes of change 
in small intestinal mucosal injury in subjects treated with TAK-062 compared with placebo 
(Leffler et al. 2015; Murray et al. 2017). This study will enroll subjects who have been 
attempting to maintain a GFD for at least 12 months, who have ongoing GI symptoms as 
measured by the CDSD, and have small intestine villous atrophy on duodenal biopsy. The use of 
SIGE bars 
 double-blind treatment periods is 
 
 
 
 The study will enroll 
2 cohorts; Cohort 1 will evaluate safety and efficacy of TAK-062 in adult subjects with the 
highest dose in the presence of SIGE bar consumption; Cohort 2 will evaluate safety and efficacy 
of TAK-062 at 3 doses (
) in adults with gluten-containing or gluten-free SIGE 
bar consumption. In addition, there will be 2 doses (
) in adolescent subjects with 
gluten-free SIGE bar consumption. The run-in period will be followed by 24 weeks of double-
blind treatment with placebo or TAK-062. Subjects will be given low doses 
 
of gluten or gluten-free SIGE in the form of a food bar throughout the study in a double-blind 
manner 
 because prior CeD studies have demonstrated a 
very large clinical study effect due to both placebo response and reduced gluten exposure. 
Randomization, placebo control, and blinding are regarded as the gold standard design elements 
for minimizing potential biases. The factorial design allows the efficient evaluation of effects of 
study treatment, SIGE, and their interaction. Because the treatment effect of SIGE is expected to 
be small, only 
 TAK-062 and placebo are planned to be evaluated with gluten-free SIGE. 
The effect of 
 TAK-062 is assumed to be no larger than the effect of 
 TAK-062 
under gluten-free SIGE. 
The run-in period will establish subject’s baseline results for efficacy evaluation, 
 
  
 
 
 
 
 
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6.2.2 
Rationale for Dose 
TAK-062 
To date, repeat-dose nonclinical studies for TAK-062 have shown no toxicity up to the limit dose 
and NOAEL of 2000 mg/kg/day. Calculation of the human equivalent dose applied to the 
observed NOAEL of 2000 mg/kg/day after a 10-fold safety factor was 1938 mg TAK-062 liquid 
formulation based on rat and 3870 mg TAK-062 liquid formulation based on monkey. Doses of 
 tested in phase 1 studies were well-tolerated and these doses are all 
less than half of the NOAEL. Safety data showed that TAK-062 was well-tolerated up to 
 
. AEs were of mild to moderate severity, not drug-related, and most commonly related to 
nasogastric tube placement. There has been 1 unrelated SAE reported across the clinical program 
to date. An in vitro experiment showed that 
 dose of TAK-062 liquid formulation 
exhibited greater activity than the 
 dose during the first 30 minutes. In the phase 1 study, 
the gluten degradation activity of TAK-062 was assessed in healthy subjects receiving placebo 
and 
 of liquid formulation before 1 g of gluten; or placebo and 
 of liquid 
formulation before 6 g of gluten. The percentage of gluten degraded relative to placebo was 
found to be comparable across 
 doses, suggesting the digestion of 
immunogenic gluten peptides of TAK-062 was similarly effective at this dose range. On the 
basis of these results, the dose levels of 
 were selected to explore the 
therapeutic benefit and efficacious dose range of TAK-062.  
TAK-062 is dosed 
 before the start of a meal because the site of 
action is in the stomach and it is expected that the enzyme will pass out of the stomach within 
4 hours after administration. 
SIGE 
Inclusion of SIGE in this study serves 2 main purposes. First, 
 
 
. TAK-062 works only on gluten, so it is essential 
that gluten be consumed to assess therapeutic efficacy. In prior CeD studies that did not include 
SIGE, significant improvements in symptoms and/or histology were observed in the placebo 
arms (Leffler et al. 2015; Murray et al. 2017). This effect has been attributed, at least in part, to 
reduction in gluten exposure as a result of trial participation (Stefanolo et al. 2020). Second, if a 
positive therapeutic effect is observed, then the inclusion of SIGE, 
 
 provides confidence that the effect seen 
in the study will confer real benefit to patients outside of a study where gluten exposures are 
known to be highly variable.  
Subjects will consume 
 with a meal for the duration of the study 
 
 in 
subjects randomized to gluten-containing bars. The typical result of this exposure is anticipated 
to be stable symptoms from initial screening in the placebo cohort rather than exacerbation of 
symptoms. 
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Emerging data have suggested that even in patients adherent to a GFD, 
 
 
 
 
 
  
 
 
While the administration of SIGE is not anticipated to exacerbate CeD-related symptoms, in 
situations where the administration of SIGE may confound the clinical evaluation of a GI 
condition that arises during the treatment period, investigators may temporarily cease 
administration of SIGE up to a maximum of 2 weeks, following discussion with the study 
medical monitor. If cessation of SIGE during the treatment period extends beyond 2 weeks, the 
subject will be withdrawn from the treatment arm due to lack of efficacy and continued in the 
study for monitoring and safety. Any investigator-determined cessation of SIGE administration 
must be recorded in the appropriate electronic case report form (eCRF). 
The adolescent group in Cohort 2 will not be exposed to SIGE because this group will be 
randomized only into the gluten-free SIGE group.  
6.2.3 
Rationale for Endpoints 
6.2.3.1 
Efficacy 
The goal of TAK-062 is to show improvement of ongoing GI symptoms and small intestinal 
mucosal injury due to gluten exposure in patients with CeD. Efficacy will be evaluated primarily 
through the demonstration of the clinical benefit of treatment as an adjunct to the GFD. Through 
this study, Takeda expects to develop a robust understanding of the dose of TAK-062 necessary 
to improve ongoing symptoms and intestinal pathology related to active CeD. 
The primary endpoint will be reduction in mean weekly CDSD score in TAK-062 treatment 
group versus placebo. Because ongoing active CeD is experienced by subjects as symptoms, 
symptom improvement is an appropriate basis of establishing effectiveness of therapies that are 
adjunctive to a GFD. 
The CDSD measures GI symptoms on a daily basis and was developed in accordance with Food 
and Drug Administration (FDA) guidance on PRO measures (Patrick et al. 2007). This measure 
allows for sensitive measurement of episodic episodes of symptoms; however, the CDSD is not 
yet validated for the intended context of use. To assess the psychometric properties of the CDSD, 
anchors (PGIS and PGIC) will be used to assess the meaningful within-patient change. 
Additional measures of celiac-related symptoms will also be assessed (eg, CeD-GSRS and 
PROMIS—Fatigue Instrument) to measure convergent validity. 
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6.2.3.2 
Tissue-Based Biomarkers: Vh:Cd and IELs  
As a complement to understanding how subjects are feeling during the study, a secondary 
endpoint of this study will be the change in Vh:Cd ratio on duodenal biopsy from baseline 
(Week -4) to the end of treatment. The Vh:Cd ratio represents mucosal architectural changes and 
a lower Vh:Cd ratio indicates more severe intestinal injury characterized by a flattening of the 
mucosa. Changes in the individual Vh and Cd measurements will also be evaluated as 
exploratory endpoints. Because ongoing small intestinal mucosal injury is a major risk factor for 
long-term complications, showing improvement in tissue histology is necessary for establishing 
effectiveness of therapies that are adjunctive to a GFD. Additionally, increases in IELs are often 
monitored as a marker of inflammation in the duodenal epithelium. The ability of TAK-062 to 
affect these histological markers will be important endpoints monitored in this study.  
Other Exploratory Biomarkers 
Exploratory analysis of intestinal gene expression (RNA) and tissue microbiome community 
may also be done but will not be a part of the clinical study report. Predose plasma and serum 
samples are also being collected to enable evaluation of novel circulating biomarkers under 
investigation and how they respond to treatment. These include microbial identification, 
exosome quantification, proteomic analysis, and quantitation of markers of extracellular matrix 
remodeling. These collections may be useful for noninvasive patient selection or disease 
monitoring.  
6.2.3.3 
 
 
 
 
 
 
 
 
  
6.2.3.4 
Urine-Based Biomarker: GIP 
As a means of monitoring gluten exposure during the study, urine samples will be collected in 
standard urine collection cups once per week for evaluation of GIP using a qualitative assay. To 
enable quantitative detection of different gluten peptides, subjects will collect urine in 
 
 on the day of a 
clinic visit and take the sample to the site. 
 
 
 
 While all efforts should be made to obtain weekly urine 
samples, missed urine GIP samples will not be considered a protocol deviation. 
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Ingested gluten is degraded into immunostimulatory peptides that can be detected in urine. 
Measurements will be taken at screening to understand if any potential subjects have evidence of 
active gluten exposure and then during the run-in period, at baseline, and all other study visits to 
monitor gluten exposure before and during study execution. Results will support conclusions 
regarding the gluten degrading capability of TAK-062.  
6.2.3.5 
Safety 
Safety will be monitored on the basis of the occurrence of TEAEs, SAEs, physical examination 
findings (in the context of AEs), vital signs (heart rate, blood pressure, temperature, respiration 
rate), ECGs, and clinical laboratory parameters (chemistry, hematology, and urinalysis). A serum 
pregnancy test will be conducted at screening and urine pregnancy tests at all other scheduled 
visits before receiving study drugs for women of childbearing potential (WOCBP). All TEAEs, 
including clinically significant treatment-emergent laboratory abnormalities, will be graded 
according to National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0. 
6.3 
Premature Termination or Suspension of Study or Study Site 
6.3.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 
• New information or other evaluation regarding the safety or efficacy of TAK-062 that 
indicates a change in the currently known benefit-risk profile such that the benefit-risk 
balance is no longer acceptable for subjects participating in the study. 
• Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety. 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites 
A study 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 study, or as otherwise permitted by the contractual agreement. 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) 
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/IECs are notified as appropriate. 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed before randomization.  
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7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria before entry into the study:  
1. The subject is able to provide written informed consent form to participate in the study 
before completing any study-related procedures. 
2. In the opinion of the investigator, the subject is willing and fully capable of understanding 
and complying with study procedures including PRO compliance and restrictions defined in 
this protocol. 
3. The subject has an adequate comprehension of a GFD assessed by the site investigator after 
review of responses to a knowledge test. The final determination of a subject’s adequate 
comprehension of a GFD is at the discretion of the investigator. 
4. The subject has at least 1 CeD-related GI symptom of moderate or greater severity, as 
measured by the CDSD, on at least 3 days out of any consecutive 7-day period during the 
screening period (Week -8 visit until Week -4 visit), felt by the investigator to be related to 
gluten exposure. The CeD-related symptom(s) may vary day by day as long as the severity of 
at least 1 symptom is moderate or greater. The subjects must meet symptom criteria to 
undergo EGD/VCE.  
5. The subject has biopsy-confirmed CeD or, in subjects with CeD without a producible initial 
biopsy report, the following additional inclusion criteria must be met: 
a) Serology (IgA-tTg) at diagnosis or subsequent visit must be at least 2 times the ULN. 
b) Histology at screening biopsy at Week -4 must be consistent with Marsh-Oberhuber score 
of 2 or greater as read by a central pathologist. 
6. The subject has been attempting to maintain a GFD for at least 12 months as self-reported by 
the subject. 
7. The subject has small intestinal villous atrophy on duodenal biopsy defined as Vh:Cd <2.5 at 
Week -4. 
8. The subject is HLA-DQ2 and/or HLA-DQ8 positive. 
9. The subject in Cohort 1 is aged 18 years and older at the time of signing the informed 
consent form. Inclusion of subjects older than 75 years of age will require discussion with the 
study medical monitor prior to enrollment.  
10. The subject in Cohort 2 is aged 12 and older at the time of signing the informed 
consent/pediatric assent forms. Subjects 12 to 17 years of age, inclusive, will only be 
included after IDMC review at IA. Inclusion of subjects older than 75 years of age will 
require discussion with the study medical monitor prior to enrollment. 
11. The subject is in a good general state of health according to clinical history and physical 
examination, in the opinion of the investigator. 
12. The subjects must have a body mass index (BMI) between 16 and 45, inclusive.  
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Note: Individuals with BMI of 40 to 45 should be discussed with the medical monitor and 
confirmed to be appropriate for endoscopy according to local site guidelines. 
13. The subject is willing and able to continue any current dietary and/or medical regimens 
(including gastric acid suppression) in effect at the first visit (Visit 1). There should be no 
changes to diet, medications (prescription or over-the-counter) or supplements during study 
participation.  
14. A male subject who is nonsterilized* and sexually active with a female partner of 
childbearing potential* agrees to use an effective method of contraception (Section 9.3.13) 
from signing of informed consent/pediatric assent forms throughout the duration of the study 
and for 100 days after last dose of study drug.  
15. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use an effective method of contraception* from signing of informed 
consent/pediatric assent forms throughout the duration of the study and for 40 days after the 
last dose of study drug. 
*Definitions and effective methods of contraception are defined in 
Section 9.3.13 and reporting responsibilities are defined in Section 9.3.14. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress. 
2. The subject has inadequate renal or hepatic function before randomization based on the 
following laboratory parameters: 
• Total bilirubin ≥1.5 × ULN unless the subject has known Gilbert’s syndrome that can 
explain the elevation of bilirubin, or 
• Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 × ULN, 
or 
• Glomerular filtration rate (GFR) <49 mL/min. For subjects with GFR 49 to 59 mL/min, 
inclusion determination should be discussed with the sponsor.  
Note: The subjects may be retested (1 time) to meet eligibility criteria at the discretion of the 
investigator. 
3. The subject has the presence of other inflammatory GI disorders or systemic autoimmune 
diseases that either have the potential to cause persistent GI symptoms similar to CeD or are 
not well controlled without the use of excluded medication.  
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• Examples of conditions that are exclusionary include inflammatory bowel disease, 
eosinophilic gastroenteritis or colitis, and microscopic colitis requiring treatment in the 
6 months before screening. 
• Examples of conditions that may be permissible after discussion with the medical 
monitor include systemic autoimmune disease such as scleroderma, psoriatic or 
rheumatoid arthritis, or lupus that is stable and without GI involvement; well-controlled 
autoimmune thyroid disease; well-controlled type 1 diabetes; or PPI-responsive 
eosinophilic esophagitis in symptomatic and histologically confirmed remission. 
4. The subject has ongoing systemic immunosuppressant, systemic corticosteroid treatment 
excluding medication given for the endoscopies, or treatment with systemic 
immunosuppressants or systemic corticosteroids in the 12 weeks before screening. 
• The subject is receiving immunosuppressive doses of corticosteroids: 3 mg per day or 
more of budesonide for more than 3 consecutive days within 3 months before screening, 
more than 20 mg of prednisone given daily or on alternative days for 2 weeks or more 
within 90 days before the first dose, any dose of oral or IV corticosteroids within 30 days 
of the first dose, or high-dose inhaled corticosteroids (>960 µg/day of beclomethasone 
dipropionate or equivalent), or other systemic immunosuppressive agents. 
5. The subject has ongoing use of over-the-counter digestive enzymes or digestive supplements, 
other than lactase, including those for gluten digestion. Probiotics are allowable if they were 
started before screening and not discontinued or changed in dose or type during the study. 
6. The subject has an inability to swallow the study drug tablet. 
7. The subject has completed the CDSD on ≤75% of the evaluable days during the run-in period 
until randomization. 
8. If more than 10% of planned enrollment in a cohort report a greater than 1 point 
improvement in PGIS during 
 run-in period (Week -2 through Day -1), further 
subjects showing this degree of improvement will be excluded from the cohort. 
9. The subject has ongoing symptoms that are considered by the investigator to be due to other 
GI conditions, including irritable bowel syndrome, small intestinal bacterial overgrowth, and 
eosinophilic disorders. 
10. The subject has active microscopic colitis requiring treatment in the 6 months before 
screening. 
• Microscopic colitis detected at screening if sigmoidoscopy is performed would exclude 
the subject. 
11. The subject has known or suspected type 2 refractory CeD or ulcerative jejunitis. 
12. The subject has ongoing chronic use (defined as >7 days continuous use) of a nonsteroidal 
anti-inflammatory drug aside from <100 mg aspirin, daily, for prophylactic use. 
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13. The subject has ongoing use, or use in the 3 months before screening, of medications known 
to cause villous abnormalities (eg, mycophenolate mofetil, angiotensin receptor blockers, 
colchicine). 
14. The subject used treatments for GI symptoms including antiemetics, antidiarrheals, 
antispasmodics, medical marijuana (use of medical marijuana indicated for non-GI 
conditions is not exclusionary) within 2 weeks of screening and during the run-in period. 
Subjects on stable doses (ie, more than 4 weeks) of an osmotic, bulking-forming or emollient 
(surface active agent) laxative are eligible, provided symptoms are considered not related to 
CeD in the opinion of the investigator. 
15. The subject has a known or suspected severe enteric infection (viral, bacterial, or parasitic) 
within 6 months before randomization. Severe enteric infection is defined as requiring 
emergency room visit or hospitalization or treatment with antibiotics or anti-infectives due to 
infection. Nonenteric viral infections, either resolved or well-controlled are not exclusionary. 
16. The subject has received any investigational compound within 12 weeks (84 days) or 5 half-
lives, whichever is longer, before enrollment into the study.  
17. The subject has a contraindication to endoscopy with duodenal biopsy. 
• Contraindication to VCE (strictures, anastomoses, etc) is not an exclusion if the subject is 
able to complete the other aspects of the study. 
18. The subject has additional food allergies (eg, tapioca syrup, oats, almonds, rice crisp, 
chocolate, almond butter, wheat gluten, cocoa butter, oat flour, glycerin, sunflower lecithin, 
salt, and natural flavors) to nongluten ingredients in the SIGE bar study food or significant 
symptoms upon ingestion of the gluten-free SIGE bar during screening. 
19. The subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to an 
aminoglycoside. 
20. Changes or planned changes to the subject’s medications or diet that could affect the study 
between screening and the final visit. 
21. The subject has a history of drug or alcohol abuse, or has ongoing use of marijuana during 
the course of the study, that in the opinion of the investigator, would interfere with the 
subject’s ability to comply with the study requirements. 
22. The subject has a known HIV infection or positive tests for hepatitis B or C. The subject has 
a known clinically significant chronically active hepatopathy of any origin, including 
cirrhosis, and subjects with persistent positive hepatitis B virus surface antigen and 
quantitative hepatitis B virus polymerase chain reaction (PCR), or positive serology for 
hepatitis C virus (HCV) and quantitative HCV PCR within 6 months before the screening 
visit. 
23. The subject is positive for severe acute respiratory syndrome coronavirus 2 at the time of 
screening and exhibits symptoms that, in the opinion of the investigator, may interfere with 
study compliance, completion, or accurate assessment of study outcomes or safety (direct 
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viral or serologic testing may be performed according to site procedures at the discretion of 
the investigator). 
24. If female, the subject is pregnant or lactating or intending to become pregnant before 
participating in this study, during the study, and within 40 days after last dose of the study 
drug; or intending to donate ova during such time period. 
25. If male, the subject intends to donate sperm during the course of this study or within 
100 days after the last dose of study drug.  
26. Subject has a history or high risk of noncompliance with treatment, study procedures or 
regular clinic visits. 
27. The subject has a known hypersensitivity reaction and/or allergy, including anaphylaxis, to 
wheat and/or gluten. 
28. The subject has a known history of hypersensitivity, idiosyncratic reaction, or intolerance to 
any ingredients or excipients in TAK-062 and/or placebo. 
29. The subject has a current diagnosis of active malignancy or is receiving treatment for active 
malignancy (hormone therapy alone is not exclusionary). Subjects with fully resected Stage 0 
(carcinoma in situ) or Stage 1 tumor without signs of recurrence may participate. All other 
individuals with malignancies diagnosed in the 5 years prior to screening are excluded. 
Region-specific Exclusion Criteria: 
30. The subject enrolling in a study in France is not affiliated to a social security scheme or a 
beneficiary of such a scheme. 
31. The subject enrolling in a study in France is deprived of their liberty by a judicial or 
administrative decision. 
7.3 
Excluded Medications 
All prior and concomitant medications taken within 90 days, including prescription and 
nonprescription medicines, will be reported in the eCRF beginning at the signing of the informed 
consent/pediatric assent forms through the final study visit. Subjects will be instructed to avoid 
all medications listed as exclusions during the entire study. 
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Subjects must be instructed to avoid: 
Digestive enzymes:  
• Any over-the-counter digestive enzymes or digestive supplements, other than lactase, 
including those for gluten digestion. Probiotics are allowable if they were started before 
screening and not discontinued or changed in dose or type during the study. 
Immunosuppressants/immunomodulators: eg, methotrexate, azathioprine, cyclosporine, 
anti–tumor necrosis factor-α agents, corticosteroids: 
• Immunosuppressive doses of corticosteroids: 3 mg per day or more of budesonide for 3 or 
more consecutive days; more than 20 mg of prednisone given daily or on alternative days for 
2 weeks or more, any dose of oral or IV corticosteroids, or high-dose inhaled corticosteroids 
(>960 µg/day of beclomethasone dipropionate or equivalent), or other systemic 
immunosuppressive agents.  
• Use of drugs that cause villous abnormalities (eg, mycophenolate mofetil, angiotensin 
receptor blockers, colchicine). 
Medications and supplements: 
• For treatment of GI symptoms including antiemetics, antidiarrheals, antispasmodics, outside 
of rescue medications described in Section 7.4. Use of stable doses (ie, more than 4 weeks) 
of an osmotic, bulking-forming or emollient (surface active agent) laxative is allowed. 
• Ongoing chronic use (defined as >7 days continuous use) of a nonsteroidal anti-inflammatory 
drug aside from <100 mg aspirin, daily, for prophylactic use. 
7.4 
Rescue Medications 
If a subject has symptoms of severe diarrhea, nausea, vomiting, or abdominal spasm that are 
considered related to their CeD, the use of the medications to treat these severe symptoms will be 
considered as rescue medications. Instructions for use of all medications (prescriptions and over-
the-counter medications), if needed, should be obtained from the study physician. Rescue 
medication use (dose, date for each occurrence) is to be communicated by the subject to 
investigator and team, and recorded as concomitant medications as well as an AE. See Appendix 
G for more information on specific medications, doses, and indications for use of rescue 
medications.  
If these rescue medications are taken 5 out of any 7-day consecutive period or if rescue 
medications are taken for more than 3 out of a 7-day consecutive period 5 times during the 
treatment period (after randomization), the subject will be withdrawn from the treatment arm due 
to lack of efficacy and continued in the study for monitoring and safety. 
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7.5 
Diet 
With the exception of the gluten with SIGE bar, subjects must adhere to their prescreening GFD 
throughout the study. There are no other restrictions on food or fluid intake during the study; 
however, subjects should not make significant dietary changes during the course of the study.  
7.6 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the eCRF using the following categories. For screen failure subjects, refer 
to Section 9.3.16. 
Discontinuation of Treatment 
1. AE. The subject has experienced an AE, including a liver enzymes and bilirubin 
abnormalities as noted below, that requires early termination because continued participation 
imposes an unacceptable risk to the subject’s health as per the investigator and/or sponsor 
criteria, or the subject is unwilling to continue because of the AE. 
• Liver enzymes and bilirubin abnormalities. 
Study drug should be discontinued immediately with appropriate clinical follow-up (including 
repeat laboratory tests, until a subject’s laboratory profile has returned to normal/baseline status, 
see Section 9.3.11) if the following circumstances occur at any time during study drug treatment: 
– ALT or AST >8 × the ULN, or 
– ALT or AST ≥5 × the ULN and persists for more than 2 weeks, or 
– ALT or AST ≥3 × the ULN in conjunction with elevated total bilirubin >2 × the ULN or 
international normalized ratio (INR) ≥1.5, or 
– ALT or AST ≥3 × the ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (≥5%). 
2. Significant protocol deviation. The discovery postrandomization that the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health as per the investigator and/or 
sponsor criteria. 
3. Lack of efficacy. The investigator has determined that the subject has a significant worsening 
of symptoms and is not benefiting from study treatment and that continued participation 
would pose an unacceptable risk to the subject or that rescue medications are taken 5 out of 
any 7-day consecutive period, rescue medications are taken for more than 3 out of a 7-day 
consecutive period 5 times, or investigator-determined cessation of SIGE administration has 
lasted more than 2 weeks. The subject will be withdrawn from the treatment due to lack of 
efficacy and continued in the study for monitoring and safety. 
Withdrawal of Subject 
4. Pregnancy. The subject is found to be pregnant. 
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Note: If the subject is found to be pregnant, the subject must be withdrawn from the study 
immediately. The procedure is described in Section 9.3.14. 
5. Lost to follow-up. The subject did not return to the clinic and multiple attempts to contact the 
subject were unsuccessful. Three attempts to contact the subject must be documented in the 
subject’s source documents.  
6. Voluntary withdrawal (withdrawal of consent). The subject (or subject’s legally acceptable 
representative) wishes to withdraw from the study. The reason for withdrawal, if provided, 
must be recorded in the eCRF. 
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 due to an AE 
should not be recorded in the “voluntary withdrawal” category. Similarly, lack of efficacy should 
not be recorded in the “voluntary withdrawal” category). 
7. Study termination by sponsor.  
8. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.7 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject from study drug or study participation treatment at 
any time during the study when the subject meets the discontinuation or withdrawal criteria 
described in Section 7.6. In addition, a subject may discontinue his or her participation without 
giving a reason at any time during the study. Should a subject’s participation be discontinued due 
to withdrawal of consent, the primary criterion for discontinuation or termination must be 
recorded by the investigator. Subjects who discontinue study treatment should be encouraged to 
have follow-up for the remainder of the study per protocol. In addition, efforts should be made to 
perform all procedures scheduled for the early termination visit as soon as possible. Discontinued 
or withdrawn subjects will not be replaced.  
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT 
8.1 
Study Drug and Materials 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study drug refers to TAK-062 or placebo defined below. TAK-062 
active tablets and placebo tablets will be supplied in blister packs and will be labeled with 
appropriate clinical labels. SIGE bars and gluten-free SIGE bars will be supplied with 
appropriate clinical labels. 
8.1.1.1 
TAK-062 
TAK-062 is a solid oral dosage form intended for nonsystemic local activity in the stomach. 
TAK-062 is supplied as 
 white to off-white modified capsule-shaped tablet containing 
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 TAK-062 enzyme, tableted in its spray-dried form. 
 
 
 
  
8.1.1.2 
Placebo 
The placebo tablet is a white to off-white, modified capsule-shaped tablet containing 
 
  
8.1.1.3 
SIGE Bars 
The SIGE bars will contain 
 (SIGE gluten) or no gluten (gluten-free 
SIGE). The detailed information on the dosing instructions of the food bars is described in the 
pharmacy manual. SIGE bars will be provided by the sponsor.  
8.1.2 
Storage 
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor or designee for destruction. Study drug must be stored under the conditions 
specified on the label and in the pharmacy manual, and remain in the original container until 
dispensed. Additional information regarding storage requirements for SIGE bars can be found in 
the pharmacy manual. 
8.1.3 
Dose and Regimen 
 
 
 
 
 Subjects should be instructed that treatment will be effective only 
for the meal with which it is taken. For this reason, food consumption between meals should be 
avoided or restricted to unprocessed gluten-free foods. 
Subjects will be randomized into study drug and SIGE treatment groups dependent on the 
enrolling study cohort. The SIGE bars are to be taken with a meal after study drug administration 
.  
Additional information regarding the dosing instructions for TAK-062 can be found in the 
pharmacy manual. 
Table 8.a describes the dosing regimens for each group in Cohort 1. 
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Table 8.a 
Dose and Regimen 
Treatment Group 
Treatment Description 
1 
TAK-062 placebo (4 placebo tablets) 
 before the start 
of a meal + SIGE bar with a meal 
: 60 subjects 
2 
TAK-062 
 (4 TAK-062 tablets) 
 before the start 
of a meal + SIGE bar with a meal 
: 60 subjects 
SIGE: simulated inadvertent gluten exposure; 
 
 
Table 8.b describes the dosing regimens for each group in Cohort 2. 
Table 8.b 
Dose and Regimen 
Treatment 
Group 
Treatment Description 
1 
TAK-062 placebo (4 placebo tablets) 
 before the start of a meal + SIGE 
bar with a meal 
: 30 subjects (adults) 
2 
TAK-062 
 (1 TAK-062 tablet, 3 placebo tablets) 
 before the start 
of a meal + SIGE bar with a meal 
: 50 subjects (adults) 
3 
TAK-062 
 (2 TAK-062 tablets, 2 placebo tablets) 
 before the 
start of a meal + SIGE bar with a meal 
: 50 subjects (adults) 
4 a 
TAK-062 placebo (4 placebo tablets) 
 before the start of a meal + 
gluten-free SIGE bar with a meal 
: 50 subjects (43 adults, 7 adolescents) 
5 a 
TAK-062 
 (4 TAK-062 tablets) 
 before the start of a meal + 
gluten-free SIGE bar with a meal 
: 50 subjects (43 adults, 7 adolescents) 
6 a 
TAK-062 
 (1 TAK-062 tablet, 3 placebo tablets) 
 before the start 
of a meal + gluten-free SIGE bar 
: 7 subjects (adolescents only) 
SIGE: simulated inadvertent gluten exposure; 
. 
a Adolescent subjects will be randomized to Groups 4, 5, and 6 only. 
 
8.1.4 
Overdose 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study subject, at a dose above the maximum scheduled dose being used in this study 
irrespective of the subject’s assigned dose according to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented in the dosing section 
of the eCRF, to capture this important safety information consistently in the database. Cases of 
overdose without manifested signs or symptoms are considered as AEs and should be captured 
with the appropriate Preferred Term of overdose in the AE eCRF. Additionally, AEs associated 
with an overdose will be documented on AE eCRF(s) according to Section 10.0. 
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2. 
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In the event of a drug overdose, the subject should be treated according to the standard practices 
of the Investigator and the site.  
There is no experience with overdose with any of TAK-062 formulations. 
8.2 
Study Drug and SIGE Assignment and Dispensing Procedures 
After confirming a subject meets all entry criteria, the investigator or the investigator’s designee 
will access the interactive response technology (IRT) to enroll the subject into 
 
 and then randomize the subject into the study at Visit 3. The identification (ID) 
numbers of the study drug and SIGE bars to be dispensed will be provided by the IRT.  
On occasion in unavoidable circumstances such as the coronavirus disease 2019 (COVID-19) 
pandemic, additional drug supply may be provided to subjects (either at an in-person visit or 
delivered to subject’s residence) to cover extended periods between on-site visits. Any additional 
re-supply must be reviewed and approved in advance by the sponsor or designee. 
If sponsor-supplied drug or SIGE bars are lost or damaged, the site can request a replacement 
from IRT. (Refer to IRT manual instructions provided separately.) The investigator or designee 
will again access IRT to request additional study drug and SIGE bars for a subject.  
Sites should follow the instructions provided in the pharmacy manual to send study drug and/or 
SIGE bars to subjects at home when an onsite visit for dispensation is not feasible.  
8.3 
Randomization Code Creation and Storage 
The sponsor/designee will generate the randomization schedule; the IRT will be used in a 
centralized fashion for subject randomization and study medication and SIGE assignment. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
8.4 
Study Drug and SIGE Blind Maintenance 
The study drug and SIGE blind will be maintained using the IRT. 
Subjects, site staff, and study team members will remain blinded to treatment assignment, 
individual subject ADA, GIP, and PK data from this study until database lock occurs for this 
study. In the event that results must be reported to the investigator before breaking the blind, all 
efforts should be made to maintain the blind. Subjects, site staff, and study team members 
involved in study operations on an everyday basis will also remain blinded to postrandomization 
histology. 
8.5 
Unblinding Procedure 
The study drug and SIGE blind shall not be broken by the investigator unless information 
concerning the study drug and SIGE is necessary for the medical treatment of the subject. All 
study assessments and causality assessment should be performed, if possible, before unblinding. 
In the event of a medical emergency, if possible, the medical monitor should be contacted before 
the study drug blind is broken to discuss the need for unblinding. 
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For unblinding a subject, the study drug and SIGE blind can be obtained by the investigator, by 
accessing the IRT. 
The sponsor must be notified as soon as possible if the study drug blind is broken. The date, 
time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, study drug must be stopped immediately and the subject 
must be withdrawn from the study but should be followed up for safety purposes. 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs and SIGE Bars 
The investigator or designee must ensure that the sponsor-supplied drug/SIGE bar is used in 
accordance with the protocol and is dispensed only to subjects enrolled in the study. To 
document appropriate use of sponsor-supplied drug/SIGE bar, the investigator or designee must 
maintain records of all sponsor-supplied drug/SIGE bar delivery to the site, site inventory, 
dispensation and use by each subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied drug/SIGE bar, the investigator or designee must verify the 
contents of the shipments against the packing list. The verifier should ensure that the quantity is 
correct, and the medication is in good condition. If quantity and conditions are acceptable, 
investigator or designee should acknowledge the receipt of the shipment by recording in IRT. If 
there are any discrepancies between the packing list versus the actual product received, Takeda 
must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied 
drugs/SIGE bar received and dispensed during his or her entire participation in the study. Proper 
drug/SIGE bar accountability includes, but is not limited to: 
• Frequently verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for the medication ID dispensed. 
• Verifying that all containers used are documented accurately on the log. 
• Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
The IRT will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug/SIGE bar is dispensed. 
The investigator or designee must record the current inventory of all sponsor-supplied 
drugs/SIGE bars on a sponsor-approved drug/SIGE bar accountability log. The following 
information will be recorded at a minimum: protocol number and title, name of investigator, site 
identifier and number, description of sponsor-supplied drugs/SIGE bar and amount dispensed 
including initials, seal, or signature of the person dispensing the drug/SIGE bar, and the date and 
amount returned to the site by the subject, including the initials, seal, or signature of the person 
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receiving the sponsor-supplied drug/SIGE bar. The log should include all required information as 
a separate entry for each subject to whom sponsor-supplied drug/SIGE bar is dispensed.  
All study drug/SIGE bar not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug/SIGE bar accountability log. 
Before site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug/SIGE bar accountability and reconciliation before sponsor-
supplied drugs/SIGE bar are returned to the sponsor or its designee for destruction or destroyed 
at the site. Accountability for clinical study material being destroyed at the site must be 
documented using a study accountability tracking document or equivalent document. In addition, 
a certificate of destruction document or equivalent must be provided by the sites that can identify 
or allow traceability to the batches, and/or medication ID numbers involved, and actual 
quantities destroyed. The investigator or designee will retain a copy of the documentation 
regarding sponsor-supplied drug/SIGE bar accountability, return, and/or destruction, and 
originals will be sent to the sponsor or designee. 
In the event of expiry date extension of sponsor-supplied drug/SIGE bar already at the study site, 
sponsor-supplied drugs/SIGE bar may be relabeled with the new expiry date at that site. In such 
cases, Takeda or its designee will prepare additional labels, certificates of analyses, and all 
necessary documentation for completion of the procedure at the sites. 
9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A. 
9.2 
Administrative Procedures 
9.2.1 
Informed Consent/Pediatric Assent Procedure 
The requirements of the informed consent/pediatric assent are described in Section 15.3. 
Informed consent/pediatric assent must be obtained before the subject enters into the study, and 
before any protocol-directed procedures are performed. 
A unique subject ID number (subject number) will be assigned to each subject at the time that 
informed consent/pediatric assent is obtained; this subject number will be used throughout the 
study. 
9.2.2 
Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include age at time of informed consent/pediatric 
assent, sex, Hispanic ethnicity, race as described by the subject, and smoking status of the 
subject at Screening. 
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Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing of 
informed consent/pediatric assent forms.  
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 90 days before signing of informed 
consent/pediatric assent forms. 
9.3 
Clinical Procedures and Assessments 
9.3.1 
Physical Examination Procedure 
A baseline physical examination (defined as the assessment performed during Visit 1) will 
consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; 
(4) respiratory system; (5) GI system; (6) dermatologic system; (7) extremities; (8) 
musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other. All subsequent 
physical examinations should assess clinically significant changes from the assessment before 
first dose examination. Clinically significant findings in physical examination will be entered as 
AEs in the eCRF. 
9.3.2 
Weight, Height, and BMI 
A subject should have weight and height measured following standard measuring procedures. 
Height is recorded in centimeters without decimal places. Weight is collected in kilograms (kg) 
with 1 decimal place. BMI will be derived as: 
Metric: 
BMI = weight (kg)/height (m)2 
The eCRF will perform the BMI calculation based on the height and weight values entered. 
9.3.3 
Vital Sign Procedure 
Vital signs will include body temperature (oral or tympanic measurement), respiratory rate, 
blood pressure (systolic and diastolic) and pulse (beats per minute). Vital signs can be performed 
in supine, semisupine, sitting or standing positions but should be performed after resting for 
5 minutes and consistently for each subject. 
9.3.4 
ECG Procedure  
A standard 12-lead ECG will be recorded and interpreted locally by the investigator (or a 
qualified observer at the study site) using 1 of the following categories: within normal limits, 
abnormal but not clinically significant, or abnormal and clinically significant. 
9.3.5 
GFD Knowledge Quiz 
Potential subjects must complete a knowledge test of what foods are and are not permitted in the 
GFD. This knowledge test is based on the scale developed by Silvester et al (Silvester et al. 
2016). It consists of 3 fill-in-the-blanks as to which grains are to be avoided (wheat, barley, rye), 
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4 true/false questions and 10 foods to assess as “allowed” “to question” or “not allowed”. All 
completed GFD knowledge quizzes are to be retained on site as source. The final determination 
of adequate comprehension of a GFD is at the discretion of the investigator. 
9.3.6 
PRO Assessments 
The schedule of administration of the following PRO assessments can be found in Schedule of 
Study Procedures (Appendix A). All PROs will be administered on an electronic device. The 
CDSD and supplemental frequency questionnaire will be administered at approximately the 
same time every day. All PROs should be done, before any other procedures on the day of the 
study visit or no more than 1 day before the study visit and in the following order: 
1. EQ-5D-5L. 
2. PGIS. 
3. PGIC. 
4. CeD Most Bothersome Symptom. 
5. PROMIS—Fatigue Instrument. 
6. CeD-GSRS. 
7. PROMIS—Cognitive Function Instrument. 
8. WPAI+CIQ:CeD. 
9. SF-12 v2. 
10. ICDSQ. 
11. CDAQ. 
12. CD-QoL. 
9.3.6.1 
CDSD v2.1 
The CDSD v2.1 is a 5-item, self-administered questionnaire that evaluates the severity of CeD 
symptoms on a daily basis. Severity is measured for the following CeD symptoms: diarrhea, 
abdominal pain, bloating, nausea, and tiredness. Symptom severity is evaluated using 5-point 
Likert-type scales (none, mild, moderate, severe, and very severe). A supplemental questionnaire 
administered with the CDSD will measure the frequency of bowel movements, vomiting, and 
diarrhea.  
9.3.6.2 
EQ-5D-5L 
The EQ-5D-5L questionnaire, developed by the EuroQol Research Foundation is a simple, valid, 
and reliable instrument used to measure general health-related quality of life (HRQOL) in 
subjects and includes 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Within each dimension, subjects choose 1 of 5 levels of health problems 
(none, slight, moderate, severe, or extreme), with levels scored 1 through 5, respectively. The 
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EQ-5D-5L visual analog score is a self-assigned rating of overall health using a visual, vertical 
scale, with a score of 0 as the worst and 100 as best possible health. The EQ-5D-5L total score 
and EQ-5D-5L visual analog score have been shown in many studies to be valid and reliable 
instruments for measuring HRQOL in subjects with GI diseases (Herdman et al. 2011).  
9.3.6.3 
PGIS 
PGIS is a 1-question instrument used as an anchor that evaluates the overall severity over the 
past 7 days. Response options are measured using a Likert-type scale (no symptoms, mild, 
moderate, severe, very severe). For validation purposes, it will be performed at Weeks -8 and -7. 
The PGIS will also be conducted on the day of every visit. 
9.3.6.4 
PGIC 
The CeD PGIC is a 1-question instrument that evaluates the change from study start to the 
present time. Response options are measured using a 7-point Likert-type scale (very much worse, 
much worse, a little worse, no change, a little improved, much improved, very much improved). 
9.3.6.5 
CeD Most Bothersome Symptom 
The CeD Most Bothersome Symptom is a 1-question instrument designed to assess the subject’s 
perception of which symptoms from those evaluated in the CDSD that the subject considers most 
bothersome.  
9.3.6.6 
PROMIS—Fatigue Instrument 
PROMIS is a set of person-centered measures that evaluates and monitors physical, mental, and 
social health in adults and children. The PROMIS Item Bank v1.0—Fatigue—Short Form 13a 
(2019b) is a battery of 13 questions for adults aged 18 years or older, which are included in the 
FACIT-Fatigue. This instrument assesses a range of self-reported symptoms, from mild 
subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of 
exhaustion that likely decreases one’s ability to execute daily activities and function normally in 
family or social roles. Fatigue is divided into the experience of fatigue (frequency, duration, and 
intensity) and the impact of fatigue on physical, mental, and social activities. This instrument has 
a 7-day recall period, and responses are measured using a 5-point scale (not at all, a little, 
somewhat, quite a bit, very much). For subjects aged 12 to 17 years, the PROMIS Pediatric Item 
Bank v2.0—Fatigue—Short Form 10a: Pediatric Fatigue will be used. This instrument has 
10 questions with a 7-day recall that are measured using a 5-point scale (never, almost never, 
sometimes, often, almost always). 
9.3.6.7 
CeD-GSRS 
The GSRS is a nondisease-specific 15-item instrument measuring the discomfort of GI 
symptoms using a modified Likert scale (no discomfort at all, minor discomfort, mild 
discomfort, moderate discomfort, moderately severe discomfort, severe discomfort, very severe 
discomfort) (Revicki et al. 1998). In this study, the 10 items relevant to CeD (CeD-GSRS) will 
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be evaluated (stomach pain/discomfort, hunger pains, nausea, rumbling in stomach, bloating, 
burping, passing gas, diarrhea, loose stools, urgent bowel movement) (Leffler et al. 2012). 
9.3.6.8 
PROMIS—Cognitive Function Instrument 
PROMIS is a set of person-centered measures that evaluates and monitors physical, mental, and 
social health in adults and children. The PROMIS Short Form v2.0—Cognitive Function 6a 
(2019a) is a subset of 6 items assessing patient-perceived cognitive deficits. Facets include 
mental acuity, concentration, verbal and nonverbal memory, verbal fluency, and perceived 
changes in these cognitive functions. The extent to which cognitive impairments interfere with 
daily functioning, whether other people observe cognitive impairments, and the impact of 
cognitive dysfunction on quality of life are also assessed. This instrument has a 7-day recall 
period, and responses are measured using a 5-point frequency scale (never, rarely, sometimes, 
often, very often). For subjects aged 12 to 17 years, a modified version of the PROMIS Pediatric 
Short Form v1.0—Cognitive Function 7a: Pediatric Cognitive Function will be used. This 
instrument has 7 items on a 5-point response scale (none of the time, a little of the time, some of 
the time, most of the time, all of the time). The original version has a 4-week recall that has been 
modified to 7 days. 
9.3.6.9 
WPAI+CIQ:CeD 
The WPAI+CIQ:CeD (Reilly et al. 2004) is a 10-question instrument questionnaire. The 
questionnaire assesses work time or academic classes lost due to CeD. Subjects also self-assess 
the impact of allergies on the performance in the workplace, at school, or during university 
classes. The recall period is the previous 7 days. 
9.3.6.10 
SF-12 v2 
The SF-12 v2 is a self-administered, validated questionnaire designed to measure generic 
HRQOL (Ware et al. 2001). This 12-item questionnaire measures 8 domains, including: Physical 
Functioning, Role-physical, Bodily Pain, General Health, Vitality, Social Functioning, 
Role-emotional, and Mental Health. Two summary scores can be calculated, the Physical 
Component Score, and the Mental Component Score. Higher scores indicate better health status.  
9.3.6.11 
ICDSQ 
The ICDSQ is a 14-question instrument that evaluates emotional wellbeing, physical 
functioning, social activities, and daily activities over the past 7 days. Responses are measured 
using a 5-point Likert-type scale (not at all, a little, moderately, very much, completely). 
9.3.6.12 
CDAQ 
The CDAQ (Crocker et al. 2018) is a validated PRO measure developed to investigate the 
HRQOL of people living with CeD with a recall period of 4 weeks. This 32-item questionnaire 
measures 5 domains: stigma, dietary burden, symptoms, social isolation, and worries and 
concerns. Responses are measured using a 5-point Likert-type scale (never, rarely, sometimes, 
often, always).  
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9.3.6.13 
CD-QoL  
The CD-QoL (Dorn et al. 2010) is a 20-item questionnaire measuring the quality of life in celiac 
patients over a 30-day time period. Responses are measured on a 5-point Likert-type scale (not at 
all, a little, moderately, very much, completely).  
9.3.7 
Placebo Reduction Plan 
9.3.7.1 
Accurate Symptom Reporting Training 
The Accurate Symptom Reporting training is an electronic learning module designed to orient 
subjects to core study questionnaires and to provide guidance on how to report symptoms 
accurately and reliably. The goal of this training is to improve the accuracy of PRO data. Once 
training is available, subjects may receive training at Visits 1, 2, and 3, as well as at Weeks 6, 10, 
16, and 22. Additional training may be performed on an as needed basis. 
9.3.7.2 
Placebo Response Reduction Training 
The placebo response reduction training teaches the subject about the appropriate expectations of 
personal benefit while participating in a clinical trial. The purpose is to provide subjects with 
truthful information that will neutralize the typically excessive expectations that drive high 
placebo responses in clinical studies. Once training is available, subjects may receive training at 
Visits 1, 2, and 3, as well as at Weeks 6, 10, 16, and 22. Additional training may be performed 
on an as needed basis. 
9.3.7.3 
Participant Scorecard 
The Participant Scorecard presents subjects with data reflecting their own performance on key 
tasks in the study, plus automated and customized tips for how to improve their performance. 
Scores are assigned for eDiary compliance, study medication adherence, and SIGE bar 
adherence, providing subjects with the opportunity to make changes to improve their 
performance on these tasks if needed. The Scorecard was designed to be viewed without any 
required human intervention in order to improve efficiency and timeliness of recommendations 
and decrease biases and burdens introduced by filtering retraining through site staff.  
9.3.7.4 
Research Subject Responsibilities Training 
The Research Subject Responsibilities training is an electronic learning module designed to 
provide a detailed overview of the key study procedures (eg, dosing, SIGE bar, diary 
completion) to the subjects. Once training is available, subjects will receive training at Visits 1, 
2, and 3, as well as at Weeks 6, 10, 16, and 22. Additional training may be performed on an as 
needed basis.  
9.3.8 
Exit Interview – United States Only 
The objective of the exit interview is to supplement, support, and facilitate the interpretation of 
data from the PRO and clinical measures. Exit interviews will be conducted by an independent 
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party with a subset of subjects who enrolled in the study from selected sites, with competitive 
enrollment. Only consented subjects and sites will be invited to participate in exit interviews. 
Interviews will be scheduled within 10 days of Week 24 (Visit 6) or early termination. The 
contents of the interview will include the following topics: 
• Disease-related symptoms before the study and their bothersomeness ratings. 
• Impact of disease on subjects’ lives before starting the clinical study. 
• Experiences with study treatment. 
• Anticipated or unanticipated benefits of treatment, impact of those benefits. 
– Impact of treatment on daily life/functioning. 
– Impact of treatment on most important/bothersome symptoms. 
• Importance or meaningfulness of perceived benefits of treatment. 
– Symptom-free days. 
– Minimal symptom days. 
• How well treatment addresses most important/bothersome symptoms. 
• Onset of benefits/changes. 
• Treatment experiences. 
• Satisfaction levels with treatment and reasons for satisfaction. 
9.3.9 
Endoscopy and Biopsy Collection 
An upper GI endoscopy and duodenal biopsy will be performed by qualified and experienced 
endoscopists. Standard procedures will be followed for conscious sedation, gastroduodenoscopy, 
and biopsy. Screening biopsy specimens must be taken and provided to the central pathology 
laboratory approximately 4 weeks before the planned baseline visit to allow sufficient time for 
processing and central review and determination of eligibility. At the time of the endoscopy, 
sigmoidoscopy with biopsy may be performed (at the discretion of the investigator) to rule out 
microscopic colitis in subjects who qualify for study inclusion based on diarrhea severity and 
who have not had previous sigmoidoscopy or colonoscopy with biopsies providing evidence of 
lack of microscopic colitis. The upper GI endoscopy will be performed at Week -4 (Visit 2) and 
at Week 24 (Visit 6) or early termination. All possibly significant macroscopic abnormalities in 
the esophagus, stomach, duodenal bulb, and descending duodenum will be documented in the 
eCRF. A minimum of 6 and up to 8 small bowel biopsy specimens will be taken from separate 
folds/circumferential areas of the distal (postbulbar, D2/D3) duodenum. Samples will be 
collected and placed into formalin for Vh:Cd, IEL, and other exploratory analyses or snap frozen 
and potentially used for microbiome or other exploratory analyses related to GI immunology. 
Hematoxylin and eosin stained slides from small bowel biopsy specimens will be used to 
perform quantitative and qualitative morphometric analysis, which includes measurement of Vh 
and Cd and calculation of their ratio (Vh:Cd).  
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Biopsies should be taken with standard biopsy forceps with 1 biopsy taken per pass and placed 
into separate specimen vials. Additional biopsies should not be taken for assessment at the local 
laboratory unless deemed necessary for subject safety in the setting of an incidental finding. 
Additional instructions will be provided in a central pathology laboratory manual. 
At the central histopathology core laboratory, the histological efficacy assessment will be 
performed using the formalin-fixed, paraffin-embedded specimens. Morphometric analysis of the 
small bowel biopsy specimens involves measurement of Vh and Cd and calculation of their 
ratios (Vh:Cd). The Vh and Cd measurements will be obtained from well oriented biopsy 
samples as previously described (Adelman et al. 2018; Taavela et al. 2013) and across multiple 
loci so as not to miss patchy forms of villous atrophy. Staining of the samples for CD3 will also 
be used for quantitation of CD3+ IEL density numbers in the tissue.  
9.3.10 
 
 
 
 
 
 
 
 
 
9.3.11 
Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. Details of 
these procedures and required safety monitoring will be given in the laboratory manual. 
Direct viral or serologic testing for COVID-19 may be performed according to site’s standard of 
care and at the discretion of the investigator. 
Table 9.a lists the tests that will be obtained for each laboratory specimen, as well as additional 
tests and various time points.  
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Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
RBC 
WBC including differential 
Hemoglobin 
Hematocrit 
Platelets 
HbA1c 
ALT 
Albumin 
ALP 
AST 
Total bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Potassium 
Sodium 
Albumin 
Protein  
Glucose  
pH 
Leukocytes 
Blood  
Bilirubin 
Urobilinogen 
Ketone 
Creatinine 
Other: 
Celiac serologies: 
IgA-tTg 
DGP 
Serum 
Urine 
CRP 
hCG a (for pregnancy) 
GIP 
Beta hCG a (for pregnancy) 
FSH (if menopause is suspected) 
HIV test 
Hepatitis B and C 
ADA 
 
ADA: antidrug antibody; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate 
aminotransferase; CRP: C-reactive protein; DGP: deaminated gliadin peptide; FSH: follicle-stimulating hormone; 
GGT: γ-glutamyl transferase; GIP: gluten immunogenic peptide; HbA1c: glycosylated hemoglobin; hCG: human 
chorionic gonadotropin; HIV: human immunodeficiency virus; Ig: immunoglobulin; RBC: red blood cell; tTg: 
tissue transglutaminase; WBC: white blood cell. 
a For female subjects of childbearing potential only. 
Test for international normalized ratio should be performed locally for elevated liver enzyme and bilirubin 
evaluation. 
 
The central laboratory will perform laboratory tests. The results of laboratory tests will be 
returned to the investigator, who is responsible for reviewing and filing these results. 
If a subject has elevated ALT ≥3 × ULN with concurrent elevated total bilirubin >2 × ULN or 
elevated INR >1.5, the investigator must contact the medical monitor within 24 hours. Hepatic 
investigations as suggested in Table F-1 of Appendix F should be initiated. Any event of 
elevated ALT ≥3 × ULN with concurrent elevated total bilirubin >2 × ULN or elevated INR >1.5 
for which an alternative etiology has not been identified must be reported as an SAE. (Refer to 
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Section 7.6 and Section 10.2.3 for the appropriate guidance on reporting abnormal liver enzymes 
and bilirubin.) 
If ALT or AST is elevated ≥3 × ULN or the total bilirubin is elevated ≥2 × ULN, the investigator 
must contact the medical monitor for consideration of additional testing, close monitoring, 
discussion of the relevant subject details and possible alternative etiologies. The abnormality 
should be recorded as an AE (please refer to Section 10.2.3).  
Abnormal laboratory tests at screening may be retested at the investigator’s discretion (see 
Section 9.3.16). 
9.3.12 
PK and Biomarker Sample Collection and Analysis 
9.3.12.1 
Collection of Blood and Plasma for PK Sampling 
Blood samples to evaluate the PK of TAK-062 in plasma will be collected at Weeks -4, 0, 3, 12, 
24, and 28 as specified in Appendix B. Approximately 10 adult subjects enrolled in Cohort 1 and 
30 adults subjects enrolled in Cohort 2 will participate in PK subgroup for a slightly more 
intensive collections at Week 0 (randomization) and Week 3 visits, including predose and 0.5, 1, 
2, 3, and 4 hours (optional) postdose collections. All other subjects will be required to provide 
PK samples at predose, 0.5, and 1 hours postdose with additional collections as optional at these 
2 visits. At Week 12, all subjects will be required to provide PK samples at predose, 0.5, and 
1 hours postdose with additional collections as optional. At Week -4, 24, and 28 visits, PK 
samples will be collected at any time during the visit.  
The actual date and time of the sample collections, as well as the date and time for the current 
dose and the most recent dose before visit, should be accurately recorded in the eCRF. When 
predose samples are scheduled, subjects should be instructed to bring their scheduled dose of 
study drug to the clinic with them so the predose sample can be collected before the study drug is 
taken. PK samples should be collected as follows: predose sample (up to 30 minutes prior to 
dosing), postdose samples at 0.5 hr (±5 minutes), 1 hr (±10 minutes), 2 hr (±10 minutes), 3 hr 
(±15 minutes), and 4 hr (±15 minutes). While all efforts should be made to obtain the PK 
samples at the scheduled nominal time (or within the designated time frame specified in 
Schedule of Study Procedures [Appendix A]), collections outside of the allowed time window 
may not be considered a protocol deviation if the actual collection time as well as date and time 
of dosing are accurately captured.  
Collected samples will be stored for batch analysis of TAK-062 using a validated analytical 
method. Detailed instruction for handling, processing, storing, and shipping of plasma samples 
are provided in the laboratory manual.  
9.3.12.2 
Biomarker Collection 
Tissue samples to evaluate IELs, Vh:Cd ratio, other qualitative and quantitative histology 
endpoints, RNA, and microbiome will be collected through duodenal biopsies as noted in 
Schedule of Study Procedures (Appendix A). Urine samples will be collected to monitor GIP 
qualitatively and quantitatively as noted in Schedule of Study Procedures (Appendix A). Predose 
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plasma and serum samples will be collected as noted in the Schedule of Study Procedures 
(Appendix A). 
9.3.13 
Contraception and Pregnancy Avoidance Procedure 
9.3.13.1 
Male Subjects and Their Female Partners 
From the time of signing of informed consent/pediatric assent forms, throughout the duration of 
the study, and for 100 days after last dose of study drug, nonsterilized** male subjects who are 
sexually active with a female partner of childbearing potential* must use an effective 
contraception in combination with their female partner using an effective method of 
contraception, as below. In addition, they must be advised not to donate sperm during this 
period. WOCBP who are partners of male subjects are also advised to use additional 
contraception as shown in the list containing effective contraception below. 
9.3.13.2 
Female Subjects and Their Male Partners 
From the time of signing of informed consent/pediatric assent forms, throughout the duration of 
the study, and for 40 days after last dose of study drug, WOCBP* who are sexually active with a 
nonsterilized male partner** must use an effective method of contraception from the list below.  
In addition they must be advised not to donate ova during this period. 
9.3.13.3 
Definitions and Procedures for Contraception and Pregnancy Avoidance 
The following definitions apply for contraception and pregnancy avoidance procedures. 
*A woman is considered a WOCBP, that is, fertile, following menarche and until becoming 
postmenopausal unless 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 aged <45 years) 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. 
** Sterilized men should be at least 1-year postbilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy. 
Highly effective contraceptive methods are defined as <1% failure rate per year when used 
consistently and correctly. Effective contraceptive methods are defined as >1% failure rate per 
year when used consistently and correctly. In this study, the minimum required level of 
contraception is effective contraception. Table 9.b lists both highly effective and effective 
methods of contraception. 
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Table 9.b 
Acceptable Contraception Methods and Lactation Guidance for This 
Study 
Highly Effective Contraceptives 
Failure rate of <1% per year  
when used consistently and correctly 
Effective Contraceptives 
Failure rate of >1% per year  
when used consistently and correctly 
User Dependent 
 
• 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation. a 
– 
Oral.  
– 
Intravaginal.  
– 
Transdermal.  
• 
Progestogen only hormonal contraception associated 
with inhibition of ovulation.  
– 
Oral.  
– 
Injectable. 
• 
Sexual abstinence. b  
• 
Refraining from donating sperm. c  
• 
Progestogen-only oral hormonal contraception, 
where inhibition of ovulation is not the primary 
mode of action. 
• 
Male or female condom with or without 
spermicide. f 
• 
Cap, diaphragm or sponge with spermicide. f 
• 
Combination of male condom with either cap, 
diaphragm, or sponge with spermicide (double 
barrier methods). 
Low User Dependency 
 
• 
Implantable progestogen only hormonal contraception 
associated with inhibition of ovulation. a 
• 
IUD.  
• 
IUS.  
• 
Bilateral tubal occlusion. 
• 
Vasectomy; vasectomized partner. d, e 
 
Measures Intended to Prevent Fetal and Neonatal Exposure via Sperm or Breastmilk 
• 
Participants with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile penetration 40 days after the last dose.  
• 
Participants who are lactating must agree not to use their breastmilk to feed an infant. 
IUD: intrauterine device; IUS: intrauterine hormone-releasing system 
a Hormonal contraceptives must be stabilized for at least 30 days before the start of the screening period. 
b Sexual abstinence is considered a highly effective method ONLY if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
c Refrain from donating sperm for the duration of the study and for 100 days after the last dose of study treatment. 
d A vasectomy is a highly effective contraceptive method ONLY if the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
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Table 9.b 
Acceptable Contraception Methods and Lactation Guidance for This 
Study 
Highly Effective Contraceptives 
Failure rate of <1% per year  
when used consistently and correctly 
Effective Contraceptives 
Failure rate of >1% per year  
when used consistently and correctly 
e For participants of childbearing ability, having a vasectomized partner is a highly effective contraception method 
provided that the partner is the participant’s sole partner and that the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used. 
f A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) 
are also considered acceptable, but not highly effective, birth control methods. 
 
Unacceptable contraceptive methods in any study that requires contraception are displayed in 
Table 9.c. 
Table 9.c 
Unacceptable Contraception Methods 
Methods that are unacceptable in any study requiring contraception 
• 
Periodic abstinence (calendar, symptothermal, postovulation methods).  
• 
Withdrawal (coitus interruptus).  
• 
Spermicides only. 
• 
Lactational amenorrhoea method (LAM). 
 
Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent/pediatric assent process and will be asked 
to sign a consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova and sperm donation during the course of the study. During the course of the 
study, regular urine human chorionic gonadotropin (hCG) pregnancy tests will be performed 
only for WOCBP and all subjects (male and female) will receive continued guidance with 
respect to the avoidance of pregnancy and sperm donation as part of the study procedures. Such 
guidance should include a reminder of the following: 
• Contraceptive requirements of the study. 
• Reasons for use of barrier methods (ie, condom) in males with pregnant partners. 
• Assessment of subject compliance through questions such as 
– Have you used the contraception consistently and correctly since the last visit? 
– Have you forgotten to use contraception since the last visit?  
– Is there a chance you could be pregnant? 
In addition to a negative serum hCG pregnancy test at screening, female subjects of childbearing 
potential must also have confirmed menses in the month before first dosing (no delayed menses), 
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a negative urine hCG pregnancy test before receiving any dose of study medication as close as 
possible and before first dose of study medication, preferably on the same day.  
9.3.14 
Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn from the study 
and any sponsor-supplied study drug should be immediately discontinued. In addition, any 
pregnancies in the partner of a male subject during the study or for 100 days after the last dose, 
should also be recorded following authorization from the subject’s partner. 
If the pregnancy occurs during administration of study drug, eg, after the randomization visit, the 
pregnancy should be reported immediately, using a pregnancy notification form, to the contact 
listed in Section 1.0. 
Should the pregnancy occur during or after administration of blinded study drug, the investigator 
must inform the subject of their right to receive treatment information. If the subject chooses to 
receive unblinded treatment information, the individual blind should be broken by the 
investigator. Subjects randomized to placebo need not be followed. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received (blinded or unblinded, as 
applicable). 
All pregnancies, including female partners of male subjects, in subjects on active study drug will 
be followed up to final outcome, using the pregnancy form. Pregnancies will remain blinded to 
the study team. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted. 
9.3.15 
Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug. These may be 
prescribed by a physician or obtained by the subject over-the-counter. Concomitant medication is 
not provided by the sponsor. At each study visit, subjects will be asked whether they have taken 
any medication other than the study drug (used from the time of signing of informed 
consent/pediatric assent forms through the end of the study), and all medication including 
vitamin supplements, over-the-counter medications, oral herbal preparations, and rescue 
medications must be recorded in the eCRF. 
9.3.16 
Documentation of Screen Failure 
Investigators must account for all subjects who sign an informed consent/pediatric assent forms. 
If the subject does not meet eligibility criteria following completion of screening assessments, 
the investigator should complete the eCRF. The investigator or designee will document the 
subject as a screen failure in IRT. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
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• Pretreatment event (PTE)/AE. 
• Screen failure (did not meet inclusion criteria or exclusion criteria). 
• Lost to follow-up. 
• Withdrawal by subject. 
• Study termination by sponsor. 
Subject ID numbers assigned to subjects who fail screening should not be reused. 
Subjects who do not meet all inclusion criteria or meet an exclusion criteria and have not been 
randomized are considered screen failures may undergo rescreening once after discussion with 
the medical monitor. Rescreening will not be permitted for subjects who screen fail due to 
Vh:Cd >2.5 or negative HLA testing. A rescreened subject will receive a new ID number. A 
subject can be re-screened 1 time. 
If a subject is rescreened, all screening tests will be repeated except the following: 
• HLA testing. 
• Hepatitis and HIV testing if it occurred within 3 months before the initial rescreening visit. 
9.3.17 
Documentation of Randomization 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase. 
If the subject is found not to be eligible for randomization, the investigator should record the 
primary reason for screen failure on the applicable eCRF. 
Randomization will be stratified by celiac serologic status at Visit 1, defined as normal or 
elevated celiac serology (1 or more of the following: IgA-tTg >1 × ULN, IgA-DGP >2 × ULN, 
or IgG-DGP >2 × ULN), mild to moderate (Vh:Cd 1.5 to <2.5) versus moderate to severe 
(Vh:Cd <1.5) histologic injury at baseline, and by the use of PPIs or histamine type 2 receptor 
antagonists (yes or no) at Visit 1. 
9.4 
Monitoring Subject Treatment Compliance 
Subjects will be required to return study drug containers/unused study drugs to the site.  
All subjects should be reinstructed about the dosing requirement during study contacts. The 
authorized study personnel conducting the re-education must document the process in the subject 
source records. Subjects will be instructed to complete a daily diary and the site will monitor 
compliance of study drug and SIGE bar. 
9.5 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). 
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Each evening, subjects will complete their daily diary electronically. 
In acknowledgement of hospital, local, state, or national government restrictions or other site 
related factors caused by unavoidable circumstances (ie, COVID-19 pandemic), which may 
prevent investigators from conducting the study according to the Schedule of Study Procedures 
(Appendix A), investigators may consult with the medical monitor to continue subjects in the 
study despite departure from the Schedule of Study Procedures (Appendix A). Investigators are 
expected to evaluate the impact to the safety of the study subjects and site personnel for subjects 
to continue.  
When a scheduled visit is not conducted in-person, site staff will speak directly with the subject 
by telephone or other medium where acceptable (eg, a computer-based video communication) 
during the visit window to assess subject safety and overall clinical status. During this contact, 
the study site physician or other qualified site staff should also, at a minimum, conduct the 
following assessments: ask about any information on AE reported by subject since last visit, this 
should be collected, as well as concomitant medication documentation. Other study assessments 
may be collected remotely as is feasible, and may involve audio or video recording if allowed 
per local, state, or country regulations. Additionally, sites may send staff or send home health 
care as contracted by the sponsor to subjects to conduct study assessments contingent upon local 
regulations.  
9.6 
Biological Sample Retention and Destruction 
The samples will be sent to a central laboratory that processes the blood, urine, and tissue 
samples and serves as a secure storage facility. The sponsor and researchers working with the 
sponsor will have access to the samples collected and any test results. All samples collected 
during the study will be stored securely for up to 15 years or less according to local regulations 
with limited access and the sponsor will require anyone who works with the samples to agree to 
hold the research information and any results in confidence.  
When subjects request disposal of a stored sample during the retention period, the site will ask 
the central laboratory or sponsor-approved vendor to destroy the sample via the sponsor 
according to the procedure. The central laboratory or sponsor-approved vendor will destroy the 
sample in accordance with the procedure and notify the site and sponsor. 
Subjects who consented and provided biomarker samples for analysis can withdraw their consent 
and request disposal of a stored sample at any time.  
The sponsor has put into place a system to protect the subject’s personal information to ensure 
optimal confidentiality and defined standard processes for sample and data collection, storage, 
analysis, and destruction. 
9.6.1 
Flexible Options for Study Procedures in Response to Pandemic 
The following information provides guidance regarding flexibility to perform study procedures 
that could be implemented for study subjects or study sites during the course of this study in 
response to a pandemic or the lasting effects of a pandemic (eg, COVID-19 or other future 
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similar unexpected public health concerns) that require physical distancing that may result in 
subjects missing their visits. 
Optional flexible measures include the following: 
• Informed consent/pediatric assent forms procedure: If necessary, informed consent/pediatric 
assent from a potential or current study subject may be obtained via electronic informed 
consent/pediatric assent capabilities, or an electronic face-to-face consent interview when 
these individuals are unable to travel to the site, based on local regulations or requirements. 
• Clinical laboratory samples: Blood draws may be conducted at home by study authorized 
personnel or a local laboratory (or relevant clinical or office facility) authorized/certified to 
perform such tests routinely. 
• ECG procedures: ECGs may be performed during a home health care visit by a qualified 
health care professional who is authorized/certified to perform such tests routinely. 
• Vital signs: Vital sign measurements may be performed during a home health care visit by a 
qualified health care professional who is authorized/certified to perform such tests routinely. 
• Physical examination: Examinations may be conducted as a nurse assessment or via 
telehealth visit, per investigator’s discretion, during home health care visits, if applicable, and 
according to local regulations/requirements.  
10.0 
PTEs AND AEs 
10.1 
Definitions 
10.1.1 
PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed the informed consent/pediatric assent forms to participate in a study but before 
administration of any study drug; it does not necessarily have to have a causal relationship with 
study participation. 
10.1.2 
AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
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10.1.3 
Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered PTEs or 
AEs.) 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require discontinuation or a change in dose of study drug or a concomitant medication. 
• Be considered unfavorable by the investigator for any reason. 
• PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as 
a PTE/AE. 
Diagnoses versus signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or 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 a PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
• Changes in laboratory values or ECG findings are only considered to be PTEs or 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 or ECG re-test and/or continued monitoring of an abnormal value or finding 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 a PTE or as an AE. 
Pre-existing conditions: 
• Pre-existing conditions (present at the time of signing of informed consent/pediatric assent 
forms) are considered concurrent medical conditions and should NOT be recorded as PTEs 
or AEs. Baseline evaluations (eg, laboratory tests, ECG, x-rays) should NOT be recorded as 
PTEs unless related to study procedures. However, if the subject experiences a worsening or 
complication of such a concurrent medical condition, the worsening or complication should 
be recorded appropriately as a PTE (worsening or complication occurs before start of study 
drug) or an AE (worsening or complication occurs after start of study drug). Investigators 
should ensure that the event term recorded captures the change in the condition (eg, 
“worsening of…”). 
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• If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) 
any occurrence of an episode should only be captured as a PTE/AE if the condition becomes 
more frequent, serious or severe in nature. Investigators should ensure that the AE term 
recorded captures the change in the condition from baseline (eg “worsening of…”). 
• If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a PTE/AE if occurring to a 
greater extent to that which would be expected. Investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”). 
Worsening of PTEs or AEs: 
• If the subject experiences a worsening or complication of a PTE after the start of study drug, 
the worsening or complication should be recorded as an AE. Investigators should ensure that 
the AE term recorded captures the change in the PTE (eg, “worsening of…”). 
• If the subject experiences a worsening or complication of an AE after any change in study 
drug, 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 intensity of AEs/serious PTEs: 
• If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity recorded. 
AEs related to gluten exposure 
• AEs related to gluten may be anticipated to include signs and/or symptoms of CeD, including 
GI symptoms and extraintestinal manifestations such as skin rash, headache, fatigue 
neurological/neurocognitive manifestations, elevation in liver enzymes and bilirubin, and 
joint pain. Symptoms collected through the CDSD, including diarrhea, bowel movement 
frequency, abdominal pain, bloating, nausea, and fatigue that occur with gluten exposure, 
should not be reported as AEs unless these events require intervention such as rescue 
medication use (see Section 7.4) and/or become SAEs. If severe symptoms require use of 
rescue medications, each episode of rescue medication use is considered as an AE. 
Preplanned procedures (surgeries or interventions): 
• Preplanned procedures (surgeries or therapies) that were scheduled before signing of 
informed consent/pediatric assent forms are not considered PTEs or AEs. However, if a 
preplanned procedure is performed early ie, after subject has started study drug (eg, as an 
emergency) due to a worsening of the pre-existing condition, the worsening of the condition 
should be recorded as a PTE or an AE. Complications resulting from any planned surgery 
should be reported as AEs if these events occur after subject has commenced study drug. 
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Elective surgeries or procedures: 
• Elective procedures performed during the study where there is no change in the subject’s 
medical condition should not be recorded as PTEs or AEs, but should be documented in the 
subject’s source documents. Complications resulting from an elective surgery should be 
reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing 
illness and lack of therapeutic efficacy. 
Overdose: 
• All cases of overdose (with or without associated AEs) will be documented in the dosing 
section of the eCRF. Additionally, overdose should be captured as an AE in the eCRF with or 
without any additional AEs. 
An overdose will be considered as a dose above the maximum recommended dose that is 
being used in this study irrespective of the assigned study arm of the subject that overdosed. 
Any administered dose above that assigned to the subject that is less than the maximum dose 
being studied will be considered as a medication dosing error, and not an overdose. 
 endoscopy procedure related AEs: 
• Any incidental safety findings from local reading of the 
 or during the 
baseline endoscopy procedure may be considered as a PTE for the study; however, before 
this is captured as PTE, the site must consult with sponsor’s study physician as the decisions 
will be made on a case by case basis.  
• These incidental safety findings will be tracked in subsequent 
/endoscopy visits and any 
changes observed from baseline findings may be captured as TEAEs after discussing with 
sponsor’s study physician. 
10.1.4 
SAEs 
An 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. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
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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. 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3). 
10.1.5 
AEs of Special Interest 
There are no AEs of special interest for TAK-062. 
10.1.6 
Intensity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
Liver AEs will be characterized per FDA guidelines (Appendix F).  
10.1.7 
Causality of AEs 
The relationship of each AE to study drug(s) will be assessed using the following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant medications and concurrent treatments. 
10.1.8 
Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
Relationship to SIGE will be assessed and recorded separately from other study procedures. 
The relationship should be assessed as related if the investigator considers that there is 
reasonable possibility that an AE is due to a study procedure. Otherwise, the relationship should 
be assessed as not related.  
10.1.9 
Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator. 
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10.1.10 Stop Date  
The stop date of the AE/PTE is the date on which the subject recovered, the AE resolved but 
with sequelae or the subject died. 
10.1.11 Pattern 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. Other events occur once or are continuous. 
10.1.12 Action Concerning Study Drug  
• Drug withdrawn: a study drug is stopped due to the particular AE. 
• Dose not changed: the particular AE did not require any dose modification and/or stopping a 
study drug. 
• Unknown: only to be used if it has not been possible to determine what action has been 
taken. 
• Not applicable: a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped 
before the onset of the AE. 
• Dose interrupted: the dose schedule was interrupted due to the particular AE. 
10.1.13 Outcome 
• Recovered/resolved: Subject returned to baseline assessment status with respect to the 
AE/PTE. 
• Recovering/resolving the intensity is lowered by 1 or more grades: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from another cause with the 
particular AE/PTE state 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 study period has gotten worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE/PTE state remaining 
“Not recovered/not resolved”. 
• Resolved with sequelae: the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis). 
• Fatal: the AEs/PTEs which are considered as the cause of death.  
• Unknown: the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
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10.2 
Procedures 
10.2.1 
Collection and Reporting of AEs 
10.2.1.1 
PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed 
consent/pediatric assent forms to participate in the study and continue until just before the 
subject is first administered study drug (Visit 3) or until screen failure. For subjects who 
discontinue before study drug administration, PTEs are collected until the subject discontinues 
study participation. 
Collection of AEs will commence from the time that the subject is first administered study drug 
(Visit 3). Routine collection of AEs will continue until 30 days after the administration of the last 
dose of study drug. 
10.2.1.2 
PTE and AE Reporting 
At each study 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 study. Subjects experiencing a 
serious PTE 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 PTEs, related or unrelated to the study procedure, need not to be followed up 
for the purposes of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values such as have returned to baseline or until there is a satisfactory explanation for 
the changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the AE is related to the study drug treatment. The 
following information will be documented for each AE: 
1. AE term. 
2. Start and stop date and time. 
3. Pattern. 
4. Intensity. 
5. Investigator’s opinion of the causal relationship between the AE and administration of study 
drug(s) (related or not related) (not completed for PTEs). 
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure. 
7. Action taken with study treatment. 
8. Outcome of event. 
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9. Seriousness. 
All PROs will not be used as a primary means to collect AEs. However, should the investigator 
become aware of a potential AE through the information collected with the instruments, proper 
follow-up with the subject for medical evaluation should be undertaken. Through this follow-up 
if it is determined that an AE not previously reported has been identified, normal reporting 
requirements should be followed. 
10.2.2 
Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
A Takeda 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 AE and the reason why the AE is categorized as serious. 
• Subject ID number. 
• Investigator’s name. 
• Name of the study drug. 
• Causality assessment. 
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1. 
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation. 
Reporting of serious PTEs will follow the procedure described for SAEs. 
10.2.3 
Reporting of Abnormal Liver Enzymes and Bilirubin 
For any subject with ALT ≥3 × ULN AND total bilirubin >2 × ULN OR INR >1.5 for which an 
alternative etiology has not been found, report the event as an SAE, contact the sponsor’s 
medical monitor within 24 hours, and follow the additional monitoring, evaluation, and follow-
up recommendations in Appendix F.  
Other Grade 3 or 4 laboratory abnormalities (per CTCAE v5.0) should be assessed for clinical 
significance by the investigator or qualified subinvestigator. Clinically significant laboratory 
abnormalities should be confirmed by repeat testing and the medical monitor should be 
contacted. 
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date (after 
the last dose), the investigator should complete a follow-up SAE form or provide other written 
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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. 
10.3.1 
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, including the European 
Medicines Agency, investigators and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is being conducted. Relative to the first awareness of 
the AE by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted 
to the regulatory authorities as expedited report within 7 days for fatal and life threatening, and 
15 days for other SAEs, unless otherwise required by national regulations. The sponsor will also 
prepare an expedited report for other safety concerns where these might materially alter the 
current benefit-risk assessment of a study drug/sponsor-supplied drug or that would be sufficient 
to consider changes in the study drug/sponsor-supplied drug administration or in the overall 
conduct of the trial. The study site also will forward a copy of all expedited reports to his or her 
IRB or IEC in accordance with local regulations. 
11.0 
STUDY-SPECIFIC COMMITTEES 
11.1 
IDMC 
According to ICH E6 (1.25) an IDMC (eg, Data and Safety Monitoring Committee, Monitoring 
Committee, Data Monitoring Committee) may be established by the sponsor to assess at intervals 
the progress of the study, the safety data, and the critical efficacy endpoints, and to recommend 
to the sponsor whether to continue, modify, or stop a study. 
The minimal description of the IDMC should include: 
• Composition (number of members and expertise). 
• Frequency of meetings/assessments. 
• Purpose and authority. 
• Scope of data review. 
Details of the IDMC roles and responsibilities are captured in the IDMC charter prior to the start 
of the trial. 
An external IDMC is warranted to ensure the drug is safe and efficacious in adults before dosing 
in adolescents. 
The primary responsibility of the IDMC is to safeguard study subjects, in particular the 
adolescent subjects, by reviewing and assessing the clinical safety data being collected during the 
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performance of the study. The IDMC will review SAEs and AEs ≥Grade 3. The IDMC will also 
meet periodically throughout the study to review cumulative safety data. Based on these data 
evaluations, the IDMC will make recommendations to the sponsor to continue the study as 
planned, or to modify, temporarily suspend, or terminate the treatment group or study. The 
IDMC will be responsible for identifying issues and making recommendations regarding the 
monitoring of the subjects for safety, including the collection of additional safety data. IDMC 
will also be reviewing IA data and notifying the sponsor of the recommendation to include 
adolescent group. The sponsor will be responsible for notifying investigators and regulatory 
authorities of any IDMC recommendations, as appropriate. 
12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the data management plan. 
AEs, PTEs, medical history, and concurrent medical conditions will be coded using the latest 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World 
Health Organization Drug Dictionary. 
12.1 
eCRFs 
Completed eCRFs are required for each subject who signs informed consent/pediatric assent 
forms. 
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff on the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. 
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 Takeda 
personnel (or designees) and will be answered by the site.  
The principal investigator must review the eCRFs for completeness and accuracy and must e-
sign 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 study database, any change of, modification of or addition to the data on the 
eCRFs should be made by the investigator with the use of change and modification records of the 
eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign, or sign and seal, and date. 
eCRFs will be reviewed for completeness and acceptability during periodic reviews by the 
sponsor or its designee. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study 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.  
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12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the ID log of all participating 
subjects, medical records, temporary media such as thermal sensitive paper, source worksheets, 
all original signed and dated informed consent/pediatric assent forms, subject authorization 
forms regarding the use of personal health information (if separate from the informed 
consent/pediatric assent forms), electronic copy of eCRFs, including the audit trail, and detailed 
records of drug disposition to enable evaluations or audits from regulatory authorities, the 
sponsor or its designees. Any source documentation printed on 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 study records should be 
retained until an amount of time specified by applicable regulatory requirements or for a time 
specified in the study site agreement between the investigator and sponsor. 
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents. 
13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized before any unblinding of study 
data for the IA. This document will provide further details regarding the definition of analysis 
variables and analysis methodology to address all study objectives. 
A blinded data review will be conducted before unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject 
evaluability, and appropriateness of the planned statistical methods. 
13.1.1 
Analysis Sets 
Full analysis set (FAS)–SIGE: All randomized subjects who are randomized to receive gluten-
containing SIGE.  
FAS–no SIGE: All randomized subjects who are randomized to gluten-free SIGE.  
Safety analysis set (SAF): All randomized subjects who received at least 1 dose of study drug.  
SAF-SIGE: All randomized subjects who received at least 1 dose of study drug and gluten-
containing SIGE.  
SAF–no SIGE: All randomized subjects who received at least 1 dose of study drug and gluten-
free SIGE.  
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Per-protocol set (PPS)–SIGE: All subjects in FAS-SIGE who do not violate the terms of the 
protocol in a way that would impact the study outcome. All decisions to exclude subjects for the 
PPS will be made before the unblinding of the study.  
The PK analysis set: All randomized subjects who received at least 1 dose of study drug with at 
least 1 measured PK concentration.  
Immunogenicity analysis set: All randomized subjects who received any TAK-062 and have the 
baseline and at least 1 postbaseline immunogenicity sample assessment.  
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics including stratification 
factors will be presented by treatment group and overall for FAS-SIGE and FAS–no SIGE. 
Summary statistics (N, mean, SD, median, minimum, and maximum) will be generated for 
continuous variables (eg, age and weight) and the number and percentage of subjects within each 
category will be presented for categorical variables (eg, sex, ethnicity, race). Individual subject 
demographic and baseline characteristics data will be listed. 
The following demographic characteristics will be summarized in the following order in the 
tables: age (years), age (categorical), sex, ethnicity, race, weight (kg), height (cm), and BMI 
(kg/m2).  
13.1.3 
Efficacy Analysis 
All efficacy analyses for the treatment period will be conducted using the FAS-SIGE and FAS–
no SIGE separately. All statistical hypothesis testing will be 2-sided using a significance level of 
0.05 unless otherwise stated. Baseline value will be defined as the most recent nonmissing results 
before the first dose of study treatment unless otherwise specified. The placebo group for 
analyses based on FAS-SIGE will include all subjects randomized to receive placebo 
 and 
gluten-containing SIGE bars 
 from Cohorts 1 and 2 unless specified otherwise. 
 
13.1.3.1 
Primary Efficacy Endpoint Analysis: Change From Baseline in Weekly CDSD GI 
Symptom Severity Score at Week 12 
The primary efficacy analysis will be based on FAS-SIGE. The weekly CDSD GI symptom 
severity score is an average of the daily GI symptom severity scores during the week. The daily 
GI symptom severity score is the average of the severity score for diarrhea, abdominal pain, 
bloating and nausea, ranging from 0 (no symptoms) to 4 (very severe). Weekly CDSD scores 
will be calculated where the CDSD is completed on at least 4 of the 7 days. When the daily diary 
is completed on less than 4 of the 7 days, the weekly CDSD GI symptom severity score will be 
considered missing in the primary analysis. The attributes of the primary estimand are: 
• Population: Subjects with clinically active CeD and small intestinal villous atrophy who are 
experiencing inadvertent gluten exposure and meet all the eligibility criteria. 
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• Variable/endpoint: Change in weekly CDSD GI symptom severity score from baseline to 
Week 12. 
• Treatments: TAK-062 (
) versus placebo. 
• Intercurrent events (ICEs): Treatment discontinuation (due to AE or other reasons), SIGE bar 
discontinuations, and use of rescue medications for CeD symptoms. 
– Strategy for addressing ICEs: A composite strategy will be used to address rescue 
medication use and treatment discontinuation due to lack of efficacy or treatment-related 
AEs. For subjects who use rescue medications for CeD-related symptoms, the severity of 
the treated GI symptom(s) in CDSD on the days when the rescue medications are used 
will be set to very severe. For subjects who discontinue treatment due to lack of efficacy 
or treatment-related AEs, the Week 12 CDSD severity score will be set to the baseline 
(Week -1) weekly CDSD GI symptom severity score. A treatment policy strategy will be 
used to address SIGE bar discontinuation (ie, the recorded weekly CDSD GI symptom 
severity score will be used regardless of whether a subject has discontinued SIGE) and 
treatment discontinuation due to reasons other than lack of efficacy or treatment-related 
AEs. 
• Population-level summary: Treatment difference (TAK-062 – placebo) in the mean change 
from baseline to Week 12 in weekly CDSD GI symptom severity score, for each dose level. 
The primary endpoint will be analyzed with a mixed model for repeated measures (MMRM) 
approach using the appropriate contrast at Week 12. The model will be based on all available 
weekly CDSD GI symptom severity scores from Week -1 through Week 12. The model will 
include treatment group, week, treatment-by-week interaction, and the randomization 
stratification factors as fixed effects and baseline CDSD GI symptom severity score as 
covariates. An unstructured covariance structure will be used to model the within-subject errors. 
If the model does not converge, additional covariance structure will be used with the order 
specified in the SAP. Two-sided tests comparing each of the TAK-062 dose groups with placebo 
at Week 12 will be conducted. The corresponding p-values, LS means of treatment differences 
and 2-sided 95% CI will be reported. The MMRM assumes data is missing at random. 
Sensitivity analysis will be performed with alternative assumption that data is missing not at 
random.  
Multiplicity control: To control the overall type I error rate for the primary endpoint, a fixed-
sequence testing procedure will be used for the comparison of 3 doses of TAK-062 versus 
placebo. Specifically, the primary endpoint tested will be conducted in the following order: 
i. 
First, 
 TAK-062 versus placebo for subjects taking gluten-containing SIGE. 
ii. 
If the test in Step 1 is statistically significant, then perform the superiority test of 
 TAK-062 versus placebo for subjects taking gluten-containing SIGE. 
iii. 
If the test in Step 2 is statistically significant, then perform the superiority test of 
 TAK-062 versus placebo for subjects taking gluten-containing SIGE. 
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Supplementary analyses for the primary estimand will include the following: 
• Estimand with the target population of subjects who satisfied study entry criteria and are on 
pre-enrollment diet. The primary endpoint will be analyzed based on FAS–no SIGE. The 
endpoint, strategy for the ICEs and population-level summary will be the same as the main 
estimand. Nominal p-values will be calculated. No hypothesis testing will be performed. 
• Estimand with the target population excluding subjects who report >1 point improvement in 
PGIS during 
 run-in period. The supplementary analysis will be performed for FAS-
SIGE and FAS–no SIGE separately. The endpoint definition, strategy for the ICEs and 
population-level summary will be the same as the main estimand. Nominal p-values will be 
calculated. No hypothesis testing will be performed. 
• Estimand with the weekly CDSD-overall (GI + Tiredness) symptom severity score based on 
daily CDSD symptom severity score that is the average of the severity score for diarrhea, 
abdominal pain, bloating, nausea, and tiredness, ranging from 0 to 4. The population, 
treatments, strategy for the ICEs and population-level summary will be the same as the main 
estimand. The analysis will be performed based on FAS-SIGE and FAS–no SIGE separately. 
Nominal p-values will be calculated. No hypothesis testing will be performed.  
• Estimands using the area under the curve (AUC) of daily CDSD GI symptom severity score 
from Day 1 through Week 12 as the endpoint. The AUC will be a summation of daily scores. 
Missing values due to study discontinuation will be imputed by last observed carried 
forward. The detailed derivation of the AUC will be provided in the SAP. The AUC will be 
analyzed using analysis of covariance (ANCOVA) based on FAS-SIGE and FAS-no SIGE 
separately. The LS means of the treatment difference compared with placebo and 2-sided 
95% CI will be presented for each TAK-062 dose group. Nominal p-values will be 
calculated. No hypothesis testing will be performed. 
• Estimands using change in CDSD GI symptom score from Week -3 (before SIGE) and from 
Week -5 (before study intervention) to Week 12 as the endpoint. The analysis method will be 
the same as the main estimand. Nominal p-values will be calculated. No hypothesis testing 
will be performed. 
Exploratory analysis: The primary endpoint of change from baseline in CDSD GI symptom 
severity score at Week 12 will also be analyzed by modeling based on combined FAS-SIGE and 
FAS-no SIGE excluding the 
 SIGE group, where the effects of treatment 
group, SIGE, and their interaction effects will be estimated in the same model.  
13.1.3.2 
Secondary Efficacy Endpoint Analysis 
The main estimands for the secondary objectives assess the treatment effect of TAK-062 
compared with placebo at Week 24 in target population based on the following 
variable/endpoint:  
• Change in Vh:Cd from baseline (measured at Week -4) to Week 24. 
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The target population, treatments, and ICEs are the same as for the primary estimand in 
Section 13.1.3.1. Composite strategy will be used to address the ICEs of treatment 
discontinuation due to lack of efficacy or treatment-related AEs, and treatment policy strategy 
for the ICEs of SIGE bar discontinuation or rescue medication use (ie, Vh:Cd measured at 
Week 24 will be used regardless of SIGE bar discontinuation or rescue medication use) and other 
reasons for discontinuations. 
The corresponding population-level summaries are: 
• Treatment difference (TAK-062 – placebo) in the change from baseline to Week 24 in 
average Vh:Cd on duodenal biopsy, for each dose level. 
The analysis will be conducted using ANCOVA. The model will include treatment group and the 
randomization stratification factors as fixed effects and baseline values as covariate. Missing 
values will be regarded as missing at random. Missing data will be handled using multiple 
imputation (details will be provided in the SAP). The LS means and 2-sided 95% CI will be 
provided for the Week 24 treatment difference between the 
 TAK-062 dose 
groups versus placebo, respectively. Nominal 2-sided p-values will be provided for the 
comparison of 
 TAK-062 versus placebo, 
 TAK-062 versus placebo, and 
 
TAK-062 versus placebo, respectively. 
Supplementary analyses will be planned as follows: 
Supplementary analyses based on subjects who satisfied study entry criteria and are on pre-
enrollment diet will be performed. The corresponding endpoints will be analyzed based on FAS–
no SIGE.  
Supplementary analyses based on the target population excluding subjects who report >1 point 
improvement in PGIS during 
 run-in period will also be performed. The analysis will be 
performed for FAS-SIGE and FAS-no SIGE separately. 
For all the above supplementary analyses, the endpoint definitions, strategy for the ICEs and 
population-level summary will be the same as for the main estimand. Nominal p-values will be 
calculated. No hypothesis testing will be performed. 
As an exploratory analysis, the endpoint of change from baseline (Week -4) in Vh:Cd 
measurements at Week 24 will also be analyzed by modeling based on combined FAS-SIGE and 
FAS–no SIGE excluding the 
 TAK-062 
 group, where the effects of 
treatment group, SIGE and their interaction effects will be estimated in the same model. 
The analysis on Vh:Cd will be performed similarly for the changes in the individual Vh and Cd 
measurements as exploratory analyses. 
13.1.3.3 
Other Efficacy Endpoint Analyses 
The endpoint of change from baseline in CDSD symptom severity item score for each individual 
symptom and change in each of the frequency questions from the supplemental questions (bowel 
movements, diarrhea, and vomiting) from Week -1 to Weeks 12 and 24 will be analyzed using 
the same approach as the primary analysis described in Section 13.1.3.1. The frequency of bowel 
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movements will be converted to an indicator for constipation (defined as fewer than 3 days of 
complete spontaneous bowel movement in a week). The weekly average of the frequency items 
will be an average of each daily frequency during the week, with constipation having values of 0 
(no constipation) or 1 (constipation) each week. Weekly frequency will be calculated where the 
CDSD is completed on at least 4 of the 7 days. When the daily diary is completed on less than 4 
of the 7 days, the weekly frequency will be considered missing. 
The change in symptom severity for each item in CDSD and in each frequency item in the 
supplemental questions from Week -3 (before SIGE) and from Week -5 (before study 
intervention) to Weeks 12 and 24 will also be analyzed. The analysis method will be the same as 
for the corresponding change from Week -1. Nominal p-values will be calculated. No hypothesis 
testing will be performed. 
PGIC score at Weeks 12 and 24 and the change from baseline in PGIS score will be assessed 
using analysis of variance model with treatment group and the randomization stratification 
factors as fixed effects. Other exploratory PRO endpoints at Weeks 12 and 24 will be analyzed 
using the same approach as in Sections 13.1.3.1 and 13.1.3.2. 
Other exploratory histology efficacy endpoints at Week 24, including change from baseline in 
histology endpoints such as Vh, Cd, IEL, quantitative Marsh, 
 for the 
first tertile of the intestine will be analyzed using the same approach as in Section 13.1.3.2.  
For binary endpoints, number and proportion of subjects will be provided for each treatment arm. 
The comparison between each dose of TAK-062 with placebo will be performed using the 
Cochran-Mantel-Haenszel test adjusted by the randomization stratification factors. The point 
estimates for the treatment difference along with 95% CI will be provided. Nominal 2-sided 
p-values will be provided. Nonresponder imputation will be used for missing data.  
All efficacy endpoints will also be summarized by descriptive statistics by treatment group at 
each visit. 
Subgroup analysis will be performed for the efficacy endpoints based on celiac serologic status, 
symptom severity and symptom type, severity of small intestine mucosal injury, gluten exposure 
by GIP urine evaluation during the run-in period, and demographics. 
13.1.4 
PK Analysis 
Measured plasma concentrations of TAK-062 over time will be summarized descriptively using 
the PK analysis set. Individual concentration data versus time will be presented in a data listing. 
Further analysis may be performed as deemed necessary and will be reported separately from the 
clinical study report.  
13.1.5 
 
 
13.1.6 
Pharmacodynamic Analysis 
The analyses for histological endpoints are described in Section 13.1.3.  
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A detailed description of the pharmacodynamic biomarker analyses related to intestinal gene 
expression and microbial community changes will be provided in a separate document, and a 
separate report will be provided. 
13.1.7 
Psychometric Analyses for CDSD 
The psychometric analysis plan (PAP) will also be finalized before the IA. The PAP will provide 
further details of the analysis methodology for the psychometric evaluation of the CDSD. A 
separate report will be provided. 
13.1.8 
Exit Interview Analysis 
Exit interviews will be qualitatively analyzed and a separate report will be provided. 
13.1.9 
Safety Analysis 
All safety analyses will be conducted using the SAF, the SAF-SIGE, and the SAF–no SIGE. 
No statistical testing or inferential statistics will be generated. All AEs will be coded using the 
latest MedDRA version. The number and percentage of subjects with TEAEs (new onset or 
worsening AEs after the first dose of study treatment regardless of relationship to study drug), 
treatment-related AEs, SAEs, and AEs leading to treatment discontinuation will be summarized 
by MedDRA primary System Organ Class and Preferred Term, overall and by severity for each 
treatment group. 
Change from baseline in clinical laboratory tests and vital signs will be summarized by treatment 
group and by visit. Subjects with markedly abnormal values for laboratory tests and vital signs 
will be summarized and listed. 
13.1.10 
Immunogenicity Analysis 
Each ADA sample will be tested first by a screening test, followed by a confirmatory test if the 
screening test is positive. An ADA test will be considered positive only when both the screening 
and confirmatory tests show positive results. Testing for neutralizing antibodies (NAbs) will be 
performed only if the ADA testing is considered positive. A positive ADA subject is defined as a 
subject who has at least 1 positive ADA result during the study, and is further categorized as: 
• Transiently positive: defined as subjects with confirmed positive ADA in at least 1 sample 
and no consecutive samples. 
• Persistently positive: defined as subjects with confirmed positive ADA in 2 or more 
consecutive positive ADA samples.  
Immunogenicity will be analyzed using the immunogenicity analysis set. Percentage of subjects 
with positive ADA blood sample results and percentage of subjects with positive neutralizing 
ADA during the study will be summarized by treatment group. Percentage of subjects with 
positive ADA will be also summarized by study visit and treatment group. The impact of 
positive ADA on PK, efficacy, and safety may be evaluated. Results of ADA and NAb tests will 
be also in listings. 
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13.2 
IA and Criteria for Early Termination 
An IA is to be performed to see if clinical efficacy and safety have been demonstrated. The IA 
will be performed when at least 75% of subjects in Cohort 1 have either completed 12 weeks of 
treatment or dropped out. The IA will include safety analysis, primary efficacy analysis, and 
histological data analysis based on available data. The decision to continue Cohort 2 and initiate 
enrollment of adolescents will be based on the safety evaluation, the conditional power for the 
primary efficacy analysis, and the analysis of Vh:Cd data. It will not lead to stopping Cohort 1 
for efficacy or futility. Thus, there will be no alpha level adjustment for the final analysis. 
Safety Considerations 
Safety will focus on the severity of reported adverse events. When the proportion of subjects 
with Grade ≥3 events related to TAK-062 is more than 20% (percentage points) higher in the 
active arm than in the placebo arm, safety will be considered not acceptable and may lead to 
early termination of the study. 
Efficacy Considerations 
For efficacy, the recommendation chart with conditional powers for CDSD GI symptom severity 
score and the probability of Vh:Cd will be used for decision making by the IDMC in conjunction 
with their clinical evaluation of the totality of the study data per Table 13.a. 
The conditional power will be calculated on the basis of the test statistic in the MMRM model of 
the primary efficacy endpoint at Week 12, and the probability for Vh:Cd at Week 24 will be 
documented in the SAP. 
The recommended decision criteria based on the conditional power for CDSD GI symptom 
severity score and the probability of Vh:Cd, after significant safety concerns are ruled out, are 
shown in Table 13.a. 
Table 13.a 
  
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Table 13.a 
  
 
The study will be completed as planned unless 1 or more of the criteria are satisfied that require 
temporary suspension or early termination of the study as described in Section 6.3. 
13.3 
Determination of Sample Size 
The planned sample size is approximately 357 subjects. For a 2-sample comparison of means, 
0.5 standardized mean difference is regarded as a medium effect size (Levin 1997). A sample 
size of 53 subjects per treatment group will provide 80% power to detect a standardized mean 
difference (mean difference/SD) of 0.55 between
 TAK-062 and placebo in the change 
from baseline CDSD weekly score (assuming common SD) for a 2-sided statistical hypothesis 
test, using a 2-sample t-test and a 5% significance level. Assuming a dropout rate of 
approximately 12%, a sample size of 60 subjects per treatment group for the 
 and placebo 
arms in the gluten-containing SIGE group in Cohort 1 will be the planned enrollment.  
The planned enrollment for Cohort 2 is 30 and 50 adults per treatment arm in the placebo and 
active arms (
 TAK-062), respectively, in the gluten-containing SIGE arms; 
50 subjects (43 adults and 7 adolescents) per arm in the 
 and placebo gluten-free SIGE 
bar arms; and 7 (adolescents only) in the 
 gluten-free SIGE bar arm.  
For the combined placebo gluten-containing SIGE groups from Cohorts 1 and 2 versus 
 
TAK-062, 86% power would be provided (based on the 2-sample t-test and the 5% significance 
level) to detect the standardized mean difference between groups (0.55) with the same 12% 
assumption for dropout rate. In addition, 82% power would be provided from the same 
assumptions for combined placebo gluten-containing SIGE group from Cohorts 1 and 2 versus 
 TAK-062 group. The analysis to detect the difference between the combined 
placebo gluten-containing SIGE group and the active group would yield a higher power. 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study 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 guarantees access to source documents by the sponsor and/or its designee 
(contract research organization) and by the IRB or IEC. In acknowledgement of hospital, local, 
state, or national government restrictions or other site related factors caused by unavoidable 
circumstances (eg, COVID-19 pandemic) that may prevent onsite monitoring visits; remote visits 
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and remote data verification may be conducted, if possible and if permitted by local standard 
operating procedures and regulation. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
investigator’s binder, study drug, subject medical records, informed consent/pediatric assent 
documentation, documentation of subject authorization to use personal health information (if 
separate from the informed consent/pediatric assent forms), and review of eCRFs and associated 
source documents. It is important that the investigator and other study personnel are available 
during the monitoring visits and that sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study 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. Before implementing changes in the study, the sponsor and the IRB/IEC must 
approve any revisions of all informed consent/pediatric assent documents and amendments to the 
protocol unless there is a subject safety issue. 
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). 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 study 
assessment.  
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study 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 study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency). If the study 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 study documents as described in Section 14.1. 
15.0 
ETHICAL ASPECTS OF THE STUDY 
This study 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 ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable ICH GCP Guideline E6 (1996), European Union Directive 
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2001/20 EC, as well as all local or regional regulatory requirements and align his or her conduct 
in accordance with the “Responsibilities of the Investigator” that are listed in Appendix C. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent/pediatric assent and investigator responsibilities. 
15.1 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject ID number. As permitted by 
all applicable laws and regulations, limited subject attributes, such as sex, age, or date of birth 
may be used to verify the subject and accuracy of the subject’s unique ID number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit the monitor or the sponsor’s designee, 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 study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent/pediatric assent process (see 
Section 15.3). 
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). 
15.2 
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 study, 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 due to 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. 
Before implementing changes in the study, the sponsor and the IRB/IEC must approve any 
revisions of all informed consent/pediatric assent documents and amendments to the protocol 
unless there is a subject safety issue. 
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 IB, a copy of the informed 
consent/pediatric assent form, and, if applicable, subject recruitment materials and/or 
advertisements and other documents required by all applicable laws and regulations, must be 
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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/pediatric assent must be obtained and submitted to the 
sponsor or designee before commencement of the study supplied drug or study-specific 
screening activity/signing a contract for the clinical study. The IRB or IEC approval must refer to 
the study by exact protocol title, number, and version date; identify versions of other documents 
(eg, informed consent/pediatric assent form) reviewed; and state the approval date. The sponsor 
will notify site once the sponsor has confirmed the adequacy of site regulatory documentation 
and, when applicable, the sponsor has received permission from competent authority to begin the 
study. Until the site receives notification, no protocol activities, including screening, may occur. 
Study 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 informed 
consent/pediatric assent form, recruitment materials intended for viewing by subjects, local 
safety reporting requirements, reports and updates regarding the ongoing review of the study 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. 
15.3 
Subject Information, Informed Consent/Pediatric Assent, and Subject 
Authorization 
Written consent documents will embody the elements of informed consent/pediatric assent 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 informed consent/pediatric assent form, 
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 study. The informed consent/pediatric assent 
forms and the subject information sheet (if applicable) further explain the nature of the study, its 
objectives, and potential risks and benefits, as well as the date informed consent/pediatric assent 
is given. The informed consent/pediatric assent forms 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 
informed consent/pediatric assent forms and if applicable, the subject authorization form. The 
informed consent form, pediatric assent form, 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 informed consent form, pediatric assent form, 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 informed consent form, pediatric assent form, subject authorization form (if applicable), 
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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/pediatric assent, 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 study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent/pediatric assent forms 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 
study. 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 informed consent/pediatric assent forms and subject authorization (if 
applicable) at the time of consent and before subject entering into the study; however, the 
sponsor may allow a designee of the investigator to sign to the extent permitted by applicable 
law. 
Once signed, the original informed consent/pediatric assent forms, 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/pediatric 
assent forms in the subject’s medical record. Copies of the signed informed consent/pediatric 
assent forms, the signed subject authorization form (if applicable), and subject information sheet 
(if applicable) shall be given to the subject. 
All revised informed consent/pediatric assent forms 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 revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised informed 
consent/pediatric assent forms. 
Physical and emotional pain for children will be addressed and minimized as much as possible 
during the trial. For procedures, analgesia will be provided per a professional at a site with 
experience in caring for and treating physical and emotional pain in patients at this age, and pain 
monitored and treated per standard of care. Blood draws may utilize lidocaine, numbing agents 
and smaller caliber needles (butterfly needles). It should be noted that pediatric patients are not 
included in the additional PK intensive blood draws.  
The volume of blood drawn will not surpass weekly or monthly safety limits for subjects ≥33 kg. 
If a subject’s weight is <33 kg, a screening blood draw may be done on 2 consecutive weeks, as 
to not surpass the weekly blood draw limit. 
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15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 
Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, is the 
sole responsibility of the sponsor. 
The investigator needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association.  
15.4.2 
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, Takeda 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 study, as defined in Takeda Policy/Standard. Takeda 
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, Takeda will assist callers in locating study 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.  
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly 
accessible websites, as required by Takeda Policy/Standard, applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study 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 study insurance against the risk of injury to study 
subjects. Refer to the study 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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16.0 
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2019b. PROMIS Fatigue Scoring Manual. 
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change in small intestinal histology in patients with celiac disease. Am J Gastroenterol, 
113(3), 339-47. 
Barratt, S. M., Leeds, J. S. and Sanders, D. S. 2011. Quality of life in Coeliac Disease is 
determined by perceived degree of difficulty adhering to a gluten-free diet, not the level 
of dietary adherence ultimately achieved. J Gastrointestin Liver Dis, 20(3), 241-5. 
Biagi, F., Campanella, J., Martucci, S., Pezzimenti, D., Ciclitira, P. J., Ellis, H. J., et al. 2004. A 
milligram of gluten a day keeps the mucosal recovery away: a case report. Nutr Rev, 
62(9), 360-3. 
Catassi, C., Fabiani, E., Iacono, G., D’Agate, C., Francavilla, R., Biagi, F., et al. 2007. A 
prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for 
patients with celiac disease. Am J Clin Nutr, 85(1), 160-6. 
Codex Alimentarius 2015. Standard for Foods for Special Dietary Use for Persons Intolerant to 
Gluten. Codex Alimentarius, Food and Agriculture Organization of the United Nations, 
World Health Organization. 
Crocker, H., Jenkinson, C. and Peters, M. 2018. Quality of life in coeliac disease: item reduction, 
scale development and psychometric evaluation of the Coeliac Disease Assessment 
Questionnaire (CDAQ). Aliment Pharmacol Ther, 48(8), 852-62. 
Dorn, S. D., Hernandez, L., Minaya, M. T., Morris, C. B., Hu, Y., Leserman, J., et al. 2010. The 
development and validation of a new coeliac disease quality of life survey (CD-QOL). 
Aliment Pharmacol Ther, 31(6), 666-75. 
Gibert, A., Kruizinga, A. G., Neuhold, S., Houben, G. F., Canela, M. A., Fasano, A., et al. 2013. 
Might gluten traces in wheat substitutes pose a risk in patients with celiac disease? A 
population-based probabilistic approach to risk estimation. Am J Clin Nutr, 97(1), 109-
16. 
Hall, N. J., Rubin, G. P. and Charnock, A. 2013. Intentional and inadvertent non-adherence in 
adult coeliac disease. A cross-sectional survey. Appetite, 68, 56-62. 
Herdman, M., Gudex, C., Lloyd, A., Janssen, M., Kind, P., Parkin, D., et al. 2011. Development 
and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life 
Res, 20(10), 1727-36. 
Leffler, D. A., Kelly, C. P., Abdallah, H. Z., Colatrella, A. M., Harris, L. A., Leon, F., et al. 
2012. A randomized, double-blind study of larazotide acetate to prevent the activation of 
celiac disease during gluten challenge. Am J Gastroenterol, 107(10), 1554-62. 
Leffler, D. A., Kelly, C. P., Green, P. H., Fedorak, R. N., DiMarino, A., Perrow, W., et al. 2015. 
Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a 
randomized controlled trial. Gastroenterology, 148(7), 1311-9 e6. 
Leonard, M. M., Cureton, P. and Fasano, A. 2017. Indications and use of the gluten 
contamination elimination diet for patients with non-responsive celiac disease. Nutrients, 
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 of powerlessness in “aging” researchers: a primer on 
statistical power in analysis of variance designs. Psychol Aging, 12(1), 84-106. 
Levy, I. and Gralnek, I. M. 2016. Complications of diagnostic colonoscopy, upper endoscopy, 
and enteroscopy. Best Pract Res Clin Gastroenterol, 30(5), 705-18. 
Ludvigsson, J. F., Leffler, D. A., Bai, J. C., Biagi, F., Fasano, A., Green, P. H., et al. 2013. The 
Oslo definitions for coeliac disease and related terms. Gut, 62(1), 43-52. 
Murray, A., Kelly, C., Green, P. H., Marcantonio, A., Wu, T.-T., Mäki, M., et al. 2017. No 
difference between latiglutenase and placebo in reducing villous atrophy or improving 
symptoms in patients with symptomatic celiac disease. Gastroenterology, 152(4), 787–
98. 
Patrick, D. L., Burke, L. B., Powers, J. H., Scott, J. A., Rock, E. P., Dawisha, S., et al. 2007. 
Patient-reported outcomes to support medical product labeling claims: FDA perspective. 
Value Health, 10 Suppl 2, S125-37. 
Pultz, I. S., Hill, M., Vitanza, J. M., Wolf, C., Saaby, L., Liu, T., et al. 2021. Gluten degradation, 
pharmacokinetics, safety, and tolerability of TAK-062, an engineered enzyme to treat 
celiac disease. Gastroenterology, 161(1), 81-93.e3. 
Reilly, M. C., Tanner, A. and Meltzer, E. O. 2004. Work Productivity and Activity Impairment 
Questionnaire plus Classroom Impairment Questions: Allergy Specific (WPAI+CIQ:AS). 
Revicki, D. A., Wood, M., Wiklund, I. and Crawley, J. 1998. Reliability and validity of the 
gastrointestinal symptom rating scale in patients with gastroesophageal reflux disease. 
Qual Life Res, 7(1), 75-83. 
 
 
 
Silvester, J. A., Weiten, D., Graff, L. A., Walker, J. R. and Duerksen, D. R. 2016. Living gluten-
free: adherence, knowledge, lifestyle adaptations and feelings towards a gluten-free diet. 
J Hum Nutr Diet, 29(3), 374-82. 
Stefanolo, J. P., Talamo, M., Dodds, S., de la Paz Temprano, M., Costa, A. F., Moreno, M. L., et 
al. 2020. Real-world gluten exposure in patients with Celiac disease on gluten-free diets, 
determined from gliadin immunogenic peptides in urine and fecal samples. Clin 
Gastroenterol Hepatol. 
 
 
 
Taavela, J., Koskinen, O., Huhtala, H., Lahdeaho, M. L., Popp, A., Laurila, K., et al. 2013. 
Validation of morphometric analyses of small-intestinal biopsy readouts in celiac disease. 
PLoS One, 8(10), e76163. 
Ware, J. J. E., Kosinski, M. and Dewey, J. E. 2001. How to score version 2 of the SF-36. SF-36 
Health Survey: manual and interpretation guide. 3rd ed. Lincoln, RI: QualityMetric 
Incorporated. 
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Appendix A Schedule of Study Procedures 
Assessment 
Screening 
Run-in 
Treatment Period 
Safety Follow-up 
Visit 1 
Visit 2 
Visit 3 a 
Visit 4 a 
Visit 5  
Visit 6/ET  
Visit 7 a 
Week -8 
Week -4 
Week 0 
Week 3 
Week 12 
Week 24 
Week 28 
Day -56 to 
Day -42 
Day -30 to -20 
Day -2 to 
Day 1 (at least 
21 days after 
Visit 2) 
Day 21 ± 5 days 
Day 84 ± 5days 
Day 168 ± 5 days 
Day 196 ± 5 days 
General Study Conduct 
Informed consent/pediatric assent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X b 
X 
X 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
GFD quiz 
X 
 
 
 
 
 
 
Physical examination (including 
height and weight) 
X 
X 
 
 
 
X 
 
Vital signs 
X 
X 
 
 
 
X 
 
ECG 
 
X 
 
 
 
X 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
PTE/AE assessment 
X 
X 
X 
X 
X 
X 
X 
Placebo response reduction/accurate 
symptoms reporting c 
X 
X 
X 
 
 
 
 
Exit interview d 
 
 
 
 
 
X 
 
Clinical laboratory tests (serum, urine, and other) 
Clinical laboratory evaluations 
(hematology and chemistry)  
X 
X 
X a 
X a 
X 
X 
X a 
Urinalysis e 
X 
 
 
X 
X 
X 
X 
Pregnancy test (hCG) f 
X 
X 
X 
X 
X 
X 
X 
FSH g 
X 
X 
 
 
 
 
 
HLA testing 
X 
 
 
 
 
 
 
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Assessment 
Screening 
Run-in 
Treatment Period 
Safety Follow-up 
Visit 1 
Visit 2 
Visit 3 a 
Visit 4 a 
Visit 5  
Visit 6/ET  
Visit 7 a 
Week -8 
Week -4 
Week 0 
Week 3 
Week 12 
Week 24 
Week 28 
Day -56 to 
Day -42 
Day -30 to -20 
Day -2 to 
Day 1 (at least 
21 days after 
Visit 2) 
Day 21 ± 5 days 
Day 84 ± 5days 
Day 168 ± 5 days 
Day 196 ± 5 days 
Clinical laboratory tests (serum, urine, and other [cont.]) 
Celiac serologies 
X 
 
 
 
X  
X 
 
Drug assignment, administration, and accountability 
Study drug administration h 
 
X-----------------------------------------------------------------------------------------------------------X 
 
Randomization to treatment 
 
 
X i 
 
 
 
 
Study drug accountability 
 
X 
X 
X 
X 
X 
 
PK/biomarkers 
Qualitative GIP j 
X  
X-----------------------------------------------------------------------------------------------------------------------------X 
Quantitative GIP k 
X 
X 
X 
X 
X 
X 
X 
Plasma sample for PK and 
biomarkers l 
 
X 
X 
X 
X  
X 
X 
Serum sample for ADA and 
biomarkers m 
 
X 
X 
X 
X  
X 
X 
EGD 
 
X 
 
 
 
X 
 
Sigmoidoscopy with biopsy n 
 
X 
 
 
 
 
 
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Assessment 
Screening 
Run-in 
Treatment Period 
Safety Follow-up 
Visit 1 
Visit 2 
Visit 3 a 
Visit 4 a 
Visit 5  
Visit 6/ET  
Visit 7 a 
Week -8 
Week -4 
Week 0 
Week 3 
Week 12 
Week 24 
Week 28 
Day -56 to 
Day -42 
Day -30 to -20 
Day -2 to 
Day 1 (at least 
21 days after 
Visit 2) 
Day 21 ± 5 days 
Day 84 ± 5days 
Day 168 ± 5 days 
Day 196 ± 5 days 
PROs p 
CDSD v2.1 q 
X----------------------------------------------------------------------------------------------------------------------X 
 
EQ-5D-5L 
CeD Most Bothersome Symptom 
PROMIS—Fatigue Instrument r 
PROMIS–Cognitive Function 
Instrument s  
CeD-GSRS t 
 
WPAI:SHP–CeD 
SF-12 v2 
ICDSQ 
CDAQ 
CD-QoL  
X 
 
X 
 
X 
 
X 
 
PGIS u 
X 
X 
X 
X 
X 
X 
 
PGIC 
 
 
X 
 
X  
X 
 
ADA: antidrug antibody; AE: adverse event; CDAQ: Coeliac Disease Questionnaire; CD-QoL: Celiac Disease Quality of Life; CDSD: Celiac Disease Symptom Diary; CeD: 
celiac disease; CeD-GSRS: Celiac Disease Gastrointestinal Symptom Rating Scale;
 cont.: continued; 
COVID-19: coronavirus disease 2019; ECG: electrocardiogram; EGD: esophagogastroduodenoscopy; EOT: end of treatment; EQ-5D-5L: EuroQol-5 Dimension-5 Levels; ET: 
early termination; FSH: follicle-stimulating hormone; GFD: gluten-free diet; GIP: gluten immunogenic peptide; hCG: human chorionic gonadotropin; HLA: human leukocyte 
antigen; ICDSQ: Impact of Celiac Disease Symptoms Questionnaire; IRT: interactive response technology; PGIC: Patient Global Impression of Change; PGIS: Patient Global 
Impression of Severity; PK: pharmacokinetic(s); PRO: patient-reported outcome; PROMIS: Patient-Reported Outcomes Measurement Information System; PTE: pretreatment 
event; SIGE: simulated inadvertent gluten exposure; SF-12: Short Form 12-Item; 
; US: United States; v: Version; 
 
; WPAI+CIQ:CeD: Work Productivity and Activity Impairment Plus Classroom Impairment Questionnaire: Celiac Disease. 
a Visits 3, 4, and 7 may be conducted virtually or at home at the discretion of the investigator due to reasons including but not limited to COVID-19. Clinical laboratory evaluations 
may be omitted per investigator discretion based on ongoing safety monitoring of the subject.  
b Subjects will ingest a gluten-free SIGE bar to confirm tolerability of nongluten ingredients as per exclusion criteria. 
c Once training is available, subjects may receive training at Visits 1, 2, and 3, as well as at Weeks 6, 10, 16, and 22.  
d Conducted only in a subset of subjects at selected sites in the US and will be scheduled within 10 days of the EOT visit or early termination. 
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e Urinalysis for safety assessment. 
f Serum pregnancy test at Week -8; all others are urine pregnancy tests. 
g FSH test will be done at least twice (at Visit 1 and 2) for those subjects who are amenorrheic for less than 12 months (see Section 9.3.13.3). 
h At the first visit (Week -8), subjects will consume 1 gluten-free SIGE bar and will be excluded if they develop significant symptoms suggestive of a confounding food 
intolerance. During the single-blind run-in period (Week -4 through Day -1), subjects will receive TAK-062 placebo 
. 
From Week 0 through the 24-week treatment period, subjects will receive gluten-containing SIGE food bar in Cohort 1 and blinded gluten-containing SIGE or gluten-free SIGE 
 in Cohort 2, with a meal after taking TAK-062 or placebo taken 
 before the start of a meal.  
i In the event that Visit 3 is unable to be conducted at the study site, this will be a telehealth visit to witness the subject taking study medication. The first dose of study drug 
administered may come after the randomization transaction due to time for shipment of study drug to the subject’s home after randomization in IRT. In this instance, the schedule 
of events will be calculated from the date of first dose of study drug administration (Day 1).  
j First morning void to be collected in standard urine collection cups for GIP testing weekly throughout the study. 
 
While all efforts should be made to obtain weekly urine samples, missed urine 
GIP samples will not be considered a protocol deviation. 
k On the day of a clinic visit, subjects will collect the first morning void in 
 and take the sample to the site. 
 
 
 
l Refer to Appendix B for information about the PK collection schedule. Predose collections for exploratory analysis of biomarkers will be performed at the same visit as PK 
sampling. Predose plasma and serum samples are also being collected to enable evaluation 
 and how they respond to treatment. 
These collections may be useful for noninvasive patient selection or disease monitoring. 
m A predose ADA will be taken on the same days as PK sample collection according to Appendix B. Predose collections for exploratory analysis of biomarkers will be performed 
at the same visit as PK sampling. Predose plasma and serum samples are also being collected to enable 
 and how they 
respond to treatment. These collections may be useful for noninvasive patient selection or disease monitoring. 
n At the time of the endoscopy, sigmoidoscopy with biopsy may be performed in subjects with diarrhea as their predominant symptom at the discretion of the investigator if there is 
a concern for active microscopic colitis as a cause of symptoms.  
 
  
p All PROs should be done, if possible, before any other procedures and in the following order: EQ-5D-5L, PGIS, PGIC, CeD Most Bothersome Symptom, PROMIS—Fatigue 
Instrument appropriate to the age of the subject; GSRS, PROMIS—Cognitive Function Instrument appropriate to the age of the subject, WPAI+CIQ:CeD, SF-12 v2, ICDSQ, 
CDAQ, and CD-QoL. 
q CDSD v2.1 and supplemental frequency questionnaire should be completed daily around the same time every day.  
r PROMIS—Fatigue Instrument: For subjects aged 12-17 years, administer the PROMIS Pediatric Item Bank v2.0—Fatigue—Short Form 10a: Pediatric Fatigue; for subjects 
≥18 years, administer the PROMIS Item Bank v1.0—Fatigue—Short Form 13a. 
s PROMIS—Cognitive Function Instrument: For subjects aged 12-17 years, administer the PROMIS Pediatric Item Bank v1.0—Cognitive Function—Short Form 7a: Pediatric 
Cognitive Function; for subjects ≥18 years, administer the PROMIS Item Bank v2.0—Cognitive Function—Short Form 6a. 
t CeD-GSRS will also be performed at Week -7 (for validation purposes). 
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u PGIS will also be performed at Weeks -8 and -7 (for validation purposes) and Week -2. On Day 0, PGIS should be performed prior to randomization. The volume of blood drawn 
will not surpass weekly or monthly safety limits for subjects ≥33 kg. If a subject’s weight is <33 kg, a screening blood draw may be done on 2 consecutive weeks, as to not surpass 
the weekly blood draw limit. 
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Appendix B Schedule of PK Samples 
Study Time 
(Week/Day) 
Week -4/ 
Visit 2 
Week 0/Randomization/Visit 3 
Week 3/Visit 4 
Week 12/  
Visit 5 
Week 24/ 
Visit 6/ET 
Week 28/ 
Safety Follow-up 
Sampling time 
(h)  
All Subjects 
PK 
Subgroup 
All Other Subjects a PK Subgroup b 
All Other 
Subjects b 
All Subjects 
All Subjects 
All Subjects 
Predose 
X d 
X 
X 
X 
X 
X 
X d 
X d 
0.5 
X 
X 
X 
X 
X 
1 
X 
X 
X 
X 
X 
2 
X 
X c 
X 
X c 
X c 
3 
X 
X c 
X 
X c 
X c 
4 
X c 
X c 
X c 
ET: early termination; h: hour; hr: hour; PK: pharmacokinetics. 
PK sampling times are relative to the most recent dose (in hours). The actual date and time of the sample collection and the date and time for the current dose and 
the dose before the in-clinic dose should be accurately recorded. PK sampling time windows are as follows: predose sample (up to 30 minutes prior to dosing), 
postdose samples at 0.5 hr (±5 minutes), 1 hr (±10 minutes), 2 hr (±10 minutes), 3 hr (±15 minutes), and 4 hr (±15 minutes). A predose antidrug antibody sample 
should be collected any time PK collections occur for all subjects. 
a If a subject not in the PK subgroup is unable to complete the visit in clinic, PK sampling at this visit will be optional. 
b If subjects are unable to complete the visit in clinic, subjects may choose to delay their PK collection to a later date but before their Week 12 visit as an 
unscheduled visit following the same collection schedule noted in Visit 4 or complete collections via home healthcare during Visit 4.  
c Optional sample collection. 
d One blood sample collected at any time during the visit. 
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Appendix C 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 study. 
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572: 
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard 
panel) screening assessments are NOT performed on potential subjects, before the receipt of 
written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements. 
6. 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 study to 
the IRB/IEC, and issue a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 56, ICH and local 
regulations, are met. 
8. Obtain valid informed consent from each subject who participates in the study, 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 informed consent/pediatric assent forms 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 study. If an informed consent/pediatric assent forms 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. 
9. Prepare and maintain adequate case histories of all persons entered into the study, 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 
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. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.  
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 
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Appendix D Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject: 
1. A statement that the study 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 study. 
7. A description of the subject’s responsibilities. 
8. A description of the conduct of the study. 
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 informed 
consent/pediatric assent forms, the subject 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 study. 
17. The anticipated expenses, if any, to the subject for participating in the study. 
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 may 
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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 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 
study. 
22. A statement that results of pharmacogenomic 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 study 
may be terminated. 
24. A written subject authorization (either contained within the informed consent/pediatric assent 
forms 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 study. 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) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, 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, Takeda 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 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), 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 study 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 study results are 
published. 
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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use effective contraception (as defined in the informed consent) 
from screening throughout the duration of the study, and for 40 days after the last dose. If a 
subject is found to be pregnant during study, study drug will be discontinued and the 
investigator will offer the subject the choice to receive unblinded treatment information. 
26. Male subjects must use effective contraception (as defined in the informed consent) from 
signing the informed consent/pediatric assent forms throughout the duration of the study, and 
for 100 days after the last dose. If the partner or wife of the subject is found to be pregnant 
during the study, the investigator will offer the subject the choice to receive unblinded 
treatment information. 
27. 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 E Investigator Consent to Use of Personal Information 
Takeda 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, the United States, and Japan), including the following: 
• Takeda, its affiliates, and licensing partners. 
• Business partners assisting Takeda, 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 Takeda and 
these other parties for research purposes including the following: 
• Assessment of the suitability of investigator for the study and/or other clinical studies. 
• Management, monitoring, inspection, and audit of the study. 
• Analysis, review, and verification of the study results. 
• Safety reporting and pharmacovigilance relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study drug. 
• Inspections and investigations by regulatory authorities relating to the study. 
• Self-inspection and internal audit within Takeda, its affiliates, and licensing partners. 
• Archiving and audit of study records. 
• Posting investigator site contact information, study 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 Takeda 
and other parties for the purposes described above. 
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Appendix F Guidance on Liver Test Abnormality Monitoring, Evaluation, and Follow-up 
Investigators must be vigilant for abnormal liver test results in subjects during the clinical study. 
Transient fluctuations in serum aminotransferases occur commonly in clinical study subjects, but 
it is crucial that the investigator identifies and evaluates subjects with possible hepatic injury. 
This guidance is intended to aid investigations of abnormal liver test results in clinical study 
subjects who had no known liver disease and had either normal or near normal baseline liver test 
results (ie, ALT <3 × the ULN, total bilirubin <1.5 × ULN, and alkaline phosphatase <1.5 × 
ULN) at the time of enrollment. 
In evaluating study subjects with abnormal liver test results, the investigator should perform 
follow-up laboratory tests to confirm the abnormal test results and monitor the subject. If the 
abnormal liver test results are confirmed, then the subject should be monitored and, if necessary, 
additional diagnostic tests should be performed as shown in Figure F-1. Suggested hepatic 
investigations are listed in Table F-1. 
Subjects With Combined Elevations in Aminotransferase and Bilirubin 
If a subject has elevated ALT ≥3 × ULN with concurrent elevated total bilirubin >2 × ULN or 
elevated INR >1.5, the investigator must contact the medical monitor within 24 hours. Hepatic 
investigations as suggested in Table F-1 should be initiated. Any event of elevated ALT ≥3 × 
ULN with concurrent elevated total bilirubin >2 × ULN or elevated INR >1.5 for which an 
alternative etiology has not been identified must be reported as an SAE. 
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Figure F-1 
Liver Test Abnormality Monitoring and Follow-up 
 
 
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Table F-1 
Hepatic Investigation 
Medical history  
• 
Concomitant medications (including over-the-counter medications, such as 
acetaminophen, and herbal supplements). 
• 
Medical conditions (eg, ischemia, hypotension, severe hypoxemia, congestive 
heart failure, sepsis).  
• 
Alcohol intake.  
• 
Hepatobiliary disorder. 
• 
Previous liver disease or metabolic syndrome (eg, obesity, insulin resistance, 
diabetes, or dyslipidemia). 
• 
Travel history. 
Physical examination 
(symptoms, signs, and 
laboratory results) 
• 
General malaise, fatigue, nausea, or vomiting. 
• 
Right upper quadrant pain or tenderness, fever, jaundice, rash. 
• 
Eosinophilia >5%. 
Hepatic/hepatobiliary 
imaging 
Perform as appropriate (eg, abdominal ultrasound, computed tomography, 
magnetic resonance imaging, or other hepatobiliary imaging). 
Viral hepatitis serology 
• 
Hepatitis A antibody (total and IgM). 
• 
Hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core 
antibody (IgM anti-HBc), hepatitis C antibodies. 
• 
Hepatitis E (IgG and IgM). 
• 
Consider polymerase chain reaction for hepatitis B, C, and E. 
• 
Consider Epstein-Barr virus serology (viral capsid antigen, Epstein-Barr 
nuclear antigen, early antigen). 
• 
Consider cytomegalovirus serology (IgG and IgM). 
Autoimmune hepatitis 
serology 
 
• 
Antinuclear antibody. 
• 
Antismooth muscle antibody. 
• 
Anti–liver-kidney microsomal antibody.  
 
 
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Figure F-2 
Liver Test Abnormalities: Considerations for Study Drug Discontinuation 
 
 
Table F-2 
Drug-Induced Severity Grading Scales 
1 Mild 
Elevated ALT and/or ALP but TBL <2.5 mg/dL and INR <1.5 
2 Moderate 
Elevated ALT and/or ALP and TBL ≥2.5 mg/dL and INR ≥1.5 
3 Moderate to Severe 
Elevated ALT, ALP, TBL, and/or INR and hospitalization prolonged due to DILI. 
4 Severe 
Elevated ALT and/or ALP and TBL ≥2.5 mg/dL and at least 1 of the following 
criteria: 
Hepatic failure (INR >1.5, ascites, or encephalopathy) 
Other organ failure due to DILI 
5 Fatal 
Death or liver transplantation to due DILI 
Source: United States Drug Induced Liver Injury Network. 
ALP: alkaline phosphatase; ALT: alanine aminotransferase; DILI: drug-induced liver injury; INR: international 
normalized ratio; TBL: total bilirubin. 
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Appendix G Rescue Medications 
If these medications are not available, alternatives may be used after discussion with the medical 
monitor. 
Anti-diarrheal medications 
Lomotil (diphenoxylate hydrocholoride 2.5 mg/atropine 0.025 mg): 2 tablets orally every 6 hours 
as needed for diarrhea (maximum 20 mg/day of diphenoxylate hydrochloride). Loperamide is 
acceptable if Lomotil not available in the study country and administered as 2 mg orally every 
4 hours as needed for diarrhea (maximum 1 6 mg daily). 
Antinausea/antiemetic medications 
Ondansetron 4 mg orally every 12 hours as needed for nausea/vomiting. 
Antispasmodic medications 
• Dicyclomine or hyoscyamine: 10 mg orally every 6 hours as needed for abdominal spasm. 
• Hyoscine butylbromide (Buscopan): 10 mg orally every 6 hours as needed for abdominal 
cramping. 
• Mebeverine (Duspatalin): 135 mg orally TID as needed for abdominal spasm. 
• Phloroglucinol (Flospan): 160 mg orally (2 80 mg tablets) for abdominal spasms; repeat 
every 2 or more hours as needed to a maximum of 6 tablets (480 mg) in 24 hours. 
• Otilonium bromide (Spasmomen): 40 mg orally TID as needed for abdominal spasm. 
• Trimebutine (Trimedine): 200 mg orally TID before meals as needed for spasms. 
• Peppermint oil. 
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Appendix H Protocol History 
Date 
Amendment Number 
Amendment Type 
Region 
16 November 2023 
5 
Substantial 
Global 
02 June 2023 
4 
Substantial (not submitted to 
sites) 
Global 
26 October 2022 
3 
Substantial 
Global 
22 July 2022 
2 
Substantial 
Global 
23 June 2022 
1 
Substantial 
Global 
18 January 2022 
Initial protocol 
Not applicable 
Global 
 
Protocol Amendment 4 Summary and Rationale: 
This document describes the changes to the protocol incorporating Amendment 4. The primary 
reason for this amendment is to update inclusion and exclusion criteria, contraception 
requirements, and rescue medication instructions.  
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only. 
Protocol Amendment 4 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1.  
Section 2.0 STUDY SUMMARY 
Updated the number of sites. 
To increase recruitment 
rate. 
2.  
Section 2.0 STUDY SUMMARY 
Corrected error in the study 
design diagram.  
Correction. 
3.  
Section 2.0 STUDY SUMMARY 
The broad term ‘mucosal injury’ 
was replaced with a specific 
description ‘villous atrophy’. 
Clarification. 
4.  
Section 2.0 STUDY SUMMARY 
Section 4.1 Background 
Section 4.3 Benefit-Risk Profile 
Section 6.1 Study Design 
Section 13.2 IA and Criteria for 
Early Termination 
Clarified the inclusion of 
adolescents in Cohort 2 by 
stating “If efficacy and safety 
data from Cohort 1 is considered 
acceptable, Cohort 2 will also 
include adolescents aged 12 to 
17 years, inclusive”. 
Enrollment of adolescent 
subjects into Cohort 2 is 
contingent upon 
independent data 
monitoring committee 
(IDMC) review. 
5.  
Section 2.0 STUDY SUMMARY 
Section 5.2.3 Safety Endpoints 
Clarified the safety endpoint of 
immunogenicity is posttreatment 
positive antidrug antibodies.  
Clarification. 
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Protocol Amendment 4 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
6.  
Section 2.0 STUDY SUMMARY 
Section 5.2.4 
Exploratory/Additional Endpoints 
Section 6.2.3.1 Efficacy 
Section 6.2.3.4 Urine-Based 
Biomarker: GIP 
Revised “weekly” to “once per 
week”. 
Clarification. 
7.  
Section 2.0 STUDY SUMMARY 
Section 6.1 Study Design 
 
 
 
  
Corrected error. 
8.  
Section 2.0 STUDY SUMMARY 
Section 6.1 Study Design 
Clarified that TAK-062 will be 
consumed immediately prior to 
meals instead of with meals. 
Clarification. 
9.  
Section 2.0 STUDY SUMMARY 
Section 7.1 Inclusion Criteria 
Section 9.3.5 GFD Knowledge Quiz 
Clarification that it is at the 
investigator’s discretion if the 
subject has adequate 
comprehension of a gluten-free 
diet (GFD).  
Clarification. 
10.  
Section 2.0 STUDY SUMMARY 
Section 7.1 Inclusion Criteria 
Section 13.1.3.1 Primary Efficacy 
Endpoint Analysis: Change From 
Baseline in Weekly CDSD GI 
Symptom Severity Score at Week 
12 
In the study summary and 
Inclusion Criterion 9, removed 
the upper age limit, and added 
“Inclusion of subjects older than 
75 years of age may be 
discussed with the study medical 
monitor.” 
To allow subjects older 
than 75 years to be 
enrolled. 
11.  
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
 
 
 
 
 
 
. 
12.  
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
In the study summary and 
Exclusion Criteria 7, clarified 
“evaluable” days and changed 
from Week -8 to the run-in 
period. 
Clarification 
13.  
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
 
In the study summary and 
Exclusion Criterion 9, “small 
intestinal bacterial overgrowth” 
was added. 
To clarify that subjects 
with small bacterial 
overgrowth will be 
excluded. 
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Protocol Incorporating Amendment No. 5 
16 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 4 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
14.  
Section 2.0 STUDY SUMMARY 
Section 13.1.3.1 Primary Efficacy 
Endpoint Analysis: Change From 
Baseline in Weekly CDSD GI 
Symptom Severity Score at Week 
12 
The description of the study 
population was simplified. 
Clarification. 
15.  
Section 3.2 Coordinating 
Investigator 
Clarified that a signatory 
coordinating investigator “may” 
be selected instead of “will” be 
selected. 
Clarification. 
16.  
Section 4.1 Background 
Added intraepithelial 
lymphocyte infiltration. 
Clarified “utility of quantitative 
and qualitative endpoints”. 
Clarifying the main 
histologic observations 
and scoring criteria used 
in assessing celiac disease 
(CeD) tissues for 
histology. Both 
quantitative and 
qualitative scoring 
methods measure mucosal 
injury and cellularity to 
grade severity. 
17.  
Section 4.3 Benefit-Risk Profile 
Section 6.2.2 Rationale for Dose 
Updated text to reflect 
1 unrelated SAE has been 
reported in the clinical program. 
Updated information. 
18.  
Section 6.1 Study Design 
Section 6.2.3.4 Urine-Based 
Biomarker: GIP 
Appendix A 
Schedule of Study 
Procedures 
Clarified consumption of SIGE 
bar related to gluten 
immunogenic peptide (GIP) 
urine collection. 
Clarification. 
19.  
Section 6.1 Study Design 
Section 9.3.10 
 
Section 13.3 Determination of 
Sample Size 
 
 
 
 
. 
 
 
 
 
 
 
20.  
Section 6.1 Study Design 
Clarified all subjects will have 
sparse pharmacokinetic (PK) 
blood samples taken. 
Clarification. 
21.  
Section 6.1 Study Design 
Section 9.3.12.1 Collection of Blood 
and Plasma for PK Sampling 
Clarified randomization is 
Week 0. 
Clarification. 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
Protocol Amendment 4 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
22.  
Figure 6.a Schematic of Study 
Design 
Corrected error in figure. 
Correction. 
23.  
Section 7.1 Inclusion Criteria 
In Inclusion Criterion 3, 
removed “after viewing of 
educational materials”. 
Correction. 
24.  
Section 7.1 Inclusion Criteria 
In Inclusion Criterion 10, added 
“Subjects 12 to 18 years of age 
will only be included after 
IDMC review”. 
Clarification. 
25.  
Section 7.1 Inclusion Criteria 
In Inclusion Criterion 12, added 
a note that individuals with body 
mass index (BMI) of 40 to 45 
should be discussed with the 
medical monitor and confirmed 
to be appropriate for endoscopy 
according to local site 
guidelines. 
To allow the subjects with 
a BMI up to 45 to be 
enrolled in the study 
26.  
Section 7.1 Inclusion Criteria 
 
 
 
.  
 
 
27.  
Section 7.2 Exclusion Criteria 
Section 7.3 Excluded Medications 
 
 
 
 
 
 
 
28.  
Section 7.2 Exclusion Criteria 
In Exclusion Criterion 23, 
revised language regarding 
coronavirus disease 2019. 
Clarification 
29.  
Section 7.2 Exclusion Criteria 
Section 7.3 Excluded Medications 
Clarified the use of stable doses 
(ie, more than 4 weeks) of an 
osmotic, bulking-forming or 
emollient (surface active agent) 
laxative is allowed. 
Clarification 
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Protocol Incorporating Amendment No. 5 
16 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 4 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
30.  
Section 7.4 Rescue Medications 
Clarified instructions for use of 
all medications (prescriptions 
and over-the-counter 
medications), if needed, will be 
obtained from the study 
physician. 
Removed ‘time’ from the 
information provided for each 
occurrence of rescue medication.  
Added “during the treatment 
period (after randomization)”. 
Clarification 
31.  
Section 9.3.1 Physical Examination 
Procedure 
Revised the timing of a baseline 
physical examination from 
before the first dose of study 
drug to during Visit 1.  
Clarification 
32.  
Section 9.3.3 Vital Sign Procedure 
Specified positions for vital sign 
readings. 
Clarification 
33.  
Section 9.3.7.1 Accurate Symptom 
Reporting Training 
Section 9.3.7.2 Placebo Response 
Reduction Training 
Appendix A Schedule of Study 
Procedures 
Clarified that subjects may 
receive training once training is 
available. 
Clarification. 
34.  
Section 9.3.7.4 Research Subject 
Responsibilities Training 
Added section on Research 
Subject Responsibilities training. 
Inadvertently admitted 
previously.  
35.  
Section 9.3.8 Exit Interview – 
United States Only 
Appendix A Schedule of Study 
Procedures 
Specified the exit interview will 
take place in the United States 
only.  
Clarification. 
36.  
Section 9.3.8 Exit Interview – 
United States Only 
Clarified only consented subjects 
would be invited to participate in 
exit interviews.  
Clarifications. 
37.  
Section 9.3.8 Exit Interview – 
United States Only 
Clarified important or 
meaningfulness of perceived 
benefits of treatment included 
symptom-free and minimal 
symptom days. 
Clarifications. 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
Protocol Amendment 4 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
38.  
Section 9.3.12.1 Collection of Blood 
and Plasma for PK Sampling 
Appendix B Schedule of PK 
Samples 
Requirement for providing PK 
samples at specific time points 
changed from Week 24 to Week 
12. At Week 24, PK samples are 
now collected at any time during 
the visit. 
 
PK sampling times changed 
from percentage-based nominal 
times, to fixed time points in 
relation to dose. 
Rich PK sampling 
changed from Week 24 to 
Week 12 to provide 
flexibility and to 
minimize the number of 
scheduled procedures at 
Week 24, which includes 
an 
esophagogastroduodenosc
opy (EGD) evaluation. 
39.  
Section 9.3.13.1 Male Subjects and 
Their Female Partners 
Section 9.3.13.3 Definitions and 
Procedures for Contraception and 
Pregnancy Avoidance 
Table 9.b 
Acceptable 
Contraception Methods and 
Lactation Guidance for This Study 
Appendix D Elements of the Subject 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
40.  
Section 9.3.16 Documentation of 
Screen Failure 
Added rescreening will not be 
allowed for a negative human 
leukocyte antigen (HLA) test. 
Clarification 
41.  
Section 9.3.9 Endoscopy and Biopsy 
Collection 
Added qualitative morphometric 
analysis to quantitative analysis. 
Clarification 
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Protocol Incorporating Amendment No. 5 
16 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 4 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
42.  
Section 9.3.9 Endoscopy and Biopsy 
Collection 
Removed details of biopsy 
preparation. 
Information provided in 
the section twice. 
Duplicate information 
removed. 
43.  
Section 9.3.16 Documentation of 
Screen Failure 
Clarified rescreening for subjects 
who failed due to VH:CD >2.5 
or negative HLA testing. 
Clarification 
44.  
Section 9.6 Biological Sample 
Retention and Destruction 
Removed “Notify sponsor of 
consent withdrawal”. 
Correction. 
45.  
Section 10.1.3 Additional Points to 
Consider for PTEs and AEs 
Added overdose definition. 
Clarification 
46.  
Section 11.1 IDMC 
Clarified the drug will be safe 
and efficacious before dosing 
adolescents. 
Clarification 
47.  
Section 13.1.3.1 Primary Efficacy 
Endpoint Analysis: Change From 
Baseline in Weekly CDSD GI 
Symptom Severity Score at Week 
12 
Removed redundant text to 
simplify subject population 
attribute description for the 
primary estimand. 
Edited for brevity. 
48.  
Section 13.1.3.1 Primary Efficacy 
Endpoint Analysis: Change From 
Baseline in Weekly CDSD GI 
Symptom Severity Score at Week 
12 
Removed “Estimand with the 
target population excluding 
subjects who report >1 point 
improvement in Patient Global 
Impression of Severity (PGIS) 
during 
 run-in period. 
The supplementary analysis will 
be performed for full analysis set 
(FAS)-SIGE and FAS–no SIGE 
separately. The endpoint 
definition, strategy for the 
intercurrent events (ICEs) and 
population-level summary will 
be the same as the main 
estimand. Nominal p-values will 
be calculated. No hypothesis 
testing will be performed” from 
supplementary analyses for 
primary estimand. 
Error, repeated twice. 
49.  
Section 13.1.3.3 Other Efficacy 
Endpoint Analyses 
Removed “Marsh-Oberhuber”. 
Correction as quantitative 
Marsh was already 
present. 
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Protocol Incorporating Amendment No. 5 
16 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 4 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
50.  
Section 13.3 Determination of 
Sample Size 
 
 
 
 
 
 
 
 
 
 
 
 
 
51.  
Appendix A Schedule of Study 
Procedures 
Revised timeline window at 
Visit 2 and 3. 
Clarification 
52.  
Appendix A Schedule of Study 
Procedures 
Add “On Day 0, PGIS should be 
performed prior to randomization.” 
Clarification. 
53.  
Appendix B Schedule of PK 
Samples 
Added Week 24/Visit 6/ET PK 
samples. 
Rich PK sampling 
changed from Week 24 to 
Week 12 to provide 
flexibility and to 
minimize the number of 
scheduled procedures at 
Week 24, which includes 
an EGD evaluation. 
54.  
Appendix F Guidance on Liver Test 
Abnormality Monitoring, 
Evaluation, and Follow-up 
 
 
 
 
 
55.  
Appendix G Rescue Medications 
 
 
 
 
 
 
Protocol Amendment 3 Summary and Rationale: 
This document describes the changes to the protocol incorporating Amendment 3. 
 
  
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only. 
For non-commercial use only


TAK-062 
 
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Protocol Incorporating Amendment No. 5 
16 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1.  
Section 2.0 STUDY SUMMARY 
Added statement that urine 
samples will be collected 
to check the levels of 
peptides associated with 
gluten ingestion during the 
screening. 
Unintentional omission. 
2.  
Section 2.0 STUDY SUMMARY 
Revised the number of 
study sites. 
Increased to support study 
recruitment. 
3.  
Section 2.0 STUDY SUMMARY 
Section 4.1 Background 
Section 6.2.1 Rationale for Study 
Design 
Added wording to clarify 
adolescents receive only 
gluten-free simulated 
inadvertent gluten 
exposure (SIGE) bars. 
Clarification of gluten 
exposure to adolescents. 
4.  
Section 2.0 STUDY SUMMARY 
Section 4.1 Background 
Section 4.3 Benefit-Risk Profile 
Section 6.1Study Design 
Section 11.2 IRC (deleted) 
 
  
 
 
 
5.  
Section 2.0 STUDY SUMMARY 
Section 5.2.4 Exploratory/Additional 
Endpoints 
Section 6.1 Study Design 
Section 7.1 Inclusion Criteria 
Section 9.3.17 (formerly Section 
9.3.16) Documentation of 
Randomization 
Villous height to crypt 
depth ratio (Vh:Cd) 
revised. 
To more accurately capture 
active celiac disease. 
6.  
Section 2.0 STUDY SUMMARY 
Section 6.1 Study Design 
Table 8.b Dose and Regimen 
 
 
 
 
 
 
 
 
 
7.  
Section 2.0 STUDY SUMMARY 
Section 6.1 Study Design 
Section 6.2.1Rationale for Study 
Design 
Table 8.b Dose and Regimen 
Section 13.3 Determination of Sample 
Size 
 
 
 
 
. 
 
  
 
 
 
 
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TAK-062 
 
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Protocol Incorporating Amendment No. 5 
16 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
8.  
Section 2.0 STUDY SUMMARY 
Section 7.1 Inclusion Criteria 
Section 13.1.3.1 Primary Efficacy 
Endpoint Analysis: Change From 
Baseline in Weekly CDSD GI 
Symptom Severity Score at Week 12 
Revised exclusion criterion 
to add a maximum of 20% 
of adult subjects without a 
producible initial biopsy 
report to be included if 
they have serology or 
histology confirmation at 
screening. 
To improve inclusivity, 
acknowledging many celiac 
patients may not have their 
initial pathology report.  
9.  
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
Added aspartate 
aminotransferase (AST) ≥3 
× upper limit of normal 
(ULN) as an exclusion 
criterion. 
This was added for 
consistency, given AST 
elevation is defined in 
treatment discontinuation. 
10.  
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
Added clarification that 
systemic corticosteroids 
may be given for 
endoscopies. 
Clarification of 
corticosteroid usage. 
11.  
Section 2.0 STUDY SUMMARY 
Section 7.4 Rescue Medications 
Section 9.3.15 Documentation of 
Concomitant Medications 
Section 13.1.3.2 Secondary Efficacy 
Endpoint Analysis 
Section 7.4 Rescue Medications 
 
 
 
. 
12.  
Section 2.0 STUDY SUMMARY 
Section 13.1.3.1 Primary Efficacy 
Endpoint Analysis: Change From 
Baseline in Weekly CDSD GI 
Symptom Severity Score at Week 12 
Section 13.3 Determination of Sample 
Size 
 
. 
 
 
13.  
Section 4.3 Benefit-Risk Profile 
A statement regarding the 
potential risk and 
subsequent monitoring of 
antidrug antibodies was 
added. 
To align with the TAK-062 
investigator’s brochure. 
14.  
Section 5.2.4 Exploratory/Additional 
Endpoints 
Appendix A 
Schedule of Study 
Procedures 
Revised change from 
baseline from Week -4 to 
Week -8 for celiac 
serology titers. 
Corrected error. 
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TAK-062 
 
Study TAK-062-2001 
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Protocol Incorporating Amendment No. 5 
16 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
15.  
Section 6.2.3.1 Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
16.  
Section 6.2.3.4 Urine-Based 
Biomarker: GIP 
Appendix A Schedule of Study 
Procedures 
Collection of urine in a 
separate container was 
added for quantitative 
analysis of gluten peptides. 
Added for clarity. 
17.  
Section 7.2 Exclusion Criteria 
 
 
 
 
 
 
18.  
Section 7.6 Criteria for Discontinuation 
or Withdrawal of a Subject 
Section 7.7 (formerly Section 7.6) 
Procedures for Discontinuation or 
Withdrawal of a Subject 
 
 
 
 
 
 
. 
19.  
Section 7.7 (formerly Section 7.6) 
Procedures for Discontinuation or 
Withdrawal of a Subject 
 
 
 
 
 
 
 
 
20.  
Section 7.7 (formerly Section 7.6) 
Procedures for Discontinuation or 
Withdrawal of a Subject 
 
 
 
 
 
 
 
 
 
21.  
Section 8.1.4 Overdose 
Added the statement 
“There is no experience 
with overdose with any of 
TAK-062 formulations.” 
To align with the TAK-062 
investigator’s brochure. 
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TAK-062 
 
Study TAK-062-2001 
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Protocol Incorporating Amendment No. 5 
16 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
22.  
Section 8.4 Study Drug and SIGE 
Blind Maintenance 
Added clarification that in 
the event that results must 
be reported to the 
investigator before 
breaking the blind, all 
efforts should be made to 
maintain the blind.  
Removed instructions that 
subjects, site staff, and 
study team members were 
to remain blinded to the 
CDSD 
 
 
Subjects, site staff, and study 
team members will remain 
blinded to treatment 
assignments; however, the 
CDSD 
 will not be 
masked.  
23.  
Section 9.3.13.1 Male Subjects and 
Their Female Partners 
Added clarification that 
female partners must also 
use a highly effective 
method of contraception. 
Also clarified sexual 
abstinence is not an 
acceptable method of 
contraception for 
individuals sexually active 
with a partner of the 
opposite sex in which 
childbearing is a potential 
outcome.  
Clarification of 
contraception and 
abstinence. 
24.  
Section 9.3.7 Placebo Reduction Plan 
Appendix A Schedule of Study 
Procedures 
Added section describing 
the placebo reduction plan 
which includes accurate 
symptom reporting 
training, placebo response 
reduction training, and 
participant scorecard. 
To further elaborate on plan 
for placebo reduction. 
25.  
Section 10.1.3 Additional Points to 
Consider for PTEs and AEs 
Clarification that adverse 
events (AEs) related to 
gluten should not be 
reported as an AE unless 
requiring an intervention 
such as rescue medication. 
To better define AE in 
context of gluten related 
symptoms 
26.  
Section 13.1.7 Psychometric Analyses 
for CDSD 
 
 
 
 
 
. 
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Protocol Incorporating Amendment No. 5 
16 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
27.  
Section 15.3 Subject Information, 
Informed Consent/Pediatric Assent, 
and Subject Authorization 
Added information 
regarding physical and 
emotional pain of children. 
To ensure clarity that the 
comfort of pediatric subjects 
is being addressed. 
 
Protocol Amendment 2 Summary and Rationale: 
This document described the changes to the protocol incorporating Amendment 2. The primary 
reasons for this amendment were to: 
• Add an exclusion criterion for subjects with known history of hypersensitivity, idiosyncratic 
reaction, or intolerance to any ingredients or excipients in TAK-062 and/or placebo. 
• Add details for tablet administration of TAK-062 and placebo. 
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only. 
Protocol Amendment 2 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1. 
Section 7.2 Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
2. 
Table 8.a Dose and Regimen 
Table 8.b Dose and Regimen 
 
 
 
 
 
 
 
Protocol Amendment 1 Summary and Rationale: 
This document describes the changes to the protocol incorporating Amendment 1. The primary 
reasons for this amendment are to: 
• Add exclusion criteria for subjects with a known hypersensitivity reaction and/or allergy, 
including anaphylaxis, to wheat and/or gluten.  
For non-commercial use only


TAK-062 
 
Study TAK-062-2001 
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Protocol Incorporating Amendment No. 5 
16 November 2023 
 
CONFIDENTIAL 
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only. 
Protocol Amendment 1 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1. 
Section 7.2 Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
For non-commercial use only


Signature Page for TAK-062-2001 Protocol Amend 5 2023-NOV-16
Title: Amendment 5 to A Phase 2, Randomized, Double-Blind, Placebo-Controlled, D
Document Number: TDN-000201165 v1.0
Approval
Clinical
21-Nov-2023 15:58:56 GMT+0000
Approval
Statistics
21-Nov-2023 16:58:24 GMT+0000
For non-commercial use only

SAP_001.pdf: 
For non-commercial use only


STATISTICAL ANALYSIS PLAN 
Study Number: TAK-062-2001 
Study Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to 
Evaluate the Efficacy and Safety of TAK-062 for the Treatment of Active Celiac Disease in 
Subjects Attempting a Gluten-Free Diet 
Phase: 2 
Version: 4.0 
Date: 03 December 2024 
Prepared by:  
, MS. 
, Statistics, Statistics and Quantitative Sciences (SQS) 
Takeda Pharmaceuticals 
Based on: 
Protocol Version: Amendment No. 5 
Protocol Date: -16 Nov 2023 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda. 
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TAK-062-2001 
Page 2 of 75
Statistical Analysis Plan 
03 Dec 2024
CONFIDENTIAL 
REVISION HISTORY 
Version 
Approval Date 
Primary Rationale for Revision 
Original version 1 
2 MAY 2022 
Not Applicable 
Version 2.0 
27 FEB 2024 
Updated based on protocol amendment 5 
Version 3.0 
23 AUG 2024 
 
Added additional exploratory endpoints. 
Version 4.0 
03 DEC 2024 
 
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TAK-062-2001 
Page 3 of 75
Statistical Analysis Plan 
03 Dec 2024
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................9 
1.1 
Objectives ......................................................................................................................9 
1.1.1 
Primary Objective ..................................................................................................9 
1.1.2 
Secondary Objectives ............................................................................................9 
1.1.3 
Exploratory/Additional Objectives ........................................................................9 
1.2 
Endpoints .....................................................................................................................10 
1.2.1 
Primary Endpoint.................................................................................................10 
1.2.2 
Secondary Endpoint.............................................................................................10 
1.2.3 
Safety Endpoints ..................................................................................................10 
1.2.4 
Exploratory/Additional Endpoints.......................................................................10 
1.3 
Estimand(s) ..................................................................................................................14 
2.0 
STUDY DESIGN...............................................................................................................14 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES .............................................17 
3.1 
Statistical Hypotheses ..................................................................................................17 
3.2 
Statistical Decision Rules ............................................................................................18 
3.3 
Multiplicity Adjustment ...............................................................................................18 
4.0 
SAMPLE-SIZE DETERMINATION ................................................................................19 
5.0 
ANALYSIS SETS .............................................................................................................19 
5.1 
Full Analysis Set-SIGE ................................................................................................19 
5.2 
Full Analysis Set-no SIGE ...........................................................................................19 
5.3 
Safety Analysis Set ......................................................................................................20 
5.4 
Safety Analysis Set-SIGE ............................................................................................20 
5.5 
Safety Analysis Set-no SIGE .......................................................................................20 
5.6 
Per protocol analysis set-SIGE ....................................................................................20 
5.7 
Pharmacokinetic Analysis Set......................................................................................20 
5.8 
Immunogenicity Analysis Set ......................................................................................20 
5.9 
Randomized Set ...........................................................................................................21 
6.0 
STATISTICAL ANALYSIS .............................................................................................21 
6.1 
General Considerations ................................................................................................21 
6.1.1 
Handling of Treatment Misallocations ................................................................21 
6.1.2 
Analysis Approach for Continuous Variables .....................................................21 
6.1.3 
Analysis Approach for Binary, Ordinal and Categorical Variables ....................22 
6.2 
Disposition of Subjects ................................................................................................23 
6.3 
Demographic and Other Baseline Characteristics .......................................................23 
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Statistical Analysis Plan 
03 Dec 2024
 
CONFIDENTIAL 
6.3.1 
Demographics ......................................................................................................23 
6.3.2 
Medical History and Concurrent Medical Conditions .........................................24 
6.3.3 
Baseline Characteristics .......................................................................................24 
6.4 
Medication History and Concomitant Medications .....................................................25 
6.4.1 
Prior Medications ................................................................................................25 
6.4.2 
Concomitant Medications ....................................................................................25 
6.5 
Efficacy Analysis .........................................................................................................25 
6.5.1 
Primary Endpoint Analysis..................................................................................25 
6.5.1.1 
Derivation of Endpoint ................................................................................25 
6.5.1.2 
Main Analytical Approach ..........................................................................28 
6.5.1.3 
Handling of Intercurrent Event ...................................................................28 
6.5.1.4 
Sensitivity Analysis .....................................................................................29 
6.5.1.5 
Supplementary Analyses .............................................................................30 
6.5.2 
Secondary Endpoint Analysis..............................................................................31 
6.5.2.1 
Derivation of Endpoint ................................................................................31 
6.5.2.2 
Main Analytical Approach ..........................................................................31 
6.5.2.3 
Sensitivity Analysis .....................................................................................32 
6.5.2.4 
Supplementary Analyses .............................................................................32 
6.5.2.5 
Exploratory Analysis ...................................................................................32 
6.5.3 
Exploratory/additional Endpoints Analysis .........................................................33 
6.5.3.1 
Derivation of Exploratory Endpoints ..........................................................39 
6.5.3.2 
Main Analytical Approach ..........................................................................52 
6.5.3.3 
Supplementary Analysis .............................................................................54 
6.5.4 
Subgroup Analyses ..............................................................................................54 
6.6 
Safety Analysis ............................................................................................................55 
6.6.1 
Adverse Events ....................................................................................................55 
6.6.2 
Adverse Events of Special Interest ......................................................................57 
6.6.3 
Clinical Laboratory Evaluations ..........................................................................57 
6.6.4 
Vital Signs ...........................................................................................................58 
6.6.5 
12-Lead ECGs .....................................................................................................58 
6.6.6 
Immunogenicity ...................................................................................................58 
6.6.7 
Extent of Exposure and Compliance ...................................................................59 
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses .................................59 
6.7.1 
Pharmacokinetic Analysis ...................................................................................59 
6.7.2 
Biomarker Analysis .............................................................................................60 
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6.8 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis........................................................................................................................60 
6.8.1 
PRO Analysis ......................................................................................................60 
6.8.2 
Health Care Utilization Analysis .........................................................................60 
6.9 
Other Analyses .............................................................................................................60 
6.10 
Interim Analyses ..........................................................................................................60 
6.11 
Independent Data Monitoring Committee ...................................................................63 
7.0 
REFERENCES ..................................................................................................................64 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................64 
9.0 
APPENDIX ........................................................................................................................65 
9.1 
Changes From the Previous Version of the SAP .........................................................65 
9.2 
Data Handling Conventions .........................................................................................65 
9.2.1 
General Data Reporting Conventions ..................................................................65 
9.2.2 
Definition of Baseline..........................................................................................65 
9.2.3 
Definition of Visit Windows ...............................................................................65 
9.2.3.1 
Study Week/Visit Windows for Efficacy Data ...........................................66 
9.2.3.2 
Visit Windows for the Analysis of Safety Data ..........................................67 
9.2.4 
Conventions for Missing Adverse Event Dates...................................................67 
9.2.5 
Conventions for Missing Concomitant Medication Dates ..................................68 
9.3 
Criteria for Markedly Abnormal Values ......................................................................69 
9.4 
Analysis Software and Sample codes ..........................................................................71 
 
 
LIST OF IN-TEXT TABLES 
Table 1.a  Estimand Frameworks...................................................................................................14 
Table 6.a  CDSD v2.1 ....................................................................................................................26 
Table 6.b  Cognitive Function Scoring Table for Adult Subjects ..................................................42 
Table 6.c  Cognitive Function Scoring Table for Subjects Aged 12-17 ........................................42 
Table 6.d  Fatigue Scoring Table for Adult Subjects.....................................................................44 
Table 6.e  Fatigue Scoring Table for Subjects Aged 12-17 ...........................................................45 
Table 6.f. CDAQ dimensions.........................................................................................................49 
Table 6.g  Original and inverted question scores ...........................................................................49 
Table 6.h  Subgroups of Interest ....................................................................................................55 
Table 6.i  Categories of Worst Post-baseline Values .....................................................................57 
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Table 9.a  Visit windows for the analysis of Primary endpoint (CDSD GI symptom severity 
score) ......................................................................................................................66 
Table 9.b  Visit windows for the Analysis of PRO data ................................................................66 
Table 9.c  Visit Windows for the Analysis of Safety Data ............................................................67 
Table 9.d  Criteria for Markedly Abnormal Values for Laboratory Parameters............................69 
Table 9.e  Criteria for Markedly Abnormal Values for Vital Signs Parameters............................71 
Table 9.f  Criteria for Markedly Abnormal Values for 12-Lead ECG Parameters ........................71 
 
 
 
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ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CD-QOL 
Celiac disease quality of life 
CDAQ 
Coeliac Disease Assessment Questionnaire 
CDSD 
Celiac Disease Symptom Diary 
CeD 
celiac disease 
CI 
confidence interval 
COVID-19 
coronavirus disease 2019  
CPK 
creatine phosphokinase 
CSR 
clinical study report 
DGP 
deaminated gliadin peptide 
ECG 
electrocardiogram 
E-DMC 
external data monitoring committee 
EGD 
esophagogastroduodenoscopy 
eCRF 
electronic case report form 
EQ-5D-5L 
EuroQol 5-Dimensions-5 Levels 
FAS 
full analysis set 
FSH 
follicle-stimulating hormone 
GFD 
gluten-free diet 
GGT 
-glutamyl transferase 
GI 
Gastrointestinal 
GIP 
gluten immunogenic peptide 
GSRS 
Gastrointestinal Symptom Rating Scale 
HbA1c 
glycosylated hemoglobin 
HLA 
human leukocyte antigen 
HRQOL 
health-related quality of life 
IA 
interim analysis 
ICDSQ 
Impact of Celiac Disease Symptoms Questionnaire 
ICE 
intercurrent events 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
identification 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IEL 
intraepithelial lymphocyte 
IgA 
Immunoglobulin A 
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IgG 
Immunoglobulin G 
INR 
international normalized ratio 
IRB 
institutional review board 
LLN 
lower limit of normal 
LS 
least squares 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed-effects model for repeated measures 
mpVCIEL 
Multi-parametric composite score of Vh:Cd and IEL 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
pharmacokinetic 
PPS 
per-protocol set 
PRO 
patient-reported outcomes 
PROMIS 
Patient-reported Outcomes Measurement Information System 
PT 
Preferred Term (MedDRA) 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SD 
standard deviation 
SF-12  
Short Form 12-Item  
SIGE 
simulated inadvertent gluten exposure 
SOC 
System Organ Class 
TEAE  
treatment-emergent adverse event 
 
 
 
 
tTG 
tissue transglutaminase 
ULN 
upper limit of normal 
 
 
VCIEL 
Composite score of Vh:Cd ratio and IEL 
Vh:Cd 
villus height to crypt depth ratio 
WHODrug 
World Health Organization Drug Dictionary 
WPAI+CIQ: CeD 
Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire: 
Celiac Disease 
 
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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Primary Objective 
The primary objective of this study is: 
• To evaluate the efficacy of TAK-062, as measured by the CDSD, for reducing celiac-
related symptoms due to gluten exposure in subjects with celiac disease (CeD) 
attempting to maintain a gluten-free diet (GFD) in treated subjects versus placebo 
controls. 
1.1.2 
Secondary Objectives 
Secondary objectives of this study are: 
• To evaluate the efficacy of TAK-062, as measured by Vh:Cd, for improvement of small 
intestine mucosal injury due to gluten exposure in subjects with CeD attempting to 
maintain a GFD in treated subjects versus placebo controls. 
• To evaluate the safety and tolerability of TAK-062. 
1.1.3 
Exploratory/Additional Objectives 
Exploratory/additional objectives of this study are: 
• To further evaluate the psychometric properties of the Celiac Disease Symptom Diary 
(CDSD) in symptomatic subjects with CeD. 
• To evaluate the efficacy of TAK-062 on reducing subjects most bothersome symptoms. 
• To evaluate the treatment effect of TAK-062 on intraepithelial lymphocyte (IEL) counts 
and quantitative and qualitative histological measures of disease severity. 
• To evaluate immunogenicity to TAK-062. 
• To evaluate the effect of TAK-062 on quality of life and additional patient-reported 
outcomes (PROs). 
• To evaluate the effect of TAK-062 on celiac serology titers. 
• To evaluate the relationship between PROs and histological measures of intestinal injury. 
• To evaluate the effect of simulated inadvertent gluten exposure (SIGE) on response to 
therapy with TAK-062. 
• To evaluate urine gluten immunogenic peptide (GIP) detection as a means of monitoring 
gluten exposure and response to therapy. 
 
 
 
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• To characterize the pharmacokinetic (PK) of TAK-062 in subjects with CeD attempting to 
maintain a GFD. 
1.2 
Endpoints 
1.2.1 
Primary Endpoint 
The primary endpoint is: 
• Change in CDSD gastrointestinal (GI) symptom severity score from baseline (Week -1) to 
Week 12. 
1.2.2 
Secondary Endpoint 
The secondary endpoint is: 
• Change in Vh:Cd from baseline (measured at Week -4) to Week 24. 
1.2.3 
Safety Endpoints 
Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), treatment-related 
TEAEs, electrocardiogram (ECG) findings, vital signs, laboratory parameters, and 
immunogenicity (posttreatment positive antidrug antibodies [ADA] in serum for TAK-062). 
1.2.4 
Exploratory/Additional Endpoints 
Exploratory/additional endpoints (baseline assessments made 
 unless 
specified otherwise) are: 
Impact of SIGE: 
• Differences in responses in CeD endpoints including PROs, celiac serology, histology 
 will be assessed between gluten-containing SIGE and gluten-free SIGE 
arms. 
PRO Outcomes: 
• Proportion of Subjects Achieving a Change from Baseline in Weekly Average CDSD at 
Week 12 ≤ - 0.25 and ≤-0.44. 
• Change in CDSD GI symptom severity score from Week -8 and Week -1 to Week 24. 
• Change in CDSD GI symptom severity score from Week -8 to Week 12. 
• Patient Global Impression of Change (PGIC) at Week 0, Week 12, and Week 24. 
• Percent of subjects reporting each symptom on the CeD Most Bothersome Symptom 
Questionnaire at each time point measured. 
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• Change from baseline to Week 12 and Week 24 in percentage of symptom-free days over 
a 14-day period. 
• Change from baseline to Week 12 and Week 24 in percentage of symptom-free days over 
a 7-day period. 
• Proportion of subjects with ≥55% of percentage of symptom-free days over a 14-day 
period at Week 24 or Early Termination visit. 
• Proportion of subjects with ≥55% of percentage of symptom-free days over a 7-day 
period at Week 24 or Early Termination Visit. 
• Proportion of subjects with change from baseline to Week 24 in percentage of symptom-
free days ≥25% over a 14-day period. 
• Change from baseline to Week 24 in average CDSD bowel movement frequency over a 
14-day period. 
• Change from baseline to Week 24 in average CDSD bowel movement frequency over a 
7-day period. 
• Change from baseline to Week 24 in percentage of symptom-free days over a 7-day 
period by PGIS category. 
• Change from baseline to Week 24 in the following PROs (average over a 14-day period): 
– CDSD total score. 
– CDSD GI score. 
– CDSD non-stool GI score. 
– CDSD Diarrhea score. 
– CDSD Abdominal pain score. 
– CDSD Bloating score. 
– CDSD Nausea score. 
• Change from baseline to Week 24 by PGIS category in the following PROs (average over 
a 7-day period): 
– CDSD total score. 
– CDSD GI score. 
– CDSD non-stool GI score. 
– CDSD Diarrhea score. 
– CDSD Abdominal pain score. 
– CDSD Bloating score. 
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– CDSD Nausea score. 
• Change from Week -8 and Week -1 to Week 12 and Week 24 in the following PROs: 
– Weekly score of the most bothersome symptom as reported by the CDSD. 
– Severity rating or frequency of each item (symptom) of the CDSD. 
– Frequency of constipation based on the CDSD. 
– Proportion of minimal symptom days per week (defined as days with none or no more 
than 1 mild score of either bloating, abdominal pain, nausea, or diarrhea) as 
reported on the CDSD. 
• Percentage of symptom-free days per week as reported on the CDSD. 
– Impact of Celiac Disease Symptoms Questionnaire (ICDSQ). 
– Patient Global Impression of Severity (PGIS). 
– Patient-reported Outcomes Measurement Information System (PROMIS)-Cognitive 
Function Instrument. 
– PROMIS-Fatigue Instrument. 
– Short Form 12-Item (SF-12) Health Survey. 
– EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) health survey. 
– Work Productivity and Activity Impairment plus Classroom Impairment 
Questionnaire: Celiac Disease (WPAI+CIQ: CeD). 
– Celiac Disease Gastrointestinal Symptom Rating Scale (CeD-GSRS). 
– Celiac Disease Assessment Questionnaire (CDAQ). 
– Celiac disease quality of life (CD-QOL) questionnaire.   
Serology titers: 
• Change from baseline (Week -8) to Week 12 and Week 24 in celiac serology titers. 
Histological endpoints: 
• Proportion of subjects achieving mucosal remission (Vh:Cd ≥3,  ≥2.7 and >2.5) at 
Week 24. 
• Change from baseline (Week -4) to Week 24 in IEL counts. 
• Change from baseline (Week -4) to Week 24 in Marsh-Oberhuber scores both 
qualitatively assessed and calculated from IEL and Vh:Cd results. 
• Change from baseline (Week -4) to Week 24 in individual Vh and Cd measurements. 
• Proportion of subjects with an increase of ≥0, ≥0.1, ≥0.2, ≥0.3 and ≥0.4 in Vh:Cd from 
baseline to Week 24. 
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The following histological endpoints were not pre-specified in the study protocol but added 
in the SAP: 
• Proportion of subjects with Vh:Cd ≥2.5 and IEL counts < 25 at Week 24. 
• Mucosal response rate defined as the proportion of subjects with an increase in Vh:Cd of  
greater than 0.4 and a reduction in IEL counts of greater than 30% from Week -4 to Week 
24. 
• Proportion of subjects with an increase in Vh:Cd of greater than 0.25 and a reduction in 
IEL counts of greater than 15% from Week -4 to Week 24. 
• Change from baseline (Week -4) to Week 24 in Composite score of Vh:Cd ratio and IEL 
(VCIEL) and Multi-parametric composite score of Vh:Cd and IEL (mpVCIEL). 
PRO and histological endpoints: 
• Proportion of subjects with an improvement in both CDSD GI symptom severity score 
and Vh:Cd from Week -4 to Week 24. 
• Proportion of subjects with an improvement in both GSRS (from Week -8) and Vh:Cd 
(from Week -4) to Week 24. 
• Proportion of subjects with Vh:Cd ≥2.7 at Week 24 and ≥55% of symptom-free days 
over a 14-day period at Week 24 for subgroup of subjects with baseline Vh:Cd ≤2.3 and 
≤40% baseline percentage of symptom-free days. 
• Proportion of subjects with change from baseline at Week 24 in Vh:Cd ≥ 0.4 and change 
from baseline at Week 24 in percentage of symptom-free days ≥ 25% over a 14-day 
period. 
 
 
 
 
 
 
 
 
 
GIP endpoints: 
• Frequency of positive urine GIP tests in subjects across the treatment groups during 
screening, run in and treatment phases. 
PK endpoints: 
• Plasma concentration of TAK-062. 
 
 
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1.3 
Estimand(s) 
Table 1.a  Estimand Frameworks 
Estimand: [Primary] 
Definition 
Attributes 
Treatment 
Population 
Variable (or 
Endpoint) 
Strategy for 
Addressing 
Intercurrent 
Event 
Population-Level 
Summary 
The primary 
estimand is the 
treatment effect 
of TAK-062 
compared to 
Placebo at Week 
12 in targeted 
patient 
population. 
TAK-062 
(
 
 
) versus 
placebo. 
Subjects aged 18 and 
years and older, who 
are HLA-DQ2 and/or 
HLA-DQ8 positive, 
have biopsy-confirmed 
disease that is clinically 
active with ongoing GI 
symptoms and small 
intestinal villous 
atrophy on duodenal 
biopsy, have been 
attempting to maintain 
a GFD for ≥12 
months, and are 
experiencing 
inadvertent gluten 
exposure. * 
Change in 
weekly 
average CDSD 
GI symptom 
severity score 
from baseline 
to Week 12. 
Composite strategy 
will be used to 
address rescue 
medication use and 
treatment 
discontinuation due 
to lack of efficacy 
or treatment-related 
AEs. Treatment 
policy strategy will 
be used to address 
SIGE bar 
discontinuation and 
treatment 
discontinuation due 
to reasons other 
than lack of 
efficacy or 
treatment-related 
AEs. 
Treatment difference 
(TAK-062 – placebo) 
in the mean change 
from baseline to Week 
12 in weekly average 
CDSD GI symptom 
severity score, for 
each dose level. 
* Adolescents (aged 12 to 17 years) and a maximum of 20% of adult subjects without a producible initial biopsy 
report confirming CeD may be enrolled if they meet the following inclusion criteria: 
a) Serology (IgA-tTg) at diagnosis or subsequent visit is at least 2 times the ULN. 
b) Histology at screening biopsy at Week -4 must be consistent with Marsh-Oberhuber score of 2 or greater as read 
by a central pathologist. 
2.0 
STUDY DESIGN 
Despite attempts to maintain a gluten-free diet (GFD), many individuals with celiac disease 
(CeD) continue to have symptoms and/or intestinal damage due to inadvertent gluten exposure. 
TAK-062 is a computationally designed enzyme intended to reduce or prevent symptoms and 
intestinal damage related to gluten exposure. This is a 2-cohort phase 2, multicenter, double-
blind, randomized, placebo-controlled study to evaluate the efficacy and safety of TAK-062 for 
treatment of ongoing symptoms and small intestinal mucosal injury due to gluten exposure in 
subjects with CeD attempting to maintain a GFD. In addition, this study is designed to further 
evaluate the psychometric properties of the Celiac Disease Symptom Diary (CDSD) v2.1, 
 
 
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, and to provide data on the optimal histologic measure for assessment of response to 
treatment in CeD. 
Approximately 357 subjects with CeD and both ongoing symptoms and small intestine villous 
atrophy on duodenal biopsy, despite attempting to maintain a GFD for at least 12 months, will 
be enrolled and randomly assigned into 1 of 2 treatment groups in the Cohort 1proof of concept 
study and 1 of 6 treatment groups in the Cohort 2 dose-ranging study (see the Number of 
Subjects section below).  
The interim analysis will be initiated when at least 75% of the subjects in Cohort 1 have either 
completed 12 weeks of treatment or have dropped out to determine inclusion of adolescents in 
Cohort 2. Cohort 1 data will be reviewed by an external independent data monitoring committee 
(IDMC) and shared with health authorities and independent ethics committees 
(IECs)/institutional review boards (IRBs) as required by region, before enrollment of 
adolescents in Cohort 2. If efficacy and safety data from Cohort 1 is considered acceptable, 
Cohort 2 will also include adolescents aged 12 to 17 years. Adolescents will receive only gluten-
free simulated inadvertent gluten exposure (SIGE) bars. 
 
Number of Subjects: 
Cohort 1 
Cohort 1 will consist of 120 adult subjects randomly assigned to receive 1 of 2 treatments: 
1. TAK-062 placebo 
 + gluten-containing SIGE bar 
: 60 subjects. 
2. TAK-062 
 + gluten-containing SIGE bar 
: 60 subjects. 
Cohort 2 
Cohort 2 will consist of approximately 216 adult subjects to be enrolled and randomly assigned 
into 1 of 5 drug and SIGE treatment groups (Groups 1-5), and approximately 21 adolescent 
subjects to be enrolled and randomly assigned into Groups 4, 5 and 6 (adolescents only). 
1. TAK-062 placebo 
 + gluten-containing SIGE bar 
: 30 subjects (adults only). 
2. TAK-062 
 + gluten-containing SIGE bar 
: 50 subjects (adults only). 
3. TAK-062 
 + gluten-containing SIGE bar 
: 50 subjects (adults only). 
4. TAK-062 placebo 
 + gluten-free SIGE bar 
: 50 subjects (43 adults, 7 adolescents). 
5. TAK-062 
 + gluten-free SIGE bar 
: 50 subjects (43 adults, 7 adolescents). 
6. TAK-062
 + gluten-free SIGE bar
: 7 subjects (adolescents only). 
This study will consist of 4 periods in each cohort: a 2- to 4-week screening period (Week -8 to 
Week -4), a 4-week single-blind placebo run-in (Week -4 to Day -1), a 24-week double-blind 
treatment period (Week 0 to Week 24), and a 4-week safety follow-up period. At the first visit 
(Week -8), subjects will consume 1 gluten-free SIGE bar to ensure no intolerance to any of the 
nongluten components of the bar. During the screening period (between Week -8 visit to Week -4 
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visit), subjects will complete the CDSD daily to confirm they have at least 1 ongoing CeD-
related gastrointestinal (GI) symptom of moderate or greater severity on at least 3 days out of 
any consecutive 7-day period. The CeD-related symptom(s) may vary day by day as long as the 
severity of at least 1 symptom is moderate or greater. Eligible subjects will undergo an 
esophagogastroduodenoscopy (EGD) with duodenal biopsy 
 for the 
assessment of villous atrophy. In addition, a subset of approximately 40 subjects in total
 
During the screening period, urine samples will be collected once per week for 
gluten immunogenic peptide (GIP) to assess systemic exposure to gluten. 
During the single-blind run-in period (Week -4 through Day -1), subjects will receive TAK-062 
placebo 
 of the start of a meal and consume SIGE bar with or without 
gluten, 
with a meal; 
 
 
 
 
 
 
 
 
 
 
Eligible subjects with villous atrophy on duodenal biopsy (defined as villous height to crypt 
depth ratio [Vh:Cd] <2.5 (<3 before protocol amendment 3) by central pathology assessment) 
will be randomly assigned to 1 of 2 treatment groups in Cohort 1 or 1 of 6 treatment groups in 
Cohort 2 to receive double-blind treatment and gluten-containing SIGE or gluten-free SIGE 
(Cohort 2) for 24 weeks (Day 1 through Week 24). Initially, all subjects who meet symptom 
criteria and histologic criteria will be randomized. If more than 10% of planned enrollment in a 
cohort report a greater than 1 point improvement in Patient Global Impression of Severity 
during 
 run-in period (Week -2 through Day -1), further subjects showing this degree of 
improvement will be excluded from the cohort. 
Randomization will be stratified by celiac serologic status at Visit 1, defined as normal or 
elevated celiac serology (1 or more of the following: IgA-tissue transglutaminase (tTg) >1 times 
the upper limit of normal [ULN], IgA-deaminated gliadin peptide [DGP] >2 × ULN, or IgG-
DGP >2 × ULN), mild to moderate (Vh:Cd 1.5 to <2.5) versus moderate to severe (Vh:Cd <1.5) 
histologic injury at baseline, and by use of proton pump inhibitors or histamine type 2 
antagonists (yes or no) at Visit 1. 
In Cohort 1, all subjects will consume gluten-containing SIGE bars 
 
 with a meal 
 In Cohort 2, adult subjects will receive either gluten-
containing or gluten-free SIGE bars with a meal 
 throughout the treatment 
period. 
 
 
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H1A: Change from Baseline to Week 12 in CDSD GI symptom severity score TAK-062 
 +Gluten-containing 
SIGE bar ≠ Change from Baseline to Week 12 in CDSD GI symptom severity score Placebo + Gluten-containing SIGE bar 
↓ 
H2 
H20: Change from Baseline to Week 12 in CDSD GI symptom severity score TAK-062 
 + Gluten-containing 
SIGE bar = Change from Baseline to Week 12 in CDSD GI symptom severity score Placebo + Gluten SIGE bar 
versus 
H2A: Change from Baseline to Week 12 in CDSD GI symptom severity score TAK-062 
 + Gluten-containing 
SIGE bar ≠ Change from Baseline to Week 12 in CDSD GI symptom severity score Placebo + Gluten-containing SIGE bar 
↓ 
H3 
H30: Change from Baseline to Week 12 in CDSD GI symptom severity score TAK-062 
 +Gluten-containing 
SIGE bar = Change from Baseline to Week 12 in CDSD GI symptom severity score Placebo + Gluten-containing SIGE bar 
versus 
H3A: Change from Baseline to Week 12 in CDSD GI symptom severity score TAK-062 
 + Gluten-containing 
SIGE bar ≠ Change from Baseline to Week 12 in CDSD GI symptom severity score Placebo + Gluten-containing SIGE bar 
3.2 
Statistical Decision Rules 
The statistical significance treatment effect will be tested against 2-sided alpha level of 0.05 
following the pre-specified fixed-sequence order from high dose to low dose for primary efficacy 
endpoint.  
1) 
TAK-062 
 + gluten-containing SIGE bar versus placebo + gluten-containing 
SIGE bar. 
2) 
TAK-062 
 + gluten-containing SIGE bar versus placebo + gluten-containing 
SIGE bar. 
3) 
TAK-062 
 + gluten-containing SIGE bar versus placebo + gluten-containing 
SIGE bar. 
3.3 
Multiplicity Adjustment 
To control the overall Type I error rate for the multiple comparisons performed for the primary 
efficacy endpoint, a fixed-sequence testing approach will be applied to the statistical testing. A 
hypothesis will only be tested if the statistical significance is achieved with the previous test (i.e., 
p < 0.05) in the sequence. Once a hypothesis fails to demonstrate the statistical significance (i.e., 
p ≥ 0.05), all subsequent hypotheses will not be tested. However, nominal p-values and 
confidence intervals for the subsequent analyses will be provided and will be considered 
exploratory. If any treatment group is not opened or terminated early, the hypothesis testing of 
that treatment group will not be performed and the formal hypothesis testing will proceed with 
the next highest dose tested in the fixed sequence testing as pre-specified above. Multiplicity will 
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not be adjusted for secondary or exploratory efficacy endpoints. Nominal p-value will be 
presented.  
4.0 
SAMPLE-SIZE DETERMINATION 
The planned sample size is approximately 357 subjects. For a 2-sample comparison of means, 
0.5 standardized mean difference is regarded as a medium effect size. A sample size of 53 
subjects per treatment group will provide 80% power to detect a standardized mean difference 
(mean difference/SD) of 0.55 between 
 TAK-062 and placebo in the change from baseline 
CDSD weekly score (assuming common SD) for a 2-sided statistical hypothesis test, using a 2-
sample t-test and a 5% significance level. Assuming a dropout rate of approximately 12%, a 
sample size of 60 subjects per treatment group for the 
 and placebo arms in Cohort 1 will 
be the planned enrollment.  
The planned enrollment for Cohort 2 is 30 and 50 subjects per treatment arm in the placebo and 
active arms (
 TAK-062), respectively, in the gluten-containing SIGE arms; 50 
subjects (43 adults and 7 adolescents) per arm in the 
 and placebo gluten-free SIGE bar 
arms; and 7 (adolescents only) in the 
 gluten-free SIGE bar arm. 
For the combined placebo gluten-containing SIGE groups from Cohorts 1 and 2 versus 
 
TAK-062, 86% power would be provided (based on the 2-sample t-test and the 5% significance 
level) to detect the standardized mean difference between groups (0.55) with the same 12% 
assumption for dropout rate. In addition, 82% power would be provided from the same 
assumptions for combined placebo gluten-containing SIGE group from Cohorts 1 and 2 versus 
 TAK-062 group. The analysis to detect the difference between the combined 
placebo gluten-containing SIGE group and the active group would yield a higher power. 
5.0 
ANALYSIS SETS 
5.1 
Full Analysis Set-SIGE 
The Full Analysis Set (FAS)-SIGE will consist of all randomized subjects who are randomized to 
receive gluten-containing SIGE. Subjects will be analyzed according to the treatment they were 
randomized to receive.  
The FAS-SIGE will be used for efficacy analysis for primary, secondary and exploratory 
efficacy endpoints.  
5.2 
Full Analysis Set-no SIGE 
The FAS-no SIGE will consist of all randomized subjects who are randomized to gluten-free 
SIGE. Subjects will be analyzed according to the treatment they were randomized to receive. 
The FAS-no SIGE will also be used for efficacy analysis for primary, secondary and exploratory 
efficacy endpoints.  
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5.3 
Safety Analysis Set 
The Safety analysis set (SAF) will consist of all randomized subjects who received at least 1 dose 
of study drug. Subjects will be analyzed according to actual treatment received. 
The SAF will be used for safety analysis.  
5.4 
Safety Analysis Set-SIGE 
The Safety analysis set (SAF)-SIGE will consist of all randomized subjects who received at least 
1 dose of study drug and gluten-containing SIGE. Subjects will be analyzed according to actual 
treatment received. 
The SAF-SIGE will be used for safety analysis for subjects who are randomized to receive 
gluten-containing SIGE.  
5.5 
Safety Analysis Set-no SIGE 
The SAF-no SIGE will consist of all randomized subjects who received at least 1 dose of study 
drug and gluten-free SIGE. Subjects will be analyzed according to actual treatment received. 
The SAF-no SIGE will be used for safety analysis for subjects who are randomized to gluten-
free SIGE.  
5.6 
Per protocol analysis set-SIGE 
The Per protocol analysis set (PPS)-SIGE will consist of all subjects in FAS-SIGE who do not 
violate the terms of the protocol in a way that would impact the study outcome. All decisions to 
exclude subjects for the PPS-SIGE will be made before the unblinding of the study.  
The PPS will be used for the sensitivity analysis of the primary efficacy endpoint. 
5.7 
Pharmacokinetic Analysis Set  
The Pharmacokinetic (PK) Analysis Set is defined as all randomized subjects who received at 
least 1 dose of study drug with at least 1 measured PK concentration. Subjects will be analyzed 
according to actual treatment received. 
The PK analysis set will be used for PK analysis.  
5.8 
Immunogenicity Analysis Set  
The Immunogenicity Analysis Set is defined as all randomized subjects who received any TAK-
062 and have the baseline and at least 1 postbaseline immunogenicity sample assessment. 
Subjects will be analyzed according to actual treatment received. 
The Immunogenicity Analysis Set will be used for immunogenicity analysis.  
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5.9 
Randomized Set  
The randomized set will consist of all subjects who were randomized. Subjects will be analyzed 
according to the treatment they were randomized to receive. 
6.0 
STATISTICAL ANALYSIS  
6.1 
General Considerations 
Unless otherwise stated, baseline values are defined as the last observed value before the first 
dose of study medication.  
All hypothesis tests and confidence intervals (CIs) will be 2-sided, and an alpha of 0.05 will be 
used for all statistical-testing, unless otherwise stated. All p-values reported will be 2-tailed and 
rounded to 3 decimal places prior to assessment of statistical significance.  
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. CIs 
intervals will be presented using the same number of decimal places as the parameter estimate. 
Where applicable, variables will be summarized descriptively by study visit. For the categorical 
variables, the counts and proportions of each possible value will be tabulated by treatment group. 
The denominator for the proportion will be based on the number of subjects who provided 
non-missing responses to the categorical variable. For continuous variables, the number of 
subjects with non-missing values, mean, median, SD, minimum, and maximum values will be 
tabulated.  
A windowing convention will be used to determine the analysis value for a given study visit for 
observed data analyses. The details of window convention are described in Section 9.2.3. 
Derived stratification factor will be used as the randomization stratification factor in the analyses 
unless specified otherwise. 
The randomization stratification factor may be dropped from the analysis models for continuous 
variables and binary, ordinal and categorical variables (next section) if the number of subjects in 
the randomization factor are skewed in a factor due to the celiac serologic status, histologic 
injury, or use of proton pump inhibitors (PPIs) or histamine 2 antagonists (yes or no). 
6.1.1 
Handling of Treatment Misallocations 
In the event of treatment (not SIGE) misallocations, the safety data will be analyzed using the 
treatment that the subject actually received, and the efficacy data will be analyzed using the 
treatment that the subject was randomized to receive regardless of the actual treatment received. 
6.1.2 
Analysis Approach for Continuous Variables 
All continuous data will be summarized descriptively by analysis visit and treatment groups 
when appropriate. The analysis for the primary and secondary endpoints is described in detail in 
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Sections 6.5.1 and 6.5.2, respectively. The remainder of this section applies to exploratory 
analyses where statistical modeling is performed. 
Longitudinal continuous data meeting the normal distribution assumption will be analyzed using 
a mixed-effects model for repeated measures (MMRM) based on the observed data only. The 
MMRM will include fixed effects for the TAK-062 treatment group, time, and treatment-by-time 
interaction, baseline randomization stratification variables and baseline outcome variables as 
covariates, and subject as a random effect. For longitudinal outcome measured daily or weekly, 
the time variable will be week. For longitudinal outcome measured at scheduled home or clinic 
visits, the time variable will be visit. An unstructured (co)variance structure will be used to 
model the within-subject errors. If the model fails to converge, another covariance structure such 
as autoregressive (1) or the compound symmetry covariance matrix may be considered in the 
order specified. Missing data will be left missing in the data.  
Continuous data meeting the normal distribution assumption with only one post-baseline value 
will be analyzed using the ANCOVA model with treatment group as the independent variable, 
and baseline randomization stratification variables and corresponding baseline outcome variable 
as covariates. As a sensitivity analysis when the proportion of missing data is between 5% and 
40%, inclusive, missing data can be imputed using multiple imputation method. The imputation 
models will include treatment group and baseline stratification variables. 
Continuous efficacy data not meeting the normal distribution assumption will first be 
transformed such that a normal distribution can be assumed. The data analysis and missing data 
handling described above can then be applied to the transformed data. When data transformation 
is not feasible, the data can be analyzed using Wilcoxon rank-sum test. The Hodges-Lehmann 
estimator of location shift and the associated 95% CI will be presented for the treatment median 
difference between each TAK-062 dose arm and placebo. When a sensitivity analysis is 
necessary, tipping point analysis will be performed. 
6.1.3 
Analysis Approach for Binary, Ordinal and Categorical Variables 
All binary, ordinal and categorical variables will be summarized descriptively by analysis visit 
and treatment groups when appropriate.  
Longitudinal binary, ordinal and categorical outcome will be analyzed using generalized linear 
mixed model. The model will include fixed effects for the TAK-062 treatment group, time, and 
treatment-by-time interaction, baseline randomization stratification variables and baseline 
outcome variables as covariates, and subject as a random effect.  For longitudinal outcome 
measured daily or weekly, the time variable will be week. For longitudinal outcome measured at 
scheduled home or clinic visits, the time variable will be visit. An unstructured (co)variance 
structure will be used to model the within-subject errors. If the model fails to converge, another 
covariance structure such as autoregressive (1) or the compound symmetry covariance matrix 
may be considered in the order specified. Missing data will be left missing in the data. Missing 
endpoint values will be adjusted for in the mixed model. 
Binary, ordinal and categorical outcome with only one post-baseline measurement will be 
analyzed using logistic regression with treatment group as the independent variable, and baseline 
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randomization stratification variables, and baseline outcome variable, where applicable, as 
covariates.  When a sensitivity analysis is necessary and the proportion of missing data is 
between 5% and 40%, inclusive, missing responses can be imputed using multiple imputation by 
fully conditional specification method. 
6.2 
Disposition of Subjects 
General study information will be provided, including the date of first subject signing Informed 
Consent Form (ICF), date of first/last study drug dose, date of last subject’s last visit/contact, 
date of last subject’s last sample collection date for primary endpoint, Medical Dictionary for 
Drug Regulatory Activities (MedDRA) Version, World Health Organization Drug Dictionary 
(WHODrug) Version, and SAS Version used for creating the datasets. 
Subject disposition will be summarized for each treatment group and overall, and will include 
the following: 
• Summary of all screened subjects, including the number of screened subjects, number of 
subjects eligible/not eligible for randomization and primary reason for ineligibility for 
randomization. 
• Summary of subjects randomized but not treated, completing study drug and completing 
study, and disposition of subjects based on the reasons for discontinuation of treatment 
and for failing to complete the study using the randomized set.  
• When calculating percentages for the reasons for not being treated, the total number of 
subjects not treated will be used as the denominator. When calculating percentages for 
the reasons for discontinuation, the total number of subjects who prematurely 
discontinued will be used as the denominator. 
• Summary of study subjects randomized by geographic region and site will be provided 
using the randomized set. 
• Summary of subjects for each pre-defined population using the randomized set: FAS, 
FAS-no SIGE, SAF, SAF-SIGE, SAF-no SIGE, PPS-SIGE, PK analysis set and 
Immunogenicity analysis set. Reasons for exclusion from the FAS, FAS-no SIGE, SAF, 
SAF-SIGE, SAF-no SIGE, PPS-SIGE, PK analysis set, and Immunogenicity analysis set 
will be summarized and listed. 
Significant protocol deviations will be summarized based on the randomized set.   
Supporting data listings for randomization scheme, screen failures, subject disposition, and 
significant protocol deviations will be provided. 
6.3 
Demographic and Other Baseline Characteristics 
6.3.1 
Demographics 
Descriptive summaries of demographic characteristics will be presented by treatment group and 
overall for FAS-SIGE, FAS-no SIGE, and SAF. 
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The following demographic characteristics will be summarized in the following order in the 
tables: age (years), age (categorical, <18, 18-<40 and >=40; adults and adolescents), sex, 
ethnicity, race, weight (kg), height (cm), and body mass index (BMI) (kg/m2). Individual 
demographic characteristics will be listed. 
6.3.2 
Medical History and Concurrent Medical Conditions 
Medical history and concurrent medical conditions will be coded using the MedDRA (Version 
23 or higher). Medical history includes all medical conditions with a stop date prior to informed 
consent. A concurrent medical condition is a condition which is present at signing of informed 
consent.   
Medical history and concurrent medical conditions will be summarized by system organ class 
(SOC), preferred term (PT) and by treatment group and overall using the SAF. The summary 
table will be sorted in alphabetical order by SOC. Within an SOC, PTs are sorted in decreasing 
frequency based on the total number of subjects. A subject will only be counted once within a 
class even if he/she has multiple conditions/symptoms.  
Individual subject medical history and concurrent medical condition data will be listed. 
6.3.3 
Baseline Characteristics 
Descriptive summaries of baseline characteristics including stratification factors will be 
presented by treatment group and overall for FAS-SIGE, FAS-no SIGE, and SAF. 
Stratification factors based on IRT data will be summarized along with the derived stratification 
factor based on lab report and collected concomitant medications in EDC. Any discrepancies will 
be presented in the data listings. Stratification factors are derived as follows. 
• Celiac serologic status, defined as normal or elevated celiac serology (1 or more of the 
following: IgA-tissue transglutaminase (tTg) > 1× the upper limit of normal [ULN], IgA–
deaminated gliadin peptide [DGP] > 2×ULN, or IgGDGP > 2×ULN) where ULN=7 
• Histologic injury (at baseline): mild to moderate (Vh:Cd 1.5 to <2.5) versus moderate to 
severe (Vh:Cd <1.5) 
• Use of proton pump inhibitors (PPIs) or histamine 2 antagonists (yes or no) at Visit 1 
The following baseline celiac disease characteristics, including, but not limited to, HLA typing, 
celiac serologic titer, duration of CeD, method of diagnosis and associated findings, pathology 
findings at diagnostic endoscopy, presence of extraintestinal symptoms and anemia, reasons for 
diagnosis, celiac serologic status, histology injury status at screening (Vh:Cd) and PPI or 
histamine 2 antagonists use, gluten-free diet status and duration will be summarized. Individual 
baseline disease characteristics will be listed. 
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6.4 
Medication History and Concomitant Medications  
6.4.1 
Prior Medications 
Prior medications are defined as mediations that started and stopped prior to the first treatment 
administration. Prior medications will be coded using the latest version of the WHODrug 
Dictionary and summarized using the SAF. 
Prior medications will be summarized by the number and percentage of subjects by preferred 
term within each therapeutic class, with therapeutic class sorted in alphabetical order and 
preferred term sorted in decreasing frequency based on the total number of subjects. If a subject 
reports taking 2 drugs belonging to the same class, he/she will only be counted once within that 
class.  
Data listing(s) for prior medications will be provided. 
6.4.2 
Concomitant Medications 
Concomitant medications are defined as medications that started prior to and were ongoing at 
initiation of first study treatment and those that started after initiation of first study treatment. 
The same analysis methods described in Section 6.4.1 will be conducted for concomitant 
medications. 
6.5 
Efficacy Analysis 
6.5.1 
Primary Endpoint Analysis 
The primary endpoint is the change from baseline to Week 12 in CDSD GI symptom severity 
score. 
6.5.1.1 
Derivation of Endpoint 
The CDSD v2.1 is a 5-item self-administered questionnaire that evaluates the severity and 
frequency of CeD symptoms on a daily basis. Severity is measured for the following CeD 
symptoms: diarrhea, abdominal pain, bloating, nausea, and tiredness. Symptom severity is 
evaluated using 5-point Likert-type scale ((0) none, (1) mild, (2) moderate, (3) severe, and (4) 
very severe). A supplemental questionnaire administered with the CDSD will measure the 
frequency of bowel movements, vomiting and diarrhea. The CDSD evaluates both severity and 
frequency of these symptoms over the previous 24 hours.  The frequency of bowel movements, 
diarrhea, and vomiting is the number of instances of each symptom in the previous 24 hours. It 
will be administered as part of the daily diary for the duration of the study, including Screening, 
Run-in and treatment periods. 
The weekly CDSD GI symptom severity score is an average of the daily GI symptom severity 
scores during the week. The daily GI symptom severity score is the average of the severity score 
for diarrhea, abdominal pain, bloating and nausea, ranging from 0 (no symptoms) to 4 (very 
severe). A lower score means less symptom severity. If any of the symptom severity score is 
missing, then the daily GI symptom severity score will set to missing. Weekly CDSD scores will 
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be calculated where the CDSD is completed on at least 4 of the 7 days. When the daily diary is 
completed on less than 4 of the 7 days, the weekly CDSD score will be considered missing in the 
primary analysis.  
In the derivations described below, the GI symptom severity scores will be used in the primary 
analyses, the overall scores will be used in the supplementary analyses and the individual 
severity scores will be used in the exploratory analyses. The CDSD daily overall score will be 
calculated as the mean of the 5-point Likert-type scales of symptom severity in diarrhea, 
abdominal pain, bloating, nausea, and tiredness. The CDSD GI-only daily score is the mean of 
the scores for diarrhea, abdominal pain, bloating, and nausea. For CDSD overall or GI-only daily 
score, if one item has a missing value then the score will be set to missing for the day. Refer to 
Table 6.a for further details. 
Table 6.a  CDSD v2.1 
CDSD v2.1 Question 
Response 
Include in 
Daily 
CDSD 
Overall 
Score? 
Include in 
Daily GI 
symptom 
severity 
score? 
1. During the past 24 hours, how severe was your 
diarrhea at its worst? 
0=None 
1=Mild 
2=Moderate 
3=Severe 
4=Very severe  
Yes 
Yes 
2. During the past 24 hours, how severe was your 
abdominal (belly) pain at its worst? 
0=None 
1=Mild 
2=Moderate 
3=Severe 
4=Very severe 
Yes 
Yes 
3. During the past 24 hours, how severe was your 
bloating (feeling as if you need to loosen 
your clothes) at its worst? 
0=None 
1=Mild 
2=Moderate 
3=Severe 
4=Very severe 
Yes 
Yes 
4. During the past 24 hours, how severe was your 
nausea (feeling as if you were going to 
vomit or throw up) at its worst? 
0=None 
1=Mild 
2=Moderate 
3=Severe 
4=Very severe 
Yes 
Yes 
5. During the past 24 hours, how severe was your 
tiredness at its worst? 
0=None 
1=Mild 
2=Moderate 
3=Severe 
Yes 
No 
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CDSD v2.1 Question 
Response 
Include in 
Daily 
CDSD 
Overall 
Score? 
Include in 
Daily GI 
symptom 
severity 
score? 
4=Very severe 
6. How many times did you vomit (throw up) in the 
past 24 hours? (Please count each time 
you vomited rather than the number of trips to the 
bathroom). 
Enter count. 
No 
No 
7. How many bowel movements (poops) did you have 
in the past 24 hours? 
Enter count. 
No 
No 
8. How many of those bowel movements (poops) 
looked like type 6 or 7 in the picture below? 
Enter count. 
No 
No 
 
Day 1 will be defined as the date of first study treatment administration. Day -1 will be defined 
as the date of the last SIGE bar administration (as recorded in ePRO) and before the first dose of 
study medication based on the data as recorded in EDC. When the first dose is not recorded in 
EDC, the date of the first dose on or after the day of randomization in the e-diary will be 
considered Day 1. 
Study day after the date of first dose of treatment will be calculated relative to Day 1 as: date of 
assessment/event – date of first dosing + 1. Study day prior to the first dosing will be calculated 
relative to Day -1 as: date of assessment/event – date of Day -1 – 1. 
The baseline CDSD score will be the weekly average score of last week of 2 weeks when the 
subject is on gluten-containing SIGE in the run-in period and the CDSD is completed on at least 
4 of the 7 days. When the daily diary is completed on less than 4 of the 7 days, first week data of 
2 weeks when the subject is on gluten-containing SIGE 
 will be included 
in the average calculation while subject is on gluten-containing SIGE.  
The analysis start date of run-in will be defined as min (date of first placebo IP in dosing diary, 
max [date of EGD, date of first SIGE bar administration at Visit 2]) as some subjects do not start 
SIGE bar until EGD is conducted. As subjects consume gluten-free SIGE bar during the first two 
weeks of run-in period, the first two weeks after the analysis start date of run-in will be excluded 
from the baseline calculation. Subject will be assumed to be on gluten-containing SIGE bar 
starting from the 3rd week of run-in period until Day -1. 
Post-baseline weekly CDSD scores will be calculated based on analysis days where the CDSD is 
completed on at least 4 of the 7 days. When the daily diary is completed on less than 4 of the 7 
days, the weekly CDSD score will be considered missing in the primary analysis. Any diary 
entered after the End of Study will be excluded from the summary. In the case that the diary is 
entered more than once on the same day, the last result based on time of entry will be used in the 
analysis. 
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The change from baseline to Weeks 12 in weekly CDSD GI symptom severity score will be 
calculated as  
Change from baseline = weekly CDSD GI symptom severity score at Week 12 – CDSD GI 
symptom severity score at baseline, 
6.5.1.2 
Main Analytical Approach 
The primary endpoint will be analyzed with a mixed model for repeated measures (MMRM) 
approach using the appropriate contrast at Week 12. The model will be based on all available 
weekly CDSD GI symptom severity scores from baseline through Week 12. The model will 
include treatment group, week, treatment-by-week interaction, and the randomization 
stratification factors as fixed effects and baseline CDSD GI symptom severity score as 
covariates, and subject as a random effect. An unstructured covariance structure will be used to 
model the within-subject errors. Restricted Maximum Likelihood (REML) will be used to fit the 
model and Kenwood-Roger method will be used to calculate degrees of freedom. If the model 
does not converge, additional covariance structure including autoregressive and compound 
symmetry will be used in the order stated. MMRM sample codes are provided in Section 9.4. 
Two-sided tests comparing each of the TAK-062 dose groups with placebo at Week 12 will be 
conducted. The corresponding p-values, least squares (LS) means of treatment differences and 2-
sided 95% CI will be reported. The MMRM assumes data is missing at random.  
Multiplicity control: To control the overall type I error rate for the primary endpoint, a fixed-
sequence testing procedure will be used for the comparison of 3 doses of TAK-062 versus 
placebo. Specifically, the primary endpoint tested will be conducted in the following order: 
i. 
First, 
 TAK-062 versus placebo for subjects taking gluten-containing SIGE in 
Cohort 1. 
ii. 
If the test in Step i) is statistically significant, then perform the superiority test of 
 
TAK-062 versus combined placebo from Cohorts 1 and 2 for subjects taking gluten-
containing SIGE. 
iii. 
If the test in Step ii) is statistically significant, then perform the superiority test of 
 
TAK-062 versus combined placebo from Cohorts 1 and 2 for subjects taking gluten-
containing SIGE. 
In steps ii) and iii), in the comparisons of 
 TAK-062 versus combined placebo and 
 
 TAK-062 versus combined placebo in the gluten-containing SIGE group, approximately 20 
subjects last enrolled in the placebo arm in Cohort 1 from the same study sites as in Cohort 2 
active treatment arms with gluten-containing SIGE will be included in the placebo arm. 
6.5.1.3 
Handling of Intercurrent Event 
A composite strategy will be used to address rescue medication use and treatment 
discontinuation due to lack of efficacy or treatment-related AEs. 
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For subjects who received rescue medications for CeD related symptoms, the severity of the 
treated symptom(s) in CDSD on the days when the rescue medications are used will be set to 
Very Severe. For subjects who discontinue treatment due to lack of efficacy or treatment-related 
AEs, the Week 12 CDSD GI severity score will be set to the baseline weekly CDSD GI severity 
score. Treatment policy strategy will be used to address SIGE bar discontinuation (ie, the 
recorded CDSD GI symptom severity score will be used regardless of whether a subject has 
discontinued SIGE) and treatment discontinuation due to reasons other than lack of efficacy or 
treatment-related AEs.  
6.5.1.4 
Sensitivity Analysis 
The following sensitivity analyses will be performed for the primary efficacy endpoint: 
• The primary efficacy endpoint analysis will be repeated using the IRT randomization 
stratification factors as the fixed effects in the MMRM. Missing data will not be imputed. 
• The primary efficacy endpoint analysis will be repeated without baseline randomization 
stratification factors as the fixed effects in the MMRM. Missing data will not be imputed. 
• The primary efficacy endpoint analysis will be repeated using the PPS-SIGE. Missing 
data will not be imputed.  
• The primary efficacy endpoint analysis will be repeated using treatment policy strategy 
(ie, the recorded CDSD GI symptom severity score will be used) to address all 
occurrences of treatment discontinuation due to any reason for all subjects. Missing data 
will not be imputed. 
• The missing not at random (MNAR) will be examined using control-based pattern 
mixture model. Fully Conditional Specification (FCS) was used for multiple imputation 
by PROC MI FCS REG. The imputation models will include baseline stratification 
variables and previous measures. The imputation model for the missing values in the 
treatment arm is constructed from the observed data in the control (placebo) arm. The 
same model will be used to impute missing values in the control arm. The estimated 
treatment effect from the imputed datasets will then be combined to generate the 
statistical inference based on MNAR. Multiple imputation sample codes are provided in 
Section 9.4. The model will be constructed in 3 steps: 
o Step 1 (Imputations): A total of 1,000 datasets will be generated with imputed 
values, based on the control group data. 
o Step 2 (Analysis of complete data sets): The primary endpoint will be analyzed 
for each of the 1000 complete imputed data sets using an ANCOVA with 
treatment group and baseline strata as factors, and the baseline value as a 
covariate. 
o Step 3 (Inference): The LS mean estimates, associated standard error, 95% CI and 
p value will be aggregated using Rubin’s rule via PROC MIANALYZE 
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• The examination of missing not at random (MNAR) using control-based imputation will 
be repeated. The primary endpoint will be analyzed with imputed data using a MMRM 
with treatment group and baseline strata as factors, and the baseline value as a covariate. 
• The primary efficacy endpoint analysis will be repeated. A composite strategy will be 
used to address SIGE bar discontinuation. For subjects with SIGE bar discontinuation, 
the Week 12 CDSD GI severity score will be set to the baseline weekly CDSD GI 
severity score.   
• The primary efficacy endpoint analysis will be repeated. A composite strategy will be 
used to address treatment discontinuation due CeD-related GI symptom worsening. For 
subjects with early termination due to CeD-related GI symptom worsening, the Week 12 
CDSD GI severity score will be set to the baseline weekly CDSD GI severity score.   
• The primary efficacy endpoint analysis will be repeated. A composite strategy will be 
used to address treatment discontinuation due CeD-related GI symptom worsening. For 
subjects with early termination due to CeD-related GI symptom worsening, the Week 12 
CDSD GI severity score will be set to the worst CDSD GI severity score.  
• The primary efficacy endpoint analysis will be repeated. For subjects who experience 
ICEs as described in Section 6.5.13, data following the ICEs will be imputed using the 
last observation carried forward (LOCF) method, based on the last available observation 
prior to the ICE. 
• Additional sensitivity analyses, such as applying different baseline derivation rules, will 
be conducted as needed. 
6.5.1.5 
Supplementary Analyses 
Supplementary analyses for the primary estimand will include the following: 
• Estimand with the target population of subjects who satisfied study entry criteria and are 
on pre-enrollment diet. The primary endpoint will be analyzed based on FAS–no SIGE. 
The endpoint, strategy for the ICEs and population-level summary will be the same as the 
main estimand. Nominal p-values will be calculated. No hypothesis testing will be 
performed. 
• Estimand with the target population excluding subjects who report >1 point improvement 
in PGIS during 
 run-in period. The supplementary analysis will be performed 
for FAS-SIGE and FAS–no SIGE separately. The endpoint definition, strategy for the 
ICEs and population-level summary will be the same as the main estimand. Nominal p-
values will be calculated. No hypothesis testing will be performed. 
• Estimand with the weekly average CDSD-overall (GI + Tiredness) symptom severity 
score based on daily CDSD symptom severity score that is the average of the severity 
score for diarrhea, abdominal pain, bloating, nausea, and tiredness, ranging from 0 (no 
symptoms) to 4 (very severe). The population, treatments, strategy for the ICEs and 
population-level summary will be the same as the main estimand. The analysis will be 
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performed based on FAS-SIGE and FAS–no SIGE separately. Nominal p-values will be 
calculated. No hypothesis testing will be performed. 
• Estimand using the area under the curve (AUC) of weekly CDSD score from Day 1 
through Week 12 as the endpoint. The AUC will be a summation of daily scores. Missing 
values due to treatment discontinuation will be imputed by last observed carried forward 
(LOCF). The AUC will be analyzed using analysis of covariance with treatment group as 
an effect and baseline weekly CDSD score as covariance to compare the treatment 
difference with placebo and 2-sided 95% CI will be presented for each TAK-062 dose 
group. Nominal p-values will be calculated. No hypothesis testing will be performed. 
AUC will be calculated as below: 
AUC = Sum of daily score from Day 1 to Week 12, 
Where the missing daily score is imputed by LOCF method. 
• Estimand using change in CDSD symptom score from Week -5 (before study intervention) 
to Week 12 as the endpoint. The analysis method will be the same as the main estimand. 
Nominal p-values will be calculated. No hypothesis testing will be performed. 
Week -5 will be defined as the week before the run-in date. 
6.5.2 
Secondary Endpoint Analysis 
The secondary endpoint is change in Vh:Cd ratio on duodenal biopsy from baseline (measured 
at Week -4) to Week 24. The Vh:Cd ratio represents mucosal architectural changes and a lower 
Vh:Cd ratio indicates more severe intestinal injury characterized by a flattening of the mucosa. 
6.5.2.1 
Derivation of Endpoint 
Tissue samples to evaluate Vh:Cd will be collected through duodenal biopsies at Week -4 (Visit 
2) and at Week 24 (Visit 6) or early termination. The change from baseline in Vh:Cd will be 
calculated as  
change from baseline = value at Week 24/ET – value at baseline, 
where baseline is defined as the result of last observed value before the first dose of study 
medication, i.e., the result at Week -4. 
6.5.2.2 
Main Analytical Approach 
The main estimand for the secondary objective assess the treatment effect of TAK-062 compared 
with placebo at Week 24 in target population based on the following variable/endpoint: 
• Change in Vh:Cd from baseline (measured at Week -4) to Week 24.  
The target population and treatments are the same as for the primary estimand in Section 0. 
Composite strategy will be used to address the ICEs of treatment discontinuation due to lack of 
efficacy or treatment-related AEs; treatment policy strategy for the ICEs of SIGE bar 
discontinuation or rescue medication use (i.e., Vh:Cd measured at Week 24 will be used 
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regardless of SIGE bar discontinuation or rescue medication use) and other reasons for 
discontinuations. 
The corresponding population-level summaries are: 
• Treatment difference (TAK-062 – placebo) in the change from baseline to Week 24 in 
average Vh:Cd on duodenal biopsy.  
The analysis will be conducted using ANCOVA. The model will include treatment group and the 
randomization stratification factors as fixed effects and baseline values as covariate. Missing 
values will be regarded as missing at random. Missing data will be handled using multiple 
imputation. The missing values will be imputed by treatment group, stratification factors, gender 
and baseline Vh:Cd via PROC MI FCS REG. 1000 complete datasets will be computed. Each of 
the 1000 imputed datasets will be analyzed using ANCOVA. The LS mean estimates, associated 
standard error, 95% CI and p value will be aggregated using Rubin’s rule via PROC 
MIANALYZE procedure. The LS means and 2-sided 95% CI will be provided for the Week 24 
treatment difference between the 
 TAK-062 dose groups versus placebo, 
respectively. Nominal 2-sided p-values will be provided for the comparison of 
 TAK-062 
versus placebo, 
 TAK-062 versus placebo and 
 TAK-062 versus placebo, 
respectively for both FAS-SIGE and FAS-no SIGE. Multiple imputation sample codes are 
provided in Section 9.4. 
6.5.2.3 
Sensitivity Analysis 
The following sensitivity analyses will be performed for the secondary endpoint: 
• The analyses will be repeated using the PPS-SIGE. Missing data will not be imputed.  
• The analyses will be conducted without missing data imputation, i.e., missing as missing. 
6.5.2.4 
Supplementary Analyses 
Supplementary analyses will be planned as follows: 
Supplementary analyses based on subjects who satisfied study entry criteria and are on pre-
enrollment diet will be performed. The corresponding endpoints will be analyzed based on FAS-
no SIGE. 
Supplementary analyses based on the target population excluding subjects who report >1 point 
improvement in PGIS during 
 run-in period will also be performed. The analysis will be 
performed for FAS-SIGE and FAS-no SIGE separately. 
For all the above supplementary analyses, the endpoint definitions, strategy for the ICEs and 
population-level summary will be the same as for the main estimand. Nominal p-values will be 
calculated. No hypothesis testing will be performed. 
6.5.2.5 
Exploratory Analysis 
As an exploratory analysis, the endpoint of change from baseline (Week -4) in Vh:Cd 
measurements at Week 24/ET will also be analyzed by modeling based on combined FAS-SIGE 
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and FAS-no SIGE excluding the 
 TAK-062 
 group, where the effects of 
treatment group, SIGE and their interaction effects will be estimated in the same model.  
The analysis on Vh:Cd will be performed similarly for the changes in the individual Vh and Cd 
measurements as exploratory analyses. 
6.5.3 
Exploratory/additional Endpoints Analysis 
Exploratory/additional endpoints will be summarized descriptively by analysis visit and 
treatment groups in both FAS-SIGE set and FAS-no SIGE set when appropriate. MMRM, 
Logistic regression model and ANCOVA will be applied when appropriate. 
Exploratory/additional endpoints are: 
Impact of SIGE: 
• Differences in responses in CeD endpoints including PROs, celiac serology, and 
histology measures will be compared between gluten-containing SIGE and gluten-free 
SIGE arms. 
Analysis will be based on subjects in Cohort 1 and the gluten-free SIGE arms (TAK-062 
 and Placebo) in Cohort 2. Descriptive statistics will be provided on the change-
from-baseline values for Weeks 12 (where applicable) and 24 for PROs, celiac serology, 
and histology measures for Control and TAK-062
. ANCOVA analysis will be 
performed with Treatment and SIGE as independent variables, and baseline 
randomization stratification variables and corresponding baseline outcome variable as 
covariates. 
PRO Outcomes: 
• Proportion of Subjects Achieving a Change from Baseline in Weekly Average CDSD at 
Week 12 ≤ - 0.25 and ≤ -0.44 
The weekly average CDSD score experiencing ICEs will be handled following rule 
6.5.1.3. Missing values not related to ICEs will be assumed missing at random and 
addressed using multiple imputation (MI) with the PROC MI FCS REG method. The 
imputation model will include treatment group, stratification factors, and previous 
measures as covariates. A total of 1,000 complete datasets will be generated. 
The response variable will be dichotomized based on the imputed CDSD weekly average 
score. Response rates for each treatment group and the treatment difference will be 
analyzed across the imputed datasets. The point estimate, standard error, confidence 
intervals, and p-values will be aggregated using Rubin’s rule, implemented with PROC 
MIANALYZE. 
• Change in weekly average CDSD GI symptom severity score from Week -8 to Week 24 
Change in weekly average CDSD GI symptom severity score from Week -8 to Week 24 
will be summarized by descriptive statistics for each treatment arm. 
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• Change in weekly average CDSD GI symptom severity score from Week -8 to Week 12. 
Change in weekly average CDSD GI symptom severity score from Week -8 to Week 12 
will be summarized by descriptive statistics for each treatment arm. 
• Patient Global Impression of Change (PGIC) at Week 0, Week 12, and Week 24. 
PGIC will be summarized as a categorical variable for Week 0, Week 12 and Week 24 by 
treatment arm. 
• Percent of subjects reporting each symptom on the CeD Most Bothersome Symptom 
Questionnaire at each time point measured. 
The number and percent of subjects reporting each symptom as the most bothersome 
symptom will be summarized by visit and treatment arm. 
• Change from baseline to Week 12 and Week 24 in percentage of symptom-free days over 
a 14-day period. 
Symptom-free days will be counted based on analysis days where the daily diary is 
completed on at least 8 of the 14 days. When the daily diary is completed on less than 8 
of the 14 days, the symptom-free day will be counted as missing. Any diary entered after 
the End of Study will be excluded from the summary. In the case that the diary is entered 
more than once on the same day, the last result based on time of entry will be used in the 
analysis. The same scenario will be applied on other additional endpoints defined over a 
14-day period. The percentage of symptom-free days is defined as the number of 
symptom-free days over the number of non-missing daily diary days over a 14-day 
period. 
• Change from baseline to Week 12 and Week 24 in percentage of symptom-free days over 
a 7-day period. 
Symptom-free days will be counted based on analysis days where the daily diary is 
completed on at least 4 of the 7 days. When the daily diary is completed on less than 4 of 
the 7 days, the symptom-free day will be counted as missing. Any diary entered after the 
End of Study will be excluded from the summary. In the case that the diary is entered 
more than once on the same day, the last result based on time of entry will be used in the 
analysis. The same scenario will be applied on other additional endpoints defined over a 
7-day period. The percentage of symptom-free days is defined as the number of 
symptom-free days over the number of non-missing daily diary days over a 7-day period. 
• Proportion of subjects with ≥55% of symptom-free days over a 14-day period at Week 
24 or Early Termination Visit 
Subgroup analysis will be also performed in subjects with ≤40% baseline percentage of 
symptom-free days. Other percentage of symptom-free days thresholds will be explored 
when appropriate. 
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• Proportion of subjects with ≥55% of symptom-free days over a 7-day period at Week 24 
or Early Termination Visit. 
Subgroup analysis will be also performed in subjects with ≤40% baseline percentage of 
symptom-free days. Other percentage of symptom-free days thresholds will be explored 
when appropriate. 
• Proportion of subjects with change from baseline to Week 24 in percentage of symptom-
free days ≥25% over a 14-day period. 
Subgroup analysis will be also performed in subjects with ≤40% baseline percentage of 
symptom-free days. Other percentage of symptom-free days thresholds will be explored 
when appropriate. 
• Change from baseline to Week 24 in average CDSD bowel movement frequency over a 
14-day period. 
Change from baseline at Week 24 in in average CDSD bowel movement frequency will 
be summarized according to the CDSD V2.1 Question 8 in Table 6.a. 
• Change from baseline to Week 24 in average CDSD bowel movement frequency over a 
7-day period. 
Change from baseline at Week 24 in in average CDSD bowel movement frequency will 
be summarized according to the CDSD V2.1 Question 8 in Table 6.a. 
• Change from baseline to Week 24 in percentage of symptom-free days over a 7-day 
period by PGIS category. 
• Change from baseline to Week 24 in the following PROs (average over a 14-day period): 
– CDSD total score. 
– CDSD GI score. 
– CDSD non-stool GI score. 
– CDSD Diarrhea score. 
– CDSD Abdominal pain score. 
– CDSD Bloating score. 
– CDSD Nausea score.   
CDSD total score, GI score, non-stool GI score, Diarrhea score, Abdominal pain score, 
Bloating score, and Nausea score will be calculated based on Table 6.a. Non-stool GI 
score includes Abdominal pain score, Bloating score and Nausea score. The analysis of 
change from baseline at Week 24 in average scores over a 14-day period will follow the 
methodology mentioned in Section 6.5.1.2. 
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• Change from baseline to Week 24 by PGIS category in the following PROs (average over 
a 7-day period): 
– CDSD total score. 
– CDSD GI score. 
– CDSD non-stool GI score. 
– CDSD Diarrhea score. 
– CDSD Abdominal pain score. 
– CDSD Bloating score. 
– CDSD Nausea score.   
CDSD total score, GI score, non-stool GI score, Diarrhea score, Abdominal pain score, 
Bloating score, and Nausea score will be calculated based on Table 6.a. Non-stool GI 
score includes Abdominal pain score, Bloating score and Nausea score. The analysis of 
change from baseline at Week 24 in average scores over a 7-day period will follow the 
methodology mentioned in Section 6.5.1.2. 
• Change from Week -8 and Week -1 to Week 12 and Week 24 in the following PROs: 
Change from Week -8 to Week 12 and Week 24, and separately, from Week -1 to Week 
12 and Week 24, will be summarized by Visit and treatment group for the following: 
– Weekly score of the most bothersome symptom as reported by the CDSD. 
– Severity rating or frequency of each item (symptom) of the CDSD. 
– Frequency of constipation based on the CDSD. 
– Proportion of minimal symptom days per week (defined as days with none or no more 
than 1 mild score of either bloating, abdominal pain, nausea, or diarrhea) as reported 
on the CDSD. 
– Proportion of symptom-free days (response of “none” for all items) per week as 
reported on the CDSD. 
– Impact of Celiac Disease Symptoms Questionnaire (ICDSQ). 
– Patient Global Impression of Severity (PGIS). 
– Patient-reported Outcomes Measurement Information System (PROMIS)-Cognitive 
Function Instrument. 
– PROMIS-Fatigue Instrument. 
– Short Form 12-Item (SF-12) Health Survey. 
– EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) health survey. 
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– Work Productivity and Activity Impairment plus Classroom Impairment 
Questionnaire: Celiac Disease (WPAI+CIQ: CeD). 
– Celiac Disease Gastrointestinal Symptom Rating Scale (CeD-GSRS). 
– Celiac Disease Assessment Questionnaire (CDAQ). 
– Celiac disease quality of life (CD-QOL) questionnaire.  
Serology titers: 
• Change from baseline (Week -8) to Week 12 and Week 24 in celiac serology titers. 
Change from Week -4 to Week 12 and Week 24 in celiac serology titers will be 
summarized by Visit and treatment group. 
Histological endpoints: 
The following will be summarized with descriptive statistics by treatment arm for Week 24 
visit and early termination visit. 
• Proportion of subjects achieving mucosal remission (Vh:Cd ≥3,  ≥2.7 and >2.5) at Week 
24. 
• Change from baseline (Week -4) to Week 24 in IEL counts. 
• Change from baseline (Week -4) to Week 24 in Marsh-Oberhuber scores, both 
qualitatively assessed and calculated from IEL and Vh:Cd results. 
• Change from baseline (Week -4) to Week 24 in individual Vh and Cd measurements. 
• Proportion of subjects with Vh:Cd ≥2.5 and IEL counts < 25 per 100 enterocytes at Week 
24. 
• Mucosal response rate defined as the proportion of subjects with an increase in Vh:Cd of  
greater than 0.4 and a reduction in IEL counts of greater than 30% from Week -4 to Week 
24. 
• Proportion of subjects with an increase in Vh:Cd of greater than 0.25 and a reduction in 
IEL counts of greater than 15% from Week -4 to Week 24. 
• Change from baseline (Week -4) to Week 24 in Composite score of Vh:Cd ratio and IEL 
(VCIEL) and Multi-parametric composite score of Vh:Cd and IEL (mpVCIEL). 
• Proportion of subjects with an increase of ≥0, ≥0.1, ≥0.2, ≥0.3 and ≥0.4 in Vh:Cd from 
baseline to Week 24 
Subgroup analysis will be also performed in subjects with baseline Vh:Cd  ≥2.3, or by 
stratification factors. 
 
PRO and histological endpoints: 
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The following will be summarized with descriptive statistics by treatment arm for Week 24 
visit and early termination visit. Improvement for CDSD and GSRS is defined as any 
reduction in score. Improvement in Vh:Cd is defined as any increase in Vh:Cd. 
• Proportion of subjects with an improvement in both weekly average CDSD GI symptom 
severity score and Vh:Cd from Week -4 to Week 24 
• Proportion of subjects with an improvement in both GSRS (from Week -8) and Vh:Cd 
(from Week -4) to Week 24 
• Proportion of subjects with Vh:Cd ≥2.7 at Week 24 and ≥55% of symptom-free days 
over a 14-day period at Week 24 for subgroup of subjects with baseline Vh:Cd ≤2.3 and 
baseline percentage of symptom-free days ≤40%. 
Other percentage of symptom-free days thresholds will be explored when appropriate. 
• Proportion of subjects with change from baseline to Week 24 in Vh:Cd ≥ 0.4 and change 
from baseline to Week 24 in percentage of symptom-free days ≥ 25% over a 14-day 
period. 
Subgroup analysis will be also performed in subjects with baseline percentage of 
symptom-free days ≤40%. Other percentage of symptom-free days thresholds will be 
explored when appropriate. 
 
 
 
GIP endpoints: 
• Frequency of positive urine GIP tests in subjects in screening and then by week across 
the different treatment groups. 
 
PK endpoints: 
• Plasma concentration of TAK-062. 
• PK parameters  
The following PK parameters will be calculated based on actual sampling time when 
applicable.  
o PK subgroup: Cmax, Tmax, AUC0-3, AUC0-t, CL/F, T1/2, and Vz/F 
 
Cmax: the maximum observed drug concentration in plasma 
Tmax: the time at which Cmax occurs  
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AUC0-3: area under the concentration time curve from zero to 3 h after TAK-062 
administration  
AUC0-t: area under the concentration time curve from zero to time of last 
quantifiable concentration  
CL/F: plasma clearance  
T1/2: terminal half life  
Vz/F: apparent volume of distribution 
o All other subjects: Cmax 
6.5.3.1 
Derivation of Exploratory Endpoints 
Impact of SIGE: 
The difference of CeD endpoints including PROs, celiac serology, histology 
 
will be assessed.  
PRO Outcomes: 
All PROs will be administered on an electronic device. The CDSD will be administered at 
approximately the same time every day. All PROs should be done, before any other procedures 
on the day of the study visit or no more than 1 day before the study visit. There is no expected 
missing item responses as the PRO instrument was set up to ask the subjects to answer the 
question only when the previous items are answered. Therefore there is no missing handling in 
the derivation of PRO endpoints unless specified otherwise. 
 
PGIC 
The Celiac Disease PGIC is a 1-question instrument that evaluates the change from study start to 
the present time on patients’ severity. Response options are measured using a 7-point Likert-type 
scale ((7) very much worse, (6) much worse, (5) a little worse, (4) no change, (3) a little 
improved, (2) much improved, (1) very much improved). The PGIC will be conducted at Week 0 
(Visit 3), Week 12 (Visit 4), Week 24 (Visit 6) or Early termination. 
The PGIC scores can be collapsed and categorized as below: 
PGIC Score 
Category 
1 = very much improved 
A = Improved 
2 = much improved 
A = Improved 
3 = a little improved 
B = Minimal – No Change 
4 = no change 
B = Minimal – No Change 
5 = a little worse 
B = Minimal – No Change 
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6 = much worse 
C = Worse 
7 = very much worse 
C = Worse 
Note: B or C are classified as “Not Improved” as dichotomized as “Improved” vs “Not Improved. 
  
CeD Most Bothersome Symptom 
The CeD Most Bothersome Symptom is a 1-question instrument designed to assess the subject’s 
perception of which symptoms from those evaluated in the CDSD that the subject considers most 
bothersome. The CeD Most Bothersome Symptom will be conducted at Week -8 (Visit 1), Week 
0 (Visit 3), Week 12 (Visit 4), Week 24 (Visit 6) or Early termination. 
 
ICDSQ 
The ICDSQ is a 14-question instrument that evaluates emotional wellbeing, physical activities, 
social activities, and daily activities over the past 7 days. Responses are measured using a 5-point 
Likert-type scale ((0) not at all, (1) a little, (2) moderately, (3) very much, (4) completely). The 
ICDSQ will be conducted at Week -8 (Visit 1), Week 0 (Visit 3), Week 12 (Visit 4), Week 24 
(Visit 6) or Early termination. 
The domain score will be calculated as the mean score of all items in each domain. The overall 
ICDSQ score will be calculated as the sum of all domain scores. A higher score implies more 
sever symptom. 
The change from baseline in domain score and overall score will be calculated as 
change from baseline = value at Visit X – value at baseline, 
where baseline is defined as the result of last observed value before the first dose of study 
medication, i.e., the result at Week 0. The change from Week -8 to post-baseline values will also 
be analyzed, where Week -8 is defined as the first available result before treatment 
administration. 
 
PGIS 
PGIS is a 1-question instrument used as an anchor that evaluates the overall severity over the 
past 7 days. Response options are measured using a Likert-type scale ((0) no symptoms, (1) mild, 
(2) moderate, (3) severe, (4) very severe). For validation purposes, it will be performed at Weeks 
-8 and -7. The PGIS will also be conducted on the day of every visit, i.e., Week -8 (Visit 1), 
Week -4 (Visit 2), Week -2, Week 0 (Visit 3)/Day -1, Week 3 (Visit 4), Week 12 (Visit 5), Week 
24 (Visit 6) or early termination.  
The change from baseline in PGIS will be calculated as 
change from baseline = value at Visit X – value at baseline, 
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where baseline is defined as the result of last observed value before the first dose of study 
medication, i.e., the result at Week 0. The change from Week -8 to post-baseline values will also 
be analyzed, where Week -8 is defined as the first available result before treatment 
administration. 
 
PROMIS-Cognitive Function Instrument 
PROMIS is a set of person-centered measures that evaluates and monitors physical, mental, and 
social health in adults and children. The PROMIS Short Form v2.0-Cognitive Function 6a is a 
subset of 6 items assessing patient-perceived cognitive deficits. Facets include mental acuity, 
concentration, verbal and nonverbal memory, verbal fluency, and perceived changes in these 
cognitive functions. The extent to which cognitive impairments interfere with daily functioning, 
whether other people observe cognitive impairments, and the impact of cognitive dysfunction on 
quality of life are also assessed. This instrument has a 7-day recall period, and responses are 
measured using a 5-point frequency scale ((5) never, (4) rarely, (3) sometimes, (2) often, (1) very 
often). For subjects aged 12 to 17 years, a modified version of the PROMIS Pediatric Short 
Form v1.0-Cognitive Function 7a: Pediatric Cognitive Function will be used. This instrument 
has 7 items on a 5-point response scale ((5) none of the time, (4) a little of the time, (3) some of 
the time, (2) most of the time, (1) all of the time). The original version has a 4-week recall that 
has been modified to 7 days.  
The PROMIS-Cognitive Function Instrument will be conducted at Week -8 (Visit 1), Week 0 
(Visit 3), Week 12 (Visit 4), Week 24 (Visit 6) or early termination. 
Raw scores (sum of all scale scores) will be converted to T-scores, using scoring tables Table 6.b 
and Table 6.c based on subject age. 
 
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Table 6.b  Cognitive Function Scoring 
Table for Adult Subjects 
 
Table 6.c  Cognitive Function Scoring 
Table for Subjects Aged 12-17 
 
 
The change from baseline in PROMIS-Cognitive Function Instrument t-score will be calculated 
as 
change from baseline = value at Visit X – value at baseline, 
where baseline is defined as the result at of last observed value before the first dose of study 
medication, i.e., the result at Week 0. The change from Week -8 to post-baseline values will also 
be analyzed, where Week -8 is defined as the first available result before treatment 
administration. 
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PROMIS-Fatigue Instrument 
PROMIS is a set of person-centered measures that evaluates and monitors physical, mental, and 
social health in adults and children. The PROMIS Item Bank v1.0-Fatigue-Short Form 13a is a 
battery of 13 questions for adults aged 18 years or older, which are included in the FACIT-
Fatigue. This instrument assesses a range of self-reported symptoms, from mild subjective 
feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that 
likely decreases one’s ability to execute daily activities and function normally in family or social 
roles. 
Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) and the 
impact of fatigue on physical, mental, and social activities. This instrument has a 7-day recall 
period, and responses are measured using a 5-point scale ((1) not at all, (2) a little, (3) 
somewhat, (4) quite a bit, (5) very much). The assigned numbers to the scale for 2 questions 
(AN5-I have energy and AN7-I am able to do my usual activities) are reversed from 5 to 1.   
For subjects aged 12 to 17 years, the PROMIS Pediatric Item Bank v2.0-Fatigue-Short Form 
10a: Pediatric Fatigue will be used. This instrument has 10 questions with a 7-day recall that 
are measured using a 5-point scale ((1) never, (2) almost never, (3) sometimes, (4) often, (5) 
almost always).  
The PROMIS-Fatigue Instrument will be conducted at Week -8 (Visit 1), Week 0 (Visit 3), 
Week 12 (Visit 4), Week 24 (Visit 6) or early termination. 
Raw scores (sum of all scale scores) will be converted to T-scores, using scoring tables Table 6.d 
and Table 6.e based on subject age. 
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Table 6.d  Fatigue Scoring Table for Adult Subjects 
 
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Table 6.e  Fatigue Scoring Table for Subjects Aged 12-17 
 
The change from baseline in PROMIS-Fatigue Instrument will be calculated as 
change from baseline = value at Visit X – value at baseline, 
where baseline is defined as the result at of last observed value before the first dose of study 
medication, i.e., the result at Week 0. The change from Week -8 to post-baseline values will also 
be analyzed, where Week -8 is defined as the first available result before treatment 
administration. 
 
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SF-12 v2 
The SF-12 v2 is a self-administered, validated questionnaire designed to measure generic 
HRQOL. This 12-item questionnaire measures 8 domains, including: Physical Functioning, 
Role-physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-emotional, and 
Mental Health. Two summary scores can be calculated, the Physical Component Score (PCS), 
and the Mental Component Score (MCS). Higher scores indicate better health status.  
The SF-12 v2 will be conducted at Week -8 (Visit 1), Week 0 (Visit 3), Week 12 (Visit 4), Week 
24 (Visit 6) or early termination. 
Raw scores range from 0 to 100 with higher scores indicating better health. Domain scores are 
calculated from raw scores such that domain scores have a mean of 50 and SD of 10. The PCS 
and MCS summary component scores also have mean of 50 and SD of 10 to allow comparisons 
with domain scores. 
Scoring the SF-12 v2 is accomplished using T-score Based scoring software from Quality Metric 
Inc. (Lincoln, RI). T-score Based scoring is standardized across the SF family of adult tools 
using the means and standard deviations from the 2009 U.S. general population. The T-score 
Based scores in the U.S. general population have a mean of 50 and a standard deviation of 10. 
The Medical Outcomes Study (MOS) tools utilize 2009 t-scores.  
T-score based scoring method scores the data in relation to U.S. general population t-scores. 
Therefore, all scores obtained that are below 50 can be interpreted as below the U.S. general 
population t-score and scores above 50 can be interpreted as above the U.S. general population t-
score. Low values represent a poor health state and high values represent a good mental health. 
The change from baseline in SF-12 v2 domain/summary score will be calculated as 
change from baseline = value at Visit X – value at baseline, 
where baseline is defined as the result at of last observed value before the first dose of study 
medication, i.e., the result at Week 0. The change from Week -8 to post-baseline values will also 
be analyzed, where Week -8 is defined as the first available result before treatment 
administration. 
 
EQ-5D-5L 
The EQ-5D-5L questionnaire, developed by the EuroQol Research Foundation is a simple, valid, 
and reliable instrument used to measure general health-related quality of life (HRQOL) in 
subjects and includes 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Within each dimension, subjects choose 1 of 5 levels of health problems ((1) 
none, (2) slight, (3) moderate, (4) severe, or (5) extreme), with levels scored 1 through 5, 
respectively.  
The EQ-5D-5L visual analog score is a self-assigned rating of overall health using a visual, 
vertical scale, with a score of 0 as the worst and 100 as best possible health. The EQ-5D-5L total 
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score and EQ-5D-5L visual analog score have been shown in many studies to be valid and 
reliable instruments for measuring HRQOL in subjects with GI diseases.  
The scores for the 5 dimensions can be combined into a 5-digit number that describes the 
patient’s health state. The health state index score will be calculated from the individual health 
profiles using country-specific value set. 
The EQ-5D-5L will be conducted at Week -8 (Visit 1), Week 0 (Visit 3), Week 12 (Visit 4), 
Week 24 (Visit 6) or Early termination. 
The change from baseline in EQ-5D-5L index score and EQ-VAS will be calculated as 
change from baseline = value at Visit X – value at baseline, 
where baseline is defined as the result at of last observed value before the first dose of study 
medication, i.e., the result at Week 0. The change from Week -8 to post-baseline values will also 
be analyzed, where Week -8 is defined as the first available result before treatment 
administration. 
 
WPAI+CIQ:CeD 
The WPAI+CIQ:CeD is a 10-question instrument questionnaire. The questionnaire assesses 
work time or academic classes lost due to CeD. Subjects also self-assess the impact of allergies 
on the performance in the workplace, at school, or during university classes. The recall period is 
the previous 7 days.  
The WPAI+CIQ:CeD will be conducted at Week -8 (Visit 1),  Week 0 (Visit 3), Week 12 (Visit 
4), Week 24 (Visit 6) or early termination. 
The derivation differs between subjects who are employed and subjects who are in school. 
For those who are employed: 
Percent work time missed due to CeD (Absenteeism) = Q2/(Q2+Q4)*100% 
Percent impairment while working due to CeD (Presenteeism) = Q5/10 
Percent overall work impairment due to CeD (Work Productivity Loss) = Q2/(Q2+Q4)+[(1-
Q2/(Q2+Q4))x(Q5/10)] 
Activity Impairment = Q10/10 
The number of subjects employed, % of all subjects employed, number of work hours missed 
due to CeD and the parameters derived above will be summarized descriptively for those who 
are employed. 
For those who are in school: 
Percent work time missed due to CeD (Absenteeism) = Q7/(Q7+Q8) 
Percent impairment while working due to CeD (Presenteeism) = Q9/10 
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Percent overall class impairment due to CeD (Class Productivity Loss) = Q7/(Q7+Q8) + [(1-
Q7/(Q7+Q8))x(Q9/10)] 
Percent activity impairment due to all health (Activity Impairment) = Q10/10 
The number of subjects in school, % of all subjects in school, number of class hours missed due 
to CeD and the parameters derived above will be summarized descriptively for those who are in 
school.  
The change from baseline in each item of WPAI+CIQ:CeD will be calculated as 
change from baseline = value at Visit X – value at baseline, 
where baseline is defined as the result at of last observed value before the first dose of study 
medication, i.e., the result at Week 0. The change from Week -8 to post-baseline values will also 
be analyzed, where Week -8 is defined as the first available result before treatment 
administration. 
 
CeD-GSRS 
The CeD-GSRS is a nondisease-specific 15-item instrument measuring the discomfort of GI 
symptoms using a modified Likert scale ((0) no discomfort at all, (1) minor discomfort, (2) mild 
discomfort, (3) moderate discomfort, (4) moderately severe discomfort, (5) severe discomfort, (6) 
very severe discomfort). In this study, the 10 items relevant to CeD will be evaluated (stomach 
pain/discomfort, hunger pains, nausea, rumbling in stomach, bloating, burping, passing gas, 
diarrhea, loose stools, urgent bowel movement).  
The CeD-GSRS will be conducted at Week -8 (Visit 1), Week 0 (Visit 3), Week 12 (Visit 4), 
Week 24 (Visit 6) or early termination. The overall score is the mean of the 10 items. The 
smaller the total GSRS score, the milder the symptoms of the subject. If one item is missing, then 
the overall score will be set to missing.  
The change from baseline in CeD-GSRS overall score will be calculated as 
change from baseline = value at Visit X – value at baseline, 
where baseline is defined as the result at of last observed value before the first dose of study 
medication, i.e., the result at Week 0. The change from Week -8 to post-baseline values will also 
be analyzed, where Week -8 is defined as the first available result before treatment 
administration. 
 
CDAQ 
The CDAQ is a validated, PRO measure developed to investigate the HRQOL of people living 
with CeD with a recall period of 4 weeks. This 32-item questionnaire measures 5 domains: 
stigma, dietary burden, symptoms, social isolation, and worries and concerns. Responses are 
measured using a 5-point Likert-type scale ((1) never, (2) rarely, (3) sometimes, (4) often, (5) 
always).  
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The CDAQ will be conducted at Week -8 (Visit 1), Week 0 (Visit 3), Week 12 (Visit 4), Week 
24 (Visit 6) or early termination. 
Table 6.f. CDAQ dimensions 
Dimension 
No. of 
questions 
Question numbers 
Stigma 
8 
2, 3, 4, 5, 6, 21, 23, 24 
Dietary burden 
8 
25, 26, 27, 28, 29, 30, 31, 32 
Symptoms 
5 
9, 10, 11, 12, 13 
Social isolation 
5 
14, 16, 17, 18, 22 
Worries and concerns 
6 
1, 7, 8, 15, 19, 20 
The scores will be inverted following below table. 
 
Table 6.g  Original and inverted question scores 
Response 
Original score 
Inverse score 
Never 
1 
5 
Rarely 
2 
4 
Sometimes 
3 
3 
Often 
4 
2 
Always 
5 
1 
For each dimension, the dimension score is calculated using the formula below and ranges from 
0 to 100, where 0 indicates poorest quality of life and 100 indicates highest quality of life.   
Stigma = (((Q2 + Q3 + Q4 + Q5 + Q6 + Q21 + Q23 + Q24) – 8) / 32) * 100 
Dietary burden = (((Q25 + Q26 + Q27 + Q28 + Q29 + Q30 + Q31 + Q32) - 8) / 32) *100 
Symptoms = (((Q9 + Q10 + Q11 + Q12 + Q13) – 5) / 20) * 100 
Social isolation = (((Q14 + Q16 + Q17 + Q18 + Q22) – 5) / 20) * 100 
Worries and concerns = (((Q1 + Q7 + Q8 + Q15 + Q19 + Q20) – 6) / 24) * 100 
 
An overall index score will be calculated. As per the dimension scores, the overall index score 
ranges from 0 to 100, where 0 indicates poorest quality of life and 100 indicates highest quality 
of life.  The formula for calculating the overall index score is: 
Overall Index Score = (Stigma score + Dietary burden score + Symptoms score + Social 
isolation score + Worries and concerns score) / 5 
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If a respondent has not completed one or more questions, then the associated dimension score(s) 
and overall index score will not be calculated.  
The change from baseline in CDAQ overall index score will be calculated as 
change from baseline = value at Visit X – value at baseline, 
where baseline is defined as the result at of last observed value before the first dose of study 
medication, i.e., the result at Week 0. The change from Week -8 to post-baseline values will also 
be analyzed, where Week -8 is defined as the first available result before treatment 
administration. 
 
CD-QoL 
The CD-QoL is a 20-item questionnaire measuring the quality of life in celiac patients over a 30-
day time period and one overall quality of life item. Responses for item 1-20 are measured on a 
5-point Likert-type scale ((1) not at all, (2) slightly, (3) moderately, (4) quite a bit, (5) a great 
deal). A lower score indicates lesser concern about QoL characteristic. Response for the overall 
questions is measured as (5) Excellent, (4) Very Good, (3) Good, (2) Fair, (1) Poor.  
The CD-QoL will be conducted at Week -8 (Visit 1), Week 0 (Visit 3), Week 12 (Visit 4), Week 
24 (Visit 6) or early termination. 
The overall CD-QoL score will be calculated as the mean of the 20 items. A lower score 
indicates higher quality of life. 
The change from baseline in CD-QoL score will be calculated as 
change from baseline = value at Visit X – value at baseline, 
where baseline is defined as the result at of last observed value before the first dose of study 
medication, i.e., the result at Week 0. The change from Week -8 to post-baseline values will also 
be analyzed, where Week -8 is defined as the first available result before treatment 
administration. 
 
Serology titers: 
Celiac Serology Titers 
IgG DGP, IgA DGP, and IgA tTG results will be collected at Week -8 (Visit 1), Week 12 (Visit 
5), Week 24 (Visit 6) and early termination.  
The fold-change from baseline to Week 24 in celiac serology titers will be calculated as  
fold-change from baseline = value at Visit X ÷ value at baseline 
where baseline is defined as the last non-missing value prior to first dose of study drug. 
 
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Histological endpoints: 
IEL 
Tissue samples to evaluate IELs will be collected through duodenal biopsies at Week -4 (Visit 2) 
and at Week 24 (Visit 6) or early termination.   
The change from baseline in IEL count will be calculated as 
change from baseline = value at Visit X – value at baseline, 
where baseline is defined as the result of last observed value before the first dose of study 
medication, i.e., the IEL count at Week -4. 
 
Marsh-Oberhuber scores 
Marsh-Oberhuber scores will be calculated from IEL and Vh:Cd results performed at Week -4 
(Visit 2) and at Week 24 (Visit 6) or early termination.  This will be done using the Q-MARSH 
scoring system described in Adelman et al. 2018, and modified according to experience at our 
Phase 2 vendor. Q-MARSH derives Marsh-Oberhuber scores of M0, M1, M2, M3a, M3b, and 
M3c from quantitative Vh:Cd and IEL count measurements. In addition, one final Marsh-
Oberhuber score per biopsy reading will be given and reported as 0, 1, 2, 3a, 3b, and 3c. 
As Marsh-Oberhuber is assessed and reported as a qualitative ordinal variable. The change from 
baseline in Marsh-Oberhuber scores,  may be calculated as follows to estimate the mean number 
of Marsh-Oberhuber stage differences: 
change from baseline = value at Visit X  – value at baseline. 
The change from baseline may also be calculated as the odds of changing from one stage to 
another using either a non-parametric estimate of the odds (or log odds) or a model based on an 
ordinal logistic regression model. 
The baseline is defined as the result of last observed value before the first dose of study 
medication, i.e., the Marsh-Oberhuber scores at Week -4. 
 
VCIEL 
The VCIEL metric is a newly described calculation that takes the quantitative Vh:Cd ratio and 
IEL counts and combines them mathematically to generate a score that is continuous and not 
categorical[3]. The relevant equation is described in Syage et al (2023)[6]  and is listed below. 
The VCIEL metric is expected to decrease in CeD patients treated with an efficacious therapy. 
This method provides a continuous quantitative metric for analysis. 
𝑉𝐶𝐼𝐸𝐿  = [𝑉ℎ: 𝐶𝑑
𝜎𝑉ℎ:𝐶𝑑
−𝐼𝐸𝐿
𝜎𝐼𝐸𝐿
] 
Where σVh:Cd and σIEL are the standard deviations of Vh:Cd and IEL, respectively. In practice, the 
standard deviations (σ) are replaced by the sampled subjects’ standard deviations, sVh:Cd and  sIEL. 
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mpVCIEL 
The multi-parametric VCIEL (mpVCIEL) metric is a vector-based measure of the L2-normalized 
Euclidean distance between two different distributions and takes the correlation between Vh:Cd 
and IEL into account. The change in mpVCIEL from baseline is defined as 
 
∆𝑚𝑝𝑉𝐶𝐼𝐸𝐿=  √[∆𝑉ℎ𝐶𝑑
∆𝐼𝐸𝐿] ∗𝑆2−1
−1 ∗[∆𝑉ℎ𝐶𝑑
∆𝐼𝐸𝐿] 
 
where ∆𝑉ℎ𝐶𝑑 is the change from baseline for Vh:Cd and ∆𝐼𝐸𝐿 is the change from baseline for 
IEL and 𝑆2−1 is the sample estimate of the covariance of ∆𝑉ℎ𝐶𝑑 and ∆𝐼𝐸𝐿.  
 
Urine GIP 
During Weeks -2 through 24 or the end of study, whichever is earlier, subjects will collect their 
first morning void urine sample weekly for qualitative GIP. Collection must be done the day 
after consuming the SIGE bar or within 6-12 hours after ingesting a SIGE bar. 
On the day of a clinic visit, subjects will collect the first morning void in CHAPS-coated cups 
and take the sample to the site for quantitative GIP. Collection must be done the day after the 
SIGE bar consumption or within 6-12 hours after ingestion of a SIGE bar. 
The change from baseline in quantitative GIP will be calculated as 
change from baseline = value at Visit X – value at baseline, 
where baseline is defined as the result of last observed value before the first dose of study 
medication, i.e., the quantitative GIP at Week 0. 
6.5.3.2 
Main Analytical Approach 
The endpoint of change from baseline in CDSD symptom severity item score for each individual 
symptom and change in each of the frequency questions (bowel movements, diarrhea, and 
vomiting) from Week -1 and from Week -8 to Weeks 12 and 24 will be analyzed using the same 
approach as the primary analysis described in Section 6.5.1.2. Week -8 is defined as the result of 
the first week before treatment administration. The frequency of bowel movements will be 
converted to an indicator for constipation (defined as fewer than 3 days of complete spontaneous 
bowel movement in a week). The weekly average of the frequency items will be an average of 
each daily frequency during the week, with constipation having values of 0 (no constipation) or 1 
(constipation) each week. Weekly frequency will be calculated where the CDSD is completed on 
at least 4 of the 7 days. When the daily diary is completed on less than 4 of the 7 days, the weekly 
frequency will be considered missing. The change in symptom severity and frequency for each 
item in CDSD from Week -3 (before SIGE) and from Week -5 (before study intervention) to 
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Weeks 12 and 24 will also be analyzed. Week -5 will be defined as the week prior to run-in start 
date. Week -3 will be defined as the second week of run-in period. The analysis method will be 
the same as for the corresponding change from Week -1 and change from Week -8. Nominal p-
values will be calculated. No hypothesis testing will be performed. 
 
PGIC 
Raw and collapsed PGIC score and dichotomized (Improved vs Not Improved) at Weeks 12 and 
24 and the change from baseline in PGIS score will be assessed using ANCOVA (proportional 
odds model for PGIC dichotomized variable) with treatment group and the randomization 
stratification factors as covariates. 
 
CDSD and other PRO endpoints 
For each subject, the change from baseline in CDSD score of subject’s most bothersome 
symptom at baseline will be calculated. The CDSD score of the most bothersome symptom will 
be analyzed using the same approach as Section 6.5.1.2. 
In addition, the change from baseline in CDSD score of subjects who reported their most 
bothersome symptom as diarrhea at baseline will be summarized separately. Same analysis will 
be conducted for nausea, abdominal pain and other most bothersome symptoms at baseline. 
Other exploratory PRO endpoints at Weeks 12 and 24 will be analyzed using the same approach 
as in Section 6.5.1.2. This includes ICDSQ domain/overall score, PROMIS-Cognitive Function 
Instrument t-score, PROMIS-Fatigue Instrument t-score, SF-12 v2 domain/summary score, EQ-
5D-5L index score, EQ-VAS, WPAI+CIQ:CeD, CeD-GSRS overall score, CDAQ overall index 
score and CD-QoL score. 
 
Celiac Serology Titers 
The fold change from Week -4 to Week 12 and Week 24 in celiac serology titers will be 
summarized by Visit and treatment group and analyzed using the same approach as in Section 
6.5.1.2. 
 
Marsh-Oberhuber and Q-MARSH scores 
Marsh-Oberhuber scores are ordinal qualitative scores and will be summarized and assessed 
using a cumulative logit model with a proportional odds structure with treatment group, baseline 
result and the randomization stratification factors as covariates. A means model may also be used 
to investigate the mean number of stages changed from baseline.  
While Q-MARSH scores are quantitative, they cannot be considered as interval variables and 
score change from baseline will be evaluated using the models described for Marsh-Oberhuber.  
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Histological endpoints, PRO and histological endpoints 
Other exploratory histology efficacy endpoints at Week 24, including change from baseline in 
histology endpoints such as Vh, Cd, IEL, mpVCIEL, quantitative Marsh, VCIEL, 
 
 for the first tertile of the intestine will be analyzed using the same approach 
as in Section 6.5.2.2.  
For binary endpoints, number and proportion of subjects will be provided for each treatment 
arm. The comparison between each dose of TAK-062 with placebo will be performed using the 
Cochran-Mantel-Haenszel test adjusted by the randomization stratification factors. The point p- 
values will be provided. Non-responder imputation will be used for missing data. 
All efficacy endpoints will also be summarized by descriptive statistics by treatment group at 
each visit. 
 
 
 
 
 
 
 
GIP endpoints 
The frequency of positive urine GIP will be summarized by treatment arms for the second half of 
the run-in period (Week -2 to Day -1) and every week during the treatment period. The change in 
the frequency of positive urine GIP from the run-in period to each of the two-week durations in 
the treatment period will be summarized by treatment arms.  
The frequency versus time and the change in frequency versus time will be plotted by treatment 
arms. 
The proportion of subjects with positive urine GIP will be summarized by treatment arms for 
each visit from Visit 1 (screening) to Visit 6 (Week 24) as well as early termination visit.  
6.5.3.3 
Supplementary Analysis 
Supplementary analyses based on subjects who satisfied study entry criteria and are on pre-
enrollment diet will be performed. The corresponding endpoints will be analyzed based on FAS-
no SIGE. 
6.5.4 
Subgroup Analyses 
The change from baseline (Week -8 and Week -1) to Week 12 and Week 24 in CDSD GI 
symptom severity score will be summarized descriptively by treatment arm for each subgroup 
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defined in Table 6.h if applicable. A forest plot will be generated to display the result of each 
analysis. When there are at least 10 subjects in each treatment arm in a subgroup, primary 
efficacy analysis will be performed on the subgroup. Missing data will not be imputed.   
Table 6.h  Subgroups of Interest 
Subgroup of Interest 
Subgroup Categories 
Age 
12-<18, 
18-<40,  
40 or older 
Adolescent vs adult 
Sex  
Female vs Male 
Race  
Non-Hispanic White vs Hispanic / Non-white 
Baseline celiac serology status 
Seronegative (IgA tTG ≤ ULN and IgG DGP ≤ 2xULN) 
vs seropositive (IgA tTG > ULN or IgG DGP > 2xULN) 
Baseline Symptom severity 
Mild – Moderate (Vh :Cd ≥ 1.5) vs Moderate – Severe 
(Vh :Cd < 1.5) 
PPI/H2RA use at Consent 
PPI/H2RA vs no PPI/H2RA 
Baseline symptom type 
Diarrhea vs. no diarrhea 
Baseline severity of small intestine mucosal injury 
Vh:Cd < mean (Vh :Cd) vs >= mean (Vh :Cd) 
Gluten exposure by GIP urine evaluation during the 
run-in period 
>1 positive sample vs 0-1 positive sample 
6.6 
Safety Analysis 
All safety analyses will be conducted using the SAF, the SAF-SIGE, and the SAF–no SIGE 
according to the actual treatment received. No statistical testing or inferential statistics will be 
generated. All AEs will be coded using the latest MedDRA version. The number and percentage 
of subjects with TEAEs (new onset or worsening AEs after the first dose of study treatment 
regardless of relationship to study drug), treatment-related AEs, SAEs, and AEs leading to 
treatment discontinuation will be summarized by MedDRA primary System Organ Class and 
Preferred Term, overall and by severity for each treatment group. 
Change from baseline in clinical laboratory tests and vital signs will be summarized by treatment 
group and by visit. Subjects with markedly abnormal values for laboratory tests and vital signs 
will be summarized and listed. 
6.6.1 
Adverse Events 
All AEs will be coded using the latest version of MedDRA. All AEs will be included in the data 
listings, but only treatment-emergent adverse events will be included in the summary tables. 
A treatment-emergent adverse event (TEAE) will be defined as an AE or serious adverse event 
(SAE) that started or worsened after first study drug administration and within 30 days of last 
dose of study drug ((AE onset date – date of last dose) ≤ 30). AEs with an end date missing or 
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on or after the first dose will be summarized as TEAEs regardless of severity and relationship to 
study medication. 
The following summaries will be presented: 
• Overview of TEAEs during the study - number and percentage of subjects, number of 
events. 
• TEAEs by system organ class (SOC) and preferred term (PT) - number and percentage of 
subjects. 
• Severity of TEAEs by SOC and PT - number and percentage of subjects. 
• Relationship of TEAEs by SOC and PT - number and percentage of subjects. 
• TEAEs leading to study discontinuation by SOC and PT - number and percentage of 
subjects. 
• Serious TEAEs by SOC and PT - number and percentage of subjects. 
• Serious TEAEs by relationship to study drug and by SOC and PT - number and 
percentage of subjects. 
• Serious TEAEs by intensity and by SOC and PT - number and percentage of subjects. 
• Most frequent TEAEs (>=5% of subjects in any treatment group, sorted by frequency) by 
PT - number and percentage of subjects. 
• TEAEs resulting in death by PT - number and percentage of subjects. 
Key guidelines for determining the incidence of AEs are as follows:  
• AEs with missing or unknown intensity will be considered as severe.  
• AEs with missing or unknown relationship to study drug will be counted as related.  
• A subject with 2 or more AEs within the same level of the MedDRA term will be counted 
only once in that level. 
• SOCs will be sorted in alphabetical order. Within an SOC, adverse events will be sorted 
in descending order of total number of subjects with the preferred term among all the 
treatment groups. 
• For the summary of TEAEs by SOC and PT and intensity, if a subject experiences more 
than 1 episode of a particular coded AE, the subject will be counted only once by the 
maximum intensity of the episode (preferred term). Similarly, if a subject has more than 1 
adverse event within an SOC, the subject will be counted only once by the maximum 
toxicity grade in that SOC. 
• In selected summaries, adverse events will be summarized by the number of events 
reported in addition to the number and percentage of subjects with events. 
 
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Data listings for TEAEs, TEAEs leading to study discontinuation, SAEs and deaths will be 
presented. The AEs will be listed by treatment, study center, subject number and onset date of 
the adverse event. The listing will contain subject identifier, age, sex, body weight, race, adverse 
event (preferred term and reported term), SOC, onset date, end date or whether the event was 
ongoing, duration, frequency, intensity, action taken concerning study drug, causality to study 
drug, the outcome, whether the adverse event was an SAE.  
6.6.2 
Adverse Events of Special Interest 
There are no AEs of special interest considered for TAK-062. 
6.6.3 
Clinical Laboratory Evaluations  
Blood samples for analysis of the Hematology, Serum Chemistry, Serum and Urine parameters 
will be summarized by visit and by treatment group using the SAF, the SAF-SIGE, and the SAF–
no SIGE.  
• Summary statistics (n, mean, SD, median, minimum, and maximum) by treatment group 
and overall for the actual values and change from baseline values. 
• Markedly abnormal values (MAVs), as defined in Section 9.3, will be summarized by 
treatment group and overall. The number and percentage of subjects with MAV values 
observed post-baseline in each of the applicable laboratory parameters will be presented. 
• In addition to the MAV summary, shift tables for certain clinical laboratory parameters of 
interest from baseline to worst post-baseline value will be presented. Each subject will be 
categorized as described in Table 6.i for the baseline value and worst post-baseline value. 
The number of subjects in each of the combinations of shifts will be presented. 
• For female subjects, pregnancy test results will be listed by treatment, study center and 
subject number. 
Table 6.i  Categories of Worst Post-baseline Values 
Parameter 
Category 1 
Category 2 
Category 3 
Category 4 
Category 5 
ALT 
>ULN and ≤3 × 
ULN 
>3 × ULN and ≤5 
× ULN 
>5 × ULN  and 
≤8 × ULN 
>8 × ULN and 
≤20 × ULN 
>20 × ULN 
AST 
>ULN and ≤3 × 
ULN 
>3 × ULN and ≤ 5 
× ULN 
>5 × ULN  and 
≤8 × ULN 
>8 × ULN and 
≤20 × ULN 
>20 × ULN 
ALT or AST 
(either 
meeting the 
criteria) 
>ULN and ≤3 × 
ULN  
>3 × ULN and ≤ 5 
× ULN 
>5 × ULN  and 
≤8 × ULN 
>8 × ULN and 
≤20 × ULN 
>20 × ULN 
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Immunogenicity will be analyzed using the immunogenicity analysis set. Percentage of subjects 
with positive ADA blood sample results and percentage of subjects with positive neutralizing 
ADA during the study will be summarized by treatment group. Percentage of subjects with 
positive ADA will be also summarized by study visit and treatment group. The impact of positive 
ADA on PK, efficacy, and safety may be evaluated. Results of ADA and NAb tests will be also in 
listings. 
6.6.7 
Extent of Exposure and Compliance 
The SAF, the SAF-SIGE, and the SAF-no SIGE will be used for all summaries in this section. 
Study drug/ SIGE bar exposure, compliance for study drug, and compliance for SIGE bar will be 
summarized by visit and by treatment group.  
• The extent of exposure will be calculated as the duration between the first and last dose 
of study drug as following: 
Date of last dose of study treatment – Date of first dose of study treatment + 1 
• Compliance for drug/SIGE bar will be calculated as the following: 
o Number of tablets taken divided by the expected number of tablets to be taken 
o Number of SIGE bar taken out of the total number of expected SIGE bars 
Study drug administration data including placebo, TAK-062, and SIGE bar will be presented in 
data listings. 
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses 
6.7.1 
Pharmacokinetic Analysis 
Measured plasma concentrations of TAK-062 over time will be summarized descriptively using 
the PK analysis set. Subjects in PK analysis set will be analyzed according to the treatment 
regimen they received and by study visit. Individual concentration data versus time will be 
presented in a data listing. 
Further analysis may be performed as deemed necessary and will be reported separately from 
the clinical study report (CSR). 
PK parameters will be summarized for each cohort using descriptive statistics (n, mean, 
SD, %CV, geometric mean, geometric mean %CV, median, minimum, maximum) by nominal 
dose group, and visit if applicable.  
Other PK parameters, as appropriate may be determined or calculated at the discretion of the 
independent clinical pharmacologist. An ad-hoc PK analysis may be conducted in blinded 
manner after Cohort 1. 
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6.7.2 
Biomarker Analysis 
The biomarker analysis will be detailed in a separate analysis plan and reported in a separate 
document. 
6.8 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis 
6.8.1 
PRO Analysis 
Analyses of PRO endpoints are described as part of the efficacy analysis in Section 6.5. 
Additional analyses for PRO validation will be analyzed separately. A separate report will be 
created. 
6.8.2 
Health Care Utilization Analysis 
Not applicable. 
6.9 
Other Analyses 
Not applicable. 
6.10 
Interim Analyses 
An IA is to be performed to assess if clinical efficacy and safety have been demonstrated. The IA 
will be performed when at least 75% of subjects in Cohort 1 have either completed 12 weeks of 
treatment or dropped out. The IA will include safety analysis, primary efficacy analysis, and 
histological data analysis based on available data. The IA will be used to decide on the addition 
of adolescents in Cohort 2. The decision will be based on the safety evaluation, the conditional 
power (CP) for the primary efficacy analysis and the analysis of Vh:Cd data.  There is no plan to 
stop the study early for efficacy or futility based on the interim efficacy analysis results. Thus, 
there will be no alpha level adjustment for the final analysis.  
The IA will be performed by an external independent data monitoring committee that maintains 
the blind of the sponsor TAK-062 study team, investigators, site staff, and study subjects to the 
study treatment assignment until the database has been locked and unblinded. Specific 
procedures and guidelines on blinding and unblinding and controlled dissemination of interim 
analysis results are described in the Data Access Management Plan and/or IDMC charter. 
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 
• New information or other evaluation regarding the safety or efficacy of TAK-062 that 
indicates a change in the currently known benefit-risk profile such that the benefit-risk 
balance is no longer acceptable for subjects participating in the study. 
• Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety. 
 
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𝐶𝑃= 𝛷(
𝑏
𝐼−𝑍(1−𝛼2
⁄ )
√1 −𝐼
) 
where  
 
I = information fraction at time of IA and is calculated as  
𝐼=
1
𝑁1 + 1
𝑁2
1
𝑛1 + 1
𝑛2
 
 
 𝑏= 𝑍𝐼∙√𝐼 and 𝑍𝐼 is the observed MMRM test statistic at interim analysis 
 𝑛1 = sample size in placebo arm at IA 
 𝑛2 = sample size in TAK-062 
 arm at IA 
 𝑁1 = total sample size in placebo arm at final analysis 
 𝑁2 = total sample size in TAK-062 
 arm at final analysis 
𝑍(1−𝛼2
⁄ ) = (1 −𝛼2
⁄ )
𝑡ℎ quantile of the standard normal distribution 
𝛷(∙) = cumulative probability of the standard normal distribution 
 
The level of conditional probability of Vh:Cd is determined using ANCOVA as specified for the 
secondary endpoint in this SAP based on the available Vh:Cd observations at Week 24 from the 
IA data snapshot.  The conditional probability level is determined by the lower limit of 1- sided 
confidence internal (CI) for change from baseline of VhCd from the ANCOVA results using the 
general linear model. 
 
P(effect size ≥ 0.1) ≥ 75% 
Lower Limit (LL) of 1-sided 75% CI of effect size ≥ 0.1 
P(effect size ≥ 0.1) ≥ 60% 
LL of 1-sided 60% CI of effect size ≥ 0.1 
P(effect size ≥ 0) ≥ 50% 
LL of 1-sided 50% CI of effect size ≥ 0 
P(Tx CFB ≥ 0.1) ≥ 50% 
LL of 1-sided 50% CI in Tx arm ≥ 0.1 
 
The recommended decision criteria based on the CP for CDSD GI symptom severity score and 
probability of Vh:Cd, key endpoints, after safety assessment, is shown below, however the DMC 
is empowered to make a recommendation based on the totality of data.  
The updates for efficacy considerations were incorporated into the DMC charter prior to the 
interim analysis and reflected in SAP version 3 to ensure consistency. 
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Conditional Power and Efficacy Decision Matrix 
 
 
Symptom Efficacy (difference between arms in CFB of CDSD GI severity score 
at Week 12) 
 
 
CPa ≥75% 
60%≤ CP <75% 30%≤ CP <60% 10%≤ CP <30% 
CP <10% 
Histology 
efficacy 
(difference 
between arms 
in CFB of 
Vh:Cdb at 
Week 24) 
P (effect size ≥
0.1) ≥75% 
High Probable 
Treatment Effect 
Intermediate 
Probable 
Treatment Effect 
Intermediate 
Probable 
Treatment Effect 
Intermediate 
Probable 
Treatment Effect 
Intermediate 
Probable 
Treatment Effect 
P (effect size ≥
0.1) ≥60% 
High Probable 
Treatment Effect 
Intermediate 
Probable 
Treatment Effect 
Intermediate 
Probable 
Treatment Effect 
Intermediate 
Probable 
Treatment Effect 
Low Probable 
Treatment Effect 
P (effect size ≥
0) ≥50% 
Intermediate 
Probable 
Treatment Effect 
Intermediate 
Probable 
Treatment Effect 
Intermediate 
Probable 
Treatment Effect 
Low Probable 
Treatment Effect 
Low Probable 
Treatment Effect 
P (Tx CFB ≥
0.1) ≥ 50% 
Intermediate 
Probable 
Treatment Effect 
Intermediate 
Probable 
Treatment Effect 
Intermediate 
Probable 
Treatment Effect 
Low Probable 
Treatment Effect 
Low Probable 
Treatment Effect 
None of the 
above 
Intermediate 
Probable 
Treatment Effect 
Low Probable 
Treatment Effect 
Low Probable 
Treatment Effect 
Low Probable 
Treatment Effect 
Low Probable 
Treatment Effect 
CDSD: Celiac Disease Symptom Diary; CFB: change from baseline; CP: conditional probability; P: probability of 
Vh:Cd; Tx: active treatment (TAK-062) group; Vh:Cd: villous height to crypt depth ratio 
a CP: the probability that the final primary efficacy analysis based on 12-week CDSD will be statistically 
significant given the observed CDSD. 
b Vh:Cd: Villus height to crypt depth ration. 
Note: ‘Effect size’ in Histology Efficacy decision criteria is defined as the treatment difference in change from 
baseline of Vh:Cd at week 24. 
 
The decision criteria will be used, in conjunction with the DMC review of totality of data, to 
determine whether to proceed with enrollment of adolescents based on the CP for CDSD GI 
symptom severity score and conditional probability of Vh:Cd, after ruling out significant safety 
concerns. 
If interim analysis results indicate probable treatment effect in the ‘High’ (probable treatment 
effect) or ‘Intermediate’ (probable treatment effect) treatment effect zones, and there are no 
safety concerns, the study may proceed with enrollment of cohort 2, per protocol and cohort 2 
may include enrollment of adolescents. If interim analysis results indicate probable treatment 
effect in the ‘Low’, and there are no safety concerns, the study may proceed with completion of 
cohort 1 (i.e., last subject in cohort 1 completes visit 7 [week 28]) and will reassess full cohort 1 
data before initiating cohort 2 enrollment. 
6.11 
Independent Data Monitoring Committee 
According to ICH E6 (1.25) an independent data monitoring committee (eg, Independent Data 
Monitoring Committee, Data and Safety Monitoring Committee, Monitoring Committee, Data 
Monitoring Committee) may be established by the sponsor to assess at intervals the progress of 
the study, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor 
whether to continue, modify, or stop a study. 
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The minimal description of the independent data monitoring committee should include: 
• Composition (number of members and expertise). 
• Frequency of meetings/assessments. 
• Purpose and authority. 
• Scope of data review. 
Details of the Independent Data Monitoring Committee (IDMC) will be captured in a charter 
prior to the start of the trial. 
An external IDMC is warranted given the inclusion of adolescents and the current stage of 
development. 
The primary responsibility of the IDMC is to safeguard study subjects, in particular the 
adolescent subjects, by reviewing and assessing the clinical safety data being collected during the 
performance of the study. The IDMC will review SAEs and AEs ≥Grade 3. The IDMC will also 
meet periodically throughout the study to review cumulative safety data. Based on these data 
evaluations, the IDMC will make recommendations to the sponsor to continue the study as 
planned, or to modify, temporarily suspend, or terminate the treatment group or study. The 
IDMC will be responsible for identifying issues and making recommendations regarding the 
monitoring of the subjects for safety, including the collection of additional safety data. IDMC 
will also be reviewing IA data and notifying the sponsor the recommendation to include 
adolescent group in Cohort 2. The sponsor will be responsible for notifying investigators and 
regulatory authorities of any IDMC recommendations, as appropriate.  
7.0 
REFERENCES 
2019a. PROMIS Cognitive Function Scoring Manual. 
2019b. PROMIS Fatigue Scoring Manual. 
Coeliac Disease Assessment Questionnaire (CDAC) Scoring Guide 2016 
Adelman, D. C., Murray, J., Wu, T. T., Maki, M., Green, P. H. and Kelly, C. P. 2018. Measuring 
change in small intestinal histology in patients with celiac disease. Am J Gastroenterol, 
113(3), 339-47 
Syage, J.A., et al., A Composite Morphometric Duodenal Biopsy Mucosal Scale for Celiac 
Disease Encompassing both Morphology and Inflammation. Clinical Gastroenterology and 
Hepatology, 2023 
Taavela, J., Koskinen, O., Huhtala, H., Lahdeaho, M. L., Popp, A., Laurila, K., et al. 2013. 
Validation of morphometric analyses of small-intestinal biopsy readouts in celiac disease. 
PLoS One, 8(10), e76163. 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
None. 
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9.0 
APPENDIX  
9.1 
Changes From the Previous Version of the SAP 
 
SAP v3.0 Summary of Changes Since the Last Version of the Approved SAP 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1. 
Section 1.2.4, Section 6.5.3 
Add more Exploratory/Additional 
Endpoints 
 
2. 
Section 1.3 
Strategy for Intercurrent event 
was updated 
 
3. 
Section 6.5.1.4 
Added additional sensitivity 
analysis 
 
4. 
 Section 6.10 
Decision criteria were updated 
and details were added for 
determining the conditional 
probability for Vh:Cd 
Clarification 
 
9.2 
Data Handling Conventions  
9.2.1 
General Data Reporting Conventions  
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. CIs 
intervals will be presented using the same number of decimal places as the parameter estimate. 
9.2.2 
Definition of Baseline  
Day 1 is defined as the date of the first dose of study drug, as recorded on the electronic case 
report form (eCRF). Other study days are defined relative to Study Day 1, unless stated 
otherwise. Study days prior to the first dose of study drug will be calculated as: [date of interest – 
date of first dose of study drug]. Study days on or after the first dose of study drug will be 
calculated as: [date of interest – date of first dose of study drug + 1]. 
In general, baseline is defined as the last non-missing measurement prior to the first dose of 
study drug or, for participants who are randomized but not dosed, the randomization date, unless 
stated otherwise. 
9.2.3 
Definition of Visit Windows  
Subjects do not always adhere strictly to the visit timing stated in the protocol. Therefore, the 
designation of visits will be based on the day of evaluation relative to the start of study drug 
rather than the nominal visit recorded in the data. Accordingly, the study is divided into 
continuous, mutually exclusive analysis windows. Unless otherwise stated, all analysis will be 
based on the analysis visit. 
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For each visit, a window will be defined such that the lower and upper bounds of each window is 
generally the midpoint between 2 consecutive study visits. The visit windows and applicable 
study day ranges are presented below in Table 9.a, Table 9.b, and Table 9.c. 
If a subject has more than one measurement included within a window, the assessment closest to 
the target day will be used. In case of ties between observations located on different sides of the 
target day, the later assessment will be used. In case of ties located on the same side of the target 
day (i.e., more than one value for the same day), the mean of the values will be used. 
9.2.3.1 Study Week/Visit Windows for Efficacy Data 
The visit windows for the analysis of efficacy data are defined in Table 9.a. 
Table 9.a  Visit windows for the analysis of Primary endpoint (CDSD GI symptom severity 
score) 
Visit 
Target Day 
Day Range 
Week -8 (Visit 1) 
Day -56 
first week upon study entry 
Week -5 
Day -35 
the week before the run-in date 
Run-in start date/Week -4 
(Visit 2) 
Day -28 
min( first placebo IP date in dosing diary, max(EGD date, V2 date) ) 
Weeks 1 – 24 * 
 
Every 7 days from treatment start date (Day 1) 
*Analysis week could differ from analysis day. To derive analysis week, first derive analysis day 1 and run-in start 
date, then derive analysis week based on these days. 
Table 9.b  Visit windows for the Analysis of PRO data  
Visit 
Target Day 
Day Range 
PGIS 
Other PRO questionnaires a 
Week -8 (Visit 1) 
Day -56 
≤ -43 
≤ -43 
Week -4 (Visit 2) 
Day -28 
-42 – -3 
-42 – -3 
Week 0 (Visit 3) 
Day 1 
-2 – 1 
-2 – 1 
Week 3 (Visit 4) 
Day 21 
2 – 40 
 
Week 12 (Visit 5) 
Day 84 
41 – 127 
2 – 127 
Week 24 (Visit 6) 
Day 168 
128 – 182 
128 – 182 
Week 28 (Visit 7) 
Day 196 
≥183 
≥183 
a The windows will be applied to following questionnaires: EQ-5D-5L, CeD Most Bothersome Symptom, PROMIS-Fatigue 
Instrument, CeD-GSRS, PROMIS–Cognitive Function Instrument, WPAI:SHP–CeD, SF-12, ICDSQ, CDAQ, CD-QOL, PGIC. 
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Note: Subjects terminated early, their assessment (if recorded as ET) may be assigned to appropriate weeks according to above 
windows. 
9.2.3.2 Visit Windows for the Analysis of Safety Data 
In the safety data summary, the treatment period ‘End of Treatment Visit’ values will be defined 
irrespective of falling in a particular window. Hence, the windowed Week 24 value may be 
different than the End of Treatment Visit value. 
Table 9.c  Visit Windows for the Analysis of Safety Data 
Visit 
Target Day 
Day Range 
Vital Sign, ECG, EGD 
Hematology, Chemistry, 
Urinalysis, hCG, 
Urine sample for GIP 
Celiac serologies, 
 
Baseline 
Day 1 
≤1 
≤ 1 
≤ 1 
Week 3 (Visit 4) 
Day 21 
 
2 – 40 
 
Week 12 (Visit 5) 
Day 84 
 
41 – 126 
2 – 126 
Week 24 (Visit 6) 
Day 168 
≥2 
127 – 182 
≥127 
Week 28 (Visit 7) 
Day 196 
 
≥183 
 
(a) For some assessments, baseline is collected on Study Day 1 before study drug administration.  
Note: Subjects terminated early, their assessment (if recorded as ET) will be assigned to appropriate weeks according to above 
windows. 
9.2.4 
Conventions for Missing Adverse Event Dates  
Every effort will be made to determine the actual onset date for the event or to obtain a reliable 
estimate for the onset date from the investigator. 
For AEs or SAEs, a missing or incomplete onset date will be imputed according to the following 
conventions: 
1. If an onset date is missing, the derived onset date will be calculated as the first non-
missing valid date from the following list (in order of precedence): 
• First study medication date. 
• Consent date (for SAEs only). 
2. If an onset date is incomplete, the derived onset date will be calculated according to the 
following: 
• Missing day, but month and year present: the day will be imputed as the 1st of the 
month. If the first study drug dose occurs in the same month and year but after the 
imputed date, the derived onset date will be set equal to the first study drug date.  
• Missing day and month, but year present: the day and month will be imputed as the 
30th June of the year. If the first study drug dose occurs in the same year but after the 
imputed date, the derived onset date will be set equal to the first study drug date. If 
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the EOS date occurs in the same year but before the imputed date, the derived onset 
date will be set equal to the first study drug date.  
For AEs or SAEs, a missing or incomplete end date will be imputed according to the following 
conventions: 
1. If an end date is missing, the derived end date will be imputed as the last assessment date, 
assuming that the last assessment occurs after the AE start. If the last assessment occurs 
prior to the AE start date, the derived end date will be imputed as the AE start date. 
2. If an end date is incomplete, the derived end date will be calculated according to the 
following: 
• Missing day, but month and year present: the day will be imputed as the last date (for 
example February 2009 will be imputed as 28 February 2009) of the month. 
• Missing day and month, but year present: the day and month will be imputed as the 
31st December of the year.  
• If the imputed AE end date occurs after the database lock date, the imputed AE end 
date will be imputed as the database lock date. 
9.2.5 
Conventions for Missing Concomitant Medication Dates  
Start and stop dates for medication history and concomitant medications are collected on the 
eCRF. Definitions of medication history and concomitant medications are defined in Section 6.4. 
In case of missing or partial dates for concomitant medications, or medication history, the 
following rules will be used: 
If the start date is partial or unknown: 
1. If the day is missing, the start day will be the first day of the month. 
2. If the month is missing: 
• If the year is the same as the year of first dose of study drug, the start month will be 
the month corresponding to 90 days prior to the date of first dose of study drug with 
exception that the month of first dose is Jan, Feb, or Mar.  
• If the year is the same as the year of first dose of study drug and the month of first 
dose is Jan, Feb, or Mar, the start month will be Jan. 
• If the year is not the same as the year of first dose of study drug, the start month will 
be Jan. 
3. If the entire date is unknown (e.g., the year is missing): 
• If eCRF indicates that the medication ended prior to the informed consent date, then 
the medication start date will be imputed to the informed consent date minus one day. 
• Otherwise, the start date will be minimum of the date of first dose of study drug and 
the medication end date. 
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If the stop date is partial, unknown or “ongoing”: 
1. If the day is missing, the stop day will be the last day of the month reported. 
2. If the month is missing:  
• If the year is the same as the year of last assessment, then the stop month will be to 
the month during which the last assessment occurred. 
• If the year is not the same as the year of the last assessment, then the end month will 
be Dec. 
3. If the entire date is unknown (e.g. the year is missing) or if the medication is “ongoing”, 
the stop year will be the year in which the last assessment occurred. If information 
collected on the eCRF indicates that the medication ended prior to the informed consent 
date, then the medication stop date will be imputed as the informed consent date minus 
one day. 
If both start date and end date are imputed and the imputed start date is greater than the imputed 
end date, then the imputed start date will be set to the imputed end date. 
No dates will be imputed for previous medications. 
9.3 
Criteria for Markedly Abnormal Values 
Table 9.d  Criteria for Markedly Abnormal Values for Laboratory Parameters 
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– 
Parameter 
– 
Unit 
– 
 
– 
Lower 
Criteria 
– 
Upper 
Criteria 
– 
Prolactin 
– 
 
– 
 
– 
- 
– 
>5 x ULN 
– 
Albumin 
– 
g/L 
– 
 
– 
<20  
– 
- 
– 
Total protein 
– 
 
– 
 
– 
<0.8 x LLN 
– 
>1.2 x 
ULN 
– 
Creatinine 
– 
 
– 
 
– 
- 
– 
>1.5 x 
ULN 
– 
Blood urea nitrogen 
– 
 
– 
 
– 
- 
– 
>3 x ULN 
– 
Creatine kinase 
(CPK) 
– 
 
– 
 
– 
- 
– 
>5 x ULN 
– 
Potassium 
– 
mmol/L 
– 
 
– 
<3.0  
– 
>5.5 
– 
Sodium 
– 
mmol/L 
– 
 
– 
<130 
– 
>155 
– 
Calcium 
– 
mmol/L 
– 
 
– 
<2.0 
– 
>2.9 
– 
Chloride 
– 
 
– 
 
– 
<0.8 x LLN 
– 
>1.2 x 
ULN 
– 
Magnesium 
– 
mmol/L 
– 
 
– 
<0.4 
– 
>1.23 
– 
Phosphate 
– 
mmol/L 
– 
 
– 
<0.6 
– 
 
– 
Total cholesterol 
– 
mmol/L 
– 
 
– 
- 
– 
>10.34 
– 
Triglycerides 
– 
mmol/L 
– 
 
– 
- 
– 
>5.7 
– 
High-density 
lipoprotein 
cholesterol  
– 
 
– 
 
– 
<LLN 
– 
- 
– 
Low-density 
lipoprotein 
cholesterol   
– 
 
– 
 
– 
- 
– 
>ULN 
– 
Glucose 
– 
mmol/L 
– 
 
– 
<2.2 
– 
>13.9 
– 
Uric Acid 
– 
 
– 
 
– 
- 
– 
>1.2 x 
ULN 
– 
ALT 
– 
 
– 
 
– 
- 
– 
> 3 x ULN 
– 
AST 
– 
 
– 
 
– 
- 
– 
> 3 x ULN 
– 
Total Bilirubin 
– 
 
– 
 
– 
- 
– 
>2 x ULN 
– 
GGT 
– 
 
– 
 
– 
- 
– 
>2.5 x 
ULN 
– 
Alkaline 
Phosphatase 
– 
 
– 
 
– 
- 
– 
>2.5 x 
ULN 
– 
Direct bilirubin 
– 
 
– 
 
– 
- 
– 
>1.5 x 
ULN 
– 
HbA1c 
– 
 
– 
 
– 
- 
– 
>1.2 x 
ULN 
– 
Red blood cells 
– 
 
– 
 
– 
<0.8 x LLN 
– 
>1.2 x 
ULN 
– 
White blood cells 
– 
x 10^9/L 
– 
 
– 
<2.0  
– 
>100 
– 
Neutrophils 
– 
x 10^9/L 
– 
 
– 
<1.0 
– 
- 
– 
Lymphocytes 
– 
x 10^9/L 
– 
 
– 
< 0.5 
– 
> 20 
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– 
Hemoglobin 
– 
g/L 
– 
 
– 
<80 
– 
>40 above 
ULN 
– 
Hematocrit 
– 
 
– 
 
– 
<0.8 x LLN 
– 
>1.2 x 
ULN 
– 
Platelets 
– 
x 10^9/L 
– 
 
– 
<75.0 
– 
>600 
– 
Mean corpuscular 
hemoglobin 
– 
 
– 
 
– 
<0.8 x LLN 
– 
>1.2 x 
ULN 
– 
PT 
– 
 
– 
 
– 
- 
– 
>2.5 x 
ULN 
– 
INR 
– 
 
– 
 
– 
- 
– 
>2.5 x 
ULN 
 
Table 9.e  Criteria for Markedly Abnormal Values for Vital Signs Parameters 
– 
Parameter 
– 
Unit 
– 
Lower Criteria  
– 
Upper Criteria 
– 
Heart Rate 
– 
bpm 
– 
<50 or decrease from 
baseline >20 
– 
>120 or increase from 
baseline of >20 
– 
Systolic 
blood 
pressure 
– 
mm 
Hg 
– 
<90 or decrease from 
baseline >20 
– 
>160 or increase from 
baseline of >20 
– 
Diastolic 
blood 
pressure 
– 
mm 
Hg 
– 
<60 or decrease from 
baseline of >10 
– 
>95 or increase from 
baseline of >10 
– 
Body 
temperature 
– 
oC 
– 
<35.0 
– 
>38.3 
– 
 
– 
 
– 
 
– 
 
 
Table 9.f  Criteria for Markedly Abnormal Values for 12-Lead ECG Parameters 
– 
Parameter 
– 
Unit 
– 
Lower Criteria  
– 
Upper Criteria 
– 
Heart rate 
– 
bpm 
– 
<50 or decrease 
from baseline 
of >20 
– 
>120 or increase from 
baseline of >20 
– 
PR 
– 
msec 
– 
<120 
– 
>200 
– 
QTcF 
Interval 
– 
msec 
– 
- 
– 
[ >500 ] or 
– 
[ >30 increase from 
baseline and >450 ] 
– 
QRS 
– 
msec 
– 
<60  
– 
>120  
9.4 
Analysis Software and Sample codes 
The below software will be used in the analyses:  
SAS® Version 9.4, or higher. 
MMRM Sample codes: 
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proc mixed  /* select derived data set (all related weeks) */ ; 
class trt subjid week strata; 
model chg = trt week strata trt*week baseline/ddfm=kenwardroger; 
repeated week / subject=subjid type=UN; 
random intercept / subject=subjid type=un; 
lsmeans trt trt*week /cl diff ; 
run; 
 
ANCOVA Sample codes: 
proc glm /* select derived data set  */ ; 
class trt strata; 
model chg = trt strata base/alpha=.05;  
lsmeans trt/stderr pdiff diff; 
run; 
 
Multiple Imputation Sample codes: 
1. For primary endpoint 
proc mi data=cdsdwk_t out=imputed seed=128 nimpute=1000 
 minimum= . . . . 0 0 0 0 0 0 0 0 0 0 0 0 0  
 maximum= . . . . 4 4 4 4 4 4 4 4 4 4 4 4 4/* double check the range 0-4*/; 
 class trt strat1 strat2 strat3; 
 var  strat1 strat2 strat3 week0 week1 week2 week3 week4 week5 week6 week7 week8 week9 
week10 week11 week12; 
fcs reg (week0= strat1 strat2 strat3); 
 fcs reg (week1= strat1 strat2 strat3 week0); 
 fcs reg (week2= strat1 strat2 strat3 week0 week1); 
 fcs reg (week3= strat1 strat2 strat3 week0 week1 week2); 
 fcs reg (week4= strat1 strat2 strat3 week0 week1 week2 week3); 
 fcs reg (week5= strat1 strat2 strat3 week0 week1 week2 week3 week4); 
 fcs reg (week6= strat1 strat2 strat3 week0 week1 week2 week3 week4 week5); 
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 fcs reg (week7= strat1 strat2 strat3 week0 week1 week2 week3 week4 week5 week6); 
 fcs reg (week8= strat1 strat2 strat3 week0 week1 week2 week3 week4 week5 week6 week7); 
 fcs reg (week9= strat1 strat2 strat3 week0 week1 week2 week3 week4 week5 week6 week7 
week8); 
 fcs reg (week10= strat1 strat2 strat3 week0 week1 week2 week3 week4 week5 week6 week7 
week8 week9); 
 fcs reg (week11= strat1 strat2 strat3 week0 week1 week2 week3 week4 week5 week6 week7 
week8 week9 week10); 
 fcs reg (week12= strat1 strat2 strat3 week0 week1 week2 week3 week4 week5 week6 week7 
week8 week9 week10 week11); 
 mnar model(week0 week1 week2 week3 week4 week5 week6 week7 week8 week9 week10 
week11 week12/ modelobs= (trt='1')); 
run;  
 
proc mixed data=final_imp(where=(avisitn=12)); 
by _imputation_; 
 class trt(ref='1') strat1 strat2 strat3; 
 model chg = trt strat1 strat2 strat3 base/ddfm=kenwardroger solution; 
 lsmeans trt /pdiff cl; 
 ods output lsmeans=lsmeans diffs=diffs; 
run; 
 
proc sort data=lsmeans; 
by trt _imputation_ ; 
run; 
proc mianalyze parms=lsmeans; 
modeleffects trt; 
ods output ParameterEstimates=lsm; 
by trt; 
run; 
 
proc sort data=diffs; 
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by _imputation_; 
run; 
proc mianalyze parms=diffs; 
modeleffects trt; 
ods output ParameterEstimates=dif; 
run; 
2. For secondary endpoint 
proc mi data=vhcd_t out=imputed seed=128 nimpute=1000 
 min = . . .. . 0 0 ; 
class trt strat1 strat2 strat3 sex; 
 var  trt strat1 strat2 strat3 sex week0 week24 ; 
 fcs reg (week0= trt strat1 strat2 strat3  sex /details);/* if there is no missing for baseline, it will 
be ignored*/ 
 fcs reg (week24= trt strat1 strat2 strat3 sex week0 /details); 
run; 
 
proc mixed data=final_imp(where=(avisitn=24)); 
by _imputation_; 
 class trt(ref='1') strat1 strat2 strat3; 
 model chg = trt strat1 strat2 strat3 base/ddfm=kenwardroger solution; 
 lsmeans trt /pdiff cl; 
 ods output lsmeans=lsmeans diffs=diffs; 
run; 
 
proc sort data=lsmeans;by trt _imputation_ ;run; 
proc mianalyze parms=lsmeans; 
modeleffects trt; 
ods output ParameterEstimates=lsm; 
by trt; 
run; 
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proc sort data=diffs; 
by _imputation_; 
run; 
proc mianalyze parms=diffs; 
modeleffects trt; 
ods output ParameterEstimates=dif; 
run; 
 
For non-commercial use only


Signature Page for TAK-062-2001_SAP_v4.0_03 Dec 2024_Final
Title: TAK-062-2001 SAP V4.0 03DEC2024
Document Number: TDN-000477385 v1.0
Approval
Statistics
04-Dec-2024 02:24:58 GMT+0000
Approval
Statistics
04-Dec-2024 03:32:59 GMT+0000
For non-commercial use only