Clinical trial NCT02038920
Conditions: Crohn's Disease
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2014-01-28; Completion date: 2019-05-21
Enrollment: 157 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study to examine the efficacy, safety, and pharmacokinetics of vedolizumab (MLN0002) in induction and maintenance therapy in Japanese participants with moderately or severely active Crohn's disease.

Detailed description:
This is a phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study to examine the efficacy, safety, and pharmacokinetics of intravenous vedolizumab (300 mg) infusion in induction and maintenance therapy in Japanese participants with moderately or severely active Crohn's disease.

Arms: arm 1: Vedolizumab 300 mg, intravenous (IV) infusion, once at Weeks 0, 2 and 6 in the induction phase. arm 2: Vedolizumab placebo-matching IV infusion once at Weeks 0, 2 and 6 in the induction phase. arm 3: Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab in induction phase and achieved Crohn's Disease Activity Index (CDAI)-70 response at Week 10 and were randomized to receive vedolizumab in maintenance phase. arm 4: Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab in induction phase and achieved CDAI-70 response at Week 10 and were randomized to receive placebo in maintenance phase. arm 5: Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab placebo-matching in induction phase and achieved CDAI-70 response at Week 10 received placebo in maintenance phase without randomization. arm 6: Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 and then every 8 weeks thereafter up to Week 94 as a maximum duration in open-label phase.
Interventions: intervention 1: Vedolizumab intervention 2: Vedolizumab placebo
Intervention descriptions: intervention 1: Vedolizumab IV injection intervention 2: Vedolizumab placebo-matching IV infusion

Protocol documents:
Prot_000.pdf: 
 
 
Title: 
Phase 
3, 
multicenter, 
randomized, 
double-blinded, 
placebo-controlled, 
parallel-group study to evaluate the efficacy, safety, and pharmacokinetics of 
intravenous MLN0002 (300 mg) infusion in induction and maintenance therapy in 
Japanese subjects with moderate or severe Crohn's disease 
 
NCT Number: NCT02038920 
Protocol Approve Date: 11-Nov-2013 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 


1.0 TITLE PAGE 
 
TAKEDA PHARMACEUTICALS 
PROTOCOL 
 
<Title> 
Phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study 
to evaluate the efficacy, safety, and pharmacokinetics of intravenous MLN0002 (300 mg) 
infusion in induction and maintenance therapy in Japanese subjects with moderate or 
severe Crohn's disease 
<Short Title> 
Phase 3 study of MLN0002 (300 mg) in treatment of Crohn's disease 
 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka 
Study Number: 
MLN0002/CCT-001 
Version Number: 
Initial version 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
Vedolizumab 
Date: 
November 11, 2013 
 
 
 
 
 
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. 


MLN0002 
 
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CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
See the Annex. 


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CONFIDENTIAL 
1.2 
Principles of Clinical Studies 
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 E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 


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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES ........................................................................................................................ 2 
1.1 
Contacts and Responsibilities of Study-Related Activities .......................................... 2 
1.2 
Principles of Clinical Studies ..................................................................................... 3 
2.0 
STUDY SUMMARY .................................................................................................... 10 
3.0 
LIST OF ABBREVIATIONS ........................................................................................ 15 
3.1 
Definitions in the Study ........................................................................................... 16 
4.0 
INTRODUCTION ......................................................................................................... 17 
4.1 
Background ............................................................................................................. 17 
4.2 
Outcome of Clinical Studies .................................................................................... 17 
4.2.1 
Summary of Outcome of Phase 1 and 2 Studies Outside Japan ........................... 18 
4.2.2 
Summary of Outcome of Phase 3 Studies Outside Japan .................................... 18 
4.2.3 
Summary of Outcome of Phase 1 Study in Japan ................................................ 19 
4.3 
Rationale for the Proposed Study ............................................................................. 19 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 20 
5.1 
Objectives ................................................................................................................ 20 
5.1.1 
Primary Objective for the Induction Phase ......................................................... 20 
5.1.2 
Secondary Objective for the Induction Phase...................................................... 20 
5.1.3 
Primary Objective for the Maintenance Phase .................................................... 20 
5.1.4 
Secondary Objective for the Maintenance Phase ................................................ 20 
5.2 
Endpoints................................................................................................................. 20 
5.2.1 
Efficacy Endpoints for the Induction Phase ........................................................ 20 
5.2.1.1 
Primary Endpoint..................................................................................... 20 
5.2.1.2 
Secondary Endpoints ............................................................................... 20 
5.2.1.3 
Exploratory Endpoints ............................................................................. 20 
5.2.2 
Efficacy Endpoints for the Maintenance Phase ................................................... 21 
5.2.2.1 
Primary Endpoint..................................................................................... 21 
5.2.2.2 
Secondary Endpoints ............................................................................... 21 
5.2.2.3 
Exploratory Endpoints ............................................................................. 21 
5.2.3 
Pharmacokinetic Endpoint ................................................................................. 21 
5.2.4 
Safety Endpoints ................................................................................................ 21 
5.2.5 
Immunogenicity Endpoint .................................................................................. 22 
6.0 
STUDY DESIGN AND DESCRIPTION ....................................................................... 23 
6.1 
Study Design ........................................................................................................... 23 


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CONFIDENTIAL 
6.2 
Justification for Study Design, Dose, and Endpoints ................................................ 25 
6.2.1 
Justification for Study Population ....................................................................... 25 
6.2.2 
Justification of Study Design and Sample Size ................................................... 26 
6.2.3 
Justification of the Placebo Group ...................................................................... 26 
6.2.4 
Justification of the Dosage and the Evaluation Period ........................................ 26 
6.2.5 
Justification of Endpoints ................................................................................... 27 
6.3 
Premature Termination or Suspension of Study or Investigational site ..................... 27 
6.3.1 
Criteria for Premature Termination or Suspension of the Study .......................... 27 
6.3.2 
Criteria for Premature Termination or Suspension of Investigational Sites ......... 28 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) ................................................................ 28 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS .............. 29 
7.1 
Inclusion Criteria ..................................................................................................... 29 
7.2 
Exclusion Criteria .................................................................................................... 30 
7.3 
Excluded Medications and Treatments ..................................................................... 33 
7.3.1 
Rescue Treatments ............................................................................................. 35 
7.3.2 
Dose Reduction Schedule of Corticosteroids ...................................................... 35 
7.4 
Subject Management ................................................................................................ 36 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject ........................................... 37 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject...................................... 38 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT ..................................................... 39 
8.1 
Study Medication and Materials ............................................................................... 39 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ..................................... 39 
8.1.1.1 
Study Drug .............................................................................................. 39 
8.1.1.2 
Materials ................................................................................................. 40 
8.1.2 
Storage ............................................................................................................... 41 
8.1.3 
Dose and Regimen ............................................................................................. 41 
8.1.4 
Overdose ............................................................................................................ 41 
8.2 
Procedures for Allocation, Prescription and Infusion of Study Drugs ....................... 42 
8.3 
Preparation and Retention of the Allocation Table ................................................... 42 
8.4 
Preservation of Blindness ......................................................................................... 42 
8.5 
Procedures for Blind-Breaking ................................................................................. 42 
8.6 
Control and Disposal of Sponsor-Supplied Drugs .................................................... 43 
9.0 
STUDY PLAN .............................................................................................................. 44 
9.1 
Study Procedures ..................................................................................................... 44 


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CONFIDENTIAL 
9.1.1 
Informed Consent Procedure .............................................................................. 44 
9.1.2 
Demographics, Medical History, and Medication History Procedure .................. 44 
9.1.3 
Physical Examination Procedure ........................................................................ 45 
9.1.4 
Weight, Height and BMI .................................................................................... 45 
9.1.5 
Vital Sign Procedure .......................................................................................... 45 
9.1.6 
Documentation of Concomitant Medications and Non-drug Therapy.................. 46 
9.1.7 
Documentation of Concurrent Medical Conditions ............................................. 46 
9.1.8 
The Patient Diary ............................................................................................... 46 
9.1.9 
CDAI Score ....................................................................................................... 47 
9.1.9.1 
Calculation of Hematocrit (Ht) level scores ............................................. 48 
9.1.10 Inflammatory Bowel Disease Questionnaire (IBDQ) .......................................... 48 
9.1.11 Laboratory Test .................................................................................................. 48 
9.1.12 Contraception and Pregnancy Avoidance Procedure ........................................... 50 
9.1.13 Pregnancy .......................................................................................................... 50 
9.1.14 ECG Procedure .................................................................................................. 51 
9.1.15 PML Evaluation ................................................................................................. 51 
9.1.16 Tuberculosis test ................................................................................................ 51 
9.1.17 Chest Imaging Procedure ................................................................................... 51 
9.1.18 Pharmacogenomic Sample Collection ................................................................ 51 
9.1.19 Pharmacokinetic Sample Collection and Analysis .............................................. 52 
9.1.20 Sample Collection for the HAHA/Neutralizing Antibody Test ........................... 52 
9.1.21 Record of Subjects Who Withdrew during the Screening Phase ......................... 52 
9.1.22 Enrollment into the induction Phase ................................................................... 53 
9.1.23 Registration of the Results of the Primary Efficacy Endpoint in the Induction 
Phase/Enrollment into the Maintenance Phase .................................................... 53 
9.1.24 Enrollment into the Open-label Cohort ............................................................... 53 
9.2 
Study Drug Compliance ........................................................................................... 54 
9.3 
Schedule of Observations and Procedures ................................................................ 54 
9.3.1 
The Screening Phase (Visit 1) ............................................................................ 54 
9.3.2 
Induction Phase .................................................................................................. 55 
9.3.2.1 
Baseline Evaluation/Enrollment into the induction Phase (Visit 2) ........... 55 
9.3.2.2 
Administration in the Induction Phase (Visits 3 and 4) ............................. 56 
9.3.2.3 
Evaluation of Primary Efficacy Endpoint (Visit 5)/Withdrawal during the 
Induction Phase ....................................................................................... 56 
9.3.3 
Maintenance Phase ............................................................................................. 57 


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CONFIDENTIAL 
9.3.3.1 
Enrollment into the maintenance Phase (Visit 6) ...................................... 57 
9.3.3.2 
Administration in the Maintenance Phase (Visits 7 through 17) ............... 57 
9.3.3.3 
Evaluation of Primary Efficacy Endpoint in the Maintenance Phase 
(Visit 18)/Withdrawal during the Maintenance Phase .............................. 58 
9.3.4 
Open-label Cohort .............................................................................................. 58 
9.3.4.1 
Enrollment into the open-label cohort (Visit 1x) ...................................... 58 
9.3.4.2 
Administration in the Open-label Cohort (Visits 2x through 24x) ............ 59 
9.3.4.3 
The Final Evaluation of the Open-label Cohort (VIST 25x)/Withdrawal 
during the Open-label Cohort ................................................................... 59 
9.3.5 
The Unscheduled Visits ..................................................................................... 60 
9.3.6 
Predefined Study Completion ............................................................................. 60 
9.3.7 
At 16 weeks after the Last Dose ......................................................................... 60 
9.3.8 
Post Study Care .................................................................................................. 61 
9.4 
Retention and Disposal of Biological Samples ......................................................... 61 
9.5 
Follow-Up Survey ................................................................................................... 61 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................ 63 
10.1 
Definitions ............................................................................................................... 63 
10.1.1 PTEs .................................................................................................................. 63 
10.1.2 AEs .................................................................................................................... 63 
10.1.3 Additional Points to Consider for PTEs and AEs ................................................ 63 
10.1.4 SAEs .................................................................................................................. 65 
10.1.5 Intensity of PTEs and AEs ................................................................................. 66 
10.1.6 Causality of AEs ................................................................................................ 66 
10.1.7 Relationship to Study Procedures ....................................................................... 66 
10.1.8 Start Dates ......................................................................................................... 67 
10.1.9 Stop Date ........................................................................................................... 67 
10.1.10 
Frequency .................................................................................................... 67 
10.1.11 
Action Concerning Study Drug .................................................................... 67 
10.1.12 
Outcome....................................................................................................... 68 
10.2 
Procedures ............................................................................................................... 68 
10.2.1 Collection and Reporting of AEs ........................................................................ 68 
10.2.1.1 PTE and AE Collection Period ................................................................. 68 
10.2.1.2 PTE and AE Reporting ............................................................................ 69 
10.2.2 Collection and Reporting of SAEs ...................................................................... 69 


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CONFIDENTIAL 
10.2.3 Drug-induced Liver Function Test Abnormal Possibly Leading to Sever Liver 
Disorder ............................................................................................................. 70 
10.3 
Follow-up of SAEs .................................................................................................. 70 
10.3.1 SAE Reports to Investigators, the IRBs and Regulatory Authorities ................... 70 
11.0 
STUDY-SPECIFIC COMMITTEES ............................................................................. 71 
11.1 
Independent Adjudication Committee for PML ........................................................ 71 
12.0 
DATA HANDLING AND RECORDKEEPING ............................................................ 72 
12.1 
CRFs (Electronic and Paper) .................................................................................... 72 
12.2 
Record Retention ..................................................................................................... 73 
13.0 
STATISTICAL METHODS .......................................................................................... 74 
13.1 
Statistical and Analytical Plans ................................................................................ 74 
13.1.1 Analysis Sets...................................................................................................... 74 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ........................... 75 
13.1.3 Efficacy Analysis ............................................................................................... 75 
13.1.4 Pharmacokinetic Analysis .................................................................................. 77 
13.1.5 Safety Analysis .................................................................................................. 78 
13.1.6 Analysis of Immunogenicity Endpoints .............................................................. 79 
13.2 
Interim Analysis and Criteria for Early Termination ................................................ 80 
13.3 
Determination of Sample Size .................................................................................. 80 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE............................................... 81 
14.1 
Study-Site Monitoring Visits ................................................................................... 81 
14.2 
Protocol Deviations.................................................................................................. 81 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................ 81 
15.0 
ETHICAL ASPECTS OF THE STUDY ........................................................................ 82 
15.1 
IRB Approval .......................................................................................................... 82 
15.2 
Subject Information, Informed Consent, and Subject Authorization ......................... 82 
15.3 
Subject Confidentiality ............................................................................................ 84 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ................................. 84 
15.4.1 Publication and Disclosure ................................................................................. 84 
15.4.2 Clinical Trial Registration .................................................................................. 84 
15.4.3 Clinical Trial Results Disclosure ........................................................................ 85 
15.5 
Insurance and Compensation for Injury .................................................................... 85 
16.0 
REFERENCES .............................................................................................................. 86 
 


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CONFIDENTIAL 
LIST OF IN-TEXT TABLES 
Table 7.a 
List of Excluded Drugs and Treatments .............................................................. 33 
Table 8.a 
Study drug ......................................................................................................... 39 
Table 8.b 
Materials ............................................................................................................ 40 
Table 8.c 
Dose and Regimen ............................................................................................. 41 
Table 9.a 
CDAI Scoring System for the Assessment of CD Activity [13] .......................... 47 
Table 9.b 
Laboratory tests.................................................................................................. 49 
Table 10.a 
Takeda Medically Significant AE List ................................................................ 66 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ................................................................................ 24 
Figure 6.b 
Schematic of Enrollments, Administrations, and Visits ...................................... 25 
Figure 8.a 
Labels on Vials .................................................................................................. 39 
Figure 8.b 
A Label on Outer Packages ................................................................................ 40 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ............................................................................ 88 
Appendix B 
Responsibilities of the Investigator ..................................................................... 92 
Appendix C 
Diagnostic Criteria for CD (Revised on January 17, 2013) ................................. 93 
Appendix D 
PML Checklists ................................................................................................. 98 
Appendix E 
Follow-Up Survey Form .................................................................................. 103 
 


MLN0002 
 
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CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound: 
MLN0002 
Study title: Phase 3, multicenter, randomized, double-blinded, 
placebo-controlled, parallel-group study to evaluate the 
efficacy, safety, and pharmacokinetics of intravenous 
MLN0002 (300 mg) infusion in induction and maintenance 
therapy in Japanese subjects with moderate or severe Crohn's 
disease 
IND No.: 
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Number: MLN0002/CCT-001 
Phase :3 
Study Design: 
This is a phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study to evaluate the 
efficacy, safety, and pharmacokinetics of MLN0002 in induction and maintenance therapies in Japanese subjects with 
moderate or severe Crohn's disease (CD). This study consists of the screening, induction and maintenance phases, and 
the open-label cohort. 
The screening phase involves screening tests of consenting subjects who visit a study site between 21 and 7 days 
before the start of treatment. Subjects meeting the eligibility criteria based on the inclusion and exclusion criteria on 
the first day of treatment (Day 1) will be enrolled into the induction phase. 
Subjects enrolled into induction phase will be randomized 1:1 to the placebo or MLN0002 group to receive the 
placebo or 300 mg of MLN0002 at Weeks 0, 2, and 6 in a double-blinded manner. The primary efficacy endpoint in 
the induction phase will be evaluated at Week 10. 
Subjects showing a CDAI-70 response to the study drug at Week 10 will be enrolled into the maintenance phase at 
Week 14. Subjects who received the placebo in the induction phase will continue to receive the placebo at Weeks 14, 
22, 30, 38, 46, and 54 in a double-blinded manner. Subjects who received MLN0002 in the induction phase will be 
randomized 1:1 to the placebo or MLN0002 group, and will receive the placebo or 300 mg of MLN0002 at Weeks 14, 
22, 30, 38, 46, and 54 in a double-blinded manner. The primary efficacy endpoint in the maintenance phase will be 
evaluated at Week 60. 
Subjects not showing a CDAI-70 response to the study drug at Week 10 can be enrolled into the open-label cohort. 
Setting the enrollment day to the open-label cohort as Week 0x, those subjects will receive 300 mg of MLN0002 at 
Weeks 0x, 2x, 6x and then every 8 weeks thereafter for 46 weeks (minimum) to 94 weeks (maximum) in an unblinded 
manner. Subjects who experienced disease worsening or received rescue treatments during the maintenance phase, or 
those who completed Week 60 of the maintenance phase can be enrolled into the open-label cohort to receive the study 
drug in the same manner. Administration of MLN0002 will be terminated in all subjects at Week 46x of the last 
subject enrolled into the open-label cohort. 
The end-of-study examination will be performed at 16 weeks after the last dose in all subjects who received the study 
drug. In addition, the follow-up survey will be performed every 6 months from the last dose of the study drug up to 2 
years or until the date of marketing approval of the study drug, whichever comes earlier. 
Primary objective for the induction phase: 
To evaluate efficacy of MLN0002 in induction therapy in Japanese subjects with moderate or severe CD. 
Secondary objective for the induction phase: 
To evaluate safety of MLN0002 in induction therapy in Japanese subjects with moderate or severe CD. 
Primary objective for the maintenance phase: 
To evaluate efficacy of MLN0002 in maintenance therapy in Japanese subjects with moderate or severe CD. 
Secondary objective for the maintenance phase: 
To evaluate safety of MLN0002 in maintenance therapy in Japanese subjects with moderate or severe CD. 


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Study No. MLN0002/CCT-001 
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Initial Protocol 
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CONFIDENTIAL 
Subjects: Japanese subjects with moderate or severe CD 
Number of Subjects: 
Approximately 110 in total. 
Maximum 152 subjects. The target number of 
subjects without a history of anti-TNFα antibody 
therapy is approximately 25% of the total. 
Number of Sites: 
Approximately 60 sites 
Dose Level(s): 
MLN0002 (300 mg) or the placebo will be 
administered by intravenous infusion at Weeks 0, 
2, 6 and every 8 weeks thereafter. 
Route of Administration: 
Intravenous infusion (IV) 
Duration of Treatment: 
54 weeks (maximum 154 weeks) 
Period of Evaluation: 
70 weeks (maximum 170 weeks) 
The follow-up survey will be performed every 6 months from the 
last dose of the study drug for up to 2 years or until the date of 
marketing approval of the study drug, whichever comes earlier. 
Main Criteria for Inclusion: 
 Subjects aged 15 to 80 (inclusive) at the time of signing the informed consent. 
 Subjects with any diagnosis of the small intestine type, the large intestine type or the small/large intestine type of CD 
based on the Revised Diagnostic Criteria for CD issued by Research Group for Intractable Inflammatory Bowel 
Disease Designated as Specified Disease by the Ministry of Health, Labor and Welfare (MHLW) of Japan (2012) at 
least 3 months before start of administration of the study drug. 
 Subjects with a CDAI score of 220≤ and ≤450 points at the first dose of the study drug, and also meeting any of the 
following; 
 Subjects with a CRP level of >0.30 mg/dL at the screening test. 
 Subjects confirmed to have irregular-to-round shaped ulcers or multiple aphtha in the small or large intestine 
extensively (≥10 lesions) in the endoscopy or the imaging test within 4 month before the first dose of the study 
drug. 
 Subjects confirmed to have longitudinal ulcers or a cobblestone appearance in the small or large intestine in the 
endoscopy or the imaging test within 4 months before the first dose of the study drug. 
 Subjects whose complication of colon cancer or dysplasia had to be ruled out by total colonoscopy at the start of the 
study drug administration (or the results from total colonoscopy performed within 1 year before giving consent are 
available), if subjects met any of the followings; subjects with extensive or limited colitis of ≥8 years duration, 
subjects aged ≥50 years, or subjects with a first-degree family history of colon cancer. 
 Subjects meeting the following treatment failure criteria with at least one of the following agents within 5 year 
before signing the informed consent: 
Corticosteroids 
- Resistance 
- Dependence 
- Intolerance 
Immunomodulators [azathioprine (AZA), 6-mercaptopurine (6-MP) or methotrexate (MTX)] 
- Refractory 
- Intolerance 
Anti-TNFα antibodies 
- Inadequate response 
- Loss of response 
- Intolerance 


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CONFIDENTIAL 
Main Criteria for Exclusion: 
 Subjects who have or are suspected of having abdominal abscess. 
 Subjects with a history of subtotal or total colectomy. 
 Subjects with a history of ≥3 enterectomy , or a history of diagnosis of short bowel syndrome. 
 Subjects with ileostomy, colostomy, or internal fistula or severe intestinal stenosis. 
 Subjects who started an oral 5-aminosalicylic acid (5-ASA), probiotics treatment, an antibiotic for CD treatment, or 
an oral corticosteroid of ≤30 mg/day within 13 days before the first dose of the study drug. Subjects who have used 
these drugs for at least 14 days before the first dose of the study drug, and who changed dosage of or discontinued 
these drugs within 13 days before the first dose of the study drug. 
 Subjects who have received 5-ASAs, corticosteroid enemas/suppositories, corticosteroid IV infusion, oral 
corticosteroid at >30 mg/day, drugs for diarrhea-predominant irritable bowel syndrome, or Chinese herbal medicine 
for the treatment of CD (e.g., Daikenchuto) within 13 days before the first dose of the study drug. 
 Subjects who have used AZA, 6-MP or MTX within 27 days before the first dose of the study drug However, this 
will not apply to subjects who have used these drugs for 83 or more days before the first dose of the study drug and 
continued the steady dose administration of the drugs for 27 or more days before the first dose of the study drug. 
 Subjects who have received cyclosporine, tacrolimus, tofacitinib or any study drugs of low-molecular compound for 
CD treatment within 27 days before the first dose of the study drug. 
 Subjects who have received adalimumab within 27 days before the first dose of the study drug or any biological 
drugs other than adalimumab within 55 days before the first dose of the study drug However, this will not apply to 
subjects who have topically received these drugs (e.g., intraocular injection for treatment of age-related macular 
degeneration). 
 Subjects who have received any live-vaccinations within 27 days before the first dose of the study drug 
 Subjects who underwent an enterectomy within 27 days before the first dose of the study drug or those anticipated to 
require an enterectomy during the study. 
 Subjects who have received leukocytapheresis or granulocyte apheresis within 27 days before the first dose of the 
study drug. 
 Subjects who received central venous nutrition therapy or enteral total nutrition therapy, or fasted within 20 days 
before the first dose of the study drug. 
 Subjects who received an enteral nutrient of >900 kcal/day or who will begin to receive an enteral nutrient of 
≤900 kcal/day within 20 days before the first dose of the study drug. Subjects who had received an enteral nutrient of 
≤900 kcal/day earlier than 21 days before the first dose of the study drug, and modified or discontinued the dosage 
within 20 days before the first dose of the study drug. 
 Subjects with an evidence of adenomatous colonic polyps that need to be removed at the start of study drug 
administration. 
 Subjects with a history or a complication of large or small intestinal dysplasia. 
Main efficacy endpoints of the induction phase: 
Primary endpoint: 
CDAI-100 response at Week 10 
Secondary endpoints: 
Clinical remission at Week 10 
Change in CRP level over time in the subpopulation of subjects with the baseline CRP level of >0.30 mg/dL 
Main efficacy endpoints of the maintenance phase: 
Primary endpoint: 
Clinical remission at Week 60 
Secondary endpoints: 
CDAI-100 response at Week 60, durable remission in the maintenance phase, and corticosteroid-free remission at 


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Week 60 
Pharmacokinetic endpoints: 
Serum MLN0002 concentration 
Safety endpoints: 
Adverse events (AEs), body weight, vital signs, electrocardiogram (ECG), clinical laboratory test (blood 
biochemistry, hematology, and urinalysis) 
Immunogenicity endpoints: 
HAHA, neutralizing antibody 
Statistical analysis plan: 
(1) Statistical analysis in the induction phase 
The following descriptive calculations will be performed in the “Full Analysis Set in the induction phase (subjects 
randomized and received the study drug at least once in the induction phase).” 
For the primary efficacy analysis, “CDAI-100 response at Week 10” (primary endpoint of the induction phase) will be 
calculated by treatment group of the induction phase. Also CDAI-100 response at Week 10 will be calculated with 
stratification according to a history of anti-TNFα antibody therapy, and the comparison between treatment groups will 
be made with the Cochran-Mantel-Haenszel (CMH) test with 2-sided significance level of 10% by using a history of 
anti-TNFα antibody therapy as a stratification factor. The results of the primary analysis of the induction phase will be 
interpreted as below to determine the efficacy of MLN0002 induction therapy. 
 
The superiority of MLN0002 over the placebo on CDAI-100 response at Week 10 in the primary analysis of the 
induction phase is demonstrated when a statistically significant difference is observed in the CDAI-100 response 
at Week 10. 
For the secondary efficacy analysis, clinical remission at Week 10 will be calculated in the same manner as those in 
the primary analysis in the induction phase. The results of the secondary analysis will be interpreted as below to 
determine the efficacy of MLN0002 induction therapy. 
 
The superiority of MLN0002 over the placebo on clinical remission at Week 10 in the primary analysis of the 
induction phase is demonstrated when a statistically significant difference is observed in both the CDAI-100 
response at Week 10 and clinical remission at Week 10. 
(2) Statistical analysis in the maintenance phase 
The following descriptive calculations will be performed in the “Full Analysis Set of the maintenance phase (subjects 
randomized and received the study drug at least once in the maintenance phase).” 
For the primary efficacy analysis, “clinical remission at Week 60” (primary endpoint of the maintenance phase)” will 
be calculated by treatment group of the maintenance phase. 
Sample size justification: 
On the basis of findings from the phase 3 double-blinded, placebo-controlled study of MLN0002 induction therapy in 
non-Japanese moderate to severe CD subjects who had failed with an anti-TNFα antibody (C13011), the CDAI-100 
response at Week 10 in MLN0002 and the placebo was estimated as 47.2% and 24.6%, respectively, clinical remission 
at Week 10 in MLN0002 and the placebo was estimated as 28.7% and 13.0%, respectively, and the CDAI-70 response 
at Week 10 in MLN0002 and the placebo was estimated as 56.9 % and 38.7%, respectively, in the study. 
When the CDAI-100 response at Week 10 in the induction phase is analyzed using Pearson's chi-square test with 
2-sided significance level of 10%, 55 subjects each (at a ratio of 1:1, total 110) will be required for the MLN0002 and 
placebo group to detect significance with a power of at least 80% for the MLN0002 and placebo group. Similarly, 76 
subjects each (total 152) will be required to detect significance with a power of at least 90%. These numbers were 
therefore selected as the numbers of evaluable subjects of the primary endpoint of the induction phase (number of 
“subjects who were randomized in the induction phase and received at least one dose of the study drugs in the 
induction phase”). When the clinical remission at Week 10 is analyzed in the same manner on the accumulated 55 to 
76 subjects to be evaluated for the primary endpoint in the induction phase, statistical significances in both the 
CDAI-100 response at Week 10 and clinical remission at Week 10 are detected with a power of 61 to 76%. 


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Number of subjects to be evaluated for the primary endpoint in the maintenance phase (number of subjects who were 
randomized and received at least one dose of the study drug in the maintenance phase) is 16 to 22 subjects in each 
group and 32 to 44 subjects in total based on the above estimation. 
 


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3.0 
LIST OF ABBREVIATIONS 
5-ASA 
5-aminosalicylic acid 
6-MP 
6-mercaptopurine 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
AZA 
Azathioprine 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CD 
Crohn’s disease 
CDAI 
Crohn’s Disease Activity Index 
CRP 
C-reactive protein 
ELISA 
Enzyme-Linked ImmunoSorbent Assay 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
γ-GTP 
γ-glutamyl transpeptidase 
HAHA 
human anti-human antibody 
HBs 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropine 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
Ht 
hematocrit 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICH 
International Conference on Harmonisation 
INR 
International normalized ratio 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MTX 
methotrexate 
PMDA 
Pharmaceutical and Medical Devices Agency 
PML 
progressive multifocal leukoencephalopathy 
SUSARs 
suspected serious unexpected adverse reactions 
TNF 
Tumor Necrosis Factor 
CD 
Ulcerative colitis 
WHO 
World Health Organization 


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3.1 
Definitions in the Study 
The definitions in the study are provided below; 
Terms 
Definitions 
Clinical remission 
CDAI score of ≤150 
CDAI-70 response 
A ≥70-point decrease in CDAI score from baseline 
CDAI-100 response 
A ≥100-point decrease in CDAI score from baseline 
Durable remission in the 
maintenance phase 
Clinical remission at ≥80% of the scheduled visits including Week 60 
Durable CDAI-100 response 
in the maintenance phase 
CDAI-100 response at ≥80% of the scheduled visits including Week 60 
Corticosteroid-free remission 
at Week 60 
Clinical remission with corticosteroid-free at Week 60, though corticosteroids were 
used at the first dose of the study drug 
Disease worsening 
In the maintenance phase, a ≥100-point increase in CDAI score from Week 10 value 
and CDAI score of ≥220 on 2 consecutive visits*, OR 
In the open-label cohort, a ≥100-point increase in CDAI score from Week 10x value 
and CDAI score of ≥220 on 2 consecutive visits* 
Sustained non-response 
CDAI-70 non-response during 20 weeks from the first dose of the study drug and 
CDAI score of ≥220 
Rescue medications 
Any new medications, increases in dose of baseline medications, or new concomitant 
therapies required for treatment for unresolved CD symptom (except abscess drainage 
or the Seton method for the anal lesion) 
Note, however, that any increases in dose or beginning use of medications permitted in 
the open-label cohort, dosed after the subject was enrolled into the open-label cohort, 
were not regarded as the rescue medications 
Treatment failure 
Disease worsening, rescue medications, or withdrawal due to study drug-related AEs 
* The 2 visits included the unscheduled visits due to CD worsening. The interval between visits was to be at least 
1 week, where possible. 


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4.0 
INTRODUCTION 
4.1 
Background 
Crohn's Disease (CD) is a granulomatous inflammatory disease most commonly found in young 
people. The disease, affecting any part of the gastrointestinal tract from the mouth throughout the 
anus, forms characteristic conditions mainly in the small and large intestine such as intestinal 
stenosis and fistula with edema and ulcers. As various complications may be induced even outside 
the gastrointestinal tract, systemic symptoms including fever, weight loss or malnutrition, or 
complication-induced symptoms including anemia, arthritis, iritis or skin lesions may emerge in 
addition to gastrointestinal symptoms including diarrhea or abdominal pain. The disease condition 
may progress with repetition of recurrence and remission, and often become resistant to treatments 
to deteriorate social activity. 
In the disease, it is believed that breakdown of the mucosal immune system by some genetic 
predisposition may lead to a exaggerated immune response against intraluminal antigens including 
enterobacteria or diet, resulting in progression and persistence of inflammation, however etiology 
is still unrevealed. A curative treatment has not been established, therefore treatment approaches 
aim to control disease activity with the remission induction therapy and the remission maintenance 
therapy in order to improve the Quality of Life (QOL). Possible treatment approaches including 
medical treatment (e.g., pharmacotherapy and nutrition therapy) and surgical treatment are 
detailed in line with the types and severities of the disease in the Revised Treatment Guideline 
(draft)[1] issued by “Research Group for Intractable Inflammatory Bowel Disease” Designated as 
Specified Disease by the MHLW of Japan. 
MLN0002 is a recombinant human immunoglobulin G1 monoclonal antibody[2] that specifically 
binds to human lymphocyte α4β7 integrin, and is currently being developed in ulcerative colitis 
(UC) and CD inside/outside Japan. 
 MLN0002 binds and inhibits α4β7 integrin, a cell membrane protein of lymphocytes, to bind its 
principal ligand of mucosal addressin cell adhesion molecule-1 (MAdCAM-1; a transmembrane 
glycoprotein markedly expressing on vascular endothelial cells in the high endothelial venule in 
the Peyer patch or the mesenteric lymph node and the arteriole in the intestinal lamina propria), 
leading to suppression of lymphocytes to migrate toward the intestinal mucosa and the gut-related 
lymphoid tissue[2]. From the above, MLN0002 is anticipated to exert efficacy with superior safety 
to conventional treatments or other biological drugs in UC and CD through suppression of 
intestinal inflammation by gastrointestinal tract-selective immunomodulatory effect not requiring 
systemic immunosuppression[3][4]. 
4.2 
Outcome of Clinical Studies 
Outside Japan, the following 4 Phase 3 studies (GEMINI Programs) were conducted in subjects 
with UC and CD in addition to the 14 Phase 1 and 2 studies. As of October, 2013, all studies were 
completed except a long-duration study in subjects with UC and CD (C13008), and applications 


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have been submitted in Europe and US. In Japan, the Phase 1 study was conducted in subjects with 
UC. 
Study Number 
Study Title 
C13006 
Phase 3, double-blinded, placebo-controlled study of induction and maintenance therapies in 
moderate to severe UC patients (GEMINI 1). 
C13007 
Phase 3, double-blinded, placebo-controlled study of induction and maintenance therapies in 
moderate to severe CD patients (GEMINI 2). 
C13011 
Phase 3, double-blinded, placebo-controlled study of induction therapy in moderate to severe CD 
patients who had failed with anti-TNFα antibodies therapy (GEMINI 3). 
C13008 
Phase 3, long-term open-label safety and efficacy study in UC or CD patients who had been 
enrolled in the Phase 2 and Phase 3 study of MLN0002. 
 
4.2.1 
Summary of Outcome of Phase 1 and 2 Studies Outside Japan 
Major outcomes in Phase 1 and 2 studies conducted outside Japan were summarized below; 
• The pharmacokinetics of MLN0002 at the doses of 2 to 10 mg/kg was linear. The elimination 
half-life of MLN0002 was 15 to 22 days[5]. 
• The α4β7 receptors were saturated after the first dose at the doses of 2 to 10 mg/kg. Saturation 
of α4β7 receptors had been dose-dependently continued for several months after the last 
dose[5]. 
• It was suggested that the human anti-human antibody to MLN0002 (anti-MLN0002 antibody; 
hereinafter referred to as HAHA) may eliminate MLN0002 from the blood, resulting in 
decrease of MLN0002 exposure and loss of saturation of α4β7 receptors. HAHA emergence 
was dose-dependently decreased. 
• MLN0002 demonstrated superiority to the placebo in all subjects as clinical remission was 
32% at Week 6 in UC and 37% at Week 8 in CD[6][7]. The frequency of AEs was not 
significantly different from that in the placebo with no particular safety issues. 
4.2.2 
Summary of Outcome of Phase 3 Studies Outside Japan 
In all 3 Phase 3 studies conducted outside Japan (C13006, C13007 and C13011), 300 mg of 
MLN0002 or the placebo were administered. In C13006 study, superiorities were demonstrated to 
the placebo in the primary endpoints, i.e., the clinical response in the induction phase and the 
clinical remission in the maintenance phase[8]. Two primary endpoints were set in the induction 
phase of C13007 study. The difference in the clinical response in CD Activity Index (CDAI)-100 
was not significant, however superiority to the placebo was demonstrated in the clinical remissions 
each in the induction phase and the maintenance phase[9]. In C13011 study, superiority to the 
placebo was not demonstrated in the primary endpoint of the clinical remission at Week 6 in the 
sub-population of subjects who had failed with anti-TNFα antibodies (75% of all population), 
however the clinical remission at Week 6 in the whole population was significantly different from 
the placebo. In addition, the significant difference from the placebo in the clinical remission at 


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Week 10 was observed both in the sub-population who had failed an anti-TNFα antibody and the 
whole population[10]. 
Furthermore, incidence of AEs and serious adverse events (SAEs) were not significantly different 
between the whole MLN0002 group and placebo group. Progressive multifocal 
leukoencephalopathy (PML) was not observed in any subjects in completed or ongoing clinical 
development programs. 
4.2.3 
Summary of Outcome of Phase 1 Study in Japan 
In Japan, the Phase 1 repeated-dose study in UC patients (CPH-001) was conducted to investigate 
safety, pharmacokinetics and pharmacodynamics of MLN0002 dosed at 150 or 300 mg in 
Weeks 0, 2 and 6. MLN0002 was well tolerated by the dose of 300 mg, and no injection site 
reaction or anaphylactic reaction was observed. In addition, serum MLN0002 concentration 
increased depending on dose ratio, and saturation of α4β7 receptors of the pharmacodynamic index 
was observed mostly continuously from the first dose[11]. 
4.3 
Rationale for the Proposed Study 
• In the 3 Phase 3 studies conducted outside Japan (C13006, C13007 and C13011), efficacy and 
safety of 300 mg of MLN0002 were investigated against the placebo each in the induction 
phase and the maintenance phase in moderate to severe UC or CD patients who had failed with 
the existing pharmacotherapy including anti-TNFα antibodies. As a result, significant 
difference from the placebo was observed in efficacy evaluation of MLN0002 in all studies. In 
addition, no particular issues were found in the safety evaluation. These results were consistent 
with the outcome obtained until Phase 2 studies. 
• In Japan, safety, serum MLN0002 concentration and saturability of α4β7 receptors were 
investigated in UC patients dosed with 150 or 300 mg of MLN0002 at Weeks 0, 2 and 6. The 
serum MLN0002 concentration resulted in similarity inside/outside Japan, and saturation of 
α4β7 receptors was observed mostly continuously from the first dose. In addition, no safety 
issues were found. 
From the above, the study was proposed as a Phase 3 study to investigate efficacy and safety of 
300 mg of MLN0002 in moderate to severe Japanese CD patients. 
Pharmacogenomic analysis may be conducted to evaluate contribution of genetic variance on drug 
response, for example, its efficacy and safety. Participation of study subjects in pharmacogenomic 
sample collection is optional. 
As pharmacogenomics is an evolving science, currently many genes and their function are not yet 
fully understood. Future data may suggest a role of some of these genes in drug response or 
diseases, which may lead to additional hypothesis-generating exploratory research on banked 
samples. 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective for the Induction Phase 
To evaluate efficacy of MLN0002 in induction therapy in Japanese subjects with moderate or 
severe CD. 
5.1.2 
Secondary Objective for the Induction Phase 
To evaluate safety of MLN0002 in induction therapy in Japanese subjects with moderate or severe 
CD. 
5.1.3 
Primary Objective for the Maintenance Phase 
To evaluate efficacy of MLN0002 in maintenance therapy in Japanese subjects with moderate or 
severe CD. 
5.1.4 
Secondary Objective for the Maintenance Phase 
To evaluate safety of MLN0002 in maintenance therapy in Japanese subjects with moderate or 
severe CD. 
5.2 
Endpoints 
5.2.1 
Efficacy Endpoints for the Induction Phase 
5.2.1.1 
Primary Endpoint 
• CDAI-100 response at Week 10 
5.2.1.2 
Secondary Endpoints 
• Clinical remission at Week 10 
• Change in CRP level over time in the subpopulation of subjects with the baseline CRP level of 
>0.30 mg/dL 
5.2.1.3 
Exploratory Endpoints 
• Clinical remission at Week 6 
• CDAI-100 response at Week 6 
• CDAI-100 response at Week 6 and Week 10, and clinical remission at Week 6 and Week 10 in 
the sub-population of subjects without a history of anti-TNFα antibody therapy and in the 
sub-population of subjects who had failed with an anti-TNFα antibody therapy 


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• CDAI-100 response at Week 6 and Week 10, and clinical remission at Week 6 and Week 10 in 
the sub-population of subjects who had failed with a corticosteroid monotherapy and an 
immunomodulator (except those failed with an anti-TNFα antibody) 
• IBDQ score change at Week 10 from baseline 
• CDAI score change over time 
5.2.2 
Efficacy Endpoints for the Maintenance Phase 
5.2.2.1 
Primary Endpoint 
• Clinical remission at Week 60 
5.2.2.2 
Secondary Endpoints 
• CDAI-100 response at Week 60 
• Durable remission in the maintenance phase 
• Corticosteroid-free remission at Week 60 
5.2.2.3 
Exploratory Endpoints 
• Clinical remission at Week 60 in the sub-population of subjects without a history of anti-TNFα 
antibody therapy and in the sub-population of subjects who had failed with an anti-TNFα 
antibody 
• IBDQ score change at Week 38 and Week 60 from Week 14 
• CDAI score change over time 
• Change in CRP level over time in the subpopulation of subjects with the baseline CRP level of 
>0.30 mg/dL 
5.2.3 
Pharmacokinetic Endpoint 
• Serum MLN0002 concentration 
5.2.4 
Safety Endpoints 
• Adverse events (AEs) 
• Body weight 
• Vital signs 
• ECG 
• Clinical laboratory test (blood biochemistry, hematology and urinalysis) 


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5.2.5 
Immunogenicity Endpoint 
• HAHA, neutralizing antibody 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-group 
study to evaluate the efficacy, safety, and pharmacokinetics of MLN0002 in induction and 
maintenance therapies in Japanese subjects with moderate or severe CD. This study consists of the 
screening, induction, maintenance phases and open-label cohort. 
The screening phase involves screening tests of consenting subjects who visit a study site between 
21 and 7 days before the start of treatment. Subjects meeting the eligibility criteria based on the 
inclusion and exclusion criteria on the first day of treatment (Day 1) will be enrolled into the 
induction phase. 
Subjects enrolled into induction phase will be randomized 1:1 to the placebo or MLN0002 group1, 
and will receive the placebo or 300 mg of MLN0002 at Weeks 0, 2, and 6 in a double-blinded 
manner. The primary efficacy evaluation in the induction phase will be performed at Week 10. 
Subjects showing a CDAI-70 response to the study drug at Week 10 will be enrolled into the 
maintenance phase at Week 14. Subjects who received the placebo in the induction phase will 
continue to receive the placebo at Weeks 14, 22, 30, 38, 46, and 54 in a double-blinded manner. 
Subjects who received MLN0002 in the induction phase will be randomized 1:1 to the placebo or 
MLN0002 group2 to receive the placebo or 300 mg of MLN0002 at Weeks 14, 22, 30, 38, 46 and 
54 in a double-blinded manner. The primary efficacy endpoint in the maintenance phase will be 
evaluated at Week 60. 
Subjects not showing a CDAI-70 response to the study drug at Week 10 can be enrolled into the 
open-label cohort. Setting the enrollment day to the open-label cohort as Week 0x, those subjects 
will receive 300 mg of MLN0002 at Weeks 0x, 2x, 6x and then every 8 weeks thereafter for 46 
weeks (minimum) to 94 weeks (maximum) in an unblinded manner. Subjects who experienced 
disease worsening or received rescue treatments during the maintenance phase, or those who 
completed Week 60 of the maintenance phase can be enrolled into the open-label cohort to receive 
the study drug in the same manner. Administration of MLN0002 will be terminated in all subjects 
at Week 46x of the last subject enrolled into the open-label cohort. 
The end-of-study examination will be performed at 16 weeks after the last dose in all subjects who 
received the study drug. In addition, the follow-up survey will be performed every 6 months from 
the last dose of the study drug up to 2 years or until the date of marketing approval of the study 
drug, whichever comes earlier (see Section 9.5). 
Planned sample size is approximately 110 subjects in total and 152 subjects at maximum. In the 
situation, the number of subjects to be randomized in the induction phase is 55 to 76 in the 
                                               
1The dynamic allocation with the treatment history with anti-TNFα antibodies, concomitant use of an 
immunomodulator or corticosteroid, and the study sites. 
2The dynamic allocation with the treatment history with anti-TNFα antibodies, concomitant use of an 
immunomodulator or a corticosteroid, the study sites, and responder/non-responder at Week 10. 


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MLN0002 group and 55 to 76 in the placebo group. The target number of subjects without a 
history of anti-TNFα antibody therapy is approximately 25% of the total. 
A schematic of the study design and a schematic of enrollments, administrations and visits are 
shown in Figure 6.a and Figure 6.b, respectively. A schedule of assessments is listed in Appendix 
A. 
Figure 6.a 
Schematic of Study Design 
 
 


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Figure 6.b 
Schematic of Enrollments, Administrations, and Visits 
 
W: Week, V: Visit 
a) 
CDAI-70 responders at Week 10 (evaluation of the primary efficacy endpoints in the induction phase) will be 
enrolled into the maintenance phase at Week 14. Non-CDAI-70 responders at Week 10 may be enrolled into the 
open-label cohort after completion of the Week 10 evaluation. 
b) 
Subjects who experienced disease worsening or received rescue treatments during the maintenance phase may be 
enrolled into the open-label cohort after completion of the evaluation at withdrawal of the maintenance phase. 
However, these subjects will be enrolled into the open-label cohort 3 to 9 weeks after the last dose in the 
maintenance phase. 
c) 
Subjects who completed Week 60 (evaluation of the primary efficacy endpoint in the maintenance phase) may be 
enrolled into the open-label cohort after completion of the Week 60 evaluation. 
6.2 
Justification for Study Design, Dose, and Endpoints 
6.2.1 
Justification for Study Population 
The Guideline for Treatment of CD[1] issued by “Research Group for Intractable Inflammatory 
Bowel Disease Designated as Specified Disease” by the MHLW of Japan (2012) recommends 
5-ASAs as the first line drug in the remission induction therapy in mild to moderate CD patients, 
and also recommends combination with the nutrition therapy in acceptable patients. Also, in 
moderate to severe patients, oral corticosteroids, antibiotics and immunomodulators are 
recommended in addition to the above treatments. Furthermore, anti-TNFα antibodies are 
recommended to non-responders to the remission induction therapy with corticosteroids or the 
nutrition therapy. However, poor response to anti-TNFα antibodies or loss of response during 
treatment with anti-TNFα antibodies are still problematic. MLN0002, having a different mode of 
action from existing therapeutic drugs, has been suggested to be efficacious in such patients by 
outcome from studies outside Japan. 
24M after 
the last 
dose
18M after 
the last 
dose
12M after 
the last 
dose
6M after 
the last 
dose
Follow-up survey
24M after 
the last 
dose
18M after 
the last 
dose
12M after 
the last 
dose
6M after 
the last 
dose
Follow-up survey


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From the above, the population in the induction phase in the study was set as moderate to severe 
Japanese CD patients who had failed with existing pharmacotherapy (any of 
corticosteroids/immunomodulators/anti-TNFα antibodies). 
6.2.2 
Justification of Study Design and Sample Size 
The Guideline for Treatment of CD[1] recommends that the remission maintenance therapy 
should apply to prevent recurrence after achievement of remission induction. However, effective 
drugs in the induction therapy are not always efficacious in the maintenance therapy. The 
randomized, double-blinded, placebo-controlled study with an induction phase and maintenance 
phase was designed to objectively evaluate efficacy and safety both in the induction therapy and 
maintenance therapy. Additionally, the enrichment design was employed to evaluate efficacy and 
safety in the maintenance phase, in which only responders to MLN0002 in the induction phase will 
be enrolled in the population to be randomized in the maintenance phase. 
For preservation of blindness, all responders at Week 10 will be enrolled into the maintenance 
phase irrespective of the drugs allocated in the induction phase. The responders who received 
MLN0002 in the induction phase will be randomized either to the placebo group or the MLN0002 
group for evaluation of efficacy and safety of the maintenance therapy, and the responders who 
received the placebo in the induction phase will be continued to be allocated to the placebo groups. 
In the ethically-established open-label cohort, it was designed that non-responders in the induction 
phase, patients who experienced disease worsening or received rescue treatments during the 
maintenance phase, or those completed Week 60 of the maintenance phase may continue to 
receive MLN0002 for 46 weeks (minimum) to 94 weeks (maximum). 
See Section 13.3 for justification of the sample size. 
6.2.3 
Justification of the Placebo Group 
Any active comparator is impossible to be used properly in the study in moderate to severe CD 
patients who had failed with existing pharmacotherapy (either of 
corticosteroids/immunomodulators/anti-TNFα antibodies). The placebo was selected as a 
comparator for objective evaluation of efficacy and safety. 
6.2.4 
Justification of the Dosage and the Evaluation Period 
In the Phase 3 study outside Japan in CD patients (C13007) dosed 300 mg of MLN0002 at 
Weeks 0, 2, 6 and subsequently every 8 weeks or 4 weeks, similar efficacy was observed in either 
dosage with no safety issues[9]. The serum MLN0002 concentration was similar inside/outside 
Japan, and saturation of α4β7 receptors was observed mostly continuously from the first dose. From 
the above, the dosage in the study was selected as 300 mg of MLN0002 to be dosed at Weeks 0, 2, 
6 and subsequently every 8 weeks in a similar manner as that in C13007 study. 
The primary efficacy endpoint in the induction phase will be evaluated at Week 10, since results 
from the Phase 3 study outside Japan in CD patients (C13011) have suggested that efficacy of the 
induction therapy is improved at Week 10 than that at Week 6. It has been decided that the 


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maintenance phase is to start from Week 14, and the primary efficacy endpoint in the maintenance 
phase will be evaluated at 46 weeks after enrollment into maintenance phase (Week 60) in the 
similar manner as that in C13007 study. 
Meanwhile, non-responders at Week 10 may be enrolled into the open-label cohort for 
re-induction of the drug and the maintenance therapy, and receive 300 mg of MLN0002 at 
Weeks 0x, 2x, 6x and subsequently every 8 weeks for 46 weeks (minimum) to 94 weeks 
(maximum). Subjects who experienced disease worsening or received rescue treatments during the 
maintenance phase, or those who completed Week 60 of the maintenance phase can be enrolled 
into the open-label cohort to receive the study drug in the same manner. As safety was 
demonstrated in the C13007 study when MLN0002 was dosed at Weeks 0, 2 and subsequently 
every 4 weeks, enrollment into the open-label cohort was judged to impose no safety issues. 
The elimination half-life of MLN0002 was 15 to 22 days at the dose of 2 to 10 mg/kg[5]. 
Additionally, saturation of α4β7 receptors was durable at the dose of 300 mg for 16 weeks after the 
last dose, and decreased subsequently over time. The end-of-study examination for safety 
evaluation after the last dose will be conducted in a similar manner as that in studies outside Japan 
in all subjects who received the study drugs at 16 weeks after the last dose that is almost ≥5-times 
longer period than the elimination half-life and by which saturation of α4β7 receptors may be 
durable. 
PML has been reported in subjects who received natalizumab, an α4 integrin antagonist[12]. 
MLN0002 is considered unlikely to increase PML risk since it specifically binds to the intestine 
tropism α4β7 integrin, and no PML was observed in clinical trials inside/outside Japan so far. 
However, the number of subjects who received MLN0002 was not large because of the clinical 
trial stage, and the potential PML risk is difficult to be ruled out. Therefore, the follow-up survey 
will be performed every 6 months up to 2 years after the last dose of the study drug for evaluation 
of potential PML risk of the drug. 
6.2.5 
Justification of Endpoints 
The CDAI score was used as the disease activity index for CD in C13007 study and C13011 
study[9][10]. The CDAI score, extensively used as an efficacy index for evaluation of CD 
inside/outside Japan, was selected as the evaluation index in the study. The clinical response and 
clinical remission based on the CDAI score were defined in the same manner as those in C13007 
study and C13011 study. 
6.3 
Premature Termination or Suspension of Study or Investigational site 
6.3.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 


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• New information or other evaluations regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study. 
• Significant violation of Good Clinical Practice (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 Investigational 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 Investigational Site(s) 
When the sponsor, the IRB or regulatory authorities has decided to suspend or terminate the study 
or participation of a study site, the sponsor will designate a procedure to be applied in the study. 
The study site should follow the designated procedures to suspend or terminate the study. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All inclusion/exclusion criteria including test results must be confirmed prior to enrollment into 
the induction phase. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria: 
1. In the opinion of the investigator, a subject is capable of understanding and complying with 
protocol requirements. 
2. A subject who is capable of entering the signature and the date on the informed consent by 
himself/herself or by the subject’s legally acceptable representative, if applicable, prior to 
initiation of study procedures. 
3. A subject aged 15 to 80 (inclusive) at the time of signing the informed consent (regardless of 
sexes). 
4. A male subject, who has no sterilization history and whose female partner has child-bearing 
potential, who agreed with taking proper contraception during the period from the time of 
signing on the informed consent form through 6 months after the last dose of the study drug. 
5. A female subject with child-bearing potential (having no history of sterilization or whose last 
menstruation was within 2 years) whose male partner is not receiving contraceptive treatment, 
and agreed to take proper contraception during the period from the time of signing on the 
informed consent form through 6 months after the last dose of the study drug. 
6. Subjects with a diagnosis of the small intestine type, the large intestine type or the small/large 
intestine type of CD based on the Revised Diagnostic Criteria for Crohn's Disease issued by 
“Research Group for Intractable Inflammatory Bowel Disease” Designated as Specified 
Disease by the MHLW of Japan (2012) (see Appendix C) at least 3 months before the start of 
administration of study drug. 
7. Subjects with the CDAI score of 220≤ and ≤450 points at the first dose of the study drug, and 
also meeting any of the following: 
 
Subjects with a CRP level of >0.30 mg/dL at the screening test. 
 
Subjects confirmed to have irregular-to-round shaped ulcers or multiple aphtha in the 
small or large intestine extensively (≥10 lesions) in the endoscopy or the imaging test 
within 4 month before the first dose of the study drug. 
 
Subjects confirmed to have longitudinal ulcers or a cobblestone appearance in the small 
or large intestine in the endoscopy or the imaging test within 4 months before the first 
dose of the study drug. 
8. Subjects whose complication of colon cancer or dysplasia had to be ruled out by total 
colonoscopy at the start of the study drug administration (or the results from total colonoscopy 
performed within 1 year before giving consent are available), if subjects met any of the 


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followings; subjects with extensive or limited colitis of ≥8 years duration, subjects aged ≥50 
years, or subjects with a first-degree family history of colon cancer. 
9. Subjects meeting the following treatment failure criteria with at least one of the following 
agents within 5 years before the time of signing on the informed consent form: 
• Corticosteroids 
– Resistance: subjects whose response was inadequate after treatment of ≥40 mg/day 
for ≥1 week 3(oral or IV) or 30 to 40 mg/day for ≥2 weeks (oral or IV). 
– Dependence: subjects for which it is difficult to reduce the dosage to <10 mg/day due 
to recurrence during gradual dose reduction (oral or IV). 
– Intolerance: subjects who were unable to receive continuous treatment due to adverse 
reactions (e.g., Cushing's syndrome, osteopenia/osteoporosis, hyperglycaemia, 
insomnia, infection). 
• Immunomodulators (AZA, 6-MP or MTX) 
– Refractory: subjects whose response was inadequate after treatment for ≥12 weeks. 
– Intolerance: subjects who were unable to receive continuous treatment due to adverse 
reactions (e.g., nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, 
lymphopenia, TPMT genetic mutation, infection). 
• Anti-TNFα antibodies 
– Inadequate response: subjects whose response was inadequate after the induction 
therapy in the dosage described in the package insert. 
– Loss of response: subjects who had recurrence during the scheduled maintenance 
therapy after achievement of clinical response (those who withdrew for other reasons 
than relapse are not applicable here). 
– Intolerance: subjects who were unable to receive continuous treatment due to adverse 
reactions (e.g., infusion-related reaction, demyelination disease, congestive heart 
failure, infection). 
7.2 
Exclusion Criteria 
Subjects meeting any of the following criteria will not be eligible in the study: 
1. Subjects having or suspected to have abdominal abscess. 
2. Subjects with a history of subtotal or total colectomy. 
3. Subjects with a history of ≥3 enterectomy , or a history of diagnosis of short bowel syndrome. 
4. Subjects with ileostomy, colostomy, internal fistula or severe intestinal stenosis. 
                                               
3The dosages of corticosteroids represent, hereafter, the converted dosage of prednisolone.   


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5. Subjects having a treatment history with natalizumab, efalizumab or rituximab. 
6. Subjects who started oral 5-ASA, probiotics, antibiotics for CD treatment, or oral 
corticosteroids (≤30 mg/day) within 13 days before the first dose of the study drug. Subjects 
who have used these drugs for at least 14 days before the first dose of the study drug, and who 
changed dosage of or discontinued these drugs within 13 days before the first dose of the study 
drug. 
7. Subjects who have received 5-ASA, corticosteroid enemas/suppositories, corticosteroid IV 
infusion, oral corticosteroid at >30 mg/day, drugs for diarrhea-predominant irritable bowel 
syndrome, or Chinese herbal medicine for the CD treatment (e.g., Daikenchuto) within 13 
days before the first dose of the study drug. 
8. Subjects who have received AZA, 6-MP or MTX within 27 days before the first dose of the 
study drug However, this will not apply to subjects who have used these drugs for 83 or more 
days before the first dose of the study drug and continued the steady dose administration of the 
drugs for 27 or more days before the first dose of the study drug. 
9. Subjects who have received cyclosporine, tacrolimus, tofacitinib or any study drugs of 
low-molecular compound for CD treatment within 27 days before the first dose of the study 
drug. 
10. Subjects who have received adalimumab within 27 days before the first dose of the study drug 
or any biologic agents other than adalimumab within 55 days before the first dose of the study 
drug. However, this will not apply to subjects who have topically received these drugs (e.g., 
intraocular injection for treatment of age-related macular degeneration). 
11. Subjects who have received any live-vaccinations within 27 days before the first dose of the 
study drug. 
12. Subjects who underwent the enterectomy within 27 days before the first dose of the study drug 
or those anticipated to require an enterectomy during the study. 
13. Subjects who have received leukocytapheresis or granulocyte apheresis within 27 days before 
the first dose of the study drug. 
14. Subjects who received central venous nutrition therapy or enteral total nutrition therapy, or 
fasted within 20 days before the first dose of the study drug. 
15. Subjects who received an enteral nutrient of >900 kcal/day or who will begin to receive an 
enteral nutrient of ≤900 kcal/day within 20 days before the first dose of the study drug. 
Subjects who had received an enteral nutrient of ≤900 kcal/day earlier than 21 days before the 
first dose of the study drug, and modified or discontinued the dosage within 20 days before the 
first dose of the study drug. 
16. Subjects who have been infected with an intestinal pathogen including clostridium difficile or 
cytomegalovirus within 27 days before the first dose of the study drug. 


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17. Subjects with evidence of adenomatous colonic polyps that need to be removed at the start of 
study drug administration. 
18. Subjects with a history or a complication of large or small intestinal dysplasia. 
19. Subjects suspected to have enteritis other than CD. 
20. Subjects indicated in the screening test as HBs antigen-positive or HCV antibody-positive 
Subjects indicated as HBc antibody-positive or HBs antibody positive even though HBs 
antigen-negative However, the criteria will not apply to those with only HBs 
antibody-positive due to HBV vaccination, HBV-DNA-negative, HCV antigen-negative or 
HCV-RNA-negative. 
21. Subjects who have or are suspected to have a history of tuberculosis (including those whose 
findings in the chest imaging procedure at screening showing anamnesis of tuberculosis) 
However, the criteria will not apply to those who had completed prophylactic treatment with 
isoniazid, and who have been receiving prophylactic isoniazid for 21 days or longer before the 
first dose of the study drug (the latter may initiate study drug administration with screening 
phase extended to 28 days at maximum for prophylactic treatment to become 21 days or 
more). 
22. Subjects indicated as positive in T-SPOT or QuantiFERON at screening test. 
23. Subjects who have a history or complication of congenital or acquired immunodeficiency 
syndrome (e.g., not-classifiable immunodeficiency, HIV infection or organ transplantation). 
24. Subjects who were affected by extraintestinal infection (e.g., pneumonia, sepsis, active 
hepatitis or pyelonephritis) within 27 days before the first dose of the study drug. 
25. Subjects who have treatment history with MLN0002. 
26. Nursing mothers during the screening phase, or female subjects indicated positive in urine 
pregnancy test either at the screening or baseline. 
27. Subjects having serious complications in the heart, lung, liver, kidney, metabolism, 
gastrointestinal system, urinary system, endocrine system or blood. 
28. Subjects with a history of an operation requiring general anesthesia within 27 days before the 
first dose of the study drug, or with a schedule of an operation requiring hospitalization during 
the study period. 
29. Subjects having a complication or a history of malignancy However, it will not apply to the 
following subjects; 
• Subjects who had a curative resection of localized skin basal cell carcinoma or had 
completed curative radiotherapy. 
• Subjects who have not experienced recurrence for 1 year or longer since completion of 
curative resection or curative radiotherapy for skin squamous cell carcinoma. 


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• Subjects who have not experienced recurrence for 3 years or longer since completion of 
curative resection or curative radiotherapy for intraepithelial carcinoma of uterine cervix. 
For subjects having a substantially distant history of malignancy (e.g., 10 years or longer 
without recurrence since treatment completion), the Investigator and the sponsor will discuss 
to decide eligibility on the basis of type of malignancy and treatment applied. 
30. Subjects having a history or a complication of the central nervous disorder, including stroke, 
multiple sclerosis, brain tumor, or neurodegenerative disease. 
31. Subjects for which any subjective symptoms in the Subjective PML checklist were found at 
the screening or baseline. 
32. Subjects for which any of the following laboratory abnormalities were found at the screening; 
• Hemoglobin 
≤8 g/dL 
• White blood cells 
≤3,000/μL 
• Lymphocytes 
≤500/μL 
• Platelets 
≤100,000/μL, or ≥1,200,000/μL 
• ALT and AST 
≥3×upper limit of normal (ULN) 
• ALP 
≥3×ULN 
• Creatinine 
≥2×ULN 
33. Subjects having a history or a complication of alcohol dependence or illicit drug use within 
one year before the first dose of the study drug. 
34. Subjects having a history or a complication of psychotic disorder that may obstruct 
compliance with the study procedures. 
7.3 
Excluded Medications and Treatments 
Excluded medications and treatments are listed in Table 7.a. However, some of the drugs may be 
used concurrently under the conditions provided in the table. Subjects will be instructed not to take 
any drugs, including over-the-counter products (OTCs), without first consulting with the 
investigator. 
Table 7.a 
List of Excluded Drugs and Treatments 
Drugs/Treatment 
Prohibited Period 1) 
Conditions in Concurrent Use 
Screening Phase/ 
Induction Phase/Maintenance Phase 
Open-label 
Cohort 
Oral 5-ASA 
Probiotics 2) 
Antibiotics for CD treatment 
Day -13 
– 16 weeks after 
the last dose 
Should be initiated before Day-14 and continued 
at the same dosage from Day-13. Dose reduction 
or discontinuation may be allowed only due to 
adverse reactions. 
Allowed to 
be used 
(without 
limitation) 
Oral corticosteroids (≤30 mg/day) 
Day -13 
– 16 weeks after Should be initiated before Day-14 and 
Same as on 


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Drugs/Treatment 
Prohibited Period 1) 
Conditions in Concurrent Use 
Screening Phase/ 
Induction Phase/Maintenance Phase 
Open-label 
Cohort 
the last dose continued at the same dosage from Day-13. 
As per the Dose Reduction Schedule for 
corticosteroids (see Section 7.3.2). 
the left 
5-ASA enemas 
5-ASA suppositories 
Day -13 
– 16 weeks after 
the last dose – 
Allowed to 
be used 
(without 
limitation) 
Corticosteroid enemas 
Corticosteroid suppositories 
(including corticosteroid pretreatment 
prior to endoscopy) 
Day -13 
– 16 weeks after 
the last dose – 
Allowed to 
be used 
(without 
limitation) 
Corticosteroid IV infusion 
Day -13 
– 16 weeks after 
the last dose – 
– 
Oral corticosteroids (>30 mg/day) 
Day -13 
– 16 weeks after 
the last dose – 
– 
Therapeutic drugs for 
diarrhea-predominant irritable bowel 
syndrome 
Day -13 
– 16 weeks after 
the last dose – 
– 
Chinese herbal medicines for UC 
treatment (eg, Daikenchuto) 
Day -13 
– 16 weeks after 
the last dose – 
– 
AZA 
6-MP 
MTX 
Day -27 
– 16 weeks after 
the last dose 
Should be initiated earlier than Day-83 and 
continued at the same dosage from Day-27. 
Dose reduction or discontinuation may be 
allowed only due to adverse reactions. 
Same as on 
the left 
Tacrolimus 
Cyclosporine 
Tofacitinib 
Day -27 
– 16 weeks after 
the last dose – 
– 
Study drugs of low-molecular 
compounds for CD treatment 
Day -27 
– 16 weeks after 
the last dose – 
– 
Adalimumab 
Day -27 
– 16 weeks after 
the last dose – 
– 
Natalizumab 
Efalizumab 
Rituximab 
MLN0002 
(previous) – 16 weeks after 
the last dose – 
– 
Other biologics than the above 
(including infliximab. Topical use was 
allowed) 
Day -55 
– 16 weeks after 
the last dose – 
– 
Live-vaccinations 
Day -27 
– 6 months after 
the last dose – 
– 
Enterectomy 
[Other surgical treatments than the 
enterectomy including 
(treatment-emergent) abscess drainage 
or the Seton method for the anal lesion 
may be performed] 
Day -27 
– 16 weeks after 
the last dose – 
– 
Leukocytapheresis or granulocyte 
apheresis 
Day -27 
– 16 weeks after 
the last dose – 
– 


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Drugs/Treatment 
Prohibited Period 1) 
Conditions in Concurrent Use 
Screening Phase/ 
Induction Phase/Maintenance Phase 
Open-label 
Cohort 
Central venous nutrition therapy 
Enteral total nutrition therapy 
Fasting 
Day -20 
– 16 weeks after 
the last dose – 
– 
Enteral nutrients (>900 kcal/day) 
Day -20 
– 16 weeks after 
the last dose – 
– 
Enteral nutrients (≤900 kcal/day) 
Day -20 
– 16 weeks after 
the last dose 
Should be initiated before Day-21 and 
continued at the same dosage from Day-20. 
The dosage may be modified after Week 10, 
however it should preferably remain the 
stable dose and not exceed the initial dosage 
at the first dose of the study drug. 
Same as the 
left 
Surgeries requiring general anesthesia 
Day -27 
– 16 weeks after 
the last dose – 
– 
1) 
Day 1 is defined as the date of the first dose of the study drug and Day -1 is defined as the day before the Day 1 for calculation. 
2) 
Such as VSL#3. The bifidobacterium preparation or any foods are not applicable. 
7.3.1 
 Rescue Treatments 
Drugs or treatments not permitted in Table 7.a may be used as rescue treatments (see Section 3.1 
for the definition) only in urgent cases such as worsening of CD otherwise safety of the subject is 
judged not to be secured. 
The subjects who received any rescue treatments in the induction phase should withdraw from the 
study. The subjects who received any rescue treatments in the maintenance phase should 
discontinue the maintenance phase and may be enrolled into the open-label cohort, however 
withdrawal should be considered in the subjects intending to receive any unavailable treatment in 
the open-label cohort. For the subjects who received any rescue treatments in the open-label cohort, 
withdrawal should be considered (see Section 7.5). 
7.3.2 
Dose Reduction Schedule of Corticosteroids 
Dosage of a corticosteroid, if used concurrently, should not be modified until Week 10 after the 
first dose of the study drug in principle. When the CDAI-70 response (see Section 3.1 for the 
definition) was achieved at Week 10 or later, the dose reduction of the corticosteroid will be 
initiated as per the following schedule from the visit when the CDAI-70 response was observed, 
where possible. 
Dose Reduction Schedule: 
• When >10 mg/day was dosed, the dosage will be gradually reduced by 5 to 10 mg/2 weeks to 
reach 10 mg/day 
• When ≤10 mg/day was dosed or achieved by gradual reduction, the dosage will be gradually 
reduced by 2.5 to 5 mg/2 weeks to achieve corticosteroid-free 


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When dose reduction is required earlier than Week 10 due to adverse reactions of the 
corticosteroid, only small doses of not more than 5 mg/2 weeks should be gradually reduced. 
When any symptoms recur with the dose reduction of the corticosteroid, the dosage may be 
increased up to the initial dose (it will not apply to rescue treatments). Subsequently, when clinical 
response was observed again, the dose reduction will be initiated preferably as per the above 
schedule from the visit when the clinical response was observed. 
Of note, higher dosage than the initial dosage, if used for recurrence, will be considered as a rescue 
treatment (see Section 7.3.1 for rescue treatments). 
7.4 
Subject Management 
1. Subjects should be instructed to be sure to see the physician and take specified examinations at 
the specified date and time. In addition, subjects should be instructed to inform the 
investigator or the sponsor immediately in the case that they cannot visit. 
2. Subjects should be instructed to make entries in the subject’s diary throughout the period from 
the time of signing on the informed consent form to the last dose of the study drug and to bring 
the diary with them at each visit. 
3. Subjects should be instructed to preferably visit under fasted condition at visits for blood 
biochemistry test. 
4. Subjects should be instructed to report any worsening of symptoms that occurred at any time 
other than visits, if any, to the investigator or the sponsor via telephone or the like to seek 
instructions. 
5. Subjects should be instructed to report details, onset date, intensity, outcome and outcome 
date of subjective symptoms/objective findings to the investigator during their visit. 
6. Subjects should be instructed to report course and details of the treatment to the investigator if 
they visited other medical institutions during the period from the time of signing on the 
informed consent form to 16 weeks after the last dose of the study drug. 
7. Subjects should be instructed to inform a physician in a medical institution of his/her 
participation in the study, if he/she visited other medical institutions during the period from 
the time of signing on the informed consent form to 16 weeks after the last dose of the study 
drug. 
8. Subjects should be instructed not to use any drugs including OTCs other than drugs instructed 
by the investigator without prior consultation (except urgent cases). 
9. Male subjects without a sterilization history and whose female partner has child-bearing 
potential should be instructed to take proper contraception during the period from the time of 
signing on the informed consent form to 6 months after the last dose of the study drugs. 


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10. Female subjects with child-bearing potential whose male partner has no sterilization history 
should be instructed to take proper contraception during the period from the time of signing on 
the informed consent form to 6 months after the last dose of the study drugs. 
11. Subjects should be instructed to avoid surfeit, extreme changes in diet, excessive 
exercise/action throughout the period from the time of signing on the informed consent form 
to the last dose of the study drug. Subjects should be instructed in an especially careful manner 
because treatment-emergent change of symptoms may lead to changes in diet. 
12. Subjects should be instructed not to donate their blood during the period from the time of 
signing on the informed consent form to 6 months after the last dose of the study drug. 
13. Subjects should be instructed to report any feelings of infusion reaction (e.g., rash, pruritus, 
flushing or urticaria) to the investigator immediately. 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of a subject from the study should be 
recorded in the case report form ([e]CRF) using the following categories. See Section 9.1.21 for 
subjects who withdrew during the screening phase. 
1. Pretreatment Events or AEs 
The subject has experienced a PTE or AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the PTE or AE. 
 
Liver Function Test Abnormalities 
Discontinuation of the study drug should be considered with appropriate clinical 
follow-up (including repeat laboratory tests, until a subject’s laboratory profile has 
returned to normal/baseline status, see Section 9.1.12), if the following circumstances 
occur at any time during study drug treatment: 
– ALT or AST >8×ULN, or 
– ALT or AST >5×ULN and persists for more than 2 weeks, or 
– ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or 
international normalized ratio (INR) >1.5, or 
– ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia. 
2. Major protocol deviation 
The discovery post-randomization in the induction phase that the subject failed to meet 
protocol inclusion criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health. 


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Note: The visit for evaluation of the primary efficacy endpoint in the induction phase (Visit 5), 
when notably deviated beyond the acceptable window (≥±15 days), should be considered as a 
major protocol deviation. 
3. Lost to follow-up 
The subject did not return to the clinic and attempts to contact the subject were unsuccessful. 
Attempts to contact the subject must be documented. 
4. Voluntary withdrawal. 
The subject wishes to withdraw from the study. The reason for withdrawal, if provided, should 
be recorded in the (e)CRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (i.e., withdrawal due to an 
AE or lack of efficacy should not be recorded in the “voluntary withdrawal” category). 
5. Study termination 
The sponsor, the IRB or regulatory authorities decided to terminate the study. 
6. Pregnancy 
The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.13. 
7. Lack of efficacy 
The investigator has determined that the subject is not benefiting from investigational 
treatment; and, continued participation would pose an unacceptable risk to the subject. 
Note: A subject who received any rescue treatments due to lack of efficacy in the induction 
phase should withdraw from the study immediately. For a subject who received any rescue 
treatments in the open-label cohort, and meets criteria for the sustained non-response or the 
disease worsening, withdrawal due to lack of efficacy will be considered 
8. Other 
Note: The specific reasons should be recorded in the “specify” field of the (e)CRF. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may terminate a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded. In 
addition, efforts should be made to perform all procedures scheduled for the early termination 
visit. 


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8.0 
CLINICAL STUDY MATERIAL MANAGEMENT 
This section contains information regarding all drugs and materials provided directly by the 
sponsor, and/or by other means, that are required by the study protocol, including important 
sections describing the management of clinical trial materials. 
8.1 
Study Medication and Materials 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
8.1.1.1 
Study Drug 
In this protocol, the term of study drugs refers to all or any of the drugs defined below. 
Table 8.a 
Study drug 
Name of the study 
drugs 
Chemical name of active ingredients 
(Nonproprietary names) 
Formulations 
Contents 
MLN0002  
300 mg for infusion 
Human IgG1 monoclonal antibody 
[vedolizumab (INN)]  
against human α4β7 integrin 
Parenteral 
solution 
Contains 300 mg* of 
MLN0002 in one vial 
Placebo for infusion 
Not applicable 
– 
Empty 
*lyophilized preparation 
 
Appearance is identical among vials of the study drugs. Each vial will be labeled to be packed into 
the outer package. The outer package will be labeled with the statement that contents are study 
drugs, the name of the study drug, quantity, the name and address of the sponsor, the serial number, 
the storage and the expiration date. Examples of labels on vials or outer packages are shown in the 
Figure 8.a and Figure 8.b, respectively. Of note, the serial numbers and expiration dates of the 
study drugs should be in accordance with the separately specified written procedure. 
Figure 8.a 
Labels on Vials 
 
 
 
For vials of MLN0002 (300 mg) 
For vials of placebo 
MLN0002/CCT-001 
MLN0002 (300 mg) for  
infusion 
Serial number: Z ............ 
MLN0002/CCT-001 
NOT for infusion to subjects 


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CONFIDENTIAL 
Figure 8.b 
A Label on Outer Packages 
 
 
8.1.1.2 
Materials 
The following materials will be used at the time of infusion of the study drugs in principle. 
However, the material control should be in accordance with the separately specified written 
procedures. 
Table 8.b 
Materials 
Intended use 
Materials 
Examples 
Preparation of 
study drugs 
A syringe for preparation 
A 5 or 10 cc latex-free syringe 
Water for injection 
Water for injection in a container with volume of 
10 mL or larger 
An injection needle for 
preparation 
An injection needle of 18G stainless steel 
Physiological saline 
Sterilized 100 mL (specification) 0.9% NaCl solution 
Infusion of 
study drugs 
An IV infusion kit 
An IV infusion kit to set the injection site beneath an 
infusion tube 
An injection needle for infusion 
A winged needle for IV infusion 
Physiological saline 
(for priming/flushing IV 
infusion lines) 
Sterilized 50, 100 or 250 mL (specification) 0.9% 
NaCl solution 
 
Study drug        1 vial 
MLN0002 DB for infusion 
MLN0002/CCT-001 
 
Drug number: 
 
               
Subject Identification Code: 
 
               
Timing for infusion: 
 
Week             
 
 
Serial number: DB ............ 
Expiration date:See the procedure for 
study drug control 
Storage: refrigerated (2 to 8 °C) 
 
 
The outer package should  
be kept to be collected  
by the Sponsor. 
 
Takeda Pharmaceutical Company 
Limited 
1-1, Doshomachi 4-chome, Chuo-ku, 
Osaka-shi 
Note 


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CONFIDENTIAL 
8.1.2 
Storage 
Temperature during storage should be refrigerated (2 to 8°C). However, it may be deviated 
temporally (for 7 days) in the range from -70 to 40°C. 
All study drugs must be kept in an appropriate, limited-access, secure place until used or returned 
to the sponsor or its designee for destruction. All sponsor-supplied study drugs must be stored 
under the conditions specified on the label, and remain in the original container until dispensed. A 
daily temperature of the study drug storage area must be determined and recorded every working 
day. 
8.1.3 
Dose and Regimen 
Table 8.c 
Dose and Regimen 
Study Drugs 
Preparation and Regimen 
Placebo for infusion 
Add 5 mL of water for injection to approximately 100 mL of saline and infuse 
intravenously over 30 minutes*. 
MLN0002 (300 mg) for 
infusion 
One vial of MLN0002 (300 mg) for infusion is reconstituted in 4.8 mL of water for 
injection. Add 5.0 mL of the solution to approximately 100 mL of saline for dilution and 
infuse intravenously over 30 minutes*. 
*May be infused over 60 minutes at maximum. 
 
Study drug preparators should prepare study drugs. A study drug preparators should not be an 
evaluator throughout induction and maintenance phases. Study drug preparators will prepare study 
drugs in line with the drug numbers prescribed by the investigator or his/her designee. The details 
of the study drug preparation method should be in accordance with the separately specified written 
procedure. 
Serious infusion reaction should be treated properly, if any, e.g., immediate use of epinephrine and 
parenteral diphenhydramine. 
8.1.4 
Overdose 
Overdose is defined as a known deliberate or accidental administration of a study drug at a dose 
above the specification in the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the (e)CRF, in order to capture this important safety information consistently in the database. 
AEs associated with an overdose will be documented on AE (e)CRF(s) according to Section 10.0, 
PTEs and AEs. 
SAEs associated with overdose should be reported in accordance with the procedure specified in 
Section 10.2.2 Collection and Reporting of SAEs. 
Subjects overdosed should be treated by the investigator based on symptoms. 


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8.2 
Procedures for Allocation, Prescription and Infusion of Study Drugs 
A study drug number will not be identical at each time. For allocation of subjects to study drugs, 
Investigators or his/her designee will access the website of the registration center at each visit for 
infusion to obtain a study drug number from the registration center. Investigators or his/her 
designee will prescribe the study based on the obtained study drug number. The study drug number 
should be recorded in (e)CRF at each administration visit. 
Details for using the website of the registration center will be in accordance with the separately 
specified written procedures. 
8.3 
Preparation and Retention of the Allocation Table 
A person in charge of allocation (appointed by the sponsor) will prepare the allocation table. 
Information of allocation should be kept in a secure place with limited access by unauthorized 
people. 
8.4 
Preservation of Blindness 
The emergency key will be kept in the emergency key control center until emergent key-breaking 
or completion of database lock of all subjects. 
In the study, allocations must not be disclosed to any person until opening of the study drug 
allocation table, while the study drug preparators may be aware of allocations in the course of 
study drug preparation. 
Furthermore, test results of serum drug concentration and HAHA/neutralizing antibody may be an 
obstacle in preservation of blindness in the study, therefore these final test results should be kept 
undisclosed outside in the test laboratory until opening of the study drug allocation table, and will 
be reported to the investigator through the sponsor upon opening. However, if a test result must be 
disclosed before opening, the test result may be reported to the sponsor or the like after necessary 
actions taken to preserve blindness (e.g., renumbering of study drugs), so that persons in charge in 
the test laboratory would be unable to identify subjects. Detailed procedures should be in 
accordance with the separately specified written procedure. 
8.5 
Procedures for Blind-Breaking 
The study drug blind will not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. 
In blind-breaking, the investigator may obtain study drug allocation information from the 
emergency key control center (see the Annex for contacts). 
In blind-breaking, the investigator will enter the date/time and rationale of the blind-breaking on 
the record of emergency key opening to be submitted to the sponsor. The same information (except 
time) will be recorded on (e)CRF. 


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If any site personnel is unblinded, the study drug must be stopped immediately and the subject 
must be withdrawn from the study. 
8.6 
Control and Disposal of Sponsor-Supplied Drugs 
The Study Drug Administrator will receive the written procedure prepared by the sponsor relating 
to handling, storing and controlling study drugs to properly control sponsor-supplied study drugs 
and materials in accordance with the written procedure. Similarly, the investigator will receive the 
same written procedures from the sponsor. The written procedure describes procedures to ensure 
proper receipt, handling, storing, controlling and prescription of the sponsor-provided study drugs 
and materials, as well as return of unused study drugs and materials to the sponsor or other 
disposition. 
The Study Drug Administrator will return unused study drugs and materials to the sponsor 
immediately after study completion in the study site. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects should be assessed by the same investigator or site personnel, where possible. The Study 
schedule is provided in Appendix A. 
9.1.1 
Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
The informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
Dosage of prior therapeutic drugs will be modified or discontinued for the study enrollment, if 
needed, after acquisition of the informed consent for participation in the study. 
Subject Identification Code will be provided for each subjects at the time of explanation of the 
informed consent, and used throughout the study. 
Pharmacogenomic Informed Consent Procedure 
A separate informed consent form pertaining to storage and banking of the sample must be 
obtained prior to collecting a blood sample for Pharmacogenomic Research for this study. The 
provision of consent to collect and analyze the pharmacogenomic sample is independent of 
consent to the other aspects of the study. 
9.1.2 
Demographics, Medical History, and Medication History Procedure 
As demographic data, dates of birth, sex and smoking histories will be obtained. In addition, the 
following CD-related items will be obtained. 
• Date Primary Disease Diagnosed 
• The following item as defined in the Revised Diagnostic Criteria for CD (Appendix C) issued 
by “Research Group for Intractable Inflammatory Bowel Disease” Designated as Specified 
Disease by the MHLW of Japan (2012) 
− 
Disease localization by extent of the CD lesions (small-intestinal, large-intestinal or 
small/large-intestinal) 
• History of treatment failure with the following drugs within 5 years before acquisition of the 
informed consent 
– Corticosteroids (resistance/dependence/intolerance) 
– Immunomodulators (AZA, 6-MP or MTX) (refractory/intolerance) 
– Anti-TNFα antibodies* (inadequate response/loss of response/intolerance) 


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* For inadequate response and loss of response, the name and the first and last 
administration dates of the drug will be recorded as well. For intolerance, the name of the 
drug and the side-effect leading to discontinuation will be recorded as well. 
For disease histories, any clinically relevant diseases or symptoms will be obtained, which were 
judged as disease histories in evaluation in the study by a physician, including extra-intestinal 
manifestations, pouchitis, infectious enteritis, toxic megacolon, stenosis, fistula that has 
recovered/resolved within 1 year before acquisition of the informed consent. In addition, any 
previous malignancies and enterectomy for CD will be obtained. Ongoing conditions or diseases 
are considered as concurrent medical conditions (see Section 9.1.7). 
For prior therapeutic drugs, all of the following will be obtained. 
• Biological drugs for CD treatment discontinued before acquisition of the informed consent. 
• Low-molecular compounds for CD treatment discontinued within 4 weeks before acquisition 
of the informed consent. 
Of note, agents applied for procedures including endoscopy will not be considered as prior 
therapeutic drugs and also not be documented in the (e)CRF. 
9.1.3 
Physical Examination Procedure 
Physical examination in the following body sites will be performed before study drug 
administration if it is the day of study drug administration. 
(1) eyes, (2) ears, nose, throat, (3) cardiovascular system, (4) respiratory system, 
(5) gastrointestinal system, (6) dermatologic system, (7) extremities, (8) musculoskeletal system, 
(9) nervous system, (10) lymph nodes, and (11) other. During infusion and 1 hour after infusion of 
the study drug, infusion reactions (e.g., rash, pruritus, flushing or urticaria) will be observed, and 
clinically relevant abnormalities will be assessed as compared to physical examination results 
performed before study drug administration. 
9.1.4 
Weight, Height and BMI 
Body weight and height will be measured before administration of the study drug if it is the day of 
study drug administration. In addition, BMI will be calculated by the sponsor with the following 
formula; 
Metric: BMI = weight (kg)/ [height (m)]2 
Height will be collected in centimeters without decimal places and weight will be collected in 
kilograms to 1 decimal place, results for BMI will be expressed with 1 decimal place. 
9.1.5 
Vital Sign Procedure 
As vital signs, body temperature (axilla), blood pressure while sitting (rest for 5 minutes or longer), 
and pulse (bpm) will be measured before administration of the study drug if it is the day of study 
drug administration. 


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9.1.6 
Documentation of Concomitant Medications and Non-drug Therapy 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
drug other than the study drug (used from the time of signing on the informed consent form 
through the end-of-study examination), and all drugs including vitamin supplements, OTC drugs, 
and oral herbal preparations, must be recorded in the (e)CRF. In addition, for concomitant drugs 
for CD treatment, class of the concomitant drug (5-ASA, corticosteroids, immunomodulators, 
enteral nutrition, or others), and applicability to a rescue treatment will be recorded in the (e)CRF. 
Concomitant treatments are defined as any treatments for CD other than pharmacotherapy, 
including enterectomy and other surgical treatments (e.g., abscess drainage or the seton method for 
the anal lesion). All concomitant treatments that were conducted during the period from 
acquisition of the informed consent until the end-of-study examination will be obtained. 
Additionally, applicability of the concomitant treatment to a rescue treatment will be recorded in 
the (e)CRF. 
Of note, agents applied for test procedures including endoscopy will not be considered as 
concomitant drugs and will also not be documented in the (e)CRF. 
9.1.7 
Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at the time of signing on the informed consent form. This includes clinically significant laboratory, 
ECG, or physical examination abnormalities noted at screening/baseline examination. The 
condition (i.e., diagnosis) should be described. In addition, CD-related extra-intestinal 
manifestations will be recorded in the (e)CRF. 
9.1.8 
The Patient Diary 
The patient diaries are used for calculation of the CDAI scores. At each visit, patient diaries to be 
entered from the visit to the next visit will be handed to subjects. A subject will be instructed to 
record the following items in the diary and bring it at the next visit. 
• Number of liquid or very soft stools 
• Scores of abdominal pain 
• Scores of general well being 
• Fever of ≥37.8°C 
• Use of antidiarrheal drugs or opiates 
Contents of the patient diaries will be confirmed at each visit. The subject will be asked about 
omissions or inconsistencies for correction, if any. The patient diaries will be collected to be 
retained after final confirmation of the contents. 


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9.1.9 
CDAI Score 
CDAI scores will be calculated as total scores of the following 8 subscores in the Table 9.a. The 
necessary information should be entered on the website of the Registration Center for calculation 
of a CDAI score. 
Table 9.a 
CDAI Scoring System for the Assessment of CD Activity [13] 
(1) Number of liquid or very soft stools 
7-day total number of liquid or very soft stools (reported on the 7 days immediately prior to 
the study visit) 
x 2 
(2) Abdominal pain 
7-day total of daily abdominal pain scores on a 3-point scale: 0=none, 1=mild, 2=moderate, 
3=severe (reported on the 7 days immediately prior to the study visit) 
x 5 
(3) General well being 
7-day total of daily general well-being scores on a 4-point scale: 0=generally well, 1=slightly 
under par, 2=poor, 3=very poor, 4=terrible (reported on the 7 days immediately prior to the 
study visit) 
x 7 
(4) Extraintestinal manifestations of CD 
Total number of checked boxes (check all that apply): 
□ Arthritis/arthralgia 
□ Iritis/uveitis 
□ Erythema nodosum/pyoderma gangrenosum/aphthous stomatitis 
□ Anal fissure, anal fistula or perianal abscess 
□ Other fistula 
□ Fever over 37.8°C during the last week 
x 20 
(5) Lomotil/Imodium/opiates for diarrhea 
Yes = 1, No = 0 
x 30 
(6) Abdominal mass 
None = 0, Questionable = 2, Definite = 5 
x 10 
(7) Hematocrit (%) 1) 
Males: subtract value from 47, Females: subtract value from 42 
x 6 
(8) Body weight 2) 
(1 – (Body weight/ Standard Weight)) × 100 
x 1 
 
Contents in the patient diary during the last 10 days before evaluation will be entered on the 
website of the registration center with regard to each subscore of number of liquid or very soft 
stools, abdominal pain, general well being, and use of an antidiarrheal drug or an opiate for 
diarrhea, as well as emergence of fever of ≥37.8°C during the last 1 week. Each subscore will be 
calculated automatically based on the patient diary during the last 7 days before evaluation except 
the following days. 
• The day of pretreatment for endoscopy 
• The day of endoscopy and the next day 


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Of note, for baseline evaluation (Visit 2), contents of the patient diary during at least 7 days except 
the above exception days should be entered on the website of the registration center for calculation 
of CDAI score. The subject visit will be adjusted to have the necessary number of days in the 
patient diary. 
9.1.9.1 
Calculation of Hematocrit (Ht) level scores 
The venous blood will be sampled for determination of Ht level for calculation of the CDAI score. 
At baseline (Visit 2), Ht level will be determined in each site on the evaluation day for calculation 
of the CDAI score, on which eligibility of the subject will be judged prior to initiation of the study 
drug. The above CDAI score will be the baseline score. If Ht level on the evaluation day is 
impossible to be obtained, instead Ht level determined during the period from 14 days before 
evaluation to the evaluation day may be used. 
At evaluation of the primary efficacy endpoint (Visit 5), Ht level will be determined in each site on 
the evaluation day for calculation of the CDAI score, on which clinical response/no-response will 
be judged in comparison with the baseline score. If Ht level on the evaluation day is impossible to 
be obtained, instead Ht level determined during the period from 14 days before evaluation to the 
evaluation day may be used. 
At all evaluation except the above, Ht level will be determined in each site on the evaluation day 
for calculation of the CDAI score, where possible, on which clinical response/no-response will be 
judged in comparison with the baseline score. If Ht level on the evaluation day is impossible to be 
obtained, the latest Ht level may be used. 
Of note, Ht level for analyses should be determined in the Laboratory Site. 
9.1.10 
Inflammatory Bowel Disease Questionnaire (IBDQ) 
The IBDQ, as composed of a total of 32 questions (each has 1 to 7 points) including abdominal 
symptoms (10 items), general condition (5 items), emotion (12 items) and social function (5 items), 
will be calculated as the total scores, and performed before administration of the study drug if it is 
the day of study drug administration. Each score will be recorded in the (e)CRF. 
9.1.11 
Laboratory Test 
Clinical laboratory test items as shown in Table 9.b will be determined. The test samples will be 
collected before administration of the study drug if it is the day of study drug administration. All 
samples will be handled in accordance with the separately specified procedures. The maximum 
amount of blood sampling will be approximately 19 mL at each visit. 


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Table 9.b 
Laboratory tests 
Blood biochemistry 
Albumin 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP) 
Amylase 
Glucose Note1) 
Total bilirubin 
Total protein 
g-glutamyl transpeptidase (γ-GTP) 
Total cholesterol 
Triglyceride 1) 
Creatinine 
Blood urea nitrogen (BUN) 
Uric acid 
Potassium 
Sodium 
Calcium 
Phosphorus 
Magnesium 
Chloride 
Hematology 
Urinalysis 
Red blood cells 
White blood cells 
Hemoglobin 
Hematocrit 
Platelets 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Qualitative (glucose, protein, occult blood, bilirubin, 
ketone body) 
Urine pH 
Urine specific gravity 
Serum immunological test (only at screening) 2) 
Urine pregnancy test 
(only in female subjects of childbearing potential) 
HBs antigen/antibody, HBc antibody, HCV antibody 
HIV antibody 
Human chorionic gonadotrophin (hCG) 
Inflammatory markers 
C-reactive protein (CRP) 
1) The samples should be preferably collected under fasted conditions. 
2) The test results of the serum immunological tests should be reported to subjects directly by investigator, and not be 
provided to the sponsor. 
 
The above laboratory test items will be determined at the laboratory site for the study except urine 
pregnancy tests. The urine pregnancy tests will be performed at the study sites. Investigator will 
assess and retain the clinical laboratory test results reported. 
If subjects experience ALT or AST >3×ULN, follow-up laboratory tests (at a minimum, ALP, 
ALT, AST, total bilirubin, γ-GTP, and INR) should be performed preferably within 48 to 72 hours 
or within 7 days at the latest after the blood sampling (see Section 7.5 and Section 10.2.3). 
If the ALT or AST remains elevated >3×ULN on these 2 consecutive occasions, the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of the study drug, discussion of the relevant subject details and possible 
alternative etiologies. 
Investigators will retain references of the clinical laboratory tests and their tracking. 


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9.1.12 
Contraception and Pregnancy Avoidance Procedure 
During the period from the time of signing on the informed consent form to 6 months after the last 
dose of the study drug, female subjects of childbearing potential (who have no history of 
sterilization or have menstruation within previous 2 years) must use proper contraception. In 
addition, during the period from the time of signing on the informed consent form to 6 month after 
the last dose of the study drug, male subjects without history of sterilization and whose female 
partner has child bearing potential must prevent pregnancy. Such subjects will be provided with 
information on acceptable methods of contraception as part of the subject informed consent 
process, and will be asked to sign a consent form stating that they understand the requirements for 
avoidance of pregnancy during the course of the study. During the course of the study, the 
specified urine pregnancy tests will be performed, and subjects will receive continued guidance 
with respect to avoiding pregnancy. 
Urine pregnancy tests performed at screening and at immediately before the first dose of the study 
drug should be confirmed to show negative. 
In addition, male subject must be advised not to donate sperm from the time of signing on the 
informed consent form to 6 months after the last dose of the study drug. 
9.1.13 
Pregnancy 
If any subject is found to be pregnant during the study, she should be withdrawn and any 
sponsor-supplied study drugs should be immediately discontinued. 
Any pregnancies occurred during the period from the first dose of the study drug (Visit 2) to 6 
months after the last dose of the study drug should be reported, using the given report form, to the 
contact listed in the Annex. In addition, any pregnancies in the partner of a male subject during the 
period from the first dose of the study drug (Visit 2) to 6 months after the last dose of the study 
drug should also be recorded following authorization from the subject’s partner. 
Should the pregnancy occur during or after administration of the blinded drug, the investigator 
must inform the subject of their right to receive treatment information. Upon subject’s request, the 
investigator will open the Emergency Key. Subjects revealed not to have received MLN0002 in 
the study are not required to be followed. 
Upon consent with the female subject or the female partner of the male subject, the investigator 
should inform their physician (an obstetrician) that the subject/female partner of the subject was 
participating in the clinical study at the time of conception with details of treatment the subject 
received (blinded or unblinded, as applicable). 
All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted. 


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9.1.14 
ECG Procedure 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the study 
site) will interpret the ECG using 1 of the following categories: within normal limits, abnormal but 
not clinically significant, or abnormal and clinically significant. 
9.1.15 
PML Evaluation 
PML will be evaluated based on the PML checklists (Appendix D), which will be performed 
before administration of the study drug if it is the day of study drug administration. 
At first, the subjective symptoms will be checked by use of the Subjective PML checklist. When 
any subjective symptoms are recognized, the corresponding objective findings will be checked by 
use of the Objective PML checklist. When any abnormalities are found in the objective findings as 
well, the subject will be evaluated in accordance with the algorithm for subject evaluation in the 
PML checklists. 
The evaluation result based on the PML checklists will be recorded in the (e)CRF. Any subjective 
symptoms or objective findings found in the PML checklists will be collected as AEs as well. 
9.1.16 
Tuberculosis test 
As a sample for tuberculosis test, 7 mL of the whole blood will be collected. The laboratory site for 
the study will collect the sample to conduct tuberculosis test by means of T-SPOT. The 
tuberculosis test using QuantiFERON may be conducted, when routinely employed in the study 
site. The test results, i.e. positive, negative, indeterminate or indeterminable, will be recorded in 
the (e)CRF. 
9.1.17 
Chest Imaging Procedure 
Existence of findings of tuberculosis will be confirmed by the chest X-ray or chest CT. The 
imaging performed within 3 months before evaluation as a part of general practice not as a test for 
the study may be used, if available. Date of Examination and existence of findings of tuberculosis 
will be recorded in the (e)CRF. 
Of note, the imaging obtained before acquisition of the informed consent may be used at screening. 
9.1.18 
Pharmacogenomic Sample Collection 
For exploratory research to identify a predictable marker of drug response, 5 mL of the whole 
blood will be once collected as a pharmacogenomic sample from subjects entered into the 
induction phase and who agreed with the pharmacogenomic research at the earliest possible time 
during the period from Visit 2 to the end of the study. 
However, the pharmacogenomic samples will not be collected from subjects with a history of an 
allogeneic bone marrow transplantation. 
See the separately specified written procedure for collecting, handling, and storing the 
pharmacogenomic samples. 


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9.1.19 
Pharmacokinetic Sample Collection and Analysis 
Pharmacokinetic samples will be collected only in study sites with a cooled centrifuge. In these 
study sites, 3 mL of the venous blood will be collected for determination of serum MLN0002 
concentration. At the visit for study drug administration, the blood should be sampled immediately 
before administration, where possible. The date and time of the blood sampling will be recorded in 
the (e)CRF. 
The collected blood will be left standing at room temperature for approximately 30 minutes and 
centrifuged at 3,000 rpm at 4°C for 10 minutes. The obtained serum will be cryopreserved in a 
preset freezer at a temperature of ≤-20°C until collection. The samples will be handled in 
accordance with the separately specified procedures. 
Serum MLN0002 concentration will be determined in 
 by means of 
Enzyme-Linked ImmunoSorbent Assay (ELISA). However, samples of subject who have not 
received MLN0002 throughout the induction and maintenance phases will not be determined. 
9.1.20 
Sample Collection for the HAHA/Neutralizing Antibody Test 
Samples for the HAHA/neutralizing antibody test will be collected only in study sites with a 
cooled centrifuge. In these study sites, 5 mL of the venous blood will be collected for the 
HAHA/neutralizing antibody test. At the visit for study drug administration, the blood should be 
sampled immediately before administration, where possible. The date and time of the blood 
sampling will be recorded in the (e)CRF. 
The collected blood will be left standing at room temperature for approximately 30 minutes and 
centrifuged at 3,000 rpm at 4°C for 10 minutes. The obtained serum will be cryopreserved in a 
preset freezer at a temperature of ≤-20°C until collection. The samples will be handled in 
accordance with the separately specified procedures. 
Serum concentration of HAHA will be determined in 
 by means of ELISA. 
However, samples of subjects who have not received MLN0002 throughout the study will not be 
determined. 
Furthermore, the serum neutralizing antibody will be determined only for the HAHA-positive 
samples. The serum neutralizing antibody will be determined in 
 
 by means of the Cell Based Assay. 
9.1.21 
Record of Subjects Who Withdrew during the Screening Phase 
The (e)CRFs will be documented for all subjects who signed the informed consent and withdrew 
during the screening phase. The primary reason for screen failure is recorded in the (e)CRF by the 
following categories: 
• Pretreatment Event/AE 
• Did not meet inclusion criteria or met exclusion criteria <specify the reason> 
• Major protocol deviation 
PPD
PPD
PPD
PPD


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• Lost to follow-up 
• Voluntary withdrawal <specify the reason> 
• Study termination 
• Pregnancy 
• Other <specify the reason> 
The Subject Identification Codes applied to subjects who withdrew during the screening phase will 
not be reused. 
9.1.22 
Enrollment into the induction Phase 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for enrollment into the induction phase at Week 0 (Visit 2). At enrollment into the induction phase, 
the following information will be registered on the website of the registration center where the 
study drug number to be dosed at Week 0 (Visit 2) will be provided. 
• Treatment history with anti-TNFα antibodies 
• Concomitant use of immunomodulators (AZA, 6-MP or MTX) 
• Concomitant use of corticosteroids 
• The subject diary data for calculation of the CDAI score at Week 0 (Visit 2) 
9.1.23 
Registration of the Results of the Primary Efficacy Endpoint in the Induction 
Phase/Enrollment into the Maintenance Phase 
The subject diary data for calculation of the CDAI score at Week 10 (Visit 5) will be registered on 
the website of the registration center, by which adjudication results for clinical 
response/no-response may be obtained. Only CDAI-70 responders at Week 10 will be enrolled 
into the maintenance phase at Week 14 (Visit 6). At enrollment into the maintenance phase, the 
study drug number to be dosed at Week 14 (Visit 6) will be obtained on to the website of the 
registration center. 
See Section 9.1.24 for non-responders at Week 10. 
9.1.24 
Enrollment into the Open-label Cohort 
Non-responders at Week 10 may be enrolled into the open-label cohort at Week 10 (Visit 5). In 
addition, either subjects who experienced disease worsening or received rescue treatments during 
the maintenance phase, or completed Week 60 of the maintenance phase may be enrolled into the 
open-label cohort. However, subjects who withdrew before the examination at Week 10 (Visit 5), 
or subjects who respond at Week 10 and withdrew before enrollment into the maintenance phase at 
Week 14 (Visit 6) are not allowed to be enrolled into the open-label cohort. 
The procedures for enrollment into the open-label cohort is provided below; 


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• Non-responders at Week 10: 
Non-responders at Week 10 will be judged whether to be enrolled into the open-label cohort 
after completion of examination at Week 10 (Visit 5). For enrolled into the open-label cohort, 
the study drug number to be dosed at Week 0x (Visit 1x) will be obtained on the website of the 
registration center. 
• Subject experienced disease worsening or received rescue treatments during the maintenance 
phase: 
Subjects who experienced disease worsening or received rescue treatments during the 
maintenance phase will be judged whether to be enrolled into open-label phase after 
completion of the evaluation at withdrawal of the maintenance phase. However, these subjects 
will be enrolled into open-label phase 3 to 9 weeks after the last dose in the maintenance phase. 
For enrollment into the open-label cohort, the study drug number to be dosed at Week 0x 
(Visit 1x) will be obtained on the website of the registration center. 
• Subjects completed Week 60: 
Subjects who completed Week 60 will be judged whether to be enrolled into the open-label 
cohort after completion of examination at Week 60 (Visit 18). For enrollment into the 
open-label cohort, the study drug number to be dosed at Week 0x (Visit 1x) will be obtained on 
the website of the registration center. 
9.2 
Study Drug Compliance 
The study drugs dosed to the subjects will be recorded in the (e)CRF for the dates, times of 
start/end of the infusion. When infusion of a study drug was not completed, dosage and reasons for 
dose incomplete will be recorded in the (e)CRF. 
9.3 
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). 
9.3.1 
The Screening Phase (Visit 1) 
Physical examination and tests are conducted 21 to 7 days before the first dose of the study drug. 
Subjects will be screened in accordance with predefined inclusion and exclusion criteria as 
described in Section 7.0. See Section 9.1.21 for procedures for documenting screening failures. 
Procedures to be completed at Screening Phase (Visit 1) include: 
• Informed consent 
• Demographic data, body height, medical history, pretreatment drugs, and complications 
• Physical examination, vital signs 
• Body weight 


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• ECG 
• Chest Imaging Procedure* 
• Tuberculosis test 
• PML checklists 
• Laboratory tests (see Appendix A for test items) 
• Concomitant drugs and treatments 
• PTEs assessment 
* Not required when a chest image performed within 3 months is available (the image taken 
outside the study and/or prior to the informed consent date is acceptable). 
9.3.2 
Induction Phase 
9.3.2.1 
Baseline Evaluation/Enrollment into the induction Phase (Visit 2) 
Subjects will be screened in accordance with predefined inclusion and exclusion criteria as 
described in Section 7.0. Subjects who meet all of the inclusion criteria and none of the exclusion 
criteria are eligible for enrollment into the induction phase at Week 0 (Visit 2) as per 
Section 9.1.22. See Section 9.1.21 for procedures for documenting subjects not eligible for 
enrollment into the induction phase. 
Tests/observations/assessments to be performed at Week 0 (Visit 2) include: 
• Physical examination, vital signs 
• Body weight 
• ECG 
• PML checklists 
• Laboratory tests (see Appendix A for test items) 
• CDAI score (including determination of Ht level. See Section 9.1.9 for details) 
• Check of the patient diary 
• IBDQ 
• Blood sampling for HAHA /neutralizing antibody test 
• Blood sampling for pharmacogenomics (in subjects providing agreements) 
• Concomitant drugs and treatments 
• Evaluation of Pretreatment Event/AE 
• Issuance of study drug numbers/administration 


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9.3.2.2 
Administration in the Induction Phase (Visits 3 and 4) 
Procedures to be completed at Week 2 (Visit 3) and Week 6 (Visit 4) include: 
• Physical examination, vital signs 
• Body weight 
• PML checklists 
• Laboratory tests (see Appendix A for test items) 
• CDAI score (including determination of Ht level. See Section 9.1.9 for details) 
• Check of the patient diary 
• Blood sampling for serum drug concentration 
• Concomitant drugs and treatments 
• Evaluation of AEs 
• Issuance of study drug numbers/administration 
9.3.2.3 
Evaluation of Primary Efficacy Endpoint (Visit 5)/Withdrawal during the Induction 
Phase 
Procedures to be completed at Week 10 (Visit 5) include: The same procedures will be completed 
at the earliest possible visit for subjects who withdrew in the course of the induction phase. 
• Physical examination, vital signs 
• Body weight 
• ECG 
• Laboratory tests (see Appendix A for test items) 
• CDAI score (including determination of Ht level. See Section 9.1.9 for details) 
• Check of the patient diary 
• IBDQ 
• Blood sampling for HAHA /neutralizing antibody test 
• Blood sampling for serum drug concentration 
• Concomitant drugs and treatments 
• Evaluation of AEs 
An adjudication result for clinical response/not-response at Week 10 (Visit 5) will be obtained 
from the registration center. Responders will be enrolled into the maintenance phase at Week 14 
(Visit 6). Non-responders may be enrolled into the open-label cohort at Week 10 (Visit 5). 


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9.3.3 
Maintenance Phase 
9.3.3.1 
Enrollment into the maintenance Phase (Visit 6) 
Responders at Week 10 (Visit 5) will be enrolled into the maintenance phase at Week 14 (Visit 6) 
in accordance with Section 9.1.23. 
Procedures to be completed at Week 14 (Visit 6) include: 
• Physical examination, vital signs 
• Body weight 
• PML checklists 
• Laboratory tests (see Appendix A for test items) 
• CDAI score (including determination of Ht level. See Section 9.1.9 for details) 
• Check of the patient diary 
• IBDQ 
• Blood sampling for serum drug concentration 
• Concomitant drugs and treatments 
• Evaluation of AEs 
• Issuance of study drug numbers/administration 
9.3.3.2 
Administration in the Maintenance Phase (Visits 7 through 17) 
Procedures to be completed at Week 18 (Visit 7) through Week 58 (Visit 17) include: 
• Physical examination, vital signs 
• Body weight 
• PML checklists (only at Visits 8, 10, 12, 14 and 16) 
• Laboratory tests (only at Visits 8, 10, 12, 14 and 16. See Appendix A for test items) 
• CDAI score (including determination of Ht level. See Section 9.1.9 for details) 
• Check of the patient diary 
• IBDQ (only at Visit 12) 
• Blood sampling for HAHA/neutralizing antibody test (only at Visit 10) 
• Blood sampling for serum drug concentration (only at Visits 8 and 10) 
• Concomitant drugs and treatments 


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• Evaluation of AEs 
• Issuance of study drug numbers/administration (only at Visits 8, 10, 12, 14 and 16) 
9.3.3.3 
Evaluation of Primary Efficacy Endpoint in the Maintenance Phase 
(Visit 18)/Withdrawal during the Maintenance Phase 
Procedures to be completed at Week 60 (Visit 18) include: The same procedures will be completed 
at earliest possible visit for subjects who withdrew in the course of the maintenance phase. 
• Physical examination, vital signs 
• Body weight 
• ECG 
• Laboratory tests (see Appendix A for test items) 
• CDAI score (including determination of Ht level. See Section 9.1.9 for details) 
• Check of the patient diary 
• IBDQ 
• Blood sampling for HAHA /neutralizing antibody test 
• Blood sampling for serum drug concentration 
• Concomitant drugs and treatments 
• Evaluation of AEs 
Subjects who completed the examination at Week 60 (Visit 18) may be enrolled into the 
open-label cohort at Week 60 (Visit 18). Furthermore, subjects who experienced disease 
worsening or received rescue treatments during the maintenance phase may be enrolled into the 
open-label cohort after completion of the evaluation at withdrawal of the maintenance phase. 
9.3.4 
Open-label Cohort 
9.3.4.1 
Enrollment into the open-label cohort (Visit 1x) 
Subjects who have been decided to be enrolled into the open-label cohort as per Section 9.1.24 will 
be enrolled into the open-label cohort. Procedures to be completed at Week 0x (Visit 1x) include: 
• PML checklists 
• Concomitant drugs and treatments 
• Evaluation of AEs 
• Issuance of study drug numbers/administration 


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9.3.4.2 
Administration in the Open-label Cohort (Visits 2x through 24x) 
Procedures to be completed at Week 2x (Visit 2x) through Week 90x (Visit 24x) include: 
• Physical examination, vital signs 
• Body weight 
• PML checklists (only at Visits 2x, 3x, 5x, 7x, 9x, 11x, 13x, 15x, 17x, 19x, 21x and 23x) 
• Laboratory tests (only at Visits 2x, 3x, 5x, 7x, 9x, 11x, 13x, 15x, 17x, 19x, 21x and 23x. See 
Appendix A for test items) 
• CDAI score (including determination of Ht level. See Section 9.1.9 for details) 
• Check of the patient diary 
• Blood sampling for HAHA /neutralizing antibody test (only at Visits 4x, 9x and 17x) 
• Concomitant drugs and treatments 
• Evaluation of AEs 
• Issuance of study drug numbers/administration (only at Visits 2x, 3x, 5x, 7x, 9x, 11x, 13x, 15x, 
17x, 19x, 21x and 23x). 
9.3.4.3 
The Final Evaluation of the Open-label Cohort (VIST 25x)/Withdrawal during the 
Open-label Cohort 
Procedures to be completed at Week 94x (Visit 25x) include: The same procedures will be 
completed at the earliest possible visit for subjects who withdrew in the course of the open-label 
cohort. 
• Physical examination, vital signs 
• Body weight 
• ECG 
• PML checklists 
• Laboratory tests (see Appendix A for test items) 
• CDAI score (including determination of Ht level. See Section 9.1.9 for details) 
• Check of the patient diary 
• Blood sampling for HAHA /neutralizing antibody test 
• Concomitant drugs and treatments 
• Evaluation of AEs 


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• Issuance of study drug numbers/administration (not for subjects who withdrew from the 
open-label cohort) 
9.3.5 
The Unscheduled Visits 
The following procedures will be preferably completed at the unscheduled visits of any subjects 
who received the study drug due to worsening of CD, etc., if any. 
• Body weight 
• CDAI score (including determination of Ht level. See Section 9.1.9 for details) 
• Check of the patient diary 
• Concomitant drugs and treatments 
• Evaluation of AEs 
Besides the above, additional tests may be performed as needed. 
The subject’s applicability to the disease worsening criteria (see Section 3.1 for definition) will be 
judged in consideration of test results performed at the unscheduled visit as well. In such cases, the 
interval between visits will be not less than 1 week, where possible. 
9.3.6 
Predefined Study Completion 
The same examination as those to be performed at Week 94x (Visit 25x) will be performed at 
study completion predefined at 46 weeks after the last subject enrollment into the open-label 
cohort. 
The sponsor will inform the investigator of the scheduled study completion date well before the 
date. 
Upon receipt of notice of the scheduled study completion date, the investigator will decide the 
termination visits for each subjects to undergo the same evaluation as those scheduled at Week 94x 
(Visit 25x). 
9.3.7 
At 16 weeks after the Last Dose 
The following evaluation will be conducted at 16 weeks after the last dose of the study drug for all 
subjects who received the study drug. Even when the study will be terminated before 16 weeks 
have passed after the last dose of the study drug, the same evaluation will also be conducted in 
principle. 
For all subjects who received the study drug, the investigator must complete the End of Study 
(e)CRF page. 
• Physical examination, vital signs 
• Body weight 


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• ECG 
• Chest Imaging Procedure* 
• PML checklists 
• Laboratory tests (see Appendix A for test items) 
• Blood sampling for HAHA /neutralizing antibody test 
• Concomitant drugs and treatments 
• Evaluation of AEs 
* Not required when a chest image performed within 3 months is available (the image taken 
outside the study is acceptable). 
9.3.8 
Post Study Care 
The study drugs will not be provided after the last dose. 
9.4 
Retention and Disposal of Biological Samples 
The samples of 5 mL of the whole blood collected for Pharmacogenomic Research will be 
cryopreserved in 
 (Annex 1). 
The retention period should be 20 years from the first sampling day for Pharmacogenomic 
Research in the study. 
Upon subject’s request of disposal of his/her samples during the retention period, the study site 
will request 
 to dispose of the samples via the sponsor 
as per the procedures. 
 will dispose of the samples in 
accordance with the procedures, which will be reported to the study site and the sponsor. However, 
the above is not applicable, when all documents (e.g., medical records) to be used for identification 
of subjects have been disposed of after study termination, so that any samples and subjects are 
impossible to be linked together. 
Of note, even though the above linkage may be possible, when Pharmacogenomic Research has 
been conducted already, the sponsor may keep the anonymized results of the Pharmacogenomic 
Research with the residual samples disposed. 
The sponsor will create a necessary written procedure as establishing a necessary control system 
for protecting subjects’ personal information and predefining the standards for collection, 
retention and disposal of samples. 
9.5 
Follow-Up Survey 
In the study, the follow-up survey will be conducted via telephone, etc., by using the follow-up 
survey form (Appendix E) every 6 months up to 2 years (maximum) after the last dose of the study 
drug or until the marketing approval date of the drug, whichever comes earlier, for any subjects 
PPD
PPD
PPD


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who received the study drug (including subjects who withdrew). The follow-up survey include the 
following items. Of note, the follow-up survey forms will be collected by the sponsor. 
The survey to be completed at 6, 12, 18 and 24 months4 after the last dose of the study drug: 
• Diagnoses of colon dysplasia, cancer, lymphoma or other types of cancer 
• Diagnoses of PML 
• Enterectomy 
The survey to be completed only once at 6 months4 after the last dose of the study drug: 
• Diagnoses of infection requiring hospitalization 
• Female subjects: pregnancy 
• Male subjects: pregnancy of his female partner 
                                               
4The window is ±1 month. 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
PTEs 
A PTE is defined as any untoward medical occurrence in a subject who has signed the informed 
consent to participate in a study but prior to 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 study subject who received a drug 
(including a study drug); it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
10.1.3 
Additional Points to Consider for PTEs and AEs 
An untoward finding generally may include: 
• A new diagnosis or those representing unexpected worsening of a pre-existing condition 
(intermittent events of pre-existing conditions of an underlying disease should not be 
considered PTEs or AEs.) 
Intermittent events of pre-existing conditions of an underlying disease in the study include 
some CD-specific symptoms such as diarrhea or abdominal pain. These symptoms, which may 
be sustained or varied in the course of the study depending on medical histories of each subject, 
will be considered as medically-predictable clinical symptoms in the disease addressed in the 
study, and therefore, not be subjected for collection of AEs. These symptoms corresponding to 
disease activity will be assessed as a part of the CDAI score. However, worsening of disease 
activity (e.g., abdominal pain aggravated beyond a normal range, or newly-observed 
symptoms or findings) will be collected as AEs. Onset or worsening of extra-intestinal 
manifestations in the course of the study will be collected as AEs. 
• Those requiring therapeutic intervention 
• Those requiring an invasive diagnostic procedure 
• Those requiring discontinuation or dose modification of the study drug or a concomitant drug 
• Those considered as unfavorable by the investigator for any reason. 
Diagnoses vs signs and symptoms: 
PTEs and AEs (hereinafter called as PTEs/AEs) will be described as diagnoses. Accompanying 
signs (including abnormal laboratory values or ECG findings) or symptoms should NOT be 


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recorded as PTEs/AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as PTEs/AEs. 
Laboratory values and ECG parameters: 
Changes in laboratory values or ECG parameters are considered as PTEs/AEs only when they are 
judged to be clinically significant (i.e., when some action or intervention is required or if 
investigator judges the change as being beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation or 
monitoring of an abnormality is not considered an intervention. 
If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only should be reported 
appropriately as a PTE or as an AE. 
Pre-existing conditions: 
Any pre-existing diseases or conditions prior to acquisition of the informed consent will be 
recorded as complications not as PTEs/AEs. Baseline evaluations (e.g., laboratory tests, ECG, 
X-rays etc.) should NOT be recorded as PTEs unless related to study procedures. However, 
abnormal findings caused by the baseline evaluation (e.g., internal hemorrhage at blood sampling) 
are recorded as PTEs to be entered in the (e)CRF. Investigators should ensure that the event term 
recorded captures the change in the condition (e.g., “worsening of…”). 
If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy), any occurrence of an 
episode should be captured as a PTE/AE only when the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the change 
in the condition from Baseline (e.g., “worsening of…”). If a subject has a degenerative concurrent 
condition (e.g., cataracts, rheumatoid arthritis), worsening of the condition should be captured as a 
PTE/AE only when occurring to a greater extent to that which would be expected. Again, 
investigators should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”). 
Worsening of PTEs/AEs: 
If the subject experiences a worsening or complication of a PTE after starting administration of the 
study drug, the worsening or complication should be recorded appropriately as an AE. 
Investigators should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”). 
If the subject experiences a worsening or complication of an AE after any change in the 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 (e.g., “worsening of…”). 
Changes in severity of AEs/Serious PTEs: 
If the subject experiences changes in severity of an AE/serious PTE, the event should be captured 
once with the maximum severity recorded. 


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Preplanned surgeries or procedures: 
Preplanned procedures (surgeries or therapies) that were scheduled prior to the time of signing on 
the informed consent form are not considered PTEs/AEs. However, if a preplanned procedure is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE/AE. Complications 
resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
Elective procedures performed where there is no change in the subject’s medical condition should 
not be recorded as PTEs/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. 
Investigator must make the distinction between exacerbation of pre-existing illness and lack of 
therapeutic efficacy. 
Overdose: 
Cases of overdose with any drug are NOT considered AEs, but instead will be documented on an 
Overdose page of the (e)CRF. Any manifested side effects at overdose will be considered AEs and 
will be recorded on the AE page of the (e)CRF. 
10.1.4 
SAEs 
SAEs are defined as the following out of any untoward medical occurrence in a study subject who 
received a drug (regardless of dosages); 
1. Results in DEATH. 
2. Is LIFE THREATENING* 
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. 
6. Other medically significant conditions  
May require intervention to prevent the above items 1 through 5, or may expose the subject to 
danger, even though the event is not immediately life-threatening or fatal or does not result in 
hospitalization. That includes any events or synonyms described in the Takeda Medically 
Significant AE List (Table 10.a). 
*The “life-threatening” here represents that life of the subject was threatened by onset of the event, 
and does not represent hypothetically that a more sever event might cause death. 


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Table 10.a 
Takeda Medically Significant AE List 
Acute respiratory failure / acute respiratory distress 
syndrome 
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia 
Malignant hypertension 
Convulsive seizures 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/Stevens-Johnson 
syndrome 
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis 
Neuroleptic malignant syndrome / malignant hyperthermia 
Spontaneous abortion / stillbirth and fetal death 
Confirmed or suspected transmission of infectious agent by a 
medicinal product 
Confirmed or suspected endotoxin shock 
 
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 10.2.3). 
10.1.5 
Intensity of PTEs and AEs 
Intensity of PTEs/AEs will be classified/defined as per the following. 
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. 
10.1.6 
Causality of AEs 
Causal relationship between AEs and study drugs will be classified/defined as per the following. 
Related: 
An AE that follows a temporal sequence from administration of a drug (including the course after 
withdrawal of the drug), or for which possible involvement of the drug can be argued, although 
factors other than the drug, such as underlying diseases, complications, concomitant drugs, and 
concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a temporal sequence from administration of a drug and/or that can 
reasonably be explained by other factors, such as underlying diseases, complications, concomitant 
drugs, and concurrent treatments. 
10.1.7 
Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs/AEs. The 
relationship should be assessed as Yes if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related. 


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10.1.8 
Start Dates 
Onset dates of PTEs/AEs will be decided as per the following criteria; 
PTEs/AEs 
Onset Dates 
Signs, symptoms or disease 
(diagnoses) 
The date when the subject or the investigator was firstly aware of the 
sign/symptom. 
Asymptomatic disease 
The date of the definitive diagnosis on or after the diagnostic examination, 
even when any obsolete findings or other estimated onset time was found in 
the examination. 
Worsening of complications or PTEs 
The date when the subject or the investigator was firstly aware of the 
worsening of the disease or symptoms. 
Newly-indicated abnormal laboratory 
values in values shown to be normal in 
the baseline test after acquisition of the 
informed consent (PTEs) 
Newly-indicated abnormal laboratory 
values after the first dose of the study 
drug (AEs) 
The date of the examination in which the clinically relevant abnormality was 
found. 
Worsening of abnormal laboratory 
values found in the baseline test after 
acquisition of the informed consent 
(PTEs) 
Worsening of abnormal laboratory 
values found at the first dose of the 
study drug (AEs) 
The date of the examination in which the medically-judged obvious 
increase/decrease/elevation/reduction was found by change of the test 
results. 
10.1.9 
Stop Date 
The stop date is defined as the date when the PTE/AE was recovered/resolved (including 
recovered/resolved with sequelae), or the date of death when caused by the PTE/AE. PTEs/AEs, 
which may not be confirmed for recovery/resolution at the study termination, will be judged as 
ongoing. 
10.1.10 Frequency 
Episodic AEs/serious PTE (e.g., vomiting) or those which occur repeatedly over a period of 
consecutive days are “intermittent.” All other events will be recorded as “ongoing.” 
10.1.11 Action Concerning Study Drug 
Action concerning study drug will be classified/defined as per the following. 
Drug withdrawn 
A study drug is stopped due to the particular AE. 
Dose not changed 
When the dose was not changed after the AE, when the dose 
discontinuation/reduction/increase was due to other AEs than the AE, or when the dose 
suspension/reduction/etc., was due to other reason (e.g., carelessness of the subject) than AEs. 
Unknown 
Only to be used if it has not been possible to determine what action has been taken. 


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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. 
10.1.12 Outcome 
Outcome of PTEs/AEs will be classified/defined as per the following. 
Classification 
Criteria for judgment 
Recovered/Resolved 
− 
Recovery or resolution of the symptom/finding 
− 
Recovery to the normal value, the value before the first dose (for AEs), or the value at 
baseline after acquisition of the informed consent (for PTEs). 
Recovering/Resolving 
− 
The severity is lowered by one or more degree(s) 
− 
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 a cause other than the particular AE/serious PTE with the 
condition remaining “recovering/resolving.” 
Not recovered/ 
not resolved 
− 
There is no change in the diagnosis, signs or symptoms; 
− 
The intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of 
the observed study period has got worse than when it started; 
− 
Irreversible congenital anomaly 
− 
The subject died from another cause with the particular AE/serious PTE state 
remaining “Not recovered/not resolved.” 
Resolved with sequelae − 
- Resulting in dysfunction obstructing daily activity 
Fatal 
− 
The PTE/AE are considered to have a direct relationship with the death. 
− 
The “direct relationship” here represents that the PTE/AE was the cause of the death, 
or clearly contributed to the death. 
− 
Outcome should not be recorded as death for the PTE/AE not adjudicated 
(judged/estimated) as the direct cause of death in the same subject. 
− 
The date of death will be recorded for fatal outcomes. 
Unknown 
− 
The course of the AE/serious PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
10.2 
Procedures 
10.2.1 
Collection and Reporting of AEs 
10.2.1.1 
PTE and AE Collection Period 
PTEs will be continuously collected during the period from acquisition of the informed consent to 
the first dose of the study drug (Visit 2), or until withdrawal when decided before the first dose of 
the study drug. 


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AEs will be continuously collected during the period from the first dose of the study drug (Visit 2) 
to the end-of-study examination at 16 weeks after the last dose of the study drug. 
10.2.1.2 
PTE and AE Reporting 
Subjects may report PTEs/AEs occurring at any other time during the study. PTEs/AEs not 
emerging at visit will be obtained from subjects with questions such as “How was your condition 
after the last visit?.” 
Investigators will follow all subjects who developed a serious PTE until recovery/resolution of the 
event or recovery of the clinically relevant abnormal test value to the baseline value after 
acquisition of the informed consent, or otherwise (for persistent/irreversible PTEs) until 
establishment of sufficient rationale for the observed change. Subjects who developed not-serious 
PTEs are not required to be followed irrespective of relationship with study procedures in the 
protocol. 
Investigators will follow all subjects who developed an AE (with or without relationship with the 
study drug) until recovery/resolution of the event or recovery of the clinically relevant abnormal 
test value to the value before the first dose of the study drug, or otherwise (for 
persistent/irreversible AEs) until establishment of sufficient rationale for the observed change. All 
PTEs/AEs should be recorded in the (e)CRF. For a PTE/AE, the name, onset date, 
recovery/resolution date, start period, frequency, severity, causal relationship with the study drug 
(related/not-related), disposition of the study drug, outcome, causal relationship with the study 
procedures (if related, the possible causal procedure), and seriousness will be recorded. 
For AEs that occurred during infusion of the study drug or the period from initiation to 1 hour after 
completion of infusion, onset time and association with infusion will be recorded in the (e)CRF. 
AEs/serious PTEs will be followed until the PTE/AE is recovered/resolved or the investigator 
judges not to follow them any longer. 
10.2.2 
Collection and Reporting of SAEs 
When a SAE occurs during the AE collection period, it should be reported according to the 
following procedure: PTEs that fulfill 1 or more of the serious criteria described in Section 10.1.4 
are also considered as SAEs to be reported and followed in the same manner. 
Investigators should report the SAE within 1 working day after onset of the SAE or receipt of the 
notice of the event onset from a subject, etc., to the sponsor (see the Annex for contacts). 
Additionally, the investigator should submit the detailed formal reports within 10 calendar days. 
Of note, the following is specified as the essential items to be reported within 1 working day, 
however, other items should be provided as much as possible. 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject Identification Code 
• Investigator’s name. 


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• Name of the study drugs 
• Causality assessment 
Any SAE spontaneously reported to the investigator following the AE collection period (including 
the follow-up survey period) should be reported to the sponsor. 
10.2.3 
Drug-induced Liver Function Test Abnormal Possibly Leading to Sever Liver 
Disorder 
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.1.11 must also be 
performed. These abnormal liver function test values, when judged not to be explained by any 
other factors, should be reported as SAEs (see Section 10.2.2). 
10.3 
Follow-up of SAEs 
For information obtained after submission of the detailed report, the investigator should describe 
them in a copy of the submitted SAE Report Form or as an independent document in order to be 
submitted to the contact listed in the Annex. Copies of any relevant data from the hospital notes 
(e.g., 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. 
10.3.1 
SAE Reports to Investigators, the IRBs and Regulatory Authorities 
The sponsor should report any suspected unexpected serious adverse reactions (SUSARs) and 
other SAEs subjected to the expedited report to regulatory authorities, investigators and the heads 
of the study sites in accordance with the laws/regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or its 
designee, SUSARs will be submitted to regulatory authorities within 7 days for fatal and 
life-threatening events and 15 days for other serious events. Similarly, the sponsor will submit 
expedited reports for other significant safety information considered to substantially affect 
benefit/risk of the study drug, or continuation of treatment or the study itself. The copies of these 
expedited report-related documents will be submitted to the IRBs in the study sites. 
 


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11.0 
STUDY-SPECIFIC COMMITTEES 
11.1 
Independent Adjudication Committee for PML 
In the study, the Independent Adjudication Committee for PML established to evaluate the PML 
risk will be utilized. When any PML risk, which may not be ruled out in a neurologist’s 
examination in accordance with the PML checklists in the Appendix D, will be adjudicated in the 
Independent Adjudication Committee for PML based on the subject data provided. Detailed 
procedures should be in accordance with the separately specified written procedure. 


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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 conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary and Japanese Drug Dictionary. 
12.1 
CRFs (Electronic and Paper) 
Completed (e)CRFs are required for each subject signed the informed consent. 
The sponsor or the its designee will provide the study sites with access authority to the eCRF. The 
sponsor will make arrangements to train appropriate site staff in the use of the eCRF. These forms 
are used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. Data will be entered directly to the (e)CRF in Japanese. 
Reasons for significant corrections should additionally be included. All new additions are to be 
made with the date and signature or seal affixed. 
The principal investigator will verify accuracy and completeness of the records in the (e)CRF and 
electrically sign on the applicable pages. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the (e)CRFs. 
The following data will not be recorded directly into the (e)CRFs; 
1) Laboratory test values (except urine pregnancy test) 
2) Serum concentrations of MLN0002 
3) HAHA assessment 
4) Neutralizing antibody assessment 
5) CDAI score (including each subscore) 
6) Adjudication of clinical response/no-response at Week 10 (Visit 5) 
7) Items of follow-up survey 
After the database lock of clinical study database, any change of, modification of or addition to the 
data on the (e)CRFs should be made by the investigator with use of change and modification 
records of (e)CRFs (Data Clarification Form) provided by the sponsor. The principal investigator 
must review the Data Clarification Form for completeness and accuracy, and must sign, or sign 
and seal, and date the form. 
The (e)CRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by study monitors. 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 (e)CRFs. The 
completed (e)CRFs 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 
Investigators or the heads of the study sites should retain the following documents in addition to 
records clearly specified in Section 12.1 and the study-specific documents for inspections or audits 
by regulatory authorities and the sponsor or its designee. These documents include the subject list 
for screening, medical records, worksheets for the study, the original informed consents with the 
signatures/dates, electronic copies of the (e)CRFs including tracking of audit certifications, and 
the drug control records. In addition, investigators and the heads of the study site should retain the 
retentive essential documents until the following 1) or 2), whichever comes later. However, when 
the sponsor requires a longer retention period than the above, the retention period and manner will 
be discussed among the sponsor and the heads of the study sites. 
1) The marketing approval day for the drug (when the study was terminated, for 3 years since 
receipt of the termination notice) 
2) The same day after 3 years as the study termination or completion day 
Furthermore, investigators and the heads of the study sites should retain the retentive essential 
documents until receipt of the notice stating that these documents should not be retained any more 
from the sponsor. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
Since the study has different objectives in the induction phase and maintenance phases/open-label 
cohort, analyses will be conducted separately among these. 
The Statistician in the study will prepare and finalize the Statistical Analysis Plan prior to 
blind-breaking. The document will provide further details regarding the definition of analysis 
variables and analysis methodology to address all study objectives. 
The double-blinded review should be conducted prior to blind-breaking. In the double-blinded 
review, accuracy and completeness of the study data, feasibility of subject evaluation, and 
acceptability of the planned analysis methodology will be evaluated. 
The data for marketing application will be analyzed, which includes data of all subjects as fixed on 
the cut-off date for marketing application. Additionally, the open-label cohort will be analyzed 
separately at the time when the last subject completed the study. 
13.1.1 
Analysis Sets 
In the study, 3 types of analysis sets will be used in the induction phase, i.e., the “Full Analysis Set 
of the induction phase,” “Per Protocol Set of the induction phase” and “Safety Analysis Set of the 
induction phase.” 
The “Full Analysis Set of the induction phase,” a primary population for the efficacy analysis in 
the induction phase, is defined as “subjects who were randomized and received at least one dose of 
the study drug in the induction phase.” 
Three types of analysis sets will be used in the maintenance phase, i.e., the “Full Analysis Set of 
the maintenance phase,” “Per Protocol Set of the maintenance phase” and “Safety Analysis Set of 
the maintenance phase.” 
The “Full Analysis Set of the maintenance phase,” a primary population for the efficacy analysis in 
the maintenance phase, is defined as “subjects who were randomized and received at least one 
dose of the study drug in the maintenance phase.” 
Two types of analysis sets will be used in the open-label cohort, i.e., the “Full Analysis Set in the 
open-label cohort” and “Safety Analysis Set in the open-label cohort.” 
The “Safety Analysis Set in the open-label cohort” in the open-label cohort, a population for the 
safety analysis, is defined as “subjects who received at least one dose of the study drug in the 
open-label cohort.” 
The detailed definitions of analysis sets are specified separately in the “Data-Handling Rules for 
Analyses.” 


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The sponsor will verify acceptability of definition of the analysis sets and the data-handling rules 
for analyses in consultation with medical specialists before database lock, if needed, and add 
matters not addressed in the plan for finalization as the “Data-Handling Rules for Analyses.” 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
The major subject backgrounds will be calculated by each “treatment group in the induction phase” 
and in the consolidated “treatment groups in the induction phase” in the “all subjects randomized 
in the induction phase.” 
The major subject backgrounds will be calculated by each “treatment group in the maintenance 
phase” and in the consolidated “treatment groups in the maintenance phase” in the “all subjects 
randomized in the maintenance phase.” 
The major subject backgrounds will be calculated in the “all subjects enrolled into the open-label 
cohort.” 
The major subject backgrounds will be calculated in “all subjects who received the placebo in the 
induction phase and enrolled into the maintenance phase.” 
13.1.3 
Efficacy Analysis 
(1) Primary Endpoint and Analysis Methodology in the Induction Phase 
[Primary endpoint] 
CDAI-100 response at Week 10 
[Primary analysis] 
The following descriptive calculations will be performed in the “Full Analysis Set in the induction 
phase.” 
“CDAI-100 response at Week 10” (primary endpoint of the induction phase) will be calculated by 
treatment group of the induction phase. Also clinical response at Week 10 will be calculated with 
stratification according to a history of anti-TNFα antibody therapy and the comparison will be 
made with the Cochran-Mantel-Haenszel (CMH) test with 2-sided significance level of 10% by 
using a history of anti-TNFα antibody therapy as a stratification factor. 
The results of the primary analysis of the induction phase will be interpreted as below to determine 
the efficacy of MLN0002 induction therapy. 
• The superiority of MLN0002 over the placebo on CDAI-100 response at Week 10 in the 
primary analysis of the induction phase is demonstrated when a statistically significant 
difference is observed in the CDAI-100 response at Week 10. 


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[Secondary analysis] 
For sensitivity point of view, robustness of the results will be confirmed in the same manner as 
those in the primary analysis described in Section 13.1.3 (1) in the “Per Protocol Set of the 
induction phase.” 
(2) Secondary Endpoints and Analysis methodologies in the Induction Phase 
[Secondary endpoints] 
Clinical remission at Week 10 
Change in CRP level over time in the subpopulation of subjects with the baseline CRP level of 
>0.30 mg/dL 
[Secondary analysis] 
Clinical remission at Week 10 will be calculated in the same manner as those in the primary 
analysis described in Section 13.1.3 (1) in the “Full Analysis Set in the induction phase.” 
The results of the secondary analysis will be interpreted as below to determine the efficacy of 
MLN0002 induction therapy. 
• The superiority of MLN0002 over the placebo on clinical remission at Week 10 in the primary 
analysis of the induction phase is demonstrated when a statistically significant difference is 
observed in both the CDAI-100 response at Week 10 and clinical remission at Week 10. 
[Other analyses] 
The following analysis will be conducted in subjects with the baseline CRP level of >0.30 mg/dL 
in the “Full Analysis Set in the induction phase”. 
Summary statistics of CRP levels measured at each evaluation in the induction phase will be 
calculated by each treatment group. 
Summary statistics of change of CRP level at each evaluation in the induction phase from that at 
baseline will be calculated by each treatment group. 
(3) Exploratory Endpoints in Induction Phase 
See Section 5.2.1.3. 
(4) Primary Endpoint and Analysis Methodology in the Maintenance Phase 
[Primary endpoint] 
Clinical remission at Week 60 
[Primary analysis] 
The following descriptive calculations will be performed in the “Full Analysis Set in the 
maintenance phase.” 


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The “clinical remission at Week 60” (primary endpoint of the maintenance phase) will be 
calculated by treatment group in the maintenance phase. 
[Secondary analysis] 
For sensitivity point of view, robustness of the results will be confirmed in the same manner as 
those in the primary analysis described in Section 13.1.3 (4) in the “Per Protocol Set of the 
maintenance phase.” 
(5) Secondary Endpoints and Analysis Methodology in the Maintenance Phase 
[Secondary endpoints] 
CDAI-100 response at Week 60 
Durable remission in the maintenance phase 
Corticosteroid-free remission at Week 60 
[Analysis methodology] 
CDAI-100 response at week 60, durable response in the maintenance phase and corticosteroid-free 
remission at Week 60 will be analyzed in the same manner as those in the primary analysis 
described in the Section 13.1.3 (4) in the “Full Analysis Set in the maintenance phase”. 
(6) Exploratory Endpoints in Maintenance Phase 
See Section 5.2.2.3. 
(7) Data Transformation and Missing Data 
Details are specified in the “Data-Handling Rules for Analyses” and the “Statistical Analysis 
Plan.” 
In the analysis of the efficacy endpoints of clinical response and clinical remission, when 
adjudications for these endpoints were missing at the time of evaluation, non-responder and 
non-remitter will be imputed. 
(8) Significance Level and Confidence Coefficient 
• Significance level: 10% (2-sided test) 
• Confidence coefficient: 95% (2-sided estimate) 
13.1.4 
Pharmacokinetic Analysis 
[Endpoints] 
Serum concentrations of MLN0002 
[Analysis methodology] 
Summary statistics for serum MLN0002 concentrations at each evaluation in the induction phase 
will be calculated in the subjects who underwent proper determination of serum MLN0002 


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concentrations out of the “Full Analysis Set of the induction phase,” and subsequently figures 
showing transition of means/standard deviations will be plotted. 
Summary statistics for serum MLN0002 concentrations at each evaluation in the maintenance 
phase will be calculated in the subjects who underwent proper determination of serum MLN0002 
concentrations out of the “Full Analysis Set of the maintenance phase” by each treatment group in 
the maintenance phase, and subsequently figures showing transition of means/standard deviations 
will be plotted. 
13.1.5 
Safety Analysis 
(1) AEs in the induction phase 
AEs will be summarized in the “Safety Analysis Set in the induction phase.” 
Treatment-emergent AEs (TEAEs) in the induction phase are defined as AEs that emerged during 
the period from the first dose of the study drug in the induction phase through the first dose of the 
study drug in the maintenance phase or open-label cohort in the subjects enrolled into the 
maintenance phase or the open-label cohort, or defined as AEs that emerged since the first dose of 
the study drug in the induction phase in the subjects not enrolled into the maintenance phase or 
open-label cohort. 
The following analyses will be conducted for TEAEs in the induction phase by treatment group in 
the induction phase. All TEAEs will be coded by use of MedDRA, and summarized based on the 
System Organ Class and Preferred Term. 
• Calculation of overall TEAEs 
• Calculation of “study drug-related” TEAEs 
• Calculation of overall TEAEs by severity 
• Calculation of “study drug-related” TEAEs by severity 
• Calculation of TEAEs leading to “dose discontinuation” in disposition. 
• Calculation of serious TEAEs 
• Calculation of overall TEAEs by start period 
(2) AEs in the maintenance phase 
TEAEs in the maintenance phase are defined as AEs that emerged during the period from the first 
dose of the study drug in the maintenance phase through the first dose of the study drug in the 
open-label cohort in the subjects who enrolled into the open-label cohort, or defined as AEs 
emerged since the first dose of the study drug in the maintenance phase in the subjects not enrolled 
into the open-label cohort. 
TEAEs in the maintenance phase will be analyzed in the same manner as those described in 
Section 13.1.5 (1) by each treatment group in the maintenance phase in the “Safety Analysis Set of 
the maintenance phase.” 


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TEAEs in the maintenance phase will be analyzed in the same manner as those described in 
Section 13.1.5 (1) in “subject allocated to the placebo group in the induction phase and who 
received the placebo in the maintenance phase.” 
(3) AEs in the Open-label Cohort 
TEAEs in the open-label cohort are defined as AEs emerged after the first dose of the study drug in 
the open-label cohort. 
TEAEs in the open-label cohort will be analyzed in the same manner as those described in the 
Section 13.1.5 (1) in the “Safety Analysis Set of the open-label cohort.” 
(4) AEs Emerged after Treatment of MLN0002 
TEAEs emerged after treatment of MLN0002 are defined as AEs emerged after the first dose of 
MLN0002. 
TEAEs emerged after treatment of MLN0002 will be analyzed in the same manner as those 
described in Section 13.1.5 (1) in “subjects who received at least one dose of MLN0002.” 
(5) Laboratory tests, 12-Lead ECG, Vital Signs and Body Weights 
The analysis sets and groups to be analyzed are the same as those described in (1), (2) and (3) in 
Section 13.1.5 in principle. 
Summary statistics of measured values and difference between pre-/post-treatments will be 
calculated by each evaluation timing. Figures showing transition of each test value will be plotted. 
Shift tables showing difference between pre-/post-treatments will be created. 
13.1.6 
Analysis of Immunogenicity Endpoints 
[Endpoints] 
HAHA, neutralizing antibody 
[Analysis methodology] 
HAHA /neutralizing antibody test results will be calculated in the subjects who underwent proper 
HAHA /neutralizing antibody test out of the “Full Analysis Set of the induction phase.” 
HAHA /neutralizing antibody test results will be calculated by each treatment group in the 
maintenance phase in the subjects who underwent a HAHA /neutralizing antibody test out of the 
“Full Analysis Set of the maintenance phase.” 
HAHA /neutralizing antibody test results will be calculated in the subjects who underwent a 
HAHA /neutralizing antibody test out of the “Full Analysis Set of the open-label cohort.” 


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13.2 
Interim Analysis and Criteria for Early Termination 
The data for marketing application will be analyzed, which includes data of all subjects as fixed on 
the cut-off date for marketing application. Continuation/termination of the study will not be judged 
based on the analysis. 
13.3 
Determination of Sample Size 
Subjects to be randomized in the induction phase: 110 to 152 subjects 
Number of subjects to be evaluated in the induction phase (number of “subjects randomized and 
who received at least one dose of the study drug in the induction phase”) 
MLN0002 group in the induction phase: 55 to 76 subjects 
Placebo group in the induction phase: 55 to 76 subjects 
Total: 110 to 152 subjects 
Subjects to be enrolled into the maintenance phase: approximately 53 to 73 subjects 
Number of subjects to be evaluated in the maintenance phase (number of “subjects randomized 
and who received at least one dose of the study drug in the maintenance phase”) 
MLN0002 group in the maintenance phase: approximately 16 to 22 subjects 
Placebo group in the maintenance phase: approximately 16 to 22 subjects 
Total: approximately 32 to 44 subjects 
[Justification of the sample size] 
On the basis of the findings from the phase 3 double-blinded, placebo-controlled study of 
MLN0002 in non-Japanese moderate to severe CD subjects who had failed with an anti-TNFα 
antibody (C13011), the CDAI-100 response at Week 10 in MLN0002 and the placebo was 
estimated as 47.2% and 24.6%, respectively, clinical remission at Week 10 in MLN0002 and the 
placebo was estimated as 28.7% and 13.0%, respectively, and the CDAI-70 response at Week 10 
in MLN0002 and the placebo was estimated as 56.9 % and 38.7%, respectively, in the study. 
When the CDAI-100 response at Week 10 in the induction phase is analyzed using Pearson's 
chi-square test with 2-sided significance level of 10%, 55 subjects each (at a ratio of 1:1, total 110 
subjects) will be required for the MLN0002 and placebo group to detect significance with a power 
of at least 80%. These numbers were therefore selected as numbers of evaluable subjects of the 
primary endpoint of the induction phase. When the clinical remission at Week 10 is analyzed in the 
same manner on the accumulated 55 to 76 subjects to be evaluated for the primary endpoint in the 
induction phase, statistical significances in both the CDAI-100 response at Week 10 and clinical 
remission at Week 10 are detected with a power of 61% to 76%.. 
Number of subjects to be evaluated for the primary endpoint in the maintenance phase will be 16 to 
22 subjects in each group and 32 to 44 subjects in total, when such results are obtained as estimated 
in the above. 


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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 (e)CRFs. Source documents are defined as original documents, data, and records. 
The investigator and head of the study site should assure the sponsor (or its designee) or the IRB to 
review source documents. 
The sponsor or its designee will review records including Investigator’s files, drugs, subjects’ 
medical records and informed consents to verify that the study is being conducted properly in 
compliance with the protocol. In addition, consistency will be verified between raw data and the 
(e)CRF. 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 
Investigators may deviate from or modify the protocol without prior written agreement with the 
sponsor and prior approval from the IRB in medically inevitable occasions including any danger in 
subjects to be avoided urgently. After that, the investigator will give notice about details and 
reasons of the deviation or modification to the sponsor and the head of the study site in writing, 
retaining a copy, and discuss revisions of the protocol with the sponsor for agreement, if needed. If 
revision is needed, a draft of the revision will be submitted to the head of the study site at the 
earliest possible time to be approved by the IRB. 
Investigators will record all deviations from the protocol. 
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 drug 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 (e.g., 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 and the head of institution guarantee 
access for quality assurance auditors to all study documents as described in Section 14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., 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 local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
15.1 
IRB Approval 
IRBs will be established in accordance with local laws/regulations in the area where the study will 
be conducted. The sponsor or its designee will obtain a document describing names and titles of 
members of the IRB If any member of the IRB directly participates in this study, written 
notification regarding his or her abstinence from voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, Investigator’s Brochure, a copy of the informed 
consent form, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or local 
IRB for approval. The sponsor or its designee will obtain an approval document for the protocol 
and the informed consent form the IRB prior to the first dose of the study (i.e., before delivery of 
sponsor-supplied drugs). The IRB approval must refer to the study by exact protocol title, number, 
and version date; identify versions of other documents (e.g., informed consent form) reviewed; 
and state the approval date. The drugs will be dispatched after sponsor’s validation of regulatory 
documents in the study site. Any procedures in the screening phase described in the protocol 
should not be started until the study site receives the drugs. 
The study site should comply with all requirements specified by the IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent 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, and submission of the Investigator’s final status report to the IRB. All IRB 
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. Subject incentives should be 
approved by the IRB and the sponsor. 
Regarding pharmacogenomic investigation using collected and stored specimens, analysis will be 
carried out at the time when detail is determined. The sponsor will create a research protocol for 
pharmacogenomics investigations and a research protocol will require prior approval of the 
company IRB in Japan. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 


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applicable laws and regulations. Written consent documents describe availability and disclosure 
(to any third-parties inside/outside Japan) of subjects’ personal information and personal medical 
information in the study. The informed consent includes detailed explanation pertaining to primary 
intention, purpose, and possible risks/benefits. The informed consent form 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. 
Investigators have responsibility for preparation, contents and approval to be obtained from the 
IRB for the informed consent. The informed consent should be approved by the IRB prior to being 
effective. 
The informed consent should be described in understandable wording for subjects. Investigators 
must explain the contents of the informed consent thoroughly to the subjects. Information should 
be provided in a proper manner as approved by the IRB both orally or in writing, where possible. 
In the event the subject is not capable of rendering adequate written informed consent, then the 
subject’s legally acceptable representative may provide such consent for the subject in accordance 
with applicable laws and regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. The 
subject or the subject’s legally acceptable representative, when he/she has decided to participate in 
the study, should enter the signature (or name/seal) and date on the informed consent prior to 
participation. Investigators should request the subject or the subject’s legally acceptable 
representative to enter his/her formal (not nicknames, etc.) signature or name/seal by use of a black 
or blue ballpoint pen. Investigators should enter the signature (or name/seal) and date on the 
informed consent prior to the subject’s participation in the study, as well. 
Investigators should retain originals of the informed consent with signatures or names/seals. 
Investigators should record the date of acquisition of the subject’s signature or name/seal on the 
informed consent in the subject’s medical record. Additionally, a copy of the informed consent 
with the signatures or names/seals will be provided to the subject. 
All revised informed consent 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 form. 
The Pharmacogenomic Research will be explained based on “the informed consent for the 
Pharmacogenomic Research in the study for MLN0002” to the subjects who were given an 
explanation by use of the informed consent of the study. Sampling for Pharmacogenomic Research 
will be performed in the subjects who gave both informed consents for the study and the 
pharmacogenomic investigation. 
When a subject requests disposal of his/her retained samples, it will be implemented according to 
Section 9.4. 


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15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs 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 process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier fields 
not collected on the subject’s [e]CRF). 
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 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 clinical 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 sponsor may publish any data and information from the study (including data and information 
generated by Investigators) without the consent of investigators. 
The investigator, when intends to publicly present information acquired in the course of the study 
at a specialized academic society, etc., should obtain prior written approval from the sponsor. 
15.4.2 
Clinical Trial Registration 
In order to ensure that information on clinical trials reach the public in a timely manner and to 
comply with applicable law, regulation and guidance, Takeda will, at a minimum, register all 
clinical trials conducted in subjects that it sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites (including JAPIC-CTI) before trial initiation. Takeda contact 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 85 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
information, along with Investigator’s city, state (for US investigators), country, and recruiting 
status will be registered and available for public viewing. 
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of this clinical trial, regardless of outcome, on ClinicalTrials.gov or 
other publicly accessible websites (including JAPIC-CTI), as required by applicable laws and/or 
regulations. 
15.5 
Insurance and Compensation for Injury 
Any health damage occurred in subjects participating in the study will be compensated according 
to the local regulation applied to the study site. The sponsor or its designee will insure subjects be 
compensated for health damage, when required in the area where the study is conducted. 
Subjects suffering/suffered health damage will be compensated in accordance with the study 
contract. Investigators will contact the sponsor or its designee for any questions pertaining to 
compensation. 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 86 of 103 
Initial Protocol 
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CONFIDENTIAL 
16.0 
REFERENCES 
[1] 
Diagnostic Criteria and Treatment Guideline for Ulcerative Colitis and Crohn's Disease. 
“Research Group for Intractable Inflammatory Bowel Disease” Designated as Specified 
Disease by the MHLW of Japan (the Group of Dr. Watanabe), the additional volume of 
Assigned Study Report in 2012. 
[2] 
Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and 
selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in 
development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009;330:864-75. 
[3] 
Edula RG, Picco MF. An evidence-based review of natalizumab therapy in the management 
of Crohn's disease. Ther Clin Risk Manag. 2009;5:935-42. 
[4] 
Tilg H, Kaser A. Vedolizumab, a humanized mAb against the α4β7 integrin for the potential 
treatment of ulcerative colitis and Crohn's disease. Curr Opin Investig Drugs. 
2010;11:1295-304. 
[5] 
Parikh A, Leach T, Wyant T, Scholz C, Sankoh S, Mould DR, et al. Vedolizumab for the 
treatment of active ulcerative colitis: A randomized controlled phase 2 dose-ranging study. 
Inflamm Bowel Dis. 2012;18:1470-9. 
[6] 
Feagan BG, Greenberg GR, Wild G, Fedorak RN, Paré P, McDonald JW, et al. Treatment of 
ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med. 
2005;352:2499-507. 
[7] 
Feagan BG, Greenberg GR, Wild G, Fedorak RN, Paré P, McDonald JW, et al. Treatment of 
active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. 
Clin Gastroenterol Hepatol. 2008;6:1370-7. 
[8] 
Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. 
Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 
2013;369(8):699-710. 
[9] 
Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. 
Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 
2013; 369(8):711-21. 
[10] Sands B; Feagan B, Rutgeerts P, Colombel J; Sandborn W; Sy R, et al. Vedolizumab 
induction therapy for patients with Crohn’s disease and prior anti-TNF failure: a randomized, 
placebo-controlled, double-blind, multicenter trial. Presented at: Crohn’s & Colitis 
Foundation of America – Advances in Inflammatory Bowel Diseases Clinical and Research 
Conference. December 13-15, 2012. Hollywood, FL. 
[11] Kobayashi K, Suzuki Y, Watanabe K, Mukae M, Yamada T, Yamagami H. The phase I, 
multicenter, open-label, dose-escalation, repeated-dose study for VDZ in Japanese CD 
patients. The 21st Japan Digestive Disease Week, Tokyo, 2013. 


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Study No. MLN0002/CCT-001 
Page 87 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
[12] Kappos L, Bates D, Edan G, Eraksoy M, Garcia-Merino A, Grigoriadis N, et al. Natalizumab 
treatment for multiple sclerosis: updated recommendations for patient selection and 
monitoring. Lancet Neurol. 2011;10:745-58. 
[13] Best W.R., Backtel J.M., Singleton J.W., et al.: Development of Crohn’s disease activity 
index. Gastroenterology 1976;70:439-444. 
 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 88 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
Appendix A Schedule of Study Procedures 
Screening, Induction Phase, Maintenance Phase 
Study 
Procedures 
 
Screening 
Induction Phase 
Maintenance Phase 
16 weeks 
after the 
last dose 
 
Unscheduled 
visitsl 
Weeka 
 
0 
2 
6 
10/ETj 
14 
18 
22 
26 
30 
34 
38 
42 
46 
50 
54 
58 
60/ETk 
 
Daya 
-21 to -7i 
1 
15 
43 
71/ETj 
99 
127 
155 
183 
211 
239 
267 
295 
323 351 
379 
407 
421/ETk 
 
Visit Windows 
(Days) a 
― 
― 
±3 
±3 
±3/ETj 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
-7 – +6 
±7/ETk 
±14 
 
Visit 
1 
2 
3 
4 
5/ETj 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18/ETk 
– 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Xm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, body height,  
medical history, prior therapies, 
complications 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Issuance of study drug 
numbers/administration 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Physical examination, vital signsb 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Body weightb 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ECGb 
Xm 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Chest Imaging Procedurec 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Tuberculosis Test 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PML checklistsb 
Xm 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Laboratory tests b 
Blood biochemistry 
Xn 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Hematology 
Xn 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Urinalysis 
Xn 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Urine pregnancy testd 
Xm 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
HBs antigen, HCV antibody, 
HIV antigen/antibody 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory markers 
Xn 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
CDAI score 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Blood sampling for hematocrit teste 
 
X 
(X) 
(X) 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 (X) 
Check of the patient diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
IBDQb 
 
X 
 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Blood sampling for 
HAHA/neutralizing antibody testf 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Blood sampling for PKf 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Blood sampling for PGxf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant drug/therapy 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
PTEs/AEsh 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Footnotes are on last table page. 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 89 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
Appendix A Schedule of Study Procedures (continued) 
Open-label Cohort 
Study 
Procedures 
 
Open-label Cohort 
continued on the next page 
Weeka 
0x 
2x 
6x 
10x 
14x 
18x 
22x 
26x 
30x 
34x 
38x 
42x 
46x 
50x 
Daya 
1x 
15x 
43x 
71x 
99x 
127x 
155x 
183x 
211x 
239x 
267x 
295x 
323x 
351x 
Visit Windows 
(Days) a 
― 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Visit 
1x 
2x 
3x 
4x 
5x 
6x 
7x 
8x 
9x 
10x 
11x 
12x 
13x 
14x 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, body height, 
medical history, prior therapies, 
complications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Issuance of study drug 
numbers/administration 
Xq 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Physical examination, vital signsb 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weightb 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECGb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest Imaging Procedurec 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis Test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PML checklistsb 
Xq 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Laboratory tests b 
Blood biochemistry 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Hematology 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testd 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
HBs antigen, HCV antibody, 
HIV antigen/antibody 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory markers 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
CDAI score 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sampling for hematocrit teste 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Check of the patient diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IBDQb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for 
HAHA/neutralizing antibody testf 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Blood sampling for PKf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for PGxf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant drug/therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PTEs/AEsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes are on last table page. 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 90 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
Appendix A Schedule of Study Procedures (continued) 
Open-label Cohort (continued) 
Study 
Procedures 
 
Open-label Cohort 
16 weeks 
after the last 
dose 
 
Unscheduled 
visitsl 
Weeka 
54x 
58x 
62x 
66x 
70x 
74x 
78x 
82x 
86x 
90x 
94x/ETp 
 
Daya 
379x 
407x 
435x 
463x 
491x 
519x 
547x 
575x 
603x 
631x 
659x/ETp 
 
Visit Windows (Days) a 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7/ETp 
±14 
 
Visit 
15x 
16x 
17x 
18x 
19x 
20x 
21x 
22x 
23x 
24x 
25x/ETp 
– 
 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, body height, medical history, 
prior therapies, complications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Issuance of study drug numbers/administration 
X 
 
X 
 
X 
 
X 
 
X 
 
Xr 
 
 
 
Physical examination, vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Body weightb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ECGb 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Chest Imaging Procedurec 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Tuberculosis Test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PML checklistsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Laboratory tests b 
Blood biochemistry 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Urine pregnancy testd 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
HBS antigen, HCV antibody,  
HIV antigen/antibody tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory markers 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
CDAI score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Blood sampling for hematocrit teste 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
(X) 
Check of the patient diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
IBDQb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for HAHA/neutralizing 
antibody testf 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Blood sampling for PKf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for PGxf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant drug/therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
PTEs/AEsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ET=early termination, PK=pharmacokinetics, IBDQ=Inflammatory Bowel Disease Questionnaire, HAHA=human anti-human antibody, PTE=pretreatment event 
a. The date of the first dose of the study drug in the induction phase is Week 0 (Day 1). The acceptable time windows are given as the number of days away from each scheduled visit. 
b. Will be performed before administration of the study drug on the day of study drug administration. 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 91 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
c. Not required when a chest image performed within 3 months is available (the image taken before the informed consent date is acceptable at screening). 
d. Will be performed only in women of childbearing potential. 
e. It should be performed on VISITs for CDAI score evaluation for calculation of the CDAI score. If the determination result on the evaluation day is impossible to be obtained, instead the 
blood sampling result within 14 days before evaluation may be used. It should be performed on VISITs for CDAI score evaluation [indicated as (X)] for calculation of the CDAI score, where 
possible. However, if the determination result on the evaluation day is impossible to be obtained, the blood should not be sampled and the latest determination result may be used for 
calculation instead. 
f. If the study drug is administrated in the visit, a blood sample should be drawn immediately before study drug administration. If the study drug is not administrated in the visit, a blood sample 
can be drawn at any time at visits. All blood sampling will be conducted only in study sites with a cooled centrifuge. 
g. Will be collected only in patients who have consented to participate in PGx research once at the earliest possible time between Visit 2 and study completion. 
h. A PTE is an event that occurred before the first dose of the study drug. An AE is an event that occurred after the first dose of the study drug. 
i. 
If patients with a history of tuberculosis or those with suspicion of it start preventive isoniazid treatment before study enrollment, screening can be conducted between Day -28 and Day-7. 
Study drug administration must be conducted 21 or more days after isoniazid administration starts. 
j. 
Patients who will prematurely withdraw from the study in the induction phase after receiving at least one dose should visit the clinical site and have examinations for discontinuation as soon 
as possible. 
k. Patients who will prematurely withdraw from the study in the maintenance phase should visit the clinical site and have examinations for discontinuation as soon as possible. Eligible patients 
will be enrolled into open-label cohort 3 to 9 weeks after the last dose of the study drug in the maintenance phase. 
l. 
An unscheduled visit will be made due to worsening of CD, etc. Additional tests will be performed as required. 
m. Can be conducted between Day -21 and Day -1. If patients with a history of tuberculosis or those with suspicion of it start preventive isoniazid treatment before study enrollment, screening 
can be conducted between Day -28 to Day -1. Study drug administration must be conducted 21 or more days after isoniazid administration starts. 
n. The test results should be obtained by Visit 2. 
o. The date of the enrollment into open-label cohort is Week 0x (Day 1x) and the study site visit on Day 1x is Visit 1x. The acceptable time windows are given as the number of days away from 
each scheduled visit. 
p. Patients who will prematurely withdraw from the study in the open-label cohort should visit the clinical site and have examinations for discontinuation as soon as possible. And the same 
examination will be conducted in the study termination scheduled 46 weeks after the last subject will be enrolled into open-label cohort. 
q. Will be performed after enrollment into open-label cohort. 
r. Will not be performed in patients who prematurely withdraw from the study. 
 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 92 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
Appendix B Responsibilities of the Investigator 
1. Execute the study properly as complying with the protocol and GCP in consideration of 
human rights, safety and welfare of subjects. 
2. In order to assign some important study-related practices to subinvestigators or study 
collaborators, prepare lists of the assignments and persons in charge to be submitted to the 
head of the study site and obtain approval. 
3. Prepare the informed consent form and revise it, when needed. 
4. Verify the contents in the study contract. 
5. Provide sufficient information about the protocol, drugs and individual assignments to 
subinvestigators and study collaborators, instruct and supervise them. 
6. Select eligible subjects to the protocol, provide explanations to them in writing, and obtain the 
written informed consents from them. 
7. Take responsibility for any study-related medical judgment. 
8. Assure subjects receive sufficient medical care together with the head of the study site for any 
study-related clinically-relevant AEs throughout the participation and the subsequent period. 
9. For a subject being treated in other institutions or other departments, provide information in 
writing of study participation and completion/withdrawal of the subject to the institution or 
the physician in other department upon subject’s approval, which should be documented. 
10. Report any occasion requiring expedited reports including SAEs to the head of the study site 
and the sponsor immediately in writing. 
11. Decide necessity for opening the emergency key of the particular subject in emergency 
situation. 
12. Complete the (e)CRFs accurately and completely with the e-signature to be submitted to the 
sponsor. 
13. Check, verify and e-sign (e)CRFs entered by subinvestigators or transcribed from raw data by 
study collaborators to be submitted to the sponsor. 
14. Be consulted for revision of the protocol or the like, when proposed by the sponsor 
15. Report study completion to the head of the study site in writing. 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 93 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
Appendix C Diagnostic Criteria for CD (Revised on January 17, 2013) 
1. Overview 
Crohn's Disease (CD) is a granulomatous inflammatory disease of unknown etiology but may be 
contributed by immune disorder, etc. It is most commonly found in young people with edema or 
ulcers that emerged primarily in the small or large intestine, leading to development of 
characteristic conditions such as intestinal stenosis or fistula. The original article described that it 
is an inflammation of the terminal ileum, however, today, the disease is known to occur in any part 
of the gastrointestinal tract from the mouth through to the anus. As various complications may be 
induced even outside the gastrointestinal tract, the disease should be treated as a systemic disease. 
While clinical manifestation may vary depending on affected sites or extent, gastrointestinal 
condition including diarrhea or abdominal pain, systemic condition including fever, weight loss or 
malnutrition, and also complication-induced condition including anemia, arthritis, iritis or skin 
lesions may emerge. Disease condition and lesions may progress with repetition of recurrence and 
remission, and often become resistant to treatments to deteriorate social activity. 
2. Major Concepts 
(1) Most Common Onset Ages: from the late 10s to 20s 
(2) Most Common Sites: mostly either of the small or large intestine or both showing lesions 
including longitudinal ulcers or a cobblestone appearance. 
(3) Clinical Symptoms: abdominal pain, diarrhea, weight loss or fever are commonly observed. 
The disease may sometimes emerge as intestinal obstruction, intestinal fistula (internal or external 
fistula), intestinal perforation or major bleeding, or may emerge as anal lesion-induced symptoms, 
fever of unknown origin, arthritis or the like without abdominal symptoms (or with unidentified 
complaint in the abdomen in a few cases). 
(4) Clinical Findings 
A. Lesions in the gastrointestinal tract 
[1]  The intestine:  
longitudinal ulcers <Note 1>, cobblestone appearance <Note 2>, 
discontinuous or skip lesions, irregular-to-round shaped ulcers, or multiple aphtha <Note 3> 
[2]  The anus: anal fissure, cavitating ulcers <Note 4>, intractable anal fistula, perianal abscess, 
edematous skin tag, anal stenosis, etc. 
[3]  The stomach and duodenum: multiple aphtha, irregular-shaped ulcers, bamboo-joint-like 
appearance, notch-like depression, cobblestone appearance, etc. 
[4]  Complications: intestinal stenosis, intestinal obstruction, internal fistula (fistula between the 
intestine - intestine, the intestine - bladder, the intestine - vagina, etc.), external fistula (fistula 
between the intestine - skin), or malignancy (intestinal cancer or anal fistula cancer) 
 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 94 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
B. Lesions outside the gastrointestinal tract (including secondary complications) 
[1]  The blood: anemia, hypercoagulability, etc. 
[2]  The joints: arthritis enteropathic, ankylosing spondylitis, etc. 
[3]  The skin: oral aphtha, erythema nodosum, pyoderma gangrenosum, erythema multiforme 
exudativum, etc. 
[4]  The eyes: iritis, uveitis, etc. 
[5]  The nutrient metabolism: growth disorder, hypoproteinemia, trace element deficiency, 
vitamin deficiency, bone disorder, etc. 
[6]  Other: primary sclerosing cholangitis, vasculitis, pancreatitis, cholelithiasis, urolithiasis, 
hepatic disorder, amyloidosis, etc. 
(5) Findings in laparotomies 
Induration longitudinally aligned on the mesenteric side, marked creeping fat, circumferential 
induration on the intestinal wall, shortening of the intestine, intestinal stenosis, fistulation (internal 
or external fistulas), intestinal massive adhesion, mesenteric lymphadenopathy, etc., may be 
observed. 
(6) Pathological Findings 
A. Macroscopic findings on resected specimens 
[1]  Longitudinal ulcers <Note 1> 
[2]  Cobblestone appearance <Note 2> 
[3]  Fistula 
[4]  Stenosis 
[5]  Irregular-to-round shaped ulcers or aphtha <Note 3> 
B. Histological findings on resected specimens 
[1]  Noncaseating epithelioid granuloma (may be found in the local lymph nodes as well) <Note 
5> 
[2]  Full thickness inflammation <Note 6> 
[3]  Local or disproportional inflammation 
[4]  Fissure 
[5]  Ulcers 
C. Histological findings on the biopsy 
[1]  Noncaseating epithelioid granuloma <Note 5> 
[2]  Disproportional inflammation 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 95 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
 
<Note 1> Ulcers of ≥4 to 5 cm in length commonly, aligned longitudinally along the intestine. The 
finding may be found in intestinal ischemic lesions or infectious enteritis, but these have different 
development or clinical courses and are rarely associated with inflammatory polyposis or a 
cobblestone appearance. Also, the finding may be found in UC, but it shows UC-specific findings 
in the surrounding mucosa. 
<Note 2> Aggregation of different sizes of protrusions on the mucosa between longitudinal ulcers 
and the surrounding small ulcers The finding may rarely be observed in intestinal ischemic lesions, 
but these have a shorter protrusion in height with more remarkable redness. 
<Note 3> These may align longitudinally in the disease. 
<Note 4> Deep and wide painful ulcers in the area from the anal canal to the lower rectum. 
<Note 5> It may also be observed in intestinal tuberculosis, etc. 
<Note 6> It is expansion of inflammation into full thickness of the wall of the gastrointestinal tract 
primarily due to aggregated lymphocytes 
3. Diagnostic Criteria 
(1) Primary Findings 
A. Longitudinal ulcers <Note 7> 
B. Cobblestone appearance 
C. Noncaseating epithelioid granuloma <Note 8> 
(2) Secondary Findings 
a. Extensive irregular-to-round shaped ulcers or aphtha in the gastrointestinal tract <Note 9> 
b. The characteristic anal lesions <Note 10> 
c. The characteristic gastroduodenal lesions <Note 11> 
 
Definitive patients: 
[1]  Patients with A or B in the primary findings <Note 12> 
[2]  Patients with C in the primary findings and a or b in the secondary findings 
[3]  Patients with all of a, b and c in the secondary findings 
 
Suspected patients: 
[1]  Patients with C in the primary findings and c in the secondary findings 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 96 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
[2]  Patients with A or B in the primary findings, however, in whom UC, intestinal Behcet's 
disease, simple ulcers or intestinal ischemic lesions may not be ruled out 
[3]  Patients only with C in the primary findings <Note 13> 
[4]  Patients only with any 2 or 1 in the secondary findings 
 
<Note 7> These, if in the small intestine, commonly emerge in the mesenteric side 
<Note 8> Diagnosis may be improved with the serial section, and preferably should be judged by a 
skilled pathologist in the gastrointestinal tract 
<Note 9> These may typically align longitudinally but sometimes may not, and should constantly 
exist for ≥3 month. Additionally, intestinal tuberculosis, intestinal Behcet's disease, simple ulcers, 
NSAIDs-induced ulcers, infectious enteritis should be ruled out. 
<Note 10> These include anal fissure, cavitating ulcers, anal fistula, perianal abscess or edematous 
skin tag, and preferably should be diagnosed by a specialist in proctology with knowledge of CD 
with reference to the Atlas for Macroscopic Findings of Anal Lesions in CD. 
<Note 11> These include a bamboo-joint-like appearance or notch-like depression, and preferably 
should be diagnosed by a skilled specialist in CD. 
<Note 12> In patients showing only longitudinal ulcers, intestinal ischemic lesions or UC should 
be ruled out. In patients showing only a cobblestone appearance, intestinal ischemic lesions should 
be ruled out. 
<Note 13> Granulomatous inflammatory diseases including intestinal tuberculosis should be ruled 
out. 
4. Types of the Disease 
The disease is classified into the small intestine type, large intestine type or small/large intestine 
type based on the existing site of longitudinal ulcers, a cobblestone appearance or stenosis. 
Patients without these findings or patients with these findings only in rare sites will be classified as 
the atypical type. The atypical type includes the multiple aphtha type, the 
cecum/appendix-localized type, the rectum type, the gastroduodenal type. 
The disease patterns include the inflammation type without complications, the fistula-forming 
type, and the stenosis type with stenotic lesions. 
[Subjoinder] Indeterminate colitis 
A patient, who is difficult to be definitively diagnosed as showing clinical and pathological 
characteristics of both CD and UC, may come to show more specific findings of either disease in 
the course of follow-up. 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 97 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
5. Classification by Severity 
Upon treatment, severity should be classified with reference to the following. 
 
CDAI# 
Concurrent medical 
conditions 
Inflammation 
(CRP level) 
Treatment Response 
Mild 
150-220 
None 
Small elevation 
 
Moderate 
220-450 
No overt complications 
including intestinal 
obstruction, etc. 
Overt elevation 
No response to treatment for 
mild cases 
Severe 
450< 
Intestinal obstruction, 
abscess, etc. 
Notable elevation 
Poor response to the treatment 
#: CDAI (Crohn's disease activity index) 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 98 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
Appendix D PML Checklists 
• The PML checklists will be utilized in visits specified in the protocol, or for a subject 
complaining such symptoms. 
• The purpose of the PML checklists is to identify any obvious neurological changes in a subject 
since the last evaluation. 
• When any subjective symptoms were identified, the corresponding tests to see objective 
findings should be performed. Any symptoms/findings found on the checklists should be 
recorded as AEs. 
• Subjects should be instructed to visit a neurologist, when any obvious neurological changes 
were observed. Examinations including MRI using a contrast agent should be performed for 
collection of information supporting the neurological change, if needed. 
• Any positive subjective symptoms or positive objective findings should be provided to the 
sponsor immediately. 
Algorithm for Subject Evaluation 
 
 
Visit 
Positive 
subjective  
PML checklist  
The study drug 
suspend  
Symptoms 
reported by a 
patient/family 
Objective  
PML checklist 
Re-initiation of 
the study 
Any signs 
suggesting 
PML? 
No 
Investigators 
consult a 
neurologist 
Yes 
Examination by 
a neurologist 
Telephone by a study 
site staff member to 
patients within one 
week for a follow-up 
to be conducted a 
week later 
Re-initiation of 
the study 
No 
White matter 
change 
suspected? 
Obtain opinion 
from Adjudication 
Committee 
MRI using a 
contrast agent 
Refer to 
Adjudication 
Committee 
PML ruled 
out ? 
No 
Yes 
Re-initiation of 
the study 
Obtain opinion 
from Adjudication 
Committee 
PCR test for JC 
virus in lumbar 
puncture + CSF 
Lesion growth 
found on MRI? 
Yes 
No 
PML ruled 
out ? 
Yes 
Re-initiation of 
the study 
No 
Obtain opinion 
from 
Adjudication 
Committee 
No 
JC virus 
detected? 
Yes 
PML 
confirmedMLN0002 
discontinuedImmune 
reconstitution 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 99 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
Subjective PML checklist 
Date:      month/      date/       year 
Subject Identification Code: 
 
Symptoms 
 
Have you had a 
significantly unusual 
experience for the 
following? 
If “yes,” describe 
symptoms specifically 
Objective test to be 
applied: results should be 
recorded in the Objective 
PML checklist 
 
Yes 
No 
 
 
1. Have you experienced 
continuous loss of vision, 
multiple vision or reading 
disorder, recently? 
 
 
 
Visual field and eye 
movement should be 
tested. 
2. Have you felt any 
continuous difficulty in 
talking, or continuous 
inability of your speech to 
be understood by others, 
recently? 
 
 
 
Natural observation should 
be performed for patient’s 
speech for dysarthria or 
aphasia. The patient should 
be requested to answer 
names of some objects and 
to repeat some phrases 
with several words. 
3. Have you felt any 
continuous muscle 
weakness in your arms or 
legs, recently? 
 
 
 
Pronator deflection test 
(Barré procedure) and/or a 
test to see ability to keep 
the arm being rotated 
Ability to hop on one foot; 
to tap with the foot and 
finger. A symmetry test in 
the muscle. 
4. Have you frequently 
banged into something, or 
felt any difficulty in 
writing characters, 
recently? 
 
 
 
The patient should be 
required to show 
spontaneous writing and be 
observed in the 
finger-to-nose test and 
heel-to-shin test and while 
walking (in a straight line 
by putting the heel of one 
foot in front of the toe of 
the other foot alternately). 
 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 100 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
Date:      month/      date/       year 
Subject Identification Code: 
 
Symptoms 
Have you had a 
significantly unusual 
experience for the 
following? 
If “yes,” describe 
symptoms specifically 
Objective test to be 
applied: results should be 
recorded in the Objective 
PML checklist 
 
Yes 
No 
 
 
5. Have you often 
experienced an inability to 
understand wording 
someone has said recently? 
 
 
 
Ability to follow a series of 
instruction (stick out the 
tongue and touch the left 
ear with the left fingers 
while keeping the eyes 
closed). 
6. Do you have any 
continuous problems in 
your memory or thinking? 
 
 
 
The patient should be 
reminded of the 3 objects 
after 1 minute or longer 
distraction ; ability to 
follow instructions 
7. Have you experienced 
continuous hypesthesia or 
other loss of sensation? 
 
 
 
Sensation should be tested 
by neighboring needle 
stimulation 
 
Conducted by (signature or name/seal) 
 
             seal     month/   date/   year 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 101 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
Objective PML checklist 
For a patient with subjective symptoms. 
Please perform the tests for objective findings corresponding to the observed subjective 
symptoms. 
 
Date:      month/      date/       year 
Subject Identification Code: 
 
Positive subjective 
symptoms 
Objective tests applied 
Test results 
Brief description of the 
observed abnormality 
Normal 
Abnormal 
1.  
Difficulty in vision and 
reading 
 
Visual field and eye movement should 
be tested. 
 
 
 
2.  
Difficulty in speech 
Spontaneous observation should be 
performed for patient’s speech for 
dysarthria or aphasia. The patient 
should be requested to answer names of 
some objects and to repeat some 
phrases with several words. 
 
 
 
 
3.  
Muscle weakness in the 
upper or lower limb 
Pronator deflection test (Barré 
procedure) and/or a test to see ability to 
keep the arm being rotated Ability to 
hop on one foot; to tap with the foot and 
finger. A symmetry test in the muscle. 
 
 
 
 
4.  
Bang into something or 
difficulty in writing 
The patient should be required to show 
spontaneous writing and observed in 
the finger-to-nose test and heel-to-shin 
test and while walking (in a straight line 
by putting the heel of one foot in front 
of the toe of the other foot alternately). 
 
 
 
 
 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 102 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
Date:      month/      date/       year 
Subject Identification Code: 
 
Positive subjective 
symptoms 
Objective tests applied 
Test results 
Brief description of the 
observed abnormality 
Normal 
Abnormal 
5.  
Difficulty in 
understanding others 
Ability to follow a series of instruction 
(stick out the tongue and touch the left 
ear with the left fingers while keeping 
the eyes closed). 
 
 
 
 
6.  
Problems in memory or 
thinking 
The patient should be reminded of the 3 
objects after 1 minute or longer 
distraction ; ability to follow 
instructions 
 
 
 
 
7.  
Problems of hypesthesia 
Sensation should be tested by 
neighboring needle stimulation 
 
 
 
 
 
• The patient whose reported symptoms were confirmed in the Objective PML checklist should 
be instructed to visit a neurologist. The patient should be followed a week after the Objective 
PML checklist for confirmation of re-manifestation of the reported subjective symptoms. 
• Any positive findings in the Objective PML checklist must be provided to the sponsor. 
 
Conducted by (signature or name/seal) 
 
             seal     month/   date/   year 


MLN0002 
 
Study No. MLN0002/CCT-001 
Page 103 of 103 
Initial Protocol 
November 11, 2013 
 
CONFIDENTIAL 
Appendix E Follow-Up Survey Form 
Subject Identification Code: 
 
Number of months after the last dose of the study drug: 
6 mo.  12 mo.  18 mo.  24 mo. 
Date:   month/   date/   year 
1. 
Have you been diagnosed with colon dysplasia (one of the precancerous lesions) or colon cancer, 
lymphoma, or other cancers since the last contact/visit in the study? 
Yes 
 
No 
 
If “yes,” please answer to the following questions:. 
 
Colon dysplasia  
Yes/No 
Date of the diagnosis:   month/   date/   year 
 
Colonic cancer 
Yes/No 
Date of the diagnosis:   month/   date/   year 
 
Lymphoma 
Yes/No 
Date of the diagnosis:   month/   date/   year 
 
Other: (Specify) 
Yes/No 
Date of the diagnosis:   month/   date/   year 
2. 
Have you been diagnosed as having progressive multifocal leukoencephalopathy (also known as 
PML) since the last contact/visit in the study? 
Yes 
 
No 
 
If “yes,” please answer to the following question:. 
 
Date of the diagnosis:   month/   date/  year 
3. 
Have you undergone an enterectomy since the last contact/visit in the study? 
Yes 
 
No 
 
If “yes,” please answer to the following questions:. 
 
Colectomy 
Yes/No 
Date of the diagnosis:   month/   date/   year 
 
Small bowel resection 
Yes/No 
Date of the diagnosis:   month/   date/   year 
The following 3 questions will be completed only once at 6 months after the last dose of the study drug. 
4. 
Have you been diagnosed as having an infection requiring hospitalization since the last study visit? 
Yes 
 
No 
 
If “yes,” please answer to the following questions:. 
 
Specify the reason for the hospitalization/diagnosis 
Reason: 
 
 
Date of the diagnosis:   month/   date/   year 
5. 
For female patients: Have you become pregnant since the last study visit? 
Yes 
 
No 
 
If “yes,” please answer to the following questions:. 
 
The PREGNANCY REPORTING FORM should be completed 
Not applicable 
 
 
Specify the estimated delivery date:   month/   date/   year 
6. 
For male patients: Has your female partner become pregnant since the last study visit? 
Yes 
 
No 
 
If “yes,” please answer to the following questions:. 
 
The PREGNANCY REPORTING FORM should be completed 
Not applicable 
 
 
Specify the estimated delivery date:   month/   date/   year 
 
Investigator (signature or name/seal) 
                        seal 
     month/      date/       year 

SAP_001.pdf: 
 
 
Title: Phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-
group study to evaluate the efficacy, safety, and pharmacokinetics of intravenous 
MLN0002 (300 mg) infusion in induction and maintenance therapy in Japanese subjects 
with moderate or severe Crohn's disease 
 
NCT Number: NCT02038920 
Statistical analysis plan Approve Date: 25-JAN-2018 
 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
 


 
 
STATISTICAL ANALYSIS PLAN 
(Induction Phase) 
 
Study Title 
: Phase 3, multicenter, randomized, double-blinded, 
placebo-controlled, parallel-group study to evaluate the efficacy, 
safety, and pharmacokinetics of intravenous MLN0002 (300 mg) 
infusion in induction and maintenance therapy in Japanese 
subjects with moderate or severe Crohn's disease 
Protocol No. 
: MLN0002/CCT-001 
Sponsor 
: Takeda Pharmaceutical Company Limited 
 
Person responsible for preparing the protocol 
 
 
 
Trial Statistician 
 
Person responsible for pharmacokinetic/pharmacodynamic analyses 
 
First version: 25 January 2018 
PPD
PPD
PPD


1 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................... 3 
HANDLING OF TIME WINDOW ...................................................................................................... 4 
OTHER HANDLING ........................................................................................................................... 7 
1 STUDY SUBJECTS, DEMOGRAPHICS, AND OTHER BASELINE CHARACTERISTICS .... 16 
1.1 Disposition of Subjects ................................................................................................................. 16 
1.1.1 Study Information .................................................................................................................. 16 
1.1.2 Disposition of All Subjects Who Did Not Enter in the Induction Phase................................ 16 
1.1.3 Subject Eligibility .................................................................................................................. 16 
1.1.4 Number of Subjects Who Entered in the Induction Phase by Site ......................................... 17 
1.1.5 Disposition of Subjects .......................................................................................................... 17 
1.1.5.1 
Disposition of Subjects ................................................................................................... 17 
1.1.6 Study Drug Completion Status and Study Visit Completion Status ...................................... 18 
1.1.7 Protocol Deviations and Analysis Sets .................................................................................. 19 
1.2 Demographic and Other Baseline Characteristics ......................................................................... 20 
1.2.1 Distribution of Baseline Demographics ................................................................................. 20 
1.2.2 Medical History, Concurrent Medical Conditions ................................................................. 24 
1.2.3 Medication History, Concomitant Medications in the Induction Phase, Concomitant 
Therapies in the Induction Phase ............................................................................................ 24 
1.3 Measurement of Compliance Status for Treatment....................................................................... 26 
1.3.1 Study Drug Exposure and Compliance in the Induction Phase.............................................. 26 
2 EFFICACY ANALYSIS ................................................................................................................. 28 
2.1 Primary Endpoints and Analysis Methodology ............................................................................ 28 
2.1.1 Primary Analysis .................................................................................................................... 28 
2.1.2 Secondary Analysis ................................................................................................................ 29 
2.2 Secondary Endpoints and Analysis Methodology ........................................................................ 29 
2.3 Other Endpoints and Analysis Methodology ................................................................................ 31 
2.3.1 Endpoints Related to CDAI Scores ........................................................................................ 31 
2.3.2 Endpoints Related to CDAI Scores Based on the Hematocrit Level at Each Study Site ....... 34 
2.3.3 Endpoints Related to CRP...................................................................................................... 37 
2.3.4 Endpoints Related to IBDQ ................................................................................................... 38 
2.3.5 Analysis in Specific Subgroup 1 ............................................................................................ 39 
2.3.6 Analysis in Specific Subgroup 2 ............................................................................................ 40 
2.3.7 Combinational Analysis of CDAI Score and CRP Level....................................................... 43 
2.4 Statistical and Analytical Issues .................................................................................................... 43 
2.4.1 Adjustments for Covariates .................................................................................................... 43 


2 
 
2.4.2 Handling of Dropouts or Missing Data .................................................................................. 44 
2.4.3 Interim Analyses and Data Monitoring .................................................................................. 44 
2.4.4 Multicenter Studies ................................................................................................................ 45 
2.4.5 Multiple Comparisons/Multiplicity ........................................................................................ 45 
2.4.6 Use of an “Efficacy Subset of Subjects” ................................................................................ 45 
2.4.7 Active-Control Studies Intended to Show Equivalence or Non-inferiority ........................... 45 
2.4.8 Examination of Subgroups ..................................................................................................... 45 
3 SAFETY ANALYSIS ...................................................................................................................... 48 
3.1 Treatment-Emergent Adverse Event ............................................................................................. 48 
3.1.1 Overview of Treatment-Emergent Adverse Events ............................................................... 48 
3.1.2 Displays of Treatment-Emergent Adverse Events ................................................................. 49 
3.2 Pretreatment Event ........................................................................................................................ 51 
3.2.1 Displays of Pretreatment Events ............................................................................................ 51 
3.3 Clinical Laboratory Evaluations and Other Safety Endpoints ...................................................... 52 
3.3.1 Clinical Laboratory Evaluations ............................................................................................ 52 
3.3.2 Vital Signs, Physical Examination, and Other Observation Items Related to Safety ............ 54 
3.4 Display of Treatment-Emergent Adverse Event (in Japanese) ..................................................... 55 
4 PHARMACOKINETIC ANALYSIS .............................................................................................. 56 
4.1 Analysis of Serum Concentrations of MLN0002 .......................................................................... 56 
4.2 Subgroup Analysis of Serum Concentrations of MLN0002 ......................................................... 56 
4.3 Serum Concentrations of MLN0002 by Efficacy Endpoints ........................................................ 56 
4.4 Serum Concentrations of MLN0002 by AVA and Neutralizing Antibody ................................... 57 
4.5 Efficacy by Serum Concentration of MLN0002 ........................................................................... 57 
5 ANALYSIS OF IMMUNOGENICITY ENDPOINTS .................................................................... 59 
5.1 AVA and the Neutralizing Antibody ............................................................................................ 59 
5.2 Efficacy by AVA and the Neutralizing Antibody ......................................................................... 59 
5.3 Subgroup Analysis of AVA and the Neutralizing Antibody ......................................................... 60 
6 SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT .................................................. 61 
History of Revision (version management) ........................................................................................ 62 
[Appendix 1] Comparison Table for Changes ...................................................................................... 1 
[Appendix 2] Definitions of Categories in Shift Table, MAV Criteria, and Criteria for Elevated Liver 
Enzyme ......................................................................................................................................... 1 
 


3 
 
Since the study has different objectives in the induction phase, the maintenance phase, and the 
open-label cohort, analyses will be conducted separately among these. Therefore, the “Statistical 
Analysis Plan” will be also prepared for the induction phase, maintenance phase, and open-label 
cohort respectively. This statistical analysis plan will describe the analytical plan in the induction 
phase. 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
• 
Treatment-emergent adverse event (TEAE) in the induction phase: An adverse event that 
emerged during the induction phase. 
• 
Concomitant medication in the induction phase: Any concomitant medication which was started 
by the day before the first dose of the study drug in the maintenance phase or open-label cohort 
(whichever comes first if both events occur) for subjects who received the study drug in the 
maintenance phase or open-label cohort. “By the day before the first dose of the study drug in 
the maintenance phase or open-label cohort (whichever comes first if both events occur)” will 
include the day before the first dose of the study drug in the maintenance phase or open-label 
cohort. Hereinafter, the same expression (by -) will be interpreted in the same manner. For 
subjects who did not receive the study drug in the maintenance phase and open-label cohort, all 
concomitant medications are included. 
• 
Concomitant therapy in the induction phase: Any concomitant therapy which was started by the 
day before the first dose of the study drug in the maintenance phase or open-label cohort 
(whichever comes first if both events occur) for subjects who received the study drug in the 
maintenance phase or open-label cohort. For subjects who did not receive the study drug in the 
maintenance phase and open-label cohort, all concomitant therapies are included. 
• 
Summary statistics: Number of subjects, mean, standard deviation, maximum, minimum, and 
quartiles. 
• 
MAV: An abbreviation for markedly abnormal value. 
• 
Study Day: The day before the first dose of the study drug in the induction phase will be 
defined as Day -1 and the day of the first dose in the induction phase will be defined as Day 1. 
• 
Follow-up Day: The day after the last dose of the study drug will be defined as Follow-up Day 
1. There will be no distinction among the induction phase, maintenance phase, and open-label 
cohort for the day of the last dose of the study drug. 
• 
Full analysis set in the induction phase: Subjects who were randomized and received at least 
one dose of the study drug in the induction phase. 
• 
Per protocol set in the induction phase: All subjects in the full analysis set in the induction 
phase who did not have any major protocol deviations, have met the minimum protocol 
provisions, and have evaluable primary endpoint(s). 
• 
Safety analysis set in the induction phase: Subjects who received at least one dose of the study 


4 
 
drug in the induction phase. 
• 
Treatment groups in the induction phase: MLN0002 group and placebo group 
• 
Anti-vedolizumab antibody (AVA): Human anti-human antibody (HAHA) in the protocol will 
be described as AVA. 
• 
Baseline: A visit at “Week 0” in “HANDLING OF TIME WINDOW” 
 
HANDLING OF TIME WINDOW 
For each test, observation, and evaluation item, evaluable data (i.e., non-missing data and data 
determined to be eligible based on “Handling Rules for Analysis Data”) will be handled according 
to the following rules. 
For acceptable windows at each visit except for Week 0, the evaluable data within the acceptable 
window for subjects who received the study drug in the maintenance phase or open-label cohort will 
be used among the data measured prior to the day of the first dose of the study drug in the 
maintenance phase or open-label cohort. The evaluable data within the acceptable window will be 
used for other subjects. If more than one datum lies within the same acceptable window, the data 
whose test/observation/evaluation date is closest to the scheduled date will be used and, if there are 
two data equidistant to the scheduled date, the data obtained later will be used. The temporal 
distance from the scheduled date will be determined based on the Study Day and Follow-up Day. 
If the date of the first dose of the study drug in the maintenance phase or open-label cohort is 
smaller than the lower limit of the acceptable window in the table, the acceptable window at that 
visit will not be applied. 
 
CDAI score*1, each CDAI subscore*2, hematocrit level*3 (tested by the central laboratory), 
inflammatory marker (CRP)  
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 2 
Study Day: 15 
2 to 28 
 
Week 6*4 
Study Day: 43 
29 to 56 
 
Week 10*5 
Study Day: 71 
57 to 84 
 
*1 CDAI-70 response, CDAI-100 response, and clinical remission will be determined based on 
CDAI scores. 
*2 Each CDAI subscore used for the calculation of CDAI scores based on the hematocrit (Ht) level at 
each study site will be used. 
*3 The Ht level will be handled as follows: 


5 
 
 If the Ht level tested on the same date as the evaluation day of the CDAI score based on the Ht 
level at each study site is available, that Ht level will be used. 
 If the Ht level tested on the same date as the evaluation day of the CDAI score based on the Ht 
level at each study site is not available, it will be handled according to the general rules 
described directly beneath “HANDLING OF TIME WINDOW.” 
*4 If the Ht level at Week 6 is missing, the same Ht level as that obtained at Week 2 will be used for 
Week 6. 
*5 If the Ht level at Week 10 is missing, the same Ht level as that obtained at Week 6 will be used for 
Week 10. However, if the Ht level at Week 2 is used for Week 6 according to the handling 
described in *4, the Ht level at Week 10 will be handled as missing. 
 
IBDQ scores (total score and each subscore [abdominal symptoms, general condition, emotion, and 
social function]) 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 10 
Study Day: 71 
2 to 84 
 
 
Vital signs, body weight 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 2 
Study Day: 15 
2 to 28 
 
Week 6 
Study Day: 43 
29 to 56 
 
Week 10 
Study Day: 71 
57 to 84 
 
Week 14 
Study Day: 99 
85 to 112 
 
16 weeks after the last 
dose*1 
Follow-up Day: 112 
 
56 to 167 
*1 Applied only to subjects who did not receive the study drug in the maintenance phase and 
open-label cohort. 


6 
 
Laboratory tests (hematology, blood biochemistry) 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 2 
Study Day: 15 
2 to 28 
 
Week 6 
Study Day: 43 
29 to 56 
 
Week 10 
Study Day: 71 
57 to 84 
 
Week 14 
Study Day: 99 
85 to 126 
 
16 weeks after the last 
dose*1 
Follow-up Day: 112 
 
56 to 167 
*1 Applied only to subjects who did not receive the study drug in the maintenance phase and 
open-label cohort. 
 
Laboratory test (urinalysis) 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 10 
Study Day: 71 
2 to 84 
 
Week 14 
Study Day: 99 
85 to 126 
 
16 weeks after the last 
dose*1 
Follow-up Day: 112 
 
56 to 167 
*1 Applied only to subjects who did not receive the study drug in the maintenance phase and 
open-label cohort. 
 


7 
 
12-lead ECG, AVA, neutralizing antibody 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 10 
Study Day: 71 
2 to 84 
 
16 weeks after the last 
dose*1 
Follow-up Day: 112 
 
56 to 167 
*1 Applied only to subjects who did not receive the study drug in the maintenance phase and 
open-label cohort. 
 
Serum concentrations of MLN0002 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 2*1 
Study Day: 15 
12 to 18 
 
Week 6*1 
Study Day: 43 
40 to 46 
 
Week 10 
Study Day: 71 
68 to 74 
 
Week 14*1 
Study Day: 99 
92 to 106 
 
*1 For Week 2, Week 6, and Week 14, only data measured from 3 hours before administration until 
immediately before administration will be used. 
 
OTHER HANDLING 
In principle, if any variable value used for calculation or adjudication is missing, the result of the 
calculation or adjudication will be handled as missing. If other handling of missing data is described, 
follow that handling. 
• 
Duration of study drug exposure in the induction phase (days): Date of the last dose of the study 
drug in the induction phase − date of the first dose of the study drug in the induction phase + 1 
• 
Duration on study after the first dose of the study drug in the induction phase (days): For 
subjects who received the study drug in the maintenance phase or open-label cohort, “(the 
smallest date in the maintenance phase or open-label cohort unless date of the first dose of the 
study drug is missing) − date of the first dose of the study drug in the induction phase” and for 
other subjects, “date of last visit or contact − date of the first dose of the study drug in the 
induction phase + 1” 
• 
BMI (kg/m2) = Weight (kg) / (Height [cm]/100)2 (round off to the first decimal place) 


8 
 
• 
Duration of CD (years): (Date of informed consent [year and month] − Date of CD diagnosis 
[year and month]) / 12 (round off to the first decimal place) 
 
Only the year and month for the date of informed consent will be used. 
 
The unit for “Date of informed consent (year and month) − Date of CD diagnosis (year and 
month)” will be “months.” 
 
If the year of CD diagnosis is unknown, the duration of CD will be handled as “Missing.” 
If only the month of CD diagnosis is unknown, the duration of CD will be calculated by 
setting the month of CD diagnosis as January. 
• 
Prior corticosteroids failure: If corticosteroids resistance, dependence, or intolerance is “Yes,” 
prior corticosteroids failure will be defined as “Yes.” Any response other than the above will be 
defined as “No.” 
• 
Classification 1 of prior corticosteroids failure: Subjects for whom prior corticosteroid failure is 
“Yes” are classified as follows:  
 
Subjects for whom corticosteroid resistance is “Yes” are classified as “Resistance.” 
 
Among subjects for whom corticosteroids resistance is not “Yes,” subjects for whom 
corticosteroid dependence is “Yes” are classified as “Dependence.” 
 
Among subjects for whom corticosteroids resistance is not “Yes” as well as corticosteroid 
dependence not being “Yes,” subjects for whom corticosteroid intolerance is “Yes” are 
classified as “Intolerance.” 
• 
Classification 2 of prior corticosteroids failure: Subjects for whom prior corticosteroid failure is 
“Yes” are classified as follows:  
 
Subjects for whom corticosteroid resistance is “Yes” or corticosteroid dependence is 
“Yes” are classified as “Refractory.” 
 
Among subjects for whom corticosteroids resistance is not “Yes” as well as corticosteroid 
dependence not being “Yes,” subjects for whom corticosteroid intolerance is “Yes” are 
classified as “Intolerance.” 
• 
Prior immunomodulators failure: If either immunomodulator refractory or intolerance is “Yes,” 
prior immunomodulators failure will be defined as “Yes.” Any response other than the above 
will be defined as “No.” 
• 
Classification of prior immunomodulators failure: Subjects for whom prior immunomodulators 
failure is “Yes” are classified as follows:  
 
Subjects for whom immunomodulator refractory is “Yes” are classified as “Refractory.” 
 
Among the subjects for whom immunomodulator refractory is not “Yes,” subjects for 
whom immunomodulatory intolerance is “Yes” are classified as “Intolerance.”  
• 
Prior TNFα antagonist failure: If inadequate response, loss of response, or intolerance to the 
TNFα antagonist is “Yes,” prior TNFα antagonist failure will be defined as “Yes.” Any 
response other than the above will be defined as “No.” 


9 
 
• 
Number of drugs of TNFα antagonist failure: Among the drugs entered to prior treatment 
failure (TNFα antagonist) for CD, subjects whose WHO Drug is coded with 1 type of drug with 
Preferred Name are classified as “Treatment failure with 1 drug.” Similarly, subjects who are 
coded with 2 types of drugs are classified as “Treatment failure with 2 drugs” and subjects who 
are coded with 3 types of drugs as “Treatment failure with 3 drugs.” Subjects who are not coded 
with any drug in the prior treatment failure (TNFα antagonist) for CD are classified as “No.” 
• 
Classification of prior TNFα antagonist failure: Subjects for whom TNFα antagonist failure is 
“Yes” are classified as follows:  
 
Subjects for whom TNFα antagonist inadequate response is “Yes” are classified as 
“Inadequate response.” 
 
Among subjects for whom TNFα antagonist inadequate response is not “Yes,” subjects for 
whom TNFα antagonist loss of response is “Yes” are classified as “Loss of response.”  
 
Among subjects for whom TNFα antagonist inadequate response is not “Yes” as well as 
TNFα antagonist loss of response not being “Yes,” subjects for whom TNFα antagonist 
intolerance is “Yes” are classified as “Intolerance.”  
• 
Prior immunomodulators failure (excluding prior TNFα antagonist failure): If prior TNFα 
antagonist failure is “No” and prior immunomodulators failure is “Yes,” prior 
immunomodulators failure (excluding prior TNFα antagonist failure) will be defined as “Yes.” 
All others will be defined as “No.” 
• 
Prior corticosteroid failure only: If prior TNFα antagonist failure is “No,” prior 
immunomodulators failure is “No,” and prior corticosteroids failure is “Yes,” prior 
corticosteroid failure only will be defined as “Yes.” All others will be defined as “No.” 
• 
Prior immunomodulators and TNFα antagonist failure: If prior immunomodulators failure is 
“Yes” and prior TNFα antagonist failure is “Yes,” prior immunomodulators and TNFα 
antagonist failure will be defined as “Yes.” All others will be defined as “No.” 
• 
Completion of the study drug infusion: If the infusion of the study drug is “Completed” or dose 
of the study drug is ≥79 mL (percentage of dose against prepared study drug of 105 mL is 
≥75%), the study drug infusion will be defined as “Completed.” All others will be defined as 
“Incompleted.” 
 
The Ht level and CDAI score will be handled as follows: 
• 
The CDAI score, CDAI subscore, and Ht levels used for analysis will be determined at the 
central laboratory unless otherwise noted. 
• 
CDAI score: The sum of CDAI subscores of (1) to (8) defined in the table below. 


10 
 
(1) Number of liquid or very soft stools during the last 1 week 
× 2 
(2) Abdominal pain during the last 1 week 
(7-day total of daily abdominal pain scores on a following scale) 
0=None, 1=Mild, 2=Moderate, 3=Severe 
× 5 
(3) Subjective general well being during the last 1 week 
(7-day total of daily general well-being scores on a following scale) 
0=Generally well, 1=Slightly under par, 2=Poor, 3=Very poor, 
4=Terrible 
× 7 
(4) Current number of the following extraintestinal manifestations of CD 
1) 
Arthritis/arthralgia 
2) 
Iritis/uveitis 
3) 
Erythema nodosum/pyoderma gangrenosum/aphthous stomatitis 
4) 
Anal fissure, anal fistula, or perianal abscess 
5) 
Other fistula 
6) 
Fever over 37.8°C during the last 1 week 
× 20 
(5) Use of antidiarrheal drugs (e.g., lopemin) or opiates for diarrhea 
0=No, 1=Yes 
× 30 
(6) Abdominal mass 
0=None, 2=Questionable, 5=Definite 
× 10 
(7) Hematocrit (%)Note 1) 
Males: subtract value from 47, Females: subtract value from 42 
× 6 
(8) Body weight : Standard weight (body-weight ratio)Note 2) 
[1 - (Body weight / Standard weight)] × 100 
× 1 
Note 1) If hematocrit subtotal <0, enter 0. 
Note 2) If body weight subtotal <-10, enter -10. 
• 
The CDAI score will be calculated using subscores on the same day of evaluation. For subscore 
(7), however, the CDAI score will be calculated using the Ht level obtained within the same 
visit window if the Ht level on the same day of evaluation is not available. 
• 
If any CDAI subscore is missing, the CDAI score will be handled as missing. 
• 
CDAI-70 response: Subjects will be classified as “CDAI-70 response” if “a ≥70-point decrease 
in CDAI score from baseline” is achieved. All others will be classified as “Non-CDAI-70 
response.” However, if any CDAI score change is missing, it will be handled as missing. Then, 
if the adjudication result at that visit is missing (including cases with no data due to study 
discontinuation) after processing “HANDLING OF TIME WINDOW,” subjects will be 
classified as “Non-CDAI-70 response.” 
• 
CDAI-100 response: Subjects will be classified as “CDAI-100 response” if “a ≥100-point 
decrease in CDAI score from baseline” is achieved. All others will be classified as 
“Non-CDAI-100 response.” However, if any CDAI score change is missing, it will be handled 
as missing. Then, if the adjudication result at that visit is missing (including cases with no data 
due to study discontinuation) after processing “HANDLING OF TIME WINDOW,” subjects 
will be classified as “Non-CDAI-100 response.” 
• 
Clinical remission: Subjects will be classified as “Clinical remission” if “CDAI score of ≤150” 
is achieved. All others will be classified as “Non-remission.” However, if any of the CDAI 
scores is missing, it will be handled as missing. Then, if the adjudication result at that visit is 


11 
 
missing (including cases with no data due to study discontinuation) after processing 
“HANDLING OF TIME WINDOW,” subjects will be classified as “Non-remission.” 
 
After the CDAI-100 response and clinical remission at each visit are determined using the above 
methods, the following durable remission and durable CDAI-100 response will be determined. 
• 
Durable remission in the induction phase: Subjects will be classified as “Durable remission” if 
“Clinical remission at Week 6 and Week 10” is achieved. All others will be classified as 
“Non-durable remission.” Then, if the adjudication result at Week 6 or Week 10 is missing, 
subjects will be classified as “Non-durable remission.” 
• 
Durable CDAI-100 response in the induction phase: Subjects will be classified as “Durable 
CDAI-100 response” if “CDAI-100 response at Week 6 and Week 10” is achieved. All others 
will be classified as “Non-durable CDAI-100 response.” Then, if the adjudication result at 
Week 6 or Week 10 is missing, subjects will be classified as “Non-durable CDAI-100 
response.” 
• 
Durable CDAI-70 response in the induction phase: Subjects will be classified as “Durable 
CDAI-70 response” if “CDAI-70 response at Week 6 and Week 10” is achieved. All others will 
be classified as “Non-durable CDAI-70 response.” Then, if the adjudication result at Week 6 or 
Week 10 is missing, subjects will be classified as “Non-durable CDAI-70 response.” 
 
In addition, the following determination will be made. 
• 
CDAI-100 response at Week 10 with CRP level of ≤1.6 mg/dL at Week 10: Subjects will be 
classified as “Yes” if “CDAI-100 response at Week 10 and CRP level of ≤1.6 mg/dL at Week 
10 are both achieved.” All others will be defined as “No.” Then, if the adjudication result of 
CDAI-100 response at Week 10 or CRP level at Week 10 is missing, subjects will also be 
classified as “No.” 
• 
Clinical remission at Week 10 with CRP level of ≤1.6 mg/dL at Week 10: Subjects will be 
classified as “Yes” if clinical remission at Week 10 and CRP level of ≤1.6 mg/dL at Week 10 
are both achieved. All others will be defined as “No.” Then, if the adjudication result of clinical 
remission at Week 10 or CRP level at Week 10 is missing, subjects will also be classified as 
“No.” 
 
IBDQ score will be handled as follows: 
• 
The questions (Q) on the same day of measurement will be used for calculation of each 
subscore and total score. After calculating each subscore and total score, the time point will be 
transferred. 
• 
IBDQ subscore for abdominal symptoms: Mean of Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, 
Q26, and Q29 (round off to the first decimal place). 


12 
 
• 
IBDQ subscore for general condition: Mean of Q2, Q6, Q10, Q14, and Q18 (round off to the 
first decimal place). 
• 
IBDQ subscore for emotion: Mean of Q3, Q7, Q11, Q15, Q19, Q21, Q23, Q25, Q27, Q30, Q31, 
and Q32 (round off to the first decimal place). 
• 
IBDQ subscore for social function: Mean of Q4, Q8, Q12, Q16, and Q28 (round off to the first 
decimal place). 
• 
IBDQ total score: Sum of all questions (round off to the first decimal place). 
 
The value of each question after imputing missing data will be used for the calculation of 
each subscore (abdominal symptoms, general condition, emotion, and social function). 
• 
The handling of missing data in calculation of each subscore (abdominal symptoms, general 
condition, emotion, and social function) and IBDQ total score will be defined as follows:  
Variable 
Handling of missing data 
IBDQ subscore for 
abdominal symptoms, 
IBDQ subscore for 
general condition, 
IBDQ subscore for 
emotion, and IBDQ 
subscore for social 
function 
• If 1 question is missing among those used for calculation of each 
subscore, the missing data will be imputed using the mean of the 
non-missing questions used for the calculation of that subscore. 
• If 2 questions are missing among those used for the calculation of each 
subscore, that subscore will be handled as missing. 
IBDQ total score 
• Among the questions used for the calculation of IBDQ total score, the 
missing data will be imputed using the mean of the non-missing 
questions used for the calculation of each subscore. However, if 5 or 
more questions are missing or more than 2 subscores are missing among 
the questions used for the calculation of IBDQ total score or 3 or more 
questions are missing among those used for calculation of a certain 
subscore, the total score will be handled as missing. 
• 
170 or higher in IBDQ total score: “Yes” if IBDQ total score is ≥170, “No” if it is <170, and 
“Missing” if it is missing. 
• 
16 or higher in change from baseline in IBDQ total score: “Yes” if the change from baseline in 
IBDQ total score is ≥16, “No” if it is <16, and “Missing” if it is missing. 
• 
-16 or lower in change from baseline in IBDQ total score: “Yes” if the change from baseline in 
IBDQ total score is ≤-16, “No” if it is >-16, and “Missing” if it is missing. 
 
Prior TNFα antagonist use, concomitant use of immunomodulators at baseline, and concomitant use 
of oral corticosteroids at baseline will be defined as follows: 


13 
 
• 
Prior TNFα antagonist use: Subjects coded with at least 1 drug of Preferred Name of WHO 
Drug in the following table for medication history will be classified as “Yes.” All others will be 
classified as “No.” 
Preferred Name 
Infliximab 
Adalimumab 
Golimumab 
• 
Concomitant use of immunomodulators at baseline: Subjects who received any concomitant 
medication (for treatment of CD) which is classified as “immunomodulator” in the concomitant 
medication (for treatment of CD) which was started before the first dose of the study drug in the 
induction phase and continued in the induction phase will be classified as “Yes.” All others will 
be classified as “No.” 
 
Any concomitant medication (for treatment of CD) which was started after the first dose of 
the study drug in the induction phase is not subject to this handling. 
• 
Concomitant use of oral corticosteroids at baseline: Subjects who received any concomitant 
medication (for treatment of CD) which is classified as “corticosteroid” and whose route of 
administration is “oral” in the concomitant medication (for treatment of CD) which was started 
before the first dose of the study drug in the induction phase and continued in the induction 
phase will be classified as “Yes.” All others will be classified as “No.” 
 
Any concomitant medication (for treatment of CD) which was started after the first dose of 
the study drug in the induction phase is not subject to this handling. 
 
Concurrent extraintestinal manifestations (based on CDAI subscore [4]), concurrent extraintestinal 
manifestations (based on case report form [CRF] concurrent medical condition section), surgical 
history for CD, medical history of fistula or concurrent medical condition related to fistula within 1 
year before signing of informed consent, and concurrent medical condition related to fistula will be 
defined as follows: 
• 
Concurrent extraintestinal manifestations (based on CDAI subscore [4]): Subjects whose CDAI 
subscore [4] at baseline is greater than 0 will be classified as “Yes.” All others will be classified 
as “No.” 
• 
Concurrent extraintestinal manifestations (based on CRF concurrent medical condition section): 
Subjects recorded to have concurrent extraintestinal manifestations of CD in the CRF 
concurrent medical condition section will be classified as “Yes.” All others will be classified as 
“No.” 
• 
Surgical history for CD: Subjects coded with at least one PT in the following table for medical 
history will be classified as “Yes.” All others will be classified as “No.” 


14 
 
Preferred Term 
Anal skin tag excision 
Colectomy 
Crohn's disease 
Enterocutaneous fistula 
Ileal operation 
Ileectomy 
Ileocolectomy 
Ileocolostomy 
Ileostomy 
Ileostomy closure 
Intestinal resection 
Proctectomy 
Sigmoidectomy 
Small intestinal resection 
Small intestine operation 
Stricturoplasty 
Urinary cystectomy 
 
• 
Medical history of fistula or concurrent medical condition related to fistula within 1 year before 
signing of informed consent: Subjects coded with at least one PT in the following table for 
medical history or concurrent medical condition will be classified as “Yes.” All others will be 
classified as “No.” 
Medical history 
Preferred Term 
Anal fistula 
Fistula of small intestine 
 
Concurrent medical condition 
Preferred Term 
Anal fistula 
Enterocutaneous fistula 
Female genital tract fistula 
 
• 
Concurrent medical condition related to fistula: Subjects coded with at least one PT in the 
following table for concurrent medical condition will be classified as “Yes.” All others will be 


15 
 
classified as “No.” 
Preferred Term 
Anal fistula 
Enterocutaneous fistula 
Female genital tract fistula 
 
Negative or positive status of the neutralizing antibody will be determined as follows: 
• 
“Positive” if the neutralizing antibody is positive for AVA and neutralizing antibody with the 
same VISIT in each subject. “Negative” if the neutralizing antibody is negative or AVA is 
negative. Neutralizing antibody will be handled as missing if it does not correspond to any of 
the above. 
After determining the negative or positive status of the neutralizing antibody at each visit with the 
above-mentioned logic, the following determination will be made: 
• 
AVA in the induction phase 
 
Subjects who were determined to be AVA-positive at any visit after the day of the first 
dose of the study drug in the induction phase will be classified as “AVA-positive.” 
 
Subjects who were determined to be AVA-negative at all visits (except for those with 
missing values) after the day of the first dose of the study drug in the induction phase will 
be classified as “AVA-negative.” 
 
Subjects whose AVA values are missing at all visits in the induction phase will be 
classified as missing. 
• 
Neutralizing antibody in the induction phase 
 
Subjects who were determined to be neutralizing antibody-positive at any visit after the 
day of the first dose of the study drug in the induction phase will be classified as 
“neutralizing antibody-positive.” 
 
Subjects who were determined to be neutralizing antibody-negative at all visits (except for 
those with missing values) after the day of the first dose of the study drug in the induction 
phase will be classified as “neutralizing antibody-negative.” 
 
Subjects whose neutralizing antibody values are missing at all visits in the induction phase 
will be classified as missing. 
 
Lymphocytes and neutrophils will be calculated with the following formula: 
• 
Lymphocytes = WBC × lymphocytes (%)  
• 
Neutrophils = WBC × neutrophils (%)  
 


16 
 
1 STUDY SUBJECTS, DEMOGRAPHICS, AND OTHER BASELINE CHARACTERISTICS 
1.1 Disposition of Subjects 
1.1.1 Study Information 
Analysis set: 
All subjects who signed the informed consent form 
Analysis variables: 
Date first subject signed the informed consent form 
 
MedDRA version 
 
WHO Drug version 
 
SAS version used for creating the datasets 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables. 
(1) Display of the analysis variables 
 
1.1.2 Disposition of All Subjects Who Did Not Enter in the Induction Phase 
Analysis set: 
All subjects who did not enter in the induction phase 
Analysis variables: 
Categories in parenthesis [  ] (hereinafter the same) 
 
Age (years) 
[Min≤ - ≤34, 35≤ - ≤Max] 
 
 
[Min≤ - ≤64, 65≤ - ≤Max] 
 
Gender 
[Male, Female] 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables. 
(1) Frequency distributions for categorical variables and 
summary statistics for continuous variables 
 
1.1.3 Subject Eligibility 
Analysis set: 
All subjects who signed the informed consent form 
Analysis variables: 
Eligibility for entering into 
the induction phase 
[Eligible, Not eligible] 
 
Reason for being not 
eligible for entering into 
the induction phase 
[Pretreatment event/Adverse event, 
Major protocol deviation, Lost to 
follow-up, Voluntary withdrawal, 
Study termination, Pregnancy, Did 
not meet entrance criteria, Other] 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables. 
When calculating percentages of the reasons for not being eligible 
for entering into the induction phase, the total number of ineligible 
subjects in the induction phase will be used as the denominator. 


17 
 
 
(1) Frequency distributions 
 
1.1.4 Number of Subjects Who Entered in the Induction Phase by Site 
Analysis set: 
All subjects who entered in the induction phase 
Analysis variables: 
Eligibility for entering into the 
induction phase 
[Eligible] 
Stratum:  
Study site 
[Site numbers will be used as 
categories] 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables for each stratum by each treatment group in the induction 
phase and in the consolidated treatment groups in the induction 
phase. 
 
(1) Frequency distributions 
 
1.1.5 Disposition of Subjects 
1.1.5.1 Disposition of Subjects 
Analysis set: 
All subjects who entered in the induction phase 
Analysis variables: 
Study drug administration 
status in the induction phase 
[Not treated] 
 
Reason for not being 
treated 
[Pretreatment event/Adverse event, 
Major protocol deviation, Lost to 
follow-up, Voluntary withdrawal, 
Study termination, Pregnancy, 
Lack of efficacy, Other] 
 
Study drug completion status 
in the induction phase 
[Completed, Incompleted] 
 
Reason for not being 
completed 
[Pretreatment event/Adverse event, 
Major protocol deviation, Lost to 
follow-up, Voluntary withdrawal, 
Study termination, Pregnancy, 
Lack of efficacy, Other] 
 
Study visit completion status 
in the induction phase 
[Completed, Incompleted] 


18 
 
 
Reason for not being 
completed 
[Pretreatment event/Adverse event, 
Major protocol deviation, Lost to 
follow-up, Voluntary withdrawal, 
Study termination, Pregnancy, 
Lack of efficacy, Other] 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by each treatment group in the induction phase and in the 
consolidated treatment groups in the induction phase. When 
calculating percentages of the reasons for not being treated, the 
total number of subjects not treated by the study drug in the 
induction phase will be used as the denominator. When calculating 
percentages of the reasons for not being completed, the total 
number of subjects who did not complete the study drug/study visit 
in the induction phase will be used as the denominator. 
 
(1) Frequency distributions 
 
1.1.6 Study Drug Completion Status and Study Visit Completion Status 
Analysis set: 
All subjects who entered in the induction phase 
Analysis variables: 
Study drug completion status 
in the induction phase 
[Completed, Incompleted] 
 
Reason for not being 
completed 
[Pretreatment event/Adverse event, 
Major protocol deviation, Lost to 
follow-up, Voluntary withdrawal, 
Study termination, Pregnancy, 
Lack of efficacy, Other] 
 
Study visit completion status 
in the induction phase 
[Completed, Incompleted] 
 
Reason for not being 
completed 
[Pretreatment event/Adverse event, 
Major protocol deviation, Lost to 
follow-up, Voluntary withdrawal, 
Study termination, Pregnancy, 
Lack of efficacy, Other] 
Categories: 
Duration of study drug 
exposure in the induction 
phase (days) 
[0, 1≤ - ≤28, 29≤ - ≤56,  
57≤ - ≤Max] 


19 
 
 
Duration on study after the 
first dose of the study drug in 
the induction phase (days) 
[0, 1≤ - ≤28, 29≤ - ≤56, 57≤ - ≤84, 
85≤ - ≤Max] 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by each treatment group in the induction phase and in the 
consolidated treatment groups in the induction phase. 
Frequency distributions will be provided for study drug completion 
status in the induction phase in the analysis of (1). Frequency 
distributions will be provided for study visit completion status in 
the induction phase in the analysis of (2). 
 
(1) Frequency distribution by duration of study drug exposure in 
the induction phase 
(2) Frequency distribution by duration on study after the first 
dose of the study drug in the induction phase 
 
1.1.7 Protocol Deviations and Analysis Sets 
1.1.7.1 
Protocol Deviations in the Induction Phase 
Analysis set: 
All subjects who entered in the induction phase 
Analysis variables: 
Protocol deviations in the 
induction phase 
[Major GCP violations, Deviations of 
protocol entry criteria, Deviations of 
discontinuation criteria, Deviations 
related to treatment procedure or dose, 
Deviations concerning excluded 
medication or therapy, Deviations to 
avoid emergency risk, Other] 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by each treatment group in the induction phase and in the 
consolidated treatment groups in the induction phase. 
Frequency distribution of subjects with protocol deviations in the 
induction phase will be provided for above each deviation category. 
A subject who has several deviations that can be classified into the 
same category will be counted once in each appropriate category 
(overlapped counting). 
(1) Frequency distributions 
 
1.1.7.2 
Analysis Sets of All Subjects Who Entered in the Induction Phase 
Analysis set: 
All subjects who entered in the induction phase 


20 
 
Analysis variables: 
Handling of subjects and subject 
data in the induction phase in 
analysis sets 
Inclusion/Exclusion of analysis sets 
Full analysis set in the induction 
phase 
Per protocol set in the induction 
phase 
Safety analysis set in the 
induction phase 
[Categories are based on the 
specifications in “Handling 
Rules for Analysis Data”] 
 
[Included] 
 
[Included] 
 
[Included] 
Analysis methodology: 
The following analyses of (1) and (2) will be performed for the 
above analysis variables by treatment group in the induction phase 
and the following analysis of (3) will be performed by each 
treatment group in the induction phase and in the consolidated 
treatment groups in the induction phase. 
A subject who corresponds to several categories in (1) and (2) will 
be counted once in each appropriate category (overlapped 
counting). 
 
(1) Frequency distributions concerning the handling of subjects in 
the induction phase in each analysis set 
(2) Frequency distributions concerning the handling of subject 
data in the induction phase in each analysis set 
(3) Frequency distributions concerning the number of subjects 
included in each analysis set 
 
1.2 Demographic and Other Baseline Characteristics 
1.2.1 Distribution of Baseline Demographics 
Analysis set: 
All subjects who entered in the induction phase 
Analysis variables: 
Age (years) 
[Min≤ - ≤34, 35≤ - ≤Max] 
[Min≤ - ≤64, 65≤ - ≤Max] 
 
Gender 
[Male, Female] 
 
Height (cm) 
 
 
Weight (kg) at baseline 
[Min≤ - ≤49.9, 50.0≤ - ≤59.9, 
60.0≤ - ≤69.9, 70.0≤ - ≤79.9, 
80.0≤ - ≤Max] 
 
BMI (kg/m2) at baseline 
[Min≤ - ≤18.4, 18.5≤ - ≤24.9, 
25.0≤ - ≤Max] 


21 
 
 
Smoking classification 
[Never smoked, Current smoker, 
Ex-smoker] 
 
Duration of CD (years) 
[Min≤ - <1, 1≤ - <3, 3≤ - <7,  
7≤ - ≤Max, Missing] 
 
Prior corticosteroids failure 
[Yes, No] 
 
Classification 1 of prior 
corticosteroids failure 
[Resistance, Dependence, 
Intolerance] 
 
Classification 2 of prior 
corticosteroids failure 
[Refractory, Intolerance] 
 
Prior immunomodulators 
failure 
[Yes, No] 
 
Classification of prior 
immunomodulators failure 
[Refractory, Intolerance] 
 
Prior TNFα antagonist failure 
[Yes, No] 
 
Number of drugs of TNFα 
antagonist failure 
[1 drug, 2 drugs, 3 drugs, None] 
 
Classification of prior TNFα 
antagonist failure 
[Inadequate response, Loss of 
response, Intolerance] 
 
Worst prior treatment failures 
[Prior TNFα antagonist failure, 
Prior immunomodulators failure 
but not TNFα antagonist failure, 
Prior corticosteroid failure only] 
 
Prior immunomodulators and 
TNFα antagonist failure 
[Yes, No] 
 
Prior TNFα antagonist use 
[Yes, No] 
 
Infliximab 
[Yes, No] 
 
Adalimumab 
[Yes, No] 
 
Golimumab 
[Yes, No] 
 
Concomitant use of enteral 
nutrient at baseline 
[Yes, No] 
 
Concomitant use of 5-ASA at 
baseline 
[Yes, No] 
 
Concomitant use of 
immunomodulators at baseline 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids at baseline 
[Yes, No] 
 
No concomitant use of oral 
[Yes, No] 


22 
 
corticosteroids and No 
concomitant use of 
immunomodulators at baseline 
 
Concomitant use of oral 
corticosteroids and No 
concomitant use of 
immunomodulators at baseline 
(concomitant use of oral 
corticosteroids only) 
[Yes, No] 
 
No concomitant use of oral 
corticosteroids and 
Concomitant use of 
immunomodulators at baseline 
(concomitant use of 
immunomodulators only) 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids and 
Concomitant use of 
immunomodulators at baseline 
[Yes, No] 
 
CDAI score at baseline 
[Min≤ - ≤220, 220< - ≤330,  
330< - ≤450, 450< - ≤Max] 
 
CDAI subscore (1): Number 
of liquid or very soft stools 
during the last 1 week at 
baseline 
 
 
CDAI subscore (2): 
Abdominal pain during the last 
1 week at baseline 
 
 
CDAI subscore (3): Subjective 
general well being during the 
last 1 week at baseline 
 
 
CDAI subscore (4): Current 
number of extraintestinal 
manifestations of CD (e.g., 
arthritis/arthralgia) at baseline 
[0, 1, 2, 3, 4, 5, 6] 
 
 
CDAI subscore (5): Use of 
antidiarrheal drugs (e.g., 
[No, Yes] 


23 
 
lopemin) or opiates for 
diarrhea at baseline 
 
CDAI subscore (6): 
Abdominal mass at baseline 
[None, Questionable, Definite] 
 
CDAI subscore (7): 
Hematocrit level at baseline 
 
 
CDAI subscore (8): Body 
weight : Standard weight 
(body-weight ratio) at baseline 
 
 
Disease localization 
[Small intestinal, Large intestinal, 
Small/Large intestinal] 
 
Concurrent extraintestinal 
manifestations (based on 
CDAI subscore [4]) 
[Yes, No] 
 
Concurrent extraintestinal 
manifestations (based on CRF 
concurrent medical condition 
section) 
[Yes, No] 
 
CRP (mg/dL) at baseline 
[Min≤ - ≤0.3, 0.3< - ≤0.5,  
0.5< - ≤1.0, 1.0< - ≤1.6,  
1.6< - ≤Max] 
 
Surgical history for CD 
[Yes, No] 
 
Medical history of fistula or 
concurrent medical condition 
related to fistula within 1 year 
before signing of informed 
consent 
[Yes, No] 
 
Concurrent medical condition 
related to fistula 
[Yes, No] 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by each treatment group in the induction phase and in the 
consolidated treatment groups in the induction phase. The same 
analysis will be performed with stratification according to “prior 
TNFα antagonist use.” 
(1) Frequency distributions for categorical variables and summary 
statistics for continuous variables 
 


24 
 
1.2.2 Medical History, Concurrent Medical Conditions 
Analysis set: 
Safety analysis set in the induction phase 
Analysis variables: 
Medical history 
 
Concurrent medical conditions (concurrent extraintestinal 
manifestations of CD) 
 
Concurrent medical conditions (other than concurrent 
extraintestinal manifestations of CD) 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by each treatment group in the induction phase and in the 
consolidated treatment groups in the induction phase. 
The analysis variables will be coded by use of MedDRA and will 
be summarized based on the SOC and PT. SOC will be sorted 
alphabetically and PT will be sorted in decreasing frequency. 
(1) Frequency distributions for medical history (by SOC and PT) 
(2) Frequency distributions for concurrent medical conditions 
(concurrent extraintestinal manifestations of CD) (by SOC and 
PT) 
(3) Frequency distributions for concurrent medical conditions 
(other than concurrent extraintestinal manifestations of CD) 
(by SOC and PT) 
 
The method of counting events when providing each frequency 
distribution will be as follows: 
[Number of subjects] 
A subject with multiple occurrences of medical history or 
concurrent medical condition within a SOC will be counted only 
once in that SOC. A subject with multiple occurrences of 
medical history or concurrent medical condition within a PT will 
be counted only once in that PT. 
 
1.2.3 Medication History, Concomitant Medications in the Induction Phase, Concomitant 
Therapies in the Induction Phase 
Analysis set: 
Safety analysis set in the induction phase 
Analysis variables: 
Medication history 
 
 
Concomitant medications (for treatment of 
CD) in the induction phase 
 
 
Classification of concomitant medications 
(for treatment of CD) in the induction phase 
[5-ASA, 
Corticosteroids, 


25 
 
Immunomodulators, 
Enteral nutrients, 
Other] 
 
Concomitant medications (for treatment of 
CD) in the induction phase that fall under 
the category of rescue treatments 
 
 
Classification of concomitant medications 
(for treatment of CD) in the induction phase 
that fall under the category of rescue 
treatments 
[5-ASA, 
Corticosteroids, 
Immunomodulators, 
Enteral nutrients, 
Other] 
 
Concomitant medications (for other than 
treatment of CD) in the induction phase 
 
 
Concomitant therapies in the induction 
phase 
[Yes, No] 
 
Concomitant therapies in the induction 
phase that fall under the category of rescue 
treatments 
[Yes, No] 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by each treatment group in the induction phase and in the 
consolidated treatment groups in the induction phase. 
Medication history, concomitant medications (for treatment of CD) 
in the induction phase, concomitant medications (for treatment of 
CD) in the induction phase that fall under the category of rescue 
treatments, and concomitant medications (for other than treatment 
of CD) in the induction phase will be coded by use of WHO Drug 
and summarized based on Preferred Name, which will be sorted in 
decreasing frequency. 
A subject who has been administered several medications with the 
same Preferred Name will be counted only once for that Preferred 
Name. 
(1) Frequency distributions for medication history 
(2) Frequency distributions for concomitant medications (for 
treatment of CD) in the induction phase that were ongoing at 
baseline and continued in the induction phase, and 
concomitant medications (for treatment of CD) in the 
induction phase that started after baseline by category 


26 
 
(3) Frequency distributions for concomitant medications (for 
treatment of CD) in the induction phase that fall under the 
category of rescue treatments that were ongoing at baseline 
and continued in the induction phase, and concomitant 
medications (for treatment of CD) in the induction phase that 
fall under the category of rescue treatments and started after 
baseline by category 
(4) Frequency distributions for concomitant medications (for 
other than treatment of CD) in the induction phase that were 
ongoing at baseline and continued in the induction phase, and 
concomitant medications (for other than treatment of CD) in 
the induction phase that started after baseline 
(5) Frequency distributions for presence or absence of 
concomitant therapies in the induction phase that were 
ongoing at baseline and continued in the induction phase and 
concomitant therapies in the induction phase that started after 
baseline 
(6) Frequency distributions for presence or absence of 
concomitant therapies in the induction phase that fall under 
the category of rescue treatments that were ongoing at 
baseline and continued in the induction phase and 
concomitant therapies in the induction phase that fall under 
the category of rescue treatments and started after baseline 
 
1.3 Measurement of Compliance Status for Treatment 
1.3.1 Study Drug Exposure and Compliance in the Induction Phase 
Analysis set: 
Safety analysis set in the induction phase 
Analysis variables: 
Duration of study drug exposure in the 
induction phase (days) 
[1≤ - ≤28, 29≤ - ≤56,  
57≤ - ≤Max] 
 
Duration on study after the first dose of 
the study drug in the induction phase 
(days) 
[1≤ - ≤28, 29≤ - ≤56,  
57≤ - ≤84, 85≤ - ≤Max] 
 
Number of the study drug infusion in 
the induction phase (times) 
[1, 2, 3] 
 
Number of completed infusions of the 
study drug in the induction phase 
(times) 
[0, 1, 2, 3] 


27 
 
 
Number of completed or incompleted 
infusions in total infusions in the 
induction phase 
[Completed, 
Incompleted] 
Analysis methodology: 
 
The following analysis will be performed for the above analysis 
variables by each treatment group in the induction phase and in the 
consolidated treatment groups in the induction phase. 
(1) Frequency distributions for categorical variables and summary 
statistics for continuous variables 
 
In the frequency distributions for number of completed or 
incompleted infusions in total infusions in the induction phase, the 
sum of the number of completed infusions in the induction phase in 
the applicable treatment group will be counted as frequency for 
“Completed” and the sum of the number of incompleted infusions 
will be counted as frequency for “Incompleted.” When calculating 
percentage, the sum of the number of completed infusions and the 
number of incompleted infusions (i.e., number of total infusions in 
the induction phase) will be used as the denominator. 
 


28 
 
2 EFFICACY ANALYSIS 
The “full analysis set in the induction phase” based on the specifications in the protocol and the 
“Handling Rules for Analysis Data” will be the main analysis set. From sensitivity point of view, the 
“per protocol set in the induction phase” will be used for an analysis performed secondarily on the 
primary endpoint in order to examine the robustness of the results. 
 
2.1 Primary Endpoints and Analysis Methodology 
2.1.1 Primary Analysis 
Analysis set: 
Full analysis set in the induction phase 
Analysis variables: 
CDAI-100 response at Week 10 
[CDAI-100 response, 
Non-CDAI-100 response] 
Stratum: 
Prior TNFα antagonist use 
[Yes, No] 
Analysis methodology: 
 
The following analysis will be performed in the “full analysis set in 
the induction phase.” 
Frequency distributions will be provided for “CDAI-100 response 
at Week 10” (the primary endpoint of the induction phase) by 
treatment group in the induction phase along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the proportion 
between treatment groups (MLN0002 group − placebo group) will 
be also calculated. The same calculation will be performed with 
stratification according to “prior TNFα antagonist use” and the 
Cochran-Mantel-Haenszel (CMH) test with two-sided significance 
level of 10% by using “prior TNFα antagonist use” as a 
stratification factor will be performed. In addition, the adjusted 
odds ratio of the MLN0002 group to the placebo group (MLN0002 
group/placebo group) and the 95% two-sided CI will be calculated. 
The results of the primary analysis of the induction phase will be 
interpreted as below to determine the efficacy of MLN0002 
induction therapy. 
 The superiority of MLN0002 over the placebo on CDAI-100 
response at Week 10 will be demonstrated when a statistically 
significant difference in CDAI-100 response at Week 10 is 
observed in the primary analysis of the induction phase. 
 


29 
 
2.1.2 Secondary Analysis 
Analysis set: 
Per protocol set in the induction phase 
Full analysis set in the induction phase 
Analysis variables: 
CDAI-100 response at Week 10 
[CDAI-100 response, 
Non-CDAI-100 response] 
Stratum: 
Prior TNFα antagonist use 
[Yes, No] 
Analysis methodology: 
 
From sensitivity point of view, the following analysis will be 
performed to examine the robustness of the results. 
(1) The CDAI-100 response at Week 10 will be analyzed in the 
same manner as those in the primary analysis in 2.1.1 in the 
“per protocol set in the induction phase. 
 
The following analysis will be performed for reference. 
(2) For the CDAI-100 response at Week 10, the CMH adjusted 
risk difference (MLN0002 group − placebo group) with “prior 
TNFα antagonist use” as a stratification factor and the 95% 
two-sided CI will be calculated in the “full analysis set in the 
induction phase.” 
(3) The CDAI-100 response at Week 10 will be analyzed in the 
same manner as those in the primary analysis in 2.1.1 in the 
“full analysis set in the induction phase” after excluding the 
subjects whose CDAI scores at Week 10 are missing. 
 
2.2 Secondary Endpoints and Analysis Methodology 
Analysis set: 
Full analysis set in the induction phase 
Analysis variables: 
Clinical remission at Week 10 
[Clinical remission, 
Non-remission] 
 
Change in CRP level over time in the 
subpopulation of subjects with the baseline 
CRP level of >0.30 mg/dL 
 
Stratum: 
Prior TNFα antagonist use 
[Yes, No] 
Visit: 
Weeks 0, 2, 6, and 10 (change in CRP level over time in the 
subpopulation of subjects with the baseline CRP level of 
>0.30 mg/dL) 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by treatment group in the induction phase. 


30 
 
The results of the secondary analysis of the induction phase will be 
interpreted as below to determine the efficacy of MLN0002 
induction therapy. 
 The superiority of MLN0002 over the placebo on clinical 
remission at Week 10 will be demonstrated when statistically 
significant differences are observed in both CDAI-100 response 
at Week 10 in the primary analysis of 2.1.1 and clinical 
remission at Week 10 in the analysis methodology (3). 
 
(1) Frequency distributions will be provided for clinical remission 
at Week 10 along with the point estimate and 95% two-sided 
CI for the proportion. The point estimate and 95% two-sided 
CI for the difference in the proportion between treatment 
groups (MLN0002 group − placebo group) will be also 
calculated. 
 
(2) Frequency distributions will be provided for clinical remission 
at Week 10 with stratification according to “prior TNFα 
antagonist use” along with the point estimate and 95% 
two-sided CI for the proportion. The point estimate and 95% 
two-sided CI for the difference in the proportion between 
treatment groups (MLN0002 group − placebo group) will be 
also calculated. 
 
(3) The CMH test with two-sided significance level of 10% by 
using “prior TNFα antagonist use” as a stratification factor 
will be performed for clinical remission at Week 10 to 
calculate the adjusted odds ratio of the MLN0002 group to the 
placebo group (MLN0002 group/placebo group) and the 95% 
two-sided CI. Also, the CMH adjusted risk difference 
(MLN0002 group − placebo group) with “prior TNFα 
antagonist use” as a stratification factor and the 95% 
two-sided CI will be calculated. 
 
(4) Summary statistics and 95% two-sided CI of the mean will be 
calculated for CRP level at each visit (baseline to Week 10) in 
the subpopulation of subjects with the baseline CRP level of 
>0.30 mg/dL.  In addition, summary statistics, the 95% 
two-sided CI of the mean, 10th and 90th percentiles will be 
calculated for changes from baseline in CRP level at each visit 
(Week 2 to Week 10) in the subpopulation of subjects with the 


31 
 
baseline CRP level of >0.30 mg/dL.  
 
(5) The same analysis as (4) will be performed with stratification 
according to “prior TNFα antagonist use” in the subpopulation 
of subjects with the baseline CRP level of >0.30 mg/dL. 
 
(6) The van Elteren test (CMH test with the modified ridit score) 
stratified by “prior TNFα antagonist use” will be performed 
for changes from baseline in CRP level at each visit (Week 2 
to Week 10) in the subpopulation of subjects with the baseline 
CRP level of >0.30 mg/dL. 
 
2.3 Other Endpoints and Analysis Methodology 
2.3.1 Endpoints Related to CDAI Scores 
Analysis set: 
Full analysis set in the induction phase 
Analysis variables: 
Clinical remission 
[Clinical remission, 
Non-remission] 
 
CDAI-100 response 
[CDAI-100 response, 
Non-CDAI-100 
response] 
 
CDAI-70 response 
[CDAI-70 response, 
Non-CDAI-70 response] 
 
Durable remission 
[Durable remission, 
Non-durable remission] 
 
Durable CDAI-100 response 
[Durable CDAI-100 
response, Non-durable 
CDAI-100 response] 
 
Durable CDAI-70 response 
[Durable CDAI-70 
response, Non-durable 
CDAI-70 response] 
 
CDAI-100 response at Week 6 and 
Week 10 and clinical remission at 
Week 6 and Week 10 in the 
subpopulation of subjects without prior 
TNFα antagonist use and in the 
subpopulation of subjects who failed 
with a TNFα antagonist 
[CDAI-100 response, 
Non-CDAI-100 
response] 
[Clinical remission, 
Non-remission] 
 
CDAI-100 response at Week 6 and 
Week 10 and clinical remission at 
[CDAI-100 response, 
Non-CDAI-100 


32 
 
Week 6 and Week 10 in the 
subpopulation of subjects who failed 
with a corticosteroid monotherapy and 
an immunomodulator (except those 
failed with a TNFα antagonist) 
response] 
[Clinical remission, 
Non-remission] 
 
CDAI score change over time 
 
 
Each CDAI subscore change over time 
 
Visit: 
Weeks 0, 2, 6, and 10 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by treatment group in the induction phase. 
 
(1) Frequency distributions will be provided for clinical remission 
at each visit along with the point estimate and 95% two-sided 
CI for the proportion. The point estimate and 95% two-sided 
CI for the difference in the proportion between treatment 
groups (MLN0002 group − placebo group) will be also 
calculated. 
 
(2) Frequency distributions will be provided for clinical remission 
at each visit with stratification according to “prior TNFα 
antagonist use” along with the point estimate and 95% 
two-sided CI for the proportion. The point estimate and 95% 
two-sided CI for the difference in the proportion between 
treatment groups (MLN0002 group − placebo group) will be 
also calculated. 
 
(3) The CMH test using “prior TNFα antagonist use” as a 
stratification factor will be performed for clinical remission at 
each visit to calculate the adjusted odds ratio of the MLN0002 
group to the placebo group (MLN0002 group/placebo group) 
and the 95% two-sided CI. Also, the CMH adjusted risk 
difference (MLN0002 group − placebo group) with “prior 
TNFα antagonist use” as a stratification factor and the 95% 
two-sided CI will be calculated. 
 
(4) The same analysis as (1) will be performed for the CDAI-100 
response at each visit. 
 
(5) The same analysis as (2) will be performed for CDAI-100 
response at each visit with stratification according to “prior 
TNFα antagonist use.” 
 
(6) The same analysis as (3) will be performed for the CDAI-100 


33 
 
response at each visit. 
 
(7) The same analysis as (1) will be performed for the CDAI-70 
response at each visit. 
 
(8) The same analysis as (2) will be performed for CDAI-70 
response at each visit with stratification according to “prior 
TNFα antagonist use.” 
 
(9) The same analysis as (3) will be performed for the CDAI-70 
response at each visit. 
 
(10) The same analysis as (1) will be performed for durable 
remission. 
 
(11) The same analysis as (2) will be performed for durable 
remission with stratification according to “prior TNFα 
antagonist use.” 
 
(12) The same analysis as (3) will be performed for durable 
remission. 
 
(13) The same analysis as (1) will be performed for durable 
CDAI-100 response. 
 
(14) The same analysis as (2) will be performed for durable 
CDAI-100 response with stratification according to “prior 
TNFα antagonist use.” 
 
(15) The same analysis as (3) will be performed for durable 
CDAI-100 response. 
 
(16) The same analysis as (1) will be performed for durable 
CDAI-70 response. 
 
(17) The same analysis as (2) will be performed for durable 
CDAI-70 response with stratification according to “prior 
TNFα antagonist use.” 
 
(18) The same analysis as (3) will be performed for durable 
CDAI-70 response. 
 
(19) The same analysis as (1) will be performed for the CDAI-100 
response and clinical remission at each visit in the 
subpopulation of subjects without prior TNFα antagonist use. 
The Pearson’s chi-square test will be also performed. 
 
(20) The same analysis as (1) will be performed for the CDAI-100 
response and clinical remission at each visit in the 
subpopulation of subjects who failed with a TNFα antagonist. 
The Pearson’s chi-square test will be also performed. 


34 
 
 
(21) The same analysis as (1) will be performed for the CDAI-100 
response and clinical remission at each visit in the 
subpopulation of subjects who failed with a corticosteroid 
monotherapy. The Pearson’s chi-square test will be also 
performed. 
 
(22) The same analysis as (1) will be performed for the CDAI-100 
response and clinical remission at each visit in the 
subpopulation of subjects who failed with an 
immunomodulator (except those failed with a TNFα 
antagonist). The Pearson’s chi-square test will be also 
performed. 
 
(23) Summary statistics and 95% two-sided CI of the mean will be 
provided for the CDAI scores at each visit along with the plot 
over time. Summary statistics and 95% two-sided CI of the 
mean will be calculated for the CDAI scores at each visit with 
stratification according to “prior TNFα antagonist use.” 
 
(24) Summary statistics and 95% two-sided CI of the mean will be 
provided for changes from baseline in the CDAI scores at each 
visit along with the plot over time. Summary statistics and 
95% two-sided CI of the mean will be calculated for changes 
from baseline in the CDAI scores at each visit with 
stratification according to “prior TNFα antagonist use.” 
 
(25) The point estimate and 95% two-sided CI for the difference in 
the least square (LS) mean between treatment groups 
(MLN0002 group − placebo group) will be calculated based 
on the analysis of covariance (ANCOVA) model with changes 
from baseline in the CDAI score at each visit as a response, 
the treatment groups in the induction phase and “prior TNFα 
antagonist use” as factors, and CDAI score at baseline as a 
covariate. 
 
(26) The same analysis as (23) will be performed for each CDAI 
subscore at each visit. 
 
(27) The same analysis as (24) will be performed for changes from 
baseline in each CDAI subscore at each visit. 
 
2.3.2 Endpoints Related to CDAI Scores Based on the Hematocrit Level at Each Study Site 
Analysis set: 
Full analysis set in the induction phase 


35 
 
Analysis variables: 
Clinical remission 
[Clinical remission, 
Non-remission] 
 
CDAI-100 response 
[CDAI-100 response, 
Non-CDAI-100 
response] 
 
CDAI-70 response 
[CDAI-70 response, 
Non-CDAI-70 response] 
 
Durable remission  
[Durable remission, 
Non-durable remission] 
 
Durable CDAI-100 response  
[Durable CDAI-100 
response, Non-durable 
CDAI-100 response] 
 
Durable CDAI-70 response 
[Durable CDAI-70 
response, Non-durable 
CDAI-70 response] 
 
CDAI score change over time 
 
 
CDAI subscore change over time 
 
Visit: 
Weeks 0, 2, 6, and 10 
Analysis methodology: 
Each analysis variable will be determined using the CDAI score 
based on the Ht level at each study site and CDAI subscores. 
The following analysis will be performed for the above analysis 
variables by treatment group in the induction phase. 
 
(1) Frequency distributions will be provided for clinical remission 
at each visit along with the point estimate and 95% two-sided 
CI for the proportion. The point estimate and 95% two-sided 
CI for the difference in the proportion between treatment 
groups (MLN0002 group − placebo group) will be also 
calculated. 
 
(2) Frequency distributions will be provided for clinical remission 
at each visit with stratification according to “prior TNFα 
antagonist use” along with the point estimate and 95% 
two-sided CI for the proportion. The point estimate and 95% 
two-sided CI for the difference in the proportion between 
treatment groups (MLN0002 group − placebo group) will be 
also calculated. 
 
(3) The CMH test using “prior TNFα antagonist use” as a 
stratification factor will be performed for clinical remission at 


36 
 
each visit to calculate the adjusted odds ratio of the MLN0002 
group to the placebo group (MLN0002 group/placebo group) 
and the 95% two-sided CI. Also, the CMH adjusted risk 
difference (MLN0002 group − placebo group) with “prior 
TNFα antagonist use” as a stratification factor and the 95% 
two-sided CI will be calculated. 
 
(4) The same analysis as (1) will be performed for the CDAI-100 
response at each visit. 
 
(5) The same analysis as (2) will be performed for CDAI-100 
response at each visit with stratification according to “prior 
TNFα antagonist use.” 
 
(6) The same analysis as (3) will be performed for the CDAI-100 
response at each visit. 
 
(7) The same analyses as (1), (2), and (3) will be performed for 
the CDAI-70 response, durable remission, durable CDAI-100 
response, and the durable CDAI-70 response respectively. 
 
(8) Summary statistics and 95% two-sided CI of the mean will be 
provided for the CDAI scores at each visit along with the plot 
over time. Summary statistics and 95% two-sided CI of the 
mean will be calculated for the CDAI scores at each visit with 
stratification according to “prior TNFα antagonist use.” 
 
(9) Summary statistics and 95% two-sided CI of the mean will be 
provided for changes from baseline in the CDAI scores at each 
visit along with the plot over time. Summary statistics and 
95% two-sided CI of the mean will be calculated for changes 
from baseline in the CDAI scores at each visit with 
stratification according to “prior TNFα antagonist use.” 
 
(10) The point estimate and 95% two-sided CI for the difference in 
the LS mean between treatment groups (MLN0002 group − 
placebo group) will be calculated based on the ANCOVA 
model with changes from baseline in the CDAI score at each 
visit as a response, the treatment groups in the induction phase 
and “prior TNFα antagonist use” as factors, and CDAI score at 
baseline as a covariate. 
 
(11) The same analysis as (8) will be performed for each CDAI 
subscore at each visit. 
 
(12) The same analysis as (9) will be performed for changes from 


37 
 
baseline in each CDAI subscore at each visit. 
 
2.3.3 Endpoints Related to CRP 
Analysis set: 
Full analysis set in the induction phase 
Analysis variables: 
CRP Level 
 
 
CRP Level (within the reference range) 
[Yes, No] 
Visit: 
Weeks 0, 2, 6, and 10 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by treatment group in the induction phase. 
 
(1) Summary statistics and 95% two-sided CI of the mean will be 
calculated for CRP level at each visit (baseline to Week 10). 
Summary statistics, 95% two-sided CI of the mean, 10th and 
90th percentiles will be calculated for changes from baseline in 
CRP level at each visit (Week 2 to Week 10). 
 
(2) The same analysis as (1) will be performed with stratification 
according to “prior TNFα antagonist use.” 
 
(3) The van Elteren test (CMH test with the modified ridit score) 
stratified by “prior TNFα antagonist use” will be performed 
for changes from baseline in CRP level at each visit (Week 2 
to Week 10). 
 
(4) In the subpopulation of subjects with the baseline CRP level 
outside the reference range (>0.30 mg/dL), frequency 
distributions will be provided for subjects with CRP level 
within the reference range at each visit (Week 2 to Week 10) 
along with the point estimate and 95% two-sided CI for the 
proportion. The Pearson’s chi-square test will be performed to 
calculate the point estimate and 95% two-sided CI for the 
difference in the proportion between treatment groups 
(MLN0002 group − placebo group). 
 
(5) The same analysis as (4) will be performed in the 
subpopulation of subjects with the baseline CRP level of 
>0.5 mg/dL. 
 
(6) The same analysis as (4) will be performed in the 
subpopulation of subjects with the baseline CRP level of 
>1.0 mg/dL. 
 


38 
 
2.3.4 Endpoints Related to IBDQ 
Analysis set: 
Full analysis set in the induction phase 
Analysis variables: 
IBDQ scores (total score and each subscore 
[abdominal symptoms, general condition, 
emotion, and social function]) 
 
 
Change from baseline in IBDQ score (total 
score and each subscore [abdominal symptoms, 
general condition, emotion, and social 
function]) 
 
 
IBDQ total score ≥170 
[Yes, No] 
 
Change from baseline in IBDQ total score ≥16 
[Yes, No] 
 
Change from baseline in IBDQ total score ≤-16 
[Yes, No] 
Visit: 
Weeks 0 and 10 (IBDQ scores [total score and each subscore 
(abdominal symptoms, general condition, emotion, and social 
function)]) 
 
Week 10 (change from baseline in IBDQ score [total score and 
each subscore (abdominal symptoms, general condition, emotion, 
and social function)], IBDQ total score ≥170, change from baseline 
in IBDQ total score ≥16, and change from baseline in IBDQ total 
score ≤-16) 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by treatment group in the induction phase. 
 
(1) Summary statistics and 95% two-sided CI of the mean will be 
calculated for IBDQ total score and each subscore (abdominal 
symptoms, general condition, emotion, and social function) at 
each visit. 
 
(2) Summary statistics and 95% two-sided CI of the mean will be 
calculated for changes from baseline in IBDQ total score and 
each subscore (abdominal symptoms, general condition, 
emotion, and social function) at Week 10. 
 
(3) The point estimate and 95% two-sided CI for the difference in 
the LS mean between treatment groups (MLN0002 group − 
placebo group) will be calculated based on the ANCOVA 
model with changes from baseline in IBDQ total score and 
each subscore (abdominal symptoms, general condition, 
emotion, and social function) at Week 10 as a response, the 
treatment groups in the induction phase as a factor, and 


39 
 
baseline values that correspond to the scores used as response 
as a covariate. 
 
(4) Frequency distributions will be provided for subjects whose 
IBDQ total score at Week 10 is ≥170 among the subjects 
whose IBDQ total score at baseline is <170 in the full analysis 
set in the induction phase along with the point estimate and 
95% two-sided CI for the proportion of subjects whose IBDQ 
total score is ≥170. The point estimate and 95% two-sided CI 
for the difference in the proportion of subjects whose IBDQ 
total score is ≥170 between treatment groups (MLN0002 
group − placebo group) will be calculated. The Pearson’s 
chi-square test will be also performed. 
 
(5) Frequency distributions will be provided for subjects whose 
IBDQ total score change at Week 10 from baseline is ≥16 and 
subjects whose IBDQ total score change at Week 10 from 
baseline is ≤-16 along with the point estimate and 95% 
two-sided CI for the proportion of subjects whose IBDQ total 
score change at Week 10 from baseline is ≥16 and proportion 
of subjects whose IBDQ total score change at Week 10 from 
baseline is ≤-16. The point estimate and 95% two-sided CI for 
the difference in the proportion of subjects whose IBDQ total 
score change at Week 10 from baseline is ≥16 and the 
proportion of subjects whose IBDQ total score change at 
Week 10 from baseline is ≤-16 between treatment groups 
(MLN0002 group − placebo group) will be calculated. The 
Pearson’s chi-square test will be also performed. 
 
2.3.5 Analysis in Specific Subgroup 1 
Analysis set: 
Subjects with the baseline CRP level of >0.3 mg/dL among the full 
analysis set in the induction phase 
Analysis variables: 
CDAI-100 response at Week 10 
[CDAI-100 response, 
Non-CDAI-100 response] 
 
Clinical remission at Week 10 
[Clinical remission, 
Non-remission] 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by treatment group in the induction phase. 
 
(1) Frequency distributions will be provided along with the point 


40 
 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 
(2) Frequency distributions will be provided with stratification 
according to “prior TNFα antagonist use” along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 
(3) The CMH test using “prior TNFα antagonist use” as a 
stratification factor will be performed to calculate the adjusted 
odds ratio of the MLN0002 group to the placebo group 
(MLN0002 group/placebo group) and the 95% two-sided CI. 
Also, the CMH adjusted risk difference (MLN0002 group − 
placebo group) with “prior TNFα antagonist use” as a 
stratification factor and the 95% two-sided CI will be 
calculated. 
 
2.3.6 Analysis in Specific Subgroup 2 
Analysis set: 
Subjects with the baseline CRP level of >0.3 mg/dL among the full 
analysis set in the induction phase 
Analysis variables: 
CDAI-100 response 
[CDAI-100 response, 
Non-CDAI-100 response] 
 
Clinical remission 
[Clinical remission, 
Non-remission] 
 
CDAI-70 response 
[CDAI-70 response, 
Non-CDAI-70 response] 
 
Durable remission 
[Durable remission, 
Non-durable remission] 
 
Durable CDAI-100 response 
[Durable CDAI-100 
response, Non-durable 
CDAI-100 response] 
 
Durable CDAI-70 response 
[Durable CDAI-70 
response, Non-durable 
CDAI-70 response] 
 
CDAI score 
 


41 
 
 
CDAI subscores 
 
 
IBDQ scores (total score and each 
subscore [abdominal symptoms, 
general condition, emotion, and social 
function]) 
 
Visit: 
Weeks 0, 2, 6, and 10 
Analysis methodology: 
The following analyses of (1), (2), and (3) will be performed for the 
above analysis variables except for CDAI score, CDAI subscores, 
and IBDQ scores by treatment group in the induction phase. The 
following analyses of (4), (5), and (6) will be performed for CDAI 
score by treatment group in the induction phase. The following 
analyses of (7) and (8) will be performed for CDAI subscores by 
treatment group in the induction phase. The following analyses of 
(9), (10), and (11) will be performed for IBDQ scores by treatment 
group in the induction phase. 
In addition, the analyses similar to those in section 1.2.1 will be 
performed. 
 
(1) Frequency distributions will be provided along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 
(2) Frequency distributions will be provided with stratification 
according to “prior TNFα antagonist use” along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 
(3) The CMH test using “prior TNFα antagonist use” as a 
stratification factor will be performed to calculate the adjusted 
odds ratio of the MLN0002 group to the placebo group 
(MLN0002 group/placebo group) and the 95% two-sided CI. 
Also, the CMH adjusted risk difference (MLN0002 group − 
placebo group) with “prior TNFα antagonist use” as a 
stratification factor and the 95% two-sided CI will be 
calculated. 
 
(4) Summary statistics and 95% two-sided CI of the mean will be 


42 
 
provided for the CDAI scores at each visit along with the plot 
over time. Summary statistics and 95% two-sided CI of the 
mean will be calculated for the CDAI scores at each visit with 
stratification according to “prior TNFα antagonist use.” 
 
(5) Summary statistics and 95% two-sided CI of the mean will be 
provided for changes from baseline in the CDAI scores at each 
visit along with the plot over time. Summary statistics and 
95% two-sided CI of the mean will be calculated for changes 
from baseline in the CDAI scores at each visit with 
stratification according to “prior TNFα antagonist use.” 
 
(6) The point estimate and 95% two-sided CI for the difference in 
the LS mean between treatment groups (MLN0002 group − 
placebo group) will be calculated based on the ANCOVA 
model with changes from baseline in the CDAI score at each 
visit as a response, the treatment groups in the induction phase 
and “prior TNFα antagonist use” as factors, and CDAI score at 
baseline as a covariate. 
 
(7) The same analysis as (4) will be performed for each CDAI 
subscore at each visit. 
 
(8) The same analysis as (5) will be performed for changes from 
baseline in each CDAI subscore at each visit. 
 
(9) Summary statistics and 95% two-sided CI of the mean will be 
calculated for IBDQ total score and each subscore (abdominal 
symptoms, general condition, emotion, and social function) at 
each visit. 
 
(10) Summary statistics and 95% two-sided CI of the mean will be 
calculated for changes from baseline in IBDQ total score and 
each subscore (abdominal symptoms, general condition, 
emotion, and social function) at Week 10. 
 
(11) The point estimate and 95% two-sided CI for the difference in 
the LS mean between treatment groups (MLN0002 group − 
placebo group) will be calculated based on the ANCOVA 
model with changes from baseline in IBDQ total score and 
each subscore (abdominal symptoms, general condition, 
emotion, and social function) at Week 10 as a response, the 
treatment groups in the induction phase as a factor, and 
baseline values that correspond to the scores used as response 


43 
 
as a covariate. 
 
2.3.7 Combinational Analysis of CDAI Score and CRP Level 
Analysis set: 
Full analysis set in the induction phase 
Analysis variables: 
CRP level of ≤1.6 mg/dL at Week 10 
[Yes, No] 
 
CDAI-100 response at Week 10 with CRP level 
of ≤1.6 mg/dL at Week 10 
[Yes, No] 
 
Clinical remission at Week 10 with CRP level of 
≤1.6 mg/dL at Week 10 
[Yes, No] 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by treatment group in the induction phase. 
 
(1) Frequency distributions will be provided along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 
(2) Frequency distributions will be provided with stratification 
according to “prior TNFα antagonist use” along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 
(3) The CMH test using “prior TNFα antagonist use” as a 
stratification factor will be performed to calculate the adjusted 
odds ratio of the MLN0002 group to the placebo group 
(MLN0002 group/placebo group) and the 95% two-sided CI. 
Also, the CMH adjusted risk difference (MLN0002 group − 
placebo group) with “prior TNFα antagonist use” as a 
stratification factor and the 95% two-sided CI will be 
calculated. 
 
2.4 Statistical and Analytical Issues 
2.4.1 Adjustments for Covariates 
Analysis set: 
Full analysis set in the induction phase 
Analysis variables: 
CDAI-100 response at Week 10 
[CDAI-100 response, 
Non-CDAI-100 
response] 


44 
 
 
Clinical remission at Week 10 
[Clinical remission, 
Non-remission] 
Adjustment factors: 
Prior TNFα antagonist use 
[Yes, No] 
 
Age (years) 
[Min≤ - ≤34,  
35≤ - ≤Max] 
 
Concomitant use of 5-ASA at baseline 
[Yes, No] 
 
Concomitant use of immunomodulators 
at baseline 
[Yes, No] 
 
Concomitant use of oral corticosteroids 
at baseline 
[Yes, No] 
 
CDAI score at baseline 
[Min≤ - ≤330,  
330< - ≤Max] 
Analysis methodology: 
Influences of the above adjustment factors on odds ratios for the 
CDAI-100 response at Week 10 and clinical remission at Week 10 
will be investigated with the following analyses. 
 
By performing the CMH test using the above adjustment factors as 
stratification factors and providing adjusted odds ratios of the 
MLN0002 group compared to the placebo group (MLN0002 
group/placebo group) along with the 95% two-sided CI estimates, 
adjusted odds ratios for the CDAI-100 response at Week 10 and 
clinical remission at Week 10 after adjusting the influence of 
stratification factors will be investigated. In addition, interactions 
between treatment and adjustment factors will be investigated using 
the Breslow-Day test. 
 
2.4.2 Handling of Dropouts or Missing Data 
The efficacy endpoints of clinical response and clinical remission will be considered as 
non-response or non-remission when adjudication for these endpoints is missing at the time 
of evaluation. 
For other endpoints, missing data and ineligible data according to the “Handling Rules for 
Analysis Data” or the SAP will be excluded from statistical analyses and estimations. 
Values below the limit of quantification will be handled as 0. 
 
2.4.3 Interim Analyses and Data Monitoring 
No interim analyses will be performed for the induction and maintenance phases. 
In the open-label cohort, the data for the marketing application as fixed on the cut-off date 


45 
 
will be analyzed after fixing the data of all subjects fixed on the cut-off date for the marketing 
application. Continuation/termination of the study, and change in clinical trial plan, and so on 
will not be judged based on the analysis. 
 
2.4.4 Multicenter Studies 
Although this is a multicenter study, interactions between treatment and study site will not be 
investigated since the target number of subjects per study site is not sufficiently large for 
meaningful analyses of the interactions. 
 
2.4.5 Multiple Comparisons/Multiplicity 
In the induction phase, the main focuses will be placed on the results of the CMH test in the 
primary analysis performed for the primary endpoint in the induction phase defined as the 
CDAI-100 response at Week 10 and the results of CMH tests performed for clinical 
remission at Week 10, among the secondary endpoints in the induction phase in the “full 
analysis set in the induction phase.” In these analyses, the MLN0002 group will be compared 
with the placebo group based on closed testing procedures to maintain the overall type I error 
rate below 10% in the induction phase. Other analytical results will be interpreted to support 
the results of the primary endpoint or to explore the characteristics of efficacy of MLN0002. 
These results will be considered one measure suggesting the trends or characteristics of 
efficacy. Thus, no adjustment for multiplicity will be performed. 
 
2.4.6 Use of an “Efficacy Subset of Subjects” 
To confirm the robustness of the primary analysis results for the primary endpoint from 
sensitivity point of view, the same analysis as for the “full analysis set in the induction phase” 
will be performed secondarily in the “per protocol set in the induction phase.” 
 
2.4.7 Active-Control Studies Intended to Show Equivalence or Non-inferiority 
Not applicable. 
 
2.4.8 Examination of Subgroups 
Analysis set: 
Full analysis set in the induction phase 
Analysis variables: 
CDAI-100 response at Week 10 
[CDAI-100 response, 
Non-CDAI-100 response] 
 
Clinical remission at Week 10 
[Clinical remission, 
Non-remission] 
Stratum: 
Age (years) 
[Min≤ - ≤34, 35≤ - ≤Max] 
 
 
[Min≤ - ≤64, 65≤ - ≤Max] 


46 
 
 
Gender 
[Male, Female] 
 
Duration of CD (years) 
[Min≤ - <7, 7≤ - ≤Max] 
 
Prior corticosteroids failure 
[Yes, No] 
 
Prior immunomodulators failure 
[Yes, No] 
 
Prior TNFα antagonist failure 
[Yes, No] 
 
Number of drugs of TNFα 
antagonist failure 
[1 drug, 2 drugs, 3 drugs, 
None] 
 
Classification of prior TNFα 
antagonist failure 
[Inadequate response, Loss 
of response, Intolerance] 
 
Worst prior treatment failures 
[Prior TNFα antagonist 
failure, Prior 
immunomodulators failure 
but not TNFα antagonist 
failure, Prior corticosteroid 
failure only] 
 
Prior immunomodulators and TNFα 
antagonist failure 
[Yes, No] 
 
Concomitant use of enteral nutrient 
at baseline 
[Yes, No] 
 
Concomitant use of 5-ASA at 
baseline 
[Yes, No] 
 
Concomitant use of 
immunomodulators at baseline 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids at baseline 
[Yes, No] 
 
No concomitant use of oral 
corticosteroids and No concomitant 
use of immunomodulators at 
baseline 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids and No concomitant 
use of immunomodulators at 
baseline (concomitant use of oral 
corticosteroids only) 
[Yes, No] 
 
No concomitant use of oral 
corticosteroids and Concomitant use 
of immunomodulators at baseline 
[Yes, No] 


47 
 
(concomitant use of 
immunomodulators only) 
 
Concomitant use of oral 
corticosteroids and Concomitant use 
of immunomodulators at baseline 
[Yes, No] 
 
CDAI score at baseline 
[Min≤ - <330, 330≤ - ≤Max] 
 
Disease localization 
[Small intestinal, Large 
intestinal, Small/Large 
intestinal] 
 
Weight (kg) at baseline 
[Min≤ - ≤59.9,  
60.0≤ - ≤Max] 
 
CRP (mg/dL) at baseline 
[Min≤ - ≤0.3, 0.3< - ≤Max] 
 
 
[Min≤ - ≤0.5, 0.5< - ≤Max] 
 
 
[Min≤ - ≤1.0, 1.0< - ≤Max] 
 
 
[Min≤ - ≤1.6, 1.6< - ≤Max] 
Analysis methodology: 
The following analysis will be performed for each of the above 
analysis variables by treatment group in the induction phase for 
each stratum. 
 
(1) Frequency distributions will be provided along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 


48 
 
3 SAFETY ANALYSIS 
3.1 Treatment-Emergent Adverse Event 
3.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis set: 
Safety analysis set in the induction phase 
Analysis variables: 
TEAEs in the induction phase 
Categories: 
Causality 
[Related, Not related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analysis methodology: 
The following summaries will be provided for the above analysis 
variables by treatment group in the induction phase. 
 
(1) Overview of TEAEs in the induction phase 
 
1) All TEAEs in the induction phase (number of events, 
number and percentage of subjects) 
 
2) Causal relationship between all TEAEs in the induction 
phase and study drug (number of events, number and 
percentage of subjects) 
 
3) Intensity of all TEAEs in the induction phase (number 
of events, number and percentage of subjects) 
 
4) TEAEs in the induction phase leading to study drug 
discontinuation (number of events, number and 
percentage of subjects) 
 
5) Serious TEAEs in the induction phase (number of 
events, number and percentage of subjects) 
 
6) Causal relationship between serious TEAEs in the 
induction phase and study drug (number of events, 
number and percentage of subjects) 
 
7) Serious TEAEs in the induction phase leading to study 
drug discontinuation (number of events, number and 
percentage of subjects) 
 
8) TEAEs in the induction phase leading to death (number 
of events, number and percentage of subjects) 
 
TEAEs will be counted according to the rules below: 
[Number of subjects] 
• In the case of “summaries by causality” 
A subject with occurrences of TEAE in the induction phase in 
both categories (i.e., Related and Not related) will be counted 
once in the Related category. 
• In the case of “summaries by intensity” 


49 
 
A subject with multiple occurrences of TEAE in the induction 
phase will be counted once for the TEAE with the maximum 
intensity. 
• In the case of summaries other than the above 
A subject with multiple occurrences of TEAE in the induction 
phase will be counted only once. 
[Number of events] 
For each summary, the total number of events will be calculated. 
 
3.1.2 Displays of Treatment-Emergent Adverse Events 
Analysis set: 
Safety analysis set in the induction phase 
Analysis variables: 
TEAEs in the induction phase 
 
Infusion reactions in the induction phase 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
 
Time of onset (day) 
[1≤ - ≤28, 29≤ - ≤56, 57≤ - 
≤84, 85≤ - ≤Max] 
 
Study drug administration in the 
induction phase (time) 
[1, 2, 3] 
Analysis methodology: 
The following summaries will be provided for the above analysis 
variables using frequency distributions by treatment group in the 
induction phase. 
TEAEs will be coded by use of MedDRA and will be summarized 
based on SOC and PT. SOC will be sorted alphabetically and PT 
will be sorted in decreasing frequency for tables provided by SOC 
and PT. SOC and PT will be sorted in decreasing frequency for 
tables provided by SOC only or PT only. 
 
(1) All TEAEs in the induction phase by SOC and PT 
 
(2) All TEAEs in the induction phase by SOC 
 
(3) All TEAEs in the induction phase by PT 
 
(4) Drug-related TEAEs in the induction phase by SOC and PT 
 
(5) Intensity of all TEAEs in the induction phase by SOC and PT 
 
(6) Intensity of drug-related TEAEs in the induction phase by 
SOC and PT 
 
(7) TEAEs in the induction phase leading to study drug 
discontinuation by SOC and PT 
 
(8) Serious TEAEs in the induction phase by SOC and PT 


50 
 
 
(9) Serious drug-related TEAEs in the induction phase by SOC 
and PT 
 
(10) All TEAEs in the induction phase by SOC and PT over time 
 
(11) Infusion reaction in the induction phase by SOC and PT 
 
(12) Infusion reaction in the induction phase by study drug 
administration in the induction phase (time) by SOC and PT 
 
(13) TEAEs in the induction phase whose date of onset is the day 
of the study drug administration or the following day by SOC 
and PT 
 
(14) TEAEs in the induction phase whose date of onset is the day 
of the study drug administration or the following day by study 
drug administration in the induction phase (time) by SOC and 
PT 
 
(15) TEAEs in the induction phase whose incidence summarized 
by PT is 3% or higher in either treatment group by SOC and 
PT 
 
The frequency distribution and incidence will be provided 
according to the rules below: 
[Number of subjects] 
• In the case of “summaries by SOC and PT, by SOC, and by PT” 
A subject with multiple occurrences of TEAE within a SOC 
will be counted only once in that SOC. A subject with 
multiple occurrences of TEAE within a PT will be counted 
only once in that PT. Percentages of TEAEs in the induction 
phase will be based on the number of subjects in the safety 
analysis set in the induction phase. 
• In the case of “summaries of intensity by SOC and PT” 
A subject with multiple occurrences of a TEAE within a SOC 
or a PT will be counted only once for the TEAE with the 
maximum intensity. Percentages of TEAEs in the induction 
phase will be based on the number of subjects in the safety 
analysis set in the induction phase. 
• In the case of “summaries by SOC and PT over time” 
A subject with a TEAE that occurs in more than one interval is 
counted in all the intervals that the TEAE occurs. For each 
time interval, a subject with multiple occurrences of TEAE 


51 
 
within a SOC or a PT will be counted only once in that SOC 
or PT. When calculating percentages of TEAEs in the 
induction phase for each time interval, the number of subjects 
at risk (i.e., “subjects who either have an exposure in the study 
or have an occurrence of a TEAE in the induction phase, 
during or after the corresponding time interval”) will be used 
as the denominator. The number of subjects whose “onset of 
any one of the TEAEs in the induction phase is within the time 
interval” will be used as the numerator. 
• In the case of “summaries of the study drug administration in 
the induction phase (time) by SOC and PT” 
A subject with a TEAE that occurs in more than one time of 
the study drug administration is counted for all the 
administrations (time) that the TEAE occurs. For each 
administration, a subject with multiple occurrences of a TEAE 
within a SOC or a PT will be counted only once in that SOC 
or PT. When calculating percentages of TEAEs in the 
induction phase for each administration (time) in the induction 
phase, the number of subjects at risk (i.e., “subjects who 
received the first, etc., study drug administration in the 
induction phase”) will be used as the denominator. The 
number of subjects whose “onset of any one of the TEAEs in 
the induction phase is at the time of the first, etc., 
administration in the induction phase” will be used as the 
numerator. 
 
3.2 Pretreatment Event 
3.2.1 Displays of Pretreatment Events 
Analysis set: 
All subjects who signed the informed consent form 
Analysis variables: 
PTE 
Analysis methodology: 
The following summaries will be provided for the above analysis 
variables using frequency distributions. 
PTEs will be coded by use of MedDRA and will be summarized 
based on SOC and PT. SOC will be sorted alphabetically and PT 
will be sorted in decreasing frequency. 
 
(1) All PTEs by SOC and PT 
(2) Serious PTEs by SOC and PT 


52 
 
 
PTE will be counted according to the rules below: 
[Number of subjects] 
A subject with multiple occurrences of PTE within a SOC will 
be counted only once in that SOC. A subject with multiple 
occurrences of PTE within a PT will be counted only once in that 
PT. 
 
3.3 Clinical Laboratory Evaluations and Other Safety Endpoints 
3.3.1 Clinical Laboratory Evaluations 
3.3.1.1 
Hematology and Blood Biochemistry 
Analysis set: 
Safety analysis set in the induction phase 
Analysis variables: 
Hematology 
 
Red blood cells 
(RBC) 
White blood cells 
(WBC) 
Hemoglobin 
 
Hematocrit 
Platelets 
 
 
WBC differentials (neutrophils/leukocytes, 
eosinophils/leukocytes, basophils/leukocytes, 
lymphocytes/leukocytes, monocytes/leukocytes) 
 
Blood biochemistry 
 
Albumin 
AST (GOT) 
ALT (GPT) 
 
ALP 
Amylase 
Glucose 
 
Total bilirubin 
Total protein 
γ-GTP 
 
Total cholesterol 
Triglyceride 
Creatinine 
 
BUN 
Uric acid 
Potassium 
 
Sodium 
Calcium 
Phosphorus 
 
Magnesium 
Chloride 
 
Categories: 
Adjudication results based on 
reference range 
[Below lower limit of normal 
range, Within normal range, Over 
upper limit of normal range] 
 
Categories in SAP Appendix 
2 (1) 
 
Visit: 
Weeks 0, 2, 6, 10, 14, and 16 weeks after the last dose of the study 
drug 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by treatment group in the induction phase. 
The subjects who received the study drug in the maintenance phase 


53 
 
or open-label cohort will be excluded from the analysis at 16 weeks 
after the last dose. 
Refer to Appendix 2 of this SAP for laboratory test items subject to 
this analysis, categories in the shift table, MAV criteria, and the 
definition of elevated liver enzyme. 
 
(1) Summary statistics for each visit and summary statistics of 
differences before and after administration for each visit 
 
(2) Case plots 
 
(3) Shift tables showing adjudication results based on normal 
reference range at baseline and each post-baseline visit 
 
(4) Shift tables showing categories of SAP Appendix 2 (1) at 
baseline and each post-baseline visit 
 
(5) Overall frequency distributions of MAV in the induction 
phase 
 
(6) Overall frequency distributions of elevated liver enzymes in 
the induction phase 
 
3.3.1.2 
Urinalysis 
Analysis set: 
Safety analysis set in the induction phase 
Analysis variables: 
pH 
 
 
Urine specific gravity 
 
 
Glucose 
 
 
Protein 
 
 
Occult blood 
 
 
Bilirubin 
 
 
Ketone body 
 
Categories: 
Adjudication results 
based on reference range 
[Below lower limit of normal range, 
Within normal range, Over upper 
limit of normal range] 
Visit: 
Weeks 0, 10, 14, and 16 weeks after the last dose of the study drug 
Analysis methodology: 
The following analyses of (1), (2), and (3) will be performed for pH 
and specific gravity by treatment group in the induction phase. The 
following analysis of (3) will be performed for the above analysis 
variables other than pH and specific gravity by treatment group in 
the induction phase. 


54 
 
The subjects who received the study drug in the maintenance phase 
or open-label cohort will be excluded from the analysis at 16 weeks 
after the last dose. 
 
(1) Summary statistics for each visit and summary statistics of 
the differences before and after administration 
 
(2) Case plots 
 
(3) Shift tables showing adjudication results based on normal 
reference range at baseline and each post-baseline visit 
 
3.3.2 Vital Signs, Physical Examination, and Other Observation Items Related to Safety 
3.3.2.1 
Vital Signs, Body Weight 
Analysis set: 
Safety analysis set in the induction phase 
Analysis variables: 
Systolic blood pressure 
 
 
Diastolic blood pressure 
 
 
Pulse 
 
 
Body temperature 
 
 
Weight 
 
Visit: 
Weeks 0, 2, 6, 10, 14, and 16 weeks after the last dose of the study 
drug 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by treatment group in the induction phase. 
The subjects who received the study drug in the maintenance phase 
or open-label cohort will be excluded from the analysis at 16 weeks 
after the last dose. 
 
(1) Summary statistics for each visit and summary statistics of 
differences before and after administration for each visit 
 
(2) Case plots 
 
3.3.2.2 
12-Lead ECG 
Analysis set: 
Safety analysis set in the induction phase 
Analysis variables: 
Findings of 12-lead ECG 
[Within normal limits, Abnormal 
but not clinically significant, 
Abnormal and clinically 
significant] 
Visit: 
Weeks 0, 10, and 16 weeks after the last dose of the study drug 
Analysis methodology: 
The following analysis will be performed for findings of 12-lead 


55 
 
ECG by treatment group in the induction phase. 
The subjects who received the study drug in the maintenance phase 
or open-label cohort will be excluded from the analysis at 16 weeks 
after the last dose. 
 
(1) Shift tables at baseline and each post-baseline visit 
 
3.4 Display of Treatment-Emergent Adverse Event (in Japanese) 
Analysis set: 
Safety analysis set in the induction phase 
Analysis variables: 
TEAE in the induction phase (by SOC and PT) 
 
Infusion reaction in the induction phase by SOC and PT 
Analysis methodology: 
Summaries similar to those in section 3.1.2 will be provided for the 
above analysis variables. SOC and PT will be displayed in 
Japanese. 
 


56 
 
4 PHARMACOKINETIC ANALYSIS 
4.1 Analysis of Serum Concentrations of MLN0002 
Analysis set: 
Subjects who underwent proper determination of serum 
concentrations of MLN0002 in the “full analysis set in the 
induction phase” 
Analysis variables: 
Serum concentrations of MLN0002 
Visit: 
Weeks 2, 6, 10, and 14 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables. When calculating the geometric mean and geometric 
CV%, the analysis will be performed by excluding data for which 
serum concentration of MLN0002 is 0. 
 
(1) Summary statistics, geometric mean, and geometric CV% 
 
(2) Mean/standard deviation plot 
 
4.2 Subgroup Analysis of Serum Concentrations of MLN0002 
Analysis set: 
Subjects who underwent proper determination of serum 
concentrations of MLN0002 in the “full analysis set in the 
induction phase” 
Analysis variables: 
Serum concentrations of MLN0002 
 
Stratum: 
Prior TNFα antagonist use 
[Yes, No] 
 
Concomitant use of 5-ASA at baseline 
[Yes, No] 
 
Concomitant use of oral corticosteroids at baseline 
[Yes, No] 
 
Concomitant use of immunomodulators at baseline 
[Yes, No] 
Visit: 
Weeks 2, 6, 10, and 14 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables for each stratum. When calculating the geometric mean 
and geometric CV%, the analysis will be performed by excluding 
data for which serum concentration of MLN0002 is 0. 
 
(1) Summary statistics, geometric mean, and geometric CV% 
 
4.3 Serum Concentrations of MLN0002 by Efficacy Endpoints 
Analysis set: 
Subjects who underwent proper determination of serum 
concentrations of MLN0002 in the “full analysis set in the 
induction phase” 
Analysis variables: 
Serum concentrations of MLN0002 
Stratum: 
CDAI-100 response at Week 10 
[CDAI-100 response, 
Non-CDAI-100 response] 


57 
 
 
Clinical remission at Week 10 
[Clinical remission, 
Non-remission] 
Visit: 
Weeks 2, 6, 10, and 14 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables for each stratum. When calculating the geometric mean 
and geometric CV%, the analysis will be performed by excluding 
data for which serum concentration of MLN0002 is 0. 
 
(1) Summary statistics, geometric mean, and geometric CV% 
 
4.4 Serum Concentrations of MLN0002 by AVA and Neutralizing Antibody 
Analysis set: 
Subjects who underwent proper determination of serum 
concentrations of MLN0002 in the “full analysis set in the 
induction phase” 
Analysis variables: 
Serum concentrations of MLN0002 
 
Stratum: 
AVA at Week 10 
[Negative, Positive] 
 
Neutralizing antibody at Week 10 
[Negative, Positive] 
 
AVA in the induction phase 
[Negative, Positive] 
 
Neutralizing antibody in the induction phase 
[Negative, Positive] 
Visit: 
Weeks 2, 6, 10, and 14 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables for each stratum. When calculating the geometric mean 
and geometric CV%, the analysis will be performed by excluding 
data for which serum concentration of MLN0002 is 0. 
 
(1) Summary statistics, geometric mean, and geometric CV% 
 
4.5 Efficacy by Serum Concentration of MLN0002 
Analysis set: 
Subjects who underwent proper determination of serum 
concentrations of MLN0002 in the “full analysis set in the 
induction phase” 
Analysis variables: 
CDAI-100 response at Week 10 
[CDAI-100 response, 
Non-CDAI-100 response] 
 
Clinical remission at Week 10 
[Clinical remission, 
Non-remission] 
Stratum: 
Serum concentrations of MLN0002 
at Week 2 
[0≤ - <Q1, Q1≤ - <Median, 
Median≤ - <Q3, Q3≤ - 
≤Max] 


58 
 
 
Serum concentrations of MLN0002 
at Week 6 
[0≤ - <Q1, Q1≤ - <Median, 
Median≤ - <Q3,  
Q3≤ - ≤Max] 
 
Serum concentrations of MLN0002 
at Week 10 
[0≤ - <Q1, Q1≤ - <Median, 
Median≤ - <Q3,  
Q3≤ - ≤Max] 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables for each stratum. Categories of stratum will be defined as 
4 categories with the first quartile (Q1), median, and third quartile 
(Q3) of the obtained data as boundaries. 
 
(1) Frequency distributions, point estimates and 95% two-sided 
CI for the proportion 
 
 


59 
 
5 ANALYSIS OF IMMUNOGENICITY ENDPOINTS 
5.1 AVA and the Neutralizing Antibody 
Analysis set: 
Subjects who underwent proper determination of AVA and the 
neutralizing antibody in the “full analysis set in the induction 
phase” 
Analysis variables: 
AVA 
[Negative, Positive] 
 
AVA titer 
[1:10, 1:50, 1:250, 1:1250, 
1:6250, 1:31250] 
 
Neutralizing antibody 
[Negative, Positive] 
 
AVA in the induction phase 
[Negative, Positive] 
 
Maximum AVA titer in the 
induction phase 
[1:10, 1:50, 1:250, 1:1250, 
1:6250, 1:31250] 
 
Neutralizing antibody in the 
induction phase 
[Negative, Positive] 
Visit: 
Weeks 0, 10, and 16 weeks after the last dose of the study drug 
(AVA, AVA titer, neutralizing antibody) 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables. 
The category of AVA titer will be defined according to the 
observed AVA titer. 
The subjects who received the study drug in the maintenance phase 
or open-label cohort will be excluded from the analysis at 16 weeks 
after the last dose. 
 
(1) Frequency distributions 
 
5.2 Efficacy by AVA and the Neutralizing Antibody 
Analysis set: 
Subjects who underwent proper determination of AVA and the 
neutralizing antibody in the “full analysis set in the induction 
phase” 
Analysis variables: 
CDAI-100 response at Week 10 
[CDAI-100 response, 
Non-CDAI-100 response] 
 
Clinical remission at Week 10 
[Clinical remission, 
Non-remission] 
Stratum: 
AVA at Week 10 
[Negative, Positive] 
 
Neutralizing antibody at Week 10 
[Negative, Positive] 
 
AVA in the induction phase 
[Negative, Positive] 


60 
 
 
Neutralizing antibody in the 
induction phase 
[Negative, Positive] 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables for each stratum. 
 
(1) Frequency distributions 
 
5.3 Subgroup Analysis of AVA and the Neutralizing Antibody 
Analysis set: 
Subjects who underwent proper determination of AVA and the 
neutralizing antibody in the “full analysis set in the induction 
phase” 
Analysis variables: 
AVA 
[Negative, Positive] 
 
Neutralizing antibody 
[Negative, Positive] 
 
AVA in the induction phase 
[Negative, Positive] 
 
Neutralizing antibody in the induction phase 
[Negative, Positive] 
Stratum: 
Concomitant use of immunomodulators at 
baseline 
[Yes, No] 
 
No concomitant use of oral corticosteroids 
and Concomitant use of immunomodulators 
at baseline (concomitant use of 
immunomodulators only) 
 
[Yes, No] 
 
Concomitant use of oral corticosteroids at 
baseline 
[Yes, No] 
 
Infusion reactions in the induction phase 
[Yes, No] 
Visit: 
Weeks 0, 10, and 16 weeks after the last dose of the study drug 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables for each stratum. 
The subjects who received the study drug in the maintenance phase 
or open-label cohort will be excluded from the analysis at 16 weeks 
after the last dose. 
 
(1) Frequency distributions 


61 
 
6 SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT 
 
Significance level of the CMH test in 2.1.1, 2.1.2 (1), 2.2(3), and 2.4.1: 10% (two-sided test) 
 
Significance level of other tests: 5% (two-sided test) 
 
Confidence coefficient: 95% (two-sided estimate) 
 
 


62 
 
History of Revision (version management) 
 
Version 
Date 
Prepared/modified by 
Comments 
First version 
25 January 2018 
 
Preparation of first version 
 
PPD


1 
 
[Appendix 1] Comparison Table for Changes 
 
N/A 
 


1 
 
[Appendix 2] Definitions of Categories in Shift Table, MAV Criteria, and Criteria for Elevated 
Liver Enzyme 
(1) 
Categories in Shift Table 
The lower limit of the normal range and the upper limit of the normal range of each test item are 
abbreviated as LLN and ULN in the table below. 
 
Test item 
Categories 
Albumin 
≥LLN, <LLN to 3 g/dL, <3 g/dL to 2 g/dL, <2 g/dL to 1 g/dL, <1 g/dL 
ALT(GPT) 
≤ULN, >ULN to 2.5×ULN, >2.5×ULN to 5.0×ULN, >5.0×ULN to 20.0×ULN, 
>20.0×ULN 
AST(GOT) 
≤ULN, >ULN to 2.5×ULN, >2.5×ULN to 5.0×ULN, >5.0×ULN to 20.0×ULN, 
>20.0×ULN 
Total bilirubin 
≤ULN, >ULN to 1.5×ULN, >1.5×ULN to 3.0×ULN, >3.0×ULN to 10.0×ULN, 
>10.0×ULN 
Creatinine 
≤ULN, >ULN to 1.5×ULN, >1.5×ULN to 3.0×ULN, >3.0×ULN to 6.0×ULN, 
>6.0×ULN 
ALP 
≤ULN, >ULN to 2.5×ULN, >2.5×ULN to 5.0×ULN, >5.0×ULN to 20.0×ULN, 
>20.0×ULN 
WBC 
≥LLN, <LLN to 3000/μL, <3000/μL to 2000/μL, <2000/μL to 1000/μL, 
<1000/μL 
WBC 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Platelets 
≥LLN, <LLN to 7.5×104/μL, <7.5×104/μL to 5.0×104/μL, <5.0×104/μL to 
2.5×104/μL, <2.5×104/μL 
Platelets 
≤ULN, >ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, >2.0×ULN to 3.0×ULN, 
>3.0×ULN 
Lymphocytes 
≥800/μL, <800/μL to 500/μL, <500/μL to 200/μL, <200/μL 
Lymphocytes (%) 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Eosinophils (%) 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Monocytes (%) 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Basophils (%) 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Hemoglobin 
≥LLN, <LLN to 10 g/dL, <10 g/dL to 8 g/dL, <8 g/dL to 6.5 g/dL, <6.5 g/dL 
Neutrophils 
≥1500/μL, <1500/μL to 1000/μL, <1000/μL to 500/μL, <500/μL 
Neutrophils (%) 
≤ULN, >ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, >2.0×ULN to 3.0×ULN, 
>3.0×ULN 
Missing data will not be included in any category. 
 


2 
 
(2) 
MAV Criteria 
1) 
Hematology and Blood Biochemistry 
For each test item, MAV will be determined according to the table below for evaluable data (i.e., 
non-missing data and data determined to be eligible based on “Handling Rules for Analysis Data”) 
obtained from the day after the first dose of the study drug in the induction phase until the day of the 
first dose of the study drug in the maintenance phase or open-label cohort for subjects who received 
the study drug in the maintenance phase or open-label cohort or from the day after the first dose of 
the study drug in the induction phase until 167 days* after the last dose of the study drug (including 
Follow-up Day 167) for subjects who did not receive the study drug in the maintenance phase and 
open-label cohort. The lower limit of the normal range and the upper limit of the normal range of 
each test item are abbreviated as LLN and ULN in the table below. 
* Day after the last dose of the study drug will be defined as Follow-up Day 1. 
 
Test item 
MAV Criteria 
Lower criteria 
Upper criteria 
Hemoglobin (g/dL) 
≤7 
- 
Lymphocytes (/μL) 
<500 
- 
WBC (/μL) 
<2000 
- 
Platelets (×104/μL) 
<7.5 
- 
Neutrophils (/μL) 
<1000 
- 
ALT(GPT) (U/L) 
- 
>3.0×ULN 
AST(GOT) (U/L) 
- 
>3.0×ULN 
Total bilirubin (mg/dL) 
- 
>2.0×ULN 
Amylase (U/L) 
- 
>2.0×ULN 
 
Classifying Subjects for the Overall Induction Phase 
For each test item and subject, MAV will be determined according to the conditions [1] to [3] 
provided below. 
[1] A subject will be classified as those “with MAV” if he/she has at least one data that “meets the 
MAV Criteria” among the evaluable data obtained from the day after the first dose of the study 
drug in the induction phase until the day of the first dose of the study drug in the maintenance 
phase or open-label cohort for subjects who received the study drug in the maintenance phase 
or open-label cohort or from the day after the first dose of the study drug in the induction phase 
until 167 days after the last dose of the study drug (including Follow-up Day 167) for subjects 
who did not receive the study drug in the maintenance phase and open-label cohort. 


3 
 
[2] A subject will be classified as those “without MAV” if he/she does not meet condition [1] and 
has at least one data that does “not meet the MAV Criteria” among the evaluable data obtained 
from the day after the first dose of the study drug in the induction phase until the day of the first 
dose of the study drug in the maintenance phase or open-label cohort for subjects who received 
the study drug in the maintenance phase or open-label cohort or from the day after the first dose 
of the study drug in the induction phase until 167 days after the last dose of the study drug 
(including Follow-up Day 167) for subjects who did not receive the study drug in the 
maintenance phase and open-label cohort. 
[3] A subject who does not meet conditions [1] or [2] will be excluded from the analysis of MAV 
for that item. 
 


4 
 
(3) 
Criteria for Elevated Liver Enzyme 
For each test item, elevated liver enzyme will be determined according to the table below for 
evaluable data (i.e., non-missing data and data determined to be eligible based on “Handling Rules 
for Analysis Data”) obtained from the day after the first dose of the study drug in the induction 
phase until the day of the first dose of the study drug in the maintenance phase or open-label cohort 
for subjects who received the study drug in the maintenance phase or open-label cohort or from the 
day after the first dose of the study drug in the induction phase until 167 days* after the last dose of 
the study drug (including Follow-up Day 167) for subjects who did not receive the study drug in the 
maintenance phase and open-label cohort. If there is more than one item that need to be considered 
for a criterion, test items measured on the same day will be used. The following abbreviations are 
used in the table below: LLN for lower limit of the normal range, ULN for upper limit of the normal 
range, ALT for alanine aminotransferase, AST for aspartate aminotransferase, Tbili for total 
bilirubin, and ALP for alkaline phosphatase. 
* Day after the last dose of the study drug will be defined as Follow-up Day 1. 
 
Label 
Criteria for “elevated liver enzyme” 
Elevated 
Not elevated 
ALT > 3×ULN 
ALT is greater than 3 times the ULN 
ALT is non-missing and less than or 
equal to 3 times the ULN 
ALT > 5×ULN 
ALT is greater than 5 times the ULN 
ALT is non-missing and less than or 
equal to 5 times the ULN 
ALT > 8×ULN 
ALT is greater than 8 times the ULN 
ALT is non-missing and less than or 
equal to 8 times the ULN 
ALT > 3×ULN 
with Tbili > 2×ULN 
ALT is greater than 3 times the ULN and 
the total bilirubin is greater than twice the 
ULN 
Either ALT is non-missing and less than 
or equal to 3 times the ULN, or the total 
bilirubin is non-missing and less than or 
equal to twice the ULN 
AST > 3×ULN 
AST is greater than 3 times the ULN 
AST is non-missing and less than or 
equal to 3 times the ULN 
AST > 5×ULN 
AST is greater than 5 times the ULN 
AST is non-missing and less than or 
equal to 5 times the ULN 
AST > 8×ULN 
AST is greater than 8 times the ULN 
AST is non-missing and less than or 
equal to 8 times the ULN 
AST > 3×ULN 
with Tbili > 2×ULN 
AST is greater than 3 times the ULN and 
the total bilirubin is greater than twice the 
ULN 
Either AST is non-missing and less than 
or equal to 3 times the ULN, or the total 
bilirubin is non-missing and less than or 
equal to twice the ULN 


5 
 
Label 
Criteria for “elevated liver enzyme” 
Elevated 
Not elevated 
ALT or AST > 3×ULN 
Either ALT or AST is greater than 3 times 
the ULN 
Both ALT and AST are non-missing and 
less than or equal to 3 times the ULN 
ALT or AST > 5×ULN 
Either ALT or AST is greater than 5 times 
the ULN 
Both ALT and AST are non-missing and 
less than or equal to 5 times the ULN 
ALT or AST > 8×ULN 
Either ALT or AST is greater than 8 times 
the ULN 
Both ALT and AST are non-missing and 
less than or equal to 8 times the ULN 
ALT or AST > 3×ULN 
with Tbili > 2×ULN 
Either ALT or AST is greater than 3 times 
the ULN and the total bilirubin is greater 
than twice the ULN 
If any of the following conditions is met: 
- Both ALT and AST are non-missing 
and less than or equal to 3 times the 
ULN. 
- Total bilirubin is non-missing and less 
than or equal to twice the ULN. 
ALT 
and 
AST 
> 
3×ULN 
Both ALT and AST are greater than 3 
times the ULN 
Either ALT is non-missing and less than 
or equal to 3 times the ULN, or AST is 
non-missing and less than or equal to 3 
times the ULN 
ALT 
and 
AST 
> 
5×ULN 
Both ALT and AST are greater than 5 
times the ULN 
Either ALT is non-missing and less than 
or equal to 5 times the ULN, or AST is 
non-missing and less than or equal to 5 
times the ULN 
ALT 
and 
AST 
> 
8×ULN 
Both ALT and AST are greater than 8 
times the ULN 
Either ALT is non-missing and less than 
or equal to 8 times the ULN, or AST is 
non-missing and less than or equal to 8 
times the ULN 
ALT 
and 
AST 
> 
3×ULN 
with Tbili > 2×ULN 
Both ALT and AST are greater than 3 
times the ULN and the total bilirubin is 
greater than twice the ULN 
If any of the following conditions is met: 
- ALT is non-missing and less than or 
equal to 3 times the ULN 
- AST is non-missing and less than or 
equal to 3 times the ULN 
- Total bilirubin is non-missing and less 
than or equal to twice the ULN 
ALP > 3×ULN 
ALP is greater than 3 times the ULN 
ALP is non-missing and less than or 
equal to 3 times the ULN 
ALP > 3×ULN 
Both ALP and ALT are greater than 3 
Either ALP is non-missing and less than 


6 
 
Label 
Criteria for “elevated liver enzyme” 
Elevated 
Not elevated 
with ALT > 3×ULN 
time the ULN 
or equal to 3 times the ULN, or ALT is 
non-missing and less than or equal to 3 
times the ULN 
ALP > 3×ULN 
with AST > 3×ULN 
Both ALP and AST are greater than 3 
times the ULN 
Either ALP is non-missing and less than 
or equal to 3 times the ULN, or AST is 
non-missing and less than or equal to 3 
times the ULN 
 
Classifying Subjects for the Overall Induction Phase 
For each criteria and subject, “elevated liver enzyme” will be determined according to the conditions 
[1] to [3] provided below. 
[1] A subject will be classified as those “with elevated liver enzyme” if he/she has at least one data 
that “meets the criteria for elevated liver enzyme” among the evaluable data obtained from the 
day after the first dose of the study drug in the induction phase until the day of the first dose of 
the study drug in the maintenance phase or open-label cohort for subjects who received the 
study drug in the maintenance phase or open-label cohort or from the day after the first dose of 
the study drug in the induction phase until 167 days after the last dose of the study drug 
(including Follow-up Day 167) for subjects who did not receive the study drug in the 
maintenance phase and open-label cohort. 
[2] A subject will be classified as those “without elevated liver enzyme” if he/she does not meet 
condition [1] and has at least one data that does “not meet the criteria for elevated liver 
enzyme” among the evaluable data obtained from the day after the first dose of the study drug 
in the induction phase until the day of the first dose of the study drug in the maintenance phase 
or open-label cohort for subjects who received the study drug in the maintenance phase or 
open-label cohort or from the day after the first dose of the study drug in the induction phase 
until 167 days after the last dose of the study drug (including Follow-up Day 167) for subjects 
who did not receive the study drug in the maintenance phase and open-label cohort. 
[3] A subject who does not meet conditions [1] or [2] will be excluded from the analysis of 
elevated liver enzyme for that item. 
 


 
 
ADDITIONAL STATISTICAL ANALYSIS PLAN 
(Induction Phase) 
 
Study Title 
: Phase 3, multicenter, randomized, double-blinded, 
placebo-controlled, parallel-group study to evaluate the efficacy, 
safety, and pharmacokinetics of intravenous MLN0002 (300 mg) 
infusion in induction and maintenance therapy in Japanese 
subjects with moderate or severe Crohn's disease 
Protocol No. 
: MLN0002/CCT-001 
Sponsor 
: Takeda Pharmaceutical Company Limited 
 
Person responsible for preparing the protocol 
 
Trial Statistician 
 
 
First version: 12 April 2018 
PPD
PPD


1 
 
 
TABLE OF CONTENTS 
1 EFFICACY ANALYSIS ................................................................................................................... 2 
1.1 Analysis in Specific Subgroup ........................................................................................................ 2 
1.2 Combinational Analysis of CDAI Score and CRP Level in Specific Subgroup ............................. 3 
1.3 Adjustments for Covariates ............................................................................................................. 4 
1.4 Examination of Subgroups .............................................................................................................. 5 
2 SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT .................................................... 5 
History of Revision (version management) .......................................................................................... 6 
[Appendix 1] Comparison Table for Changes ...................................................................................... 1 
 


2 
 
The same methods of summaries and handling as those in the Statistical Analysis Plan (Induction 
Phase) for Study CCT-001 will be applied, unless otherwise stated. 
 
1 EFFICACY ANALYSIS 
1.1 Analysis in Specific Subgroup 
Analysis set: 
Subjects with the baseline CRP level of >1.6 mg/dL among the full 
analysis set in the induction phase 
Analysis variables: 
CDAI-100 response 
[CDAI-100 response, 
Non-CDAI-100 response] 
 
Clinical remission 
[Clinical remission, 
Non-remission] 
 
CDAI-70 response 
[CDAI-70 response, 
Non-CDAI-70 response] 
 
Durable remission 
[Durable remission, 
Non-durable remission] 
 
Durable CDAI-100 response 
[Durable CDAI-100 
response, Non-durable 
CDAI-100 response] 
 
Durable CDAI-70 response 
[Durable CDAI-70 response, 
Non-durable CDAI-70 
response] 
 
CDAI score 
 
Visit: 
Weeks 0, 2, 6, and 10 
Analysis methodology: 
The following analyses of (1), (2), and (3) will be performed for the 
above analysis variables except for CDAI score by treatment group 
in the induction phase. The following analyses of (4), (5), and (6) 
will be performed for CDAI score by treatment group in the 
induction phase. 
 
(1) Frequency distributions will be provided along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 
(2) Frequency distributions will be provided with stratification 
according to “prior TNFα antagonist use” along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 


3 
 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 
(3) The Cochran-Mantel-Haenszel (CMH) test using “prior TNFα 
antagonist use” as a stratification factor will be performed to 
calculate the adjusted odds ratio of the MLN0002 group to the 
placebo group (MLN0002 group/placebo group) and the 95% 
two-sided CI. Also, the CMH adjusted risk difference 
(MLN0002 group − placebo group) with “prior TNFα 
antagonist use” as a stratification factor and the 95% 
two-sided CI will be calculated. 
 
(4) Summary statistics and 95% two-sided CI of the mean will be 
provided for the CDAI scores at each visit along with the plot 
over time. Summary statistics and 95% two-sided CI of the 
mean will be calculated for the CDAI scores at each visit with 
stratification according to “prior TNFα antagonist use.” 
 
(5) Summary statistics and 95% two-sided CI of the mean will be 
provided for changes from baseline in the CDAI scores at each 
visit along with the plot over time. Summary statistics and 
95% two-sided CI of the mean will be calculated for changes 
from baseline in the CDAI scores at each visit with 
stratification according to “prior TNFα antagonist use.” 
 
(6) The point estimate and 95% two-sided CI for the difference in 
the least square (LS) mean between treatment groups 
(MLN0002 group − placebo group) will be calculated based 
on the analysis of covariance (ANCOVA) model with changes 
from baseline in the CDAI score at each visit as a response, 
the treatment groups in the induction phase and “prior TNFα 
antagonist use” as factors, and CDAI score at baseline as a 
covariate. 
 
1.2 Combinational Analysis of CDAI Score and CRP Level in Specific Subgroup 
Analysis set: 
Subjects with the baseline CRP level of >1.6 mg/dL among the full 
analysis set in the induction phase 
Analysis variables: 
CRP level of ≤1.6 mg/dL 
[Yes, No] 
 
CDAI-100 response with CRP level of ≤1.6 mg/dL [Yes, No] 
 
Clinical remission with CRP level of ≤1.6 mg/dL 
[Yes, No] 
Visit: 
Weeks 0, 2, 6, and 10 


4 
 
Analysis methodology: 
The following analysis will be performed for the above analysis 
variables by treatment group in the induction phase. 
 
(1) Frequency distributions will be provided along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 
(2) Frequency distributions will be provided with stratification 
according to “prior TNFα antagonist use” along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 
(3) The CMH test using “prior TNFα antagonist use” as a 
stratification factor will be performed to calculate the adjusted 
odds ratio of the MLN0002 group to the placebo group 
(MLN0002 group/placebo group) and the 95% two-sided CI. 
Also, the CMH adjusted risk difference (MLN0002 group − 
placebo group) with “prior TNFα antagonist use” as a 
stratification factor and the 95% two-sided CI will be 
calculated. 
 
1.3 Adjustments for Covariates 
Analysis set: 
Full analysis set in the induction phase 
Analysis variables: 
CDAI-100 response at Week 10 
[CDAI-100 response, 
Non-CDAI-100 response] 
 
Clinical remission at Week 10 
[Clinical remission, 
Non-remission] 
Adjustment factors: 
Disease localization 
[Small intestinal, Large 
intestinal, Small/Large 
intestinal] 
 
 
[Small intestinal or Large 
intestinal, Small/Large 
intestinal] 
Analysis methodology: 
Influences of the above adjustment factors on odds ratios for the 
CDAI-100 response at Week 10 and clinical remission at Week 10 
will be investigated with the following analyses. 


5 
 
 
By performing the CMH test using the above adjustment factors as 
stratification factors and providing adjusted odds ratios of the 
MLN0002 group compared to the placebo group (MLN0002 
group/placebo group) along with the 95% two-sided CI estimates, 
adjusted odds ratios for the CDAI-100 response at Week 10 and 
clinical remission at Week 10 after adjusting the influence of 
stratification factors will be investigated. In addition, interactions 
between treatment and adjustment factors will be investigated using 
the Breslow-Day test. 
 
1.4 Examination of Subgroups 
Analysis set: 
Full analysis set in the induction phase 
Analysis variables: 
CDAI-100 response at Week 10 
[CDAI-100 response, 
Non-CDAI-100 response] 
 
Clinical remission at Week 10 
[Clinical remission, 
Non-remission] 
Stratum: 
Disease localization 
[Small intestinal or Large 
intestinal, Small/Large 
intestinal] 
Analysis methodology: 
The following analysis will be performed for each of the above 
analysis variables by treatment group in the induction phase for 
each stratum. 
 
(1) Frequency distributions will be provided along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 
 
2 SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT 
 
Significance level of the CMH test in 1.3: 10% (two-sided test) 
 
Significance level of other tests: 5% (two-sided test) 
 
Confidence coefficient: 95% (two-sided estimate) 
 
 


6 
 
History of Revision (version management) 
 
Version 
Date 
Prepared/modified by 
Comments 
First version 12 April 2018 
 
Preparation of first version 
 
PPD


1 
 
[Appendix 1] Comparison Table for Changes 
 
N/A 
 
 


 
 
STATISTICAL ANALYSIS PLAN 
(Maintenance Phase) 
 
Study Title 
: Phase 3, multicenter, randomized, double-blinded, placebo-controlled, 
parallel-group study to evaluate the efficacy, safety, and pharmacokinetics 
of intravenous MLN0002 (300 mg) infusion in induction and maintenance 
therapy in Japanese subjects with moderate or severe Crohn's disease 
Protocol No. 
: MLN0002/CCT-001 
Sponsor 
: Takeda Pharmaceutical Company Limited 
 
Person responsible for preparing the protocol 
 
Trial Statistician 
 
Person responsible for pharmacokinetic/pharmacodynamic analyses 
 
First version: 25 January 2018 
PPD
PPD
PPD


 
1 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................... 3 
HANDLING OF TIME WINDOW ...................................................................................................... 4 
OTHER HANDLING ........................................................................................................................... 9 
1 STUDY SUBJECTS, DEMOGRAPHICS, AND OTHER BASELINE CHARACTERISTICS .... 20 
1.1 Disposition of Subjects ................................................................................................................. 20 
1.1.1 Study Information .................................................................................................................. 20 
1.1.2 Disposition of All Subjects Who Did Not Enter in the Maintenance Phase .......................... 20 
1.1.3 Subject Eligibility .................................................................................................................. 20 
1.1.4 Number of Subjects Who Entered in the Maintenance Phase by Site .................................... 20 
1.1.5 Disposition of Subjects .......................................................................................................... 21 
1.1.5.1 
Disposition of Subjects ................................................................................................... 21 
1.1.6 Study Drug Completion Status and Study Visit Completion Status ...................................... 21 
1.1.7 Protocol Deviations and Analysis Sets .................................................................................. 22 
1.2 Demographic and Other Baseline Characteristics ......................................................................... 24 
1.2.1 Distribution of Baseline Demographics ................................................................................. 24 
1.2.2 Medical History, Concurrent Medical Conditions ................................................................. 27 
1.2.3 Medication History, Concomitant Medications in the Maintenance Phase, Concomitant 
Therapies in the Maintenance Phase ....................................................................................... 28 
1.3 Measurement of Compliance Status for Treatment....................................................................... 29 
1.3.1 Study Drug Exposure and Compliance in the Maintenance Phase ........................................ 29 
2 EFFICACY ANALYSIS ................................................................................................................. 31 
2.1 Primary Endpoints and Analysis Methodology ............................................................................ 31 
2.1.1 Primary Analysis .................................................................................................................... 31 
2.1.2 Secondary Analysis ................................................................................................................ 31 
2.2 Secondary Endpoints and Analysis Methodology ........................................................................ 31 
2.3 Other Endpoints and Analysis Methodology ................................................................................ 32 
2.3.1 Endpoints Related to CDAI Scores ........................................................................................ 32 
2.3.2 Endpoints Related to CDAI Scores Based on the Hematocrit Level at Each Study Site ....... 35 
2.3.3 Endpoints Related to CRP...................................................................................................... 37 
2.3.4 Endpoints Related to IBDQ ................................................................................................... 38 
2.3.5 Endpoints Related to Oral Corticosteroid Dosage ................................................................. 40 
2.3.6 Endpoints Related to Time to Event ...................................................................................... 40 
2.4 Statistical and Analytical Issues .................................................................................................... 41 
2.4.1 Adjustments for Covariates .................................................................................................... 41 
2.4.2 Handling of Dropouts or Missing Data .................................................................................. 41 
2.4.3 Interim Analyses and Data Monitoring .................................................................................. 41 


 
2 
 
2.4.4 Multicenter Studies ................................................................................................................ 41 
2.4.5 Multiple Comparisons/Multiplicity ........................................................................................ 41 
2.4.6 Use of an “Efficacy Subset” of Subjects ................................................................................ 41 
2.4.7 Active-Control Studies Intended to Show Equivalence or Non-inferiority ........................... 41 
2.4.8 Examination of Subgroups ..................................................................................................... 42 
3 SAFETY ANALYSIS ...................................................................................................................... 44 
3.1 Treatment-Emergent Adverse Event ............................................................................................. 44 
3.1.1 Overview of Treatment-Emergent Adverse Events ............................................................... 44 
3.1.2 Displays of Treatment-Emergent Adverse Events ................................................................. 45 
3.2 Pretreatment Event ........................................................................................................................ 47 
3.2.1 Displays of Pretreatment Events ............................................................................................ 47 
3.3 Clinical Laboratory Evaluations and Other Safety Endpoints ...................................................... 47 
3.3.1 Clinical Laboratory Evaluations ............................................................................................ 47 
3.3.2 Vital Signs, Physical Examination, and Other Observation Items Related to Safety ............ 49 
3.4 Display of Treatment-Emergent Adverse Event (in Japanese) ..................................................... 49 
4 PHARMACOKINETIC ANALYSIS .............................................................................................. 50 
4.1 Analysis of Serum Concentrations of MLN0002 .......................................................................... 50 
4.2 Subgroup Analysis of Serum Concentrations of MLN0002 ......................................................... 50 
4.3 Serum Concentrations of MLN0002 by Efficacy Endpoints ........................................................ 50 
4.4 Serum Concentrations of MLN0002 by AVA and Neutralizing Antibody ................................... 51 
4.5 Efficacy by Serum Concentration of MLN0002 ........................................................................... 51 
5 ANALYSIS OF IMMUNOGENICITY ENDPOINTS .................................................................... 53 
5.1 AVA and the Neutralizing Antibody ............................................................................................ 53 
5.2 Efficacy by AVA and the Neutralizing Antibody ......................................................................... 53 
5.3 Subgroup Analysis of AVA and the Neutralizing Antibody ......................................................... 54 
6 SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT .................................................. 55 
History of Revision (version management) ........................................................................................ 56 
[Appendix 1] Comparison Table for Changes ...................................................................................... 1 
[Appendix 2] Definitions of Categories in Shift Table, MAV Criteria, and Criteria for Elevated Liver 
Enzyme ......................................................................................................................................... 1 
 


 
3 
 
Since the study has different objectives in the induction phase, the maintenance phase, and the 
open-label cohort, analyses will be conducted separately among these. Therefore, the “Statistical 
Analysis Plan” will be also prepared for the induction phase, maintenance phase, and open-label 
cohort, respectively. This statistical analysis plan will describe the analytical plan in the maintenance 
phase.  
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
• 
Treatment-emergent adverse event (TEAE) in the maintenance phase: An adverse event that 
emerged during the maintenance phase. 
• 
All subjects entered in the maintenance phase: Of subjects who achieved CDAI-70 response at 
Week 10, those who were enrolled into the maintenance phase. 
• 
Concomitant medication in the maintenance phase: Any concomitant medication which was 
started by the day before the first dose of the study drug in the open-label cohort for subjects 
who received the study drug in the open-label cohort. “By the day before the first dose of the 
study drug in the open-label cohort” will include the day before the first dose of the study drug 
in the open-label cohort. Hereinafter, the same expression (by -) will be interpreted in the same 
manner. For subjects who did not receive the study drug in the open-label cohort, all 
concomitant medications are included. 
• 
Concomitant therapy in the maintenance phase: Any concomitant therapy which was started by 
the day before the first dose of the study drug in the open-label cohort for subjects who received 
the study drug in the open-label cohort. For subjects who did not receive the study drug in the 
open-label cohort, all concomitant therapies are included. 
• 
Summary statistics: Number of subjects, mean, standard deviation, maximum, minimum, and 
quartiles. 
• 
MAV: An abbreviation for markedly abnormal value. 
• 
Study Day: The day before the first dose of the study drug in the induction phase will be 
defined as Day -1 and the day of the first dose in the induction phase will be defined as Day 1. 
• 
Follow-up Day: The day after the last dose of the study drug will be defined as Follow-up 
Day 1. There will be no distinction among the induction phase, maintenance phase, and 
open-label cohort for the day of the last dose of the study drug. 
• 
Full analysis set in the maintenance phase: Subjects who were randomized and received at least 
one dose of the study drug in the maintenance phase. The full analysis set in the maintenance 
phase will not include subjects who received placebo in the induction phase and were enrolled 
into the maintenance phase. 
• 
Per protocol set in the maintenance phase: All subjects in full analysis set in the maintenance 
phase who did not have any major protocol deviations, have met the minimum protocol 
provisions, and have evaluable primary endpoint(s). 
• 
Safety analysis set in the maintenance phase: Subjects who received at least one dose of the 
study drug in the maintenance phase. 
• 
Treatment groups in the induction phase: MLN0002 group and placebo group. 
• 
Treatment groups in the maintenance phase: MLN0002 group and placebo group. 
• 
Anti-vedolizumab antibody (AVA): Human anti-human antibody (HAHA) in the protocol will 
be described as AVA. 
• 
Subjects in the placebo continuation group: Subjects who were allocated to the placebo group in 
the induction phase and received the placebo in the maintenance phase. 
• 
Treatment groups in the maintenance phase and subjects in the placebo continuation group: 


 
4 
 
MLN0002 group, placebo group, and subjects in the placebo continuation group. 
• 
CDAI-70 responders at Week 10: Subjects who were determined to have achieved CDAI-70 
response at Week 10 on the website of the registration center. 
• 
Baseline: A visit at “Week 0” in the “HANDLING OF TIME WINDOW” 
 
HANDLING OF TIME WINDOW 
For each test, observation, and evaluation item, evaluable data (i.e., non-missing data and data 
determined to be eligible based on “Handling Rules for Analysis Data”) will be handled according 
to the following rules. 
For acceptable windows of evaluation items other than oral corticosteroid dosage at each visit except 
for Week 0, the evaluable data within the acceptable window for subjects who received the study 
drug in the maintenance phase or open-label cohort will be used among the data measured prior to 
the day of the first dose of the study drug in the open-label cohort. The evaluable data within the 
acceptable window will be used for other subjects. If more than one evaluable datum lies within the 
same acceptable window, the data whose test/observation/evaluation date is closest to the scheduled 
date will be used and, if there are two data equidistant to the scheduled date, the data obtained later 
will be used. The temporal distance from the scheduled date will be determined based on the Study 
Day and Follow-up Day. 
Oral corticosteroid dosage is described in “OTHER HANDLING.” 
If the date of the first dose of the study drug in the open-label cohort is smaller than the lower limit 
of the acceptable window in the table, the acceptable window at that visit will not be applied. 
 
CDAI score*1, each CDAI subscore*2 (both based on the hematocrit [Ht] level at each study site) 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 2 
Study Day: 15 
2 to 28 
 
Week 6*3 
Study Day: 43 
29 to 56 
 
Week 10*4 
Study Day: 71 
57 to 84 
 
Week 14 
Study Day: 99 
85 to 112 
 
Week 18 
Study Day: 127 
113 to 140 
 
Week 22 
Study Day: 155 
141 to 168 
 
Week 26 
Study Day: 183 
169 to 196 
 
Week 30 
Study Day: 211 
197 to 224 
 
Week 34 
Study Day: 239 
225 to 252 
 
Week 38 
Study Day: 267 
253 to 280 
 
Week 42 
Study Day: 295 
281 to 308 
 
Week 46 
Study Day: 323 
309 to 336 
 
Week 50 
Study Day: 351 
337 to 364 
 
Week 54 
Study Day: 379 
365 to 392 
 


 
5 
 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 58 
Study Day: 407 
393 to 413 
 
Week 60*5 
Study Day: 421 
414 to 448 
 
Week 60 (LOCF)*6 
  
 
 
*1 CDAI-70 response, CDAI-100 response, and clinical remission will be determined by using both 
CDAI score based on the Ht level at each study site and CDAI score based on the Ht level at the 
central laboratory, respectively. 
*2 Each CDAI subscore used for the calculation of CDAI scores based on the Ht level at each study 
site will be used. 
*3 If the CDAI subscore (7) at Week 6 is missing, the same CDAI subscore (7) as that obtained at 
Week 2 will be used for Week 6. 
*4 If the CDAI subscore (7) at Week 10 is missing, the same CDAI subscore (7) as that obtained at 
Week 6 will be used for Week 10. However, if the CDAI subscore (7) at Week 2 is used for Week 
6 according to the handling described in *3, the CDAI subscore (7) at Week 10 will be handled as 
missing. 
*5 If the CDAI subscore (7) at Week 60 is missing, the same CDAI subscore (7) as that obtained at 
Week 58 will be used for Week 60. If the CDAI score at Week 60 is missing, the same CDAI 
score as that obtained at Week 58 will be used for Week 60. 
*6 For Week 60 (LOCF), the latest data during the period from the day after the first dose of the 
study drug in the maintenance phase until the day of the first dose of the study drug in the 
open-label cohort will be used for subjects who received the study drug in the open-label cohort. 
For subjects who did not receive the study drug in the open-label cohort, the latest data during the 
period from the day after the first dose of the study drug in the maintenance phase onwards will be 
used. 
 
Ht level*1 (tested by the central laboratory), inflammatory marker (CRP)  
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 2 
Study Day: 15 
2 to 28 
 
Week 6*2 
Study Day: 43 
29 to 56 
 
Week 10*3 
Study Day: 71 
57 to 84 
 
Week 14 
Study Day: 99 
85 to 126 
 
Week 22 
Study Day: 155 
127 to 182 
 
Week 30 
Study Day: 211 
183 to 238 
 
Week 38 
Study Day: 267 
239 to 294 
 
Week 46 
Study Day: 323 
295 to 350 
 
Week 54 
Study Day: 379 
351 to 399 
 


 
6 
 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 60 
Study Day: 421 
400 to 448 
 
Week 60 (LOCF)*4 
  
 
 
*1 The Ht level will be handled as follows: 
 If the Ht level tested on the same date as the evaluation day of the CDAI score based on the 
Ht level at each study site is available, that Ht level will be used. 
 If the Ht level tested on the same date as the evaluation day of the CDAI score based on the 
Ht level at each study site is not available, it will be handled according to the general rules 
described directly beneath the “HANDLING OF TIME WINDOW.” 
*2 If the Ht level at Week 6 is missing, the same Ht level as that obtained at Week 2 will be used for 
Week 6. 
*3 If the Ht level at Week 10 is missing, the same Ht level as that obtained at Week 6 will be used for 
Week 10. However, if the Ht level at Week 2 is used for Week 6 according to the handling 
described in *2, the Ht level at Week 10 will be handled as missing. 
*4 For Week 60 (LOCF), the latest data during the period from the day after the first dose of the 
study drug in the maintenance phase until the day of the first dose of the study drug in the 
open-label cohort will be used for subjects who received the study drug in the open-label cohort. 
For subjects who did not receive the study drug in the open-label cohort, the latest data during the 
period from the day after the first dose of the study drug in the maintenance phase onwards will be 
used. 
 
IBDQ scores (total score and each subscore [abdominal symptoms, general condition, emotion, and 
social function]) 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 10 
Study Day: 71 
2 to 84 
 
Week 14 
Study Day: 99 
85 to 182 
 
Week 38 
Study Day: 267 
183 to 343 
 
Week 60 
Study Day: 421 
344 to 448 
 
Week 60 (LOCF)*1 
  
 
 
*1 For Week 60 (LOCF), the latest data during the period from the day after the first dose of the 
study drug in the maintenance phase until the day of the first dose of the study drug in the 
open-label cohort will be used for subjects who received the study drug in the open-label cohort. 
For subjects who did not receive the study drug in the open-label cohort, the latest data during the 
period from the day after the first dose of the study drug in the maintenance phase onwards will be 
used. 
 


 
7 
 
Laboratory tests (hematology, blood biochemistry) 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 2 
Study Day: 15 
2 to 28 
 
Week 6 
Study Day: 43 
29 to 56 
 
Week 10 
Study Day: 71 
57 to 84 
 
Week 14 
Study Day: 99 
85 to 126 
 
Week 22 
Study Day: 155 
127 to 182 
 
Week 30 
Study Day: 211 
183 to 238 
 
Week 38 
Study Day: 267 
239 to 294 
 
Week 46 
Study Day: 323 
295 to 350 
 
Week 54 
Study Day: 379 
351 to 399 
 
Week 60 
Study Day: 421 
400 to 448 
 
16 weeks after the last dose*1 
Follow-up Day: 112 
 
56 to 167 
*1 Applied only to subjects who did not receive the study drug in the open-label cohort. 
 
Laboratory test (urinalysis) 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 10 
Study Day: 71 
2 to 84 
 
Week 14 
Study Day: 99 
85 to 126 
 
Week 60 
Study Day: 421 
127 to 448 
 
16 weeks after the last dose*1 
Follow-up Day: 112 
 
56 to 167 
*1 Applied only to subjects who did not receive the study drug in the open-label cohort. 
 
Vital signs, body weight 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 2 
Study Day: 15 
2 to 28 
 
Week 6 
Study Day: 43 
29 to 56 
 
Week 10 
Study Day: 71 
57 to 84 
 
Week 14 
Study Day: 99 
85 to 112 
 


 
8 
 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 18 
Study Day: 127 
113 to 140 
 
Week 22 
Study Day: 155 
141 to 168 
 
Week 26 
Study Day: 183 
169 to 196 
 
Week 30 
Study Day: 211 
197 to 224 
 
Week 34 
Study Day: 239 
225 to 252 
 
Week 38 
Study Day: 267 
253 to 280 
 
Week 42 
Study Day: 295 
281 to 308 
 
Week 46 
Study Day: 323 
309 to 336 
 
Week 50 
Study Day: 351 
337 to 364 
 
Week 54 
Study Day: 379 
365 to 392 
 
Week 58 
Study Day: 407 
393 to 413 
 
Week 60 
Study Day: 421 
414 to 448 
 
16 weeks after the last dose*1 
Follow-up Day: 112 
 
56 to 167 
*1 Applied only to subjects who did not receive the study drug in the open-label cohort. 
 
12-lead ECG 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 10 
Study Day: 71 
2 to 84 
 
Week 60 
Study Day: 421 
85 to 448 
 
16 weeks after the last dose*1 
Follow-up Day: 112 
 
56 to 167 
*1 Applied only to subjects who did not receive the study drug in the open-label cohort. 
 
AVA, neutralizing antibody 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
-28 to 1 
 
Week 10 
Study Day: 71 
2 to 84 
 
Week 30 
Study Day: 211 
85 to 315 
 
Week 60 
Study Day: 421 
316 to 448 
 
16 weeks after the last dose*1 
Follow-up Day: 112 
 
56 to 167 
*1 Applied only to subjects who did not receive the study drug in the open-label cohort. 


 
9 
 
 
Serum concentrations of MLN0002 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 2*1 
Study Day: 15 
12 to 18 
 
Week 6*1 
Study Day: 43 
40 to 46 
 
Week 10 
Study Day: 71 
68 to 74 
 
Week 14*1 
Study Day: 99 
92 to 106 
 
Week 22*1 
Study Day: 155 
148 to 162 
 
Week 30*1 
Study Day: 211 
204 to 218 
 
Week 60 
Study Day: 421 
414 to 428 
 
*1 For Weeks 2, 6, 14, 22, and 30, only data measured from 3 hours before administration until 
immediately before administration will be used. 
 
OTHER HANDLING 
In principle, if any variable value used for calculation or adjudication is missing, the result of the 
calculation or adjudication will be handled as missing. If other handling of missing data is described, 
follow that handling. 
• 
Duration of study drug exposure in the maintenance phase (days): Date of the last dose of the 
study drug in the maintenance phase − Date of the first dose of the study drug in the 
maintenance phase + 1 
• 
Duration on study after the first dose of the study drug in the maintenance phase (days): For 
subjects who received the study drug in the open-label cohort, “Date of the first dose of the 
study drug in the open-label cohort − Date of the first dose of the study drug in the maintenance 
phase” and for other subjects, “Date of last visit or contact − Date of the first dose of the study 
drug in the maintenance phase + 1” 
• 
BMI (kg/m2) = Weight (kg) / (Height [cm]/100)2 (round off to the first decimal place) 
• 
Duration of CD (years): (Date of informed consent [year and month] − Date of CD diagnosis 
[year and month]) / 12 (round off to the first decimal place) 
 
Only the year and month for the date of informed consent will be used. 
 
The unit for “Date of informed consent (year and month) − Date of CD diagnosis (year and 
month)” will be “months.” 
 
If the year of CD diagnosis is unknown, the duration of CD will be handled as “Missing.” 
If only the month of CD diagnosis is unknown, the duration of CD will be calculated by 
setting the month of CD diagnosis as January. 
• 
Prior corticosteroids failure: If corticosteroid resistance, dependence, or intolerance is “Yes,” 
prior corticosteroids failure will be defined as “Yes.” Any response other than the above will be 
defined as “No.” 
• 
Classification 1 of prior corticosteroids failure: Subjects for whom prior corticosteroids failure 
is “Yes” are classified as follows:  
 
Subjects for whom corticosteroid resistance is “Yes” are classified as “Resistance.” 
 
Among subjects for whom corticosteroid resistance is not “Yes,” subjects for whom 
corticosteroid dependence is “Yes” are classified as “Dependence.” 


 
10 
 
 
Among subjects for whom corticosteroid resistance is not “Yes” as well as corticosteroid 
dependence not being “Yes,” subjects for whom corticosteroid intolerance is “Yes” are 
classified as “Intolerance.” 
• 
Classification 2 of prior corticosteroids failure: Subjects for whom prior corticosteroids failure 
is “Yes” are classified as follows:  
 
Subjects for whom corticosteroid resistance is “Yes” or corticosteroid dependence is 
“Yes” are classified as “Refractory.” 
 
Among subjects for whom corticosteroid resistance is not “Yes” as well as corticosteroid 
dependence not being “Yes,” subjects for whom corticosteroid intolerance is “Yes” are 
classified as “Intolerance.” 
• 
Prior immunomodulators failure: If either immunomodulator refractory or intolerance is “Yes,” 
prior immunomodulators failure will be defined as “Yes.” Any response other than the above 
will be defined as “No.” 
• 
Classification of prior immunomodulators failure: Subjects for whom prior immunomodulators 
failure is “Yes” are classified as follows:  
 
Subjects for whom immunomodulator refractory is “Yes” are classified as “Refractory.” 
 
Among the subjects for whom immunomodulator refractory is not “Yes,” subjects for 
whom immunomodulatory intolerance is “Yes” are classified as “Intolerance.”  
• 
Prior TNFα antagonist failure: If inadequate response, loss of response, or intolerance to the 
TNFα antagonist is “Yes,” prior TNFα antagonist failure will be defined as “Yes.” Any 
response other than the above will be defined as “No.” 
• 
Number of drugs of TNFα antagonist failure: Among the drugs entered to prior treatment 
failure (TNFα antagonist) for CD, subjects whose WHO Drug is coded with 1 type of drug with 
Preferred Name are classified as “Treatment failure with 1 drug.” Similarly, subjects who are 
coded with 2 types of drugs are classified as “Treatment failure with 2 drugs” and subjects who 
are coded with 3 types of drugs as “Treatment failure with 3 drugs.” Subjects who are not coded 
with any drug in the prior treatment failure (TNFα antagonist) for CD are classified as “None.” 
• 
Classification of prior TNFα antagonist failure: Subjects for whom prior TNFα antagonist 
failure is “Yes” are classified as follows:  
 
Subjects for whom TNFα antagonist inadequate response is “Yes” are classified as 
“Inadequate response.” 
 
Among subjects for whom TNFα antagonist inadequate response is not “Yes,” subjects for 
whom TNFα antagonist loss of response is “Yes” are classified as “Loss of response.” 
 
Among subjects for whom TNFα antagonist inadequate response is not “Yes” as well as 
TNFα antagonist loss of response not being “Yes,” subjects for whom TNFα antagonist 
intolerance is “Yes” are classified as “Intolerance.” 
• 
Prior immunomodulators failure (excluding prior TNFα antagonist failure): If prior TNFα 
antagonist failure is “No” and prior immunomodulators failure is “Yes,” prior 
immunomodulators failure (excluding prior TNFα antagonist failure) will be defined as “Yes.” 
All others will be defined as “No.” 
• 
Prior corticosteroids failure only: If prior TNFα antagonist failure is “No,” prior 
immunomodulators failure is “No,” and prior corticosteroids failure is “Yes,” prior 
corticosteroids failure only will be defined as “Yes.” All others will be defined as “No.” 
• 
Prior immunomodulators and TNFα antagonist failure: If prior immunomodulators failure is 
“Yes” and prior TNFα antagonist failure is “Yes,” prior immunomodulators and TNFα 
antagonist failure will be defined as “Yes.” All others will be defined as “No.” 
• 
Completion of the study drug infusion: If the infusion of the study drug is “Completed” or dose 


 
11 
 
of the study drug is ≥79 mL (percentage of dose against prepared study drug of 105 mL is 
≥75%), the study drug infusion will be defined as “Completed.” All others will be defined as 
“Incompleted.” 
 
The Ht level and CDAI score will be handled as follows: 
• 
The CDAI score, CDAI subscore, and Ht levels used for analysis will be determined at the 
central laboratory unless otherwise noted. 
• 
CDAI score: The sum of CDAI subscores of (1) to (8) defined in the table below. 
(1) Number of liquid or very soft stools during the last 1 week 
× 2 
(2) Abdominal pain during the last 1 week 
(7-day total of daily abdominal pain scores on a following scale) 
0=None, 1=Mild, 2=Moderate, 3=Severe 
× 5 
(3) Subjective general well being during the last 1 week 
(7-day total of daily general well-being scores on a following scale) 
0=Generally well, 1=Slightly under par, 2=Poor, 3=Very poor, 
4=Terrible 
× 7 
(4) Current number of the following extraintestinal manifestations of CD 
1) 
Arthritis/arthralgia 
2) 
Iritis/uveitis 
3) 
Erythema nodosum/pyoderma gangrenosum/aphthous stomatitis 
4) 
Anal fissure, anal fistula, or perianal abscess 
5) 
Other fistula 
6) 
Fever over 37.8°C during the last 1 week 
× 20 
(5) Use of antidiarrheal drugs (e.g., lopemin) or opiates for diarrhea 
0=No, 1=Yes 
× 30 
(6) Abdominal mass 
0=None, 2=Questionable, 5=Definite 
× 10 
(7) Hematocrit (%)Note 1) 
Males: subtract value from 47, Females: subtract value from 42 
× 6 
(8) Body weight : Standard weight (body-weight ratio)Note 2) 
[1 − (Body weight / Standard weight)] × 100 
× 1 
Note 1) If hematocrit subtotal <0, enter 0. 
Note 2) If body weight subtotal <-10, enter -10. 
• 
The CDAI score will be calculated using subscores on the same day of evaluation. For subscore 
(7), however, the CDAI score will be calculated using the Ht level obtained within the same 
visit window if the Ht level on the same day of evaluation is not available. 
• 
If any CDAI subscore is missing, the CDAI score will be handled as missing. 
• 
CDAI-70 response: Subjects will be classified as “CDAI-70 response” if “a ≥70-point decrease 
in CDAI score from baseline” is achieved. All others will be classified as “Non-CDAI-70 
response.” However, if any CDAI score change is missing, it will be handled as missing. Then, 
if the adjudication result at that visit is missing (including cases with no data due to study 
discontinuation) after processing the “HANDLING OF TIME WINDOW,” subjects will be 
classified as “Non-CDAI-70 response.” 
• 
CDAI-100 response: Subjects will be classified as “CDAI-100 response” if “a ≥100-point 
decrease in CDAI score from baseline” is achieved. All others will be classified as 


 
12 
 
“Non-CDAI-100 response.” However, if any CDAI score change is missing, it will be handled 
as missing. Then, if the adjudication result at that visit is missing (including cases with no data 
due to study discontinuation) after processing the “HANDLING OF TIME WINDOW,” 
subjects will be classified as “Non-CDAI-100 response.” 
• 
Clinical remission: Subjects will be classified as “Clinical remission” if a “CDAI score of 
≤150” is achieved. All others will be classified as “Non-remission.” However, if any of the 
CDAI scores is missing, it will be handled as missing. Then, if the adjudication result at that 
visit is missing (including cases with no data due to study discontinuation) after processing the 
“HANDLING OF TIME WINDOW,” subjects will be classified as “Non-remission.” 
 
After the CDAI-70 response, CDAI-100 response, and clinical remission at each visit are determined 
using the above methods, the following durable CDAI-70 response in the maintenance phase, 
durable CDAI-100 response in the maintenance phase, and durable remission in the maintenance 
phase will be determined. 
• 
Durable CDAI-70 response in the maintenance phase: If “CDAI-70 response” is observed at 
≥80% of visits after Week 10 except Week 60 (LOCF), subjects will be classified as “Durable 
CDAI-70 response.” All others will be classified as “Non-durable CDAI-70 response.” 
• 
Durable CDAI-100 response in the maintenance phase: If “CDAI-100 response” is observed at 
≥80% of visits after Week 10 except Week 60 (LOCF), subjects will be classified as “Durable 
CDAI-100 response.” All others will be classified as “Non-durable CDAI-100 response.” 
• 
Durable remission in the maintenance phase: If “Clinical remission” is observed at ≥80% of 
visits after Week 10 except Week 60 (LOCF), subjects will be classified as “Durable 
remission.” All others will be classified as “Non-durable remission.” 
 
For CDAI scores based on the Ht level at the central laboratory, “≥80% of visits after 
Week 10” will be defined as “7 or more out of 8 visits (Weeks 10, 14, 22, 30, 38, 46, 54, 
and 60).” 
 
For CDAI scores based on the Ht level at each study site, “≥80% of visits after Week 10” 
will be defined as “12 or more out of 14 visits (Weeks 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 
50, 54, 58, and 60).” 
 
• 
Disease worsening: All CDAI scores at visits including unscheduled ones during the period 
from the day after the first dose of the study drug in the maintenance phase until the day of the 
first dose of the study drug in the open-label cohort for subjects who received the study drug in 
the open-label cohort, and all CDAI scores at visits including unscheduled ones during the 
period from the day after the first dose of the study drug in the maintenance phase onwards for 
subjects who did not receive the study drug in the open-label cohort will be handled as follows: 
 
If the CDAI scores based on the Ht level at the central laboratory increase by ≥100 points 
from that of Week 10 and become ≥220 points on 2 consecutive visits by confirming them 
in ascending order of visit date, subjects will be classified as “Yes” for disease worsening 
based on the Ht level at the central laboratory. The onset date of disease worsening based 
on the Ht level at the central laboratory will be defined as the earlier date of these visits, 
after excluding missing values. 
 
The disease worsening based on the Ht level at each study site will be determined in the 
same manner as above using the CDAI scores based on the Ht level at each study site and 
the onset date of disease worsening based on the Ht level at each study site will be 
specified. 
 
A subject for whom disease worsening based on the Ht level at the central laboratory was 


 
13 
 
determined to be “Yes” or disease worsening based on the Ht level at each study site was 
determined to be “Yes” will be defined as “Yes” for disease worsening. 
 
The onset date of disease worsening will be defined as the earlier date on which either the 
onset of disease worsening based on the Ht level at the central laboratory or the onset of 
disease worsening based on the Ht level at each study site was observed. 
 
Time to disease worsening: A subject for whom disease worsening was determined to be 
“Yes” will be handled as an event case, and the period of “Onset date of disease worsening 
− Date of the first dose of the study drug in the maintenance phase + 1” will be used for 
analysis. A subject for whom disease worsening was not determined to be “Yes” will be 
handled as a censored case, and the period of “Date of the last measurement of CDAI 
score – Date of the first dose of the study drug in the maintenance phase + 1” will be used 
for analysis. 
• 
Rescue treatments: All concomitant medications (for treatment of CD) or therapies that started 
during the period from the day of the first dose of the study drug in the maintenance phase until 
the day before the first dose of the study drug in the open-label cohort for subjects who received 
the study drug in the open-label cohort, and all concomitant medications (for treatment of CD) 
or therapies that started during the period from the day of the first dose of the study drug in the 
maintenance phase onwards for subjects who did not receive the study drug in the open-label 
cohort will be handled as follows: 
 
Subjects with at least one concomitant medication or therapy that falls under the category 
of rescue treatment are classified as “Yes” for rescue treatments, and the start date of 
rescue treatment will be defined as the earliest date among the started dates of the 
concomitant rescue medications or therapies, after excluding missing values. 
• 
Discontinuation due to a study drug-related adverse event: The study drug completion status in 
the maintenance phase will be handled as follows: 
 
Subjects who discontinued the study drug due to “Pretreatment event/Adverse event” are 
classified as “Yes” for discontinuation due to study drug-related adverse events, and the 
onset date of discontinuation due to the study drug-related adverse event will be defined as 
the date of the study drug discontinuation. 
• 
Time to treatment failure 
 
If any of the study discontinuation due to disease worsening, rescue treatments, or study 
drug-related adverse event is “Yes,” treatment failure will be defined as “Yes,” and the 
onset date of the treatment failure will be defined as the earliest date among the onset dates 
of the above events, after excluding missing values. 
 
Time to treatment failure: 
 
A subject for whom treatment failure was determined to be “Yes” will be treated as 
an event case, and the time to treatment failure will be defined as the period of “Onset 
date of treatment failure − Date of the first dose of the study drug in the maintenance 
phase + 1.” 
 
A subject for whom treatment failure was not determined to be “Yes” will be treated 
as a censored case. 
 
For censored subjects who received the study drug in the open-label cohort, the 
period of “Previous date of the first dose of the study drug in the open-label cohort − 
Date of the first dose of the study drug in the maintenance phase + 1” will be used for 
analysis. 
 
For censored subjects who did not receive the study drug in the open-label cohort, the 
period of “Date of last visit or contact in the maintenance phase − Date of the first 


 
14 
 
dose of the study drug in the maintenance phase + 1” will be used for analysis. 
 
 
IBDQ score will be handled as follows: 
• 
The questions (Q) on the same day of measurement will be used for calculation of each 
subscore and total score. After calculating each subscore and total score, the time point will be 
transferred. 
• 
IBDQ subscore for abdominal symptoms: Mean of Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, 
Q26, and Q29 (round off to the first decimal place). 
• 
IBDQ subscore for general condition: Mean of Q2, Q6, Q10, Q14, and Q18 (round off to the 
first decimal place). 
• 
IBDQ subscore for emotion: Mean of Q3, Q7, Q11, Q15, Q19, Q21, Q23, Q25, Q27, Q30, Q31, 
and Q32 (round off to the first decimal place). 
• 
IBDQ subscore for social function: Mean of Q4, Q8, Q12, Q16, and Q28 (round off to the first 
decimal place). 
• 
IBDQ total score: Sum of all questions (round off to the first decimal place). 
 
The value of each question after imputing missing data will be used for the calculation of 
each subscore (abdominal symptoms, general condition, emotion, and social function). 
• 
The handling of missing data in calculation of each subscore (abdominal symptoms, general 
condition, emotion, and social function) and IBDQ total score will be defined as follows:  
Variable 
Handling of missing data 
IBDQ subscore for 
abdominal symptoms, 
IBDQ subscore for 
general condition, 
IBDQ subscore for 
emotion, and IBDQ 
subscore for social 
function 
• If 1 question is missing among those used for calculation of each 
subscore, the missing data will be imputed using the mean of the 
non-missing questions used for the calculation of that subscore. 
• If 2 questions are missing among those used for the calculation of each 
subscore, that subscore will be handled as missing. 
IBDQ total score 
• Among the questions used for the calculation of IBDQ total score, the 
missing data will be imputed using the mean of the non-missing 
questions used for the calculation of each subscore. However, if 5 or 
more questions are missing or 2 or more subscores are missing among 
the questions used for the calculation of IBDQ total score or 3 or more 
questions are missing among those used for calculation of a certain 
subscore, the total score will be handled as missing. 
• 
170 or higher in IBDQ total score: “Yes” if IBDQ total score is ≥170, “No” if it is <170, and 
“Missing” if it is missing. 
• 
-16 or lower in change from Week 10 in IBDQ total score: “Yes” if the change from Week 10 
in IBDQ total score is ≤-16, “No” if it is >-16, and “Missing” if it is missing. 
• 
16 or higher in change from baseline in IBDQ total score: “Yes” if the change from baseline in 
IBDQ total score is ≥16, “No” if it is <16, and “Missing” if it is missing. 
• 
Time to -16 or lower in change from Week 10 in IBDQ total score 
 
For subjects who received the study drug in the open-label cohort, IBDQ total scores after 
Week 10 measured by the day of the first dose of the study drug in the open-label cohort 
will be used. For subjects who did not receive the study drug in the open-label cohort, all 


 
15 
 
IBDQ total scores after Week 10 will be used. 
 
A subject whose IBDQ total score change from Week 10 was ≤-16 will be treated as an 
event case, and time to -16 or lower in change from Week 10 in IBDQ total score will be 
defined as the period of “Earliest date when IBDQ total score change from Week 10 is 
≤-16 − Measuring date of IBDQ total score at Week 10 + 1.” 
 
A subject whose IBDQ total score change from Week 10 was never ≤-16 will be treated as 
a censored case, and time to -16 or lower in change from Week 10 in IBDQ total score will 
be defined as the period of “Last measuring date of IBDQ total score − Measuring date of 
IBDQ total score at Week 10 + 1.” 
 
Prior TNFα antagonist use, concomitant use of immunomodulators at baseline, and concomitant use 
of oral corticosteroids at baseline will be defined as follows: 
• 
Prior TNFα antagonist use: Subjects coded with at least 1 drug of Preferred Name of WHO 
Drug in the following table for medication history will be classified as “Yes.” All others will be 
classified as “No.” 
 
Preferred Name 
Infliximab 
Adalimumab 
Golimumab 
 
• 
Concomitant use of immunomodulators at baseline: Subjects who received any concomitant 
medication (for treatment of CD) which is classified as “immunomodulator” in the concomitant 
medication (for treatment of CD) which was started before the first dose of the study drug in the 
induction phase and continued in the induction phase will be classified as “Yes.” All others will 
be classified as “No.” 
 
Any concomitant medication (for treatment of CD) which was started after the first dose of 
the study drug in the induction phase is not subject to this handling. 
 
• 
Concomitant use of oral corticosteroids at baseline: Subjects who received any concomitant 
medication (for treatment of CD) which is classified as “corticosteroid” and whose route of 
administration is “oral” in the concomitant medication (for treatment of CD) which was started 
before the first dose of the study drug in the induction phase and continued in the induction 
phase will be classified as “Yes.” All others will be classified as “No.” 
 
Any concomitant medication (for treatment of CD) which was started after the first dose of 
the study drug in the induction phase is not subject to this handling. 
 
• 
Concomitant use of oral corticosteroids at Week 10: Regarding the “oral corticosteroid dosage” 
defined below, subjects whose oral corticosteroid dosage is larger than 0 at Week 10 will be 
classified as “Yes.” All others will be classified as “No.” 
 
Concurrent extraintestinal manifestations (based on CDAI subscore [4]), concurrent extraintestinal 
manifestations (based on case report form [CRF] concurrent medical condition section), surgical 
history for CD, medical history of fistula or concurrent medical condition related to fistula within 1 
year before signing of informed consent, and concurrent medical condition related to fistula will be 
defined as follows: 
• 
Concurrent extraintestinal manifestations (based on CDAI subscore [4]): Subjects whose CDAI 


 
16 
 
subscore [4] at baseline is greater than 0 will be classified as “Yes.” All others will be classified 
as “No.” 
• 
Concurrent extraintestinal manifestations (based on CRF concurrent medical condition section): 
Subjects recorded to have concurrent extraintestinal manifestations of CD in the CRF 
concurrent medical condition section will be classified as “Yes.” All others will be classified as 
“No.” 
• 
Surgical history for CD: Subjects coded with at least one PT in the following table for medical 
history will be classified as “Yes.” All others will be classified as “No.” 
 
 
 
Preferred Term 
Anal skin tag excision 
Colectomy 
Crohn's disease 
Enterocutaneous fistula 
Ileal operation 
Ileectomy 
Ileocolectomy 
Ileocolostomy 
Ileostomy 
Ileostomy closure 
Intestinal resection 
Proctectomy 
Sigmoidectomy 
Small intestinal resection 
Small intestine operation 
Stricturoplasty 
Urinary cystectomy 
 
• 
Medical history of fistula or concurrent medical condition related to fistula within 1 year before 
signing of informed consent: Subjects coded with at least one PT in the following table for 
medical history or concurrent medical condition will be classified as “Yes.” All others will be 
classified as “No.” 
Medical history 
Preferred Term 
Anal fistula 
Fistula of small intestine 
 
Concurrent medical condition 
Preferred Term 
Anal fistula 
Enterocutaneous fistula 
Female genital tract fistula 
 
• 
Concurrent medical condition related to fistula: Subjects coded with at least one PT in the 


 
17 
 
following table for concurrent medical condition will be classified as “Yes.” All others will be 
classified as “No.” 
Preferred Term 
Anal fistula 
Enterocutaneous fistula 
Female genital tract fistula 
 
Among concomitant medications (for treatment of CD) in the maintenance phase, the medication 
which is classified as “corticosteroid” and whose route of administration is “oral” will be classified 
as “oral corticosteroids” and handled as follows: 
• 
The acceptable window in the table of TIME WINDOW for oral corticosteroid dosage will be 
handled as follows: For acceptable windows at each visit except for Week 0, the smallest value 
among the day of the first dose of the study drug in the open-label cohort (defining the day of 
the first dose of the study drug in the induction phase as Day 1) and upper limit of the 
acceptable window in the table after excluding missing values will be defined as the upper limit 
of the acceptable window for subjects who received the study drug in the open-label cohort. If 
the date of the first dose of the study drug in the open-label cohort is smaller than the lower 
limit of the acceptable window in the table, the acceptable window at that visit will not be 
applied. 
 
TIME WINDOW for oral corticosteroid dosage 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 0 
Study Day: 1 
1 
 
Week 2 
Study Day: 15 
2 to 28 
 
Week 6 
Study Day: 43 
29 to 56 
 
Week 10 
Study Day: 71 
57 to 84 
 
Week 14 
Study Day: 99 
85 to 112 
 
Week 18 
Study Day: 127 
113 to 140 
 
Week 22 
Study Day: 155 
141 to 168 
 
Week 26 
Study Day: 183 
169 to 196 
 
Week 30 
Study Day: 211 
197 to 224 
 
Week 34 
Study Day: 239 
225 to 252 
 
Week 38 
Study Day: 267 
253 to 280 
 
Week 42 
Study Day: 295 
281 to 308 
 
Week 46 
Study Day: 323 
309 to 336 
 
Week 50 
Study Day: 351 
337 to 364 
 
Week 54 
Study Day: 379 
365 to 392 
 
Week 58 
Study Day: 407 
393 to 413 
 


 
18 
 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
Week 60 
Study Day: 421 
414 to 448 
 
Week 60 (LOCF) 
  
 
 
 
• 
Oral corticosteroid dosage at each visit other than Week 60 (LOCF): Oral corticosteroid dosage 
for each Study Day period will be defined as the sum of daily doses of oral corticosteroids 
(converted dosage of prednisolone) used for each Study Day period. For the Study Day period 
when oral corticosteroids are not used, the daily dose will be “0.” Oral corticosteroid dosage at 
each visit will be the mean of oral corticosteroid dosage for each Study Day period within the 
acceptable window of each visit. 
• 
Oral corticosteroid dosage at Week 60 (LOCF): Oral corticosteroid dosage at the last visit 
during the period from Week 14 to Week 16 will be used, after excluding missing values. 
 
• 
Corticosteroid-free remission at Week 60: “Corticosteroid-free remission” if concomitant use of 
corticosteroids at baseline is “Yes,” oral corticosteroid dosage at Week 60 is “0 mg/day” and 
clinical remission at Week 60 is “Clinical remission.” All others will be defined as 
“Non-corticosteroid-free remission.” 
 
For Week 60 of clinical remission at Week 60, the visit after processing the “HANDLING 
OF TIME WINDOW” will be used. 
 
Negative or positive status of the neutralizing antibody will be determined as follows: 
• 
“Positive” if the neutralizing antibody is positive for AVA and neutralizing antibody with the 
same VISIT in each subject. “Negative” if the neutralizing antibody is negative or AVA is 
negative. The neutralizing antibody will be handled as missing if it does not correspond to any 
of the above. 
 
After determining the negative or positive status of the neutralizing antibody at each visit with the 
above-mentioned logic, the following determination will be made: 
• 
AVA in the induction and maintenance phases 
 
Subjects in the induction and maintenance phases who were determined to be 
AVA-positive at any visit after the day of the first dose of the study drug in the induction 
phase, and in the maintenance phase will be classified as “AVA-positive.” 
 
Subjects in the induction and maintenance phases who were determined to be 
AVA-negative at all visits (except for those with missing values) after the day of the first 
dose of the study drug in the induction phase, and in the maintenance phase will be 
classified as “AVA-negative.” 
 
Subjects whose AVA values are missing at all visits in the induction and maintenance 
phases will be classified as missing. 
• 
Persistently positive in the induction and maintenance phases 
 
“Subjects in the induction and maintenance phases who were determined to be 
AVA-positive in at least 2 consecutive samples sorted by date of blood collection after the 
day of the first dose of the study drug in the induction phase” will be classified as 
persistently positive. 
• 
Transiently positive in the induction and maintenance phases 
 
Subjects in the induction and maintenance phases who do not correspond to “subjects in 


 
19 
 
the induction and maintenance phases who were determined to be AVA-positive in at least 
2 consecutive samples sorted by date of blood collection after the day of the first dose of 
the study drug in the induction phase,” and were determined to be AVA-positive in at least 
one sample collected after the day of the first dose of the study drug in the induction phase 
will be classified as transiently positive. 
• 
Neutralizing antibody in the induction and maintenance phases 
 
Subjects in the induction and maintenance phases who were determined to be positive for 
neutralizing antibodies at any visit after the day of the first dose of the study drug in the 
induction phase, and in the maintenance phase will be classified as “Positive for 
neutralizing antibodies.” 
 
Subjects in the induction and maintenance phases who were determined to be negative for 
neutralizing antibodies at all visits (except for those with missing values) after the day of 
the first dose of the study drug in the induction phase, and in the maintenance phase will 
be classified as “Negative for neutralizing antibodies.” 
 
Subjects whose neutralizing antibody values are missing at all visits in the induction and 
maintenance phases will be classified as missing. 
 
Lymphocytes and neutrophils will be calculated with the following formula: 
• 
Lymphocytes = WBC × lymphocytes (%)  
• 
Neutrophils = WBC × neutrophils (%)  
 


 
20 
 
1 STUDY SUBJECTS, DEMOGRAPHICS, AND OTHER BASELINE CHARACTERISTICS 
1.1 Disposition of Subjects 
1.1.1 Study Information 
Analysis set: 
All subjects who signed the informed consent form 
Analysis variables: 
Date first subject signed the informed consent form 
 
Date of last visit or contact in the maintenance phase, whichever 
comes later 
 
MedDRA version 
 
WHO Drug version 
 
SAS version used for creating the datasets 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
 
(1) 
Display of the analysis variables 
 
1.1.2 Disposition of All Subjects Who Did Not Enter in the Maintenance Phase 
Analysis set: 
All subjects who achieved CDAI-70 response at Week 10 and did 
not enter in the maintenance phase 
Analysis variables: 
Categories in parenthesis [  ] (hereinafter the same) 
 
Age (years) 
[Min≤ - ≤34, 35≤ - ≤Max] 
 
 
[Min≤ - ≤64, 65≤ - ≤Max] 
 
Gender 
[Male, Female] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each treatment group in the induction phase and in the 
consolidated treatment groups in the induction phase. 
(1) 
Frequency distributions for categorical variables and 
summary statistics for continuous variables 
 
1.1.3 Subject Eligibility 
Analysis set: 
Subjects who achieved CDAI-70 response at Week 10 
Analysis variables: 
Eligibility for entering into the 
maintenance phase 
[Eligible, Not eligible] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by treatment group in the induction phase. 
 
(1) 
Frequency distributions 
 
1.1.4 Number of Subjects Who Entered in the Maintenance Phase by Site 
Analysis set: 
All subjects who entered in the maintenance phase 
Analysis variables: 
Eligibility for entering into the 
maintenance phase 
[Eligible] 
Stratum:  
Study site 
[Site numbers will be used as 
categories] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables for each stratum by each “treatment group in the 
maintenance phase and subjects in the placebo continuation group” 
and in the consolidated “treatment groups in the maintenance phase 
and subjects in the placebo continuation group.” 
 
(1) 
Frequency distributions 


 
21 
 
 
1.1.5 Disposition of Subjects 
1.1.5.1 
Disposition of Subjects 
Analysis set: 
All subjects who entered in the maintenance phase 
Analysis variables: 
Study drug administration status in 
the maintenance phase 
[Not treated] 
 
Reason for not being treated 
[Pretreatment event/Adverse 
event, Major protocol 
deviation, Lost to follow-up, 
Voluntary withdrawal, Study 
termination, Pregnancy, 
Lack of efficacy, Other] 
 
Study drug completion status in the 
maintenance phase 
[Completed, Incompleted] 
 
Reason for not being completed 
[Pretreatment event/Adverse 
event, Major protocol 
deviation, Lost to follow-up, 
Voluntary withdrawal, Study 
termination, Pregnancy, 
Lack of efficacy, Other] 
 
Study visit completion status in the 
maintenance phase 
[Completed, Incompleted] 
 
Reason for not being completed 
[Pretreatment event/Adverse 
event, Major protocol 
deviation, Lost to follow-up, 
Voluntary withdrawal, Study 
termination, Pregnancy, 
Lack of efficacy, Other] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each “treatment group in the maintenance phase and 
subjects in the placebo continuation group” and in the consolidated 
“treatment groups in the maintenance phase and subjects in the 
placebo continuation group.” When calculating the percentages of 
the reasons for not being treated, the number of subjects who did not 
receive the study drug in the maintenance phase will be used as the 
denominator. When calculating the percentages of the reasons for 
not being completed, the number of subjects who did not complete 
the study drug/study visit in the maintenance phase will be used as 
the denominator. 
 
(1) 
Frequency distributions 
 
1.1.6 Study Drug Completion Status and Study Visit Completion Status 
Analysis set: 
All subjects who entered in the maintenance phase 
Analysis variables: 
Study drug completion status in the 
maintenance phase 
[Completed, Incompleted] 


 
22 
 
 
Reason for not being completed 
[Pretreatment event/Adverse 
event, Major protocol 
deviation, Lost to follow-up, 
Voluntary withdrawal, Study 
termination, Pregnancy, 
Lack of efficacy, Other] 
 
Study visit completion status in the 
maintenance phase 
[Completed, Incompleted] 
 
Reason for not being completed 
[Pretreatment event/Adverse 
event, Major protocol 
deviation, Lost to follow-up, 
Voluntary withdrawal, Study 
termination, Pregnancy, 
Lack of efficacy, Other] 
Categories: 
Duration of study drug exposure in 
the maintenance phase (days) 
[0, 1≤ - ≤56, 57≤ - ≤112, 
113≤ - ≤168, 169≤ - ≤224, 
225≤ - ≤280, 281≤ - ≤336, 
337≤ - ≤392, 393≤ - ≤Max] 
 
Duration on study after the first dose 
of the study drug in the maintenance 
phase (days) 
[0, 1≤ - ≤56, 57≤ - ≤112, 
113≤ - ≤168, 169≤ - ≤224, 
225≤ - ≤280, 281≤ - ≤336, 
337≤ - ≤392, 393≤ - ≤Max] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each “treatment group in the maintenance phase and 
subjects in the placebo continuation group” and in the consolidated 
“treatment groups in the maintenance phase and subjects in the 
placebo continuation group.” 
Frequency distributions will be provided for study drug completion 
status in the maintenance phase in the analysis of (1). Frequency 
distributions will be provided for study visit completion status in the 
maintenance phase in the analysis of (2). 
 
(1) Frequency distribution by duration of study drug exposure in 
the maintenance phase 
(2) Frequency distribution by duration on study after the first dose 
of the study drug in the maintenance phase 
 
1.1.7 Protocol Deviations and Analysis Sets 
1.1.7.1 
Protocol Deviations in the Maintenance Phase 
Analysis set: 
All subjects who entered in the maintenance phase 
Analysis variables: 
Protocol deviations in the 
maintenance phase 
[Major GCP violations, Deviations of 
protocol entry criteria, Deviations of 
discontinuation criteria, Deviations 
related to treatment procedure or dose, 
Deviations concerning excluded 
medication or therapy, Deviations to 
avoid emergency risk, Other] 


 
23 
 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each “treatment group in the maintenance phase and 
subjects in the placebo continuation group” and in the consolidated 
“treatment groups in the maintenance phase and subjects in the 
placebo continuation group.” 
Frequency distribution of subjects with protocol deviations in the 
maintenance phase will be provided for each deviation category 
above. A subject who has several deviations that can be classified 
into the same category will be counted once in each appropriate 
category (overlapped counting). 
(1) Frequency distributions 
 
1.1.7.2 
Analysis Sets of All Subjects Randomized in the Maintenance Phase 
Analysis set: 
All subjects randomized in the maintenance phase 
Analysis variables: 
Handling of subjects and subject 
data in the maintenance phase in 
analysis sets 
Inclusion/Exclusion of analysis sets 
Full analysis set in the 
maintenance phase 
Per protocol set in the 
maintenance phase 
[Categories are based on the 
specifications in “Handling 
Rules for Analysis Data”] 
 
[Included] 
 
[Included] 
Analysis methodology: The following analyses of (1) and (2) will be performed for the 
above analysis variables by treatment group in the maintenance 
phase and the following analysis of (3) will be performed by 
treatment group in the maintenance phase and in the consolidated 
treatment groups in the maintenance phase. 
A subject who corresponds to several categories in (1) and (2) will 
be counted once in each appropriate category (overlapped counting). 
 
(1) 
Frequency distributions concerning the handling of subjects in 
the maintenance phase in each analysis set 
(2) 
Frequency distributions concerning the handling of subject 
data in the maintenance phase in each analysis set 
(3) 
Frequency distributions concerning the number of subjects 
included in each analysis set 
 
1.1.7.3 Analysis Sets of All Subjects Who Entered in the Maintenance Phase 
Analysis set: 
All subjects who entered in the maintenance phase 
Analysis variables: 
Handling of subjects and subject 
data in the maintenance phase in 
analysis sets 
Inclusion/Exclusion of analysis sets 
Safety analysis set in the 
maintenance phase 
[Categories are based on the 
specifications in “Handling 
Rules for Analysis Data”] 
 
[Included] 


 
24 
 
Analysis methodology: The following analyses of (1) and (2) will be performed for the 
above analysis variables by each “treatment group in the 
maintenance phase and subjects in the placebo continuation group” 
and the following analysis of (3) will be performed by each 
“treatment group in the maintenance phase and subjects in the 
placebo continuation group” and in the consolidated “treatment 
groups in the maintenance phase and subjects in the placebo 
continuation group.” 
A subject who corresponds to several categories in (1) and (2) will 
be counted once in each appropriate category (overlapped counting). 
 
(1) 
Frequency distributions concerning the handling of subjects in 
the maintenance phase in the analysis set 
(2) 
Frequency distributions concerning the handling of subject 
data in the maintenance phase in the analysis set 
(3) 
Frequency distributions concerning the number of subjects 
included in the analysis set 
 
1.2 Demographic and Other Baseline Characteristics 
1.2.1 Distribution of Baseline Demographics 
Analysis set: 
All subjects who entered in the maintenance phase 
Analysis variables: 
Age (years) 
[Min≤ - ≤34, 35≤ - ≤Max] 
 
 
[Min≤ - ≤64, 65≤ - ≤Max] 
 
Gender 
[Male, Female] 
 
Height (cm) 
 
 
Weight (kg) at baseline 
[Min≤ - ≤49.9, 50.0≤ - ≤59.9, 
60.0≤ - ≤69.9, 70.0≤ - ≤79.9, 
80.0≤ - ≤Max] 
 
BMI (kg/m2) at baseline 
[Min≤ - ≤18.4, 18.5≤ - ≤24.9, 
25.0≤ - ≤Max] 
 
Smoking classification 
[Never smoked, Current 
smoker, Ex-smoker] 
 
Duration of CD (years) 
[Min≤ - <1, 1≤ - <3, 3≤ - <7, 
7≤ - ≤Max, Missing] 
 
Prior corticosteroids failure 
[Yes, No] 
 
Classification 1 of prior 
corticosteroids failure 
[Resistance, Dependence, 
Intolerance] 
 
Classification 2 of prior 
corticosteroids failure 
[Refractory, Intolerance] 
 
Prior immunomodulators failure 
[Yes, No] 
 
Classification of prior 
immunomodulators failure 
[Refractory, Intolerance] 
 
Prior TNFα antagonist failure 
[Yes, No] 
 
Number of drugs of TNFα 
antagonist failure 
[1 drug, 2 drugs, 3 drugs, 
None] 
 
Classification of prior TNFα 
antagonist failure 
[Inadequate response, Loss 
of response, Intolerance] 


 
25 
 
 
Worst prior treatment failures 
[Prior TNFα antagonist 
failure, Prior 
immunomodulators failure 
but not TNFα antagonist 
failure, Prior corticosteroids 
failure only] 
 
Prior immunomodulators and TNFα 
antagonist failure 
[Yes, No] 
 
Prior TNFα antagonist use 
[Yes, No] 
 
Infliximab 
[Yes, No] 
 
Adalimumab 
[Yes, No] 
 
Golimumab 
[Yes, No] 
 
Concomitant use of enteral nutrient 
at baseline 
[Yes, No] 
 
Concomitant use of 5-ASA at 
baseline 
[Yes, No] 
 
Concomitant use of 
immunomodulators at baseline 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids at baseline 
[Yes, No] 
 
No concomitant use of oral 
corticosteroids and No concomitant 
use of immunomodulators at 
baseline 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids and No concomitant 
use of immunomodulators at 
baseline (concomitant use of oral 
corticosteroids only) 
[Yes, No] 
 
No concomitant use of oral 
corticosteroids and Concomitant use 
of immunomodulators at baseline 
(concomitant use of 
immunomodulators only) 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids and Concomitant use 
of immunomodulators at baseline 
[Yes, No] 
 
CDAI score at baseline 
[Min≤ - ≤220, 220< - ≤330, 
330< - ≤450, 450< - ≤Max] 
 
CDAI score at Week 10 
[Min≤ - ≤150, 150< - ≤220, 
220< - ≤330, 330< - ≤450, 
450< - ≤Max] 
 
CDAI-70 response at Week 10 
[CDAI-70 response, 
Non-CDAI-70 response] 
 
CDAI-100 response at Week 10 
[CDAI-100 response, 
Non-CDAI-100 response] 


 
26 
 
 
Clinical remission at Week 10 
[Clinical remission, 
Non-remission] 
 
CDAI subscore (1): Number of 
liquid or very soft stools during the 
last 1 week at baseline 
 
 
CDAI subscore (2): Abdominal pain 
during the last 1 week at baseline 
 
 
CDAI subscore (3): Subjective 
general well being during the last 1 
week at baseline 
 
 
CDAI subscore (4): Current number 
of extraintestinal manifestations of 
CD (e.g., arthritis/arthralgia) at 
baseline 
[0, 1, 2, 3, 4, 5, 6] 
 
CDAI subscore (5): Use of 
antidiarrheal drugs (e.g., lopemin) or 
opiates for diarrhea at baseline 
[No, Yes] 
 
CDAI subscore (6): Abdominal 
mass at baseline 
[None, Questionable, 
Definite] 
 
CDAI subscore (7): Hematocrit 
level at baseline 
 
 
CDAI subscore (8): Body weight : 
Standard weight (body-weight ratio) 
at baseline 
 
 
Disease localization 
[Small intestinal, Large 
intestinal, Small/Large 
intestinal] 
 
Concurrent extraintestinal 
manifestations (based on CDAI 
subscore [4]) 
[Yes, No] 
 
Concurrent extraintestinal 
manifestations (based on CRF 
concurrent medical condition 
section) 
[Yes, No] 
 
CRP (mg/dL) at baseline 
[Min≤ - ≤0.3, 0.3< - ≤0.5, 
0.5< - ≤1.0, 1.0< - ≤1.6, 
1.6< - ≤Max] 
 
Surgical history for CD 
[Yes, No] 
 
Medical history of fistula or 
concurrent medical condition related 
to fistula within 1 year before 
signing of informed consent 
[Yes, No] 
 
Concurrent medical condition 
related to fistula 
[Yes, No] 
 
Number of the study drug infusions 
in the induction phase 
[1, 2, 3] 


 
27 
 
 
Clinical remission at Week 10 
(based on the CDAI scores 
calculated using the Ht level at each 
study site) 
[Clinical remission, 
Non-remission] 
 
Concomitant use of oral 
corticosteroids at Week 10 
[Yes, No] 
 
Oral corticosteroid dosage (mg/day) 
at Week 10 
[0< - ≤10, 10< - ≤Max] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each “treatment group in the maintenance phase and 
subjects in the placebo continuation group” and in the consolidated 
“treatment groups in the maintenance phase and subjects in the 
placebo continuation group.” The similar analysis will be performed 
with stratification according to “prior TNFα antagonist use.” 
(1) Frequency distributions for categorical variables and summary 
statistics for continuous variables 
 
1.2.2 Medical History, Concurrent Medical Conditions 
Analysis set: 
Safety analysis set in the maintenance phase 
Analysis variables: 
Medical history 
 
Concurrent medical conditions (concurrent extraintestinal 
manifestations of CD) 
 
Concurrent medical conditions (other than concurrent extraintestinal 
manifestations of CD) 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each “treatment group in the maintenance phase and 
subjects in the placebo continuation group” and in the consolidated 
“treatment groups in the maintenance phase and subjects in the 
placebo continuation group.” 
The analysis variables will be coded by use of MedDRA and will be 
summarized based on the SOC and PT. SOC will be sorted 
alphabetically and PT will be sorted in decreasing frequency. 
(1) Frequency distributions for medical history (by SOC and PT) 
(2) Frequency distributions for concurrent medical conditions 
(concurrent extraintestinal manifestations of CD) (by SOC and 
PT) 
(3) Frequency distributions for concurrent medical conditions 
(other than concurrent extraintestinal manifestations of CD) (by 
SOC and PT) 
 
The method of counting events when providing each frequency 
distribution will be as follows: 
[Number of subjects] 
A subject with multiple occurrences of medical history or 
concurrent medical condition within a SOC will be counted only 
once in that SOC. A subject with multiple occurrences of medical 
history or concurrent medical condition within a PT will be 
counted only once in that PT. 


 
28 
 
 
1.2.3 Medication History, Concomitant Medications in the Maintenance Phase, Concomitant 
Therapies in the Maintenance Phase 
Analysis set: 
Safety analysis set in the maintenance phase 
Analysis variables: 
Medication history 
 
 
Concomitant medications (for treatment of 
CD) in the maintenance phase 
 
 
Classification of concomitant medications 
(for treatment of CD) in the maintenance 
phase 
[5-ASA, 
Corticosteroids, 
Immunomodulators, 
Enteral nutrients, 
Other] 
 
Concomitant medications (for treatment of 
CD) in the maintenance phase that fall 
under the category of rescue treatments 
 
 
Classification of concomitant medications 
(for treatment of CD) in the maintenance 
phase that fall under the category of rescue 
treatments 
[5-ASA, 
Corticosteroids, 
Immunomodulators, 
Enteral nutrients, 
Other] 
 
Concomitant medications (for other than 
treatment of CD) in the maintenance phase 
 
 
Concomitant therapies in the maintenance 
phase 
[Yes, No] 
 
Concomitant therapies in the maintenance 
phase that fall under the category of rescue 
treatments 
[Yes, No] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each “treatment group in the maintenance phase and 
subjects in the placebo continuation group” and in the consolidated 
“treatment groups in the maintenance phase and subjects in the 
placebo continuation group.” 
Medication history, concomitant medications (for treatment of CD) 
in the maintenance phase, concomitant medications (for treatment of 
CD) in the maintenance phase that fall under the category of rescue 
treatments, and concomitant medications (for other than treatment of 
CD) in the maintenance phase will be coded by use of WHO Drug 
and summarized based on Preferred Name, which will be sorted in 
decreasing frequency. 
A subject who has been administered several medications with the 
same Preferred Name will be counted only once for that Preferred 
Name. 
(1) Frequency distributions for medication history 
(2) Frequency distributions for concomitant medications (for 
treatment of CD) in the maintenance phase that were ongoing 
at the first dose of the study drug in the maintenance phase and 
continued in the maintenance phase, and concomitant 


 
29 
 
medications (for treatment of CD) in the maintenance phase 
that started after the first dose of the study drug in the 
maintenance phase by category 
(3) Frequency distributions for concomitant medications (for 
treatment of CD) in the maintenance phase that fall under the 
category of rescue treatments, were ongoing at the first dose of 
the study drug in the maintenance phase and continued in the 
maintenance phase, and concomitant medications (for treatment 
of CD) in the maintenance phase that fall under the category of 
rescue treatments and started after the first dose of the study 
drug in the maintenance phase by category 
(4) Frequency distributions for concomitant medications (for other 
than treatment of CD) in the maintenance phase that were 
ongoing at the first dose of the study drug in the maintenance 
phase and continued in the maintenance phase, and 
concomitant medications (for other than treatment of CD) in 
the maintenance phase that started after the first dose of the 
study drug in the maintenance phase 
(5) Frequency distributions for presence or absence of concomitant 
therapies in the maintenance phase that were ongoing at the 
first dose of the study drug in the maintenance phase and 
continued in the maintenance phase, and concomitant therapies 
in the maintenance phase that started after the first dose of the 
study drug in the maintenance phase 
(6) Frequency distributions for presence or absence of concomitant 
therapies in the maintenance phase that fall under the category 
of rescue treatments, were ongoing at the first dose of the study 
drug in the maintenance phase and continued in the 
maintenance phase, and concomitant therapies in the 
maintenance phase that fall under the category of rescue 
treatments and started after the first dose of the study drug in 
the maintenance phase 
 
1.3 Measurement of Compliance Status for Treatment 
1.3.1 Study Drug Exposure and Compliance in the Maintenance Phase 
Analysis set: 
Safety analysis set in the maintenance phase 
Analysis variables: 
Duration of study drug exposure in the 
maintenance phase (days) 
[1≤ - ≤56,  
57≤ - ≤112,  
113≤ - ≤168, 
169≤ - ≤224, 
225≤ - ≤280, 
281≤ - ≤336, 
337≤ - ≤392, 
393≤ - ≤Max] 
 
Duration on study after the first dose of the 
study drug in the maintenance phase (days) 
[1≤ - ≤56,  
57≤ - ≤112,  
113≤ - ≤168, 


 
30 
 
169≤ - ≤224, 
225≤ - ≤280, 
281≤ - ≤336, 
337≤ - ≤392, 
393≤ - ≤Max] 
 
Number of the study drug infusion in the 
maintenance phase (times) 
[1, 2, 3, 4, 5, 6] 
 
Number of completed infusions of the study 
drug in the maintenance phase (times) 
[0, 1, 2, 3, 4, 5, 6] 
 
Number of completed or incompleted infusions 
in total infusions in the maintenance phase 
[Completed, 
Incompleted] 
Analysis methodology: 
 
The following analysis will be performed for the above analysis 
variables by each “treatment group in the maintenance phase and 
subjects in the placebo continuation group” and in the consolidated 
“treatment groups in the maintenance phase and subjects in the 
placebo continuation group.” 
(1) Frequency distributions for categorical variables and summary 
statistics for continuous variables 
 
In the frequency distributions for number of completed or 
incompleted infusions in total infusions in the maintenance phase, 
the sum of the number of completed infusions in the maintenance 
phase in the applicable treatment group will be counted as frequency 
for “Completed” and the sum of the number of incompleted 
infusions will be counted as frequency for “Incompleted.” When 
calculating the percentage, the sum of the number of completed 
infusions and the number of incompleted infusions (i.e., number of 
total infusions in the maintenance phase) will be used as the 
denominator. 
 


 
31 
 
2 EFFICACY ANALYSIS 
The “full analysis set in the maintenance phase” based on the specifications in the protocol and the 
“Handling Rules for Analysis Data” will be the main analysis set. From sensitivity point of view, the 
“per protocol set in the maintenance phase” will be used for an analysis performed secondarily on 
the primary endpoint in order to examine the robustness of the results. 
 
2.1 Primary Endpoints and Analysis Methodology 
2.1.1 Primary Analysis 
Analysis set: 
Full analysis set in the maintenance phase 
Analysis variables: 
Clinical remission at Week 60 
[Clinical remission, 
Non-remission] 
Stratum:  
Prior TNFα antagonist use 
[Yes, No] 
Analysis methodology: 
 
The following analysis will be performed in the “full analysis set in 
the maintenance phase.” 
Frequency distributions will be provided for “clinical remission at 
Week 60” (the primary endpoint of the maintenance phase) by 
treatment group in the maintenance phase along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the proportion 
between treatment groups (MLN0002 group − placebo group) will 
be also calculated. The similar calculation will be performed with 
stratification according to the “prior TNFα antagonist use.” The 
Pearson’s chi-square test will be performed to calculate the odds 
ratio of the MLN0002 group to the placebo group (MLN0002 
group/placebo group) and the 95% two-sided CI for reference. 
 
2.1.2 Secondary Analysis 
Analysis set: 
Per protocol set in the maintenance phase 
Analysis variables: 
Clinical remission at Week 60 
[Clinical remission, 
Non-remission] 
Stratum:  
Prior TNFα antagonist use 
[Yes, No] 
Analysis methodology: 
 
From sensitivity point of view, the following analysis will be 
performed to examine the robustness of the results. 
(1) 
The clinical remission at Week 60 will be analyzed in the 
same manner as those in the primary analysis in 2.1.1 in the 
“per protocol set in the maintenance phase.” 
 
2.2 Secondary Endpoints and Analysis Methodology 
Analysis set: 
Full analysis set in the maintenance phase 
Subjects who were receiving oral corticosteroids concomitantly at 
baseline in the full analysis set in the maintenance phase 
Analysis variables: 
CDAI-100 response at Week 60 
[CDAI-100 response, 
Non-CDAI-100 
response] 
 
Durable remission in the maintenance 
phase 
[Durable remission, 
Non-durable remission] 


 
32 
 
 
Corticosteroid-free remission at Week 60 
[Corticosteroid-free 
remission, 
Non-corticosteroid-free 
remission] 
Stratum:  
Prior TNFα antagonist use 
[Yes, No] 
Analysis 
methodology: 
The following analysis will be performed for the above analysis 
variables by treatment group in the maintenance phase. 
Corticosteroid-free remission at Week 60 will be analyzed in “subjects 
who were receiving corticosteroids concomitantly at baseline in the 
full analysis set in the maintenance phase.” All other variables will be 
analyzed in the “full analysis set in the maintenance phase.” 
 
(1) Frequency distributions will be provided for each analysis 
variable along with the point estimate and 95% two-sided CI for 
the proportion. The point estimate and 95% two-sided CI for the 
difference in the proportion between treatment groups (MLN0002 
group − placebo group) will be also calculated. 
 
(2) Frequency distributions will be provided for each analysis 
variable with stratification according to “prior TNFα antagonist 
use” along with the point estimate and 95% two-sided CI for the 
proportion. The point estimate and 95% two-sided CI for the 
difference in the proportion between treatment groups (MLN0002 
group − placebo group) will be also calculated. 
 
(3) The Pearson’s chi-square test will be performed to calculate the 
odds ratio of the MLN0002 group to the placebo group 
(MLN0002 group/placebo group) and the 95% two-sided CI. 
 
2.3 Other Endpoints and Analysis Methodology 
2.3.1 Endpoints Related to CDAI Scores 
Analysis set: 
Full analysis set in the maintenance phase 
Analysis variables: 
Clinical remission 
[Clinical remission, 
Non-remission] 
 
CDAI-100 response 
[CDAI-100 response, 
Non-CDAI-100 
response] 
 
CDAI-70 response 
[CDAI-70 response, 
Non-CDAI-70 
response] 
 
Durable CDAI-100 response in the 
maintenance phase 
[Durable CDAI-100 
response, 
Non-durable 
CDAI-100 response] 
 
Durable CDAI-70 response in the 
maintenance phase 
[Durable CDAI-70 
response, 
Non-durable 
CDAI-70 response] 
 
Clinical remission at Week 60 in the 
subpopulation of subjects without prior 
[Clinical remission, 
Non-remission] 


 
33 
 
TNFα antagonist use and in the 
subpopulation of subjects who failed with a 
TNFα antagonist 
 
 
Clinical remission at Week 60 in the 
subpopulation of subjects who failed with a 
corticosteroid monotherapy and an 
immunomodulator (except those failed 
with a TNFα antagonist) 
[Clinical remission, 
Non-remission] 
 
CDAI score change over time 
 
 
Each CDAI subscore change over time 
 
 
Change from Week 10 in CDAI score over 
time 
 
 
Change from Week 10 in each CDAI 
subscore over time 
 
Visit: 
Weeks 0, 2, 6, 10, 14, 22, 30, 38, 46, 54, and 60 (clinical remission, 
CDAI-100 response, and CDAI-70 response) 
 
Weeks 0, 2, 6, 10, 14, 22, 30, 38, 46, 54, 60, and Week 60 (LOCF) 
(CDAI score and each CDAI subscore) 
 
Week 60 (durable CDAI-100 response in the maintenance phase and 
durable CDAI-70 response in the maintenance phase) 
 
Weeks 2, 6, 10, 14, 22, 30, 38, 46, 54, 60, and Week 60 (LOCF) 
(change from baseline in CDAI score and change from baseline in 
each CDAI subscore) 
 
Weeks 14, 22, 30, 38, 46, 54, 60, and Week 60 (LOCF) (change 
from Week 10 in CDAI score and change from Week 10 in each 
CDAI subscore) 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by treatment group in the maintenance phase. 
 
(1) Frequency distributions will be provided for clinical remission 
at each visit along with the point estimate and 95% two-sided 
CI for the proportion. The point estimate and 95% two-sided CI 
for the difference in the proportion between treatment groups 
(MLN0002 group − placebo group) will be also calculated. 
 
(2) Frequency distributions will be provided for clinical remission 
at each visit with stratification according to “prior TNFα 
antagonist use” along with the point estimate and 95% 
two-sided CI for the proportion. The point estimate and 95% 
two-sided CI for the difference in the proportion between 
treatment groups (MLN0002 group − placebo group) will be 
also calculated. 
 
(3) The Pearson’s chi-square test will be performed for clinical 
remission at each visit to calculate the odds ratio of the 
MLN0002 group to the placebo group (MLN0002 
group/placebo group) and the 95% two-sided CI. 
 
(4) The same analysis as (1) will be performed for the CDAI-100 
response at each visit. 
 
(5) The same analysis as (2) will be performed for CDAI-100 


 
34 
 
response at each visit with stratification according to “prior 
TNFα antagonist use.” 
 
(6) The same analysis as (3) will be performed for the CDAI-100 
response at each visit. 
 
(7) The same analysis as (1) will be performed for the CDAI-70 
response at each visit. 
 
(8) The same analysis as (2) will be performed for CDAI-70 
response at each visit with stratification according to “prior 
TNFα antagonist use.” 
 
(9) The same analysis as (3) will be performed for the CDAI-70 
response at each visit. 
 
(10) The same analysis as (1) will be performed for the durable 
CDAI-100 response in the maintenance phase. 
 
(11) The same analysis as (2) will be performed for the durable 
CDAI-100 response in the maintenance phase with 
stratification according to “prior TNFα antagonist use.” 
 
(12) The same analysis as (3) will be performed for the durable 
CDAI-100 response in the maintenance phase. 
 
(13) The same analysis as (1) will be performed for the durable 
CDAI-70 response in the maintenance phase. 
 
(14) The same analysis as (2) will be performed for the durable 
CDAI-70 response in the maintenance phase with stratification 
according to “prior TNFα antagonist use.” 
 
(15) The same analysis as (3) will be performed for the durable 
CDAI-70 response in the maintenance phase. 
 
(16) The same analysis as (1) will be performed for clinical 
remission at each visit in the subpopulation of subjects without 
prior TNFα antagonist use. 
 
(17) The same analysis as (1) will be performed for clinical 
remission at each visit in the subpopulation of subjects who 
failed with a TNFα antagonist. 
 
(18) The same analysis as (1) will be performed for clinical 
remission at each visit in the subpopulation of subjects who 
failed with a corticosteroid monotherapy. 
 
(19) The same analysis as (1) will be performed for clinical 
remission at each visit in the subpopulation of subjects who 
failed with an immunomodulator (except those failed with a 
TNFα antagonist). 
 
(20) Summary statistics and the 95% two-sided CI of the mean will 
be provided for the CDAI scores at each visit along with the 
plot over time. Summary statistics and the 95% two-sided CI of 
the mean will be calculated for the CDAI scores at each visit 
with stratification according to “prior TNFα antagonist use.” 
 
(21) Summary statistics and the 95% two-sided CI of the mean will 
be provided for changes from baseline in the CDAI scores at 
each visit along with the plot over time. Summary statistics and 
the 95% two-sided CI of the mean will be calculated for 


 
35 
 
changes from baseline in the CDAI scores at each visit with 
stratification according to “prior TNFα antagonist use.” 
 
(22) The point estimate and 95% two-sided CI for the difference in 
the least square (LS) mean between treatment groups 
(MLN0002 group − placebo group) will be calculated based on 
the analysis of covariance (ANCOVA) model with change from 
baseline in the CDAI score at Week 60 (LOCF) as a response, 
the treatment group in the maintenance phase as a factor, and 
CDAI score at baseline as a covariate. 
 
(23) The same analysis as (20) will be performed for each CDAI 
subscore at each visit. 
 
(24) The same analysis as (21) will be performed for changes from 
baseline in each CDAI subscore at each visit. 
 
(25) The same analysis as (21) will be performed for changes from 
Week 10 in CDAI score at each visit. 
 
(26) The point estimate and 95% two-sided CI for the difference in 
the LS mean between treatment groups (MLN0002 group − 
placebo group) will be calculated based on the ANCOVA 
model with change from Week 10 in the CDAI score at Week 
60 (LOCF) as a response, the treatment group in the 
maintenance phase as a factor, and CDAI score at Week 10 as a 
covariate. 
 
(27) The same analysis as (21) will be performed for changes from 
Week 10 in each CDAI subscore at each visit. 
 
2.3.2 Endpoints Related to CDAI Scores Based on the Hematocrit Level at Each Study Site 
Analysis set: 
Full analysis set in the maintenance phase 
Analysis variables: 
Clinical remission 
[Clinical remission, 
Non-remission] 
 
CDAI-100 response 
[CDAI-100 response, 
Non-CDAI-100 
response] 
 
CDAI-70 response 
[CDAI-70 response, 
Non-CDAI-70 
response] 
 
Durable remission in the maintenance 
phase 
[Durable remission, 
Non-durable 
remission] 
 
Durable CDAI-100 response in the 
maintenance phase 
[Durable CDAI-100 
response, 
Non-durable 
CDAI-100 response] 
 
Durable CDAI-70 response in the 
maintenance phase 
[Durable CDAI-70 
response, 
Non-durable 
CDAI-70 response] 
 
CDAI score change over time 
 


 
36 
 
 
Each CDAI subscore change over time 
 
Visit: 
Weeks 0, 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, and 
60 (clinical remission, CDAI-100 response, and CDAI-70 response) 
 
Weeks 0, 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 60, 
and Week 60 (LOCF) (CDAI score and each CDAI subscore) 
 
Weeks 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 60, and 
Week 60 (LOCF) (change from baseline in CDAI score, change 
from baseline in each CDAI subscore) 
 
Week 60 (durable remission in the maintenance phase, durable 
CDAI-100 response in the maintenance phase, and durable CDAI-70 
response in the maintenance phase) 
Analysis methodology: Each analysis variable will be determined using the CDAI score 
based on the Ht level at each study site and CDAI subscores. 
The following analysis will be performed for the above analysis 
variables by treatment group in the maintenance phase. 
 
(1) Frequency distributions will be provided for clinical remission 
at each visit along with the point estimate and 95% two-sided 
CI for the proportion. The point estimate and 95% two-sided CI 
for the difference in the proportion between treatment groups 
(MLN0002 group − placebo group) will be also calculated. 
 
(2) Frequency distributions will be provided for clinical remission 
at each visit with stratification according to “prior TNFα 
antagonist use” along with the point estimate and 95% 
two-sided CI for the proportion. The point estimate and 95% 
two-sided CI for the difference in the proportion between 
treatment groups (MLN0002 group − placebo group) will be 
also calculated. 
 
(3) The Pearson’s chi-square test will be performed for clinical 
remission at each visit to calculate the odds ratio of the 
MLN0002 group to the placebo group (MLN0002 
group/placebo group) and the 95% two-sided CI. 
 
(4) The same analysis as (1) will be performed for the CDAI-100 
response at each visit. 
 
(5) The same analysis as (2) will be performed for CDAI-100 
response at each visit with stratification according to “prior 
TNFα antagonist use.” 
 
(6) The same analysis as (3) will be performed for the CDAI-100 
response at each visit. 
 
(7) The same analyses as (1), (2), and (3) will be performed for the 
CDAI-70 response, durable remission in the maintenance 
phase, durable CDAI-100 response in the maintenance phase, 
and the durable CDAI-70 response in the maintenance phase 
respectively. 
 
(8) Summary statistics and the 95% two-sided CI of the mean will 
be provided for the CDAI scores at each visit along with the 
plot over time. Summary statistics and the 95% two-sided CI of 
the mean will be calculated for the CDAI scores at each visit 


 
37 
 
with stratification according to “prior TNFα antagonist use.” 
 
(9) Summary statistics and the 95% two-sided CI of the mean will 
be provided for changes from baseline in the CDAI scores at 
each visit along with the plot over time. Summary statistics and 
the 95% two-sided CI of the mean will be calculated for 
changes from baseline in the CDAI scores at each visit with 
stratification according to “prior TNFα antagonist use.” 
 
(10) The point estimate and 95% two-sided CI for the difference in 
the LS mean between treatment groups (MLN0002 group − 
placebo group) will be calculated based on the ANCOVA 
model with change from baseline in the CDAI score at Week 
60 (LOCF) as a response, the treatment group in the 
maintenance phase as a factor, and CDAI score at baseline as a 
covariate. 
 
(11) The same analysis as (8) will be performed for each CDAI 
subscore at each visit. 
 
(12) The same analysis as (9) will be performed for changes from 
baseline in each CDAI subscore at each visit. 
 
2.3.3 Endpoints Related to CRP 
Analysis set: 
Full analysis set in the maintenance phase 
Analysis variables: 
CRP Level 
 
 
CRP Level (within the reference range) 
[Yes, No] 
Visit: 
Weeks 0, 2, 6, 10, 14, 22, 30, 38, 46, 54, 60, and Week 60 (LOCF) 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by treatment group in the maintenance phase. 
 
(1) Summary statistics and the 95% two-sided CI of the mean will 
be calculated for CRP level at each visit. Summary statistics, 
the 95% two-sided CI of the mean, and the 10 and 90 
percentiles will be calculated for changes from baseline in CRP 
level at each visit (Week 2 to Week 60 [LOCF]). 
 
(2) The same analysis as (1) will be performed with stratification 
according to “prior TNFα antagonist use.” The Wilcoxon rank 
sum test will be performed for changes from baseline in CRP 
level at Week 60 (LOCF). 
 
(3) In the subpopulation of subjects with the baseline CRP level 
outside the reference range (>0.30 mg/dL), frequency 
distributions will be provided for subjects with CRP level 
within the reference range at each visit (Week 2 to Week 60 
[LOCF]) along with the point estimate and 95% two-sided CI 
for the proportion. The point estimate and 95% two-sided CI 
for the difference in the proportion between treatment groups 
(MLN0002 group − placebo group) will be calculated. The 
Pearson’s chi-square test will be also performed for the 
proportion of subjects whose CRP level at Week 60 (LOCF) is 
within the reference range.  
 
(4) The same analysis as (3) will be performed in the 


 
38 
 
subpopulation of subjects with the baseline CRP level of 
>0.5 mg/dL. 
 
(5) The same analysis as (3) will be performed in the 
subpopulation of subjects with the baseline CRP level of 
>1.0 mg/dL. 
 
2.3.4 Endpoints Related to IBDQ 
Analysis set: 
Full analysis set in the maintenance phase 
Analysis variables: 
IBDQ scores (total score and each subscore 
[abdominal symptoms, general condition, emotion, and 
social function]) 
 
 
Change from Week 14 in IBDQ score (total score and 
each subscore [abdominal symptoms, general 
condition, emotion, and social function]) 
 
 
Change from Week 10 in IBDQ score (total score and 
each subscore [abdominal symptoms, general 
condition, emotion, and social function]) 
 
 
Change from baseline in IBDQ score (total score and 
each subscore [abdominal symptoms, general 
condition, emotion, and social function]) 
 
 
IBDQ total score ≥170 
[Yes, No] 
 
Change from baseline in IBDQ total score ≥16 
[Yes, No] 
 
Change from Week 10 in IBDQ total score ≤-16 
[Yes, No] 
 
Time to -16 or lower in change from Week 10 in 
IBDQ total score 
 
Visit: 
Weeks 0, 10, 14, 38, 60, and Week 60 (LOCF) (IBDQ score) 
 
Weeks 38, 60, and Week 60 (LOCF) (change from Week 14 in 
IBDQ score) 
 
Weeks 14, 38, 60, and Week 60 (LOCF) (change from Week 10 in 
IBDQ score , and change from Week 10 in IBDQ total score ≤-16) 
 
Weeks 10, 14, 38, 60, and Week 60 (LOCF) (IBDQ total score 
≥170, change from baseline in IBDQ score, change from baseline in 
IBDQ total score ≥16, change from baseline in IBDQ total score 
≤16) 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by treatment group in the maintenance phase. 
 
(1) Summary statistics and the 95% two-sided CI of the mean will 
be calculated for IBDQ total score and each subscore 
(abdominal symptoms, general condition, emotion, and social 
function) at each visit. 
 
(2) Summary statistics and the 95% two-sided CI of the mean will 
be calculated for changes from Week 14 in IBDQ total score 
and each subscore (abdominal symptoms, general condition, 
emotion, and social function) at each visit. 
 
(3) The point estimate and 95% two-sided CI for the difference in 
the LS mean between treatment groups (MLN0002 group − 
placebo group) will be calculated based on the ANCOVA 


 
39 
 
model with change from Week 14 in IBDQ total score and each 
subscore (abdominal symptoms, general condition, emotion, 
and social function) at Week 60 (LOCF) as a response, the 
treatment group in the maintenance phase as a factor, and Week 
14 value that corresponds to the score used as response as a 
covariate. 
 
(4) Summary statistics and the 95% two-sided CI of the mean will 
be calculated for changes from Week 10 in IBDQ total score 
and each subscore (abdominal symptoms, general condition, 
emotion, and social function) at each visit. 
 
(5) The point estimate and 95% two-sided CI for the difference in 
the LS mean between treatment groups (MLN0002 group − 
placebo group) will be calculated based on the ANCOVA 
model with change from Week 10 in IBDQ total score and each 
subscore (abdominal symptoms, general condition, emotion, 
and social function) at Week 60 (LOCF) as a response, the 
treatment group in the maintenance phase as a factor, and Week 
10 value that corresponds to the score used as response as a 
covariate. 
 
(6) Summary statistics and the 95% two-sided CI of the mean will 
be calculated for changes from baseline in IBDQ total score 
and each subscore (abdominal symptoms, general condition, 
emotion, and social function) at each visit. 
 
(7) The point estimate and 95% two-sided CI for the difference in 
the LS mean between treatment groups (MLN0002 group − 
placebo group) will be calculated based on the ANCOVA 
model with change from baseline in IBDQ total score and each 
subscore (abdominal symptoms, general condition, emotion, 
and social function) at Week 60 (LOCF) as a response, the 
treatment group in the maintenance phase as a factor, and 
baseline value that corresponds to the score used as response as 
a covariate. 
 
(8) Frequency distributions will be provided for the proportion of 
subjects whose IBDQ total score at each visit is ≥170 in 
subjects whose IBDQ total score at baseline is <170 among the 
full analysis set in the maintenance phase along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be calculated. The Pearson’s chi-square test 
will be also performed at Week 60 (LOCF). 
 
(9) Frequency distributions will be provided for subjects whose 
IBDQ total score change from baseline is ≥16 and subjects 
whose IBDQ total score change from Week 10 is ≤-16 at each 
visit along with the point estimate and 95% two-sided CI for 
the proportions of subjects whose IBDQ total score change 
from baseline is ≥16 and subjects whose IBDQ total score 


 
40 
 
change from Week 10 is ≤-16 at each visit. The point estimate 
and 95% two-sided CI for the difference in each proportion 
between treatment groups (MLN0002 group − placebo group) 
at each visit will be calculated. The Pearson’s chi-square test 
will be also performed at Week 60 (LOCF). 
 
(10) The cumulative survival rate on the onset date of “change from 
Week 10 in IBDQ total score ≤-16” will be calculated and 
plotted by treatment group using the Kaplan-Meier method, and 
a log-rank test will be performed. The time to events (unit=day) 
will be summarized (25, 50, and 75 percentiles) and the CIs for 
25, 50, and 75 percentiles will be provided, respectively. Also, 
the cumulative survival rate of each event will be calculated at 
6 months (183 days) and 12 months (365 days). 
 
(11) For the time to -16 or lower in change from Week 10 in IBDQ 
total score, the hazard ratio of the MLN0002 group against the 
placebo group (MLN0002 group/placebo group) and the 95% 
two-sided CI will be calculated using the Cox regression model 
with treatment group as explanatory variable. 
 
2.3.5 Endpoints Related to Oral Corticosteroid Dosage 
Analysis set: 
Subjects who were receiving oral corticosteroids concomitantly at 
baseline in the full analysis set in the maintenance phase 
Analysis variables: 
Oral corticosteroid dosage 
 
 
Oral corticosteroid dosage change from Week 10 
 
Visit: 
Weeks 0, 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 60, 
and Week 60 (LOCF) (oral corticosteroid dosage) 
 
Weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 60, and Week 
60 (LOCF) (oral corticosteroid dosage change from Week 10) 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by treatment group in the maintenance phase. 
 
(1) Summary statistics and the 95% two-sided CI of the mean will 
be calculated for oral corticosteroid dosage at each visit. 
 
(2) Summary statistics and the 95% two-sided CI of the mean will 
be calculated for oral corticosteroid dosage change from Week 
10 at each visit, and also, the point estimate and 95% two-sided 
CI for the difference in the mean between treatment groups 
(MLN0002 group − placebo group) will be calculated. 
 
2.3.6 Endpoints Related to Time to Event 
Analysis set: 
Full analysis set in the maintenance phase 
Analysis variables: 
Time to disease worsening 
 
Time to treatment failure 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by treatment group in the maintenance phase. 
 
(1) The cumulative survival rate on the onset date of each event 
will be calculated and plotted by treatment group using the 
Kaplan-Meier method. The time to events (unit=day) will be 


 
41 
 
summarized (25, 50, and 75 percentiles) and the CIs for 25, 50, 
and 75 percentiles will be provided, respectively. Also, the 
cumulative survival rate of each event will be calculated at 6 
months (183 days) and 12 months (365 days). 
 
(2) The log-rank test will be performed. 
 
(3) The hazard ratio of the MLN0002 group against the placebo 
group (MLN0002 group/placebo group) and the 95% two-sided 
CI will be calculated using the Cox regression model with 
treatment group as independent variable. 
 
2.4 Statistical and Analytical Issues 
2.4.1 Adjustments for Covariates 
Covariate-adjusted analysis will not be performed for the maintenance phase because the 
sample size is too small for meaningful analysis. 
 
2.4.2 Handling of Dropouts or Missing Data 
The efficacy endpoints of clinical response or clinical remission will be considered as 
non-response or non-remission when adjudication for these endpoints is missing at the time of 
evaluation. 
For other endpoints, missing data, and ineligible data according to the “Handling Rules for 
Analysis Data” or the SAP will be excluded from statistical analyses and estimations. 
Values below the limit of quantification will be handled as 0. 
 
2.4.3 Interim Analyses and Data Monitoring 
No interim analyses will be performed for the induction and maintenance phases. 
For the open-label cohort, after the data obtained from all the subjects by the cut-off date for 
marketing authorization application is locked, the data up to the cut-off date for marketing 
authorization application will be analyzed. Continuation/termination of the study, change in 
clinical trial plan, and so on will not be judged based on the analysis. 
 
2.4.4 Multicenter Studies 
Although this is a multicenter study, interactions between treatment and study site will not be 
investigated since the target number of subjects per study site is not sufficiently large for 
meaningful analyses of the interactions. 
 
2.4.5 Multiple Comparisons/Multiplicity 
Not applicable. 
 
2.4.6 Use of an “Efficacy Subset” of Subjects 
To confirm the robustness of the primary analysis results for the primary endpoint from 
sensitivity point of view, the same analysis as for the “full analysis set in the maintenance 
phase” will be performed secondarily in the “per protocol set in the maintenance phase.” 
 
2.4.7 Active-Control Studies Intended to Show Equivalence or Non-inferiority 
Not applicable. 
 


 
42 
 
2.4.8 Examination of Subgroups 
Analysis set: 
Full analysis set in the maintenance phase 
Analysis variables: 
Clinical remission at Week 60 
[Clinical remission, 
Non-remission] 
Stratum:  
Age (years) 
[Min≤ - ≤34, 35≤ - ≤Max] 
 
 
[Min≤ - ≤64, 65≤ - ≤Max] 
 
Gender 
[Male, Female] 
 
Duration of CD (years) 
[Min≤ - <7, 7≤ - ≤Max] 
 
Prior corticosteroids failure 
[Yes, No] 
 
Prior immunomodulators failure 
[Yes, No] 
 
Prior TNFα antagonist failure 
[Yes, No] 
 
Number of drugs of TNFα antagonist 
failure 
[1 drug, 2 drugs, 3 drugs, 
None] 
 
Classification of prior TNFα 
antagonist failure 
[Inadequate response, Loss 
of response, Intolerance] 
 
Worst prior treatment failures 
[Prior TNFα antagonist 
failure,  
Prior immunomodulators 
failure but not TNFα 
antagonist failure,  
Prior corticosteroids failure 
only] 
 
Prior immunomodulators and TNFα 
antagonist failure 
[Yes, No] 
 
Concomitant use of enteral nutrient at 
baseline 
[Yes, No] 
 
Concomitant use of 5-ASA at baseline [Yes, No] 
 
Concomitant use of 
immunomodulators at baseline 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids at baseline 
[Yes, No] 
 
No concomitant use of oral 
corticosteroids and No concomitant 
use of immunomodulators at baseline 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids and No concomitant 
use of immunomodulators at baseline 
(concomitant use of oral 
corticosteroids only) 
[Yes, No] 
 
No concomitant use of oral 
corticosteroids and Concomitant use 
of immunomodulators at baseline 
(concomitant use of 
immunomodulators only) 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids and Concomitant use 
of immunomodulators at baseline 
[Yes, No] 


 
43 
 
 
CDAI score at baseline 
[Min≤ - ≤330,  
330< - ≤Max] 
 
Clinical remission at Week 10 
[Clinical remission, 
Non-remission] 
 
Disease localization 
[Small intestinal, Large 
intestinal, Small/Large 
intestinal] 
 
Weight (kg) at baseline 
[Min≤ - ≤59.9,  
60.0≤ - ≤Max] 
 
CRP (mg/dL) at baseline 
[Min≤ - <0.3, 0.3≤ - ≤Max] 
 
 
[Min≤ - <0.5, 0.5≤ - ≤Max] 
 
 
[Min≤ - <1.0, 1.0≤ - ≤Max] 
 
 
[Min≤ - ≤1.6, 1.6< - ≤Max] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables for each stratum by treatment group in the maintenance 
phase. 
 
(1) Frequency distributions will be provided along with the point 
estimate and 95% two-sided CI for the proportion. The point 
estimate and 95% two-sided CI for the difference in the 
proportion between treatment groups (MLN0002 group − 
placebo group) will be also calculated. 
 


 
44 
 
3 SAFETY ANALYSIS 
3.1 Treatment-Emergent Adverse Event 
3.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis set: 
Safety analysis set in the maintenance phase 
Analysis variables: 
TEAEs in the maintenance phase 
Categories: 
Causality 
[Related, Not related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analysis methodology: The following summaries will be provided for the above analysis 
variables by each “treatment group in the maintenance phase and 
subjects in the placebo continuation group.” 
 
(1) 
Overview of TEAEs in the maintenance phase 
 
1) All TEAEs in the maintenance phase (number of events, 
number and percentage of subjects) 
 
2) Causal relationship between all TEAEs in the 
maintenance phase and study drug (number of events, 
number and percentage of subjects) 
 
3) Intensity of all TEAEs in the maintenance phase (number 
of events, number and percentage of subjects) 
 
4) TEAEs in the maintenance phase leading to study drug 
discontinuation (number of events, number and 
percentage of subjects) 
 
5) Serious TEAEs in the maintenance phase (number of 
events, number and percentage of subjects) 
 
6) Causal relationship between serious TEAEs in the 
maintenance phase and study drug (number of events, 
number and percentage of subjects) 
 
7) Serious TEAEs in the maintenance phase leading to 
study drug discontinuation (number of events, number 
and percentage of subjects) 
 
8) TEAEs in the maintenance phase leading to death 
(number of events, number and percentage of subjects) 
 
TEAEs will be counted according to the rules below: 
[Number of subjects] 
• In the case of “summaries by causality” 
A subject with occurrences of TEAE in both categories (i.e., 
“Related” and “Not related”) will be counted once in the 
“Related” category. 
• In the case of “summaries by intensity” 
A subject with multiple occurrences of TEAE will be counted 
once for the TEAE with the maximum intensity. 
• In the case of summaries other than the above 
A subject with multiple occurrences of TEAE will be counted 
only once. 
[Number of events] 
For each summary, the total number of events will be calculated. 
 


 
45 
 
3.1.2 Displays of Treatment-Emergent Adverse Events 
Analysis set: 
Safety analysis set in the maintenance phase 
Analysis variables: 
TEAEs in the maintenance phase 
 
Infusion reactions in the maintenance phase 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
 
Time of onset (day) 
[1≤ - ≤56, 57≤ - ≤112,  
113≤ - ≤168, 169≤ - ≤224, 
225≤ - ≤280, 281≤ - ≤336, 
337≤ - ≤392, 393≤ - ≤Max] 
 
Study drug administration in the 
maintenance phase (time) 
[1, 2, 3, 4, 5, 6] 
Analysis methodology: The following summaries will be provided for the above analysis 
variables using frequency distributions by each “treatment group in 
the maintenance phase and subjects in the placebo continuation 
group.” 
TEAEs will be coded by use of MedDRA and will be summarized 
based on SOC and PT. SOC will be sorted alphabetically and PT 
will be sorted in decreasing frequency for tables provided by SOC 
and PT. SOC and PT will be sorted in decreasing frequency for 
tables provided by SOC only or PT only. 
Categories for time of onset (day) will be determined based on the 
number of days by defining the day of the first dose of the study 
drug in the maintenance phase as day 1. 
 
(1) 
All TEAEs in the maintenance phase by SOC and PT 
 
(2) 
All TEAEs in the maintenance phase by SOC 
 
(3) 
All TEAEs in the maintenance phase by PT 
 
(4) 
Drug-related TEAEs in the maintenance phase by SOC and 
PT 
 
(5) 
Intensity of all TEAEs in the maintenance phase by SOC and 
PT 
 
(6) 
Intensity of drug-related TEAEs in the maintenance phase by 
SOC and PT 
 
(7) 
TEAEs in the maintenance phase leading to study drug 
discontinuation by SOC and PT 
 
(8) 
Serious TEAEs in the maintenance phase by SOC and PT 
 
(9) 
Serious drug-related TEAEs in the maintenance phase by 
SOC and PT 
 
(10) 
All TEAEs in the maintenance phase by SOC and PT over 
time 
 
(11) 
Infusion reactions in the maintenance phase by SOC and PT 
 
(12) 
Infusion reactions in the maintenance phase by study drug 
administration in the maintenance phase (time) by SOC and 
PT 
 
(13) 
TEAEs in the maintenance phase whose onset date is the day 
of the study drug administration or the following day by 


 
46 
 
SOC and PT 
 
(14) 
TEAEs in the maintenance phase whose onset date is the day 
of the study drug administration or the following day by 
study drug administration in the maintenance phase (time) by 
SOC and PT 
 
(15) 
TEAEs in the maintenance phase whose incidence 
summarized by PT is 10% or higher in either treatment 
group or subjects in the placebo continuation group by SOC 
and PT 
 
The frequency distribution and incidence will be provided according 
to the rules below: 
[Number of subjects] 
• In the case of “summaries by SOC and PT, by SOC, and by PT” 
A subject with multiple occurrences of TEAE within a SOC 
will be counted only once in that SOC. A subject with 
multiple occurrences of TEAE within a PT will be counted 
only once in that PT. Percentages of TEAE in the 
maintenance phase will be based on the number of subjects in 
the safety analysis set in the maintenance phase. 
• In the case of “summaries of intensity by SOC and PT” 
A subject with multiple occurrences of TEAE within a SOC 
or a PT will be counted only once for the TEAE with the 
maximum intensity. Percentages of TEAE in the maintenance 
phase will be based on the number of subjects in the safety 
analysis set in the maintenance phase. 
• In the case of “summaries by SOC and PT over time” 
A subject with a TEAE that occurs in more than one interval 
is counted in all the intervals that the TEAE occurs. For each 
time interval, a subject with multiple occurrences of TEAE 
within a SOC or a PT will be counted only once in that SOC 
or PT. When calculating the percentages of TEAEs in the 
maintenance phase for each time interval, the number of 
subjects at risk (i.e., “subjects who either have an exposure in 
the study or have an occurrence of TEAE in the maintenance 
phase, during or after the corresponding time interval”) will 
be used as the denominator. The number of subjects whose 
“onset of any one of the TEAEs in the maintenance phase is 
within the time interval” will be used as the numerator. 
• In the case of “summaries of the study drug administration in the 
maintenance phase (time) by SOC and PT” 
A subject with a TEAE that occurs in more than one time of 
the study drug administration is counted for all the 
administrations (time) that the TEAE occurs. For each 
administration, a subject with multiple occurrences of TEAE 
within a SOC or a PT will be counted only once in that SOC 
or PT. When calculating the percentages of TEAEs in the 
maintenance phase for each administration (time) in the 


 
47 
 
maintenance phase, the number of subjects at risk (i.e., 
“subjects who received the first, etc., study drug 
administration in the maintenance phase”) will be used as the 
denominator. The number of subjects whose “onset of any one 
of the TEAEs in the maintenance phase is at the time of the 
first, etc., study drug administration in the maintenance 
phase” will be used as the numerator. 
 
3.2 Pretreatment Event 
3.2.1 Displays of Pretreatment Events 
Not applicable. 
 
3.3 Clinical Laboratory Evaluations and Other Safety Endpoints 
3.3.1 Clinical Laboratory Evaluations 
3.3.1.1 
Hematology and Blood Biochemistry 
Analysis set: 
Safety analysis set in the maintenance phase 
Analysis variables: 
Hematology 
 
Red blood cells 
(RBC) 
White blood cells 
(WBC) 
Hemoglobin 
 
Hematocrit 
Platelets 
 
 
WBC differentials (neutrophils/leukocytes, 
eosinophils/leukocytes, basophils/leukocytes, 
lymphocytes/leukocytes, monocytes/leukocytes) 
 
Blood biochemistry 
 
Albumin 
AST (GOT) 
ALT (GPT) 
 
ALP 
Amylase 
Glucose 
 
Total bilirubin 
Total protein 
γ-GTP 
 
Total cholesterol 
Triglyceride 
Creatinine 
 
BUN 
Uric acid 
Potassium 
 
Sodium 
Calcium 
Phosphorus 
 
Magnesium 
Chloride 
 
Categories: 
Adjudication results based on 
reference range 
[Below lower limit of normal 
range, Within normal range, 
Over upper limit of normal 
range] 
 
Categories in SAP Appendix 2 (1) 
 
Visit: 
Weeks 0, 2, 6, 10, 14, 22, 30, 38, 46, 54, 60, and 16 weeks after the 
last dose of the study drug 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each “treatment group in the maintenance phase and 
subjects in the placebo continuation group.” 
The subjects who received the study drug in the open-label cohort 
will be excluded from the analysis at 16 weeks after the last dose. 
Refer to Appendix 2 of this SAP for laboratory test items subject to 
this analysis, categories in the shift table, MAV criteria, and the 


 
48 
 
definition of elevated liver enzyme. 
 
(1) 
Summary statistics for each visit and summary statistics of 
differences before and after administration for each visit 
 
(2) 
Case plots 
 
(3) 
Shift tables showing adjudication results based on normal 
reference range at baseline and each post-baseline visit 
 
(4) 
Shift tables showing categories of SAP Appendix 2 (1) at 
baseline and each post-baseline visit 
 
(5) 
Overall frequency distributions of MAV in the maintenance 
phase 
 
(6) 
Overall frequency distributions of elevated liver enzymes in 
the maintenance phase 
 
3.3.1.2 
Urinalysis 
Analysis set: 
Safety analysis set in the maintenance phase 
Analysis variables: 
pH 
 
 
Urine specific gravity 
 
 
Glucose 
 
 
Protein 
 
 
Occult blood 
 
 
Bilirubin 
 
 
Ketone body 
 
Categories: 
Adjudication results based on 
reference range 
[Below lower limit of normal 
range, Within normal range, 
Over upper limit of normal 
range] 
Visit: 
Weeks 0, 10, 14, 60, and 16 weeks after the last dose of the study 
drug 
Analysis methodology: The following analyses of (1), (2), and (3) will be performed for pH 
and specific gravity by each “treatment group in the maintenance 
phase and subjects in the placebo continuation group.” The 
following analysis of (3) will be performed for the above analysis 
variables other than pH and specific gravity by each “treatment 
group in the maintenance phase and subjects in the placebo 
continuation group.” 
The subjects who received the study drug in the open-label cohort 
will be excluded from the analysis at 16 weeks after the last dose. 
 
(1) 
Summary statistics for each visit and summary statistics of 
differences before and after administration 
 
(2) 
Case plots 
 
(3) 
Shift tables showing adjudication results based on normal 
reference range at baseline and each post-baseline visit 
 


 
49 
 
3.3.2 Vital Signs, Physical Examination, and Other Observation Items Related to Safety 
3.3.2.1 
Vital Signs, Body Weight 
Analysis set: 
Safety analysis set in the maintenance phase 
Analysis variables: 
Systolic blood pressure 
 
 
Diastolic blood pressure 
 
 
Pulse 
 
 
Body temperature 
 
 
Weight 
 
Visit: 
Weeks 0, 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 60, 
and 16 weeks after the last dose of the study drug 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each “treatment group in the maintenance phase and 
subjects in the placebo continuation group.” 
The subjects who received the study drug in the open-label cohort 
will be excluded from the analysis at 16 weeks after the last dose. 
 
(1) 
Summary statistics for each visit and summary statistics of 
differences before and after administration for each visit 
 
(2) 
Case plots 
 
3.3.2.2 
12-Lead ECG 
Analysis set: 
Safety analysis set in the maintenance phase 
Analysis variables: 
Findings of 12-lead ECG 
[Within normal limits, Abnormal but 
not clinically significant, Abnormal 
and clinically significant] 
Visit: 
Weeks 0, 10, 60, and 16 weeks after the last dose of the study drug 
Analysis methodology: The following analysis will be performed for the findings of 12-lead 
ECG by each “treatment group in the maintenance phase and 
subjects in the placebo continuation group.” 
The subjects who received the study drug in the open-label cohort 
will be excluded from the analysis at 16 weeks after the last dose. 
 
(1) 
Shift table at baseline and each post-baseline visit 
 
3.4 Display of Treatment-Emergent Adverse Event (in Japanese) 
Analysis set: 
Safety analysis set in the maintenance phase 
Analysis variables: 
TEAEs in the maintenance phase by SOC and PT 
 
Infusion reactions in the maintenance phase by SOC and PT 
Analysis methodology: Summaries similar to those in section 3.1.2 will be provided for the 
above analysis variables. SOC and PT will be displayed in Japanese. 
 


 
50 
 
4 PHARMACOKINETIC ANALYSIS 
4.1 Analysis of Serum Concentrations of MLN0002 
Analysis set: 
Subjects who underwent proper determination of serum 
concentrations of MLN0002 in the “full analysis set in the 
maintenance phase” 
Analysis variables: 
Serum concentrations of MLN0002 
 
Visit: 
Weeks 2, 6, 10, 14, 22, 30, and 60 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by treatment group in the maintenance phase. When 
calculating the geometric mean and geometric CV%, the analysis 
will be performed by excluding data for which serum concentration 
of MLN0002 is 0. 
 
(1) 
Summary statistics, geometric mean, and geometric CV% 
 
(2) 
Mean/standard deviation plot 
 
4.2 Subgroup Analysis of Serum Concentrations of MLN0002 
Analysis set: 
Subjects who underwent proper determination of serum 
concentrations of MLN0002 in the “full analysis set in the 
maintenance phase” 
Analysis variables: 
Serum concentrations of MLN0002 
 
Stratum:  
Prior TNFα antagonist use 
[Yes, No] 
 
Concomitant use of 5-ASA at baseline 
[Yes, No] 
 
Concomitant use of oral corticosteroids 
at baseline 
[Yes, No] 
 
Concomitant use of immunomodulators 
at baseline 
[Yes, No] 
Visit: 
Weeks 2, 6, 10, 14, 22, 30, and 60 
Analysis methodology: The following analysis will be performed for the above analysis 
variables for each stratum by treatment group in the maintenance 
phase. When calculating the geometric mean and geometric CV%, 
the analysis will be performed by excluding data for which serum 
concentration of MLN0002 is 0. 
 
(1) 
Summary statistics, geometric mean, and geometric CV% 
 
4.3 Serum Concentrations of MLN0002 by Efficacy Endpoints 
Analysis set: 
Subjects who underwent proper determination of serum 
concentrations of MLN0002 in the “full analysis set in the 
maintenance phase” 
Analysis variables: 
Serum concentrations of MLN0002 
 
Stratum:  
Clinical remission at Week 60 
[Clinical remission, 
Non-remission] 
Visit: 
Weeks 2, 6, 10, 14, 22, 30, and 60 
Analysis methodology: The following analysis will be performed for the above analysis 
variables for each stratum by treatment group in the maintenance 
phase. When calculating the geometric mean and geometric CV%, 
the analysis will be performed by excluding data for which serum 
concentration of MLN0002 is 0. 


 
51 
 
 
(1) 
Summary statistics, geometric mean, and geometric CV% 
 
4.4 Serum Concentrations of MLN0002 by AVA and Neutralizing Antibody 
Analysis set: 
Subjects who underwent proper determination of serum 
concentrations of MLN0002 in the “full analysis set in the 
maintenance phase” 
Analysis variables: 
Serum concentrations of MLN0002 
 
Stratum:  
AVA in the induction and maintenance 
phases 
[Negative, Positive] 
 
Persistently positive in the induction 
and maintenance phases 
[Yes, No] 
 
Transiently positive in the induction 
and maintenance phases 
[Yes, No] 
 
Neutralizing antibody in the induction 
and maintenance phases 
[Negative, Positive] 
Visit: 
Weeks 2, 6, 10, 14, 22, 30, and 60 
Analysis methodology: The following analysis will be performed for the above analysis 
variables for each stratum by treatment group in the maintenance 
phase. When calculating the geometric mean and geometric CV%, 
the analysis will be performed by excluding data for which serum 
concentration of MLN0002 is 0. 
 
(1) 
Summary statistics, geometric mean, and geometric CV% 
 
4.5 Efficacy by Serum Concentration of MLN0002 
Analysis set: 
Subjects who underwent proper determination of serum 
concentrations of MLN0002 in the “full analysis set in the 
maintenance phase” 
Analysis variables: 
Clinical remission at Week 60 
[Clinical remission, 
Non-remission] 
Stratum:  
Serum concentrations of 
MLN0002 at Week 2 
[0≤ - <Q1, Q1≤ - <Median, 
Median≤ - <Q3, Q3≤ - ≤Max] 
 
Serum concentrations of 
MLN0002 at Week 6 
[0≤ - <Q1, Q1≤ - <Median, 
Median≤ - <Q3, Q3≤ - ≤Max] 
 
Serum concentrations of 
MLN0002 at Week 10 
[0≤ - <Q1, Q1≤ - <Median, 
Median≤ - <Q3, Q3≤ - ≤Max] 
 
Serum concentrations of 
MLN0002 at Week 14 
[0≤ - <Q1, Q1≤ - <Median, 
Median≤ - <Q3, Q3≤ - ≤Max] 
 
Serum concentrations of 
MLN0002 at Week 22 
[0≤ - <Q1, Q1≤ - <Median, 
Median≤ - <Q3, Q3≤ - ≤Max] 
 
Serum concentrations of 
MLN0002 at Week 30 
[0≤ - <Q1, Q1≤ - <Median, 
Median≤ - <Q3, Q3≤ - ≤Max] 
 
Serum concentrations of 
MLN0002 at Week 60 
[0≤ - <Q1, Q1≤ - <Median, 
Median≤ - <Q3, Q3≤ - ≤Max] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables for each stratum by treatment group in the maintenance 
phase. Categories of stratum will be defined as 4 categories with the 
first quartile (Q1), median, and third quartile (Q3) of the obtained 


 
52 
 
data in the MLN0002 group as boundaries. 
 
(1) 
Frequency distributions, and point estimates and the 95% 
two-sided CI for the proportion 
 


 
53 
 
5 ANALYSIS OF IMMUNOGENICITY ENDPOINTS 
5.1 AVA and the Neutralizing Antibody 
Analysis set: 
Subjects who underwent proper determination of AVA and the 
neutralizing antibody in the “full analysis set in the maintenance 
phase” 
Analysis variables: 
AVA 
[Negative, Positive] 
 
AVA titer 
[1:10, 1:50, 1:250, 1:1250, 
1:6250, 1:31250] 
 
Persistently positive in the induction 
and maintenance phases 
[Yes, No] 
 
Transiently positive in the induction 
and maintenance phases 
[Yes, No] 
 
Neutralizing antibody 
[Negative, Positive] 
 
AVA in the induction and 
maintenance phases 
[Negative, Positive] 
 
Maximum AVA titer in the 
induction and maintenance phases 
[1:10, 1:50, 1:250, 1:1250, 
1:6250, 1:31250] 
 
Neutralizing antibody in the 
induction and maintenance phases 
[Negative, Positive] 
Visit: 
Weeks 0, 10, 30, 60, and 16 weeks after the last dose of the study 
drug (AVA, AVA titer, neutralizing antibody) 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by treatment group in the maintenance phase. 
The category of AVA titer will be defined according to the observed 
AVA titer. 
The subjects who received the study drug in the open-label cohort 
will be excluded from the analysis at 16 weeks after the last dose. 
 
(1) 
Frequency distributions 
 
5.2 Efficacy by AVA and the Neutralizing Antibody 
Analysis set: 
Subjects who underwent proper determination of AVA and the 
neutralizing antibody in the “full analysis set in the maintenance 
phase” 
Analysis variables: 
Clinical remission at Week 60 
[Clinical remission, 
Non-remission] 
Stratum:  
AVA in the induction and 
maintenance phases 
[Negative, Positive] 
 
Persistently positive in the induction 
and maintenance phases 
[Yes, No] 
 
Transiently positive in the induction 
and maintenance phases 
[Yes, No] 
 
Neutralizing antibody in the 
induction and maintenance phases 
[Negative, Positive] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables for each stratum by treatment group in the maintenance 
phase. 
 
(1) 
Frequency distributions 


 
54 
 
 
5.3 Subgroup Analysis of AVA and the Neutralizing Antibody 
Analysis set: 
Subjects who underwent proper determination of AVA and the 
neutralizing antibody in the “full analysis set in the maintenance 
phase” 
Analysis variables: 
AVA in the induction and maintenance 
phases 
[Negative, Positive] 
 
Persistently positive in the induction and 
maintenance phases 
[Yes, No] 
 
Transiently positive in the induction and 
maintenance phases 
[Yes, No] 
 
Neutralizing antibody in the induction 
and maintenance phases 
[Negative, Positive] 
Stratum:  
Concomitant use of immunomodulators 
at baseline 
[Yes, No] 
 
No concomitant use of oral 
corticosteroids and Concomitant use of 
immunomodulators at baseline 
(concomitant use of immunomodulators 
only) 
[Yes, No] 
 
Concomitant use of oral corticosteroids at 
baseline 
[Yes, No] 
 
Infusion reactions in the induction and 
maintenance phases 
[Yes, No] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables for each stratum by treatment group in the maintenance 
phase. 
The subjects who received the study drug in the open-label cohort 
will be excluded from the analysis at 16 weeks after the last dose. 
 
(1) 
Frequency distributions 
 


 
55 
 
6 SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT 
 
Significance level: 5% (two-sided test) 
 
Confidence coefficient: 95% (two-sided estimate) 
 
 


 
56 
 
History of Revision (version management) 
 
Version 
Date 
Prepared/modified by 
Comments 
First version 25 January 2018 
 
Preparation of first version 
 
PPD


 
1 
 
[Appendix 1] Comparison Table for Changes 
 
N/A 
 


 
1 
 
[Appendix 2] Definitions of Categories in Shift Table, MAV Criteria, and Criteria for Elevated 
Liver Enzyme 
(1) 
Categories in Shift Table 
The lower limit of the normal range and the upper limit of the normal range of each test item are 
abbreviated as LLN and ULN in the table below. 
 
Test item 
Categories 
Albumin 
≥LLN, <LLN to 3 g/dL, <3 g/dL to 2 g/dL, <2 g/dL to 1 g/dL, <1 g/dL 
ALT (GPT) 
≤ULN, >ULN to 2.5×ULN, >2.5×ULN to 5.0×ULN, >5.0×ULN to 20.0×ULN, 
>20.0×ULN 
AST (GOT) 
≤ULN, >ULN to 2.5×ULN, >2.5×ULN to 5.0×ULN, >5.0×ULN to 20.0×ULN, 
>20.0×ULN 
Total bilirubin 
≤ULN, >ULN to 1.5×ULN, >1.5×ULN to 3.0×ULN, >3.0×ULN to 10.0×ULN, 
>10.0×ULN 
Creatinine 
≤ULN, >ULN to 1.5×ULN, >1.5×ULN to 3.0×ULN, >3.0×ULN to 6.0×ULN, 
>6.0×ULN 
ALP 
≤ULN, >ULN to 2.5×ULN, >2.5×ULN to 5.0×ULN, >5.0×ULN to 20.0×ULN, 
>20.0×ULN 
WBC 
≥LLN, <LLN to 3000/μL, <3000/μL to 2000/μL, <2000/μL to 1000/μL, 
<1000/μL 
WBC 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Platelets 
≥LLN, <LLN to 7.5×104/μL, <7.5×104/μL to 5.0×104/μL, <5.0×104/μL to 
2.5×104/μL, <2.5×104/μL 
Platelets 
≤ULN, >ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, >2.0×ULN to 3.0×ULN, 
>3.0×ULN 
Lymphocytes 
≥800/μL, <800/μL to 500/μL, <500/μL to 200/μL, <200/μL 
Lymphocytes (%) 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Eosinophils (%) 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Monocytes (%) 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Basophils (%) 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Hemoglobin 
≥LLN, <LLN to 10 g/dL, <10 g/dL to 8 g/dL, <8 g/dL to 6.5 g/dL, <6.5 g/dL 
Neutrophils 
≥1500/μL, <1500/μL to 1000/μL, <1000/μL to 500/μL, <500/μL 
Neutrophils (%) 
≤ULN, >ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, >2.0×ULN to 3.0×ULN, 
>3.0×ULN 
Missing data will not be included in any category. 
 


 
2 
 
(2) 
MAV Criteria 
1) 
Hematology and Blood Biochemistry 
For each test item, MAV will be determined according to the table below for evaluable data (i.e., 
non-missing data and data determined to be eligible based on the “Handling Rules for Analysis 
Data”) obtained from the day after the first dose of the study drug in the maintenance phase until the 
day of the first dose of the study drug in the open-label cohort for subjects who received the study 
drug in the open-label cohort or from the day after the first dose of the study drug in the maintenance 
phase until 167 days* after the last dose of the study drug (including Follow-up Day 167) for 
subjects who did not receive the study drug in the open-label cohort. The lower limit of the normal 
range and the upper limit of the normal range of each test item are abbreviated as LLN and ULN in 
the table below. 
* Day after the last dose of the study drug will be defined as Follow-up Day 1. 
 
Test item 
MAV Criteria 
Lower criteria 
Upper criteria 
Hemoglobin (g/dL) 
≤7 
- 
Lymphocytes (/μL) 
<500 
- 
WBC (/μL) 
<2000 
- 
Platelets (×104/μL) 
<7.5 
- 
Neutrophils (/μL) 
<1000 
- 
ALT (GPT) (U/L) 
- 
>3.0×ULN 
AST (GOT) (U/L) 
- 
>3.0×ULN 
Total bilirubin (mg/dL) 
- 
>2.0×ULN 
Amylase (U/L) 
- 
>2.0×ULN 
 
Classifying Subjects for the Overall Maintenance Phase 
For each test item and subject, MAV will be determined according to the conditions [1] to [3] 
provided below. 
[1] A subject will be classified as those “with MAV” if he/she has at least one data that “meets the 
MAV Criteria” among the evaluable data obtained from the day after the first dose of the study 
drug in the maintenance phase until the day of the first dose of the study drug in the open-label 
cohort for subjects who received the study drug in the open-label cohort or from the day after 
the first dose of the study drug in the maintenance phase until 167 days after the last dose of the 
study drug (including Follow-up Day 167) for subjects who did not receive the study drug in 
the open-label cohort. 
[2] A subject will be classified as those “without MAV” if he/she does not meet condition [1] and 
has at least one data that does “not meet the MAV Criteria” among the evaluable data obtained 
from the day after the first dose of the study drug in the maintenance phase until the day of the 
first dose of the study drug in the open-label cohort for subjects who received the study drug in 
the open-label cohort or from the day after the first dose of the study drug in the maintenance 
phase until 167 days after the last dose of the study drug (including Follow-up Day 167) for 
subjects who did not receive the study drug in the open-label cohort. 
[3] A subject who does not meet conditions [1] or [2] will be excluded from the analysis of MAV 
for that item. 
 


 
3 
 
(3) 
Criteria for Elevated Liver Enzyme 
For each test item, elevated liver enzyme will be determined according to the table below for 
evaluable data (i.e., non-missing data and data determined to be eligible based on the “Handling 
Rules for Analysis Data”) obtained from the day after the first dose of the study drug in the 
maintenance phase until the day of the first dose of the study drug in the open-label cohort for 
subjects who received the study drug in the open-label cohort or from the day after the first dose of 
the study drug in the maintenance phase until 167 days* after the last dose of the study drug 
(including Follow-up Day 167) for subjects who did not receive the study drug in the open-label 
cohort. If there is more than one item that need to be considered for a criterion, test items measured 
on the same day will be used. The following abbreviations are used in the table below: LLN for 
lower limit of the normal range, ULN for upper limit of the normal range, ALT for alanine 
aminotransferase, AST for aspartate aminotransferase, Tbili for total bilirubin, and ALP for alkaline 
phosphatase. 
* Day after the last dose of the study drug will be defined as Follow-up Day 1. 
 
Label 
Criteria for “elevated liver enzyme” 
Elevated 
Not elevated 
ALT > 3×ULN 
ALT is greater than 3 times the ULN 
ALT is non-missing and less than or 
equal to 3 times the ULN 
ALT > 5×ULN 
ALT is greater than 5 times the ULN 
ALT is non-missing and less than or 
equal to 5 times the ULN 
ALT > 8×ULN 
ALT is greater than 8 times the ULN 
ALT is non-missing and less than or 
equal to 8 times the ULN 
ALT > 3×ULN  
with Tbili > 2×ULN 
ALT is greater than 3 times the ULN and 
the total bilirubin is greater than twice 
the ULN 
Either ALT is non-missing and less than 
or equal to 3 times the ULN, or the total 
bilirubin is non-missing and less than or 
equal to twice the ULN 
AST > 3×ULN 
AST is greater than 3 times the ULN 
AST is non-missing and less than or 
equal to 3 times the ULN 
AST > 5×ULN 
AST is greater than 5 times the ULN 
AST is non-missing and less than or 
equal to 5 times the ULN 
AST > 8×ULN 
AST is greater than 8 times the ULN 
AST is non-missing and less than or 
equal to 8 times the ULN 
AST > 3×ULN  
with Tbili > 2×ULN 
AST is greater than 3 times the ULN and 
the total bilirubin is greater than twice 
the ULN 
Either AST is non-missing and less than 
or equal to 3 times the ULN, or the total 
bilirubin is non-missing and less than or 
equal to twice the ULN 
ALT or AST > 3×ULN 
Either ALT or AST is greater than 3 
times the ULN 
Both ALT and AST are non-missing and 
less than or equal to 3 times the ULN 
ALT or AST > 5×ULN 
Either ALT or AST is greater than 5 
times the ULN 
Both ALT and AST are non-missing and 
less than or equal to 5 times the ULN 
ALT or AST > 8×ULN 
Either ALT or AST is greater than 8 
times the ULN 
Both ALT and AST are non-missing and 
less than or equal to 8 times the ULN 
ALT or AST > 3×ULN  
with Tbili > 2×ULN 
Either ALT or AST is greater than 3 
times the ULN and the total bilirubin is 
greater than twice the ULN 
If any of the following conditions is met: 
- Both ALT and AST are non-missing 
and less than or equal to 3 times the 
ULN 


 
4 
 
Label 
Criteria for “elevated liver enzyme” 
Elevated 
Not elevated 
- Total bilirubin is non-missing and less 
than or equal to twice the ULN 
ALT and AST > 3×ULN 
Both ALT and AST are greater than 3 
times the ULN 
Either ALT is non-missing and less than 
or equal to 3 times the ULN, or AST is 
non-missing and less than or equal to 3 
times the ULN 
ALT and AST > 5×ULN 
Both ALT and AST are greater than 5 
times the ULN 
Either ALT is non-missing and less than 
or equal to 5 times the ULN, or AST is 
non-missing and less than or equal to 5 
times the ULN 
ALT and AST > 8×ULN 
Both ALT and AST are greater than 8 
times the ULN 
Either ALT is non-missing and less than 
or equal to 8 times the ULN, or AST is 
non-missing and less than or equal to 8 
times the ULN 
ALT and AST > 3×ULN  
with Tbili > 2×ULN 
Both ALT and AST are greater than 3 
times the ULN and the total bilirubin is 
greater than twice the ULN 
If any of the following conditions is met: 
- ALT is non-missing and less than or 
equal to 3 times the ULN 
- AST is non-missing and less than or 
equal to 3 times the ULN 
- Total bilirubin is non-missing and less 
than or equal to twice the ULN 
ALP > 3×ULN 
ALP is greater than 3 times the ULN 
ALP is non-missing and less than or 
equal to 3 times the ULN 
ALP > 3×ULN  
with ALT > 3×ULN 
Both ALP and ALT are greater than 3 
time the ULN 
Either ALP is non-missing and less than 
or equal to 3 times the ULN, or ALT is 
non-missing and less than or equal to 3 
times the ULN 
ALP > 3×ULN 
with AST > 3×ULN 
Both ALP and AST are greater than 3 
times the ULN 
Either ALP is non-missing and less than 
or equal to 3 times the ULN, or AST is 
non-missing and less than or equal to 3 
times the ULN 
 
Classifying Subjects for the Overall Maintenance Phase 
For each criteria and subject, “elevated liver enzyme” will be determined according to the conditions 
[1] to [3] provided below. 
[1] A subject will be classified as those “with elevated liver enzyme” if he/she has at least one data 
that “meets the criteria for elevated liver enzyme” among the evaluable data obtained from the 
day after the first dose of the study drug in the maintenance phase until the day of the first dose 
of the study drug in the open-label cohort for subjects who received the study drug in the 
open-label cohort, or from the day after the first dose of the study drug in the maintenance 
phase until 167 days after the last dose of the study drug (including Follow-up Day 167) for 
subjects who did not receive the study drug in the open-label cohort. 
[2] A subject will be classified as those “without elevated liver enzyme” if he/she does not meet 
condition [1] and has at least one data that does “not meet the criteria for elevated liver 
enzyme” among the evaluable data obtained from the day after the first dose of the study drug 


 
5 
 
in the maintenance phase until the day of the first dose of the study drug in the open-label 
cohort for subjects who received the study drug in the open-label cohort, or from the day after 
the first dose of the study drug in the maintenance phase until 167 days after the last dose of the 
study drug (including Follow-up Day 167) for subjects who did not receive the study drug in 
the open-label cohort. 
[3] A subject who does not meet conditions [1] or [2] will be excluded from the analysis of 
elevated liver enzyme for that item. 
 


 
 
STATISTICAL ANALYSIS PLAN 
(Open-Label Cohort) 
 
Study Title 
: Phase 3, multicenter, randomized, double-blinded, placebo-controlled, 
parallel-group study to evaluate the efficacy, safety, and pharmacokinetics 
of intravenous MLN0002 (300 mg) infusion in induction and maintenance 
therapy in Japanese subjects with moderate or severe Crohn's disease 
Protocol No. 
: MLN0002/CCT-001 
Sponsor 
: Takeda Pharmaceutical Company Limited 
 
Person responsible for preparing the protocol 
 
 
Trial Statistician 
 
Person responsible for pharmacokinetic/pharmacodynamic analyses 
 
First version: 25 January 2018 
PPD
PPD
PPD


1 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................... 3 
HANDLING OF TIME WINDOW ...................................................................................................... 4 
OTHER HANDLING ......................................................................................................................... 10 
1 STUDY SUBJECTS, DEMOGRAPHICS, AND OTHER BASELINE CHARACTERISTICS .... 17 
1.1 Disposition of Subjects ................................................................................................................. 17 
1.1.1 Study Information .................................................................................................................. 17 
1.1.2 Disposition of All Subjects Who Did Not Enter in the Open-label Cohort ........................... 17 
1.1.3 Subject Eligibility .................................................................................................................. 17 
1.1.4 Number of Subjects Who Entered in the Open-label Cohort by Site ..................................... 17 
1.1.5 Disposition of Subjects .......................................................................................................... 18 
1.1.5.1 
Disposition of Subjects ................................................................................................... 18 
1.1.6 Study Drug Completion Status and Study Visit Completion Status ...................................... 18 
1.1.7 Protocol Deviations and Analysis Sets .................................................................................. 19 
1.2 Demographic and Other Baseline Characteristics ......................................................................... 20 
1.2.1 Distribution of Baseline Demographics ................................................................................. 20 
1.2.2 Medical History, Concurrent Medical Conditions ................................................................. 23 
1.2.3 Medication History, Concomitant Medications, Concomitant Therapies .............................. 23 
1.3 Measurement of Compliance Status for Treatment....................................................................... 25 
1.3.1 Study Drug Exposure and Compliance .................................................................................. 25 
2 EFFICACY ANALYSIS ................................................................................................................. 27 
2.1 Other Endpoints and Analysis Methodology ................................................................................ 27 
2.1.1 Endpoints Related to CDAI Scores ........................................................................................ 27 
2.1.2 Endpoints Related to CDAI Scores Based on the Hematocrit Level at Each Study Site ....... 28 
2.1.3 Endpoints Related to CRP...................................................................................................... 29 
2.2 Statistical and Analytical Issues .................................................................................................... 30 
2.2.1 Adjustments for Covariates .................................................................................................... 30 
2.2.2 Handling of Dropouts or Missing Data .................................................................................. 30 
2.2.3 Interim Analyses and Data Monitoring .................................................................................. 30 
2.2.4 Multicenter Studies ................................................................................................................ 30 
2.2.5 Multiple Comparisons/Multiplicity ........................................................................................ 30 
2.2.6 Use of an “Efficacy Subset” of Subjects ................................................................................ 30 
2.2.7 Active-Control Studies Intended to Show Equivalence or Non-inferiority ........................... 30 
2.2.8 Examination of Subgroups ..................................................................................................... 30 
3 SAFETY ANALYSIS ...................................................................................................................... 31 
3.1 Treatment-Emergent Adverse Event ............................................................................................. 31 
3.1.1 Overview of Treatment-Emergent Adverse Events ............................................................... 31 


2 
 
3.1.2 Displays of Treatment-Emergent Adverse Events ................................................................. 32 
3.2 Pretreatment Event ........................................................................................................................ 34 
3.2.1 Displays of Pretreatment Events ............................................................................................ 34 
3.3 Clinical Laboratory Evaluations and Other Safety Endpoints ...................................................... 34 
3.3.1 Clinical Laboratory Evaluations ............................................................................................ 34 
3.3.2 Vital Signs, Physical Examination, and Other Observation Items Related to Safety ............ 35 
4 DISPLAY OF TREATMENT-EMERGENT ADVERSE EVENT (IN JAPANESE) ..................... 37 
4.1 Display of Treatment-Emergent Adverse Event (in Japanese) ..................................................... 37 
5 ANALYSIS OF IMMUNOGENICITY ENDPOINTS .................................................................... 38 
5.1 AVA and the Neutralizing Antibody ............................................................................................ 38 
5.2 Efficacy by AVA and the Neutralizing Antibody ......................................................................... 38 
5.3 Subgroup Analysis of AVA and the Neutralizing Antibody ......................................................... 39 
6 SAFETY ANALYSIS OF MLN0002 TREATMENT ..................................................................... 40 
6.1 Measurement of Compliance Status for Treatment....................................................................... 40 
6.1.1 MLN0002 Exposure and Compliance in the Treatment Period ............................................. 40 
6.2 Treatment-Emergent Adverse Event ............................................................................................. 40 
6.2.1 Overview of Treatment-Emergent Adverse Events ............................................................... 40 
6.2.2 Displays of Treatment-Emergent Adverse Events ................................................................. 41 
6.3 Display of Treatment-Emergent Adverse Event (in Japanese) ..................................................... 43 
7 ANALYSIS OF FOLLOW-UP SURVEY AND PML CHECKLIST ............................................. 44 
7.1 Analysis of Follow-up Survey ...................................................................................................... 44 
7.2 Analysis of PML Checklist ........................................................................................................... 44 
8 SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT .................................................. 45 
History of Revision (version management) ........................................................................................ 46 
[Appendix 1] Comparison Table for Changes ...................................................................................... 1 
[Appendix 2] Definitions of Categories in Shift Table, MAV Criteria, and Criteria for Elevated Liver 
Enzyme ......................................................................................................................................... 1 
 


3 
 
Since the study has different objectives in the induction phase, the maintenance phase, and the 
open-label cohort, analyses will be conducted separately among these. Therefore, the “Statistical 
Analysis Plan” will be also prepared for the induction phase, maintenance phase, and open-label 
cohort, respectively. This statistical analysis plan will describe the analytical plan in the open-label 
cohort. 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
• 
Treatment-emergent adverse event (TEAE) in the open-label cohort: An adverse event that 
emerged during the open-label cohort. 
• 
TEAEs emerged after treatment of MLN0002: TEAEs whose onset date is after the first dose of 
MLN0002 
• 
Concomitant medication in the open-label cohort: All concomitant medications. 
• 
Concomitant therapy in the open-label cohort: All concomitant therapies. 
• 
Summary statistics: Number of subjects, mean, standard deviation, maximum, minimum, and 
quartiles. 
• 
MAV: An abbreviation for markedly abnormal value. 
• 
Study Day: The day before the first dose of the study drug in the induction phase will be 
defined as Day -1 and the day of the first dose in the induction phase will be defined as Day 1. 
• 
Study Day in the Open-label Cohort: The day before the first dose of the study drug in the 
open-label cohort will be defined as Day -1x and the day of the first dose in the open-label 
cohort will be defined as Day 1x. 
• 
Follow-up Day: The day after the last dose of the study drug will be defined as Follow-up 
Day 1. There will be no distinction among the induction phase, maintenance phase, and 
open-label cohort for the day of the last dose of the study drug. 
• 
Full analysis set in the open-label cohort: Subjects who received at least one dose of the study 
drug in the open-label cohort. 
• 
Safety analysis set in the open-label cohort: Subjects who received at least one dose of the study 
drug in the open-label cohort.  
• 
Determination of CDAI-70 response at Week 10: Determination of CDAI-70 response or 
non-CDAI-70 response at Week 10 on the website of the registration center. 
• 
Route to open-label cohort: Routes 1 to 8. See the following table for details of each route. 
 
Name 
Study 
Drug in the 
Induction 
Phase 
CDAI-70 
Response  
at Week 10 
Study Drug 
in the 
Maintenance 
Phase 
Study Drug 
Completion 
Status in the 
Maintenance 
Phase 
Features 
Route 1 
MLN0002 
CDAI-70 
response 
MLN0002 
Completed 
 
Route 2 
MLN0002 
CDAI-70 
response 
MLN0002 
Discontinued Reinduction to subjects with 
treatment failure in the 
maintenance phase (loss of 
response) 
Route 3 
MLN0002 
CDAI-70 
response 
Placebo 
Completed 
 
Route 4 
MLN0002 
CDAI-70 
response 
Placebo 
Discontinued Reinduction to subjects who 
achieved treatment success 


4 
 
Name 
Study 
Drug in the 
Induction 
Phase 
CDAI-70 
Response  
at Week 10 
Study Drug 
in the 
Maintenance 
Phase 
Study Drug 
Completion 
Status in the 
Maintenance 
Phase 
Features 
in the induction phase and 
were subsequently observed 
without any administration 
of the study drug but 
relapsed after that 
Route 5 
MLN0002 
Non-CDAI-70 
response 
- 
- 
Reinduction to subjects with 
treatment failure in the 
induction phase (inadequate 
response) 
Route 6 
Placebo 
CDAI-70 
response 
Placebo 
Completed 
 
Route 7 
Placebo 
CDAI-70 
response 
Placebo 
Discontinued  
Route 8 
Placebo 
Non-CDAI-70 
response 
- 
- 
 
 
• 
Anti-vedolizumab antibody (AVA): Human anti-human antibody (HAHA) in the protocol will 
be described as AVA. 
• 
Baseline: A visit at “Week 0” in the “HANDLING OF TIME WINDOW” 
 
HANDLING OF TIME WINDOW 
For each test, observation, and evaluation item, evaluable data (i.e., non-missing data and data 
determined to be eligible based on “Handling Rules for Analysis Data”) will be handled according 
to the following rules. 
The evaluable data within the acceptable window will be used. If more than one evaluable datum 
lies within the same acceptable window, the data whose test/observation/evaluation date is closest to 
the scheduled date will be used and, if there are two data equidistant to the scheduled date, the data 
obtained later will be used. The temporal distance from the scheduled date will be determined based 
on the Study Day, Study Day in the Open-label Cohort, and Follow-up Day. 
 
CDAI score*1, each CDAI subscore*2 (both based on the hematocrit [Ht] level at each study site)  
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day in the 
Open-label Cohort 
Follow-up 
Day 
Week 0 
Study Day: 1 
-28 to 1*3 
 
Week 0x 
Study Day in the Open-label Cohort: 1 
Day after the first 
dose of the study 
drug in the 
induction phase to 1 
 
Week 2x 
Study Day in the Open-label Cohort: 15 
2 to 28 
 


5 
 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day in the 
Open-label Cohort 
Follow-up 
Day 
Week 6x 
Study Day in the Open-label Cohort: 43 
29 to 56 
 
Week 10x 
Study Day in the Open-label Cohort: 71 
57 to 84 
 
Week 14x 
Study Day in the Open-label Cohort: 99 
85 to 112 
 
Week 18x 
Study Day in the Open-label Cohort: 127 
113 to 140 
 
Week 22x 
Study Day in the Open-label Cohort: 155 
141 to 168 
 
Week 26x 
Study Day in the Open-label Cohort: 183 
169 to 196 
 
Week 30x 
Study Day in the Open-label Cohort: 211 
197 to 224 
 
Week 34x 
Study Day in the Open-label Cohort: 239 
225 to 252 
 
Week 38x 
Study Day in the Open-label Cohort: 267 
253 to 280 
 
Week 42x 
Study Day in the Open-label Cohort: 295 
281 to 308 
 
Week 46x 
Study Day in the Open-label Cohort: 323 
309 to 336 
 
Week 50x 
Study Day in the Open-label Cohort: 351 
337 to 364 
 
Week 54x 
Study Day in the Open-label Cohort: 379 
365 to 392 
 
Week 58x 
Study Day in the Open-label Cohort: 407 
393 to 420 
 
Week 62x 
Study Day in the Open-label Cohort: 435 
421 to 448 
 
Week 66x 
Study Day in the Open-label Cohort: 463 
449 to 476 
 
Week 70x 
Study Day in the Open-label Cohort: 491 
477 to 504 
 
Week 74x 
Study Day in the Open-label Cohort: 519 
505 to 532 
 
Week 78x 
Study Day in the Open-label Cohort: 547 
533 to 560 
 
Week 82x 
Study Day in the Open-label Cohort: 575 
561 to 588 
 
Week 86x 
Study Day in the Open-label Cohort: 603 
589 to 616 
 
Week 90x 
Study Day in the Open-label Cohort: 631 
617 to 644 
 
Week 94x 
Study Day in the Open-label Cohort: 659 
645 to 686 
 
Week 94x 
(LOCF)*4 
Study Day in the Open-label Cohort:  
2 to  
 
*1 CDAI-70 response, CDAI-100 response, and clinical remission will be determined by using both 
CDAI score based on the Ht level at each study site and CDAI score based on the Ht level at the 
central laboratory, respectively. 
*2 Each CDAI subscore used for the calculation of CDAI scores will be used. 
*3 At Week 0, the acceptable window will be defined based on the Study Day, not on the Study Day 
in the Open-label Cohort. 
*4 For Week 94x (LOCF), the latest data during the period from the day after the first dose of the 
study drug in the open-label cohort onwards will be used. 


6 
 
 
Ht level*1 (tested by the central laboratory), inflammatory marker (CRP) 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day in the 
Open-label Cohort 
Follow-up 
Day 
Week 0 
Study Day: 1 
-28 to 1*2 
 
Week 0x 
Study Day in the Open-label Cohort: 1 
Day after the first 
dose of the study 
drug in the 
induction phase to 1 
 
Week 2x 
Study Day in the Open-label Cohort: 15 
2 to 28 
 
Week 6x 
Study Day in the Open-label Cohort: 43 
29 to 56 
 
Week 14x 
Study Day in the Open-label Cohort: 99 
57 to 126 
 
Week 22x 
Study Day in the Open-label Cohort: 155 
127 to 182 
 
Week 30x 
Study Day in the Open-label Cohort: 211 
183 to 238 
 
Week 38x 
Study Day in the Open-label Cohort: 267 
239 to 294 
 
Week 46x 
Study Day in the Open-label Cohort: 323 
295 to 350 
 
Week 54x 
Study Day in the Open-label Cohort: 379 
351 to 406 
 
Week 62x 
Study Day in the Open-label Cohort: 435 
407 to 462 
 
Week 70x 
Study Day in the Open-label Cohort: 491 
463 to 518 
 
Week 78x 
Study Day in the Open-label Cohort: 547 
519 to 574 
 
Week 86x 
Study Day in the Open-label Cohort: 603 
575 to 630 
 
Week 94x 
Study Day in the Open-label Cohort: 659 
631 to 686 
 
Week 94x 
(LOCF)*3 
Study Day in the Open-label Cohort:  
2 to  
 
*1 The Ht level will be handled as follows: 
 If the Ht level tested on the same date as the evaluation day of the CDAI score based on the 
Ht level at each study site is available, that Ht level will be used. 
 If the Ht level tested on the same date as the evaluation day of the CDAI score based on the 
Ht level at each study site is not available, it will be handled according to the general rules 
described directly beneath the “HANDLING OF TIME WINDOW.” 
*2 At Week 0, the acceptable window will be defined based on the Study Day, not on the Study Day 
in the Open-label Cohort. 
*3 For Week 94x (LOCF), the latest data during the period from the day after the first dose of the 
study drug in the open-label cohort onwards will be used. 
 


7 
 
Laboratory tests (hematology, blood biochemistry) 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day in the 
Open-label Cohort 
Follow-up 
Day 
Week 0 
Study Day: 1 
-28 to 1*1 
 
Week 0x 
Study Day in the Open-label Cohort: 1 
Day after the first 
dose of the study 
drug in the 
induction phase to 1 
 
Week 2x 
Study Day in the Open-label Cohort: 15 
2 to 28 
 
Week 6x 
Study Day in the Open-label Cohort: 43 
29 to 56 
 
Week 14x 
Study Day in the Open-label Cohort: 99 
57 to 126 
 
Week 22x 
Study Day in the Open-label Cohort: 155 
127 to 182 
 
Week 30x 
Study Day in the Open-label Cohort: 211 
183 to 238 
 
Week 38x 
Study Day in the Open-label Cohort: 267 
239 to 294 
 
Week 46x 
Study Day in the Open-label Cohort: 323 
295 to 350 
 
Week 54x 
Study Day in the Open-label Cohort: 379 
351 to 406 
 
Week 62x 
Study Day in the Open-label Cohort: 435 
407 to 462 
 
Week 70x 
Study Day in the Open-label Cohort: 491 
463 to 518 
 
Week 78x 
Study Day in the Open-label Cohort: 547 
519 to 574 
 
Week 86x 
Study Day in the Open-label Cohort: 603 
575 to 630 
 
Week 94x 
Study Day in the Open-label Cohort: 659 
631 to 686 
 
16 weeks after the 
last dose*2 
Follow-up Day: 112 
 
56 to 167 
*1 At Week 0, the acceptable window will be defined based on the Study Day, not on the Study Day 
in the Open-label Cohort. 
 
Laboratory test (urinalysis), 12-lead ECG 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day in the 
Open-label Cohort 
Follow-up 
Day 
Week 0 
Study Day: 1 
-28 to 1*1 
 
Week 0x 
Study Day in the Open-label Cohort: 1 
Day after the first 
dose of the study 
drug in the 
induction phase to 1 
 
Week 94x 
Study Day in the Open-label Cohort: 659 
2 to 686 
 


8 
 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day in the 
Open-label Cohort 
Follow-up 
Day 
16 weeks after the 
last dose 
Follow-up Day: 112 
 
56 to 167 
*1 At Week 0, the acceptable window will be defined based on the Study Day. 
 
Vital signs, body weight 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day in the 
Open-label Cohort 
Follow-up 
Day 
Week 0 
Study Day: 1 
-28 to 1*1 
 
Week 0x 
Study Day in the Open-label Cohort: 1 
Day after the first 
dose of the study 
drug in the 
induction phase to 1 
 
Week 2x 
Study Day in the Open-label Cohort: 15 
2 to 28 
 
Week 6x 
Study Day in the Open-label Cohort: 43 
29 to 56 
 
Week 10x 
Study Day in the Open-label Cohort: 71 
57 to 84 
 
Week 14x 
Study Day in the Open-label Cohort: 99 
85 to 112 
 
Week 18x 
Study Day in the Open-label Cohort: 127 
113 to 140 
 
Week 22x 
Study Day in the Open-label Cohort: 155 
141 to 168 
 
Week 26x 
Study Day in the Open-label Cohort: 183 
169 to 196 
 
Week 30x 
Study Day in the Open-label Cohort: 211 
197 to 224 
 
Week 34x 
Study Day in the Open-label Cohort: 239 
225 to 252 
 
Week 38x 
Study Day in the Open-label Cohort: 267 
253 to 280 
 
Week 42x 
Study Day in the Open-label Cohort: 295 
281 to 308 
 
Week 46x 
Study Day in the Open-label Cohort: 323 
309 to 336 
 
Week 50x 
Study Day in the Open-label Cohort: 351 
337 to 364 
 
Week 54x 
Study Day in the Open-label Cohort: 379 
365 to 392 
 
Week 58x 
Study Day in the Open-label Cohort: 407 
393 to 420 
 
Week 62x 
Study Day in the Open-label Cohort: 435 
421 to 448 
 
Week 66x 
Study Day in the Open-label Cohort: 463 
449 to 476 
 
Week 70x 
Study Day in the Open-label Cohort: 491 
477 to 504 
 
Week 74x 
Study Day in the Open-label Cohort: 519 
505 to 532 
 
Week 78x 
Study Day in the Open-label Cohort: 547 
533 to 560 
 
Week 82x 
Study Day in the Open-label Cohort: 575 
561 to 588 
 


9 
 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day in the 
Open-label Cohort 
Follow-up 
Day 
Week 86x 
Study Day in the Open-label Cohort: 603 
589 to 616 
 
Week 90x 
Study Day in the Open-label Cohort: 631 
617 to 644 
 
Week 94x 
Study Day in the Open-label Cohort: 659 
645 to 686 
 
16 weeks after the 
last dose 
Follow-up Day: 112 
 
56 to 167 
*1 At Week 0, the acceptable window will be defined based on the Study Day, not on the Study Day 
in the Open-label Cohort. 
 
AVA, neutralizing antibody 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day in the 
Open-label Cohort 
Follow-up 
Day 
Week 0 
Study Day: 1 
-28 to 1*1 
 
Week 0x 
Study Day in the Open-label Cohort: 1 
Day after the first 
dose of the study 
drug in the 
induction phase to 1 
 
Week 10x 
Study Day in the Open-label Cohort: 71 
2 to 84 
 
Week 30x 
Study Day in the Open-label Cohort: 211 
85 to 322 
 
Week 62x 
Study Day in the Open-label Cohort: 435 
323 to 546 
 
Week 94x 
Study Day in the Open-label Cohort: 659 
547 to 686 
 
16 weeks after the 
last dose 
Follow-up Day: 112 
 
56 to 167 
*1 At Week 0, the acceptable window will be defined based on the Study Day, not on the Study Day 
in the Open-label Cohort. 
 
Follow-up survey 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up 
Day 
6 months after the 
last dose 
Follow-up Day: 182 
 
1 to 273 
12 months after the 
last dose 
Follow-up Day: 365 
 
274 to 455 
18 months after the 
last dose 
Follow-up Day: 547 
 
456 to 638 


10 
 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up 
Day 
24 months after the 
last dose 
Follow-up Day: 730 
 
639 to 820 
 
OTHER HANDLING 
In principle, if any variable value used for calculation or adjudication is missing, the result of the 
calculation or adjudication will be handled as missing. If other handling of missing data is described, 
follow that handling. 
• 
Duration of study drug exposure in the open-label cohort (days): Date of the last dose of the 
study drug in the open-label cohort − Date of the first dose of the study drug in the open-label 
cohort + 1 
• 
Duration on study after the first dose of the study drug in the open-label cohort (days): Date of 
last visit or contact − Date of the first dose of the study drug in the open-label cohort + 1 
• 
Duration of MLN0002 exposure (days): Date of the last dose of MLN0002 − Date of the first 
dose of MLN0002 + 1 
• 
Duration on study after the first dose of MLN0002 (days): Date of last visit or contact − Date of 
the first dose of MLN0002 + 1 
• 
BMI (kg/m2) = Weight (kg) / (Height [cm]/100)2 (round off to the first decimal place) 
• 
Duration of CD (years): (Date of informed consent [year and month] − Date of CD diagnosis 
[year and month]) / 12 (round off to the first decimal place) 
 
Only the year and month for the date of informed consent will be used. 
 
The unit for “Date of informed consent (year and month) − Date of CD diagnosis (year and 
month)” will be “months.” 
 
If the year of CD diagnosis is unknown, the duration of CD will be handled as “Missing.” 
If only the month of CD diagnosis is unknown, the duration of CD will be calculated by 
setting the month of CD diagnosis as January. 
• 
Prior corticosteroids failure: If corticosteroid resistance, dependence, or intolerance is “Yes,” 
prior corticosteroids failure will be defined as “Yes.” Any response other than the above will be 
defined as “No.” 
• 
Classification 1 of prior corticosteroids failure: Subjects for whom prior corticosteroids failure 
is “Yes” are classified as follows:  
 
Subjects for whom corticosteroid resistance is “Yes” are classified as “Resistance.” 
 
Among subjects for whom corticosteroid resistance is not “Yes,” subjects for whom 
corticosteroid dependence is “Yes” are classified as “Dependence.” 
 
Among subjects for whom corticosteroid resistance is not “Yes” as well as corticosteroid 
dependence not being “Yes,” subjects for whom corticosteroid intolerance is “Yes” are 
classified as “Intolerance.” 
• 
Classification 2 of prior corticosteroids failure: Subjects for whom prior corticosteroids failure 
is “Yes” are classified as follows:  
 
Subjects for whom corticosteroid resistance is “Yes” or corticosteroid dependence is 
“Yes” are classified as “Refractory.” 
 
Among subjects for whom corticosteroid resistance is not “Yes” as well as corticosteroid 
dependence not being “Yes,” subjects for whom corticosteroid intolerance is “Yes” are 
classified as “Intolerance.” 


11 
 
• 
Prior immunomodulators failure: If either immunomodulator refractory or intolerance is “Yes,” 
prior immunomodulators failure will be defined as “Yes.” Any response other than the above 
will be defined as “No.” 
• 
Classification of prior immunomodulators failure: Subjects for whom prior immunomodulators 
failure is “Yes” are classified as follows:  
 
Subjects for whom immunomodulator refractory is “Yes” are classified as “Refractory.” 
 
Among the subjects for whom immunomodulator refractory is not “Yes,” subjects for 
whom immunomodulatory intolerance is “Yes” are classified as “Intolerance.”  
• 
Prior TNFα antagonist failure: If inadequate response, loss of response, or intolerance to the 
TNFα antagonist is “Yes,” prior TNFα antagonist failure will be defined as “Yes.” Any 
response other than the above will be defined as “No.” 
• 
Number of drugs of TNFα antagonist failure: Among the drugs entered to prior treatment 
failure (TNFα antagonist) for CD, subjects whose WHO Drug is coded with 1 type of drug with 
Preferred Name are classified as “Treatment failure with 1 drug.” Similarly, subjects who are 
coded with 2 types of drugs are classified as “Treatment failure with 2 drugs” and subjects who 
are coded with 3 types of drugs as “Treatment failure with 3 drugs.” Subjects who are not coded 
with any drug in the prior treatment failure (TNFα antagonist) for CD are classified as “None.” 
• 
Classification of prior TNFα antagonist failure: Subjects for whom prior TNFα antagonist 
failure is “Yes” are classified as follows:  
 
Subjects for whom TNFα antagonist inadequate response is “Yes” are classified as 
“Inadequate response.” 
 
Among subjects for whom TNFα antagonist inadequate response is not “Yes,” subjects for 
whom TNFα antagonist loss of response is “Yes” are classified as “Loss of response.” 
 
Among subjects for whom TNFα antagonist inadequate response is not “Yes” as well as 
TNFα antagonist loss of response not being “Yes,” subjects for whom TNFα antagonist 
intolerance is “Yes” are classified as “Intolerance.” 
• 
Prior immunomodulators failure (excluding prior TNFα antagonist failure): If prior TNFα 
antagonist failure is “No” and prior immunomodulators failure is “Yes,” prior 
immunomodulators failure (excluding prior TNFα antagonist failure) will be defined as “Yes.” 
All others will be defined as “No.” 
• 
Prior corticosteroids failure only: If prior TNFα antagonist failure is “No,” prior 
immunomodulators failure is “No,” and prior corticosteroids failure is “Yes,” prior 
corticosteroids failure only will be defined as “Yes.” All others will be defined as “No.” 
• 
Prior immunomodulators and TNFα antagonist failure: If prior immunomodulators failure is 
“Yes” and prior TNFα antagonist failure is “Yes,” prior immunomodulators and TNFα 
antagonist failure will be defined as “Yes.” All others will be defined as “No.” 
• 
Completion of the study drug infusion: If the infusion of the study drug is “Completed” or dose 
of the study drug is ≥79 mL (percentage of dose against prepared study drug of 105 mL is 
≥75%), the study drug infusion will be defined as “Completed.” All others will be defined as 
“Incompleted.” 
 
The Ht level and CDAI score will be handled as follows: 
• 
The CDAI score, CDAI subscore, and Ht levels used for analysis will be determined at the 
central laboratory unless otherwise noted. 
• 
CDAI score: The sum of CDAI subscores of (1) to (8) defined in the table below. 


12 
 
(1) Number of liquid or very soft stools during the last 1 week 
× 2 
(2) Abdominal pain during the last 1 week 
(7-day total of daily abdominal pain scores on a following scale) 
0=None, 1=Mild, 2=Moderate, 3=Severe 
× 5 
(3) Subjective general well being during the last 1 week 
(7-day total of daily general well-being scores on a following scale) 
0=Generally well, 1=Slightly under par, 2=Poor, 3=Very poor, 
4=Terrible 
× 7 
(4) Current number of the following extraintestinal manifestations of CD 
1) 
Arthritis/arthralgia 
2) 
Iritis/uveitis 
3) 
Erythema nodosum/pyoderma gangrenosum/aphthous stomatitis 
4) 
Anal fissure, anal fistula, or perianal abscess 
5) 
Other fistula 
6) 
Fever over 37.8°C during the last 1 week 
× 20 
(5) Use of antidiarrheal drugs (e.g., lopemin) or opiates for diarrhea 
0=No, 1=Yes 
× 30 
(6) Abdominal mass 
0=None, 2=Questionable, 5=Definite 
× 10 
(7) Hematocrit (%)Note 1) 
Males: subtract value from 47, Females: subtract value from 42 
× 6 
(8) Body weight : Standard weight (body-weight ratio)Note 2) 
[1 − (Body weight / Standard weight)] × 100 
× 1 
Note 1) If hematocrit subtotal <0, enter 0. 
Note 2) If body weight subtotal <-10, enter -10. 
• 
The CDAI score will be calculated using subscores on the same day of evaluation. For subscore 
(7), however, the CDAI score will be calculated using the Ht level obtained within the same 
visit window if the Ht level on the same day of evaluation is not available. 
• 
If any CDAI subscore is missing, the CDAI score will be handled as missing. 
• 
CDAI-70 response: Subjects will be classified as “CDAI-70 response” if “a ≥70-point decrease 
in CDAI score from baseline” is achieved. All others will be classified as “Non-CDAI-70 
response.” However, if any CDAI score change is missing, it will be handled as missing. Then, 
if the adjudication result at that visit is missing (including cases with no data due to study 
discontinuation) after processing the “HANDLING OF TIME WINDOW,” subjects will be 
classified as “Non-CDAI-70 response.” 
• 
CDAI-100 response: Subjects will be classified as “CDAI-100 response” if “a ≥100-point 
decrease in CDAI score from baseline” is achieved. All others will be classified as 
“Non-CDAI-100 response.” However, if any CDAI score change is missing, it will be handled 
as missing. Then, if the adjudication result at that visit is missing (including cases with no data 
due to study discontinuation) after processing the “HANDLING OF TIME WINDOW,” 
subjects will be classified as “Non-CDAI-100 response.” 
• 
Clinical remission: Subjects will be classified as “Clinical remission” if a “CDAI score of 
≤150” is achieved. All others will be classified as “Non-remission.” However, if any of the 
CDAI scores is missing, it will be handled as missing. Then, if the adjudication result at that 
visit is missing (including cases with no data due to study discontinuation) after processing the 
“HANDLING OF TIME WINDOW,” subjects will be classified as “Non-remission.” 


13 
 
 
Prior TNFα antagonist use, concomitant use of immunomodulators at baseline, and concomitant use 
of oral corticosteroids at baseline will be defined as follows: 
• 
Prior TNFα antagonist use: Subjects coded with at least 1 drug of Preferred Name of WHO 
Drug in the following table for medication history will be classified as “Yes.” All others will be 
classified as “No.” 
 
Preferred Name 
Infliximab 
Adalimumab 
Golimumab 
 
• 
Concomitant use of immunomodulators at baseline: Subjects who received any concomitant 
medication (for treatment of CD) which is classified as “immunomodulator” in the concomitant 
medication (for treatment of CD) which was started before the first dose of the study drug in the 
induction phase and continued in the induction phase will be classified as “Yes.” All others will 
be classified as “No.” 
 
Any concomitant medication (for treatment of CD) which was started after the first dose of 
the study drug in the induction phase is not subject to this handling. 
 
• 
Concomitant use of oral corticosteroids at baseline: Subjects who received any concomitant 
medication (for treatment of CD) which is classified as “corticosteroid” and whose route of 
administration is “oral” in the concomitant medication (for treatment of CD) which was started 
before the first dose of the study drug in the induction phase and continued in the induction 
phase will be classified as “Yes.” All others will be classified as “No.” 
 
Any concomitant medication (for treatment of CD) which was started after the first dose of 
the study drug in the induction phase is not subject to this handling. 
 
Concurrent extraintestinal manifestations (based on CDAI subscore [4]), concurrent extraintestinal 
manifestations (based on case report form [CRF] concurrent medical condition section), surgical 
history for CD, medical history of fistula or concurrent medical condition related to fistula within 1 
year before signing of informed consent, and concurrent medical condition related to fistula will be 
defined as follows: 
• 
Concurrent extraintestinal manifestations (based on CDAI subscore [4]): Subjects whose CDAI 
subscore [4] at baseline is greater than 0 will be classified as “Yes.” All others will be classified 
as “No.” 
• 
Concurrent extraintestinal manifestations (based on CRF concurrent medical condition section): 
Subjects recorded to have concurrent extraintestinal manifestations of CD in the CRF 
concurrent medical condition section will be classified as “Yes.” All others will be classified as 
“No.” 
• 
Surgical history for CD: Subjects coded with at least one PT in the following table for medical 
history will be classified as “Yes.” All others will be classified as “No.” 


14 
 
Preferred Term 
Anal skin tag excision 
Colectomy 
Crohn's disease 
Enterocutaneous fistula 
Ileal operation 
Ileectomy 
Ileocolectomy 
Ileocolostomy 
Ileostomy 
Ileostomy closure 
Intestinal resection 
Proctectomy 
Sigmoidectomy 
Small intestinal resection 
Small intestine operation 
Stricturoplasty 
Urinary cystectomy 
 
• 
Medical history of fistula or concurrent medical condition related to fistula within 1 year before 
signing of informed consent: Subjects coded with at least one PT in the following table for 
medical history or concurrent medical condition will be classified as “Yes.” All others will be 
classified as “No.” 
Medical history 
Preferred Term 
Anal fistula 
Fistula of small intestine 
 
Concurrent medical condition 
Preferred Term 
Anal fistula 
Enterocutaneous fistula 
Female genital tract fistula 
 
• 
Concurrent medical condition related to fistula: Subjects coded with at least one PT in the 
following table for concurrent medical condition will be classified as “Yes.” All others will be 
classified as “No.” 
Preferred Term 
Anal fistula 
Enterocutaneous fistula 
Female genital tract fistula 
 
Negative or positive status of the neutralizing antibody will be determined as follows: 
• 
“Positive” if the neutralizing antibody is positive for AVA and neutralizing antibody with the 
same VISIT in each subject. “Negative” if the neutralizing antibody is negative or AVA is 
negative. The neutralizing antibody will be handled as missing if it does not correspond to any 


15 
 
of the above. 
 
After determining the negative or positive status of the neutralizing antibody at each visit with the 
above-mentioned logic, the following determination will be made: 
• 
AVA in the induction phase, maintenance phase, and open-label cohort 
 
Subjects who were determined to be AVA-positive at any visit after the day of the first 
dose of the study drug in the induction phase, in the maintenance phase, or in the 
open-label cohort will be classified as “AVA-positive.” 
 
Subjects who were determined to be AVA-negative at all visits (except for those with 
missing values) after the day of the first dose of the study drug in the induction phase, in 
the maintenance phase, and in the open-label cohort will be classified as “AVA-negative.” 
 
Subjects whose AVA values are missing at all visits after the day of the first dose of the 
study drug in the induction phase, in the maintenance phase, and in the open-label cohort 
will be classified as missing. 
• 
Persistently positive in the induction phase, maintenance phase, and open-label cohort 
 
“Subjects who were determined to be AVA-positive in at least 2 consecutive samples 
sorted by date of blood collection after the day of the first dose of the study drug in the 
induction phase” will be classified as persistently positive. 
• 
Transiently positive in the induction phase, maintenance phase, and open-label cohort 
 
Subjects who do not correspond to “subjects who were determined to be AVA-positive in 
at least 2 consecutive samples sorted by date of blood collection after the day of the first 
dose of the study drug in the induction phase,” and were determined to be AVA-positive in 
at least one sample collected after the day of the first dose of the study drug in the 
induction phase will be classified as transiently positive. 
• 
Neutralizing antibody in the induction phase, maintenance phase, and open-label cohort 
 
Subjects who were determined to be positive for neutralizing antibodies at any visit after 
the day of the first dose of the study drug in the induction phase, in the maintenance phase, 
or in the open-label cohort will be classified as “Positive for neutralizing antibodies.” 
 
Subjects who were determined to be negative for neutralizing antibodies at all visits 
(except for those with missing values) after the day of the first dose of the study drug in 
the induction phase, in the maintenance phase, and in the open-label cohort will be 
classified as “Negative for neutralizing antibodies.” 
 
Subjects whose neutralizing antibody values are missing at all visits after the day of the 
first dose of the study drug in the induction phase, in the maintenance phase, and in the 
open-label cohort will be classified as missing. 
• 
Start date of concomitant medication/therapy in the open-label cohort that falls under the 
category of rescue treatment: The earliest date among the following dates in the open-label 
cohort. 
 
Date of the first dose of concomitant medication (for treatment of CD) that falls under the 
category of rescue treatment 
 
Date of initiation of concomitant therapy that falls under the category of rescue treatment 
• 
Start date of concomitant medication/therapy in the open-label cohort: The earliest date among 
the following dates in the open-label cohort. 
 
Date of the first dose of concomitant medication (for treatment of CD) 
 
Date of initiation of concomitant therapy 
 


16 
 
Lymphocytes and neutrophils will be calculated with the following formula: 
• 
Lymphocytes = WBC × lymphocytes (%)  
• 
Neutrophils = WBC × neutrophils (%)  
 


17 
 
1 STUDY SUBJECTS, DEMOGRAPHICS, AND OTHER BASELINE CHARACTERISTICS 
1.1 Disposition of Subjects 
1.1.1 Study Information 
Analysis set: 
All subjects who signed the informed consent form 
Analysis variables: 
Date first subject signed the informed consent form 
 
Date of the last visit or contact in the open-label cohort, whichever 
comes latest 
 
MedDRA version 
 
WHO Drug version 
 
SAS version used for creating the datasets 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
 
(1) 
Display of the analysis variables 
 
1.1.2 Disposition of All Subjects Who Did Not Enter in the Open-label Cohort 
Analysis set: 
All subjects who received at least one dose of the study drug in the 
induction or maintenance phases and did not enter in the open-label 
cohort 
Analysis variables: 
Categories in parenthesis [  ] (hereinafter the same) 
 
Age (years) 
[Min≤ - ≤34, 35≤ - ≤Max] 
 
 
[Min≤ - ≤64, 65≤ - ≤Max] 
 
Gender 
[Male, Female] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
(1) 
Frequency distributions for categorical variables and 
summary statistics for continuous variables 
 
1.1.3 Subject Eligibility 
Analysis set: 
Subjects who received at least one dose of the study drug in the 
induction or maintenance phases 
Analysis variables: 
Eligibility for entering into the 
open-label cohort 
[Eligible, Not eligible] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
 
(1) 
Frequency distributions 
 
1.1.4 Number of Subjects Who Entered in the Open-label Cohort by Site 
Analysis set: 
All subjects who entered in the open-label cohort 
Analysis variables: 
Eligibility for entering into the 
open-label cohort 
[Eligible] 
Stratum:  
Study site 
[Site numbers will be used as 
categories] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables for each stratum. 
 
(1) 
Frequency distributions 
 


18 
 
1.1.5 Disposition of Subjects 
1.1.5.1 
Disposition of Subjects 
Analysis set: 
All subjects who entered in the open-label cohort 
Analysis variables: 
Study drug administration status 
in the open-label cohort 
[Not treated] 
 
Reason for not being treated 
[Pretreatment event/Adverse 
event, Major protocol deviation, 
Lost to follow-up, Voluntary 
withdrawal, Study termination, 
Pregnancy, Lack of efficacy, 
Other] 
 
Study drug completion status in 
the open-label cohort 
[Completed, Incompleted] 
 
Reason for not being 
completed 
[Pretreatment event/Adverse 
event, Major protocol deviation, 
Lost to follow-up, Voluntary 
withdrawal, Study termination, 
Pregnancy, Lack of efficacy, 
Other] 
 
Study visit completion status in 
the open-label cohort 
[Completed, Incompleted] 
 
Reason for not being 
completed 
[Pretreatment event/Adverse 
event, Major protocol deviation, 
Lost to follow-up, Voluntary 
withdrawal, Study termination, 
Pregnancy, Lack of efficacy, 
Other] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. When calculating the percentages of the reasons for not 
being treated, the number of subjects who did not receive the study 
drug in the open-label cohort will be used as the denominator. When 
calculating the percentages of the reasons for not being completed, 
the number of subjects who did not complete the study drug/study 
visit in the open-label cohort will be used as the denominator. 
 
(1) 
Frequency distributions 
 
1.1.6 Study Drug Completion Status and Study Visit Completion Status 
Analysis set: 
All subjects who entered in the open-label cohort 
Analysis variables: 
Study drug completion status in 
the open-label cohort 
[Completed, Incompleted] 
 
Reason for not being 
completed 
[Pretreatment event/Adverse 
event, Major protocol deviation, 
Lost to follow-up, Voluntary 
withdrawal, Study termination, 
Pregnancy, Lack of efficacy, 
Other] 


19 
 
 
Study visit completion status in 
the open-label cohort 
[Completed, Incompleted] 
 
Reason for not being 
completed 
[Pretreatment event/Adverse 
event, Major protocol deviation, 
Lost to follow-up, Voluntary 
withdrawal, Study termination, 
Pregnancy, Lack of efficacy, 
Other] 
Categories: 
Duration of study drug exposure 
in the open-label cohort (days) 
[0, 1≤ - ≤42, 43≤ - ≤98,  
99≤ - ≤210, 211≤ - ≤322,  
323≤ - ≤434, 435≤ - ≤546,  
547≤ - ≤Max] 
 
Duration on study after the first 
dose of the study drug in the 
open-label cohort (days) 
[0, 1≤ - ≤42, 43≤ - ≤98,  
99≤ - ≤210, 211≤ - ≤322, 
323≤ - ≤434, 435≤ - ≤546, 
547≤ - ≤Max] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
Frequency distributions will be provided for study drug completion 
status in the open-label cohort in the analysis of (1). Frequency 
distributions will be provided for study visit completion status in the 
open-label cohort in the analysis of (2). 
 
(1) 
Frequency distribution by duration of study drug exposure in 
the open-label cohort 
(2) 
Frequency distribution by duration on study after the first 
dose of the study drug in the open-label cohort 
 
1.1.7 Protocol Deviations and Analysis Sets 
1.1.7.1 
Protocol Deviations in the Open-label Cohort 
Analysis set: 
All subjects who entered in the open-label cohort 
Analysis variables: 
Protocol deviations in the 
open-label cohort 
[Major GCP violations, 
Deviations of protocol entry 
criteria, Deviations of 
discontinuation criteria, 
Deviations related to treatment 
procedure or dose, Deviations 
concerning excluded medication 
or therapy, Deviations to avoid 
emergency risk, Other] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
Frequency distribution of subjects with protocol deviations in the 
open-label cohort will be provided for each deviation category 
above. A subject who has several deviations that can be classified 
into the same category will be counted once in each appropriate 
category (overlapped counting). 
(1) 
Frequency distributions 


20 
 
 
1.1.7.2 
Analysis Sets of All Subjects Who Entered in the Open-label Cohort 
Analysis set: 
All subjects who entered in the open-label cohort 
Analysis variables: 
Handling of subjects and subject 
data in the open-label cohort in 
analysis sets 
Inclusion/Exclusion of analysis sets 
Full analysis set in the open-label 
cohort 
Safety analysis set in the 
open-label cohort 
[Categories are based on the 
specifications in “Handling 
Rules for Analysis Data”] 
 
[Included] 
 
[Included] 
Analysis methodology: The following analyses of (1) to (3) will be performed for the above 
analysis variables. 
A subject who corresponds to several categories in (1) and (2) will 
be counted once in each appropriate category (overlapped counting). 
 
(1) Frequency distributions concerning the handling of subjects in 
the open-label cohort in each analysis set 
(2) Frequency distributions concerning the handling of subject data 
in the open-label cohort in each analysis set 
(3) Frequency distributions concerning the number of subjects 
included in each analysis set 
 
1.2 Demographic and Other Baseline Characteristics 
1.2.1 Distribution of Baseline Demographics 
Analysis set: 
All subjects who entered in the open-label cohort 
Analysis variables: 
Age (years) 
[Min≤ - ≤34, 35≤ - ≤Max] 
 
 
[Min≤ - ≤64, 65≤ - ≤Max] 
 
Gender 
[Male, Female] 
 
Height (cm) 
 
 
Weight (kg) at baseline 
[Min≤ - ≤49.9, 50.0≤ - ≤59.9, 
60.0≤ - ≤69.9, 70.0≤ - ≤79.9, 
80.0≤ - ≤Max] 
 
BMI (kg/m2) at baseline 
[Min≤ - ≤18.4, 18.5≤ - ≤24.9, 
25.0≤ - ≤Max] 
 
Smoking classification 
[Never smoked, Current 
smoker, Ex-smoker] 
 
Duration of CD (years) 
[Min≤ - <1, 1≤ - <3, 3≤ - <7,  
7≤ - ≤Max, Missing] 
 
Prior corticosteroids failure 
[Yes, No] 
 
Classification 1 of prior 
corticosteroids failure 
[Resistance, Dependence, 
Intolerance] 
 
Classification 2 of prior 
corticosteroids failure 
[Refractory, Intolerance] 
 
Prior immunomodulators failure 
[Yes, No] 
 
Classification of prior 
immunomodulators failure 
[Refractory, Intolerance] 
 
Prior TNFα antagonist failure 
[Yes, No] 


21 
 
 
Number of drugs of TNFα 
antagonist failure 
[1 drug, 2 drugs, 3 drugs, 
None] 
 
Classification of prior TNFα 
antagonist failure 
[Inadequate response, Loss 
of response, Intolerance] 
 
Worst prior treatment failures 
[Prior TNFα antagonist 
failure, Prior 
immunomodulators failure 
but not TNFα antagonist 
failure, Prior corticosteroids 
failure only] 
 
Prior immunomodulators and TNFα 
antagonist failure 
[Yes, No] 
 
Prior TNFα antagonist use 
[Yes, No] 
 
Infliximab 
[Yes, No] 
 
Adalimumab 
[Yes, No] 
 
Golimumab 
[Yes, No] 
 
Concomitant use of enteral nutrient 
at baseline 
[Yes, No] 
 
Concomitant use of 5-ASA at 
baseline 
[Yes, No] 
 
Concomitant use of 
immunomodulators at baseline 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids at baseline 
[Yes, No] 
 
No concomitant use of oral 
corticosteroids and No concomitant 
use of immunomodulators at 
baseline 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids and No concomitant 
use of immunomodulators at 
baseline (concomitant use of oral 
corticosteroids only) 
[Yes, No] 
 
No concomitant use of oral 
corticosteroids and Concomitant use 
of immunomodulators at baseline 
(concomitant use of 
immunomodulators only) 
[Yes, No] 
 
Concomitant use of oral 
corticosteroids and Concomitant use 
of immunomodulators at baseline 
[Yes, No] 
 
CDAI score at baseline 
[Min≤ - ≤220, 220< - ≤330, 
330< - ≤450, 450< - ≤Max] 
 
CDAI subscore (1): Number of 
liquid or very soft stools during the 
last 1 week at baseline 
 


22 
 
 
CDAI subscore (2): Abdominal pain 
during the last 1 week at baseline 
 
 
CDAI subscore (3): Subjective 
general well being during the last 1 
week at baseline 
 
 
CDAI subscore (4): Current number 
of extraintestinal manifestations of 
CD (e.g., arthritis/arthralgia) at 
baseline 
[0, 1, 2, 3, 4, 5, 6] 
 
CDAI subscore (5): Use of 
antidiarrheal drugs (e.g., lopemin) or 
opiates for diarrhea at baseline 
[No, Yes] 
 
CDAI subscore (6): Abdominal 
mass at baseline 
[None, Questionable, 
Definite] 
 
CDAI subscore (7): Hematocrit 
level at baseline 
 
 
CDAI subscore (8): Body weight : 
Standard weight (body-weight ratio) 
at baseline 
 
 
Disease localization 
[Small intestinal, Large 
intestinal, Small/Large 
intestinal] 
 
Concurrent extraintestinal 
manifestations (based on CDAI 
subscore [4]) 
[Yes, No] 
 
Concurrent extraintestinal 
manifestations (based on CRF 
concurrent medical condition 
section) 
[Yes, No] 
 
CRP (mg/dL) at baseline 
[Min≤ - ≤0.3, 0.3< - ≤0.5, 
0.5< - ≤1.0, 1.0< - ≤1.6, 
1.6< - ≤Max] 
 
Surgical history for CD 
[Yes, No] 
 
Medical history of fistula or 
concurrent medical condition related 
to fistula within 1 year before 
signing of informed consent 
[Yes, No] 
 
Concurrent medical condition 
related to fistula 
[Yes, No] 
 
Number of MLN0002 infusions in 
the induction and maintenance 
phases 
[1, 2, 3, 4, 5, 6, 7, 8, 9] 
 
Route to the open-label cohort 
[Route 1, Route 2, Route 3, 
Route 4, Route 5, Route 6, 
Route 7, Route 8] 


23 
 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
(1) Frequency distributions for categorical variables and summary 
statistics for continuous variables 
 
1.2.2 Medical History, Concurrent Medical Conditions 
Analysis set: 
Safety analysis set in the open-label cohort 
Analysis variables: 
Medical history 
 
Concurrent medical conditions (concurrent extraintestinal 
manifestations of CD) 
 
Concurrent medical conditions (other than concurrent extraintestinal 
manifestations of CD) 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
The analysis variables will be coded by use of MedDRA and will be 
summarized based on the SOC and PT. SOC will be sorted 
alphabetically and PT will be sorted in decreasing frequency. 
(1) Frequency distributions for medical history (by SOC and PT) 
(2) Frequency distributions for concurrent medical conditions 
(concurrent extraintestinal manifestations of CD) (by SOC and 
PT) 
(3) Frequency distributions for concurrent medical conditions 
(other than concurrent extraintestinal manifestations of CD) (by 
SOC and PT) 
 
The method of counting events when providing each frequency 
distribution will be as follows: 
[Number of subjects] 
A subject with multiple occurrences of medical history or 
concurrent medical condition within a SOC will be counted only 
once in that SOC. A subject with multiple occurrences of medical 
history or concurrent medical condition within a PT will be counted 
only once in that PT. 
 
1.2.3 Medication History, Concomitant Medications, Concomitant Therapies 
Analysis set: 
Safety analysis set in the open-label cohort 
Analysis variables: 
Medication history 
 
 
Concomitant medications (for treatment of 
CD) in the open-label cohort 
 
 
Classification of concomitant medications 
(for treatment of CD) in the open-label 
cohort 
[5-ASA, 
Corticosteroids, 
Immunomodulators, 
Enteral nutrients, 
Other] 
 
Concomitant medications (for treatment of 
CD) in the open-label cohort that fall under 
the category of rescue treatments 
 


24 
 
 
Classification of concomitant medications 
(for treatment of CD) in the open-label 
cohort that fall under the category of 
rescue treatments 
[5-ASA, 
Corticosteroids, 
Immunomodulators, 
Enteral nutrients, 
Other] 
 
Concomitant medications (for other than 
treatment of CD) in the open-label cohort 
 
 
Concomitant therapies in the open-label 
cohort 
[Yes, No] 
 
Concomitant therapies in the open-label 
cohort that fall under the category of 
rescue treatments 
[Yes, No] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
Medication history, concomitant medications (for treatment of CD) 
in the open-label cohort, concomitant medications (for treatment of 
CD) in the open-label cohort that fall under the category of rescue 
treatments, and concomitant medications (for other than treatment of 
CD) in the open-label cohort will be coded by use of WHO Drug 
and summarized based on Preferred Name, which will be sorted in 
decreasing frequency. 
A subject who has been administered several medications with the 
same Preferred Name will be counted only once for that Preferred 
Name. 
(1) Frequency distributions for medication history 
(2) Frequency distributions for concomitant medications (for 
treatment of CD) in the open-label cohort that were ongoing at 
the first dose of the study drug in the open-label cohort and 
continued in the open-label cohort, and concomitant 
medications (for treatment of CD) in the open-label cohort that 
started after the first dose of the study drug in the open-label 
cohort by category 
(3) Frequency distributions for concomitant medications (for 
treatment of CD) in the open-label cohort that fall under the 
category of rescue treatments, were ongoing at the first dose of 
the study drug in the open-label cohort and continued in the 
open-label cohort, and concomitant medications (for treatment 
of CD) in the open-label cohort that fall under the category of 
rescue treatments and started after the first dose of the study 
drug in the open-label cohort by category 
(4) Frequency distributions for concomitant medications (for other 
than treatment of CD) in the open-label cohort that were 
ongoing at the first dose of the study drug in the open-label 
cohort and continued in the open-label cohort, and concomitant 
medications (for other than treatment of CD) in the open-label 
cohort that started after the first dose of the study drug in the 
open-label cohort 


25 
 
(5) Frequency distributions for presence or absence of concomitant 
therapies in the open-label cohort that were ongoing at the first 
dose of the study drug in the open-label cohort and continued in 
the open-label cohort, and concomitant therapies in the 
open-label cohort that started after the first dose of the study 
drug in the open-label cohort 
(6) Frequency distributions for the presence or absence of 
concomitant therapies in the open-label cohort that fall under 
the category of rescue treatments, were ongoing at the first dose 
of the study drug in the open-label cohort and continued in the 
open-label cohort, and concomitant therapies in the open-label 
cohort that fall under the category of rescue treatments and 
started after the first dose of the study drug in the open-label 
cohort 
 
1.3 Measurement of Compliance Status for Treatment 
1.3.1 Study Drug Exposure and Compliance 
Analysis set: 
Safety analysis set in the open-label cohort 
Analysis variables: 
Duration of study drug exposure in the 
open-label cohort (days) 
[1≤ - ≤42,  
43≤ - ≤98,  
99≤ - ≤210,  
211≤ - ≤322,  
323≤ - ≤434,  
435≤ - ≤546,  
547≤ - ≤Max] 
 
Duration on study after the first dose of the 
study drug in the open-label cohort (days) 
[1≤ - ≤42,  
43≤ - ≤98,  
99≤ - ≤210,  
211≤ - ≤322,  
323≤ - ≤434,  
435≤ - ≤546,  
547≤ - ≤Max] 
 
Number of study drug infusions in the 
open-label cohort (times) 
[1, 2, 3, 4, 5, 6, 7, 
8, 9, 10, 11, 12, 
13, 14] 
 
Number of completed infusions of the study 
drug in the open-label cohort (times) 
[0, 1, 2, 3, 4, 5, 6, 
7, 8, 9, 10, 11, 
12, 13, 14] 
 
Number of completed or incompleted infusions 
in total infusions in the open-label cohort 
[Completed, 
Incompleted] 
Analysis methodology: 
 
The following analysis will be performed for the above analysis 
variables. 
(1) Frequency distributions for categorical variables and summary 
statistics for continuous variables 
 
In the frequency distributions for number of completed or 
incompleted infusions in total infusions in the open-label cohort, the 
sum of the number of completed infusions in the open-label cohort 


26 
 
will be counted as frequency for “Completed,” and the sum of the 
number of incompleted infusions will be counted as frequency for 
“Incompleted.” When calculating the percentage, the sum of the 
number of completed infusions and the number of incompleted 
infusions (i.e., number of total infusions in the open-label cohort) 
will be used as the denominator. 
 


27 
 
2 EFFICACY ANALYSIS 
2.1 Other Endpoints and Analysis Methodology 
2.1.1 Endpoints Related to CDAI Scores 
Analysis set: 
Full analysis set in the open-label cohort 
Analysis variables: 
Clinical remission 
[Clinical remission, 
Non-remission] 
 
CDAI-100 response 
[CDAI-100 response, 
Non-CDAI-100 
response] 
 
CDAI-70 response 
[CDAI-70 response, 
Non-CDAI-70 
response] 
 
CDAI score change over time 
 
 
Each CDAI subscore change over time 
 
Stratum:  
Route to the open-label cohort 
[Route 1, Route 2,  
Route 3, Route 4,  
Route 5, Route 6,  
Route 7, Route 8] 
Visit: 
Weeks 0, 0x, 2x, 6x, 14x, 22x, 30x, 38x, 46x, 54x, 62x, 70x, 78x, 
86x, 94x, and Week 94x (LOCF) (Clinical remission, CDAI-100 
response, CDAI-70 response, CDAI score change over time, each 
CDAI subscore change over time) 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
 
(1) Frequency distributions will be provided for clinical remission 
at each visit along with the point estimate and 95% two-sided 
CI for the proportion. 
 
(2) Frequency distributions will be provided for clinical remission 
at each visit with stratification according to “prior TNFα 
antagonist use” along with the point estimate and 95% 
two-sided CI for the proportion. 
 
(3) The same analysis as (1) will be performed for the CDAI-100 
response at each visit. 
 
(4) The same analysis as (2) will be performed for CDAI-100 
response at each visit with stratification according to “prior 
TNFα antagonist use.” 
 
(5) The same analysis as (1) will be performed for the CDAI-70 
response at each visit. 
 
(6) The same analysis as (2) will be performed for CDAI-70 
response at each visit with stratification according to “prior 
TNFα antagonist use.” 
 
(7) Summary statistics and the 95% two-sided CI of the mean will 
be provided for the CDAI scores at each visit along with the 
plot over time. 
 
(8) Summary statistics and the 95% two-sided CI of the mean will 
be provided for changes from baseline in the CDAI scores at 
each visit along with the plot over time. 


28 
 
 
(9) The same analysis as (7) will be performed for each CDAI 
subscore at each visit. 
 
(10) The same analysis as (8) will be performed for changes from 
baseline in each CDAI subscore at each visit. 
 
(11) The same analysis as (1) will be performed for clinical 
remission at each visit by route to the open-label cohort. 
 
(12) The same analysis as (2) will be performed for clinical 
remission at each visit by route to the open-label cohort. 
 
(13) The same analysis as (1) will be performed for CDAI-100 
response at each visit by route to the open-label cohort. 
 
(14) The same analysis as (2) will be performed for CDAI-100 
response at each visit by route to the open-label cohort. 
 
(15) The same analysis as (1) will be performed for CDAI-70 
response at each visit by route to the open-label cohort. 
 
(16) The same analysis as (2) will be performed for CDAI-70 
response at each visit by route to the open-label cohort. 
 
(17) The same analysis as (7) will be performed for CDAI score at 
each visit by route to the open-label cohort. 
 
(18) The same analysis as (8) will be performed for changes from 
baseline in the CDAI scores at each visit by route to the 
open-label cohort. 
 
2.1.2 Endpoints Related to CDAI Scores Based on the Hematocrit Level at Each Study Site 
Analysis set: 
Full analysis set in the open-label cohort 
Analysis variables: 
Clinical remission 
[Clinical remission, 
Non-remission] 
 
CDAI-100 response 
[CDAI-100 response, 
Non-CDAI-100 
response] 
 
CDAI-70 response 
[CDAI-70 response, 
Non-CDAI-70 
response] 
 
CDAI score change over time 
 
 
Each CDAI subscore change over time 
 
Visit: 
Weeks 0, 0x, 2x, 6x, 10x, 14x, 18x, 22x, 26x, 30x, 34x, 38x, 42x, 
46x, 50x, 54x, 58x, 62x, 66x, 70x, 74x, 78x, 82x, 86x, 90x, 94x, and 
Week 94x (LOCF) (Clinical remission, CDAI-100 response, CDAI 
score change over time, each CDAI subscore change over time) 
Analysis methodology: Each analysis variable will be determined using the CDAI score 
based on the Ht level at each study site and CDAI subscores. 
The following analysis will be performed for the above analysis 
variables. 
 
(1) Frequency distributions will be provided for clinical remission 
at each visit along with the point estimate and 95% two-sided 
CI for the proportion. 
 
(2) Frequency distributions will be provided for clinical remission 
at each visit with stratification according to “prior TNFα 


29 
 
antagonist use” along with the point estimate and 95% 
two-sided CI for the proportion. 
 
(3) The same analysis as (1) will be performed for the CDAI-100 
response at each visit. 
 
(4) The same analysis as (2) will be performed for CDAI-100 
response at each visit with stratification according to “prior 
TNFα antagonist use.” 
 
(5) The same analysis as (1) will be performed for the CDAI-70 
response at each visit. 
 
(6) The same analysis as (2) will be performed for CDAI-70 
response at each visit with stratification according to “prior 
TNFα antagonist use.” 
 
(7) Summary statistics and the 95% two-sided CI of the mean will 
be provided for the CDAI scores at each visit along with the 
plot over time. 
 
(8) Summary statistics and the 95% two-sided CI of the mean will 
be provided for changes from baseline in the CDAI scores at 
each visit along with the plot over time. 
 
(9) The same analysis as (5) will be performed for each CDAI 
subscore at each visit. 
 
(10) The same analysis as (6) will be performed for changes from 
baseline in each CDAI subscore at each visit. 
 
2.1.3 Endpoints Related to CRP 
Analysis set: 
Full analysis set in the open-label cohort 
Analysis variables: 
CRP Level 
 
 
CRP Level (within the reference range) 
[Yes, No] 
Visit: 
Weeks 0, 0x, 2x, 6x, 14x, 22x, 30x, 38x, 46x, 54x, 62x, 70x, 78x, 
86x, 94x, and Week 94x (LOCF) 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
 
(1) Summary statistics and the 95% two-sided CI of the mean will 
be calculated for CRP level at each visit (baseline to Week 60). 
Summary statistics, the 95% two-sided CI of the mean, and the 
10 and 90 percentiles will be calculated for changes from 
baseline in CRP level at each visit (Week 2 to Week 60). 
 
(2) The same analysis as (1) will be performed with stratification 
according to “prior TNFα antagonist use.” 
 
(3) In the subpopulation of subjects with the baseline CRP level 
outside the reference range (>0.30 mg/dL), frequency 
distributions will be provided for subjects with CRP level 
within the reference range at each visit (Week 0x to Week 94x 
[LOCF]) along with the point estimate and 95% two-sided CI 
for the proportion. 
 
(4) The same analysis as (3) will be performed in the 
subpopulation of subjects with the baseline CRP level of 
>0.5 mg/dL. 


30 
 
 
(5) The same analysis as (3) will be performed in the 
subpopulation of subjects with the baseline CRP level of 
>1.0 mg/dL. 
 
2.2 Statistical and Analytical Issues 
2.2.1 Adjustments for Covariates 
Not applicable in the open-label cohort. 
 
2.2.2 Handling of Dropouts or Missing Data 
The efficacy endpoints of clinical response or clinical remission will be considered as 
non-response or non-remission when adjudication for these endpoints is missing at the time of 
evaluation. 
For other endpoints, missing data, and ineligible data according to the “Handling Rules for 
Analysis Data” or the SAP will be excluded from statistical analyses and estimations. 
Values below the limit of quantification will be handled as 0. 
 
2.2.3 Interim Analyses and Data Monitoring 
No interim analyses will be performed for the induction and maintenance phases. 
For the open-label cohort, after the data obtained from all the subjects by the cut-off date for 
marketing authorization application is locked, the data up to the cut-off date for marketing 
authorization application will be analyzed. Continuation/termination of the study, change in 
clinical trial plan, and so on will not be judged based on the analysis. 
 
2.2.4 Multicenter Studies 
Since a single-arm design is employed in the open-label cohort of this study, interactions 
between treatment and study site will not be investigated. 
 
2.2.5 Multiple Comparisons/Multiplicity 
Not applicable in the open-label cohort. 
 
2.2.6 Use of an “Efficacy Subset” of Subjects 
Not applicable in the open-label cohort. 
 
2.2.7 Active-Control Studies Intended to Show Equivalence or Non-inferiority 
Not applicable. 
 
2.2.8 Examination of Subgroups 
Not applicable in the open-label cohort. 
 


31 
 
3 SAFETY ANALYSIS 
3.1 Treatment-Emergent Adverse Event 
3.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis set: 
Safety analysis set in the open-label cohort 
Analysis variables: 
TEAEs in the open-label cohort 
Categories: 
Causality 
[Related, Not related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analysis methodology: The following summaries will be provided for the above analysis 
variables. 
 
(1) Overview of TEAEs in the open-label cohort 
 
1) All TEAEs in the open-label cohort (number of events, 
number and percentage of subjects) 
 
2) Causal relationship between all TEAEs in the open-label 
cohort and study drug (number of events, number and 
percentage of subjects) 
 
3) Intensity of all TEAEs in the open-label cohort (number 
of events, number and percentage of subjects) 
 
4) TEAEs in the open-label cohort leading to study drug 
discontinuation (number of events, number and 
percentage of subjects) 
 
5) Serious TEAEs in the open-label cohort (number of 
events, number and percentage of subjects) 
 
6) Causal relationship between serious TEAEs in the 
open-label cohort and study drug (number of events, 
number and percentage of subjects) 
 
7) Serious TEAEs in the open-label cohort leading to study 
drug discontinuation (number of events, number and 
percentage of subjects) 
 
8) TEAEs in the open-label cohort leading to death (number 
of events, number and percentage of subjects) 
 
TEAEs will be counted according to the rules below: 
[Number of subjects] 
• In the case of “summaries by causality” 
A subject with occurrences of TEAE in both categories (i.e., 
“Related” and “Not related”) will be counted once in the 
“Related” category. 
• In the case of “summaries by intensity” 
A subject with multiple occurrences of TEAE will be counted 
once for the TEAE with the maximum intensity. 
• In the case of summaries other than the above 
A subject with multiple occurrences of TEAE will be counted 
only once. 
[Number of events] 
For each summary, the total number of events will be calculated. 
 


32 
 
3.1.2 Displays of Treatment-Emergent Adverse Events 
Analysis set: 
Safety analysis set in the open-label cohort 
Analysis variables: 
TEAEs in the open-label cohort 
 
Infusion reactions in the open-label cohort 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
 
Time of onset (day) 
[1≤ - ≤42, 43≤ - ≤98, 99≤ - ≤210, 
211≤ - ≤322, 323≤ - ≤434,  
435≤ - ≤546, 547≤ - ≤Max] 
 
Study drug administration in 
the open-label cohort (time) 
[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 
13, 14] 
Analysis methodology: The following summaries will be provided for the above analysis 
variables using frequency distributions. 
TEAEs will be coded by use of MedDRA and will be summarized 
based on SOC and PT. SOC will be sorted alphabetically and PT 
will be sorted in decreasing frequency for tables provided by SOC 
and PT. SOC and PT will be sorted in decreasing frequency for 
tables provided by SOC only or PT only. 
Categories for time of onset (day) will be determined based on the 
number of days by defining the day of the first dose of the study 
drug in the open-label cohort as day 1. 
 
(1) 
All TEAEs in the open-label cohort by SOC and PT 
 
(2) 
All TEAEs in the open-label cohort by SOC 
 
(3) 
All TEAEs in the open-label cohort by PT 
 
(4) 
Drug-related TEAEs in the open-label cohort by SOC and 
PT 
 
(5) 
Intensity of all TEAEs in the open-label cohort by SOC and 
PT 
 
(6) 
Intensity of drug-related TEAEs in the open-label cohort by 
SOC and PT 
 
(7) 
TEAEs in the open-label cohort leading to study drug 
discontinuation by SOC and PT 
 
(8) 
Serious TEAEs in the open-label cohort by SOC and PT 
 
(9) 
Serious drug-related TEAEs in the open-label cohort by SOC 
and PT 
 
(10) 
All TEAEs in the open-label cohort by SOC and PT over 
time 
 
(11) 
Infusion reactions in the open-label cohort by SOC and PT 
 
(12) 
Infusion reactions in the open-label cohort by study drug 
administration in the open-label cohort (time) by SOC and 
PT 
 
(13) 
TEAEs in the open-label cohort whose onset date is the day 
of the study drug administration or the following day by 
SOC and PT 
 
(14) 
TEAEs in the open-label cohort whose onset date is the day 
of the study drug administration or the following day by 


33 
 
study drug administration in the open-label cohort (time) by 
SOC and PT 
 
(15) 
TEAEs in the open-label cohort whose incidence 
summarized by PT is 3% or higher by SOC and PT 
 
The frequency distribution and incidence will be provided according 
to the rules below: 
[Number of subjects] 
• In the case of “summaries by SOC and PT, by SOC, and by PT” 
A subject with multiple occurrences of TEAE within a SOC will 
be counted only once in that SOC. A subject with multiple 
occurrences of TEAE within a PT will be counted only once in 
that PT. Percentages of TEAEs in the open-label cohort will be 
based on the number of subjects in the safety analysis set in the 
open-label cohort. 
• In the case of “summaries of intensity by SOC and PT” 
A subject with multiple occurrences of TEAE within a SOC or a 
PT will be counted only once for the TEAE with the maximum 
intensity. Percentages of TEAEs in the open-label cohort will be 
based on the number of subjects in the safety analysis set in the 
open-label cohort. 
• In the case of “summaries by SOC and PT over time” 
A subject with a TEAE that occurs in more than one interval is 
counted in all the intervals that the TEAE occurs. For each time 
interval, a subject with multiple occurrences of TEAE within a 
SOC or a PT will be counted only once in that SOC or PT. 
When calculating the percentages of TEAEs in the open-label 
cohort for each time interval, the number of subjects at risk (i.e., 
“subjects who either have an exposure in the study or have an 
occurrence of TEAE in the open-label cohort, during or after the 
corresponding time interval”) will be used as the denominator. 
The number of subjects whose “onset of any one of the TEAEs 
in the open-label cohort is within the time interval” will be used 
as the numerator. 
• In the case of “summaries of the study drug administration in the 
open-label cohort (time) by SOC and PT” 
A subject with a TEAE that occurs in more than one time of the 
study drug administration is counted for all the administrations 
(time) that the TEAE occurs. For each administration, a subject 
with multiple occurrences of TEAEs within a SOC or a PT will 
be counted only once in that SOC or PT. When calculating the 
percentages of TEAEs in the open-label cohort for each 
administration (time) in the open-label cohort, the number of 
subjects at risk (i.e., “subjects who received the first, etc., study 
drug administration in the open-label cohort”) will be used as 
the denominator. The number of subjects whose “onset of any 
one of the TEAEs in the open-label cohort is at the time of the 
first, etc., study drug administration in the open-label cohort” 


34 
 
will be used as the numerator. 
 
3.2 Pretreatment Event 
3.2.1 Displays of Pretreatment Events 
Not applicable. 
 
3.3 Clinical Laboratory Evaluations and Other Safety Endpoints 
3.3.1 Clinical Laboratory Evaluations 
3.3.1.1 
Hematology and Blood Biochemistry 
Analysis set: 
Safety analysis set in the open-label cohort 
Analysis variables: 
Hematology 
 
Red blood cells 
(RBC) 
White blood cells 
(WBC) 
Hemoglobin 
 
Hematocrit 
Platelets 
 
 
WBC differentials (neutrophils/leukocytes, 
eosinophils/leukocytes, basophils/leukocytes, 
lymphocytes/leukocytes, monocytes/leukocytes) 
 
Blood biochemistry 
 
Albumin 
AST (GOT) 
ALT (GPT) 
 
ALP 
Amylase 
Glucose 
 
Total bilirubin 
Total protein 
γ-GTP 
 
Total cholesterol 
Triglyceride 
Creatinine 
 
BUN 
Uric acid 
Potassium 
 
Sodium 
Calcium 
Phosphorus 
 
Magnesium 
Chloride 
 
Categories: 
Adjudication results based on 
reference range 
[Below lower limit of normal 
range, Within normal range, 
Over upper limit of normal 
range] 
 
Categories in SAP Appendix 2 (1) 
 
Visit: 
Weeks 0, 0x, 2x, 6x, 14x, 22x, 30x, 38x, 46x, 54x, 62x, 70x, 78x, 
86x, 94x, and 16 weeks after the last dose of the study drug 
(hematology, blood biochemistry) 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
Refer to Appendix 2 of this SAP for laboratory test items subject to 
this analysis, categories in the shift table, MAV criteria, and the 
definition of elevated liver enzyme. 
 
(1) 
Summary statistics for each visit and summary statistics of 
differences before and after administration for each visit 
 
(2) 
Case plots 
 
(3) 
Shift tables showing adjudication results based on normal 
reference range at baseline and each post-baseline visit 
 
(4) 
Shift tables showing categories of SAP Appendix 2 (1) at 
baseline and each post-baseline visit 


35 
 
 
(5) 
Overall frequency distributions of MAV in the open-label 
cohort 
 
(6) 
Overall frequency distributions of elevated liver enzymes in 
the open-label cohort 
 
3.3.1.2 
Urinalysis 
Analysis set: 
Safety analysis set in the open-label cohort 
Analysis variables: 
pH 
 
 
Urine specific gravity 
 
 
Glucose 
 
 
Protein 
 
 
Occult blood 
 
 
Bilirubin 
 
 
Ketone body 
 
Categories: 
Adjudication results based on 
reference range 
[Below lower limit of normal 
range, Within normal range, 
Over upper limit of normal 
range] 
Visit: 
Weeks 0, 0x, 94x, and 16 weeks after the last dose of the study drug 
Analysis methodology: The following analysis of (1), (2), and (3) will be performed for pH 
and specific gravity. The following analysis of (3) will be performed 
for the above analysis variables other than pH and specific gravity. 
 
(1) 
Summary statistics for each visit and summary statistics of 
differences before and after administration 
 
(2) 
Case plots 
 
(3) 
Shift tables showing adjudication results based on normal 
reference range at baseline and each post-baseline visit 
 
3.3.2 Vital Signs, Physical Examination, and Other Observation Items Related to Safety 
3.3.2.1 
Vital Signs, Body Weight 
Analysis set: 
Safety analysis set in the open-label cohort 
Analysis variables: 
Systolic blood pressure 
 
 
Diastolic blood pressure 
 
 
Pulse 
 
 
Body temperature 
 
 
Weight 
 
Visit: 
Weeks 0, 0x, 2x, 6x, 10x, 14x, 18x, 22x, 26x, 30x, 34x, 38x, 42x, 
46x, 50x, 54x, 58x, 62x, 66x, 70x, 74x, 78x, 82x, 86x, 90x, 94x, and 
16 weeks after the last dose of the study drug 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
 
(1) 
Summary statistics for each visit and summary statistics of 
differences before and after administration for each visit 
 
(2) 
Case plots 
 


36 
 
3.3.2.2 
12-Lead ECG 
Analysis set: 
Safety analysis set in the open-label cohort 
Analysis variables: 
Findings of 12-lead ECG 
[Within normal limits, Abnormal but 
not clinically significant, Abnormal 
and clinically significant] 
Visit: 
Weeks 0, 0x, 94x, and 16 weeks after the last dose of the study drug 
Analysis methodology: The following analysis will be performed for the findings of 12-lead 
ECG. 
 
(1) 
Shift table at baseline and each post-baseline visit 
 


37 
 
4 DISPLAY OF TREATMENT-EMERGENT ADVERSE EVENT (IN JAPANESE) 
4.1 Display of Treatment-Emergent Adverse Event (in Japanese) 
Analysis set: 
Safety analysis set in the open-label cohort 
Analysis variables: 
TEAEs in the open-label cohort by SOC and PT 
 
Infusion reactions in the open-label cohort by SOC and PT 
Analysis methodology: Summaries similar to those in section 3.1.2 will be provided for the 
above analysis variables. SOC and PT will be displayed in Japanese. 
 


38 
 
5 ANALYSIS OF IMMUNOGENICITY ENDPOINTS 
5.1 AVA and the Neutralizing Antibody 
Analysis set: 
Subjects who underwent proper determination of AVA and 
neutralizing antibody in the “full analysis set in the open-label 
cohort” 
Analysis variables: 
AVA 
[Negative, Positive] 
 
AVA titer 
[1:10, 1:50, 1:250, 1:1250, 
1:6250, 1:31250] 
 
Persistently positive in the induction 
phase, maintenance phase, and 
open-label cohort 
[Yes, No] 
 
Transiently positive in the induction 
phase, maintenance phase, and 
open-label cohort 
[Yes, No] 
 
Neutralizing antibody 
[Negative, Positive] 
 
AVA in the induction phase, 
maintenance phase, and open-label 
cohort 
[Negative, Positive] 
 
Maximum AVA titer in the induction 
phase, maintenance phase, and 
open-label cohort 
[1:10, 1:50, 1:250, 1:1250, 
1:6250, 1:31250] 
 
Neutralizing antibody in the induction 
phase, maintenance phase, and 
open-label cohort 
[Negative, Positive] 
Visit: 
Weeks 0, 0x, 10x, 30x, 62x, 94x, and 16 weeks after the last dose of 
the study drug (AVA, AVA titer, neutralizing antibody) 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
The category of AVA titer will be defined according to the observed 
AVA titer. 
 
(1) 
Frequency distributions 
 
5.2 Efficacy by AVA and the Neutralizing Antibody 
Analysis set: 
Subjects who underwent proper determination of AVA and 
neutralizing antibody in the “full analysis set in the open-label 
cohort” 
Analysis variables: 
Clinical remission at Week 94x (LOCF) 
[Clinical remission, 
Non-remission] 
Stratum:  
AVA in the induction phase, maintenance 
phase, and open-label cohort 
[Negative, Positive] 
 
Persistently positive in the induction phase, 
maintenance phase, and open-label cohort 
[Yes, No] 
 
Transiently positive in the induction phase, 
maintenance phase, and open-label cohort 
[Yes, No] 
 
Neutralizing antibody in the induction 
phase, maintenance phase, and open-label 
cohort 
[Negative, Positive] 


39 
 
Analysis methodology: The following analysis will be performed for the above analysis 
variables for each stratum. 
 
(1) 
Frequency distributions 
 
5.3 Subgroup Analysis of AVA and the Neutralizing Antibody 
Analysis set: 
Subjects who underwent proper determination of AVA and 
neutralizing antibody in the “full analysis set in the open-label 
cohort” 
Analysis variables: 
AVA in the induction phase, maintenance 
phase, and open-label cohort 
[Negative, Positive] 
 
Persistently positive in the induction phase, 
maintenance phase, and open-label cohort 
[Yes, No] 
 
Transiently positive in the induction phase, 
maintenance phase, and open-label cohort 
[Yes, No] 
 
Neutralizing antibody in the induction 
phase, maintenance phase, and open-label 
cohort 
[Negative, Positive] 
Stratum:  
Concomitant use of immunomodulators at 
baseline 
[Yes, No] 
 
No concomitant use of oral corticosteroids 
and Concomitant use of 
immunomodulators at baseline 
(concomitant use of immunomodulators 
only) 
[Yes, No] 
 
Concomitant use of oral corticosteroids at 
baseline 
[Yes, No] 
 
Infusion reactions in the induction phase, 
maintenance phase, and open-label cohort 
[Yes, No] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables for each stratum. 
 
(1) 
Frequency distributions 
 


40 
 
6 SAFETY ANALYSIS OF MLN0002 TREATMENT 
6.1 Measurement of Compliance Status for Treatment 
6.1.1 MLN0002 Exposure and Compliance in the Treatment Period 
Analysis set: 
Subjects who received at least one dose of MLN0002 
Analysis variables: 
Duration of MLN0002 exposure 
(days) 
[1≤ - ≤84, 85≤ - ≤168,  
169≤ - ≤252, 253≤ - ≤336, 
337≤ - ≤420, 421≤ - ≤504,  
505≤ - ≤588, 589≤ - ≤672,  
673≤ - ≤756, 757≤ - ≤840,  
841≤ - ≤924, 925≤ - ≤1008,  
1009≤ - ≤Max] 
 
Duration on study after the first dose 
of MLN0002 (days) 
[1≤ - ≤84, 85≤ - ≤168,  
169≤ - ≤252, 253≤ - ≤336,  
337≤ - ≤420, 421≤ - ≤504,  
505≤ - ≤588, 589≤ - ≤672,  
673≤ - ≤756, 757≤ - ≤840,  
841≤ - ≤924, 925≤ - ≤1008,  
1009≤ - ≤Max] 
 
Number of MLN0002 infusions 
(times) 
[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 
11, 12, 13, 14, 15, 16, 17, 
18, 19, 20, 21, 22, 23] 
 
Number of completed MLN0002 
infusions (times) 
[0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 
11, 12, 13, 14, 15, 16, 17, 
18, 19, 20, 21, 22, 23] 
 
Number of completed or 
incompleted MLN0002 infusions in 
total infusions 
[Completed, Incompleted] 
Analysis methodology: 
 
The following analysis will be performed for the above analysis 
variables. 
(1) Frequency distributions for categorical variables and summary 
statistics for continuous variables 
 
In the frequency distributions for number of completed or 
incompleted MLN0002 infusions in total infusions, the sum of the 
number of completed MLN0002 infusions will be counted as 
frequency for “Completed,” and the sum of the number of 
incompleted MLN0002 infusions will be counted as frequency for 
“Incompleted.” When calculating the percentage, the sum of the 
number of completed infusions and the number of incompleted 
infusions (i.e., number of total MLN0002 infusions) will be used as 
the denominator. 
 
6.2 Treatment-Emergent Adverse Event 
6.2.1 Overview of Treatment-Emergent Adverse Events 
Analysis set: 
Subjects who received at least one dose of MLN0002 
Analysis variables: 
TEAEs after the first dose of MLN0002 
Categories: 
Causality 
[Related, Not related] 
 
Intensity 
[Mild, Moderate, Severe] 


41 
 
Analysis methodology: The following summaries will be provided for the above analysis 
variables. 
 
(1) 
Overview of TEAEs after the first dose of MLN0002 
 
1) All TEAEs after the first dose of MLN0002 (number of 
events, number and percentage of subjects) 
 
2) Causal relationship between all TEAEs after the first 
dose of MLN0002 and study drug (number of events, 
number and percentage of subjects) 
 
3) Intensity of all TEAEs after the first dose of MLN0002 
(number of events, number and percentage of subjects) 
 
4) TEAEs after the first dose of MLN0002 leading to study 
drug discontinuation (number of events, number and 
percentage of subjects) 
 
5) Serious TEAEs after the first dose of MLN0002 (number 
of events, number and percentage of subjects) 
 
6) Causal relationship between serious TEAEs after the first 
dose of MLN0002 and study drug (number of events, 
number and percentage of subjects) 
 
7) Serious TEAEs after the first dose of MLN0002 leading 
to study drug discontinuation (number of events, number 
and percentage of subjects) 
 
8) TEAEs after the first dose of MLN0002 leading to death 
(number of events, number and percentage of subjects) 
 
TEAEs will be counted according to the rules below: 
[Number of subjects] 
• In the case of “summaries by causality” 
A subject with occurrences of TEAE in both categories (i.e., 
“Related” and “Not related”) will be counted once in the 
“Related” category. 
• In the case of “summaries by intensity” 
A subject with multiple occurrences of TEAE will be counted 
once for the TEAE with the maximum intensity. 
• In the case of summaries other than the above 
A subject with multiple occurrences of TEAE will be counted 
only once. 
[Number of events] 
For each summary, the total number of events will be calculated. 
 
6.2.2 Displays of Treatment-Emergent Adverse Events 
Analysis set: 
Subjects who received at least one dose of MLN0002 
Analysis variables: 
TEAEs after the first dose of MLN0002 
 
Infusion reactions after the first dose of MLN0002 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
 
Time of onset (day) 
[1≤ - ≤84, 85≤ - ≤168,  
169≤ - ≤252, 253≤ - ≤336,  
337≤ - ≤420, 421≤ - ≤504,  
505≤ - ≤588, 589≤ - ≤672,  


42 
 
673≤ - ≤756, 757≤ - ≤840,  
841≤ - ≤924, 925≤ - ≤1008,  
1009≤ - ≤Max] 
 
MLN0002 administration (time) 
[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 
11, 12, 13, 14, 15, 16, 17, 
18, 19, 20, 21, 22, 23] 
Analysis methodology: The following summaries will be provided for the above analysis 
variables using frequency distributions. 
TEAEs will be coded by use of MedDRA and will be summarized 
based on SOC and PT. SOC will be sorted alphabetically and PT 
will be sorted in decreasing frequency for tables provided by SOC 
and PT. SOC and PT will be sorted in decreasing frequency for 
tables provided by SOC only or PT only. 
Categories for time of onset (day) will be determined based on the 
number of days by defining the day of the first dose of MLN0002 as 
day 1. 
 
(1) 
All TEAEs after the first dose of MLN0002 by SOC and PT 
 
(2) 
All TEAEs after the first dose of MLN0002 by SOC 
 
(3) 
All TEAEs after the first dose of MLN0002 by PT 
 
(4) 
Drug-related TEAEs after the first dose of MLN0002 by SOC 
and PT 
 
(5) 
Intensity of all TEAEs after the first dose of MLN0002 by 
SOC and PT 
 
(6) 
Intensity of drug-related TEAEs after the first dose of 
MLN0002 by SOC and PT 
 
(7) 
TEAEs after the first dose of MLN0002 leading to study drug 
discontinuation by SOC and PT 
 
(8) 
Serious TEAEs after the first dose of MLN0002 by SOC and 
PT 
 
(9) 
Serious drug-related TEAEs after the first dose of MLN0002 
by SOC and PT 
 
(10) All TEAEs after the first dose of MLN0002 by SOC and PT 
over time 
 
(11) Infusion reactions after the first dose of MLN0002 by SOC 
and PT 
 
(12) Infusion reactions after the first dose of MLN0002 by 
MLN0002 administration (time) by SOC and PT 
 
(13) TEAEs after the first dose of MLN0002 whose onset date is 
the day of MLN0002 administration or the following day by 
SOC and PT 
 
(14) TEAEs after the first dose of MLN0002 whose onset date is 
the day of MLN0002 administration or the following day by 
MLN0002 administration (time) by SOC and PT 
 
(15) TEAEs after the first dose of MLN0002 whose incidence 
summarized by PT is 3% or higher by SOC and PT 


43 
 
 
The frequency distribution and incidence will be provided according 
to the rules below: 
[Number of subjects] 
• In the case of “summaries by SOC and PT, by SOC, and by PT” 
A subject with multiple occurrences of TEAE within a SOC will 
be counted only once in that SOC. A subject with multiple 
occurrences of TEAE within a PT will be counted only once in 
that PT. Percentages of TEAE after the first dose of MLN0002 
will be based on the number of subjects who received at least 
one dose of MLN0002. 
• In the case of “summaries of intensity by SOC and PT” 
A subject with multiple occurrences of TEAE within a SOC or a 
PT will be counted only once for the TEAE with the maximum 
intensity. Percentages of TEAE after the first dose of MLN0002 
will be based on the number of subjects who received at least 
one dose of MLN0002. 
• In the case of “summaries by SOC and PT over time” 
A subject with a TEAE that occurs in more than one interval is 
counted in all the intervals that the TEAE occurs. For each time 
interval, a subject with multiple occurrences of TEAE within a 
SOC or a PT will be counted only once in that SOC or PT. 
When calculating the percentages of TEAEs after the first dose 
of MLN0002 for each time interval, the number of subjects at 
risk (i.e., “subjects who either have an exposure in the study or 
have an occurrence of TEAE after the first dose of MLN0002, 
during or after the corresponding time interval”) will be used as 
the denominator. The number of subjects whose “onset of any 
one of the TEAEs after the first dose of MLN0002 is within the 
time interval” will be used as the numerator. 
• In the case of “summaries of MLN0002 administration (time) by 
SOC and PT” 
A subject with a TEAE that occurs in more than one time of 
MLN0002 administration is counted for all the administrations 
(time) that the TEAE occurs. For each administration, a subject 
with multiple occurrences of TEAE within a SOC or a PT will 
be counted only once in that SOC or PT. When calculating the 
percentages of TEAEs after the first dose of MLN0002 for each 
administration (time), the number of subjects at risk (i.e., 
“subjects who received the first, etc., MLN0002 
administration”) will be used as the denominator. The number of 
subjects whose “onset of any one of the TEAEs after the first 
dose of MLN0002 is at the time of the first, etc., MLN0002 
administration” will be used as the numerator. 
 
6.3 Display of Treatment-Emergent Adverse Event (in Japanese) 
Analysis set: 
Subjects who received at least one dose of MLN0002 
Analysis variables: 
TEAEs after the first dose of MLN0002 by SOC and PT 


44 
 
 
Infusion reactions after the first dose of MLN0002 by SOC and PT 
Analysis methodology: Summaries similar to those in section 6.2.2 will be provided for the 
above analysis variables. SOC and PT will be displayed in Japanese. 
 
 
7 ANALYSIS OF FOLLOW-UP SURVEY AND PML CHECKLIST 
7.1 Analysis of Follow-up Survey 
Analysis set: 
Subjects who received at least one dose of MLN0002 
Analysis variables: 
1. Have you been diagnosed with colon dysplasia 
(one of the precancerous lesions) or colon 
cancer, lymphoma, or other types of cancer 
since the last contact or visit in the study? 
[Yes, No] 
 
Colon dysplasia 
[Yes, No] 
 
Colon cancer 
[Yes, No] 
 
Lymphoma 
[Yes, No] 
 
Other types of cancer 
[Yes, No] 
 
2. Have you been diagnosed as having 
progressive multifocal leukoencephalopathy 
(also known as PML) since the last contact or 
visit in the study? 
[Yes, No] 
 
3. Have you undergone enterectomy since the last 
contact or visit in the study? 
[Yes, No] 
 
Colectomy 
[Yes, No] 
 
Small bowel resection 
[Yes, No] 
 
4. Have you been diagnosed as having an 
infection requiring hospitalization since the last 
study visit? 
[Yes, No] 
 
5. For female subjects: Have you become 
pregnant since the last study visit? 
[Yes, No,  
Not applicable] 
 
6. For male subjects: Has the female partner 
become pregnant since the last study visit? 
[Yes, No,  
Not applicable] 
Visit: 
6, 12, 18, and 24 months after the last dose of study drug (1. to 3.) 
 
6 months after the last dose of the study drug (4. to 6.) 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
 
(1) Frequency distributions at each visit 
The analysis for variable 5 will be performed in female subjects. 
The analysis for variable 6 will be performed in male subjects. 
 
7.2 Analysis of PML Checklist 
Analysis set: 
Subjects who received at least one dose of MLN0002 and have 
available data on the subjective PML checklist 
Analysis variables: 
Subjective symptoms 
[Yes, No] 
 
Objective findings 
[Yes, No, Not available] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
If a subject has multiple findings reported at different visits, he/she 


45 
 
will be classified as follows: 
 
“Yes”: “Yes” at any visit 
 
“No”: “No” at all visits after excluding missing values and other 
than the above 
 
“Not available”: Missing at all visits and other than the above 
(no evaluation) 
 
(1) 
Frequency distributions 
 
 
8 SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT 
 
Confidence coefficient: 95% (two-sided estimate) 
 


46 
 
History of Revision (version management) 
 
Version 
Date 
Prepared/modified by 
Comments 
First version 25 January 2018 
 
Preparation of first version 
 
PPD


1 
 
[Appendix 1] Comparison Table for Changes 
 
N/A 
 


1 
 
[Appendix 2] Definitions of Categories in Shift Table, MAV Criteria, and Criteria for Elevated 
Liver Enzyme 
(1) 
Categories in Shift Table 
The lower limit of the normal range and the upper limit of the normal range of each test item are 
abbreviated as LLN and ULN in the table below. 
Test item 
Categories 
Albumin 
≥LLN, <LLN to 3 g/dL, <3 g/dL to 2 g/dL, <2 g/dL to 1 g/dL, <1 g/dL 
ALT (GPT) 
≤ULN, >ULN to 2.5×ULN, >2.5×ULN to 5.0×ULN, >5.0×ULN to 20.0×ULN, 
>20.0×ULN 
AST (GOT) 
≤ULN, >ULN to 2.5×ULN, >2.5×ULN to 5.0×ULN, >5.0×ULN to 20.0×ULN, 
>20.0×ULN 
Total bilirubin 
≤ULN, >ULN to 1.5×ULN, >1.5×ULN to 3.0×ULN, >3.0×ULN to 10.0×ULN, 
>10.0×ULN 
Creatinine 
≤ULN, >ULN to 1.5×ULN, >1.5×ULN to 3.0×ULN, >3.0×ULN to 6.0×ULN, 
>6.0×ULN 
ALP 
≤ULN, >ULN to 2.5×ULN, >2.5×ULN to 5.0×ULN, >5.0×ULN to 20.0×ULN, 
>20.0×ULN 
WBC 
≥LLN, <LLN to 3000/μL, <3000/μL to 2000/μL, <2000/μL to 1000/μL, 
<1000/μL 
WBC 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Platelets 
≥LLN, <LLN to 7.5×104/μL, <7.5×104/μL to 5.0×104/μL, <5.0×104/μL to 
2.5×104/μL, <2.5×104/μL 
Platelets 
≤ULN, >ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, >2.0×ULN to 3.0×ULN, 
>3.0×ULN 
Lymphocytes 
≥800/μL, <800/μL to 500/μL, <500/μL to 200/μL, <200/μL 
Lymphocytes (%) 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Eosinophils (%) 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Monocytes (%) 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Basophils (%) 
≤ULN, >ULN to 1.25×ULN, >1.25×ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, 
>2.0×ULN 
Hemoglobin 
≥LLN, <LLN to 10 g/dL, <10 g/dL to 8 g/dL, <8 g/dL to 6.5 g/dL, <6.5 g/dL 
Neutrophils 
≥1500/μL, <1500/μL to 1000/μL, <1000/μL to 500/μL, <500/μL 
Neutrophils (%) 
≤ULN, >ULN to 1.5×ULN, >1.5×ULN to 2.0×ULN, >2.0×ULN to 3.0×ULN, 
>3.0×ULN 
Missing data will not be included in any category. 
 


2 
 
(2) 
MAV Criteria 
1) 
Hematology and Blood Biochemistry 
For each test item, MAV will be determined according to the table below for evaluable data (i.e., 
non-missing data and data determined to be eligible based on the “Handling Rules for Analysis 
Data”) obtained from the day after the first dose of the study drug in the open-label cohort until 167 
days* after the last dose of the study drug (including Follow-up Day 167). The lower limit of the 
normal range and the upper limit of the normal range of each test item are abbreviated as LLN and 
ULN in the table below. 
* Day after the last dose of the study drug will be defined as Follow-up Day 1. 
 
Test item 
MAV Criteria 
Lower criteria 
Upper criteria 
Hemoglobin (g/dL) 
≤7 
- 
Lymphocytes (/μL) 
<500 
- 
WBC (/μL) 
<2000 
- 
Platelets (×104/μL) 
<7.5 
- 
Neutrophils (/μL) 
<1000 
- 
ALT (GPT) (U/L) 
- 
>3.0×ULN 
AST (GOT) (U/L) 
- 
>3.0×ULN 
Total bilirubin (mg/dL) 
- 
>2.0×ULN 
Amylase (U/L) 
- 
>2.0×ULN 
 
Classifying Subjects for the Overall Open-label Cohort 
For each test item and subject, MAV will be determined according to the conditions [1] to [3] 
provided below. 
[1] A subject will be classified as those “with MAV” if he/she has at least one data that “meets the 
MAV Criteria” among the evaluable data obtained from the day after the first dose of the study 
drug in the open-label cohort until 167 days after the last dose of the study drug (including 
Follow-up Day 167). 
[2] A subject will be classified as those “without MAV” if he/she does not meet condition [1] and 
has at least one data that does “not meet the MAV Criteria” among the evaluable data obtained 
from the day after the first dose of the study drug in the open-label cohort until 167 days after 
the last dose of the study drug (including Follow-up Day 167). 
[3] A subject who does not meet conditions [1] or [2] will be excluded from the analysis of MAV 
for that item. 
 


3 
 
(3) 
Criteria for Elevated Liver Enzyme 
For each test item, elevated liver enzyme will be determined according to the table below for 
evaluable data (i.e., non-missing data and data determined to be eligible based on the “Handling 
Rules for Analysis Data”) obtained from the day after the first dose of the study drug in the 
open-label cohort until 167 days* after the last dose of the study drug (including Follow-up Day 
167). If there is more than one item that need to be considered for a criterion, test items measured on 
the same day will be used. The following abbreviations are used in the table below: LLN for lower 
limit of the normal range, ULN for upper limit of the normal range, ALT for alanine 
aminotransferase, AST for aspartate aminotransferase, Tbili for total bilirubin, and ALP for alkaline 
phosphatase. 
* Day after the last dose of the study drug will be defined as Follow-up Day 1. 
 
Label 
Criteria for “elevated liver enzyme” 
Elevated 
Not elevated 
ALT > 3×ULN 
ALT is greater than 3 times the ULN 
ALT is non-missing and less than or 
equal to 3 times the ULN 
ALT > 5×ULN 
ALT is greater than 5 times the ULN 
ALT is non-missing and less than or 
equal to 5 times the ULN 
ALT > 8×ULN 
ALT is greater than 8 times the ULN 
ALT is non-missing and less than or 
equal to 8 times the ULN 
ALT > 3×ULN  
with Tbili > 2×ULN 
ALT is greater than 3 times the ULN and 
the total bilirubin is greater than twice 
the ULN 
Either ALT is non-missing and less than 
or equal to 3 times the ULN, or the total 
bilirubin is non-missing and less than or 
equal to twice the ULN 
AST > 3×ULN 
AST is greater than 3 times the ULN 
AST is non-missing and less than or 
equal to 3 times the ULN 
AST > 5×ULN 
AST is greater than 5 times the ULN 
AST is non-missing and less than or 
equal to 5 times the ULN 
AST > 8×ULN 
AST is greater than 8 times the ULN 
AST is non-missing and less than or 
equal to 8 times the ULN 
AST > 3×ULN  
with Tbili > 2×ULN 
AST is greater than 3 times the ULN and 
the total bilirubin is greater than twice 
the ULN 
Either AST is non-missing and less than 
or equal to 3 times the ULN, or the total 
bilirubin is non-missing and less than or 
equal to twice the ULN 
ALT or AST > 3×ULN 
Either ALT or AST is greater than 3 
times the ULN 
Both ALT and AST are non-missing and 
less than or equal to 3 times the ULN 
ALT or AST > 5×ULN 
Either ALT or AST is greater than 5 
times the ULN 
Both ALT and AST are non-missing and 
less than or equal to 5 times the ULN 
ALT or AST > 8×ULN 
Either ALT or AST is greater than 8 
times the ULN 
Both ALT and AST are non-missing and 
less than or equal to 8 times the ULN 
ALT or AST > 3×ULN  
with Tbili > 2×ULN 
Either ALT or AST is greater than 3 
times the ULN and the total bilirubin is 
greater than twice the ULN 
If any of the following conditions is met: 
- Both ALT and AST are non-missing 
and less than or equal to 3 times the 
ULN 
- Total bilirubin is non-missing and 
less than or equal to twice the ULN 
ALT and AST > 3×ULN 
Both ALT and AST are greater than 3 
Either ALT is non-missing and less than 


4 
 
Label 
Criteria for “elevated liver enzyme” 
Elevated 
Not elevated 
times the ULN 
or equal to 3 times the ULN, or AST is 
non-missing and less than or equal to 3 
times the ULN 
ALT and AST > 5×ULN 
Both ALT and AST are greater than 5 
times the ULN 
Either ALT is non-missing and less than 
or equal to 5 times the ULN, or AST is 
non-missing and less than or equal to 5 
times the ULN 
ALT and AST > 8×ULN 
Both ALT and AST are greater than 8 
times the ULN 
Either ALT is non-missing and less than 
or equal to 8 times the ULN, or AST is 
non-missing and less than or equal to 8 
times the ULN 
ALT and AST > 3×ULN  
with Tbili > 2×ULN 
Both ALT and AST are greater than 3 
times the ULN and the total bilirubin is 
greater than twice the ULN 
If any of the following conditions is met: 
- ALT is non-missing and less than or 
equal to 3 times the ULN 
- AST is non-missing and less than or 
equal to 3 times the ULN 
- Total bilirubin is non-missing and 
less than or equal to twice the ULN 
ALP > 3×ULN 
ALP is greater than 3 times the ULN 
ALP is non-missing and less than or 
equal to 3 times the ULN 
ALP > 3×ULN  
with ALT > 3×ULN 
Both ALP and ALT are greater than 3 
time the ULN 
Either ALP is non-missing and less than 
or equal to 3 times the ULN, or ALT is 
non-missing and less than or equal to 3 
times the ULN 
ALP > 3×ULN  
with AST > 3×ULN 
Both ALP and AST are greater than 3 
times the ULN 
Either ALP is non-missing and less than 
or equal to 3 times the ULN, or AST is 
non-missing and less than or equal to 3 
times the ULN 
 
Classifying Subjects for the Overall Open-label Cohort 
For each criteria and subject, “elevated liver enzyme” will be determined according to the conditions 
[1] to [3] provided below. 
[1] A subject will be classified as those “with elevated liver enzyme” if he/she has at least one data 
that “meets the criteria for elevated liver enzyme” among the evaluable data obtained from the 
day after the first dose of the study drug in the open-label cohort until 167 days after the last 
dose of the study drug (including Follow-up Day 167). 
[2] A subject will be classified as those “without elevated liver enzyme” if he/she does not meet 
condition [1] and has at least one data that does “not meet the criteria for elevated liver 
enzyme” among the evaluable data obtained from the day after the first dose of the study drug 
in the open-label cohort until 167 days after the last dose of the study drug (including 
Follow-up Day 167). 
[3] A subject who does not meet conditions [1] or [2] will be excluded from the analysis of 
elevated liver enzyme for that item.