Clinical trial NCT02284906
Conditions: Mild Cognitive Impairment Due to Alzheimer's Disease
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2015-02-12; Completion date: 2018-05-08
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the effect of pioglitazone at 24 months compared with placebo on cognitive decline in high-risk participants who have completed the AD-4833/TOMM40\_301 study \[NCT01931566\] with an adjudicated diagnosis of mild cognitive impairment (MCI) due to Alzheimer's Disease (AD).

Detailed description:
The drug being tested in this study is called pioglitazone. This study is designed to further evaluate the safety and effectiveness of pioglitazone on cognitive function in participants who have completed the AD-4833/TOMM40\_301. This study will look at the effectiveness of pioglitazone on cognitive decline in high-risk participants who have completed the AD-4833/TOMM40\_301 study with a diagnosis of mild cognitive impairment (MCI) due to Alzheimer's Disease (AD).

The study enrolled 40 participants, but is dependent on how many decide to continue treatment in an extension phase after completing the main (301) study. Participants will continue to receive the same study medication they received during the pivotal AD-4833/TOMM40\_301 study, either:

* Pioglitazone 0.8 mg tablets or
* Placebo (this is a tablet that looks like the study drug but has no active ingredient).

All participants will be asked to take one tablet at the same time each day throughout the study.

This multi-centre trial, like its precedent pivotal trial, will be conducted worldwide. The overall time to participate in this study is minimum 2 years and a maximum of 7 years depending on when participants roll over from the 301 study. Participants will make approximately 2 visits per year to the clinic, and will be contacted by telephone 3 months after each treatment visit for a follow-up assessment, and 2 weeks after the final visit.

Arms: arm 1: Pioglitazone 0.8 mg, tablets, orally, once, daily, for minimum of 2 years. arm 2: Pioglitazone placebo-matching tablets, orally, once, daily, for minimum of 2 years.
Interventions: intervention 1: Pioglitazone intervention 2: Placebo
Intervention descriptions: intervention 1: Pioglitazone tablets intervention 2: Pioglitazone placebo-matching tablets

Protocol documents:
Prot_001.pdf: 


•
Title: A Blinded Long-term Extension Study to Evaluate the Safety and Efficacy of Pioglitazone 
(AD-4833 Sustained Release 0.8 mg Daily) to Slow the Progression of Cognitive Decline in Subjects 
Who Have Completed the AD-4833/TOMM40_301 Study With Diagnosis of Mild Cognitive 
Impairment Due to Alzheimer Disease
NCT Number: NCT02284906
Protocol Approve Date: 19 January 2016
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.
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.


PROTOCOL AMENDMENT
A Blinded Long-term Extension Study to Evaluate the Safety and Efficacy of Pioglitazone 
(AD-4833 Sustained Release 0.8 mg Daily) to Slow the Progression of Cognitive Decline in 
Subjects Who Have Completed the AD-4833/TOMM40_301 Study With Diagnosis of Mild 
Cognitive Impairment Due to Alzheimer Disease
AD-4833/TOMM40_303 Extension Study of the Safety and Efficacy of Pioglitazone to Slow 
Cognitive Decline in Subjects With Mild Cognitive Impairment Due to Alzheimer Disease
Sponsor:
Takeda Development Center Americas, Inc. 
One Takeda Parkway
Deerfield, IL 60015 USA
Takeda Development Centre Europe Ltd.
61 Aldwych 
London, WC2B 4AE, UK
Takeda Development Center Asia, Pte Ltd
21 Biopolis Road
Nucleos North Tower. Level 4
Singapore 138567
Study Number:
AD-4833/TOMM40_303
IND Number:
112,403
EudraCT Number:
2013-004984-30
Compound:
AD-4833 
Date:
19 January 2016
Amendment Number:
3
Amendment History: 
Date
Amendment Number
Amendment Type
Region
21 March 2014
Initial Protocol
Not Applicable
Global
31 March 2015
1
Substantial
Global
29 July 2015
2
Substantial
Global
19 January 2016
3
Substantial
Global
Document generated using Protocol Phase 2-4 Template, G-TMPL-RD-005 Version: 03
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 


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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.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
TDC sponsored investigators per country requirements will be provided with emergency medical 
contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Issue
North America Contact
Europe Contact 
Australia Contact
Serious adverse 
event and 
pregnancy 
reporting
Medical 
Monitor
(medical advice 
on protocol, 
compound, and 
medical 
management of 
subjects)
Responsible 
Medical Officer 
(carries overall 
responsibility 
for the conduct 
of the study)
Protected Personal Data
Confidential Company Information


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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical 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.
SIGNATURES
Protected Personal Data


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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also protect the rights, safety, privacy, and well-being of 
study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B—Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State)
Location of Facility (Country)


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1.3
Protocol Amendment 3 Summary of Changes
This document describes changes in reference to the Protocol incorporating Amendment 3. 
The primary purpose of this amendment is to update the protocol regarding laboratory exclusion 
criteria and to remove the adjudication process for diagnosis of dementia. Full details on changes 
of text are given in Appendix G. The following is a summary of the changes made in the 
amendment;
1. Removal of exclusion criterion #3.
Justification: HbA1c >8% as a criteria for exclusion has been removed because, while this 
assessment will still be collected at Baseline, it is no longer considered an important eligibility 
criterion for this study. Any medical concerns with a subject’s baseline HbA1c result will be 
handled on a case by case basis. While the intent to prohibit insulin, triple oral antidiabetic 
therapy and PPAR-γ agonists remains, since insulin and PPAR-γ agonists are already in the 
Excluded Medications and Treatments Table 7.a, triple oral antidiabetic therapy will be added 
to the table to be consistent with the original exclusion intent.
2. Correction to exclusion criterion #8.
Justification: Criterion #8 was modified to allow the eligibility decision to be based on the 
laboratory results available prior to the AD-4833/TOMM40_301 EOS/303 Baseline visit to 
confirm/ensure eligibility for this extension study. 
3. Removed the adjudication process for confirmation of the diagnosis of dementia and added 
CDR Global score of ≥1.0 as a minimum standard for consistency in diagnosis of AD 
dementia.
Justification: The study investigators are more familiar with the criteria for the diagnosis of 
Alzheimer’s Disease (AD) than for Mild Cognitive Impairment due to AD and therefore, can 
reliably make this diagnosis without the need for the confirmation by the Adjudication 
Committee. Additionally, conversion from MCI due to AD to AD dementia is a secondary 
endpoint for this study and the AD data will be analyzed for trends, not statistical significance.
4. Removed MRI and CT scan (for subjects with contraindication to MRI) at the Unscheduled 
Visit to support the possible dementia diagnosis. 
Justification: With the removal of the adjudication process for confirmation of the diagnosis of 
dementia, the MRI or CT scan for the purpose of supporting the diagnosis as an endpoint event 
is not required.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................3
1.1
Contacts.....................................................................................................................3
1.2
Approval....................................................................................................................4
1.3
Protocol Amendment 3 Summary of Changes............................................................6
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
Principal Investigator/Coordinating Investigator ......................................................15
3.3
List of Abbreviations ...............................................................................................16
3.4
Corporate Identification...........................................................................................17
4.0
INTRODUCTION.........................................................................................................18
4.1
Background .............................................................................................................18
4.2
Rationale for the Proposed Study.............................................................................20
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................21
5.1
Objectives................................................................................................................21
5.1.1
Primary Objective ..............................................................................................21
5.1.2
Secondary Objectives.........................................................................................21
5.1.3
Additional Objectives.........................................................................................21
5.1.3.1 Safety Objective...........................................................................................21
5.1.3.2 Exploratory Objectives.................................................................................21
5.2
Endpoints.................................................................................................................22
5.2.1
Primary Endpoint...............................................................................................22
5.2.2
Secondary Endpoint ...........................................................................................22
5.2.3
Additional Endpoints .........................................................................................22
5.2.3.1 Safety Endpoint............................................................................................22
5.2.3.2 Exploratory Endpoints..................................................................................22
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................25
6.1
Study Design ...........................................................................................................25
6.2
Subject Flow Based on Cognitive and Functional Assessments................................27
6.2.1
Assessments at Baseline Visit (Visit 1) ..............................................................27
6.2.2
Assessments at Scheduled Study Visits ..............................................................28
6.2.3
Assessments at an Unscheduled Visit for Suspected Cognitive or Functional 
Decline ..............................................................................................................28
6.3
Randomization Procedure........................................................................................29


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6.4
Justification for Study Design, Dose, and Endpoints ................................................29
6.4.1
Study Design......................................................................................................29
6.4.2
Study Dose.........................................................................................................32
6.4.3
Study Endpoints.................................................................................................32
6.5
Premature Termination or Suspension of Study or Investigational Site.....................33
6.5.1
Criteria for Premature Termination or Suspension of the Study..........................33
6.5.2
Criteria for Premature Termination or Suspension of Investigational Sites .........33
6.5.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................33
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............34
7.1
Inclusion Criteria .....................................................................................................34
7.2
Exclusion Criteria ....................................................................................................34
7.3
Excluded Medications and Treatments.....................................................................35
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................38
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................39
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................40
8.1
Study Medication and Materials...............................................................................40
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................40
8.1.1.1 Investigational Drug.....................................................................................40
8.1.1.2 Sponsor-Supplied Drug ................................................................................40
8.1.2
Storage...............................................................................................................40
8.1.3
Dose and Regimen .............................................................................................40
8.1.4
Overdose............................................................................................................41
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................41
8.3
Randomization Code Creation and Storage..............................................................42
8.4
Investigational Drug Blind Maintenance ..................................................................42
8.5
Unblinding Procedure..............................................................................................42
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................42
9.0
STUDY PLAN ..............................................................................................................45
9.1
Study Procedures.....................................................................................................45
9.1.1
Informed Consent Procedure..............................................................................45
9.1.1.1 Pharmacogenomic Informed Consent Procedure...........................................45
9.1.1.2 Project Partner Acknowledgement Form/Informed Consent Procedure.........45
9.1.2
Demographics, Medical History, and Medication History Procedure..................46
9.1.3
Physical Examination Procedure ........................................................................46
9.1.4
Weight and Height .............................................................................................46


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9.1.5
Vital Sign Procedure..........................................................................................47
9.1.6
Documentation of Concomitant Medications......................................................47
9.1.7
Documentation of Concurrent Medical Conditions.............................................47
9.1.8
Procedures for Clinical Laboratory Samples.......................................................47
9.1.9
Pregnancy ..........................................................................................................49
9.1.10 ECG Procedure..................................................................................................49
9.1.11 Pharmacogenomic Sample Collection ................................................................49
9.1.12 Documentation of Baseline Failure ....................................................................50
9.1.13 Documentation of Study Entrance......................................................................50
9.1.14 Assessments.......................................................................................................51
9.1.14.1
Cognitive Test at Baseline Visit (Visit 1)................................................51
9.1.14.2
Efficacy Assessments .............................................................................51
9.1.14.3
Subject-Reported Outcome Questionnaires.............................................53
9.1.14.4
Project Partner Reported Questionnaires.................................................53
9.1.14.5
Other Assessments .................................................................................54
9.1.14.6
Assessment of Suicidal Ideation and Behavior........................................55
9.1.14.7
MRI Assessment ....................................................................................55
9.1.14.8
Health Economics and Outcomes Research Assessments........................56
9.1.14.9
Diet and Exercise Evaluation..................................................................56
9.1.15 Order of Assessments.........................................................................................56
9.1.15.1
Language Considerations........................................................................58
9.1.16 Tester Qualification and Certification.................................................................58
9.1.17 Imaging..............................................................................................................59
9.2
Monitoring Subject Treatment Compliance..............................................................59
9.3
Schedule of Observations and Procedures................................................................59
9.3.1
Study Entrance (Baseline)..................................................................................59
9.3.2
Treatment Phase.................................................................................................60
9.3.3
Unscheduled Visit..............................................................................................60
9.3.3.1 Unscheduled Visits for Emerging Concerns (including Safety).....................60
9.3.3.2 Unscheduled Visit for Suspected Cognitive or Functional Decline ...............60
9.3.4
Final Visit or Early Termination.........................................................................60
9.3.5
Follow-up ..........................................................................................................61
9.3.6
Poststudy Care ...................................................................................................61
9.4
Biological Sample Retention and Destruction ..........................................................61
9.4.1
Pharmacogenomics ............................................................................................61


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................62
10.1
Definitions...............................................................................................................62
10.1.1 Pretreatment Events ...........................................................................................62
10.1.2 AEs....................................................................................................................62
10.1.3 Additional Points to Consider for PTEs and AEs................................................62
10.1.4 SAEs..................................................................................................................64
10.1.5 Special Interest AEs...........................................................................................65
10.1.6 Causality of AEs ................................................................................................65
10.1.7 Relationship to Study Procedures.......................................................................66
10.2
Procedures...............................................................................................................66
10.2.1 Collection and Reporting of AEs........................................................................66
10.2.1.1
PTE and AE Collection Period ...............................................................66
10.2.1.2
PTE and AE Reporting ...........................................................................66
10.2.1.3
Special Interest AE Reporting.................................................................67
10.2.2 Collection and Reporting of SAEs......................................................................69
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................70
10.3
Follow-up of SAEs ..................................................................................................70
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....70
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................71
11.1
Independent Data and Safety Monitoring Board.......................................................71
12.0
DATA HANDLING AND RECORDKEEPING............................................................72
12.1
CRFs (Electronic and Paper)....................................................................................72
12.2
Record Retention .....................................................................................................72
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 ...........................74
13.1.3 Efficacy Analysis...............................................................................................74
13.1.4 Other Analyses...................................................................................................76
13.1.5 Safety Analysis ..................................................................................................76
13.2
Determination of Sample Size..................................................................................77
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................78
14.1
Study-Site Monitoring Visits ...................................................................................78
14.2
Protocol Deviations..................................................................................................78
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................78


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15.0
ETHICAL ASPECTS OF THE STUDY........................................................................79
15.1
IRB and/or IEC Approval ........................................................................................79
15.2
Subject Information, Informed Consent, and Subject Authorization .........................80
15.3
Subject Confidentiality ............................................................................................81
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................81
15.4.1 Publication and Disclosure.................................................................................81
15.4.2 Clinical Trial Registration..................................................................................82
15.4.3 Clinical Trial Results Disclosure ........................................................................82
15.5
Insurance and Compensation for Injury....................................................................82
16.0
REFERENCE3S............................................................................................................83
LIST OF IN-TEXT TABLES
Table 6.a
Cognitive Test Battery for the Extension AD-4833/TOMM40_303 Study..........31
Table 7.a
Excluded Medications and Treatments...............................................................36
Table 8.a
Sponsor-Supplied Drug......................................................................................41
Table 9.a
Clinical Laboratory Tests...................................................................................48
Table 9.b
Order of Assessments.........................................................................................57
Table 10.a
Takeda Medically Significant AE List................................................................65
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................27
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................87
Appendix B
Responsibilities of the Investigator.....................................................................89
Appendix C
Elements of the Subject Informed Consent.........................................................91
Appendix D
Investigator Consent to Use of Personal Information..........................................94
Appendix E
Collection, Shipment, and Storage of Pharmacogenomic Samples......................95
Appendix F
Operational Criteria for AD [23] ........................................................................96
Appendix G
Detailed Description of Amendments to Text.....................................................99


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compound:
AD-4833
Title of Protocol: A Blinded Long-term Extension Study to 
Evaluate the Safety and Efficacy of Pioglitazone (AD-4833 
Sustained Release 0.8 mg Daily) to Slow the Progression of 
Cognitive Decline in Subjects Who Have Completed the 
AD-4833/TOMM40_301 Study With Diagnosis of Mild 
Cognitive Impairment Due to Alzheimer Disease
IND No.: 112,403
EudraCT No.:
2013-004984-30
Study Number: AD-4833/TOMM40_303
Phase: 3
Study Design:
This is a blinded, placebo-controlled, multicenter, parallel group long-term extension study. The study is designed to 
further evaluate the efficacy and safety of pioglitazone on cognitive function in subjects who have an adjudicated 
diagnosis of mild cognitive impairment (MCI) due to Alzheimer disease (AD) (according to the National Institute on 
Aging/Alzheimer’s Association definition) and have completed the pivotal AD-4833/TOMM40_301 study with a 
diagnosis of MCI due to AD. Subjects who have an adjudicated diagnosis of MCI due to AD in the 301 study may be 
eligible to participate in this extension study depending on their site’s participation in the 303 study. The treatment 
assignment from the pivotal study will remain unchanged, that is, subjects will continue to receive the same study 
medication they received during the pivotal AD-4833/TOMM40_301 study, either pioglitazone or placebo. The 
extension study will follow subjects from the time they complete the pivotal AD-4833/TOMM40_301 study until 2 
years after the pivotal AD-4833/TOMM40_301 study is concluded, allowing the last subject enrolling into the 
extension study a follow up period of 2 years in the extension study. Of the 222 potential subjects from both the high-
and low-risk arms of the pivotal AD-4833/TOMM40_301 study it is expected that approximately 149 subjects will 
enroll into this extension study. 
Primary Objective:
!
To evaluate the effect of pioglitazone at 24 months compared with placebo on cognitive decline in high-risk 
subjects who have completed the AD-4833/TOMM40_301 study with an MCI due to AD diagnosis.
Secondary Objective:
!
To evaluate the effect of pioglitazone compared with placebo on the delay of onset of AD dementia in high-risk 
study subjects.
Additional Objectives
Safety Objective:
!
To evaluate long-term safety and tolerability of pioglitazone during the course of the treatment.
Exploratory Objectives:
!
 
!
!
 
!
!
!
Company Confidential Information


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!
!
!
!
!
!
Subject Population: Male and female subjects, at least 65 years of age at time of Baseline Visit, who have completed 
the pivotal AD-4833/TOMM40_301 study with an adjudicated diagnosis of MCI due to AD.
Number of Subjects:
Approximately 149 subjects will be enrolled.
Number of Sites:
Estimated total: up to 60 in North America, Europe, 
Australia.
Dose Level(s):
AD-4833 sustained release 0.8 mg tablet once daily (QD)
Placebo QD
Route of Administration:
Oral
Duration of Treatment:
Minimum of 2 years (24 months)
Period of Evaluation:
Minimum 2-year Blinded Treatment period
Main Criteria for Inclusion:
!
The subject completed the pivotal AD-4833/TOMM40_301 study with an adjudicated diagnosis of MCI due to 
AD without ongoing serious adverse events from study AD-4833/TOMM40_301.
!
The subject must be living independently or in nonmedical residential care.
!
The subject has a project partner able to separately consent on his/her own behalf and take part in the study (with 
the intent to do so as long as the subject is enrolled), providing information on the cognitive, functional, and 
behavioral status of the subject (and self reported, if voluntarily agreed to) and assisting with observation of 
adverse events and monitoring of study medication, if needed. (Project partners participating in the pivotal 
AD-4833/TOMM40_301 study are encouraged to participate in this extension study in this capacity.)
Main Criteria for Exclusion:
!
The subject completed the pivotal AD-4833/TOMM40_301 study with an adjudicated diagnosis of AD dementia.
!
The subject has a current diagnosis of significant psychiatric illness, per Diagnostic and Statistical Manual of 
Mental Disorders, 4th Edition (including but not limited to major depressive disorder, anxiety disorders) and is in 
an acute phase/episode, or the subject has a current diagnosis or history of schizophrenia or bipolar disorder.
!
The subject has a clinically significant unstable illness, for example, hepatic impairment or renal insufficiency, or 
cardiovascular, pulmonary, gastrointestinal (including s/p gastric bypass), endocrine, neurological, 
Company Confidential Information


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rheumatologic, immunologic, infectious, skin and subcutaneous tissue disorders, or metabolic disturbance.

The subject is required to take excluded medications as specified in the Excluded Medications Section. 

The subject had any of the following values at the second comprehensive medical follow-up visit in the 
AD-4833/TOMM40_301 study (or time of last collection in the pivotal 301 study):

A serum total bilirubin value >1.5× upper limit of normal (ULN).

A serum alanine aminotransferase or aspartate aminotransferase value >2×ULN.

Unexplained microscopic/macroscopic hematuria on one repeat examination within 2 weeks.

The subject has a disease or takes medication that, in the opinion of the investigator, could interfere with the 
assessments of safety, tolerability, or efficacy, or prevent the subject from adequately participating in the study or 
continue for the anticipated duration of the study.

The subject has any cancer that has been in remission for less than 2 years from the extension study Baseline Visit. 
Subjects with basal cell or stage I squamous cell carcinoma of the skin will be eligible. Subjects with current 
diagnosis of bladder cancer are not eligible irrespective of the remission status.

The subject has a current diagnosis of macular edema or macular degeneration.

The subject has a history or current diagnosis of congestive heart failure, New York Heart Association class 
III-IV.
Main Criteria for Evaluation and Analyses:
Efficacy:
The primary endpoint for this study:

Change from extension study Baseline to 24 months on the composite score of the cognitive test battery. 
Secondary endpoint for this study:

Time to diagnosis of AD dementia.
Statistical Considerations:
The primary null hypothesis in this study assumes that there is no difference in the cognitive decline of MCI due to AD 
between the placebo-treated and active-treated subjects in the high-risk group. The alternative hypothesis is that there 
is a difference in cognitive decline between pioglitazone and placebo. The change in the composite cognitive test 
battery score from extension study Baseline to 24 months will be analyzed using mixed models repeated measures 
(MMRM). The other secondary endpoints will be analyzed using MMRM, analysis of covariance, logistic regression, 
survival analyses, or chi-squared tests as appropriate to the data. As for the primary analysis, the secondary endpoints 
will be tested at the 2-sided 0.05 level. The ability of demonstrating a difference between active and placebo may be 
limited by study design as the determination of number of subjects is not based on statistical consideration and the 
subjects are not randomized at the beginning of this study.
Sample Size Justification: 
The sample size for this study was not based on statistical considerations. Subjects who have an event of MCI due to 
AD, without a diagnosis of AD dementia, in the pivotal AD-4833/TOMM40_301 study may be eligible to enroll into 
this extension study, depending on their site’s participation in the 303 study. In the pivotal AD-4833/TOMM40_301 
study, approximately 222 subjects (including both high and low risk, and including all races and ethnicities) are 
expected to have an event of MCI due to AD or AD dementia. Approximately 149 of 222 subjects (67%) are 
anticipated to consent to participate in the 303 extension study.


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.


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3.3
List of Abbreviations
AA
Alzheimer’s Association
Aβ
amyloid-beta
AD
Alzheimer’s Disease
ADCS ADL-MCI
Alzheimer’s Disease Cooperative Study Activities of Daily Living – Mild Cognitive 
Impairment
ADCS CGIC-MCI
Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change – Mild 
Cognitive Impairment
ADCS IADL
Alzheimer’s Disease Cooperative Study Instrumental Activities of Daily Living
ADCS-RUI
Alzheimer’s Disease Cooperative Study- Resource Use Inventory
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BVMT-R
Brief Visuospatial Memory Test – Revised
CDR
Clinical Dementia Rating
CDR-SB
Clinical Dementia Rating – Sum of Boxes
CFR
Code of Federal Regulations
CHF
congestive heart failure
C-SSRS
Columbia-Suicide Severity Rating Scale
CVLT-II
California Verbal Learning Test – 2nd Edition
DSMB
Data and Safety Monitoring Board
ECG
electrocardiogram
eCRF
electronic case report form
EQ-5D
Euro Quality of Life-5D includes single item measures of: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression
FDA
Food and Drug Administration
FAS
full analysis set
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
HbA1c
glycosylated hemoglobin
HDPE
high-density polyethylene
HRQoL
health-related quality of life
ICH
International Conference on Harmonisation
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IVRS
interactive voice response system
IWRS
interactive web response system
LFT
liver function test
MCI
mild cognitive impairment
MCI-AD
mild cognitive impairment due to Alzheimer’s Disease


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MedDRA
Medical Dictionary for Regulatory Activities
MetS
metabolic syndrome
MINT
Multilingual Naming Test
MMRM
mixed models repeated measures
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
NIA
National Institute on Aging
NPI-Q
Neuropsychiatric Inventory Questionnaire
PPAR-γ
peroxisome proliferator-activated receptor gamma
PRO
patient reported outcome
PTE
pretreatment event
QD
once daily
rCBF
regional cerebral blood flow
RU
resource utilization
SAE
serious adverse event
SAP
statistical analysis plan
SR
sustained release
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TMT
Trail Making Test
TOMM40
translocase of the outer mitochondrial membrane 40 homolog
TZD
thiazolidinedione
ULN
upper limit of normal
vMRI
volumetric magnetic resonance imaging
WAIS
Weschler Adult Intelligence Scale
WPAI:MM-CG
Work Productivity and Activity Impairment Questionnaire: Mood and Mental State, 
Caregiver Version
3.4
Corporate Identification 
TDC (Asia)
Takeda Development Center (Asia) Pte Ltd
TDC (Europe)
Takeda Development Centre (Europe) Ltd.
TDC (Americas)
Takeda Development Center, Inc.
TDC
TCRS, TDC (Europe) and/or TDC (Americas), as applicable
TPC
Takeda Pharmaceutical Company Limited
Takeda
TDC (Asia), TDC (Americas), TDC (Europe), and/or TPC, as applicable


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4.0
INTRODUCTION
4.1
Background
Alzheimer disease (AD) is a progressive and fatal brain disorder that causes the death of brain cells 
and atrophy of the brain. It is the most common type of dementia: 50% to 80% of all dementia 
cases are diagnosed as AD [1]. The disease pathoetiology includes disturbances in synaptic 
function, energy, lipid metabolism, and inflammatory responses within the brain [2]. Symptoms 
include loss of memory, reasoning, and other brain functions. The hallmarks of the advanced 
stages of AD brain neuropathology are amyloid-beta (Aβ) plaques, composed of microscopic 
aggregates of Aβ peptides that deposit in the brain parenchyma, and intracellular tau protein 
hyperphosphorylation and accumulation. These features are accompanied by impairment of 
neuronal metabolism and function.
AD is characterized as being either early (before 65 years of age) or late (after 65 years of age) 
onset, referring to the age of onset of declines in cognitive performance and physical functioning 
[3]. Both forms involve steady cognitive decline in the years after onset [4,5], with late-onset AD 
being the most common form, accounting for approximately 96% of AD cases in the United States 
[3].
While the exact sequence of events leading to AD manifestation remains a subject of debate, the 
pathophysiologic changes that underlie the clinical presentation are known to begin decades 
before the first symptoms appear, and to develop slowly over what is now recognized as a 
preclinical/presymptomatic phase. The prodromal, symptomatic phase is marked by impaired 
cognition, commonly described as mild cognitive impairment (MCI). This phase describes the first 
point at which cognitive impairment is noted, without significant effects on functional abilities. As 
a person’s cognitive ability continues to deteriorate and activities of daily living also become 
impaired, the MCI phase converts to clinical AD dementia. The gradually progressing clinical 
symptoms of AD are characterized by cognitive deficits (eg, learning and retaining new 
information, difficulty handling complex tasks, impaired reasoning ability), accompanied by 
neuropsychiatric symptoms (eg, apathy, diminished interest, agitation, depression, and delusions), 
and in later phase of the disease motor systems abnormalities [6]. 
Although not all persons with MCI will develop AD, the conversion rate from MCI to AD in the 
general population is about 15% per year, or 5 to 10 times that of cognitively normal individuals.
Overall, this slow, progressive trajectory of decline is now recognized as the continuum of AD 
[7-9].
There is great interest in finding treatments to prevent AD by intervening at an even earlier stage 
than diagnosed MCI [10]. By the time clinical symptoms appear, neurons may have died or 
undergone irreversible damage. Thus a strategy of delaying the onset of the disease, rather than 
waiting to treat symptoms, could have substantial medical, economic, and societal impact.
Pioglitazone is currently being investigated in the AD-4833/TOMM40_301 study as a treatment to 
delay the onset of MCI due to AD in cognitively normal elderly subjects at high risk of developing 
symptoms of cognitive decline associated with AD based on the translocase of the outer 


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mitochondrial membrane 40 homolog (TOMM40) rs10524523 and apolipoprotein E genotype as 
well as age. 
Pioglitazone HCl (marketed globally under ACTOS and other trade names), is an oral antidiabetic 
agent indicated for the treatment of type 2 diabetes mellitus (T2DM). It belongs to the 
thiazolidinedione (TZD) class of drugs and exhibits a mechanism of action different from the 
sulfonylureas, the biguanides, or the -glucosidase inhibitors.
The mechanism of action of pioglitazone involves primarily the decrease of insulin resistance in 
muscle and other tissues. Pioglitazone is a potent and highly selective agonist of peroxisome 
proliferator-activated receptor-gamma (PPAR-), which is found in tissues important for insulin 
action (including adipose tissue, skeletal muscle, liver, and the brain) [11]. Activation of PPAR-
nuclear receptors modulates the transcription of a number of insulin-responsive genes involved in 
the control of glucose and lipid metabolism.
The mechanism of action through which PPAR-agonists affect AD pathophysiology is not 
known at this time; in vitro and in vivo animal models of AD have demonstrated effects of PPAR-γ 
agonists that could be relevant in AD treatment and prevention, although the mechanism of action 
through which this activity occurs is not known at this time. Effects of PPAR-agonists in AD 
models include potentiation of glucose-induced thermogenesis and oxygen consumption in brain 
homogenates; inhibitory effects on Aβ-stimulated proinflammatory responses and neurotoxicity; 
neuroprotective effects through reductions in microglial activation, inflammatory gene expression, 
and Aβ deposition in the brain; and normalization of cerebral blood flow (perfusion) and cerebral 
glucose uptake (metabolism). 
In addition, PPAR-receptors have direct effects on mitochondrial function and adenosine 
triphosphate production. It is thought that mitochondria may play a chief role in the cerebral 
hypometabolism observed in AD. It is postulated that PPAR-agonists will improve 
mitochondrial function in AD [12], and this may be the source of favorable outcomes on memory 
and cognition in AD patients that have been observed in some recent clinical studies of PPAR-
agonists [13-17].
The efficacy of pioglitazone on cognition, regional cerebral blood flow (rCBF), and plasma levels 
of Aβ40 and Aβ42 has been demonstrated in a 6-month, randomized, open-controlled pilot study 
in subjects with mild AD accompanied with T2DM. Since launch in the United States in July 1999, 
through 31 January 2012, the total patient-years of exposure to pioglitazone (including 
monotherapy and fixed-dose combination) globally is estimated to be approximately 29,542,000 
[18]. Clinical experience has not identified differences in effectiveness or safety between the 
elderly (≥65 years of age) and younger subjects, although small numbers of subjects ≥75 years of 
age limit this conclusion. 
Adverse events (AEs) associated with pioglitazone, listed in the Warnings and Precautions section 
of the Company Core Data Sheet [19], for subjects with T2DM and at doses considerably higher 
(15-45 mg) than the intended dose in this clinical development program (sustained release [SR] 
0.8 mg) were as follows: edema, body weight increase, decreases in hemoglobin and hematocrit, 
increases (or elevations) in creatine kinase (creatine phosphokinase), congestive heart failure 


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(CHF) and peripheral edema due to dose-related fluid retention, cardiac failure, hepatocellular 
dysfunction (post-marketing event), macular edema (post-marketing event), increased incidence 
of fractures in female population, hypoglycemia, and bladder cancer. A detailed discussion of the 
safety profile of pioglitazone is provided in the Investigator’s Brochure [11]. 
Sato et al conducted a 6-month, randomized, open-controlled pilot study of pioglitazone efficacy 
on cognition, rCBF, and plasma Aβ40 and Aβ42 [20]. Study subjects were 42 AD patients with 
T2DM, half of whom were treated with 15 to 30 mg pioglitazone daily; all subjects continued on 
their previous T2DM treatment (including sulfonylureas, biguanides, and α-glucosidase 
inhibitors). Subjects receiving pioglitazone demonstrated significantly improved cognition 
(Mini-Mental State Examination [MMSE], Alzheimer’s Disease Assessment Scale - Cognitive 
Subscale), Wechsler Memory Scale-revised logical memory-I) and rCBF at 6 months compared 
with Baseline (Visit 2), while untreated subjects did not. Untreated subjects did, however, have 
increased plasma Aβ40 /Aβ42 ratio, while there was no significant change in pioglitazone-treated 
subjects.
The National Institute on Aging (NIA) is currently sponsoring a pioglitazone study to investigate 
novel treatments to delay progression to dementia in patients with MCI and metabolic syndrome 
(MetS) [21]. Adults aged 55 years or older with both MetS and MCI at Baseline (Visit 2) are 
randomized to a 6-month intervention with either (1) treatment with pioglitazone, (2) endurance 
exercise training, or (3) control (placebo and no exercise). It is proposed that treatment with the 
TZD pioglitazone or endurance exercise training will improve cognitive function compared with
controls, as evidenced by either improvement, stabilization, or lesser decline in performance on 
cognitive testing. 
4.2
Rationale for the Proposed Study
The design of this extension study would allow the evaluation of the efficacy of pioglitazone in 
reducing the change in cognitive decline in subjects who have been diagnosed with MCI due to 
AD in the pivotal AD-4833/TOMM40_301 study. Progression from MCI due to AD to a diagnosis 
of AD dementia is expected in a subset of the subjects.
This extension study will provide continued treatment and follow-up for consenting participants 
who complete the pivotal AD-4833/TOMM40_301 study after receiving an adjudicated diagnosis 
of MCI due to AD. Although MCI due to AD is a condition that can carry a substantial risk of 
dementia, the exact magnitude of this risk is uncertain given that the MCI due to AD construct 
itself is relatively new and had not been operationalized until the AD-4833/TOMM40_301 study. 
While anticipated not to be statistically powered due to constraints of sample size and feasible 
follow-up duration, this extension study will be first to examine the efficacy of pioglitazone in 
reducing the change in cognitive decline in subjects with established diagnosis of MCI due to AD 
according to the criteria developed by the NIA and the Alzheimer’s Association (AA) in Albert et 
al, 2011 [22]. As a secondary objective, the study will prospectively explore the efficacy of 
pioglitazone in delaying the conversion from MCI due to AD diagnosis to diagnosis of AD 
dementia [23]. Finally, long-term exposure data will be gathered to further assess the safety profile 
of once-daily (QD) low-dose pioglitazone in the elderly.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective 
!
The objective of this study is to evaluate the effect of pioglitazone at 24 months compared with 
placebo on cognitive decline in high-risk subjects who have completed the 
AD-4833/TOMM40_301 study with an adjudicated diagnosis of MCI due to AD.
5.1.2
Secondary Objectives 
!
To evaluate the effect of pioglitazone compared with placebo on the delay of onset of AD 
dementia in high-risk study subjects.
5.1.3
Additional Objectives
5.1.3.1
Safety Objective
!
To evaluate long-term safety and tolerability of pioglitazone during the course of the 
treatment.
5.1.3.2
Exploratory Objectives
!
!
!
!
!
!
!
!
!
Company Confidential Information


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!
!
!
!
5.2
Endpoints
5.2.1
Primary Endpoint 
!
Change from extension study Baseline to 24 months in the composite score of the cognitive 
test battery. 
5.2.2
Secondary Endpoint 
!
Time to diagnosis of AD dementia [23].
5.2.3
Additional Endpoints
5.2.3.1
Safety Endpoint
!
Safety and tolerability: AEs (including AEs of special interest), vital signs, body weight, 
electrocardiogram (ECG), magnetic resonance imaging (MRI), clinical laboratory data, and 
physical examination findings.
5.2.3.2
Exploratory Endpoints
!
Company Confidential Information
Company Confidential Information


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!
!
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!
!
!
!
!
!
Company Confidential Information


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! Company Confidential Information


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a blinded, placebo-controlled, multicenter, parallel group long-term extension study. The 
study is designed to further evaluate the efficacy and safety of pioglitazone on cognitive function 
in subjects who have completed the pivotal AD-4833/TOMM40_301 study with an adjudicated 
diagnosis of MCI due to AD (according to the NIA/AA definition [22]). Subjects who have an 
adjudicated diagnosis of MCI due to AD in the 301 study and meet the entry criteria described in 
Section 7.0, may be eligible to participate in the 303 extension study depending on their site’s 
participation in the 303 study. The treatment assignment from the pivotal study will remain 
unchanged, that is, subjects will continue to receive the same study medication they received 
during the pivotal AD-4833/TOMM40_301 study, either pioglitazone or placebo.
The study participants will be men or women, at least 65 years of age at the time of the extension 
study Baseline Visit. The extension study will follow subjects from the time they complete the 
pivotal AD-4833/TOMM40_301 study for a minimum of approximately 2 years and a maximum 
of approximately 7 years, that is, the extension study will be terminated 2 years after the pivotal 
AD-4833/TOMM40_301 study is concluded, allowing the last subject enrolling into the extension 
study a follow up period of approximately 2 years in the extension study. Although MCI due to AD 
is the primary endpoint event expected in the 301 study, AD dementia is a diagnostic event that 
also counts toward the total needed for that event-driven study; however, subjects diagnosed with
AD dementia in the pivotal AD-4833/TOMM40_301 study will not be eligible to participate in 
this extension study.
Each subject must have a project partner able to separately consent on his or her own behalf and 
take part in the study to provide information on the cognitive, functional, and behavioral status of 
the subject and to assist with monitoring of study medication, if needed, for as long as the subject 
remains in the study. It is recommended that the same project partner (spouse, adult child, or other 
person familiar with the participant’s health and daily functioning) participating in the pivotal 
AD-4833/TOMM40_301 study will also participate in the extension study. 
The data collected in the pivotal AD-4833/TOMM40_301 study will be used in the analyses of the 
extension study. This includes results of all cognitive, psychiatric, and medical assessments 
performed at all scheduled pivotal AD-4833/TOMM40_301 study visits and any subsequent 
comprehensive medical follow-up evaluations as stipulated in the pivotal 
AD-4833/TOMM40_301 study protocol. The End of Study Visit of the pivotal 
AD-4833/TOMM40_301 study will serve as the Baseline Visit for the extension study once 
appropriate informed consent is signed, with additional assessments carried out as outlined in 
Section 6.2. 
A 0.8 mg tablet of SR pioglitazone or placebo will be used in this extension study, the same as that 
used in the pivotal AD-4833/TOMM40_301 study. The tablet will be administered QD for a 
minimum period of 24 months, in accordance with the extension study duration. Study medication 
will be dispensed at the end of the extension study Baseline Visit and subjects will be instructed to 


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take the first dose of study medication in the morning on the day following the extension study 
Baseline Visit (if all eligibility criteria are confirmed).
Based on the underlying assumptions, of the approximately 222 potential subjects from both the 
high- (approximately 213 potential subjects) and low-risk (approximately 9 potential subjects) 
arms of the pivotal AD-4833/TOMM40_301 study it is expected that approximately 67% will 
enroll into this extension study (ie, a total of approximately 149 subjects). While it is preferred that 
subjects and their project partners consent to the AD-4833/TOMM40_303 study while attending 
the AD-4833/TOMM40_301 End of Study Visit, subjects will be allowed to return to the clinic 
and consent for the extension study within 1 month of the AD-4833/TOMM40_301 End of Study 
Visit, as described in the Schedule of Study Procedures. They will complete the 
AD-4833/TOMM40_303 baseline evaluations (if needed) once informed consent is provided and 
within the 1 month window.
Subjects and their project partners are expected to attend on-site study visits every 6 months after 
Baseline, for regular assessments of safety, efficacy, and treatment compliance. In addition, the 
subject will be contacted for telephone-based safety checks between visits. While it is preferred 
that subject’s project partners attend the on-site study visits, it is not required and they may offer 
their information via telephone. Project partners who voluntarily take part in completion of the 2 
self reported project partner questionnaires (outline in Section 9.1.14.4), will be required to attend 
the study visits when the questionnaires are obtained. If between in clinic visits, worsening of 
cognitive impairment, potential AD dementia, or a potential safety issue is suspected, requiring 
further evaluation of the subject, an unscheduled clinic visit may be conducted as described in 
Section 6.2.3. Up to 60 sites globally may participate in this study (the same sites that participated 
in the AD-4833/TOMM40_301 study, although all sites may not participate in 303).
The last MRI scan or that obtained at a second consecutive comprehensive medical follow-up 
evaluation in the AD-4833/TOMM40_301 study will serve as the baseline vMRI time point for 
this study. This baseline vMRI scan will be reviewed against the vMRI measure acquired in this 
extension study. Subjects with contraindications for vMRI assessments will not be excluded from
the extension study for this reason. 
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in
Appendix A.


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Figure 6.a
Schematic of Study Design
6.2
Subject Flow Based on Cognitive and Functional Assessments
6.2.1
Assessments at Baseline Visit (Visit 1)
The End of Study Visit of the pivotal AD-4833/TOMM40_301 study will serve as the Baseline 
Visit for the extension study once appropriate informed consent and partner acknowledgment, or 
consent (if needed) are signed (or within a 1 month window from the 301 End of Study Visit). The 
data collected at the End of Study Visit of the pivotal AD-4833/TOMM40_301 study, including 
the most recent cognitive assessments, will supplement the additional AD-4833/TOMM40_303 
study baseline visit procedures and will be used as the baseline values for each subject. At this 
visit, after extension study informed consent for the subjects and acknowledgement, or consent (if 
needed) from their partners are signed, the ADCS CGIC-MCI Baseline assessment will be 


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completed with the subject and project partner. The ADCS ADL-MCI will also be completed by 
the project partner.
At the end of the extension study Baseline Visit (Visit 1), a blood sample will be collected for 
glycosylated hemoglobin (HbA1c) testing, and study medication will be dispensed.
6.2.2
Assessments at Scheduled Study Visits
Neuropsychological testing and functional assessments will be conducted at each scheduled visit 
(see Appendix A for a full listing) using a broad cognitive test battery and functional 
measurements (including investigator’s clinical judgment) as described in Section 9.1.14 and in 
Appendix A. The extension study’s cognitive test battery is the same as that employed in the 
pivotal study and consists of the Brief Visuospatial Memory Test – Revised (BVMT-R), 
California Verbal Learning Test – 2nd Edition (CVLT-II), Semantic Fluency, Lexical/Phonemic 
Fluency, Digit Span (forward and backwards), Multilingual Naming Test (MiNT), Trail Making 
Tests (TMT) Parts A and B, and the Clock-drawing test (see Section 9.1.14). The scores from each 
neuropsychological instrument described above will be converted to a common metric (z-score).
In addition, subjects will be administered the MMSE. Subjects will be evaluated for depression
using the GDS. Activities of daily living (ADCS ADL-MCI) will be assessed with the project
partner. Additional details regarding test administration will be provided in the Training Manual 
provided by the vendor selected by Takeda.
In addition, investigators, certified and trained accordingly, will complete the Clinical Dementia 
Rating (CDR). The investigator who completes the CDR is independent and cannot be the same 
person who administers the cognitive battery. Sites should make an attempt to use the same 
investigator to complete the CDR at each assessment. Without referring to the cognitive test 
battery or the MMSE, the investigator will complete the CDR scale and assign a CDR global score 
and CDR-SB scores.
The physician, preferably an experienced neurologist or psychiatrist, will review the totality of 
available information once fully scored (ie, medical history, CDR ratings, and CDR-SB scores;
ADCS-CGIC-MCL, ADCS ADL-MCI, GDS, and NPI-Q data; cognitive test results; and 
laboratory test results). At this point he/she in consultation with the site neuropsychologist, will 
determine whether the diagnosis of the subject has changed from MCI due to AD. If possible or 
probable AD dementia is diagnosed, the subject will be considered to have completed the study. If 
non-AD dementia is diagnosed, the subject will be withdrawn from the study. The physician can 
be the same individual who completed the CDR. 
6.2.3
Assessments at an Unscheduled Visit for Suspected Cognitive or Functional Decline
There are 2 types of Unscheduled Visits in this study: (1) Unscheduled Visits conducted to address 
any emerging concerns, including safety, and; (2) Unscheduled Visits conducted to evaluate 
suspected cognitive or functional decline.
Unscheduled Visits conducted to address any emerging concerns, including safety, are described 
in Section 9.3.3. 


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Unscheduled Visits to evaluate suspected cognitive or functional decline may be conducted, as 
needed, for study subjects outside of regularly scheduled visits based on either of the following 
trigger criteria being met: (1) the subject or their project partner express concern of the subject’s 
cognitive or functional decline to the principal investigator or coordinator between regularly 
scheduled study visits and/or (2) a non-study physician expresses concern (with or without 
prescription of any dementia drug treatment) between regularly scheduled visits. Based on these 
triggers, the principal investigator will decide whether evidence is present to suspect a diagnosis of 
possible or probable AD dementia [23]. If a diagnosis of possible or probable AD dementia is 
suspected, an Unscheduled Visit to further evaluate suspected cognitive or functional decline 
should take place within approximately 1 month, of this provisional diagnosis. A CDR Global 
score of ≥1.0 will be required in order to set a consistent minimum standard for AD dementia as an 
endpoint in the study. Visit procedures for the unscheduled visit for suspected cognitive or 
functional decline are noted in Appendix A. 
6.3
Randomization Procedure
Subjects will continue the treatment assignment they were assigned in the pivotal 
AD-4833/TOMM40_301 in a blinded fashion, taking either pioglitazone or placebo. 
6.4
Justification for Study Design, Dose, and Endpoints
6.4.1
Study Design
The design of this extension study is one that allows evaluation of the efficacy of pioglitazone on 
cognitive decline in subjects who have been diagnosed with MCI due to AD from the pivotal 
AD-4833/TOMM40_301 study. Cognitive and functional status of study participants will be 
closely monitored using validated neuropsychological and functional instruments in a quantifiable 
construct that is sensitive to the continued brain changes that precede the diagnosis of AD 
dementia. Progression of cognitive decline to diagnosis of AD dementia is expected in a subset of 
the subjects.
The annual conversion rate from any form of MCI to the diagnosis of AD ranges from 3.3% to 
41% per year, with memory deficits and older age identified as risk factors. In the Cache County 
study, composed of populations similar to that expected to enroll to the extension study, 
conversion rate was 46% over 3 years. Rates of progression to dementia are generally higher for 
specialized or clinic-based samples (eg, 15% per year) and for classifications in which an amnestic 
syndrome predominates (eg, 13% biannually). A minimum of 2 years follow up from completion 
of the pivotal AD-4833/TOMM40_301 study per subject (ie, 2.5 years from onset of MCI due to 
AD diagnosis) is therefore expected to yield a substantial number of conversions to diagnosis of 
AD dementia, despite the constraints of study size and expected high dropout rates consequent to 
multiple years of concatenated follow-up in the pivotal and extension clinical trials. 
There are currently no approved therapies for subjects with any type of MCI. However, multiple 
clinical trials have been conducted over the past decade in MCI populations in an attempt to reduce 
the rate of cognitive decline and extend time to progression to AD diagnosis. The majority of 
studies conducted to date recruited subjects at a mean age of 70, used various criteria to define 


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MCI eligibility, and employed a diverse set of cognitive, functional, and clinical instruments to 
evaluate progression. Most of the studies defined the primary endpoint as time to, or incidence of, 
AD diagnosis, an approach that required large sample sizes and long follow-up durations. Another 
drawback of this approach is reflected in reports of lower than expected conversion rate to AD 
diagnosis. Other studies targeted change from baseline in global cognition (or also global function) 
and lasted 6 months to 1 year, with 250 to 800 subjects enrolled. 
All of these previously conducted studies missed their primary endpoints. Some postulated that the 
measurements used were insensitive to the early AD phases of MCI and that the follow-up 
durations were likely too short. While anticipated to be statistically underpowered, the current 
extension study is therefore designed to focus on the more tangible primary endpoint, that is, 
overall change from Baseline in cognitive performance over 24 months, which has become the 
generally accepted approach by the field experts and regulators, as published by the Task Force on 
Designing Clinical Trials in early (predementia) AD in 2011 [24]. 
Experience with TZDs in MCI populations is very limited. Three relevant studies were conducted 
with rosiglitazone: in a pilot study (N=30), Watson et al demonstrated that 6 months of 
rosiglitazone treatment in elderly with normal glucose tolerance and MCI or early-AD was 
beneficial on cognitive measures of delayed recall and selective attention as compared with 
placebo [15]. In an observational study, elderly subjects with amnestic MCI and T2DM were 
followed up for 36 weeks, with the combination therapy metformin/rosiglitazone reported as
associated with stable cognitive performance on all neuropsychological tests over time, contrary to 
comparator groups treated with metformin alone or a well-controlled diet without active treatment
[25]. Results of The Rosiglitazone Effects on Cognition for Adults in Later Life study, completed 
in mid-2010 (ClinicalTrials.gov identifier: NCT00242593) in subjects with MCI over 18 months 
follow-up, have yet to be reported. 
For pioglitazone, a pilot, 6-month follow-up study in subjects with AD and amnestic MCI with 
T2DM has been reported, showing significant improvement in the drug arm in global cognition 
and verbal memory measures. However, only 1 prior clinical study was conducted with 
pioglitazone in MCI cases solely: the “pioglitazone or exercise to treat mild cognitive impairment 
(POEM)” study (NCT00736996). In this study, treatment with high-dose pioglitazone (30-45 mg) 
or endurance exercise training were hypothesized to improve, stabilize, or attenuate decline in 
cognitive function over 6 months compared with control. This short-term study enrolled adults 
aged 55 years or older with both MetS and MCI at baseline. Results have not been published yet. 
The battery of cognitive tests used in the extension AD-4833/TOMM40_303 study is identical to 
the cognitive test battery employed in the pivotal AD-4833/TOMM40_301 study (Table 6.a), and 
is appropriate for the target age range. It also carries a relatively low burden to study participants 
and their partners. This battery was specifically selected to characterize subtle early changes in 
cognition across 5 different domains suitable for detecting the first signs of MCI due to AD (ie, 
incipient MCI due to AD), and to follow-up the progression of cognitive impairment onward. 
Instruments capturing functional and clinical decline are also used, with outcomes analyzed as 
secondary endpoints, complementary to the composite cognitive decline score. Furthermore, 
because this extension study clearly defines MCI due to AD at eligibility, it is anticipated to yield


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a high conversion rate to AD dementia, as has been noted in clinical trials of MCI [26] and 
longitudinal studies [27]. 
The composition of the cognitive test battery selected for this extension study is the same as that 
used in the pivotal AD-4833/TOMM40_301 study, thus allowing for continuity of measurement 
from the beginning of the pivotal AD_4833/TOMM40_301 study throughout to end of the 
extension AD-4833/TOMM40_303 study. The progression endpoints are therefore uniquely 
equipped to investigate changes in cognitive, functional and clinical performance not only from 
enrollment into the extension study, but also from enrollment into the pivotal study, using data 
collected throughout all semiannual assessments conducted in between. 
Table 6.a
Cognitive Test Battery for the Extension AD-4833/TOMM40_303 Study
Cognitive Domain
Tests
Episodic Memory
CVLT-II
BVMT-R
Executive Function
TMT (Part B)
WAIS-III Digit Span Test – backwards span
Language
MINT
Semantic Fluency (animals)
Lexical/phonemic fluency
Attention
WAIS-III Digit Span Test – forward span
TMT (Part A)
Visuospatial
Clock Drawing Test
Copy of BVMT figures
WAIS= Wechsler Adult Intelligence Scale.
Note: The neuropsychological test battery of the extension study is identical to that used in the pivotal
AD_4833/TOMM40_301 study and includes 12 measures derived from 8 neuropsychological tests: The CVLT-II 
involves 2 primary measures (ie, short delay recall, and long delay recall); BVMT-R has 2 measures (ie, copy and 
recall); Digit Span has 2 measures (ie, forward and backward span); and TMT has 2 measures (ie, Parts A and B). 
There is 1 total score for each of the remaining tests: clock drawing, MINT, animal fluency, and letters F, A, and S. 
In secondary prevention and early intervention clinical trials of AD, subjects enroll into the clinical 
trial with a pre-existing cognitive impairment that predisposes them to convert to AD dementia. 
However, not all cases of MCI convert to AD, with some subjects maintaining stable cognitive 
performance with minimal functional impairment for many years and others revert back to normal 
cognition. It is therefore essential that therapeutics investigated within the frameworks of early 
intervention targeting this stage along the AD continuum display a highly favorable safety profile. 
To this end, extensive pioglitazone exposure data has been gathered thus far in thousands of 
patients globally at doses significantly higher than the dose employed by the pivotal 
AD-4833/TOMM40_301 study, which is intended to be used in this extension 
AD-4833/TOMM40_303 study as well. The favorable safety profile of pioglitazone was 
underscored by the meta-analysis presented at the Food and Drug Administration (FDA) Joint 
Meeting of the Endocrinologic and Metabolic Drug Advisory Committee and the Drug Safety and 
Risk Management Advisory Committee Meeting, 2010. The meta-analysis included 35 trials 
covering 22,131 patients, of whom 12,213 (55%) were randomized to pioglitazone and 9918 


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(45%) to the comparator. Overall, across all trials for pioglitazone, the estimated major adverse 
cardiovascular events (defined as cardiovascular death, stroke, or myocardial infarction) risk was 
lower for pioglitazone compared with control (hazard ratio=0.80; 95% CI=0.70-0.93).
Brain alterations have been shown to occur early on in AD predisposed individuals, preceding
clinical manifestation of cognitive decline. Furthermore, neuroimaging modalities have been 
proposed as potentially useful techniques for prediction of progression in subjects with MCI. The 
sensitivity and specificity of the different modalities or biomarkers are a subject of intense 
research in the early stages of the AD continuum, with incipient MCI being of particular interest. 
Of these, vMRI has been shown to capture gross neuronal loss causing whole brain and regional 
brain atrophy, typical of cognitive decline processes along the AD continuum. These atrophic 
changes seem to correlate well with clinical disease stage, as well as cognitive and functional 
decline in cognitively impaired individuals. The grey matter shrinkage affects the cortical and 
subcortical brain, and is particularly apparent in the medial-temporal lobe in AD brains. The 
general pattern of atrophy starts at the hippocampus and the entorhinal cortex, which are the 
regions most notably affected in the MCI stage. To this end, a report by the Alzheimer’s Disease 
Neuroimaging Initiative has recently identified volumetric atrophy of the hippocampus as the 
second earliest AD biomarker to become dynamic, with the first being impairment in episodic 
memory (reflected through performance on a verbal learning test). Nonetheless, increased brain 
atrophy rates have also been reported in cognitively normal elderly with low cerebrospinal fluid 
amyloid depositions (Aβ1-42). Assessments of vMRI will be collected at the extension study 
Baseline (last MRI completed in 301 study) and at study termination to test for correlation with 
disease progression within and across study arms. 
6.4.2
Study Dose
Subjects will retain their original blinded treatment assignment, either a 0.8 mg SR tablet of 
pioglitazone or a matching placebo tablet will be used, the same as that used in the pivotal 
AD-4833/TOMM40_301 study. The tablet will be administered QD for a minimum period of 
24 months.
6.4.3
Study Endpoints
This study is an extension to the pivotal AD-4833/TOMM40_301 study and as such may be 
statistically underpowered due to constraints of sample size and feasible follow-up duration. The 
primary objective is to examine the efficacy of pioglitazone on cognitive decline in subjects with 
established diagnosis of MCI due to AD according to the criteria developed by the NIA/AA [22]. 
As a secondary objective, the study will prospectively explore the efficacy of pioglitazone in 
delaying the conversion from MCI due to AD to diagnosis of AD dementia. In parallel, long-term 
exposure data will be gathered, so as to further characterize the safety profile of daily 
administration of low-dose pioglitazone in the elderly.
This study acknowledges the importance of both cognitive and functional decline as key 
components along the continuum of AD and includes both of these recommended outcomes. One 
of the core clinical criteria for the MCI due to AD diagnosis is preservation of independence in 
functional abilities. As participants in the extension study are followed up, however, simultaneous 


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decline in functional, as well as cognitive performance is expected. This course will most likely 
lead to AD dementia. The progression of decline in the extension study will be assessed 
comprehensively on 5 cognitive domains, as well as functional ratings obtained through structured 
interviews of participants and their project partners, compared between pioglitazone and placebo 
treated subjects. 
6.5
Premature Termination or Suspension of Study or Investigational Site
6.5.1
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.

New information or other evaluation regarding the safety or efficacy of the study medication 
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.

The independent DSMB recommends that the study should be suspended or terminated. 

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.

In the instance that the pivotal AD-4833/TOMM40_301 study is prematurely terminated based 
on futility analysis, that is, the study is unlikely to demonstrate treatment efficacy.
6.5.2
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.
6.5.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria: 
1. The subject completed the pivotal AD-4833/TOMM40_301 study with an adjudicated 
diagnosis of MCI due to AD without ongoing serious adverse events (SAEs) from 
AD-4833/TOMM40_301.
2. The subject is male or female and is at least 65 years of age at the time of the Baseline Visit.
3. In the opinion of the investigator, the subject is capable of understanding and complying with 
the protocol requirements.
4. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form (ICF) and any required privacy authorization prior to the 
initiation of any study procedures. 
5. The subject must be living independently or in nonmedical residential care.
6. Subject has a project partner able to separately consent on his/her own behalf and take part in 
the study (with the intent to do so as long as the subject is enrolled), providing information on 
the cognitive, functional, and behavioral status of the subject (and self reported, if voluntarily 
agreed to) and assisting with observation of AEs and monitoring of study medication, if 
needed. Project partners participating in the pivotal AD-4833/TOMM40_301 study are 
encouraged to participate in this extension study in this capacity. 
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject completed the pivotal AD-4833/TOMM40_301 study with an adjudicated 
diagnosis of AD dementia [23].
2. The subject has a current diagnosis of significant psychiatric illness, per Diagnostic and 
Statistical Manual of Mental Disorders, 4th Edition (including but not limited to major 
depressive disorder, anxiety disorders) and is in an acute phase/episode, or the subject has a 
current diagnosis or history of schizophrenia or bipolar disorder.
3. The subject has a clinically significant unstable illness, for example, hepatic impairment or 
renal insufficiency, or cardiovascular, pulmonary, gastrointestinal (including s/p gastric 
bypass surgery), endocrine, neurological, rheumatologic, immunologic, infectious, skin and 
subcutaneous tissue disorders, or metabolic disturbance.
4. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
pivotal, child, sibling) or may consent under duress. 


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5. The subject is required to take excluded medications as specified in the Excluded Medications 
Section. 
6. The subject has a history of hypersensitivity or allergies to pioglitazone or related compounds. 
7. The subject had any of the following values at the second comprehensive medical follow-up 
visit in the AD-4833/TOMM40_301 study (or time of last collection in the pivotal 301 study):
a.
A serum total bilirubin value >1.5× upper limit of normal (ULN).
b. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2×ULN.
c.
Unexplained microscopic/macroscopic hematuria on one repeat examination within 
2 weeks.
8. The subject has a disease or takes medication that, in the opinion of the investigator, could 
interfere with the assessments of safety, tolerability, or efficacy, or prevent the subject from 
adequately participating in the study or continue for the anticipated duration of the study.
9. The subject has received any investigational compound, with the exception of treatment during 
the AD-4833/TOMM40_301 study, within 30 days prior to Baseline or 5 half-lives prior to 
Baseline or is currently participating in another study that entails the administration of an 
investigational or marketed drug, supplement, or intervention including, but not limited to diet, 
exercise, lifestyle, or invasive procedure. 
10. The subject has any cancer that has been in remission for less than 2 years from the extension 
study Baseline Visit. Subjects with basal cell or stage I squamous cell carcinoma of the skin 
will be eligible. Subjects with current diagnosis of bladder cancer are not eligible irrespective 
of the remission status.
11. The subject has a current diagnosis of macular edema or macular degeneration.
12. The subject has a history or current diagnosis of CHF, New York Heart Association class 
III-IV.
7.3
Excluded Medications and Treatments
Subjects must be instructed not to take any medication, including over-the-counter products, 
without first consulting with the investigator. The medical monitor should be contacted for 
questions regarding episodic use. To date, there are no approved therapies for subjects with any 
type of MCI. However, if an approved drug becomes available for the indication of MCI due to 
AD during the conduct of this trial, it may be offered to the subject by the investigator and the 
subject may be able to continue their participation in this extension, based on discussions with the 
medical monitor. If the subject plans to take any other cognitive enhancing treatments, these also 
MUST be discussed with the medical monitor prior to initiation of such treatments. Table 7.a
describes medications disallowed prior to enrollment and medications disallowed during the 
course of the study.


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Table 7.a
Excluded Medications and Treatments
Drug Class
Use Parameters (Subject Disposition)
At Extension Study Baseline Visit
During the Study
Acetylcholinesterase 
inhibitors (ie, donepezil, 
rivastigmine, galantamine, 
and huperzine)
Prohibited, any prior use 
(Subject not eligible)
Prohibited, if initiated (Subject must be 
discontinued)
Memantine
Prohibited, any prior use 
(Subject not eligible)
Prohibited, if initiated (Subject must be 
discontinued)
Amphetamine and 
dextroamphetamine 
(psychostimulants, ie, 
amphetamine and 
dextroamphetamine 
[Adderall], 
methylphenidate 
[Concerta], 
dextroamphetamine 
[Dexedrine])
Prohibited, any prior use 
(Subject not eligible)
Prohibited, if initiated
(Subject must be discontinued)
Anticholinergic drugs
Conditional, if stable dose at least 3 
months prior to enrollment
(Subject eligible if condition met)
Allowed, if any prior episodic use, eg, 
inhaler to treat seasonal allergies. Oral 
medication should not be taken within 5 
days of the Baseline Visit. 
(Subject eligible)
Conditional, if initiated, but should be on 
stable dose at least 3 months prior to next 
scheduled study visit
(Subject continues if condition met [a])
Allowed, if episodic use, eg, inhaler to 
treat seasonal allergies. Oral medication 
should not be taken within 5 days of the 
study visit. 
(Subject continues)
Antidepressants
Conditional, if stable dose at least 
3 months prior to enrollment
(Subject eligible if condition met)
Conditional, if initiated, but should be on 
stable dose at least 3 months prior to next 
scheduled study visit
(Subject continues if condition met [a])
Antipsychotic drugs (eg,
olanzapine, haloperidol)
Prohibited, any prior or concurrent use 
for treatment of psychosis in subjects with 
schizophrenia or bipolar disorder
Conditional, if stable dose for at least 
3 months prior to enrollment for 
conditions other than schizophrenia or
bipolar disorder (eg, use in a subject with 
depression)
(Subject eligible if condition met)
Conditional, if initiated, but should be on 
stable dose at least 3 months prior to next 
scheduled study visit for conditions other 
than schizophrenia or bipolar disorder (eg, 
use in a subject with depression)
(Subject continues if condition met [a])
Footnotes are on last table page.


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Table 7.a
Excluded Medications and Treatments (continued)
Drug Class
Use Parameters (Subject Disposition)
At Extension Study Baseline Visit
During the Study
Benzodiazepines and 
nonbenzodiazepines sleep 
aides (zopiclone, 
eszopiclone, zolpidem)
Conditional, if stable dose at least 3 
months prior to enrollment
(Subject eligible if condition met)
Past episodic use is allowed
Conditional, if initiated for chronic use, 
but should be on stable dose at least 
3 months prior to next scheduled study 
visit
(Subject continues if condition met [a])
Episodic use is allowed
Anticonvulsants
Conditional, if stable dose at least 3 
months prior to enrollment
(Subject eligible if condition met)
Conditional, if initiated, but should be on 
stable dose at least 3 months prior to next 
scheduled study visit
(Subject continues if condition met [a])
Barbiturates
Conditional, if stable dose at least 3 
months prior to enrollment
(Subject eligible if condition met)
Prohibited, if chronic use initiated 
(Subject must be discontinued)
Dopamine agonists [used 
for restless leg syndrome]
(eg, ropinerole [Requip], 
pramipexole [Mirapex], 
rotigotine transdermal 
system [Neupro], 
gabapentin enacarbil 
[Horizant])
Conditional, if stable dose at least 
3 months prior to enrollment
(Subject eligible if condition met [a])
Conditional, if initiated, but should be on 
stable dose at least 3 months prior to next 
scheduled study visit
(Subject continues if condition met [a])
L-Dopa/carbidopa or any 
other Parkinson’s 
medication for the 
treatment of Parkinson’s 
Disease
Prohibited, any prior use 
(Subject not eligible)
Prohibited, if initiated 
(Subject must be discontinued)
Strong CYP2C8 inhibitors 
(eg, gemfibrozil)
Conditional, if prior use was stopped 
30 days or 5 half-lives, whichever is 
longer, prior to enrollment
(Subject eligible if condition met)
Prohibited, if chronic use initiated 
(Subject must be discontinued)
Allowed, if episodic use 
(Subject continues)
CYP2C8 inducers (eg, 
rifampin)
Conditional, if prior use was stopped 30 
days or 5 half-lives, whichever is longer, 
prior to enrollment
(Subject eligible if condition met)
Prohibited, if chronic use initiated 
(Subject must be discontinued)
Allowed, if episodic use 
(Subject continues)
Insulin
Prohibited, if any prior chronic use 
(Subject not eligible)
Allowed, if any prior episodic use, eg, to 
treat nonketotic hyperglycemic coma
(Subject eligible)
Prohibited, if chronic use initiated 
(Subject must be discontinued)
Allowed, if episodic use 
(Subject continues)
PPAR-agonists (other 
than study drug) 
Prohibited, if initiated 
Prohibited, if initiated 
(Subject must be discontinued)
Triple Oral Antibiotic 
Therapy
Prohibited, if initiated
Prohibited, if initiated 
(Subject must be discontinued)
Chemotherapy drugs(b)
No use in the past 2 years before the 
Extension study Baseline Visit
Prohibited, if initiated 
(Subject must be discontinued)
Footnotes are on the following page.


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CYP=cytochrome P-450.
(a) If condition is not met, neuropsychological battery data for the next scheduled study visit may be censured.
(b) Low doses for non-cancerous conditions will be allowed on a case-by-case basis following approval by the medical 
monitor.
7.4
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study should be 
recorded in the electronic case report form (eCRF) using the following categories. For baseline 
failure subjects, refer to Section 9.1.12.
1. Pretreatment event (PTE) or AE. 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. For guidance on 
withdrawal criteria due to AEs of special interest please refer to Section 10.2.1.3.

Liver Function Test (LFT) Abnormalities
Based on local country criteria, subjects in a clinical trial who experience ALT and/or AST
>3×ULN and total bilirubin >2×ULN and satisfy the following 2 criteria: (1) the liver injury is 
hepatocellular in nature and there is not a prominent cholestatic component; (2) there is no 
more likely alternative cause than drug induced liver injury, such as acute viral hepatitis A or 
B, or other acute liver disease.
If ALT or AST >3×ULN, laboratory tests should be repeated within a maximum of 7 days, and 
preferably within 48 to 72 hours. If the ALT or AST remains elevated >3×ULN on these 
2 consecutive occasions, and this observation cannot be explained by concomitant disease or 
another alternative etiology, the abnormality should be recorded as an AE. The investigator 
must contact the Medical Monitor for consideration of immediate discontinuation of study 
medication, discussion of the relevant subject details and possible alternative etiologies.
In addition, study medication should be discontinued immediately with appropriate clinical 
follow-up, including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal, if the following circumstances occur at any time during study medication 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 (>5%).
2. Significant protocol deviation. The discovery post–study entry that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health.
3. Voluntary withdrawal. The subject or project partner wishes to withdraw from the study.


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Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE or lack of efficacy should not be recorded in the “voluntary withdrawal” category).
4. 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. Type and date of last 
contact should be recorded on the eCRF.
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.5
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 7.4. 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. Discontinued or withdrawn subjects will not be replaced. 
In addition to normal follow-up contact attempts, a subject’s project partner should be contacted if 
the subject is suspected to be lost to follow-up.


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to AD-4833 SR 0.8 mg tablets and placebo orally 
administered tablets. 
8.1.1.1
Investigational Drug 
AD-4833 Tablets Placebo
AD-4833 tablet placebo is manufactured by Takeda Pharmaceutical Company Limited, Osaka, 
Japan. The oral administration tablets are pale red plain tablets. Each high-density polyethylene 
(HDPE) bottle contains 100 tablets and a desiccant and has a child resistant cap. The bottles will be 
labeled with a blinded single panel or booklet label that will contain pertinent study information in 
local languages. 
AD-4833 SR 0.8 mg Tablet
AD-4833 SR 0.8 mg tablet is manufactured by Takeda Pharmaceutical Company Limited, Osaka, 
Japan. The oral administration tablets are pale red plain tablets. Each HDPE bottle contains 100 
tablets and a desiccant and has a child resistant cap. The bottles will be labeled with a blinded 
single panel or booklet label that will contain pertinent study information in local languages.
8.1.1.2
Sponsor-Supplied Drug 
Sponsor-supplied drugs referenced in other sections of the protocol include the following: 
AD-4833 SR 0.8 mg and placebo tablets.
8.1.2
Storage
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. All sponsor-supplied drugs must be stored 
under the conditions specified on the label, and remain in the original container until dispensed. A 
daily temperature log of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
This is a placebo-controlled, blinded, parallel group study comparing AD-4833 SR 0.8 mg tablet to 
placebo. Subjects will keep the treatment assignment they were randomized into in the pivotal 
AD-4833/TOMM40_301 in a blinded fashion, taking either pioglitazone or placebo.
Table 8.a describes the dose and tablet count that will be provided to each group. 


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Table 8.a
Sponsor-Supplied Drug
Treatment 
Group
Dose
Treatment Description
Active
Placebo
1 
Placebo QD 
Zero active tablets 
One AD-4833 tablet placebo 
2 
AD-4833 SR 
0.8 mg tablet QD 
One AD-4833 SR 0.8 mg 
tablet 
Zero placebo tablets 
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. AEs 
associated with an overdose will be documented on AE CRF(s) according to Section 10.0, 
Pretreatment Events and Adverse Events.
SAEs of overdose should be reported according to the procedure outlined in Section 10.2.2, 
Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically. In the event of 
deliberate or accidental drug overdose, general symptomatic and supportive measures should be 
used. 
8.2
Investigational Drug Assignment and Dispensing Procedures
The investigator or investigator’s designee will access the interactive web response system
(IWRS) at Baseline to obtain the subject study number. The investigator or the investigator’s 
designee will utilize the IWRS to continue each qualified subject into the same treatment 
assignment from the pivotal AD-4833/TOMM40_301 study at Baseline (Visit 1). During this 
contact, the investigator or designee will provide the necessary subject-identifying information, to 
identify the subject’s treatment assignment from the pivotal AD-4833/TOMM40_301 study 
randomization table. 
The investigator or investigator’s designee will access the IWRS at each dispensing visit to obtain 
Med ID Numbers for 2 bottles containing 100 tablets each of either AD-4833 SR 0.8 mg or 
placebo based on the subject’s randomized treatment arm. Subjects will be instructed to take 1 
tablet per day, orally, at the same time of day, preferably in the morning, or as directed. Take with 
or without food. 
Subjects should be informed as follows that if they miss a scheduled dose: 

If it is almost time for the next dose (within 12 hours), skip the missed dose and take the next 
dose when it is due.


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
Otherwise, take the missed dose as soon as it is remembered, and then go back to taking the 
investigational drug as usual. 

Do not take a double dose to make up for a missed dose.
Study drug is to be kept in the container provided until the dose is to be taken. The first dose is to 
be taken the morning after the Baseline Visit. The investigator or investigator’s designee will 
utilize the IWRS for Med ID assignment at every subsequent dispensing visit. If sponsor-supplied 
drug AD-4833 SR 0.8 mg tablets or placebo is lost or damaged, the site can request a replacement 
from the IWRS. (Refer to the IWRS manual provided separately.) 
The site will receive a confirmation email from the IWRS providing the Med IDs assigned at each 
dispensing visit. The site will print, date and initial the email and file in the subject’s file as 
documentation of correct dispensing.
8.3
Randomization Code Creation and Storage 
The subjects will not be re-randomized at the beginning of the extension study. Subjects will 
continue to receive the same medication from the pivotal AD-4833/TOMM40_301 study, either 
AD-4833 SR 0.8 mg or placebo.
The IWRS vendor generated the randomization schedule for the 301 study. All randomization 
information will be stored in a secured area, accessible only by authorized personnel.
8.4
Investigational Drug Blind Maintenance 
The investigational drug blind will be maintained using the IWRS. 
8.5
Unblinding Procedure 
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. In the 
event of a medical emergency, if possible, the medical monitor should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding. 
For unblinding a subject, the investigational drug blind can be obtained by the investigator, by 
accessing the interactive voice response system (IVRS)/IWRS. 
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study.
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee. This includes AD-4833 SR 0.8 mg and placebo tablets. 


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The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with
the approved protocol and is dispensed only to subjects enrolled in the study. To document 
appropriate use of sponsor-supplied drug AD-4833 SR 0.8 mg and placebo, the investigator must 
maintain records of all sponsor-supplied drug delivery to the site, site inventory, dispensation and 
use by each subject, and return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, the 
medication is received within the labeled storage conditions, and is in good condition. If quantity 
and conditions are acceptable, investigator or designee should acknowledge the receipt of the 
shipment by recording in IWRS. If there are any discrepancies between the packing list versus the 
actual product received, Takeda must be contacted to resolve the issue. The packing list should be 
filed in the investigator’s essential document file.
The investigator must maintain 100% accountability for all sponsor-supplied drugs received and 
dispensed during his or her entire participation in the study. Proper drug accountability includes, 
but is not limited to:

Continuously monitoring expiration dates if expiry/retest date is provided to the investigator.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot (or Medication ID or job number) used to 
prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The investigator must record the current inventory of all sponsor-supplied drugs, AD-4833 SR 
0.8 mg and placebo, on a sponsor-approved drug accountability log or within IWRS. The 
following information will be recorded at a minimum (as applicable to IWRS): protocol number 
and title, name of investigator, site identifier and number, description of sponsor-supplied drugs, 
date and amount dispensed including initials of the person dispensing the drug, and the date and 
amount returned to the site by the subject, including the initials of the person receiving the 
sponsor-supplied drug. The log should include all required information as a separate entry for each 
subject to whom sponsor-supplied drug is dispensed.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the sponsor or its designee for destruction. The investigator will retain a 
copy of the documentation regarding clinical study material accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of clinical study 
material during the study conduct. On expiry date notification from the sponsor or designee, the 


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site must complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the sponsor or its designee for destruction.
In the event of expiry date extension of supplies already at the study site, supplies may be relabeled 
with the new expiry date at that site. In such cases, Takeda or its designee will prepare additional 
labels, certificates of analyses, and all necessary documentation for completion of the procedure at 
the sites.


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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 are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
Study subjects are asked to give informed consent to have their study assessments audio recorded. 
The study assessments (including the CDR interviews) may be audio-recorded for continuous 
quality control, training, and calibration purposes. Vendors experienced in providing training and 
quality control of CDR interviews will review the recordings and provide feedback to the 
investigative site and sponsor. The recordings may be used by the vendors for internal quality 
control as part of the training and calibration process for the vendors’ clinicians. Only the vendor 
will have access to the recordings. The recordings will be transferred from investigative sites to the 
vendor in an encrypted, secure manner with secure protocols: Hypertext Transfer Protocol Secure, 
File Transfer Protocol Secure, and Secure Sockets Layer. The vendor will store the recordings on a 
secure, password protected server. Recordings will be deleted 1 year after the last subject visit.
9.1.1.1
Pharmacogenomic Informed Consent Procedure
Informed consent to participate in the phamacogenomics component of the study and to storage 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
9.1.1.2
Project Partner Acknowledgement Form/Informed Consent Procedure 
The subjects must have a project partner able to complete an Acknowledgement Form, or an ICF 
(if needed) on his or her own behalf and take part in the study to provide information on the 
cognitive, functional, and behavioral status of the subject and self reported, if voluntarily agreed to 
and to assist with monitoring of study medication, if needed, for as long as the subject is in the 
study. While it is preferred that the Project Partner attend study visits with the subject, they may 
elect to provide the subject information noted above, via telephone. Project partners who 
voluntarily take part in the completion of 2 self reported project partner questionnaires (outline in 
Section 9.1.14.4), will be required to attend the study visits when the questionnaires are obtained. 
The Project Partner Acknowledgement Form, or ICF (if needed) must be obtained from the project 


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partner prior to the project partner completing any of the project partner protocol directed 
procedures. This includes the reported questionnaires and interviews outlined in Section 9.1.14.4. 
Should the project partner change during the course of the study, an Acknowledgement Form, or 
ICF (if needed) must be obtained from the new project partner prior to any of the project partner 
protocol directed procedures being performed. 
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information collected during the pivotal AD-4833/TOMM40_301 study will be 
utilized in this study. This information includes, date of birth or age, sex, Hispanic ethnicity, race 
as described by the subject, years of education and academic degrees, bilingualism, years lived in 
the country/region, socioeconomic status, drinking habits, and smoking status of the subject. In 
countries that do not allow collection of date of birth, a subject’s age will be collected.
For this extension study, medical history refers to any significant conditions or diseases relevant to 
the disease under study that stopped at or prior to signing of informed consent for the extension 
study, and may include resolved AEs from the pivotal AD-4833/TOMM40_301 study. AEs that
resolved during the pivotal study but were significant, that is, represented a new diagnosis (eg, 
myocardial infarction) and/or resulted in unplanned surgery or procedure (eg, coronary artery 
bypass graft surgery) or met any of the seriousness criteria should be recorded into the medical 
history. Non-serious adverse events such as headache or nausea which resolved during the pivotal 
study do not need to be recorded into the medical history of this extension study.
Ongoing conditions are considered concurrent medical conditions (see Section 9.1.7). Medical 
history will be collected at Baseline, coinciding with the pivotal AD-4833/TOMM40_301 End of 
Study Visit. 
Medication history will be obtained during the pivotal AD-4833/TOMM40_301 study, and will 
not be collected during this study. Concomitant medications will be collected (see Section 9.1.6).
9.1.3
Physical Examination Procedure
A baseline physical and neurological examination having been conducted as part of the End of 
Study Visit for the pivotal AD-4833/TOMM40_301 study, will serve as baseline data for the 
extension AD-4833/TOMM40_303 study. The examinations will consist of the following body 
systems: (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. All subsequent physical and neurological 
examinations should assess clinically significant changes from the baseline examination. Physical 
examination will be performed at each yearly visit (eg, Month 12, 24) of blinded treatment, 
Unscheduled Visit, and End of Study Visit/Early Withdrawal Visit. Neurological examination will 
be performed at every 6 month visit and yearly visit, during blinded treatment, Unscheduled Visit, 
and End of Study Visit/Early Withdrawal Visit.
9.1.4
Weight and Height 
A subject should have weight measured while wearing indoor clothing and with shoes off. 


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Weight and height, measured as part of the End of Study Visit for the pivotal 
AD-4833/TOMM40_301 study, will serve as baseline data for the extension 
AD-4833/TOMM40_303 study. Within the extension study, weight will be measured at every 6 
month visit and yearly visit during blinded treatment, and End of Study Visit/Early Withdrawal 
Visit. Weight will be collected in kilograms to 1 decimal place. 
9.1.5
Vital Sign Procedure
Vital signs will include body temperature (oral or tympanic measurement), sitting blood pressure 
(5 minutes), and pulse (beats per minute). 
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before the scheduled blood draw. 
Vital signs, measured as part of the End of Study Visit for the pivotal AD-4833/TOMM40_301 
study, will serve as baseline data for the extension AD-4833/TOMM40_303 study. Within the 
extension study, vital signs will be measured at each 6-month, and yearly in-clinic visit of blinded
treatment, Unscheduled Visit and at the End of Study Visit/Early Withdrawal Visit. 
9.1.6
Documentation of Concomitant Medications
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 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF.
9.1.7
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at baseline examination. The condition (ie, diagnosis) should be 
described. 
9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 21 mL, and the approximate total volume of 
blood for the study is 129 mL. The approximate total volume of blood will vary based on timing of 
subject’s enrollment into the study, and the extent of their duration of treatment. Details of these 
procedures and required safety monitoring will be given in the laboratory manual. Laboratory 
samples will be taken at the time points stipulated in the Schedule of Study Procedures 
(Appendix A).


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis (c)
Red blood cells
White blood cells count with 
differentials
(Neutrophils, eosinophils, basophils, 
lymphocytes, monocytes)
Hemoglobin
Hematocrit
Platelets
HbA1c (b)
ALT
Alkaline phosphatase
AST
Total bilirubin
Direct bilirubin (a)
Total protein
Albumin
Creatinine
Blood urea nitrogen
γ-Glutamyl transferase
Potassium
Sodium
Glucose
Calcium, 
Parathyroid hormone
Thyrotropin, free T4
Vitamin B12, folate (d)
Rapid plasma reagin (e)
pH
Specific gravity
Protein
Glucose
Blood
Nitrite
(a) Assess only if total bilirubin ≥2.0 mg/dL.
(b) To be done at Baseline and at the End of Study Visit.
(c) Microscopic examination (leucocytes, erythrocytes, and casts) should be performed only if any of the urine 
evaluations are abnormal.
(d) As part of the Unscheduled Visit to rule out other causes of dementia.
(e) At End of Study only.
The central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results.
If subjects experience ALT or AST >3×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, γ-glutamyl transferase, and INR) should be 
performed within a maximum of 7 days and preferably within 48 to 72 hours after the abnormality 
was found.
(Please refer to Section 7.4 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal LFTs in relation to ALT or AST >3×ULN in conjunction with 
total bilirubin >2×ULN.)
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 study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal LFTs for reporting requirements).
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used.


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9.1.9
Pregnancy
Women of childbearing potential will not be included in this study.
9.1.10 ECG Procedure 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. The 
following parameters will be recorded on the eCRF from the subject’s ECG trace: heart rate, QT 
interval, QRS interval, and QT (corrected). The ECG conducted at the End of Study visit for the 
pivotal AD-4833/TOMM40_301 study will serve as the baseline measurement. ECG will be 
recorded at each yearly visit (eg, Month 12, 24) of blinded treatment, and End of Study Visit/Early 
Withdrawal Visit. 
9.1.11 Pharmacogenomic Sample Collection
DNA and RNA form the basis for the genes that make the body produce proteins such as enzymes, 
drug transporters or drug targets, and may be evaluated for the genetic contribution of how the 
drug is broken down, or how the drug affects the body. This is called a “Pharmacogenomics 
research study.” Specific purposes of this study include:

Identifying genetic reasons why certain people respond differently to pioglitazone

Finding out more information about how pioglitazone works.

Generating information needed for research, development, and regulatory approval of tests to 
predict response to pioglitazone.

Identifying variations in genes related to the biological target of pioglitazone.
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of pioglitazone and other study medications, and for improving the efficiency, design and 
study methods of future research studies.
Prior to sampling of whole blood for pharmacogenomic analysis, every subject must sign informed 
consent/be consented in order to participate in the study. As the pharmacogenomics study is 
subject-optional, if a subject declines participation in the pharmacogenomics study, it will not have 
any bearing on the subject’s ability to participate in the main study.
Two whole blood samples (2.5 mL per sample) will be collected at each time point at the 
Month 12 Visit for the duration of the study, an Unscheduled Visit, and at the End of Study Visit 
for RNA pharmacogenomic analysis from each subject in the study, into a PAXGene tube. Note: if 
samples are collected at an Unscheduled Visit, they will not be required to be collected at the End 
of Study Visit.
See Appendix E for directions on collecting, handling, and storing pharmacogenomic samples. 
These samples are optional and should be collected from those subjects who provide independent 
consent to do so.


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Samples for RNA analysis will be stored and analyses may be performed to examine whether 
variation in gene expression plays a role in the mode of action of pioglitazone, the development of 
AD, mitochondrial function/dysfunction, and neurodegeneration.
In the event of an unexpected AE or the observation of unusual response, RNA may be isolated 
from the samples and analyses may be performed to evaluate a genetic or genomic association with 
response to pioglitazone. These investigations may be limited to a focused candidate gene study 
or, if appropriate, genome-wide association studies may be performed to identify regions of the 
genome associated with variability in drug response. Samples will only be used for investigations 
related to disease and absorption, disposition, metabolism, excretion, or response to drug or class 
of drugs under study in the context of this clinical program. They will not be used for broad, 
exploratory, unspecified disease or population genetic analysis.
The RNA samples will be identified by a unique sample identifier (coded) and stored for up to 
15 years after the last subject visit for the study at a facility selected by the sponsor. The sample 
and any data generated from it can only be linked back to the subject by clinical site personnel. 
Pharmacogenomic data from this sample will not be provided back to the investigator or the 
subject.
9.1.12 Documentation of Baseline Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to not be eligible at the Baseline Visit, the investigator should complete the 
appropriate eCRF. The IVRS/IWRS should be contacted as a notification of baseline failure.
The primary reason for baseline failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria.

Major protocol deviation.

Lost to follow-up.

Voluntary withdrawal, specify reason.

Study termination.

Other, specify reason.
Subject numbers assigned to subjects who fail baseline should not be reused.
9.1.13 Documentation of Study Entrance
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for continuation in the extension of the pivotal AD-4833/TOMM40_301 treatment phase. The 
IWRS should be contacted as a notification for the Baseline Visit. The IWRS will automatically 
continue the treatment assignment, AD-4833 0.8 mg SR tablets or AD-4833 placebo, for each 
subject from the pivotal AD-4833/TOMM40_301 study.


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If the subject is found to be not eligible for the treatment phase, the investigator should record the 
primary reason for failure on the appropriate eCRF. The IWRS should be contacted as a 
notification of baseline failure.
9.1.14 Assessments
9.1.14.1 Cognitive Test at Baseline Visit (Visit 1) 
The End of Study Visit of the pivotal AD-4833/TOMM40_301 study will serve as the Baseline 
Visit for the extension study once appropriate informed consent is signed (or within a 1-month 
window). At this visit, after extension study informed consent is given by both subjects and their 
partners, the project partners will also complete the ADCS ADL-MCI and ADCS-CGIC-MCI. The 
data collected at End of Study Visit of the pivotal AD-4833/TOMM40_301 study, the extension 
AD-4833/TOMM40_303 study Baseline Visit and results of the most recent cognitive test battery
assessment in the pivotal AD-4833/TOMM40_301 study are intended to provide the baseline 
(ie, before extension study medication) values for each subject on the cognitive assessments. 
9.1.14.2 Efficacy Assessments 
Cognitive testing will be conducted at each Month 12 Visit and at the End of Study Visit using a 
broad cognitive test battery. The instruments used in the battery are those commonly used to 
evaluate AD in the clinical setting. They are commercially available tests with well-documented 
validation in US and European populations and are in common use globally. The cognitive test 
battery is identical to the cognitive test battery employed semiannually towards the primary 
endpoint of the pivotal AD-4833/TOMM40_301 study. 

Brief Visuospatial Memory Test - Revised (BVMT-R [28]): The original, as well as 1 of the 5 
equivalent alternate forms of the BVMT-R will be used to assess immediate and delayed 
nonverbal memory. The subject is presented with a card depicting 6 simple designs. After the 
designs are studied for a brief time period, the card is removed and the subject must 
immediately draw the designs from memory. Between 15-30 minutes after the initial 
presentation, the subject is asked to draw the designs again. Immediately thereafter, a yes/no 
recognition trial is administered. Form 4 is the BVMT-R alternate form that will also be used 
along with Form 1 in this study based on published validation data suggesting these 2 forms (1 
and 4) have optimal psychometric characteristics over the other alternative versions (highest 
alternative form reliability). The forms will be alternated between visits according to a 
predetermined counterbalance schedule. 

California Verbal Learning Test – 2nd Edition (CVLT-II [29]): (list learning and delayed 
recall). The CVLT-II is a comprehensive and detailed assessment of verbal learning and 
memory that uses a multiple-trial list-learning task. A list of 16 words (List A), including 4 
words from each of 4 semantic categories (animals, vegetables, furniture, modes of 
transportation) is presented and the subject is asked to recall immediately after presentation. A 
second list of 16 words (List B) is then presented for 1 trial. This second list contains words 
drawn from 2 semantic categories of List A (animals, vegetables) and 2 new categories 
(musical instruments, parts of a house). After presentation of List B, recall of List A is assessed 


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with free recall and cued recall procedures. Long-term delayed recall and recognition memory 
of List A are tested between 15-30 minutes later. Indices of learning include total number of 
words correctly recalled across Trials 1 to 5. Memory retention is assessed with Short Delay 
Free Recall, Long Delay Free Recall, and Yes/No Recognition. One alternative form of the 
CVLT-II is available and will be tested as well. The lists will be alternated between visits
according to a predetermined counterbalance schedule.

Digit Span [30]: The Wechsler Adult Intelligence Scale (WAIS) –Third Edition Digit Span 
subtest is used to assess auditory attention and working memory. Both forward and backward 
span is assessed. Both tests consist several number sequences that the psychometrist reads 
aloud 1 at a time. After each sequence is read, the subject must repeat the digits back in the 
same (forward) or reverse (backward) order.

Multilingual Naming Test (MINT [31]): The MINT is a test of confrontation naming ability 
that was designed to measure this aspect of language in bilingual or multilingual speakers of 
English, Spanish, Chinese (Mandarin), or Hebrew. The MINT has been validated with oral 
proficiency interviews for its classification of bilinguals into language dominance groups, and 
for measuring degree of bilingualism using index scores. Preliminary studies support its 
sensitivity to detecting mild naming deficits [31]. The test is comprised of 32 items, which are 
presented to the participant in increasing order of difficulty. The maximum score is 32.

Trail Making Test (TMT [32]) A and B: Originally a subtest of the Army Core Battery, the 
TMT measures visual attention and scanning, motor integration, working memory, and set 
shifting. For Part A, the participant is required to connect in sequential order numbered circles 
scattered across a page. Time to complete the task is recorded. Trails B is similar to Trails A 
but requires connecting numbers and letters scattered on a page by alternating between the 2 
categories in sequential order (1-A, 2-B, 3-C, and so on) and time to completion is recorded.

Semantic Fluency [33]: Semantic fluency measures verbal production, semantic memory, and 
language. Subjects are asked to name as many examples of animals as possible in 1 minute. 

Lexical/Phonemic Fluency [33]: For lexical fluency, the subject is asked to produce as many 
words as possible that begin with a specified letter. Subjects will have one minute to produce 
exemplars for each letter (eg, F, A, and S for English). The number of words from each letter 
will be combined for a total score.

BVMT-R Constructional Praxis: Brief Visuospatial Memory Test - Revised (BVMT-R [28]): 
Two-dimensional constructional praxis will be assessed using Form 1 of the 2 equivalent 
alternate forms of the BVMT-R. The subject is presented with a card depicting 6 simple 
designs and asked to copy the figures on the record form. Total score will be calculated based 
on a point system that codes the overall accuracy of reproduction of the 6 figures.

Clock drawing test [34] is an easily administered test that taps elements of visuospatial 
analysis, planning, organization, and semantic knowledge. The scoring method evaluates the 
subject’s ability to reproduce 3 key elements: clock face (2 points), placement of hands 
(4 points), and placement of numbers (4 points). Total score will be calculated, summing 
across the 3 error subtypes, with higher scores indicating better performance.


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9.1.14.3 Subject-Reported Outcome Questionnaires
In addition to occurring yearly with the cognitive test battery, the following assessment will also 
be conducted at each 6 month study visit and End of Study Visit to monitor for psychiatric 
symptoms that might confound the diagnosis or require treatment:
!
Geriatric Depression Scale (GDS [35]): This is a 15-item self-administered yes/no question 
test constructed for brief screening of depression in elderly persons. 
9.1.14.4 Project Partner Reported Questionnaires
In addition to occurring yearly with the cognitive test battery, the following assessments will also 
be conducted with the subject’s project partner at each 6-month study visit and the End of Study 
Visit:
!
!
!
!
!
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9.1.14.5 Other Assessments
In addition to occurring yearly with the cognitive test battery, the following assessments will also 
be conducted according to the Schedule of Study Procedures (the CDR and ADCS CGIC-MCI, 
exclusively, will also be conducted at an Unscheduled Visit) to monitor for psychiatric symptoms 
that might confound the diagnosis or require treatment:
!
Mini-Mental State Examination (MMSE [40]): This measurement of global cognitive function 
includes 11 items that tap orientation to time and place, language, verbal registration, memory, 
and praxis. Scores on this instrument range from 0 to 30, prior to adjustment, with lower scores 
indicating greater cognitive impairment. Scores below 24 are generally considered impaired 
and suggestive of dementia. However, scores are influenced by education, age, and premorbid 
function. Individuals with high premorbid function can have an early dementia and scores 
above the commonly accepted cut point; individuals with low education or older age can have 
low scores and yet be cognitively normal. The MMSE will be administered by a certified 
tester.
!
Clinical Dementia Rating (CDR [41]): The CDR is a clinician-completed structured interview 
with participant and informant designed to assess an individual’s cognitive and functional 
performance in 6 areas for purposes of determining the severity of dementia symptoms. The 6 
areas assessed include: memory, orientation, judgment and problem solving, community 
affairs, home and hobbies, and personal care. A categorical outcome of 0, 0.5, 1, 2, or 3 is 
generated. A CDR global score of 0 indicates normal function. Whereas, a CDR global score 
of 0.5 indicate questionable dementia and ratings of 1, 2, and 3, indicate progressively more 
severe impairment, corresponding to mild, moderate, and severe dementia, respectively. More 
recently, continuous measures on the CDR were introduced by summing the 6 individual 
domain scores, resulting in a “sum of boxes” (CDR-SB) score. Clinicians will complete the 
global rating, as well as determine individual box ratings.
!
Assessment of HRQoL will be done using the EQ-5D measure from the EuroQOL Group. 
These assessments will be completed by all subjects enrolled in the study.
!
Healthcare RU during the study period will be measured by the ADCS RUI. The ADCS RUI
includes questions pertaining but not limited to hospitalization (all cause), emergency room 
visits, unscheduled physician office visits, major diagnostic procedures, concomitant 
Medications, use of nonmedical care costs (home health aids, etc), durable medical equipment, 
caregiver burden. The ADCS RUI should be completed by the subject and project partner 
together. The ADCS RUI will be completed for all subjects enrolled in the study.
!
Alzheimer ‘s disease Cooperative Study Clinical Global Impression of Change – Mild 
Cognitive Impairment (ADCS CGIC-MCI [42]): This measure captures change in the 
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participant’s condition between the Baseline Visit, coinciding with the pivotal 
AD-4833/TOMM40_301 End of Study Visit, and each 6-month follow-up time point, 
Unscheduled Visit and End of Study Visit. It is intended to determine whether any treatment 
effects are detectable by an experienced clinician during a comprehensive interview. The 
clinician rates the subject on a 7 point scale (1: marked improvement ranging to 7: marked 
deterioration). At Baseline, each of the subsequent 6 month visits, Unscheduled Visit and End 
of Study Visit, the clinician collects information from the subject and informant in an interview 
fashion. At the Baseline Visit, all available information is used by the physician to develop a 
comprehensive assessment of how the individual is doing. At follow-up the clinician focuses 
on observations of the subject’s cognitive, functional, and behavioral performance at the time 
of the evaluation and in the prior 6 months to make an assessment of whether the individual 
appears to be changing from the study Baseline. The global impression of the subject will be 
completed by the investigator at the end of each follow-up study visit.
9.1.14.6 Assessment of Suicidal Ideation and Behavior
In addition to occurring yearly with the cognitive test battery, the following assessment will also 
be conducted at each 6-month study visit, End of Study Visit and Follow-up Visit, to monitor for 
psychiatric symptoms that might confound the diagnosis or require treatment:

The Columbia–Suicide Severity Rating Scale (C-SSRS; [43]) was developed by researchers at 
Columbia University as a tool to help systematically assess suicidal ideation and behavior in 
subjects during participation in a clinical trial. The C-SSRS is composed of 3 questions 
addressing suicidal behavior and 5 questions addressing suicidal ideation, with sub questions 
assessing the severity. The tool is administered via interview with the subject.
Suicidality Events: A completed suicide is always an SAE based on its fatal outcome.
Additionally, for the purpose of this development program, active suicidal behaviors such as 
“suicidal intention with a definite plan” and “suicide attempt” will also be collected as SAEs.
Unless the event meets other serious criteria, suicidal thoughts or suicidal ideations that do not 
include a definite plan or action will be collected as non-serious AEs in accordance with the 
standard AE reporting requirements (eg, if a pre-existing suicidal ideation recorded on the baseline
C-SSRS got worse during the study, it should be reported as an AE). A subject presenting with 
self-mutilation or other types of self-injury should be questioned by the investigator to clarify if the 
action was suicidal in intent. If the event was suicidal in intent, the investigator should include 
suicidal behavior as part of the verbatim term on the eCRF that is, “slit wrists/suicidal behavior”. 
Such an event will be collected as an SAE. Acts of self-mutilation or self-injury without suicidal 
intention, that is, self-imposed cigarette burns, will be collected as nonserious AEs.
9.1.14.7 MRI Assessment 
Subjects enrolled in the extension study will be required (unless medically contraindicated) to 
participate in a vMRI scan where volumetric measurements will be taken, for the purpose of 
assessing atrophy of the brain. vMRI scans will take place at the following time points, as noted in 
the Schedule of Study Procedures (Appendix A): extension study Baseline (last MRI collected at 


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End of Study Visit or second comprehensive medical follow-up visit for the pivotal 
AD-4833/TOMM40_301 study) and at extension study End of Study/Early Withdrawal Visit.
9.1.14.8 Health Economics and Outcomes Research Assessments 
Both the HRQoL and RU assessments will be completed by all subjects enrolled in the study. The 
HRQoL instruments will not be used as a primary means to collect AEs. However, should the 
investigator become aware of potential AEs through the information collected with this 
instrument, proper follow-up with the patient for medical evaluation should be undertaken. If it is 
determined through this follow-up that an AE not previously reported has been identified, normal 
reporting requirements should be applied.
9.1.14.9 Diet and Exercise Evaluation
All postmenopausal women should be encouraged to employ lifestyle practices that reduce the risk 
of bone loss and osteoporotic fractures: maintaining a healthy weight, eating a balanced diet, 
obtaining adequate calcium and vitamin D, participating in appropriate exercise, avoiding 
excessive alcohol consumption, not smoking. An adequate intake of both calcium and vitamin D is 
important for bone health and is recognized as an important component of any osteoporosis 
prevention drug regimen [44]. Among women age 75 and older, muscle strengthening and balance 
exercises have been shown to reduce the risk of falls and fall-related injuries by 75% [45]. 
Weight-bearing exercise can be as simple as brisk walking. Diet and exercise evaluation will be 
performed at every 6 and 12 month visit during the treatment phase, and End of Study Visit/Early 
Withdrawal Visit. 
9.1.15 Order of Assessments
Sites should make every attempt to adhere to the assessment schedule in Table 9.b. Should an 
interruption occur during the visit, the subject may return to the site within 2 weeks to complete the 
assessments. The ADCS-CGIC-MCI may be administered in parallel with, or before other testing, 
as long as the tester is blinded to any adverse events or other tests.


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Table 9.b
Order of Assessments
Cognitive Test/Questionnaire
Visit
Assessor
MMSE
Every 6 and 12 month visit during the 
Treatment Period, End of Study/Early 
Withdrawal Visit
Certified tester
Cognitive Test Battery (completed in 
this order)
Every yearly visit during the treatment 
period, End of Study/Early Withdrawal 
Visit
Certified tester
1. CVLT-II Trials 1-5; Short delay 
recall trials.
2. BVMT-R: Learning Trials 1-3.
3. Digit Span Forward
4. Digit Span Backward
5. Trails A
6. Trails B
7. CVLT-II: Delayed recall (15-30 
minutes should have elapsed from end 
of short recall and long-delay)
8. CVLT-II: Recognition Trial
9. BVMT-R: Delayed recall 
(15-30 minutes should have elapsed 
from Trial 3 to delay)
10. BVMT-R: Recognition Trial
11. BVMT-R: Copy Trial
12. MINT
13. Semantic fluency (animals)
14. Lexical fluency
15. Clock Drawing Test
GDS
Every 6 and 12 month visits during the 
Treatment Period, End of Study/Early 
Withdrawal Visit
Study subject
EQ-5D
Month 24 visit during the Treatment 
Period, End of Study/Early Withdrawal 
Visit 
Study subject
ADCS ADL-MCI
At 303 study Baseline Visit (ADCS 
ADL- MCI), then every 6 and 12 month 
visits during the Treatment Period, End 
of Study/Early Withdrawal Visit (ADCS 
ADL-MCI)
Trained tester


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Table 9.b
Order of Assessments (continued)
Cognitive Test/Questionnaire
Visit
Assessor
NPI-Q
Every 6 and 12 month visits during the 
Treatment Period, End of Study/Early 
Withdrawal Visit 
Project partner
ADCS RUI
Every 6 and 12 month visits during the 
Treatment Period, End of Study/Early 
Withdrawal Visit 
Trained tester
CDR
Every 6 and 12 month visits during the 
Treatment Period, Unscheduled Visit, 
and End of Study/Early Withdrawal Visit
Investigator/subinvestigator
ADCS CGIC-MCI
At 303 study Baseline Visit, then every 6
and 12 month visits during the Treatment 
Period, End of Study/Early Withdrawal 
Visit and Unscheduled Visit
Trained tester
AE assessment
Every 3, 6, 9, and 12 month visit, 
Unscheduled Visit, End of Study/Early 
Withdrawal Visit and Follow-up Visit
Investigator/subinvestigator
C-SSRS
Every 6 and 12 month visits during the 
Treatment Period, End of Study/Early 
Withdrawal Visit and Follow-up Visit
Certified tester
9.1.15.1 Language Considerations 
The assessments will be used in local language (ie, language used locally which the subject and 
investigator are both fluent in; this may include English and is not confined to the language that is 
native to the subject’s race/nationality) versions. Only validated translations provided by Takeda 
(if applicable) are to be used. Some minor differences in test administration may occur in order to 
make the test results consistent across languages and cultures. For example, verbal fluency letters 
F, A, and S will vary across languages based upon the frequency of letters in the local language. 
Language fluency will be captured within the eCRF. 
A certified tester at the site will administer the MMSE and cognitive test battery. Additional details 
and requirements will be provided in the training manual provided by a vendor chosen by Takeda. 
9.1.16 Tester Qualification and Certification 
In order to ensure satisfactory training of testers and quality execution with regards to data 
collection, testers assigned to this study will be required to adhere to certain requirements prior to 
participation in the trial. Furthermore, the trial will include additional steps related to monitoring 
the quality of tester activity. The training materials and requirements may be adjusted or modified 
as needed throughout the course of the trial. 
All testers will be required to successfully complete the full scope of tester training requirements 
prior to testing any subjects in this study. Testers who successfully complete all requirements will 
be approved for participation in the study by Takeda and/or its designee before enrollment may 


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commence at sites. Testers who do not meet all the qualification and training requirements may be 
prohibited from participating as testers on this trial. Takeda and/or its designee may revoke a 
tester’s certification during the trial. 
Investigators completing the CDR will be required to be certified and trained. The investigator 
who completes the CDR is independent and cannot be the same person who administers the 
cognitive battery. Sites should make an attempt to use the same investigator to complete the CDR 
at each assessment. 
9.1.17 Imaging 
Prior to the start of the study, each site should identify a study MRI machine. Each MRI machine 
will be qualified by the imaging vendor before starting the study, if not already qualified as part of 
participation in the pivotal AD-4833/TOMM40_301 study. Documentation of qualification will be 
sent to the site by the imaging vendor, which should be retained in the site’s study files as evidence 
of quality control approval. Each MRI will be read by the local radiologist at each site for 
immediate medical action whenever necessary. The results of the local reading will be recorded in 
the eCRF. Detailed instructions for the processing and shipping of images will be provided 
separately. 
Subjects who have contraindications for MRI procedure (such as unremovable ferromagnetic 
dental work, cardiac pacemakers, etc) will not be excluded from the study.
9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring study medication containers to each dispensing site visit. The 
number of pills returned will be captured in the subject’s source documentation and eCRF. The 
project partner will also be asked to assess the subject’s compliance. 
Compliance will be reviewed during each 3, 6, 9, and 12 month visit and at the End of Study/Early 
Withdrawal Visit. During telephone visits that will occur yearly on the 3 month and 9 month 
interval, treatment compliance should be evaluated during the conversation. 
If a subject is persistently noncompliant with the study medication, defined as missing >20% of 
dosing for the required visit period (eg, 6 months), it may be appropriate to withdraw the subject 
from the study. All subjects should be reinstructed about the dosing requirement during study 
contacts. The authorized study personnel conducting the re-education must document the process 
in the subject source records.
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
Study Entrance (Baseline)
Study entrance (Baseline) will take place on Day 0, and will coincide with the End of Study Visit 
of the pivotal AD-4833/TOMM40_301 study, which will serve as the Baseline Visit for the 


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extension study once appropriate informed consent is signed. See Appendix A for a list of 
procedures that will be performed. Subjects will be entered into IWRS after informed consent is 
provided. It is anticipated that this visit will take about 4 hours in length.
While it is preferred that subjects and their project partners consent to the 
AD-4833/TOMM40_303 study while attending the AD-4833/TOMM40_301 study End of Study 
Visit, subjects will be allowed to return to the clinic and consent for the extension study within 1 
month of the AD-4833/TOMM40_301 End of Study Visit. They will complete the 
AD-4833/TOMM40_303 baseline evaluations (that were not completed at the 
AD-4833/TOMM40_301 End of Study Visit or last Comprehensive Medical Follow-up Visit) 
once informed consent is provided and within the 1 month window. 
9.3.2
Treatment Phase
See Appendix A for list of procedures that will be performed and documented during the treatment 
period. Telephone visits will occur yearly on the 3 month and 9 month interval and clinic visits will 
occur yearly on the 6 month and 12 month interval. It is anticipated the treatment clinic visits will 
be about 3 to 4 hours in length. 
9.3.3
Unscheduled Visit
There are 2 types of Unscheduled Visits in this study: 1) Unscheduled Visits conducted to address 
any emerging concerns, including safety, and 2) Unscheduled Visits conducted to evaluate 
suspected cognitive or functional decline after meeting a trigger relating to cognitive status (see 
Section 6.2.3).
9.3.3.1
Unscheduled Visits for Emerging Concerns (including Safety)
Unscheduled Visits conducted to address any other emerging concerns, including safety, may 
occur at any time between regularly scheduled in-clinic study visits. Depending on the nature of 
the (noncognitive) concerns, the investigator is expected to conduct whatever assessments are 
necessary to manage the needs of the subject appropriately. 
9.3.3.2
Unscheduled Visit for Suspected Cognitive or Functional Decline
An unscheduled visit may be conducted if worsening of cognitive impairment or potential AD 
dementia is suspected in between regularly scheduled visits when 1 of the triggers described in 
Section 6.2.3 has been met. A CDR Global score of ≥1.0 will be required in order to set a 
consistent minimum standard for AD dementia as an endpoint in the study. This type of 
Unscheduled Visit will include the assessments noted in Appendix A. It is anticipated this visit 
will be about 3 to 4 hours in length, if an MRI is completed during the visit.
9.3.4
Final Visit or Early Termination
The End of Study/Early Withdrawal Visit is an ad hoc visit that, for study completion, will take 
place as soon as possible after a regularly scheduled or unscheduled study visit, either at study end,
at extension study termination, after a subject has withdrawn prematurely from the study, or after 


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the subject has been diagnosed with AD or non-AD dementia. The efficacy assessments will not 
need to be captured at this visit in cases where the secondary endpoint of AD dementia diagnosis 
has been reached or if it is less than 3 months from the last administration of the assessment. 
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.
9.3.5
Follow-up
Follow-up will begin the first day after the End of Study/Early Withdrawal Visit and will continue 
until 2 weeks later.
Subjects will be contacted for a Safety Follow-up call approximately 2 weeks after the End of 
Study/Early Termination Visit. See Appendix A for list of procedures that will be performed and 
documented. Subjects who withdraw their consent should still be contacted for a Safety Follow-up 
call, but the contact should only be recorded in the subjects records (and not the eCRF), according 
to data protection regulations. 
9.3.6
Poststudy Care
The study medication will not be available upon completion of the subject’s participation in the 
study. The subject should be returned to the care of a physician and standard therapies as required.
9.4
Biological Sample Retention and Destruction
9.4.1
Pharmacogenomics
In this study, specimens for analysis will be collected as described in Appendix E. The samples 
will be retained at a central storage vendor for up to but not longer than 15 years or as required by 
applicable law. The sponsor has put into place a system to protect the subjects’ personal 
information to ensure optimal confidentiality and defined standard processes for sample and data 
collection, storage, analysis, and destruction. 
The sponsor and researchers working with the sponsor will have access to the samples collected 
and any test results. All samples collected during the study will be stored securely with limited 
access and the sponsor will require anyone who works with the samples to agree to hold the 
research information and any results in confidence.
Subjects who consented and provided a pharmacogenomic sample for RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time. Notify sponsor of consent 
withdrawal.


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Events
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory 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:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory 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.


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
If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, 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 
(eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs /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.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 


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worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as adverse events.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as adverse 
events.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The principal investigator must make the distinction between exacerbation of 
pre-existing illness and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizures
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Special Interest AEs 
A special interest AE (serious or nonserious) is one of scientific and medical concern specific to 
the compound or program, for which ongoing monitoring and rapid communication by the 
investigator to Takeda may be appropriate. Such events may require further investigation in order 
to characterize and understand them and would be described in protocols and instructions provided 
for investigators as to how and when they should be reported to Takeda. AEs of special interest are 
listed in Section 10.2.1.3.
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Yes:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug can be 
argued, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
No:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.


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10.1.7 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and 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 No.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication
(Baseline Visit) or until baseline failure. For subjects who discontinue prior to study medication
administration, PTEs are collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication (Baseline Visit [Day 0]).Collection of AEs will commence from the time that the 
subject is first administered study medication (Baseline Visit). Routine collection of AEs will 
continue until the Follow-up Visit.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:

Event term.

Start and stop date.

Severity.

Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (yes or no) (not completed for PTEs).


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
Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.

Action concerning study medication (not applicable for PTEs).

Outcome of event.

Seriousness.
10.2.1.3 Special Interest AE Reporting 
Special Interest Adverse Event (serious or nonserious) is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication by 
the investigator to Takeda may be appropriate. Such events may require further investigation in 
order to characterize and understand them and would be described in protocols and instructions 
provided for investigators as to how and when they should be reported to Takeda. 
This extension study will be conducted in elderly subjects diagnosed with MCI due to AD. 
Pioglitazone appears to be safe and well tolerated in the elderly population, based on the available 
information from healthy volunteers and subjects with T2DM in Takeda-sponsored trials or from 
patients with AD in Takeda-supported studies [13,14]. Based on the available safety information 
in the diabetic population, the following safety procedures will be implemented when specific AEs 
of special interest are reported during the study. All such AEs will be reported to the sponsor in an 
expedited manner irrespective of the event’s seriousness or causal relationship:
1. Congestive heart failure (CHF): Subjects and their project partners will be advised to promptly 
report signs and symptoms of heart failure (eg, excessive, rapid weight gain, dyspnea, and/or 
edema). Any subject with CHF class III-IV will be excluded from the study. If a subject 
develops CHF after enrollment, the subject will be withdrawn from the study. Assessment of 
subjects for signs and symptoms of CHF will take place at every study visit.
2. Macular edema: All subjects and their project partners will be asked to promptly report 
symptoms potentially associated with macular edema (eg, blurred vision, distortion of images, 
missing areas, dimming or “graying-out” of vision from loss of contrast sensitivity, and 
changes in the way color is perceived). If symptoms are reported, the subject will undergo a 
funduscopic examination. Any subject who develops macular edema will stop taking study 
medication, be withdrawn from the study, and be managed by his or her regular physician 
using the current standard of care.
3. Hepatic effects: Subjects and their project partners will be advised to promptly report signs and 
symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal 
discomfort, dark urine or jaundice. If ALT or AST >3×ULN, laboratory tests should be 
repeated within a maximum of 7 days, and preferably within 48 to 72 hours. If the ALT or AST 
remains elevated >3×ULN on these 2 consecutive occasions, and this observation cannot be 
explained by concomitant disease or another alternative etiology, the abnormality should be 
recorded on an AE page. The investigator must contact the Medical Monitor for consideration 


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of immediate discontinuation of study medication, discussion of the relevant subject details 
and possible alternative etiologies.
4. Bone fractures: All female subjects, regardless of their clinical risk factors for osteoporosis, 
should be encouraged to eat a balanced diet and participate in appropriate exercise, avoid 
cigarette smoke, and excessive alcohol consumption. All postmenopausal women should be 
encouraged to employ lifestyle practices that reduce the risk of bone loss and osteoporotic 
fractures: maintaining a healthy weight, eating a balanced diet, obtaining adequate calcium and 
vitamin D, participating in appropriate exercise, avoiding excessive alcohol consumption, not 
smoking. An adequate intake of both calcium and vitamin D is important for bone health and is 
recognized as an important component of any osteoporosis prevention drug regimen [44]. 
Among women aged 75 years and older, muscle strengthening and balance exercises have 
been shown to reduce the risk of falls and fall-related injuries by 75% [45]. Weight-bearing 
exercise can be as simple as brisk walking. All suspected or confirmed bone fracture will be 
followed-up for an X-ray confirmation, outcome, and any healing complications. Current 
standards of care for assessing and maintaining bone health will be applied.
5. Bladder cancer: Subjects and their project partners will be advised to promptly report any signs 
or symptoms that could be consistent with bladder cancer such as hematuria, urinary urgency, 
urinary frequency, or dysuria. Any subject with previous or active bladder cancer will be 
excluded. All subjects will be tested for evidence of hematuria (macroscopic or microscopic).
In the event of unexplained hematuria (3 or more red blood cells per high power field on 
microscopic urine test), confirmed by a repeat test (within 14 days of the initial assessment), 
subject will be referred to a urologist for additional follow-up testing according to local 
standard diagnostic approach. If the diagnosis of the bladder cancer cannot be excluded the 
subject will be withdrawn from the study.
6. Subjects with T2DM who are on a stable antidiabetic regimen for at least 3 months prior to 
enrollment that does not require the use of insulin, oral triple therapy, and/or PPAR-γ agonists 
will be allowed in the study. Subjects who develop a new onset T2DM during the study will be 
referred to an endocrinologist. If the use of prohibited medications (such as insulin or PPAR-γ 
agonists) is considered necessary, the subject will be withdrawn from the study. Pioglitazone 
alone especially at a low dose is not likely to cause hypoglycemia in elderly subjects without 
T2DM. However, subjects with T2DM taking pioglitazone with an insulin secretagogue (eg, 
sulfonylurea or glitinide) may be at increased risk for developing hypoglycemia. Therefore the 
subjects with the following AEs will be closely monitored using the following event 
categories:

Severe hypoglycemia: an event requiring assistance of another person to actively
administer carbohydrate, glucagon, or other resuscitative actions. Blood glucose may not 
be available. 

Documented symptomatic hypoglycemia: typical symptoms of hypoglycemia 
accompanied by blood glucose ≤70 mg/dL (3.9 mmol/L).


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
Asymptomatic hypoglycemia: Blood glucose ≤70 mg/dL (3.9 mmol/L), but with no typical 
symptoms.

Probable symptomatic hypoglycemia: Symptoms of hypoglycemia that are not 
accompanied by blood glucose determination ≤70 mg/dL (3.9 mmol/L).

Relative hypoglycemia: Symptoms of hypoglycemia, but with a measured blood glucose 
>70 mg/dL (3.9 mmol/L). 
If this special interest AE, which occurs during the Treatment Period or the Follow-up Period, is 
considered to be clinically significant based on the criteria below, it should be recorded in a 
Special Interest Form or an SAE Form. The form should be completed and reported to Takeda 
Pharmacovigilance or appropriate safety vendor within 24 hours.
Special interest AE criteria include:

Laboratory value threshold if applicable.

Premature termination for the special interest AE, if applicable.

Any other specific criteria.
The special interest AEs have to be recorded as AEs in the eCRF. An evaluation form along with 
all other required documentation must be submitted to the sponsor.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s)

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of serious PTEs will follow the procedure described for SAEs.


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10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms, and results of any additional diagnostic tests performed.
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 9.1.8 must also be 
performed. In addition, an LFT Increases eCRF must be completed and transmitted with the 
Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency, investigators and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted 
within 7 days for fatal and life-threatening events and 15 days for other serious events, unless 
otherwise required by national regulations. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment of an 
investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal products administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.


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11.0
STUDY-SPECIFIC COMMITTEES
11.1
Independent Data and Safety Monitoring Board 
In addition to regular sponsor surveillance, the safety of subjects will be evaluated by an 
independent DSMB. The DSMB will meet periodically to review all safety data from the study, 
including AEs of special interest. This group will include individuals with expertise in, 
endocrinology, neuro-radiology, cardiology, AD specialist, and statistics. 
Details of the Independent DSMB will be captured in a charter prior to the start of the trial.


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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 
Drug Dictionary.
12.1
CRFs (Electronic and Paper)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are entered directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs 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 eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper should be 
copied and certified, source worksheets, all original signed and dated informed consent forms, 
subject authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), electronic copy of eCRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. Furthermore, International Conference on Harmonisation (ICH) E6 Section 4.9.5 
requires the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 
2 years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 


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discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the Clinical Study Site Agreement between the investigator 
and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to study database lock or 
unblinding of subject’s treatment assignment. This document will provide further details regarding 
the definition of analysis variables and analysis methodology to address all study objectives. 
A data review will be conducted prior to clinical database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods. Analogous to the pivotal AD-4833/TOMM40_301 study, the primary 
efficacy analysis population will be for high-risk non-Hispanic/Latino Caucasian subjects. An 
additional analysis will be done for all high-risk subjects (including subjects of all races and 
ethnicities).
13.1.1 Analysis Sets
All efficacy variables will be analyzed using the full analysis set (FAS). The FAS will consist of all 
participating subjects. The FAS will be analyzed according to the treatment to which each subject 
was randomized in the pivotal 301 study. All safety variables will be analyzed using the safety 
population, which will consist of all subjects who receive at least 1 dose of blinded study 
medication. The safety population will be analyzed according the actual treatment each subject 
received. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized using the FAS with 
descriptive statistics or frequency counts as appropriate.
13.1.3 Efficacy Analysis
The primary null hypothesis in this study assumes that there is no difference in the cognitive 
decline of MCI due to AD between the placebo-treated and active-treated subjects in the high risk 
group. The alternative hypothesis is that there is a difference in cognitive decline between 
pioglitazone and placebo in the high-risk group. The ability of demonstrating a difference between 
active and placebo may be limited by study design as the determination of number of subjects is 
not based on statistical considerations and the subjects are not randomized at the beginning of this 
study.
In order to test the primary null hypothesis, the change in the composite cognitive test battery score 
from extension study baseline to 24 months will be analyzed using mixed models repeated 
measures (MMRM), controlling for age group, educational level, study site, and sex. If this test is 
significant at the 5% level, it can be concluded that pioglitazone was effective in reducing the 
change in cognitive decline in subjects with a diagnosis of MCI due to AD at Baseline.
Composite scores will be derived from the test battery consistent with practices used in the pivotal 
AD-4833/TOMM40_301 study. Each test in the battery falls into 1 of the following cognitive 


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domains: Episodic Memory (CVLT-II, BVMT-R), Executive Function (Trail Making Part B, 
Digit Span Backwards), Language (Animals, Lexical/Phonemic Fluency), Attention (Digit Span 
Forward, Trail Making Part A), and Visuospatial (Clock Drawing, BVMT-Copy). Only the 
domains of episodic memory, executive function, language, and attention will be used for the 
calculation of composite score (ie, Clock Drawing, BVMT-Copy, and the MINT, which do not 
allow generation of standard z scores, will only be used for diagnostic purposes and will be 
excluded from the calculation of the composite score). To form the composite, z-scores will be 
calculated for each test, each z-score for the domain will be averaged, and then all relevant 
domains will be averaged to form the composite. Because there are 2 tests for each domain, the 
composite can still be calculated if 1 test is missing. In the case of memory, however, both tests are 
required to calculate the composite.
All data collected in the study will be listed and summarized either by mean, SD, median, 
minimum, and maximum for continuous data or by frequency tables for categorical data.
Similar to the primary efficacy endpoint, the secondary endpoints of change from Baseline will be 
analyzed using available data and MMRM for each of the following 2 choices for Baseline:

Baseline of the AD-4833/TOMM40_303 study.

Baseline of the AD-4833/TOMM40_301 study.
And 2 choices for evaluation end period, as appropriate: 

Two-year postenrolment into the AD-4833/TOMM40_303 study.

End of the AD-4833/TOMM40_303 study.
Other secondary endpoints will examine change from Baseline by visit (ie, Months 6, 12, 18, 30, 
36, and up to the last visit, depending on the schedule of visits for any given endpoint) and will be 
analyzed using MMRM. For the time to onset of AD dementia secondary endpoint, time-to-event 
data will be analyzed to compare the placebo and active groups using a Cox proportional hazards 
model, including an investigation of the effects of covariates (including age, educational level, 
study site, and sex). As for the primary analysis, the secondary endpoints will be tested at the 
2-sided 0.05 level. Note that the population for this study consists of subjects who had an event of 
MCI due to AD in the pivotal AD-4833/TOMM40_301 study and consented to participate in the 
AD-4833/TOMM40_303 study. This study is not powered to show a difference with respect to 
time-to-event of AD dementia, and the time-to-event analysis will be provided for informational 
purposes.
The primary endpoint of cognitive decline at 24 months is a continuous variable and will include 
all available data. Subjects who discontinue from the extension study prior to its conclusion will be 
censored for the analysis of time to AD dementia diagnosis. For completeness, follow-up 
information will be collected on as many subjects as possible, including the reason for 
discontinuation. For other continuous variables such as test scores, MMRM using all available 
data will be used to evaluate changes by visit.


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The rules for handling missing items from each of the scales are designed so that as much reliable 
data as possible can be used in the analyses when calculating total scores.
Missing data may occur in the course of the study or may be due to drop-out. With regard to
neuropsychological data collection within the study, missing data can occur under several
scenarios. In an interview setting administration of some portions of the test battery may be
precluded by tester error or factors attributable to the patient (illness, refusal, or other problems).
Neuropsychological technicians will be trained to avoid missing data whenever possible. In the
event that an item or a test is missing, technicians will be trained to record the reason for missing
data. When tests are scored, the reason for missing data will be coded in a uniform, standardized
manner across sites. Test scores will be prorated wherever possible.
There may still be missing values for the continuous variables and the analyses for continuous 
variables are based on a Missing at Random assumption. As a sensible sensitivity analysis, the 
pattern mixture models using standard SAS STAT procedures will be performed. This method 
uses sequential regression and multiple imputation methodology to impute missing values after 
subjects’ discontinuation from the study. The missing values from both control and experimental 
treatment arms are imputed based on the available data from control subjects and through using 
PROC MI’s methodology for imputation of monotone missing data patterns to impute the outcome 
variables at consecutive visits in a sequential (chain) manner.
The following variables will also be analyzed in a manner similar to the primary efficacy endpoint 
and secondary efficacy endpoints and using MMRM: CDR-SB, ADCS CGIC-MCI, ADCS 
ADL-MCI and NPI-Q, and GDS.
13.1.4 Other Analyses
Any sensitivity or other analyses (eg, using additional covariates) will be described in the SAP.
13.1.5 Safety Analysis
Adverse Events
AEs will be reported throughout the study by the subject and/or project partner.
Treatment-emergent AEs are any new or worsened events that occurred within 30 days following 
discontinuation of study medication from the subject’s completion of the 
AD-4833/TOMM40_303 extension study. AEs will be coded using MedDRA and will be 
summarized by system organ class and preferred term.
AEs that were reported more than once by a subject during the same period will be counted only 
once for that subject and period at the maximum severity.
Clinical Evaluations
Observed values and changes from extension study Baseline in clinical safety laboratory tests, 
vital signs, ECG parameters, and body weight will be summarized for each treatment group using 
descriptive techniques. Values outside normal ranges and potentially clinically significant values 


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will be flagged and tabulated. Physical examination findings will also be summarized for each 
treatment group.
13.2
Determination of Sample Size
The sample size for this study was not based on statistical considerations. Subjects who have an 
adjudicated diagnosis of MCI due to AD (without a diagnosis of AD dementia) in the pivotal 
AS-4833/TOMM40_301 study may be eligible to enroll into this extension study depending on 
their site’s participation in the 303 study. In the pivotal AD-4833/TOMM40_301 study, 
approximately 222 subjects (approximately 213 high-risk and approximately 9 low-risk subjects) 
are expected to have an event of MCI due to AD or AD dementia. It is expected that approximately 
149 subjects (ie, 67% of the 222 subjects) will consent to participate in this 303 extension study.


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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 eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the medical 
monitor (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospective approved deviation) from the inclusion or exclusion criteria.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and 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 (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable 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. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those US sites unwilling to provide names and titles of all members 
due to privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the 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 or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will notify the site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the 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 or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.


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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 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. 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.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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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.
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, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s 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 (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
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, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.


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15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, Takeda will, at a minimum register all 
clinical trials conducted in patients that it sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites before trial initiation. Takeda contact information, along with 
investigator’s city, state (for US investigators), country, and recruiting status will be registered and 
available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of this clinical trial, regardless of outcome, on ClinicalTrials.gov or 
other publicly accessible websites, as required by applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.


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16.0
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Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, et al. Validation 
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Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia 
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Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. 
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Schneider LS, Raman R, Schmitt FA, Doody RS, Insel P, Clark CM, et al. Characteristics 
and performance of a modified version of the ADCS-CGIC CIBIC+ for mild cognitive 
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Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings 
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Appendix A
Schedule of Study Procedures
Baseline
(Coincides With 
301 End of 
Study Visit (a)
Unscheduled 
Visit (b)
End of Study 
Visit/Early 
Withdrawal (c)
Follow-up Visit
Month
0 (Day 0)
Repeated Yearly
EoS/EW+0.5 (e)
3 (d)
6
9 (d)
12
Visit Window
+30 days
±2 
wks
±2 
wks
±2 
wks
±2 
wks
Informed consent 
(subject)
X
Informed consent 
(pharmacogenomic)
X
Informed consent 
(project partner)
X
Incl/excl criteria
X
Medical history
X
Concurrent conditions
X
Body weight and 
height(g)
X (f)
X
X
X
Review of concurrent 
medications
X
X
X
X
X
X
X
X
Contact IWRS
X
X
X
X
Dispense study drug
X
X
X
Collect study drug
X
X
X
Compliance review 
X
X
X
X
X
AEs (including AEs of 
Special Interest) 
X (f)
X
X
X
X
X
X
X
Physical examination
X (f)
X
X
X
Vital signs
X (f)
X
X
X
X
Neurological 
examination
X (f)
X
X
X
X
12-lead ECG
X (f)
X
X
vMRI (h)
X (f)
X
Clinical chemistry,
hematology and 
urinalysis labs
X (f)
X
X (i)
X
HbA1c test (j)
X
X
Pharmacogenomic RNA 
samples
X
X (k)
X (l)
C-SSRS
X (f)
X
X
X
X
Diet and exercise 
evaluation
X (f)
X
X
X
MMSE (d)
X (f)
X
X
X
CVLT-II
X (f)
X
X
BVMT-R
X (f)
X
X
Lexical fluency
X (f)
X
X
Semantic fluency
X (f)
X
X
MINT 
X (f)
X
X
Digit Span 
X (f)
X
X
Trail Making Tests 
X (f)
X
X
Clock Drawing
X (f)
X
X
Footnotes are on last table page.


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Appendix A
Schedule of Study Procedures (continued)
Baseline
(Coincides 
With 301 End 
of Study Visit
(a)
Unscheduled 
Visit (b)
End of Study 
Visit/Early 
Withdrawal (c)
Follow-up Visit
Month
0 (Day 0)
Repeated Yearly
EoS/EW+0.5 (e)
3 (d)
6
9 (d)
12
GDS
X (f)
X
X
X
CDR 
X (f)
X
X
X
X
ADCS ADL- MCI
X 
X
X
X
NPI-Q
X (f)
X
X
X
ADCS CGIC-MCI 
X
X
X
X(m)
X
ADCS RUI
X (f)
X
X
X
EQ-5D (subject) (o)
X (f)
X
EQ-5D (project partner) 
n)
X
X
WPAI(n)
X
X
EoS=End of Study, EW=Early Withdrawal.
(a) Subjects who are unable to consent for the extension study or to complete all extension study baseline visit evaluations at the 
same time as their End of Study Visit for the pivotal AD-4833/TOMM40_301 study will be allowed to return to the clinic and to 
complete these evaluations within a 1 month window.
(b) Procedures listed should be conducted in the event of an Unscheduled Visit for suspected cognitive or functional decline.
Procedures related to Unscheduled Visits for any other emerging concern, such as safety, are at the discretion of the investigator. 
(c) End of Study/Early Withdrawal Visit is an ad hoc visit that, for study completion, would take place as soon as possible after a 
regularly scheduled or unscheduled study visit, either at study end, at extension study termination, after a subject has withdrawn 
prematurely from the study or after the subject has been diagnosed with AD or non-AD dementia. The efficacy assessments will not 
need to be captured at this visit in cases where the secondary endpoint of AD dementia diagnosis has been reached or if it is less than 
3 months from the last administration of the assessment.
(d) Telephone contact with the subject (should be every 3 months between the semiannual clinic visits for the duration of the study)
(e) Telephone call approximately 2 weeks after the End of Study or Early Withdrawal Visit. 
(f) These assessments, conducted as part of the end of study visit for the pivotal AD-4833/TOMM40_301 study or at most recent 
comprehensive medical Follow-up Visit, will serve as baseline data for the extension AD-4833/TOMM40_303 study.
(g) Height will only be collected at the end of study visit for the pivotal AD-4833/TOMM40_301 study or at most recent 
comprehensive medical Follow-up Visit, and will serve as baseline data for the extension AD-4833/TOMM40_303 study
(h) vMRI assessments will take place at extension study Baseline (ie, coinciding with the End of Study Visit for the pivotal 
AD-4833/TOMM40_301 study or most recent MRI or that obtained at the second consecutive comprehensive medical follow-up 
Visit) and at extension study end. 
(i) Standard blood chemistry and tests used in evaluating cognitively impaired and dementia patients (eg, thyroid profile, vitamin 
B12).
(j) A blood sample will be collected at the extension Baseline Visit and End of Study/Early Withdrawal Visit for HbA1c testing.
(k) If an Unscheduled Visit is conducted, RNA samples will be collected during this visit. In this instance, RNA samples will not 
need to be collected at the End of Study/Early Withdrawal Visit.
(l) RNA samples will only be collected at the End of Study/Early Withdrawal Visit if samples were not collected at an Unscheduled 
Visit. 
(m) ADCS CGIG-MCI will only need to be administered if it occurs greater than 3 months from the last administration of this 
assessment.
(n) EQ-5D will be completed by subject at Month 24 and at End of Study in the extension study and the EQ-5D and WPAI will be 
completed by project partner at Baseline, Month 24 and End of Study.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572: 
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 


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participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.


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25. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix E
Collection, Shipment, and Storage of Pharmacogenomic Samples
Two 2.5 mL whole blood samples for RNA extraction will be collected from each subject who 
agreed to pharmacogenomic participating in the informed consent form. A sample will be 
collected at each Month 12 visit, Unscheduled Visit, or End of Study Visit (if not collected at an 
Unscheduled Visit) for the duration of the study into PAXgene tubes.
Instructions for Processing and Shipping of Whole Blood Samples for RNA Analysis

Ensure that the PAXGene Blood RNA tubes are at room temperature prior to collection.

Collect the venous blood into 2 plastic PAXgene tubes (2.5 mL) for each time point.

Mix immediately by gently inverting the tube several times (at least 8-10 times) to mix the 
additive with the collected blood.

Set PAXgene tubes at room temperature for 2 to 3 hours and then store frozen at -20°C until 
shipment.

Ship RNA samples frozen on dry ice per the instructions in the laboratory manual.
Sample Shipment
RNA pharmacogenomic samples will be shipped frozen after collection.
Ship samples only on Monday, Tuesday, or Wednesday, and at least 2 days prior to a national 
holiday, to minimize the possibility of samples in transit over a weekend or holiday. The 
laboratory must confirm arrival of the shipped samples. 
For instructions on shipping and packing follow the laboratory manual and shipping instructions 
provided by the central laboratory.
Before shipping, ensure the sample tubes are tightly sealed. Ship samples to central storage vendor 
per shipping instructions in the laboratory manual.
Sample Storage
Covance will store the RNA samples in a secure storage space with adequate measures to protect 
confidentiality. The samples will be retained while research on AD-4833/TOMM40 continues for 
up to but not longer than 15 years or as required by applicable law.
The storage provider has validated procedures in place for transport, delivery, retention, retrieval, 
and destruction of the specimens, and will appropriately retain the specimens.


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Appendix F
Operational Criteria for AD [23]
Dementia:
A. Cognitive problems observed interfere with the individual’s ability to function at work or 
at usual activities.
B. This functional change represents a decline from previous levels of functioning and 
performing as captured in this trial by clinician impression of change since Baseline or by 
clear impairments on scales of daily functional ability (eg, ADCS ADL-MCI; CDR scale 
with informant; CGIC; Informant Questionnaire on Cognitive Decline).
C. The disorder is not explained by delirium or major psychiatric disorder.
D. Cognitive impairment is detected and diagnosed through a combination of (1) 
history-taking from the patient and a knowledgeable informant and (2) an objective 
cognitive assessment, either a “bedside” mental status examination (eg, MMSE) or 
neuropsychological testing.
E. The cognitive or behavioral impairment involves a minimum of 2 of the following 
domains, established by the testing battery or from interval history and clinical interview:
i.
Memory: CVLT-II; BVMT-R
a.
Defined as an impaired ability to acquire and retain new information. 
Clinical symptoms could include repetitive questions, getting lost in 
familiar areas, forgetting appointments or important events, misplacing 
personal objects. 
ii.
Executive/ Reasoning: Trail Making; Digit Span
a.
Defined as impaired reasoning and ability to handle complex tasks. Can 
be manifest as poor judgment, poor understanding of safety risks; 
impaired money management; poor decision making; trouble in 
planning or executing sequential activities. 
iii.
Visuospatial: Copy of BVMT figures; Clock Drawing Test
a.
Defined as problems in visuoperceptual analysis. Could be manifest by 
difficulty in recognition of faces, objects despite good acuity. Trouble 
with operating simple implements (eg, tools or utensils), or trouble with 
spatial awareness, dressing etc.
iv.
Language: Verbal fluency (F, A, and S test), animal fluency, MINT naming
a.
Defined as newly acquired problems with speaking, reading, or writing. 
Symptoms may include word search, speech hesitation, speech errors, 
writing and spelling difficulty.


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v.
Personality or comportment: informant interview and NPI
a.
Defined as changes in personality, behavior, or comportment. 
Symptoms may include mood fluctuations, agitation, impaired 
motivation, apathy, loss of empathy, social withdrawal, compulsive or 
obsessive behaviors, social inappropriateness.
The differentiation between dementia and MCI rests on the determination of whether or not 
there is significant interference in the ability to function at work or in usual daily activities. This 
is a clinical judgment which relies on a skilled clinician assessing current function based on 
knowledge of the individual participant’s circumstance and information from a knowledgeable 
informant.
The endpoint of AD dementia will be specified if the participant (after fulfilling dementia criteria 
above) fulfills criteria for possible or probable AD dementia. Possible or probable AD dementia, 
are defined by the NIA/AA criteria [23] and operationalized in this study as follows:

Probable AD:
1. Meets criteria A through E for dementia as noted above AND the following 
characteristics (2-6):
2. A CDR Global score of ≥1.0 will be required in order to set a consistent minimum 
standard for AD dementia as an endpoint in the study.
3. Insidious onset (over months or years, not sudden over hours or days).
4. Clear worsening of cognition across visits—by report or by documented worsening 
upon repeated cognitive test scores or MMSE.
5. Initial and most prominent impairment1 is documented on 1 of the following domains:
a.
Amnestic: Impaired new learning and memory, as evidenced in the clinician 
examination, history, or by impairment on at least 1 of the following subtests:
i. BVMT-R Delayed recall.
ii. CVLT-II, short-delay, free recall.
iii. CVLT-II, long-delay, free recall.
b. Nonamnestic: Impairment on performance on at least 1 test of visuospatial 
ability, language, or executive function: Trails A, Trails B, Digit Span Total, 
MINT, Semantic fluency, Lexical fluency, or Clock Drawing Test; or based on 
observation, or clinical history.
6. Evidence of cognitive dysfunction in at least 1 other domain noted in criteria #4. 
7. Absence of clinical history or laboratory tests that suggest another condition can 
explain the cognitive decline in its entirety. 


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
Possible AD:
1. Meets criteria for dementia, as defined above and criteria a and b are met:
a.
Initial and most prominent impairment is documented on 1 of the following 
domains: amnestic or nonamnestic, as defined for probable AD and
b. Evidence of cognitive dysfunction in 1 other domain from amnestic or 
nonamnestic domains, as defined for probable AD. 

HOWEVER, possible AD is distinguished from probable AD by either of the following 2 
characteristics:

1) Etiology is mixed or complex: presence of medical condition, a neurological 
disease, or medication use that can partially explain the deficits, or
2) Atypical course as determined by the investigator (eg, sudden onset; pronounced 
aphasia), or insufficient historical detail or objective cognitive documentation of 
progressive decline.
If probable or possible AD is confirmed the visit at which the AD dementia diagnosis was made 
will be considered the onset time for the secondary endpoint. Subjects will be referred to standard 
of care and will be considered study completers.
If probable or possible AD or non-AD dementia is not confirmed, subject will remain in the study, 
unless there is a medical reason to withdraw the subject from the study. 
Non-AD dementia: for example, vascular dementia, dementia due to Parkinson disease, 
frontal temporal dementia, or dementia due to other less common causes will be withdrawn 
from the study.


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Appendix G
Detailed Description of Amendments to Text
This appendix describes changes in reference to Protocol incorporating Amendment 3. 
Page 2, Section 1.1, Contacts
Existing Text
Issue
North America Contact
Europe Contact 
Australia Contact
Serious 
adverse event 
and 
pregnancy 
reporting
Medical 
Monitor
(medical 
advice on 
protocol, 
compound, 
and medical 
management 
of subjects)
Responsible 
Medical 
Officer 
(carries 
overall 
responsibility 
for the 
conduct of the 
study)
Protected Personal Data
Confidential Company Information


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Revised Text
Issue
North America Contact
Europe Contact 
Australia Contact
Serious adverse 
event and 
pregnancy 
reporting
Medical 
Monitor
(medical advice 
on protocol, 
compound, and 
medical 
management of 
subjects)
Responsible 
Medical Officer 
(carries overall 
responsibility 
for the conduct 
of the study)
Rationale for Amendment
To update with current Medical personnel.
Page 3, Section 1.2, Approval
Takeda signatories have been updated to reflect current roles and titles.
Company Confidential Information


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Rationale for Amendment
Update to reflect change in personnel and titles for Takeda signatories.
Page 11, Section 2.0, Primary Objective
Existing Text
To evaluate the effect of pioglitazone at 24 months compared with placebo on cognitive decline in 
subjects who have completed the AD-4833/TOMM40_301 study with an MCI due to AD 
diagnosis.
Revised Text
To evaluate the effect of pioglitazone at 24 months compared with placebo on cognitive decline in 
high-risk subjects who have completed the AD-4833/TOMM40_301 study with an MCI due to 
AD diagnosis.
Rationale for Amendment
To be consistent with objective as stated in Section 5.1.1 of protocol.
Page 12-13, Section 2.0, Main Criteria for Inclusion and Exclusion
Existing Text
Main Criteria for Inclusion:

The subject completed the pivotal AD-4833/TOMM40_301 study with an adjudicated 
diagnosis of MCI due to AD without ongoing serious adverse events from study 
AD-4833/TOMM40_301.

The subject must be living independently or in nonmedical residential care.

The subject has a project partner able to separately consent on his/her own behalf and take part 
in the study (with the intent to do so as long as the subject is enrolled), providing information 
on the cognitive, functional, and behavioral status of the subject and assisting with observation 
of adverse events and monitoring of study medication, if needed. (Project partners 
participating in the pivotal AD-4833/TOMM40_301 study are encouraged to participate in this 
extension study in this capacity.)
Main Criteria for Exclusion:

The subject completed the pivotal AD-4833/TOMM40_301 study with a diagnosis of AD 
dementia.

The subject has a current diagnosis of significant psychiatric illness, per Diagnostic and 
Statistical Manual of Mental Disorders, 4th Edition (including but not limited to major 
depressive disorder, anxiety disorders) and is in an acute phase/episode, or the subject has a 
current diagnosis or history of schizophrenia or bipolar disorder.

The subject has a glycosylated hemoglobin >8% at the extension study Baseline Visit or 
requires treatment with insulin, triple oral antidiabetic therapy, or a peroxisome 
proliferator-activated receptor-gamma agonist. 


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
The subject has a clinically significant unstable illness, for example, hepatic impairment or 
renal insufficiency, or cardiovascular, pulmonary, gastrointestinal (including s/p gastric 
bypass), endocrine, neurological, rheumatologic, immunologic, infectious, skin and 
subcutaneous tissue disorders, or metabolic disturbance.

The subject is required to take excluded medications as specified in the Excluded Medications 
Section. 

The subject had any of the following values at the extension study Baseline Visit:
A serum total bilirubin value >1.5× upper limit of normal (ULN).
A serum alanine aminotransferase or aspartate aminotransferase value >2×ULN.
Unexplained microscopic/macroscopic hematuria on one repeat examination within 
2 weeks.

The subject has a disease or takes medication that, in the opinion of the investigator, could 
interfere with the assessments of safety, tolerability, or efficacy, or prevent the subject from 
adequately participating in the study or continue for the anticipated duration of the study.

The subject has any cancer that has been in remission for less than 2 years from the extension 
study Baseline Visit. Subjects with basal cell or stage I squamous cell carcinoma of the skin 
will be eligible. Subjects with current diagnosis of bladder cancer are not eligible irrespective 
of the remission status.

The subject has a current diagnosis of macular edema or macular degeneration.

The subject has a history or current diagnosis of congestive heart failure, New York Heart 
Association class III-IV.
Revised Text
Main Criteria for Inclusion:

The subject completed the pivotal AD-4833/TOMM40_301 study with an adjudicated 
diagnosis of MCI due to AD without ongoing serious adverse events from study 
AD-4833/TOMM40_301.

The subject must be living independently or in nonmedical residential care.

The subject has a project partner able to separately consent on his/her own behalf and take part 
in the study (with the intent to do so as long as the subject is enrolled), providing information 
on the cognitive, functional, and behavioral status of the subject (and self reported, if 
voluntarily agreed to) and assisting with observation of adverse events and monitoring of 
study medication, if needed. (Project partners participating in the pivotal 
AD-4833/TOMM40_301 study are encouraged to participate in this extension study in this 
capacity.)
Main Criteria for Exclusion:

The subject completed the pivotal AD-4833/TOMM40_301 study with an adjudicated
diagnosis of AD dementia.


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
The subject has a current diagnosis of significant psychiatric illness, per Diagnostic and 
Statistical Manual of Mental Disorders, 4th Edition (including but not limited to major 
depressive disorder, anxiety disorders) and is in an acute phase/episode, or the subject has a 
current diagnosis or history of schizophrenia or bipolar disorder.

The subject has a clinically significant unstable illness, for example, hepatic impairment or 
renal insufficiency, or cardiovascular, pulmonary, gastrointestinal (including s/p gastric 
bypass), endocrine, neurological, rheumatologic, immunologic, infectious, skin and 
subcutaneous tissue disorders, or metabolic disturbance.

The subject is required to take excluded medications as specified in the Excluded Medications 
Section. 

The subject had any of the following values at the second comprehensive medical follow-up 
visit in the AD-4933/TOMM40_301 study (or time of last collection in the pivotal 301 
study):
A serum total bilirubin value >1.5× upper limit of normal (ULN).
A serum alanine aminotransferase or aspartate aminotransferase value >2×ULN.
Unexplained microscopic/macroscopic hematuria on one repeat examination within 
2 weeks.

The subject has a disease or takes medication that, in the opinion of the investigator, could 
interfere with the assessments of safety, tolerability, or efficacy, or prevent the subject from 
adequately participating in the study or continue for the anticipated duration of the study.

The subject has any cancer that has been in remission for less than 2 years from the extension 
study Baseline Visit. Subjects with basal cell or stage I squamous cell carcinoma of the skin 
will be eligible. Subjects with current diagnosis of bladder cancer are not eligible irrespective 
of the remission status.

The subject has a current diagnosis of macular edema or macular degeneration.

The subject has a history or current diagnosis of congestive heart failure, New York Heart 
Association class III-IV.
Rationale for Amendment
To reflect the language as stated in Section 7.0 of the protocol. HbA1c >8% as a criteria for 
exclusion has been removed because, while this assessment will still be collected at Baseline, it is 
no longer considered an important eligibility criterion for this study. Any medical concerns with a 
subject’s baseline HbA1c result will be handled on a case by case basis. Criterion regarding liver 
function tests was modified to allow the eligibility decision to be based on the laboratory results 
available prior to the AD-4833/TOMM40_301 EOS/303 Baseline visit to confirm/ensure 
eligibility for this extension study. 
Page 24, Section 6.1, Study Design, fifth and seventh paragraph, 
Existing Text
A 0.8 mg tablet of SR pioglitazone or placebo will be used in this extension study, the same as that 
used in the pivotal AD-4833/TOMM40_301 study. The tablet will be administered QD for a 


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minimum period of 24 months, in accordance with the extension study duration. Study medication 
will be dispensed at the end of the extension study Baseline Visit and subjects will be instructed to 
take the first dose of study medication in the morning on the day following the extension study 
Baseline Visit.
Subjects and their project partners are expected to attend on-site study visits every 6 months after 
Baseline, for regular assessments of safety, efficacy, and treatment compliance. In addition, the 
subject will be contacted for telephone-based safety checks between visits. While it is preferred 
that subject’s project partners attend the on-site study visits, it is not required and they may offer 
their information via telephone. Project partners who voluntarily take part in completion of the 2 
self reported project partner questionnaires (outline in Section 9.1.14.4), will be required to attend 
the study visits when the questionnaires are obtained. If between in clinic visits, worsening of 
cognitive impairment, potential AD dementia, or a potential safety issue is suspected, requiring 
further evaluation of the subject, an unscheduled clinic visit may be conducted as described in 
Section 6.2.3. Suspected dementia cases will be forwarded for evaluation by an independent 
Cognitive Impairment Adjudication Committee (CIAC) as described in Section 6.2.4. Up to 60 
sites globally may participate in this study (the same sites that participated in the 
AD-4833/TOMM40_301 study, although all sites may not participate in 303).
Revised Text
A 0.8 mg tablet of SR pioglitazone or placebo will be used in this extension study, the same as that 
used in the pivotal AD-4833/TOMM40_301 study. The tablet will be administered QD for a 
minimum period of 24 months, in accordance with the extension study duration. Study medication 
will be dispensed at the end of the extension study Baseline Visit and subjects will be instructed to 
take the first dose of study medication in the morning on the day following the extension study 
Baseline Visit (if all eligibility criteria are confirmed).
Subjects and their project partners are expected to attend on-site study visits every 6 months after 
Baseline, for regular assessments of safety, efficacy, and treatment compliance. In addition, the 
subject will be contacted for telephone-based safety checks between visits. While it is preferred 
that subject’s project partners attend the on-site study visits, it is not required and they may offer 
their information via telephone. Project partners who voluntarily take part in completion of the 2 
self reported project partner questionnaires (outline in Section 9.1.14.4), will be required to attend 
the study visits when the questionnaires are obtained. If between in clinic visits, worsening of 
cognitive impairment, potential AD dementia, or a potential safety issue is suspected, requiring 
further evaluation of the subject, an unscheduled clinic visit may be conducted as described in 
Section 6.2.3. Up to 60 sites globally may participate in this study (the same sites that participated 
in the AD-4833/TOMM40_301 study, although all sites may not participate in 303).
Rationale for Amendment
To clarify when study drug for this extension study should begin. 
To remove the adjudication process from the study.


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Page 27, Section 6.2.2, Assessments at Scheduled Study Visits, third paragraph
Existing Text
The physician, preferably an experienced neurologist or psychiatrist, will review the totality of 
available information once fully scored (ie, medical history, CDR ratings, and CDR-SB scores;
ADCS-CGIC-MCL, ADCS ADL-MCI, GDS, and NPI-Q data; cognitive test results; and 
laboratory test results). At this point he/she in consultation with the site neuropsychologist, will 
determine whether the diagnosis of the subject has changed from MCI due to AD. If a diagnosis of 
AD dementia is suspected, the investigator will determine whether to send the subject’s case to 
adjudication, described in Section 6.2.4. The physician can be the same individual who completed 
the CDR. 
Revised Text
The physician, preferably an experienced neurologist or psychiatrist, will review the totality of 
available information once fully scored (ie, medical history, CDR ratings, and CDR-SB scores;
ADCS-CGIC-MCL, ADCS ADL-MCI, GDS, and NPI-Q data; cognitive test results; and 
laboratory test results). At this point he/she in consultation with the site neuropsychologist, will 
determine whether the diagnosis of the subject has changed from MCI due to AD. If possible or 
probable AD dementia is diagnosed, the subject will be considered a have completed the 
study. If non-AD dementia is diagnosed, the subject will be withdrawn from the study. The 
physician can be the same individual who completed the CDR. 
Rationale for Amendment
To remove the adjudication process for confirmation of the diagnosis of dementia.
Page 28, Section 6.2.3, Assessments at an Unscheduled Visit for Suspected Cognitive or 
Functional Decline, third paragraph
Existing Text
Unscheduled Visits to evaluate suspected cognitive or functional decline may be conducted, as 
needed, for study subjects outside of regularly scheduled visits based on either of the following 
trigger criteria being met: (1) the subject or their project partner express concern of the subject’s 
cognitive or functional decline to the principal investigator or coordinator between regularly 
scheduled study visits and/or (2) a non-study physician expresses concern (with or without 
prescription of any dementia drug treatment) between regularly scheduled visits. Based on these 
triggers, the principal investigator will decide whether evidence is present to suspect a diagnosis of 
possible or probable AD dementia [23]. If a diagnosis of possible or probable AD dementia is 
suspected, an Unscheduled Visit to further evaluate suspected cognitive or functional decline 
should take place within 1 month of this provisional diagnosis. Visit procedures for the 
unscheduled visit for suspected cognitive or functional decline are noted in Appendix A.
Revised Text
Unscheduled Visits to evaluate suspected cognitive or functional decline may be conducted, as 
needed, for study subjects outside of regularly scheduled visits based on either of the following 


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CONFIDENTIAL
trigger criteria being met: (1) the subject or their project partner express concern of the subject’s 
cognitive or functional decline to the principal investigator or coordinator between regularly 
scheduled study visits and/or (2) a non-study physician expresses concern (with or without 
prescription of any dementia drug treatment) between regularly scheduled visits. Based on these 
triggers, the principal investigator will decide whether evidence is present to suspect a diagnosis of 
possible or probable AD dementia [23]. If a diagnosis of possible or probable AD dementia is 
suspected, an Unscheduled Visit to further evaluate suspected cognitive or functional decline 
should take place within approximately 1 month of this provisional diagnosis. A CDR Global 
score of ≥1.0 will be required in order to set a consistent minimum standard for AD 
dementia as an endpoint for the study. Visit procedures for the unscheduled visit for suspected 
cognitive or functional decline are noted in Appendix A.
Rationale for Amendment
To allow greater flexibility in when the Unscheduled Visit occurs and to ensure consistency in the 
diagnosis of AD dementia as an endpoint for the study.
Page 29-31, Section 6.2.4, Adjudication
Existing Text
After each regularly scheduled visit, or an Unscheduled Visit relating to cognitive status, the 
investigator in consultation with the site neuropsychologist, will consider the totality of 
information collected for the subject and decide subject flow within the study (ie, send or not to 
adjudication). Suspected cases of dementia will be sent to the CIAC. If a subject is assigned a 
dementia diagnosis as judged by the investigator [22], then he/she will complete a diagnostic 
worksheet and send the case to adjudication. When adjudication is required, data from all 
previous visits may be shared with the adjudication committee, who will be blinded to the subject’s 
treatment-assignment. The adjudication process will result in 1 of 2 possible outcomes of clinical 
assessment: (1) AD dementia (possible or probable); (2) does not meet criteria for AD dementia. 
Operational criteria for adjudicated diagnoses are noted in Appendix F.
The adjudication flow of subjects through the study, as described above, is illustrated in Figure 
6.b. 


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CONFIDENTIAL
Figure 6.b
Subject Flow Chart
Footnotes are on following page.
301 End of Study Visit
Join 303 study
Baseline Visit
a
301 Study ended
>2 yr. ago
d
303 End Of Study Visit
Unscheduled Visit
g
Yes 
Office Visit Review
(6 & 12 mo.)f
Unscheduled Visit Review 
No
301 Follow Up Visit
a
303 Follow Up Visit
a
3 Month
b
12 Month
c
6 Month
c
Trigger for 
Adjudication?h
Yes
9 Month
b
Yes
Suspect Trigger
Phone Visit Review
(3 & 9 mo.)e 
No
CIAC report 
Subject 
disposition by 
PI
j
Does not meet AD Dementia
No
CIAC adjudication
i
- Meets AD dementia
- Does not meet AD dementia
Continue 
Routine 
Visit
Yes
No
No
Meets AD Dementia


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(a) AD-4833/TOMM40_301 Follow-up phone call.
(b) The Baseline Visit will coincide with the End of Study Visit for the pivotal AD-4833/TOMM40_301 study. The 
randomization scheme to pioglitazone or placebo from the pivotal AD-4833/TOMM40_301 study will remain 
unchanged. After the Baseline Visit, subjects and their project partners will enter a repetitive yearly regularly 
scheduled Visit Cycle, ending at (1) subject diagnosed to an endpoint, (2) subject withdrawal, or (3) study end.
(c) Subjects will be assessed by the site staff after every regularly scheduled visit (3, 6, 9, 12 months). 
(d) Once the pivotal AD-4833/TOMM40_301 study has been completed for 2 years, subjects in the 
AD-4833/TOMM40_303 study will have an End of Study Visit and Follow-up Visit scheduled. 
(e) If (1), the subject or their project partner express concern of the subject’s cognitive or functional decline to the 
principal investigator or coordinator between regularly scheduled study visits (including but not limited to phone 
visits at 3 and 9 months) and/or (2) a non-study physician expresses concern (with or without prescription of any 
dementia drug treatment) between regularly scheduled visits.
(f) At each regularly scheduled visit review, the subject will be reviewed for cognitive functional and clinical 
performance, and conversion to AD dementia. If possible or probable diagnosis of AD is suspected, the principal 
investigator will decide subject flow within the study (ie, send or not to adjudication).
(g) If the principal investigator suspects the subject may possibly meet possible or probable AD dementia based on 
concerns raised as noted in Section 6.2.3, the principal investigator will conduct the procedures listed in the 
Unscheduled Visit in Appendix A. If, after evaluation, the principal investigator does not suspect the subject needs to 
be sent to adjudication, they will return to the regularly scheduled Visit Schedule. The triggers warranting evaluation 
are described in Section 6.2.
(h) At the Unscheduled Visit Review or after regularly scheduled visits, the investigator will consider the totality of 
information collected for the subject and decide subject flow within the study (ie, send or not to adjudication) based on 
the criteria in Section 6.2.4. Those subjects not sent for adjudication will return to the regularly scheduled Visit 
Schedule. The investigator will send to adjudication subjects whom they judged has reached one of the study 
outcomes.
(i) All data from any subject visit may be shared with the CIAC. The adjudication process possible outcomes are 
described in Section 6.2.4.
(j) If the CIAC determines that the subject does not meet AD dementia, the principal investigator will determine at this 
time, based on clinical judgment, the subject’s ability to continue in study.
In addition to regular sponsor surveillance, the ethical and safety interests of subjects will be 
evaluated by an independent Data and Safety Monitoring Board (DSMB) in a manner that will 
protect, as far as possible, the scientific integrity of the study.
Revised Text
The entire section has been deleted.
Rationale for Amendment
To remove the adjudication process for confirmation of the diagnosis of dementia.
Page 31, Section 6.4.1, Study Design, tenth paragraph, last sentence
Existing Text
Assessments of vMRI will be collected at the extension study Baseline (last MRI completed in 301 
study) as part of the scan collected to support a diagnosis sent for adjudication or at study 
termination to test for correlation with disease progression within and across study arms. 


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Revised Text
Assessments of vMRI will be collected at the extension study Baseline (last MRI completed in 301 
study) and at study termination to test for correlation with disease progression within and across 
study arms. 
Rationale for Amendment
As a result of adjudication being removed, the MRI to rule out other causes of dementia has also 
been removed.
Page 33-34, Section 7.2, Exclusion Criteria, #3 and 8
Existing Text
3. The subject has an HbA1c >8% at the extension study Baseline Visit or requires treatment with 
insulin, triple oral antidiabetic therapy or a PPAR-agonist. 
8. The subject had any of the following values at the extension study Baseline Visit:
a) A serum total bilirubin value >1.5× upper limit of normal (ULN).
b) A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2×ULN.
c) Unexplained microscopic/macroscopic hematuria on one repeat examination within 
2 weeks.
Revised Text
7. The subject had any of the following values at the second comprehensive medical follow-up 
visit in the AD-4833/TOMM40_301 study (or time of last collection in the pivotal 301 
study):
a) A serum total bilirubin value >1.5× upper limit of normal (ULN).
b) A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2×ULN.
c) Unexplained microscopic/macroscopic hematuria on one repeat examination within 
2 weeks.
Rationale for Amendment
HbA1c >8% as a criteria for exclusion has been removed because, while this assessment will still 
be collected at Baseline, it is no longer considered an important eligibility criterion for this study. 
Any medical concerns with a subject’s baseline HbA1c result will be handled on a case by case 
basis.
Criterion #8 was modified to allow the laboratory results to be available prior to the 
AD-4833/TOMM40_301 EOS/303 Baseline visit to confirm/ensure eligibility for this extension 
study.


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Page 36, Table 7.a, Excluded Medications and Treatments
Added to existing Table
Triple Oral Antibiotic 
Therapy
Prohibited, if initiated
Prohibited, if initiated 
(Subject must be discontinued)
Rationale for Amendment
The exclusion of triple oral antidiabetic therapy has been removed in exclusion criterion #3 and 
added to the Excluded Medications and Treatments Table 7.a (insulin and PPAR-γ agonist where 
already included in Table 7.a). 
Page 54, Section 9.1.14.7, MRI Assessment
Existing Text
The MRI collected in this extension study may be used for both structural and volumetric analyses, 
to support the possible dementia diagnosis and to support the imaging endpoint, respectively. 
Subjects enrolled in the extension study will be required (unless medically contraindicated) to 
participate in a vMRI scan where volumetric measurements will be taken, for the purpose of 
assessing atrophy of the brain. vMRI scans will take place at the following time points, as noted in 
the Schedule of Study Procedures (Appendix A): extension study Baseline (last MRI collected at 
End of Study Visit or second Comprehensive Medical Follow-up Visit for the pivotal 
AD-4833/TOMM40_301 study) and in extension study as part of the scan collected to support a 
diagnosis sent for adjudication or at End of Study/Early Withdrawal Visit.
MRI will be collected when cognitive or functional decline is suspected, to rule out other causes of 
dementia and provide supplemental information for the CIAC review of suspected dementia cases. 
For subjects who have contraindications for MRI procedure (such as unremovable ferromagnetic 
dental work, cardiac pacemakers, etc) a computerized axial tomography (CT) scan may be 
performed instead.
Revised Text
Subjects enrolled in the extension study will be required (unless medically contraindicated) to 
participate in a vMRI scan where volumetric measurements will be taken, for the purpose of 
assessing atrophy of the brain. vMRI scans will take place at the following time points, as noted in 
the Schedule of Study Procedures (Appendix A): extension study Baseline (last MRI collected at 
End of Study Visit or second Comprehensive Medical Follow-up Visit for the pivotal 
AD-4833/TOMM40_301 study) and at extension study End of Study/Early Withdrawal Visit.
Rationale for Amendment
As a result of adjudication being removed, the MRI to rule out other causes of dementia has also 
been removed.


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Page 58, Section 9.1.17, Imaging
Existing Text
Prior to the start of the study, each site should identify a study MRI and CT machine. Each MRI 
machine will be qualified by the imaging vendor before starting the study, if not already qualified 
as part of participation in the pivotal AD-4833/TOMM40_301 study. Documentation of 
qualification will be sent to the site by the imaging vendor, which should be retained in the site’s 
study files as evidence of quality control approval. Each MRI and CT scan will be read by the local 
radiologist at each site for immediate medical action whenever necessary. The results of the local 
reading will be recorded in the eCRF. Detailed instructions for the processing and shipping of 
images will be provided separately. 
For Subjects who have contraindications for MRI procedure (such as unremovable ferromagnetic 
dental work, cardiac pacemakers, etc) a CT scan may be performed instead.
Revised Text
Prior to the start of the study, each site should identify a study MRI machine. Each MRI machine 
will be qualified by the imaging vendor before starting the study, if not already qualified as part of 
participation in the pivotal AD-4833/TOMM40_301 study. Documentation of qualification will be 
sent to the site by the imaging vendor, which should be retained in the site’s study files as evidence 
of quality control approval. Each MRI will be read by the local radiologist at each site for 
immediate medical action whenever necessary. The results of the local reading will be recorded in 
the eCRF. Detailed instructions for the processing and shipping of images will be provided 
separately. 
Subjects who have contraindications for MRI procedure (such as unremovable ferromagnetic 
dental work, cardiac pacemakers, etc) will not be excluded from the study.
Rationale for Amendment
As a result of adjudication being removed, the MRI to rule out other causes of dementia has also 
been removed.
Page 59, Section 9.3.3.2, Unscheduled Visit for suspected Cognitive or Functional Decline
Existing Text
An unscheduled visit may be conducted if worsening of cognitive impairment or potential AD 
dementia is suspected in between regularly scheduled visits when 1 of the triggers described in 
Section 6.2.3 has been met. This type of Unscheduled Visit will include the assessments noted in 
Appendix A. It is anticipated this visit will be about 3 to 4 hours in length, if an MRI is completed 
during the visit.
Revised Text
An unscheduled visit may be conducted if worsening of cognitive impairment or potential AD 
dementia is suspected in between regularly scheduled visits when 1 of the triggers described in 
Section 6.2.3 has been met. A CDR Global score of ≥1.0 will be required in order to set a 


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CONFIDENTIAL
consistent minimum standard for AD dementia as an endpoint for the study. This type of 
Unscheduled Visit will include the assessments noted in Appendix A. It is anticipated this visit 
will be about 3 to 4 hours in length, if an MRI is completed during the visit.
Rationale for Amendment
To ensure consistency in the diagnosis of AD dementia as an endpoint for the study.
Page 59, Section 9.3.4, Final Visit or Early Termination
Existing Text
The End of Study/Early Withdrawal Visit is an ad hoc visit that, for study completion, will take 
place as soon as possible after a regularly scheduled study visit, either at study end, or at extension 
study termination, or after a subject has withdrawn prematurely from the study. In cases where the 
secondary endpoint of AD dementia diagnosis has been reached, the efficacy assessments will not 
need to be captured at this visit.
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.
Revised Text
The End of Study/Early Withdrawal Visit is an ad hoc visit that, for study completion, will take 
place as soon as possible after a regularly scheduled or unscheduled study visit, either at study 
end, at extension study termination, after a subject has withdrawn prematurely from the study, or 
after the subject has been diagnosed with AD or non-AD dementia. The efficacy assessments will 
not need to be captured at this visit in cases where the secondary endpoint of AD dementia 
diagnosis has been reached or if it is less than 3 months from the last administration of the 
assessment. 
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.
Rationale for Amendment
To clarify when the End of Study/Early Withdrawal Visit should occur and what procedures will 
need to be completed at the visit.
Page 60, Section 9.3.5, Follow-up
Existing Text
Follow-up will begin the first day after the End of Study/Early Withdrawal Visit and will continue 
until 2 weeks later.
Subjects will be contacted for a Safety Follow-up call approximately 2 weeks after the End of 
Study/Early Termination Visit. See Appendix A for list of procedures that will be performed and 
documented. Subjects who withdraw their consent should still be contacted for a Safety Follow-up 
call, but the contact should only be recorded in the medical records (and not the eCRF), according 
to data protection regulations. 


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Revised Text
Follow-up will begin the first day after the End of Study/Early Withdrawal Visit and will continue 
until 2 weeks later.
Subjects will be contacted for a Safety Follow-up call approximately 2 weeks after the End of 
Study/Early Termination Visit. See Appendix A for list of procedures that will be performed and 
documented. Subjects who withdraw their consent should still be contacted for a Safety Follow-up 
call, but the contact should only be recorded in the subjects records (and not the eCRF), according 
to data protection regulations. 
Rationale for Amendment
To provide clarity on where the Follow-up call will be documented for subjects that do not have 
medical records.
Page 70, Section 11.2, Adjudication Committee
Existing Text
The Cognitive Impairment Adjudication Committee that adjudicated primary endpoint events in 
the pivotal AD-4833/TOMM40_301 study will adjudicate clinical diagnoses of AD in this study. 
The Adjudication Committee will meet periodically, review data on suspected cases of dementia, 
and perform final adjudication of the diagnosis of AD dementia. Materials to be reviewed will 
include the complete dossier for the 303 study subject, whose case is forwarded for adjudication, 
and may include all appropriate records from the pivotal AD-4833/TOMM40_301 study, 
including assessment results conducted during the subject’s participation in 
AD-4833/TOMM40_301
Revised Text
Removed the entire section.
Rationale for Amendment
To remove the adjudication process for confirmation for the diagnosis of dementia.


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Page 86, Appendix A, Schedule of Study Procedures
Existing Text
Appendix A
Schedule of Study Procedures
Baseline
(Coincides 
With 301 End 
of Study Visit 
(a)
Unscheduled 
Visit (b)
End of Study 
Visit/Early 
Withdrawal (c)
Follow-up Visit
Month
0 (Day 0)
Repeated Yearly
EoS/EW+0.5 (e)
3 (d)
6
9 (d)
12
Visit Window
+30 days
±2 
wks
±2 
wks
±2 
wks
±2 
wks
Informed consent 
(subject)
X
Informed consent 
(pharmacogenomic)
X
Informed consent 
(project partner)
X
Incl/excl criteria
X
Medical history
X
Concurrent conditions
X
Body weight and 
height(g)
X (f)
X
X
X
Review of concurrent 
medications
X
X
X
X
X
X
X
X
Contact IWRS
X
X
X
X
Dispense study drug
X
X
X
Collect study drug
X
X
X
Compliance review 
X
X
X
X
X
AEs (including AEs of 
Special Interest) 
X (f)
X
X
X
X
X
X
X
Physical examination
X (f)
X
X
X
Vital signs
X (f)
X
X
X
X
Neurological 
examination
X (f)
X
X
X
X
12-lead ECG
X (f)
X
X
vMRI (h)(i)
X (f)
X(i)
X
Clinical chemistry and 
hematology labs
X (f)
X
X (j)
X
HbA1c test (k)
X
X
Pharmacogenomic RNA 
samples
X
X (l)
X (m)
C-SSRS
X (f)
X
X
X
X
Diet and exercise 
evaluation
X (f)
X
X
X
MMSE (d)
X (f)
X
X
X
CVLT-II
X (f)
X
X
BVMT-R
X (f)
X
X
Lexical fluency
X (f)
X
X
Semantic fluency
X (f)
X
X
MINT 
X (f)
X
X
Digit Span 
X (f)
X
X


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Baseline
(Coincides 
With 301 End 
of Study Visit 
(a)
Unscheduled 
Visit (b)
End of Study 
Visit/Early 
Withdrawal (c)
Follow-up Visit
Month
0 (Day 0)
Repeated Yearly
EoS/EW+0.5 (e)
3 (d)
6
9 (d)
12
Trail Making Tests 
X (f)
X
X
Clock Drawing
X (f)
X
X
Footnotes are on last table page.
Appendix A
Schedule of Study Procedures (continued)
Baseline
(Coincides 
With 301 End 
of Study Visit
(a)
Unscheduled 
Visit (b)
End of Study 
Visit/Early 
Withdrawal (c)
Follow-up Visit
Month
0 (Day 0)
Repeated Yearly
EoS/EW+0.5 (e)
3 (d)
6
9 (d)
12
GDS
X (f)
X
X
X
CDR 
X (f)
X
X
X
X
ADCS ADL- MCI
X 
X
X
X
NPI-Q
X (f)
X
X
X
ADCS CGIC-MCI 
X
X
X
X(n)
X
ADCS RUI
X (f)
X
X
X
EQ-5D (subject) (o)
X (f)
X
EQ-5D (project partner) 
(o)
X
X
WPAI(o)
X
X
EoS=End of Study, EW=Early Withdrawal.
(a) Subjects who are unable to consent for the extension study or to complete all extension study baseline visit evaluations at the 
same time as their End of Study Visit for the pivotal AD-4833/TOMM40_301 study will be allowed to return to the clinic and to 
complete these evaluations within a 1 month window.
(b) Procedures listed should be conducted in the event of an Unscheduled Visit for suspected cognitive or functional decline. 
Procedures related to Unscheduled Visits for any other emerging concern, such as safety, are at the discretion of the investigator. 
(c) End of Study/Early Withdrawal Visit is an ad hoc visit that, for study completion, would take place as soon as possible after a 
regularly scheduled study visit, either at study end, occurring concurrently with completion of the pivotal AD-4833/TOMM40_301 
study or at extension study termination, or after a subject has withdrawn prematurely from the study. In cases where the secondary 
endpoint of AD dementia diagnosis has been reached, the efficacy assessments will not need to be captured at this visit.
(d) Telephone contact with the subject (should be every 3 months between the semiannual clinic visits for the duration of the study)
(e) Telephone call approximately 2 weeks after the End of Study or Early Withdrawal Visit. 
(f) These assessments, conducted as part of the end of study visit for the pivotal AD-4833/TOMM40_301 study or at most recent 
comprehensive medical Follow-up Visit, will serve as baseline data for the extension AD-4833/TOMM40_303 study.
(g) Height will only be collected at the end of study visit for the pivotal AD-4833/TOMM40_301 study or at most recent 
comprehensive medical Follow-up Visit, and will serve as baseline data for the extension AD-4833/TOMM40_303 study
(h) vMRI assessments will take place at extension study Baseline (ie, coinciding with the End of Study Visit for the pivotal 
AD-4833/TOMM40_301 study or most recent MRI or that obtained at the second consecutive comprehensive medical Follow-up 
Visit) and for adjudication or at extension study end. 
(i) MRI will be collected for suspected cognitive or functional decline to rule out other causes of dementia and provide 
supplemental information for the CIAC review of suspected dementia cases. The MRI collected in this extension study may be used 
for both structural and volumetric analyses, to support the possible dementia diagnosis and to support the imaging endpoint, 
respectively.
(j) Standard blood chemistry and tests used in evaluating cognitively impaired and dementia patients (eg, thyroid profile, vitamin 
B12).
(k) A blood sample will be collected at the extension Baseline Visit and End of Study/Early Withdrawal Visit for HbA1c testing.


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(l) If an Unscheduled Visit is conducted, RNA samples will be collected during this visit. In this instance, RNA samples will not 
need to be collected at the End of Study/Early Withdrawal Visit.
(m) RNA samples will only be collected at the End of Study/Early Withdrawal Visit if samples were not collected at an 
Unscheduled Visit. 
(n) This assessment will only need to be administered at the unscheduled visit if it occurs greater than 3 months from the last 
administration of this assessment.
(o) EQ-5D will be completed by subject at Month 24 and at End of Study in the extension study and the EQ-5D and WPAI will be 
completed by project partner at Baseline, Month 24 and End of Study.
Revised Text
Appendix A
Schedule of Study Procedures
Baseline
(Coincides 
With 301 End 
of Study Visit 
(a)
Unscheduled 
Visit (b)
End of Study 
Visit/Early 
Withdrawal (c)
Follow-up Visit
Month
0 (Day 0)
Repeated Yearly
EoS/EW+0.5 (e)
3 (d)
6
9 (d)
12
Visit Window
+30 days
±2 
wks
±2 
wks
±2 
wks
±2 
wks
Informed consent 
(subject)
X
Informed consent 
(pharmacogenomic)
X
Informed consent 
(project partner)
X
Incl/excl criteria
X
Medical history
X
Concurrent conditions
X
Body weight and 
height(g)
X (f)
X
X
X
Review of concurrent 
medications
X
X
X
X
X
X
X
X
Contact IWRS
X
X
X
X
Dispense study drug
X
X
X
Collect study drug
X
X
X
Compliance review 
X
X
X
X
X
AEs (including AEs of 
Special Interest) 
X (f)
X
X
X
X
X
X
X
Physical examination
X (f)
X
X
X
Vital signs
X (f)
X
X
X
X
Neurological 
examination
X (f)
X
X
X
X
12-lead ECG
X (f)
X
X
vMRI (h)
X (f)
X
Clinical chemistry, 
hematology and 
urinalysis labs
X (f)
X
X i)
X
HbA1c test (j)
X
X
Pharmacogenomic RNA 
samples
X
X (k)
X (l)
C-SSRS
X (f)
X
X
X
X
Diet and exercise 
evaluation
X (f)
X
X
X


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Baseline
(Coincides 
With 301 End 
of Study Visit 
(a)
Unscheduled 
Visit (b)
End of Study 
Visit/Early 
Withdrawal (c)
Follow-up Visit
Month
0 (Day 0)
Repeated Yearly
EoS/EW+0.5 (e)
3 (d)
6
9 (d)
12
MMSE (d)
X (f)
X
X
X
CVLT-II
X (f)
X
X
BVMT-R
X (f)
X
X
Lexical fluency
X (f)
X
X
Semantic fluency
X (f)
X
X
MINT 
X (f)
X
X
Digit Span 
X (f)
X
X
Trail Making Tests 
X (f)
X
X
Clock Drawing
X (f)
X
X
Footnotes are on last table page.
Appendix A
Schedule of Study Procedures (continued)
Baseline
(Coincides 
With 301 End 
of Study Visit
(a)
Unscheduled 
Visit (b)
End of Study 
Visit/Early 
Withdrawal (c)
Follow-up Visit
Month
0 (Day 0)
Repeated Yearly
EoS/EW+0.5 (e)
3 (d)
6
9 (d)
12
GDS
X (f)
X
X
X
CDR 
X (f)
X
X
X
X
ADCS ADL- MCI
X 
X
X
X
NPI-Q
X (f)
X
X
X
ADCS CGIC-MCI 
X
X
X
X(m)
X
ADCS RUI
X (f)
X
X
X
EQ-5D (subject) (n)
X (f)
X
EQ-5D (project partner) 
(n)
X
X
WPAI(n)
X
X
EoS=End of Study, EW=Early Withdrawal.
(a) Subjects who are unable to consent for the extension study or to complete all extension study baseline visit evaluations at the 
same time as their End of Study Visit for the pivotal AD-4833/TOMM40_301 study will be allowed to return to the clinic and to 
complete these evaluations within a 1 month window.
(b) Procedures listed should be conducted in the event of an Unscheduled Visit for suspected cognitive or functional decline. 
Procedures related to Unscheduled Visits for any other emerging concern, such as safety, are at the discretion of the investigator. 
(c) End of Study/Early Withdrawal Visit is an ad hoc visit that, for study completion, would take place as soon as possible after a 
regularly scheduled or unscheduled study visit, either at study end, at extension study termination, after a subject has withdrawn 
prematurely from the study or after the subject has been diagnosed with AD or non-AD dementia. The efficacy assessments 
will not need to be captured at this visit in cases where the secondary endpoint of AD dementia diagnosis has been reached 
or if it is less than 3 months from the last administration of the assessment.
(d) Telephone contact with the subject (should be every 3 months between the semiannual clinic visits for the duration of the study)
(e) Telephone call approximately 2 weeks after the End of Study or Early Withdrawal Visit. 
(f) These assessments, conducted as part of the end of study visit for the pivotal AD-4833/TOMM40_301 study or at most recent 
comprehensive medical Follow-up Visit, will serve as baseline data for the extension AD-4833/TOMM40_303 study.
(g) Height will only be collected at the end of study visit for the pivotal AD-4833/TOMM40_301 study or at most recent 
comprehensive medical Follow-up Visit, and will serve as baseline data for the extension AD-4833/TOMM40_303 study
(h) vMRI assessments will take place at extension study Baseline (ie, coinciding with the End of Study Visit for the pivotal 


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CONFIDENTIAL
AD-4833/TOMM40_301 study or most recent MRI or that obtained at the second consecutive Comprehensive Medical Follow-up 
Visit) and at extension study end. 
(i) Standard blood chemistry and tests used in evaluating cognitively impaired and dementia patients (eg, thyroid profile, vitamin 
B12).
(j) A blood sample will be collected at the extension Baseline Visit and End of Study/Early Withdrawal Visit for HbA1c testing.
(k) If an Unscheduled Visit is conducted, RNA samples will be collected during this visit. In this instance, RNA samples will not 
need to be collected at the End of Study/Early Withdrawal Visit.
(l) RNA samples will only be collected at the End of Study/Early Withdrawal Visit if samples were not collected at an Unscheduled 
Visit. 
(m) The ADCSCGIC-MCI assessment will only need to be administered if it occurs greater than 3 months from the last 
administration of this assessment. 
(n) EQ-5D will be completed by subject at Month 24 and at End of Study in the extension study and the EQ-5D and WPAI will be 
completed by project partner at Baseline, Month 24 and End of Study.
Rationale for Amendment
To update Appendix A to reflect all protocol changes.
Page 95, Appendix F, Operational Criteria for AD
Existing Text
Dementia:
A. Cognitive problems observed interfere with the individual’s ability to function at work or 
at usual activities.
B. This functional change represents a decline from previous levels of functioning and 
performing as captured in this trial by clinician impression of change since Baseline or by 
clear impairments on scales of daily functional ability (eg, ADCS ADL-MCI; CDR scale 
with informant; CGIC; Informant Questionnaire on Cognitive Decline).
C. The disorder is not explained by delirium or major psychiatric disorder.
D. Cognitive impairment is detected and diagnosed through a combination of (1) 
history-taking from the patient and a knowledgeable informant and (2) an objective 
cognitive assessment, either a “bedside” mental status examination (eg, MMSE) or 
neuropsychological testing.
E. The cognitive or behavioral impairment involves a minimum of 2 of the following 
domains, established by the testing battery or from interval history and clinical interview:
i.
Memory: CVLT-II; BVMT-R
a.
Defined as an impaired ability to acquire and retain new information. 
Clinical symptoms could include repetitive questions, getting lost in 
familiar areas, forgetting appointments or important events, misplacing 
personal objects. 
ii.
Executive/ Reasoning: Trail Making; Digit Span
a.
Defined as impaired reasoning and ability to handle complex tasks. Can 
be manifest as poor judgment, poor understanding of safety risks; 


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impaired money management; poor decision making; trouble in 
planning or executing sequential activities. 
iii.
Visuospatial: Copy of BVMT figures; Clock Drawing Test
a.
Defined as problems in visuoperceptual analysis. Could be manifest by 
difficulty in recognition of faces, objects despite good acuity. Trouble 
with operating simple implements (eg, tools or utensils), or trouble with 
spatial awareness, dressing etc.
iv.
Language: Verbal fluency (F, A, and S test), animal fluency, MINT naming
a.
Defined as newly acquired problems with speaking, reading, or writing. 
Symptoms may include word search, speech hesitation, speech errors, 
writing and spelling difficulty.
v.
Personality or comportment: informant interview and NPI
a.
Defined as changes in personality, behavior, or comportment. 
Symptoms may include mood fluctuations, agitation, impaired 
motivation, apathy, loss of empathy, social withdrawal, compulsive or 
obsessive behaviors, social inappropriateness.
The differentiation between dementia and MCI rests on the determination of whether or not 
there is significant interference in the ability to function at work or in usual daily activities. This 
is a clinical judgment which relies on a skilled clinician assessing current function based on 
knowledge of the individual participant’s circumstance and information from a knowledgeable 
informant.
The endpoint of AD dementia will be specified if the participant (after fulfilling dementia criteria 
above) fulfills criteria for possible or probable AD dementia. Possible or probable AD dementia, 
are defined by the NIA/AA criteria [23] and operationalized in this study as follows:

Probable AD:
1. Meets criteria A through E for dementia as noted above AND the following 
characteristics (2-6):
2. Insidious onset (over months or years, not sudden over hours or days).
3. Clear worsening of cognition across visits—by report or by documented worsening 
upon repeated cognitive test scores or MMSE.
4. Initial and most prominent impairment1 is documented on 1 of the following domains:
a.
Amnestic: Impaired new learning and memory, as evidenced in the clinician 
examination, history, or by impairment on at least 1 of the following subtests:
i. BVMT-R Delayed recall.
ii. CVLT-II, short-delay, free recall.
iii. CVLT-II, long-delay, free recall.


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b. Nonamnestic: Impairment on performance on at least 1 test of visuospatial 
ability, language, or executive function: Trails A, Trails B, Digit Span Total, 
MINT, Semantic fluency, Lexical fluency, or Clock Drawing Test; or based on 
observation, or clinical history.
5. Evidence of cognitive dysfunction in at least 1 other domain noted in criteria #4. 
6. Absence of clinical history or laboratory tests that suggest another condition can 
explain the cognitive decline in its entirety. 

Possible AD:
1. Meets criteria for dementia, as defined above and criteria a and b are met:
a.
Initial and most prominent impairment is documented on 1 of the following 
domains: amnestic or nonamnestic, as defined for probable AD and
b. Evidence of cognitive dysfunction in 1 other domain from amnestic or 
nonamnestic domains, as defined for probable AD. 

HOWEVER, possible AD is distinguished from probable AD by either of the following 2 
characteristics:

1) Etiology is mixed or complex: presence of medical condition, a neurological 
disease, or medication use that can partially explain the deficits, or
2) Atypical course as determined by the investigator (eg, sudden onset; pronounced 
aphasia), or insufficient historical detail or objective cognitive documentation of 
progressive decline.
If probable or possible AD is confirmed, subject will count toward the total number of events 
needed for the secondary efficacy analysis; the visit at which the AD dementia diagnosis was made 
will be considered the onset time for the secondary endpoint. Subjects will be referred to standard 
of care and will be considered study completers.
If probable or possible AD or non-AD dementia is not confirmed, subject will remain in the study, 
unless there is a medical reason to withdraw the subject from the study. 
Non-AD dementia: for example, vascular dementia, dementia due to Parkinson disease, 
frontal temporal dementia, or dementia due to other less common causes will be withdrawn 
from the study.
Revised Text
Dementia:
A. Cognitive problems observed interfere with the individual’s ability to function at work or 
at usual activities.
B. This functional change represents a decline from previous levels of functioning and 
performing as captured in this trial by clinician impression of change since Baseline or by 


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clear impairments on scales of daily functional ability (eg, ADCS ADL-MCI; CDR scale 
with informant; CGIC; Informant Questionnaire on Cognitive Decline).
C. The disorder is not explained by delirium or major psychiatric disorder.
D. Cognitive impairment is detected and diagnosed through a combination of (1) 
history-taking from the patient and a knowledgeable informant and (2) an objective 
cognitive assessment, either a “bedside” mental status examination (eg, MMSE) or 
neuropsychological testing.
E. The cognitive or behavioral impairment involves a minimum of 2 of the following 
domains, established by the testing battery or from interval history and clinical interview:
i.
Memory: CVLT-II; BVMT-R
a.
Defined as an impaired ability to acquire and retain new information. 
Clinical symptoms could include repetitive questions, getting lost in 
familiar areas, forgetting appointments or important events, misplacing 
personal objects. 
ii.
Executive/ Reasoning: Trail Making; Digit Span
a.
Defined as impaired reasoning and ability to handle complex tasks. Can 
be manifest as poor judgment, poor understanding of safety risks; 
impaired money management; poor decision making; trouble in 
planning or executing sequential activities. 
iii.
Visuospatial: Copy of BVMT figures; Clock Drawing Test
a.
Defined as problems in visuoperceptual analysis. Could be manifest by 
difficulty in recognition of faces, objects despite good acuity. Trouble 
with operating simple implements (eg, tools or utensils), or trouble with 
spatial awareness, dressing etc.
iv.
Language: Verbal fluency (F, A, and S test), animal fluency, MINT naming
a.
Defined as newly acquired problems with speaking, reading, or writing. 
Symptoms may include word search, speech hesitation, speech errors, 
writing and spelling difficulty.
v.
Personality or comportment: informant interview and NPI
a.
Defined as changes in personality, behavior, or comportment. 
Symptoms may include mood fluctuations, agitation, impaired 
motivation, apathy, loss of empathy, social withdrawal, compulsive or 
obsessive behaviors, social inappropriateness.
The differentiation between dementia and MCI rests on the determination of whether or not 
there is significant interference in the ability to function at work or in usual daily activities. This 
is a clinical judgment which relies on a skilled clinician assessing current function based on 


AD-4833
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CONFIDENTIAL
knowledge of the individual participant’s circumstance and information from a knowledgeable 
informant.
The endpoint of AD dementia will be specified if the participant (after fulfilling dementia criteria 
above) fulfills criteria for possible or probable AD dementia. Possible or probable AD dementia, 
are defined by the NIA/AA criteria [23] and operationalized in this study as follows:

Probable AD:
1. Meets criteria A through E for dementia as noted above AND the following 
characteristics (2-6):
2. A CDR Global score of ≥1.0 will be required in order to set a consistent minimum 
standard for AD dementia as an endpoint in the study.
3. Insidious onset (over months or years, not sudden over hours or days).
4. Clear worsening of cognition across visits—by report or by documented worsening 
upon repeated cognitive test scores or MMSE.
5. Initial and most prominent impairment1 is documented on 1 of the following domains:
a.
Amnestic: Impaired new learning and memory, as evidenced in the clinician 
examination, history, or by impairment on at least 1 of the following subtests:
i. BVMT-R Delayed recall.
ii. CVLT-II, short-delay, free recall.
iii. CVLT-II, long-delay, free recall.
b. Nonamnestic: Impairment on performance on at least 1 test of visuospatial 
ability, language, or executive function: Trails A, Trails B, Digit Span Total, 
MINT, Semantic fluency, Lexical fluency, or Clock Drawing Test; or based on 
observation, or clinical history.
6. Evidence of cognitive dysfunction in at least 1 other domain noted in criteria #4. 
7. Absence of clinical history or laboratory tests that suggest another condition can 
explain the cognitive decline in its entirety. 

Possible AD:
1. Meets criteria for dementia, as defined above and criteria a and b are met:
a.
Initial and most prominent impairment is documented on 1 of the following 
domains: amnestic or nonamnestic, as defined for probable AD and
b. Evidence of cognitive dysfunction in 1 other domain from amnestic or 
nonamnestic domains, as defined for probable AD. 


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
HOWEVER, possible AD is distinguished from probable AD by either of the following 2 
characteristics:

1) Etiology is mixed or complex: presence of medical condition, a neurological 
disease, or medication use that can partially explain the deficits, or
2) Atypical course as determined by the investigator (eg, sudden onset; pronounced 
aphasia), or insufficient historical detail or objective cognitive documentation of 
progressive decline.
If probable or possible AD is confirmed the visit at which the AD dementia diagnosis was made 
will be considered the onset time for the secondary endpoint. Subjects will be referred to standard 
of care and will be considered study completers.
If probable or possible AD or non-AD dementia is not confirmed, subject will remain in the study, 
unless there is a medical reason to withdraw the subject from the study. 
Non-AD dementia: for example, vascular dementia, dementia due to Parkinson disease, 
frontal temporal dementia, or dementia due to other less common causes will be withdrawn 
from the study.
Rationale for Amendment
The amendment adds the requirement of a CDR Global score of ≥1.0 for AD dementia.


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Protected Personal Data

SAP_000.pdf: 
• Named persons or organizations associated with the study.
• Proprietary information, such as scales or coding systems, which are considered confidential information 
under prior agreements with license holder.
• Other information as needed to protect confidentiality of Takeda or partners, personal information, or to 
otherwise protect the integrity of the clinical study. 
Title: A Blinded Long-term Extension Study to Evaluate the Safety and Efficacy of Pioglitazone 
(AD-4833 Sustained Release 0.8 mg Daily) to Slow the Progression of Cognitive Decline in Subjects 
Who Have Completed the AD-4833/TOMM40_301 Study With Diagnosis of Mild Cognitive 
Impairment Due to Alzheimer Disease
NCT Number: NCT02284906
SAP Approve Date: 14 September 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: 


STATISTICAL ANALYSIS PLAN
STUDY NUMBER: AD-4833/TOMM40_303
A Blinded Long-term Extension Study to Evaluate the Safety and Efficacy of Pioglitazone 
(AD-4833 Sustained Release 0.8 mg Daily) to Slow the Progression of Cognitive Decline in 
Subjects Who Have Completed the AD-4833/TOMM40_301 Study With Diagnosis of Mild 
Cognitive Impairment Due to Alzheimer Disease
AD-4833/TOMM40_303 Extension Study of the Safety and Efficacy of Pioglitazone to Slow 
Cognitive Decline in Subjects With Mild Cognitive Impairment Due to Alzheimer Disease
PHASE 3
Version: Final
Date: 14 September 2018
Prepared by:
Based on:
Protocol Version: Amendment 3
Protocol Date: 19 January 2016
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.
Protected Personal Data


AD-4833/TOMM40_303
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CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.


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2.0
TABLE OF CONTENTS
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
List of In-Text Tables............................................................................................................4
List of In-Text Figures...........................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
INTRODUCTION...........................................................................................................6
5.0
OBJECTIVES .................................................................................................................7
5.1
Primary Objectives ....................................................................................................7
5.2
Secondary Objectives.................................................................................................7
5.3
Additional Objectives ................................................................................................7
5.3.1
Safety Objective...................................................................................................7
5.3.2
Exploratory Objectives.........................................................................................7
5.4
Study Design .............................................................................................................8
6.0
ANALYSIS ENDPOINTS.............................................................................................11
6.1
Primary Endpoint.....................................................................................................11
6.2
Secondary Endpoint.................................................................................................11
6.3
Additional Endpoints ...............................................................................................11
6.3.1
Safety Endpoint .................................................................................................11
6.3.2
Exploratory Endpoints .......................................................................................11
7.0
DETERMINATION OF SAMPLE SIZE.......................................................................13
8.0
METHODS OF ANALYSIS AND PRESENTATION...................................................14
8.1
General Principles....................................................................................................14
8.1.1
Summary Statistics and Precision.......................................................................14
8.1.2
Definition of Study Day and Study Visit Windows.............................................14
8.1.3
Imputation of partial/missing AE dates...............................................................16
8.1.4
Statistical Software ............................................................................................17
8.2
Analysis Sets ...........................................................................................................17
8.3
Disposition of Subjects ............................................................................................18
8.4
Demographic and Other Baseline Characteristics.....................................................18
8.5
Medical History and Concurrent Medical Conditions...............................................19
8.6
Medication History and Concomitant Medications...................................................19
8.7
Study Drug Exposure and Compliance.....................................................................19
8.8
Efficacy Analysis.....................................................................................................20
8.8.1
Primary Efficacy Endpoint.................................................................................20


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8.8.2
Secondary Efficacy Endpoint .............................................................................21
8.8.3
Additional Efficacy Endpoint.............................................................................21
8.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................22
8.10
Pharmacogenomic Analysis .....................................................................................22
8.11
Other Outcomes.......................................................................................................22
8.12
Safety Analysis........................................................................................................22
8.12.1 Adverse Events ..................................................................................................22
8.12.2 Clinical Laboratory Evaluations .........................................................................23
8.12.3 Vital Signs .........................................................................................................25
8.12.4 12-Lead ECGs ...................................................................................................25
8.12.5 Magnetic Resonance Imaging (MRI)..................................................................25
8.12.6 Physical and Neurological Examination .............................................................26
8.13
Interim Analysis ......................................................................................................26
8.14
Changes in the Statistical Analysis Plan...................................................................26
9.0
REFERENCES..............................................................................................................27
LIST OF IN-TEXT TABLES
Table 8.a
Visit Windows ...................................................................................................15
Table 8.b
Clinical Laboratory Tests...................................................................................24
LIST OF IN-TEXT FIGURES
Figure 5.a
Schematic of Study Design ................................................................................10
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................28
Appendix B
Criteria for Identification of Markedly Abnormal Laboratory Values .................31
Appendix C
Criteria for Abnormal Changes from Baseline of Vital Signs..............................34
Appendix D 
Criteria for Out-of-Range Values for the 12-Lead ECG Parameters....................35
Appendix E 
Cognitive Test Battery .......................................................................................36


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3.0
LIST OF ABBREVIATIONS
AA 
Alzheimer’s Association
AD
Alzheimer’s Disease
ADCS ADL-MCI
Alzheimer’s Disease Cooperative Study Activities of Daily Living – Mild 
Cognitive Impairment
ADCS CGIC-MCI 
Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change –
Mild Cognitive Impairment
ADCS-RUI
Alzheimer’s Disease Cooperative Study- Resource Use Inventory
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BVMT-R
Brief Visuospatial Memory Test – Revised
CDR-SB 
Clinical Dementia Rating – Sum of Boxes
CDT
Clock Drawing Test
CVLT-II
California Verbal Learning Test – 2nd Edition
ECG
electrocardiogram
eCRF
electronic case report form
EQ-5D
Euro Quality of Life-5D includes single item measures of: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression
GDS
Geriatric Depression Scale
HbA1c
glycosylated hemoglobin
HRQoL
health-related quality of life
MCI
mild cognitive impairment
MCI-AD
mild cognitive impairment due to Alzheimer’s Disease
MedDRA
Medical Dictionary for Regulatory Activities
MINT
Multilingual Naming Test
MRI
magnetic resonance imaging
NIA
National Institute on Aging
NPI-Q
Neuropsychiatric Inventory Questionnaire
PTE
pretreatment event
QD 
once daily
RU
resource utilization
SAE
serious adverse event
SAP
statistical analysis plan
SR
sustained release
TOMM40
translocase of the outer mitochondrial membrane 40 homolog
vMRI
volumetric magnetic resonance imaging
WPAI:MM-CG
Work Productivity and Activity Impairment Questionnaire: Mood and Mental State,
Caregiver Version


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4.0
INTRODUCTION
This document describes the statistical analyses to be performed and data presentations to be
produced for this double-blind, placebo-controlled, multicenter, parallel group long-term 
extension study to further evaluate the efficacy and safety of pioglitazone on cognitive function 
in subjects who have completed the pivotal AD-4833/TOMM40_301 study with an adjudicated 
diagnosis of MCI due to AD (according to the NIA/AA definition [1]).
This study was an extension of Study AD-4833/TOMM40_301 (TOMORROW). The interim 
futility assessment in AD-4833/TOMM40_301 conducted in January 2018 showed that the 
available efficacy data for pioglitazone didn’t meet pre-specified sponsor criteria for 
continuation of AD-4833/TOMM40_301. Therefore, Study AD-4833/TOMM40_301 was 
terminated; and consequently, this study was terminated.
The purpose of this statistical analysis plan (SAP) is to ensure the credibility of the study
findings by specifying the statistical approaches to the analysis of the double-blind data prior to
database lock. It also reflects the impact of the early termination of the study on the analysis 
planned in the protocol. This SAP was developed based on the International Conference on 
Harmonisation (ICH) E3 and E9 Guidelines and in reference to the following document:

ProtAmend-2016-01-19-APP-3---000001.pdf (AD-4833/TOMM40_303 Protocol 
Amendment #3 (Final Version), dated 19 January 2016.)
Any deviations during the analysis and reporting process from the current statistical analysis plan
will be described and justified in the final report. Analysis issues that suggest changes to the
principal features stated in the protocol will be documented in a protocol amendment. Otherwise,
the statistical analysis plan will be updated through an amendment with the changes in the
analyses documented in the amendment.


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5.0
OBJECTIVES
5.1
Primary Objectives

The objective of this study is to evaluate the effect of pioglitazone at 24 months compared 
with placebo on cognitive decline in high-risk subjects who have completed the 
AD-4833/TOMM40_301 study with an adjudicated diagnosis of MCI due to AD.
5.2
Secondary Objectives

To evaluate the effect of pioglitazone compared with placebo on the delay of onset of AD 
dementia in high-risk study subjects.
5.3
Additional Objectives
5.3.1
Safety Objective

To evaluate long-term safety and tolerability of pioglitazone during the course of the 
treatment.
5.3.2
Exploratory Objectives
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
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5.4
Study Design
This is a double-blind, placebo-controlled, multicenter, parallel group long-term extension study. 
The study is designed to further evaluate the efficacy and safety of pioglitazone on cognitive 
function in subjects who have completed the pivotal AD-4833/TOMM40_301 study with an
adjudicated diagnosis of MCI due to AD. Subjects who have an adjudicated diagnosis of MCI 
due to AD in the 301 study and meet the entry criteria described in Protocol [2] Section 7.0, may
be eligible to participate in the 303 extension study depending on their site’s participation in the 
303 study. The treatment assignment from the pivotal study will remain unchanged, that is, 
subjects will continue to receive the same study medication they received during the pivotal 
AD-4833/TOMM40_301 study, either pioglitazone or placebo.
The study participants will be men or women, at least 65 years of age at the time of the extension 
study Baseline Visit. The extension study will follow subjects from the time they complete the 
pivotal AD-4833/TOMM40_301 study for a minimum of approximately 2 years and a maximum 
of approximately 7 years, that is, the extension study will be terminated 2 years after the pivotal 
AD-4833/TOMM40_301 study is concluded, allowing the last subject enrolling into the 
extension study a follow up period of approximately 2 years in the extension study. Although 
MCI due to AD is the primary endpoint event expected in the 301 study, AD dementia is a 
diagnostic event that also counts toward the total needed for that event-driven study; however, 
subjects diagnosed with AD dementia in the pivotal AD-4833/TOMM40_301 study will not be 
eligible to participate in this extension study.
Each subject must have a project partner able to separately consent on his or her own behalf and 
take part in the study to provide information on the cognitive, functional, and behavioral status of 
the subject and to assist with monitoring of study medication, if needed, for as long as the subject 
remains in the study. It is recommended that the same project partner (spouse, adult child, or 
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other person familiar with the participant’s health and daily functioning) participating in the 
pivotal AD-4833/TOMM40_301 study will also participate in the extension study. 
The data collected in the pivotal AD-4833/TOMM40_301 study will be used in the analyses of 
the extension study. This includes results of all cognitive, psychiatric, and medical assessments 
performed at all scheduled pivotal AD-4833/TOMM40_301 study visits and any subsequent 
comprehensive medical follow-up evaluations as stipulated in the pivotal 
AD-4833/TOMM40_301 study protocol. The End of Study Visit of the pivotal 
AD-4833/TOMM40_301 study will serve as the Baseline Visit for the extension study once 
appropriate informed consent is signed, with additional assessments carried out as outlined in 
Protocol Section 6.2. 
A 0.8 mg tablet of SR pioglitazone or placebo will be used in this extension study, the same as 
that used in the pivotal AD-4833/TOMM40_301 study. The tablet will be administered QD for a 
minimum period of 24 months, in accordance with the extension study duration. Study 
medication will be dispensed at the end of the extension study Baseline Visit and subjects will be 
instructed to take the first dose of study medication in the morning on the day following the 
extension study Baseline Visit (if all eligibility criteria are confirmed).
Based on the underlying assumptions, of the approximately 222 potential subjects from both the 
high- (approximately 213 potential subjects) and low-risk (approximately 9 potential subjects) 
arms of the pivotal AD-4833/TOMM40_301 study it is expected that approximately 67% will 
enroll into this extension study (ie, a total of approximately 149 subjects). While it is preferred 
that subjects and their project partners consent to the AD-4833/TOMM40_303 study while 
attending the AD-4833/TOMM40_301 End of Study Visit, subjects will be allowed to return to 
the clinic and consent for the extension study within 1 month of the AD-4833/TOMM40_301 
End of Study Visit, as described in the Schedule of Study Procedures. They will complete the 
AD-4833/TOMM40_303 baseline evaluations (if needed) once informed consent is provided and 
within the 1 month window.
Subjects and their project partners are expected to attend on-site study visits every 6 months after 
Baseline, for regular assessments of safety, efficacy, and treatment compliance. In addition, the 
subject will be contacted for telephone-based safety checks between visits. While it is preferred 
that subject’s project partners attend the on-site study visits, it is not required and they may offer 
their information via telephone. Project partners who voluntarily take part in completion of the 
2 self reported project partner questionnaires (outline in Protocol Section 9.1.14.4), will be 
required to attend the study visits when the questionnaires are obtained. If between in clinic 
visits, worsening of cognitive impairment, potential AD dementia, or a potential safety issue is 
suspected, requiring further evaluation of the subject, an unscheduled clinic visit may be 
conducted as described in Protocol Section 6.2.3. Up to 60 sites globally may participate in this 
study (the same sites that participated in the AD-4833/TOMM40_301 study, although all sites 
may not participate in 303).
The last MRI scan or that obtained at a second consecutive comprehensive medical follow-up 
evaluation in the AD-4833/TOMM40_301 study will serve as the baseline vMRI time point for 
this study. This baseline vMRI scan will be reviewed against the vMRI measure acquired in this 


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extension study. Subjects with contraindications for vMRI assessments will not be excluded 
from the extension study for this reason. 
A schematic of the study design is included as Figure 5.a Schematic of Study Design. A schedule 
of assessments is listed in Appendix A.
Figure 5.a
Schematic of Study Design


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6.0
ANALYSIS ENDPOINTS
6.1
Primary Endpoint 

Change from extension study Baseline to 24 months in the composite score of the cognitive 
test battery. 
6.2
Secondary Endpoint 

Time to diagnosis of AD dementia.
6.3
Additional Endpoints
6.3.1
Safety Endpoint

Safety and tolerability: AEs (including AEs of special interest), vital signs, body weight, 
electrocardiogram (ECG), magnetic resonance imaging (MRI), clinical laboratory data, and 
physical examination findings.
6.3.2
Exploratory Endpoints
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7.0
DETERMINATION OF SAMPLE SIZE
The sample size for this study was not based on statistical considerations. Subjects who have an 
adjudicated diagnosis of MCI due to AD (without a diagnosis of AD dementia) in the pivotal 
AS-4833/TOMM40_301 study may be eligible to enroll into this extension study depending on 
their site’s participation in the 303 study. In the pivotal AD-4833/TOMM40_301 study, 
approximately 222 subjects (approximately 213 high-risk and approximately 9 low-risk subjects) 
are expected to have an event of MCI due to AD or AD dementia. It is expected that 
approximately 149 subjects (ie, 67% of the 222 subjects) will consent to participate in this 
303 extension study.


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8.0
METHODS OF ANALYSIS AND PRESENTATION
8.1
General Principles 
The enrollment to this study has been terminated at the time of the SAP development. Due to 
limited number of enrolled subjects and insufficient treatment duration, all efficacy data will be 
listed without summarization nor analysis.
8.1.1
Summary Statistics and Precision
All study-related raw data for enrolled subjects, including derived data, will be presented in data 
listings. All tabulations of results will include summaries for all three treatment groups: high-risk 
placebo, high-risk pioglitazone, and low-risk placebo.
Disposition, demographic and baseline characteristics, study drug exposure, and safety data will 
be summarized descriptively by treatment groups. 
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation (SD) or standard error (SE) as appropriate, minimum, median, and maximum. 
The number of decimal places displayed for each statistic will be determined as follows:

Mean and median: 1 more than the number of reported decimal places. (For electronic case 
report form (eCRF) data, the number of reported decimal places will be equal to the number 
of decimal places allotted in the eCRF.)

SD and SE: 2 more than the number of reported decimal places allotted in the eCRF.

Minimum and maximum: equal to the number of reported decimal places allotted in the 
eCRF.
For categorical data, frequency counts and percentages will be presented. Percentages will be 
reported to 1 decimal place. In summary tables for categorical data for which categories are 
defined on the eCRF, all categories will be presented as specified, even if the subject count 
within that category is zero. For other categorical data (eg, adverse events), only categories with 
at least 1 subject will be presented.
8.1.2
Definition of Study Day and Study Visit Windows
A windowing convention will be used to determine the analysis value for a given study visit that 
applies to observed data.
Study Day 1 is defined to be the date of the first dose of study medication, which is the day 
following the extension study Baseline Visit (Day -1). Other study days are relative to Study 
Day 1. Relative day is calculated as (date of interest – date of first dose +1) for study days on or 
after the date of first dose and as (date of interest – date of first dose) for study days prior to the 
first dose date.
The assessments performed at the End of Study Visit of the pivotal AD-4833/TOMM40_301 
study are expected to serve as the Baseline for the extension study once appropriate informed 


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consent is signed. However, not all subjects are able to consent for the extension study or to 
complete all extension study baseline visit evaluations at the same time as their End of Study 
Visit for the pivotal AD-4833/TOMM40_301 study. Therefore, the baseline value for a variable 
is defined as the most recent non-missing observation before the first dose of extension study 
medication. 
See Appendix A for list of procedures that will be performed and documented during the 
treatment period. Telephone visits will occur yearly on the 3 month and 9 month interval and 
clinic visits will occur yearly on the 6 month and 12 month interval. For each visit, a window 
will be defined such that the lower and upper bounds of each window is generally the midpoint 
between 2 consecutive study visits. The visit windows and applicable study day ranges are 
presented below in Table 8.a. 
Table 8.a
Visit Windows
Nominal Visit 
Month
Nominal Visit 
Day
vMRI, HbA1c, EQ-
5D, WPAI
Height, ECG, Chemistry, 
Hematology and Urinalysis, 
PE, etc.(b)
All Other 
Variables 
Baseline
-1 (a)
≤1
≤1
≤1
6
183
2—273
12
365
2—547
274—456
18
548
457—638
24
731
548—912
639—821
30
913
822—1003
36
1096
913—1277
1004—1186
42
1278
1187—1369
48
1461
1278—1643
1370—1551
54
1644
1552—1734
60
1826
1644—1917
1735—1917
66/Final (c)
2009
>1
≥1918
≥1918
(a) Consistent with SDTM dataset standards, date of first dose of double-blind study drug is defined as Day 1, and 
the day before is defined as Day –1. Per the protocol, the first dose of double-blind study drug is to be taken the 
morning after the Baseline Visit.
(b) These procedures are performed in a 12 months interval: Height, ECG, Chemistry, Hematology and Urinalysis, 
PE, Pharmacogenomic RNA samples, CVLT-II, BVMT-R, Lexical fluency, Semantic fluency, MINT, Digit span, 
Trail making tests, and Clock drawing. No baseline assessment for Pharmacogenomic RNA samples.
(c) The extension study will be terminated 2 years after the pivotal 301 study is concluded.
For safety variables, visit windows are exhaustive and the lower and upper bounds of each 
window are the midpoints between the scheduled visit days for the current visit and the adjacent 
visits.
More than 1 result for a parameter may be obtained in a visit window. In such an event, the result 
with the date closest to the scheduled visit day will be used. In the event of 2 observations 
equidistant to the scheduled visit day, the later of the observations will be used.


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Adverse events that start more than 30 days after the last dose of double-blind study medication 
(start date – last dose date >30) will be listed, but excluded from the summaries and analyses. 
For other safety data, data that are obtained more than 7 days after the last dose of double-blind 
study medication (visit date – last dose date > 7) will be listed, but excluded from summaries and 
analyses.
If the date of first dose of double-blind study drug collected in the eCRF is missing, then for 
summary purposes the day after the first dispense date will be used as an estimate for the date of 
first dose. However, if all dispensed study drug is returned, then the subject is assumed to have 
not taken any study drug, and the first dose date will not be imputed.
If the date of last double-blind study drug dose collected in the eCRF is missing, then the earliest 
of the following dates will be used for the last dose date for analysis and summary purposes: date 
of death, date of last visit (recorded in the eCRF), last double-blind study drug return date, and 
the last double-blind study drug dispense date (following the last drug return date) + 200 days
(ie, the double-blind study drug dispensing interval corresponding to the number of study drug 
tablets dispensed).
The study window convention will not be applied to the eCRF data listings. The data listings for 
eCRF data will display the raw data as collected and entered in the eCRF. 
8.1.3
Imputation of partial/missing AE dates
8.1.3.1
Imputation of missing or partial dates of AE start dates
The following methods will be used to impute missing or partial dates of AE start dates.

Month/year available and day missing:
–
If the month and year are the same as those in the first dose date and the event is not 
indicated as a pre-treatment event, the first dose date is to be used to impute the AE start 
date.
–
If the month and year are the same as those in the first dose date and the event is 
indicated as a pre-treatment event, the date prior to the first dose date is to be used to 
impute the AE start date. If the date prior to the first dose date is in previous month/year, 
set the start month/year to the previous month/year. 
–
If the month and year are different from those in the first dose date, the first day of the 
month will be used for the start date.

Year available and month/day missing:
–
If the year is the same as the year of the first dose and the event is not indicated as a 
pre-treatment event, the first dose date is to be used to impute the AE start date.
–
If the year is the same as the year of the first dose date and the event is indicated as a 
pre-treatment event, the date prior to the first dose date is to be used to impute the AE 


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start date. If the date prior to the first dose date is in previous month/year, set the start 
month/year to the previous month/year.
–
If the year is not the same as the year of the first dose date, set the start date as January 1.

Year/month/day all missing:
–
If the event is not indicated as a pre-treatment event, the first dose date is to be used to 
impute the AE start date.
–
If the event is indicated as a pre-treatment event, the date prior to the first dose date is to 
be used to impute the AE start date. 
8.1.3.2
Imputation of missing or partial dates of AE end dates
The following methods will be used to impute missing or partial dates of AE end dates.
If the event is indicated as ongoing at the end of the study, no imputation is needed.
If the event is not indicated as ongoing:

Month/year available and day missing:
–
Use the last day of the month to impute the AE end date. If the imputed end date is before 
the AE start date, keep the end date same as the start date. If the subject died, use the date 
of death to impute the end date. 

Year available and month/day missing:
–
If the year is the same as or before the year of the last dose, set the end date as 
December 31.
–
If the year is after the year of the last dose, set the end date as January 1.

Year/month/day all missing:
–
Impute the end date as December 31 of the last dose year. If the imputed end date is 
before the AE start date, keep the end date same as the start date. If the subject died, use 
the date of death to impute the end date. 
8.1.4
Statistical Software
All statistical analyses will be performed using the SAS System® Version 9.2 or higher.
8.2
Analysis Sets
The Safety Analysis Set will include all subjects who were enrolled and received at least 1 dose 
of double-blind study medication in 303. All demographic and safety variables will be analyzed 
using the Safety Analysis Set. In safety summaries, subjects will be analyzed according to the 
actual treatment each subject received. In the event that a subject receives more than one 
treatment, the actual treatment will be defined as the one which is used most frequently. If the 


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two most common treatments are used with equal frequency, then the randomized treatment 
during the pivotal 301 study will be used as the actual treatment.
8.3
Disposition of Subjects
Disposition for all enrolled subjects will be summarized by treatment group and overall.
Disposition categories include: 

Number of enrolled / enrolled but not treated subjects.

Number of subjects completing the study drug/visits.

Number of subjects who prematurely discontinued the study drug/visits.

The primary reason for premature discontinuation of the study drug/visits.
The reasons for premature discontinuation of the study drug and study visits include: 
pretreatment event/adverse event, major protocol deviation, lost to follow-up, voluntary 
withdrawal, study termination, and other.
A summary of baseline failures and listing of inclusion/exclusion criteria responses for subjects 
who failed at least one entrance criterion will be provided.
Significant protocol deviations captured on the electronic Case Report Form (eCRF) will be
listed and summarized. 
8.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics including date of birth or age, gender, Hispanic/Latino 
ethnicity, race as identified by the subject, non-Hispanic/Latino Caucasian determination, years 
of education, primary language, ability to communicate in primary language, bilingualism, years 
lived in the country/region, smoking status, drinking habit, height, weight, body mass index 
(BMI), diabetic status, and baseline statin use will be listed and summarized for each treatment 
group and overall. The demographic and baseline characteristics summary will be based on the 
safety analysis set in the extension AD-4833/TOMM40_303 study. All demographic information 
utilized in this study was collected during the start of the pivotal AD-4833/TOMM40_301 study 
except height and weight, which will be collected at the baseline visit of the extension study.
In countries that do not allow collection of date of birth, a subject’s age will be collected at each 
post-Baseline Study Visit, Unscheduled Visit (as needed), and at the End of Study / Early 
Withdrawal Visit.
Height and weight values will be presented in metric units (cm and kg respectively). BMI is 
calculated as [weight (kg)/height (m) 2], using the weight and height collected at Baseline. 
Race is classified into White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander. In addition, ethnicity (Hispanic or Latino) is 
also captured.


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For continuous variables, the number of non-missing values and the mean, median, SD, 
minimum and maximum will be tabulated by treatment group and overall. For the categorical 
variables, the count and percentages of each possible value will be tabulated by treatment group 
and overall.
All individual demographic and baseline data will be listed by treatment, study center and 
subject number.
8.5
Medical History and Concurrent Medical Conditions
For this extension study, medical history refers to any significant conditions or diseases relevant 
to the disease under study that stopped at or prior to signing of informed consent for the 
extension study, and may include resolved AEs from the pivotal AD-4833/TOMM40_301 study.
AEs that resolved during the pivotal study but were significant, that is, represented a new 
diagnosis (eg, myocardial infarction) and/or resulted in unplanned surgery or procedure 
(eg, coronary artery bypass graft surgery) or met any of the seriousness criteria should be 
recorded into the medical history. Non-serious adverse events such as headache or nausea which 
resolved during the pivotal study do not need to be recorded into the medical history of this 
extension study.
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at baseline examination. The condition (ie, diagnosis) 
should be described. 
Medical history and concurrent medical conditions data will be listed.
8.6
Medication History and Concomitant Medications
Medication history will be obtained during the pivotal AD-4833/TOMM40_301 study, and will 
not be collected during this study. 
Concomitant medication is any drug given in addition to the study medication that the subjects 
continued taking or took from time of Informed Consent through end of study. 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 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF.
The concomitant medications data will be listed.
8.7
Study Drug Exposure and Compliance
The summary of study drug exposure and compliance will be based on the safety analysis set.
Duration of exposure to double-blind study medication is defined as (date of last dose – date of 
first dose + 1). 


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Treatment duration will be summarized by duration category in months and the number of
subjects in each duration category by treatment group.

<6 months (1 to 161 days).

6 to <12 months (162 to 344 days).

12 to <18 months (345 to 526 days).

18 to <24 months (527 to 709 days).

24 to <30 months (710 to 892 days).

30 to <36 months (893 to 1074 days).

36 to <42 months (1075 to 1257 days).

>=42 months (>=1258 days).
Treatment duration (months) will also be summarized using descriptive statistics (n, mean, SD,
median, minimum, and maximum).
Percent of study drug compliance is defined as {(number of tablets dispensed – number of tablets
returned)/(date of last dose – date of first dose +1)}x100%. If a value for the number of returned
tablets is missing or the return date is missing, then 100% compliance will be assigned for each
day up to the number of tablets dispensed, up to the date of return, or up to the date of the last
visit, whichever is earliest.
For each treatment group, study medication compliance will be summarized by compliance
category (<80%, 80 to 120%, and >120%) and the number of subjects in each compliance
category. Study medication compliance will also be summarized as a continuous variable using
descriptive statistics (n, mean, SD, median, minimum, and maximum) for each treatment group.
All study drug administration and accountability data will be listed by treatment, study site, and
subject number. The following variables will be listed: subject identifier, visit, first and last dose
dates, medication identification number, drug dispensed and drug returned dates, number of
tablets dispensed and returned, and percent compliance.
8.8
Efficacy Analysis
Since the enrollment of the extension study was terminated when there were 40 subjects 
enrolled, and very few subjects achieved their 24 months visits (the primary endpoint visit) or 
greater, the efficacy data will only be listed but not summarized due to the lack of enrollment and 
observed data at the time of study termination.
8.8.1
Primary Efficacy Endpoint
The composite score of the cognitive test battery through 24 months will be listed.
The cognitive test battery by domain is described in Appendix E. Composite scores will be 
derived from the test battery consistent with practices used in the pivotal AD-833/TOMM40_301 


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study. Each test in the battery falls into 1 of the following cognitive domains: Episodic Memory 
(CVLT-II, BVMT-R), Executive Function (Trail Making Part B, Digit Span Backwards), 
Language (Animals, Lexical/Phonemic Fluency), Attention (Digit Span Forward, Trail Making 
Part A), and Visuospatial (Clock Drawing, BVMT-Copy). As listed below, only the domains of 
episodic memory, executive function, language, and attention will be used for the calculation of 
composite score (ie, Clock Drawing, BVMT-Copy, and the MINT, which do not allow 
generation of standard z scores, will only be used for diagnostic purposes and will be excluded 
from the calculation of the composite score). 
Episodic Memory domain 
CVLT-II Short-delay free recall correct
CVLT-II Long-delay free recall correct 
BVMT-R Delayed Recall
Executive Function domain
Trail Making (Part B) – Total Seconds
WAIS-III Digit Span – Backward
Language domain
Semantic fluency (animals)
Lexical/phonemic fluency (letters “F-A-S”)
Attention
WAIS-III Digit Span – Forward 
Trail Making Test (Part A) – Total Seconds
To form the composite score, z-scores will be calculated for each test. The z-scores for measures 
in each domain will be averaged to create the four domain scores, and all four domain scores will 
be averaged to form the cognitive battery composite score. Because there are two tests for each 
domain, the domain score can still be calculated if one test is missing. One exception is the case 
of memory domain, where at least one subtest from each of the episodic memory tests (CVLT-II 
and BMVT-R) is required to calculate the composite (ie, BVMT-R Delayed Recall must be 
non-missing; and CVLT-II Short-delay free recall correct and/or CVLT-II Long-delay free recall 
correct must be non-missing). For the calculation of the memory domain score, the following 
3 measures are used (and given equal weight): CVLT-II Short-delay free recall correct, CVLT-II 
Long-delay free recall correct, and BVMT-R Delayed Recall. If any of the domain scores is 
missing, then the composite score is set to missing.
For any visit, the z-score for a measure is calculated by taking the value for the measure at that 
visit, subtracting off the baseline mean for that measure, and then dividing by the baseline 
standard deviation for that measure. The baseline mean and baseline standard deviation for a 
measure will be calculated using all of the non-missing baseline values for subjects in the 
primary efficacy analysis population of high-risk, non-Hispanic/Latino Caucasian subjects.
8.8.2
Secondary Efficacy Endpoint
Time from Day 1 to the visit date that the subject meets the diagnostic criteria for AD dementia 
will be listed.
8.8.3
Additional Efficacy Endpoint
Not applicable.


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8.9
Pharmacokinetic/Pharmacodynamic Analysis
Not applicable.
8.10
Pharmacogenomic Analysis
Pharmacogenomic data will be listed.
8.11
Other Outcomes
Not applicable.
8.12
Safety Analysis
All summaries of safety data are based on subjects in the Safety Analysis Set. Safety endpoints: 
AEs, vital signs, body weight, electrocardiogram (ECG), magnetic resonance imaging (MRI), 
clinical laboratory data, and physical examination findings will be collected and summarized. 
Unless otherwise specified, the safety data will be summarized by treatment group and overall.
8.12.1 Adverse Events
AEs will be reported throughout the study by the subject and/or project partner.
8.12.1.1 Pretreatment Events
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation.
Pretreatment events/ serious events will be summarized by system organ class and preferred 
term.
8.12.1.2 Adverse Events
An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation 
subject administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a drug whether or not it is considered related to the drug.
Treatment-emergent AEs (TEAEs) are any new or worsened events that occurred after the first 
dose of study medication and within 30 days following discontinuation of study medication from 
the subject’s completion of the AD-4833/TOMM40_303 extension study. 
Serious adverse events (SAEs) with onset that occurs after receiving study drug and within 
30 days after receiving the last dose of study drug will be summarized.
All adverse events will be included in the data listings but only treatment-emergent adverse 
events will be included in the summary tables. AEs will be coded using MedDRA and will be 


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summarized by system organ class and preferred term. AEs that were reported more than once by 
a subject during the same period will be counted only once for that subject and period at the 
maximum severity. AEs with missing severity will be classified as having the highest severity. 
AEs with missing relationship will be classified as being related to study drug.
The following summaries will be presented:

Overview of TEAEs during the study.

TEAEs by SOC and preferred term.

TEAEs by SOC and preferred term by gender (male and female).

TEAEs by SOC and preferred term by age group (<75, >=75).

Relationship of TEAEs to study drug by SOC, and preferred term. 

Intensity of TEAEs by SOC and preferred term.

Drug-related TEAEs by SOC and preferred term.

Intensity of drug-related TEAEs by SOC and preferred term.

TEAEs leading to study discontinuation by SOC and preferred term.

Treatment-emergent SAEs by SOC and preferred term.

Most frequent TEAEs and non-serious TEAEs (>=5% based on total number of safety set
subjects in any treatment group) by SOC and preferred term.

Standardized MedDRA quaries (SMQs) and Takeda MedDRA quaries (TMQs) were used to 
determine the following adverse events of special interest (AESIs):
–
Congestive Heart Failure.
–
Macular Edema.
–
Hepatic Effects.
–
Bone Fractures.
–
Bladder Cancer.
–
Hypoglycemic Events.
The following listings of information from the liver function test eCRF pages will also be 
presented: Study drug interruption, signs and symptoms, event history, test results and reports, 
and additional comments.
8.12.2 Clinical Laboratory Evaluations
Table 8.b is a list of all protocol-specified clinical laboratory tests. The central laboratory will
perform laboratory tests for serum chemistries, hematology, and urinalysis. All laboratory test 
parameters will be displayed in individual subject data listings in SI units.


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For each laboratory parameter, the following will be displayed for each scheduled time point
(each visit and end of study):

Summary statistics by treatment group and overall for the actual values and 
change-from-Baseline values.

Shift tables for the change from Baseline to each post-baseline time point will be presented.

Markedly abnormal values for laboratory parameters, as defined in Appendix B, will be 
summarized by treatment group and overall. 
Listings of all laboratory data will be provided. Laboratory data outside of the normal reference
range will be flagged on the listings along with values meeting MAV criteria. The listings will 
also include the age (at consent) and gender of the subject. Listings of MAV laboratory values 
will also be presented. Direct bilirubin and rapid plasma reagin (RPR) will not be summarized 
but will be listed.
Table 8.b
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis (c)
Red blood cells
White blood cells count with 
differentials
(Neutrophils, eosinophils, basophils, 
lymphocytes, monocytes)
Hemoglobin
Hematocrit
Platelets
HbA1c (b)
ALT
Alkaline phosphatase
AST 
Total bilirubin
Direct bilirubin (a)
Total protein
Albumin
Creatinine
Blood urea nitrogen
γ-Glutamyl transferase
Potassium
Sodium
Glucose
Calcium, 
Parathyroid hormone
Thyrotropin, free T4
Vitamin B12, folate (d)
Rapid plasma reagin (e)
pH
Specific gravity
Protein
Glucose
Blood
Nitrite
(a) Assess only if total bilirubin ≥2.0 mg/dL.
(b) To be done at Baseline and at the End of Study Visit.
(c) Microscopic examination (leucocytes, erythrocytes, and casts) should be performed only if any of the urine 
evaluations are abnormal.
(d) As part of the Unscheduled Visit to rule out other causes of dementia.
(e) At End of Study only.
If a lab test with quantitative results has a value that is reported using a non-numeric qualifier 
(eg, less than (<) a certain value, or greater than (>) a certain value), the given numeric value will 
be used in the summary statistics, ignoring the non-numeric qualifier. However, these values will 
be displayed as is when the individual subject data listings are presented.


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8.12.3 Vital Signs
Within the extension study, vital signs will be measured at each 6-month, and yearly in-clinic 
visit of double-blind treatment, Unscheduled Visit and at the End of Study Visit/Early 
Withdrawal Visit. 
Vital signs include body temperature, sitting blood pressure, and pulse. Vital signs and weight at 
scheduled visits and their changes from Baseline will be summarized for each treatment group 
and overall using descriptive statistics by visit and end of study. The number and percentage of 
subjects with at least one post-Baseline MAV vital sign value during the double-blind treatment 
period will be presented for each variable over all visits. A listing of MAV vital signs values will 
also be presented. The criteria for identification of MAV vital signs values are provided in 
Appendix C.
8.12.4 12-Lead ECGs
ECG will be recorded at each yearly visit (eg, Month 12, 24) of double-blind treatment, and End 
of Study Visit/Early Withdrawal Visit. 
ECG variables at scheduled visits and their changes from Baseline will be summarized for each
treatment group and overall using descriptive statistics by study visit and end of study. A shift 
table for the investigator’s ECG interpretation will provide the number of subjects in each of the 
appropriate categories (Normal, Abnormal but not clinically significant, or Abnormal and 
clinically significant) at the scheduled visit relative to the Baseline status. The number and 
percentage of subjects with at least one post-Baseline MAV ECG value during the blind
treatment period will be presented for each variable over all visits. A listing of MAV ECG values
will also be presented. The criteria for identification of MAV ECG values are provided in 
Appendix D.
8.12.5 Magnetic Resonance Imaging (MRI)
Subjects enrolled in the extension study will be required (unless medically contraindicated) to 
participate in a vMRI scan where volumetric measurements will be taken, for the purpose of 
assessing atrophy of the brain. vMRI scans will take place at extension study Baseline (last MRI 
collected at End of Study Visit or second comprehensive medical follow-up visit for the pivotal 
AD-4833/TOMM40_301 study) and at extension study End of Study/Early Withdrawal Visit.
The following volumetric measurements will be determined on MRI scans obtained at Baseline 
and End of Study/Early Withdrawal Visits of all subjects:

Left and Right Hippocampus Volume (baseline/Visit 1 only).

Ventricle Volume (baseline/Visit 1 only).

Whole Brain Volume (baseline/Visit 1 only).

Hippocampal Atrophy (End of Study/Early Withdrawal Visit).

Ventricular Enlargement (End of Study/Early Withdrawal Visit).


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
Whole Brain Atrophy (End of Study/Early Withdrawal Visit).
The possible categories for the MRI interpretation results recorded in the CRF are: Within 
Normal Limits; Abnormal, Not Clinical Significant; and Abnormal, Clinical Significant. All
MRI scan interpretation results will be presented in the listings.
8.12.6 Physical and Neurological Examination
A baseline physical and neurological examination having been conducted as part of the End of 
Study Visit for the pivotal AD-4833/TOMM40_301 study, will serve as baseline data for the 
extension AD-4833/TOMM40_303 study. Physical examination will be performed at each yearly 
visit (eg, Month 12, 24) of double-blind treatment, Unscheduled Visit, and End of Study 
Visit/Early Withdrawal Visit. Neurological examination will be performed at every 6 month visit 
and yearly visit, during double-blind treatment, Unscheduled Visit, and End of Study Visit/Early 
Withdrawal Visit. All physical and neurological examination findings will be listed by treatment, 
study center and subject number.
8.13
Interim Analysis
Not applicable.
8.14
Changes in the Statistical Analysis Plan 
For the efficacy analysis, the primary null hypothesis in the study protocol assumes that there is 
no difference in the cognitive decline of MCI due to AD between the placebo-treated and 
active-treated subjects in the high risk group. The alternative hypothesis is that there is a 
difference in cognitive decline between pioglitazone and placebo in the high-risk group. In order 
to test the primary null hypothesis, the change in the composite cognitive test battery score from
extension study baseline to 24 months will be analyzed using mixed models repeated measures 
(MMRM), controlling for age group, educational level, study site, and sex. If this test is 
significant at the 5% level, it can be concluded that pioglitazone was effective in reducing the 
change in cognitive decline in subjects with a diagnosis of MCI due to AD at Baseline. For the 
time to onset of AD dementia secondary endpoint, time-to-event data will be analyzed to 
compare the placebo and active groups using a Cox proportional hazards model, including an 
investigation of the effects of covariates (including age, educational level, study site, and sex).
The other efficacy endpoints will be analyzed in a manner similar to the primary efficacy 
endpoint and using MMRM. However, due to limited number of enrolled subjects and 
insufficient treatment duration, all the efficacy analysis will not be performed as planned.


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9.0
REFERENCES
1. Albert MS, Dekosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis 
of mild cognitive impairment due to Alzheimer's disease: Recommendations from the 
National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for 
Alzheimer's disease. Alzheimers Dement 2011;7(3):270-9.
2. A Blinded Long-term Extension Study to Evaluate the Safety and Efficacy of Pioglitazone 
(AD-4833 Sustained Release 0.8 mg Daily) to Slow the Progression of Cognitive Decline in 
Subjects Who Have Completed the AD-4833/TOMM40_301 Study With Diagnosis of Mild 
Cognitive Impairment Due to Alzheimer Disease. AD-4833/TOMM40_303 Extension Study 
of the Safety and Efficacy of Pioglitazone to Slow Cognitive Decline in Subjects With Mild 
Cognitive Impairment Due to Alzheimer Disease. Takeda Development Center Americas, 
Inc., Protocol No. AD-4833/TOMM40_303, Amendment #3, dated 19 January, 2016.


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Appendix A
Schedule of Study Procedures
Baseline
(Coincides 
With 301 End 
of Study Visit 
(a)
Unscheduled 
Visit (b)
End of Study 
Visit/Early 
Withdrawal (c)
Follow-up Visit
Month
0 (Day -1)
Repeated Yearly
EoS/EW+0.5 (e)
3 (d)
6
9 (d)
12
Visit Window
+30 days
±2 
wks
±2 
wks
±2 
wks
±2 
wks
Informed consent 
(subject)
X
Informed consent 
(pharmacogenomic)
X
Informed consent 
(project partner)
X
Incl/excl criteria
X
Medical history
X
Concurrent conditions
X
Body weight and 
height(g)
X (f)
X
X
X
Review of concurrent 
medications
X
X
X
X
X
X
X
X
Contact IWRS
X
X
X
X
Dispense study drug
X
X
X
Collect study drug
X
X
X
Compliance review
X
X
X
X
X
AEs (including AEs of 
Special Interest)
X (f)
X
X
X
X
X
X
X
Physical examination
X (f)
X
X
X
Vital signs
X (f)
X
X
X
X
Neurological 
examination
X (f)
X
X
X
X
12-lead ECG
X (f)
X
X
vMRI (h)
X (f)
X
Clinical chemistry, 
hematology and 
urinalysis labs
X (f)
X
X (i)
X
HbA1c test (j)
X
X
Pharmacogenomic RNA 
samples
X
X (k)
X (l)
C-SSRS
X (f)
X
X
X
X
Diet and exercise 
evaluation
X (f)
X
X
X
MMSE (d)
X (f)
X
X
X


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Baseline
(Coincides 
With 301 End 
of Study Visit 
(a)
Unscheduled 
Visit (b)
End of Study 
Visit/Early 
Withdrawal (c)
Follow-up Visit
Month
0 (Day -1)
Repeated Yearly
EoS/EW+0.5 (e)
3 (d)
6
9 (d)
12
CVLT-II
X (f)
X
X
BVMT-R
X (f)
X
X
Lexical fluency
X (f)
X
X
Semantic fluency
X (f)
X
X
MINT
X (f)
X
X
Digit Span
X (f)
X
X
Trail Making Tests
X (f)
X
X
Clock Drawing
X (f)
X
X
GDS
X (f)
X
X
X
CDR
X (f)
X
X
X
X
ADCS ADL- MCI
X
X
X
X
NPI-Q
X (f)
X
X
X
ADCS CGIC-MCI
X
X
X
X(m)
X
ADCS RUI
X (f)
X
X
X
EQ-5D (subject) (n)
X (f)
X
EQ-5D (project partner) 
(n)
X
X
WPAI(n)
X
X
EoS=End of Study, EW=Early Withdrawal.
(a) Subjects who are unable to consent for the extension study or to complete all extension study baseline visit evaluations at the 
same time as their End of Study Visit for the pivotal AD-4833/TOMM40_301 study will be allowed to return to the clinic and to 
complete these evaluations within a 1 month window.
(b) Procedures listed should be conducted in the event of an Unscheduled Visit for suspected cognitive or functional decline.
Procedures related to Unscheduled Visits for any other emerging concern, such as safety, are at the discretion of the investigator. 
(c) End of Study/Early Withdrawal Visit is an ad hoc visit that, for study completion, would take place as soon as possible after a
regularly scheduled or unscheduled study visit, either at study end, at extension study termination, after a subject has withdrawn
prematurely from the study or after the subject has been diagnosed with AD or non-AD dementia. The efficacy assessments will 
not need to be captured at this visit in cases where the secondary endpoint of AD dementia diagnosis has been reached or if it is 
less than 3 months from the last administration of the assessment.
(d) Telephone contact with the subject (should be every 3 months between the semiannual clinic visits for the duration of the
study).
(e) Telephone call approximately 2 weeks after the End of Study or Early Withdrawal Visit. 
(f) These assessments, conducted as part of the end of study visit for the pivotal AD-4833/TOMM40_301 study or at most recent 
comprehensive medical Follow-up Visit, will serve as baseline data for the extension AD-4833/TOMM40_303 study.
(g) Height will only be collected at the end of study visit for the pivotal AD-4833/TOMM40_301 study or at most recent 
comprehensive medical Follow-up Visit, and will serve as baseline data for the extension AD-4833/TOMM40_303 study.
(h) vMRI assessments will take place at extension study Baseline (ie, coinciding with the End of Study Visit for the pivotal 
AD-4833/TOMM40_301 study or most recent MRI or that obtained at the second consecutive comprehensive medical follow-up 
Visit) and at extension study end. 
(i) Standard blood chemistry and tests used in evaluating cognitively impaired and dementia patients (eg, thyroid profile, vitamin 
B12).
(j) A blood sample will be collected at the extension Baseline Visit and End of Study/Early Withdrawal Visit for HbA1c testing.
(k) If an Unscheduled Visit is conducted, RNA samples will be collected during this visit. In this instance, RNA samples will not 


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need to be collected at the End of Study/Early Withdrawal Visit.
(l) RNA samples will only be collected at the End of Study/Early Withdrawal Visit if samples were not collected at an 
Unscheduled Visit. 
(m) ADCS CGIG-MCI will only need to be administered if it occurs greater than 3 months from the last administration of this
assessment.
(n) EQ-5D will be completed by subject at Month 24 and at End of Study in the extension study and the EQ-5D and WPAI will 
be completed by project partner at Baseline, Month 24 and End of Study.


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Appendix B
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Low Abnormal
High Abnormal
Red blood cells
<0.8 x LLN
>1.2 x ULN
White blood cells
<0.5 x LLN
>1.5 x ULN
Neutrophils
<0.5 x LLN
>1.5 x ULN
Eosinophils
--
>2 x ULN
Basophils
--
>3 x ULN
Lymphocytes
<0.5 x LLN
>1.5 x ULN
Monocytes
--
>2 x ULN
Hemoglobin
<0.8 x LLN
>1.2 x ULN
Hematocrit
<0.8 x LLN
>1.2 x ULN
Platelets (conventional)
<75 x 103/L
>600 x 103/L
Platelets (SI)
<75 x 109/L
>600 x 109/L
HbA1c (conventional)
--
>7%
HbA1c (SI)
--
>0.07


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Chemistry—Criteria for Markedly Abnormal Values
Parameter
Low Abnormal
High Abnormal
ALT
--
>3 x ULN
Alkaline phosphatase
--
>3 x ULN
AST
--
>3 x ULN
Total bilirubin (conventional)
--
>2.0 mg/dL
Total bilirubin (SI)
--
>34.2 mol/L
Direct bilirubin
--
>2 x ULN
GGT
--
>3 x ULN
Total protein
<0.8 x LLN
>1.2 x ULN
Albumin (conventional)
<2.5 g/dL
--
Albumin (SI)
<25 g/L
--
Creatinine (conventional)
--
>2 mg/dL
Creatinine (SI)
--
>177 mol/L
Blood urea nitrogen (conventional)
--
>30 mg/dL
Blood urea nitrogen (SI)
--
>10.7 mmol/L
Potassium (conventional)
<3.0 mEq/L
>6.0 mEq/L
Potassium (SI)
<3.0 mmol/L
>6.0 mmol/L
Sodium (conventional)
<130 mEq/L
>150 mEq/L
Sodium (SI)
<130 mmol/L
>150 mmol/L
Glucose (conventional)
<50 mg/dL
>350 mg/dL
Glucose (SI)
<2.8 mmol/L
>19.4 mmol/L
Calcium (conventional)
<7.0 mg/dL
>11.5 mg/dL
Calcium (SI)
<1.75 mmol/L
>2.88 mmol/L
Thyroid Stimulating Hormone (TSH)
<0.8 x LLN
>2.0 x ULN
Vitamin B12 (conventional)
<125 pg/mL
--
Vitamin B12 (SI)
<92 pmol/L
--
Folate (conventional)
<2.2 pg/dL
>17.5 pg/dL
Folate (SI)
<5.0 nmol/L
>39.7 nmol/L
Parathyroid hormone (PTH)
<0.8 x LLN
>2.0 x ULN
Free thyroxine (Free T4)
<0.8 x LLN
>2.0 x ULN
Rapid plasma reagin (RPR)
positive
positive
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, N/A=not applicable, ULN=upper limit of normal.


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Urinalysis—Criteria for Markedly Abnormal Values
Parameter
Low Abnormal
High Abnormal
pH
N/A
N/A
Specific Gravity
N/A
N/A
Protein
N/A
N/A
Glucose
N/A
N/A
Blood
N/A
N/A
Nitrite
N/A
N/A


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Appendix C
Criteria for Abnormal Changes from Baseline of Vital Signs
Vital Sign
Criterion Value
Change Relative to Baseline
Systolic arterial blood pressure
>180 mm Hg
Increase of 20 mm Hg
<85 mm Hg
Decrease of 20 mm Hg
Diastolic arterial blood pressure
>110 mm Hg
Increase of 15 mm Hg
<50 mm Hg
Decrease of 15 mm Hg
Pulse
>120 bpm
<50 bpm
Body Temperature
>37.7 degrees Celsius
<35.6 degrees Celsius
Weight
Change of greater than 7% body weight
Both the criterion value and the change from Baseline must be met.


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Appendix D
Criteria for Out-of-Range Values for the 12-Lead ECG Parameters
Criteria
ECG Parameter
Lower Criteria
Upper Criteria
Heart Rate
<50 bpm
>120 bpm
QT Interval
<280 msec
460 msec
QTc Interval
<340 msec
500 msec OR
450 msec and 30 msec
change from baseline


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Appendix E
Cognitive Test Battery
Cognitive Domain
Tests*
Episodic Memory
California Verbal Learning Test – 2nd Edition (CVLT-II)
Brief Visuospatial Memory Test – Revised (BVMT-R)
Executive Function
Trail Making Test (Part B)
WAIS-III Digit Span Test – backwards span
Language
Multilingual Naming Test (MINT)**
Semantic Fluency (animals)
Lexical/phonemic Fluency (letters “F-A-S”)
Attention
WAIS-III Digit Span Test – forward span
Trail Making Test (Part A)
Visuospatial
Clock Drawing Test (CDT)**
Copy of BVMT-R figures**
* Note: There are 12 measures derived from 8 neuropsychological tests in the battery: The CVLT-II test involves 
2 primary measures (ie, short delay recall, and long delay recall); BVMT-R has 2 measures (ie, copy and recall); 
Digit Span has 2 measures (ie, forward and backward span); and Trails has 2 measures (ie, Parts A and B). There is 
one total score for each of the remaining tests: clock drawing, MINT, animal fluency and lexical fluency. 
**Clock Drawing, BVMT-Copy, and the MINT, which do not allow generation of standard z scores will only be 
used for diagnostic purposes and will be excluded from the calculation of the composite score.


 
  
 
 
 
 
 
 
 
 
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