Clinical trial NCT01931566
Conditions: Mild Cognitive Impairment Due to Alzheimer's Disease
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2013-08-01; Completion date: 2018-09-06
Enrollment: 3494 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to qualify the biomarker risk algorithm for prognosis of the risk of developing Mild Cognitive Impairment due to Alzheimer's Disease (MCI-AD), and also to evaluate the efficacy of pioglitazone compared with placebo to delay the onset of MCI-AD in cognitively-normal participants who are at high-risk for developing MCI within 5 years.

Detailed description:
This study has two goals. One of these goals is to see if a new genetic test can determine if participants are at risk of developing Mild Cognitive Impairment due to Alzheimer's Disease (MCI-AD) within the next five years. The other goal is to evaluate the study drug called pioglitazone. Pioglitazone is being tested to delay the onset of MCI-AD. This study will look at the effectiveness of pioglitazone in delaying the onset of MCI-AD in cognitively-normal people who are at high-risk of developing MCI-AD, as identified by the biomarker in the non-Hispanic/Latino Caucasian participants.

This multi-centre trial will be conducted worldwide. The study will enroll approximately 3500 subjects. Participants will be assigned to high or low risk groups for developing MCI- AD within the next five years, based on the results of the biomarker risk algorithm. Participants in the high risk group will be randomly assigned to one of the two treatment groups-which will remain unknown to the participant and study doctor during the study (unless there is an urgent medical need):

* Pioglitazone tablet
* Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient.

Participants in the low risk group will be assigned to placebo. The assignment of each participant to the high or low risk group, as well as the participant's treatment assignment, will remain undisclosed to the participants and study doctor during the study (unless there is an urgent medical need).

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

The overall time to participate in this study is approximately 5 years. Participants will make up to 14 visits 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 placebo-matching tablets, orally, once daily to participants assigned to low risk group for developing MCI-AD for up to 5 years. arm 2: Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years. arm 3: Pioglitazone 0.8 mg, sustained release (SR) tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.
Interventions: intervention 1: Pioglitazone intervention 2: Pioglitazone placebo
Intervention descriptions: intervention 1: Pioglitazone SR tablets intervention 2: Pioglitazone placebo-matching tablets

Protocol documents:
Prot_000.pdf: 


•
Title: A Double Blind, Randomized, Placebo Controlled, Parallel Group Study to Simultaneously 
Qualify a Biomarker Algorithm for Prognosis of Risk of Developing Mild Cognitive Impairment 
due to Alzheimer’s Disease (MCI due to AD) and to Test the Safety and Efficacy of Pioglitazone 
(AD-4833 SR 0.8 mg QD) to Delay the Onset of MCI due to AD in Cognitively Normal Subjects
NCT Number: NCT01931566
Protocol Approve Date: 27 September 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 (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PROTOCOL
A Double Blind, Randomized, Placebo Controlled, Parallel Group Study to Simultaneously 
Qualify a Biomarker Algorithm for Prognosis of Risk of Developing Mild Cognitive 
Impairment due to Alzheimer’s Disease (MCI due to AD) and to Test the Safety and 
Efficacy of Pioglitazone (AD-4833 SR 0.8 mg QD) to Delay the Onset of MCI due to AD in 
Cognitively Normal Subjects
Biomarker Qualification for Risk of MCI due to AD and Safety and Efficacy Evaluation of 
Pioglitazone (AD-4833 SR 0.8 mg QD) in Delaying its Onset
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015
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_301
IND Number:
112,403
EudraCT Number:
2012-003111-58
Compound:
AD-4833
Date:
27 September 2016
Amendment Number:
6
Amendment History: 
Date
Amendment Number
Amendment Type
Region
07 February 2013
Initial Protocol
Not applicable
Global
09 April 2013
1
Substantial
Global
19 March 2014
2
Substantial
Global
10 November 2014
3
Substantial
Global
15 April 2015
4
Substantial
Local-Russia
24 July 2015
5
Substantial
Global
27 September 2016
6
Substantial
Global
Document generated using Protocol Phase 2-4 Template, G-TMPL-RD-005 Version: 03
CONFIDENTIAL PROPERTY OF TAKEDA


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This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
TDC sponsored European and Asian Pacific investigators 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
European 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)
PPD


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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
PPD


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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 6 Summary of Changes 
This document describes the changes in reference to the Protocol Incorporating Amendment 
No. 6.
The primary purpose of this amendment is to update the protocol regarding revisions to plans for 
the Futility Analysis as well as to introduce adjustments to the protocol that will help reduce 
subject burden. Full details on changes of text are given in Appendix J. The following is a 
summary of the key changes made in the amendment:
1. The efficacy futility analysis has been revised to occur once 33% of events have accrued, 
rather than at 50%.
Justification: This change will reduce the time to an initial assessment of futility, protecting 
study subjects and the Sponsor from continuation of an ultimately futile study, while keeping 
the risk of a futility ‘false negative’ finding at an acceptably low probability. (Pivotal study 
futility analyses are commonly performed with 25-50% of the final planned number of 
events.)
2. An “operational futility” analysis has been added. This will enable an assessment of whether 
the study can feasibly be completed within an acceptable timeframe, based on the accrual 
rate of adjudicated cases meeting the event definition.
Justification: Given the low but steady dropout rate projected and observed, a delay in study 
completion could lead to an overall dropout rate greater than 50%, potentially making
interpretation of the study data difficult, even if the formal primary efficacy analysis is 
positive. In addition, a multi-year delay in study completion increases the risk that the study 
could yield less relevant results with continued developments in Alzheimer disease (AD) 
diagnosis and treatment.
3. The timing of required magnetic resonance imaging (MRI) scans has been clarified as well as 
removing the requirement to perform an MRI scan if a scan has been performed for the study 
within the preceding 6 months.
Justification: These changes have been implemented to remove ambiguity over the required 
timing of MRI scans as well as to eliminate a requirement for unnecessary scans from being 
performed, thereby reducing burden on sites and subjects.
4. Additional options for the performance of the Comprehensive Medical Follow-Up Visit have 
been introduced, including the ability to perform assessments during routine Month 6 or 
Month 12 visits in certain situations and during Home Visits or by telephone (for project 
partners) in exceptional circumstances.
Justification: These adjustments have been made to provide greater flexibility to sites and 
subjects in scheduling these visits. In exceptional circumstances, sites will now have the 
ability to perform selected assessments at a subject’s home or by telephone, with prior 


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approval of the Sponsor. This modification has been made to help mitigate the risk of critical 
primary endpoint related data not being collected due to challenges associated with 
conducting the study with an elderly population in which subjects approaching endpoint are 
repeatedly triggering which requires additional visits, increasing subject burden and study 
fatigue. 
5. Microscopic urine screens will be standard on all urine sample collections at routine visits 
rather than as a reflex in the event of abnormalities detected on macroscopic examination.
Justification: This change has been made to eliminate the need for additional site visits, 
which will decrease subject burden.
6. Formal limits for assessment of compliance with study drug have been introduced.
Justification: Limits have been introduced to the protocol to help facilitate consistency in 
global monitoring and reporting of subjects that are not compliant with administration of 
study drug.
7. Clarification provided over Adverse Event of Special Interest (AESI) follow-up and 
reporting of macular degeneration and hypoglycemia.
Justification: Clarification provided to ensure consistency in follow-up of macular edema and 
to eliminate ambiguity over reporting of hypoglycemia as an AESI, ensuring consistency 
across all subjects.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................3
1.1
Contacts.....................................................................................................................3
1.2
Approval....................................................................................................................4
1.3
Protocol Amendment 6 Summary of Changes............................................................6
2.0
STUDY SUMMARY ....................................................................................................14
3.0
STUDY REFERENCE INFORMATION ......................................................................18
3.1
Study-Related Responsibilities.................................................................................18
3.2
Principal Investigator/Coordinating Investigator ......................................................18
3.3
List of Abbreviations ...............................................................................................19
3.4
Corporate Identification...........................................................................................22
4.0
INTRODUCTION.........................................................................................................23
4.1
Background .............................................................................................................23
4.2
Rationale for the Proposed Study.............................................................................25
4.2.1
Genetic Risk Factors for AD ..............................................................................26
4.2.2
Pioglitazone .......................................................................................................29
4.2.3
Mild Cognitive Impairment due to Alzheimer’s Disease (MCI due to AD).........30
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................33
5.1
Objectives................................................................................................................33
5.1.1
Primary Objectives.............................................................................................33
5.1.2
Key Secondary Objectives .................................................................................33
5.1.3
Additional Objectives.........................................................................................33
5.2
Endpoints.................................................................................................................34
5.2.1
Primary Endpoints .............................................................................................34
5.2.2
Key Secondary Endpoints ..................................................................................34
5.2.3
Additional Endpoints .........................................................................................34
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................36
6.1
Study Design ...........................................................................................................36
6.2
Subject Flow based on Neuropsychological and Functional Assessments.................39
6.2.1
Assessments at Screening Visit (Visit 1) ............................................................39
6.2.2
Assessments at Baseline (Visit 2).......................................................................40
6.2.3
Assessments at Randomization (Visit 3).............................................................40
6.2.4
Assessments after Randomization ......................................................................40


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6.3
Justification for Study Design, Dose, and Endpoints ................................................46
6.3.1
Study Design......................................................................................................46
6.3.2
Study Dose.........................................................................................................47
6.3.3
Study Endpoints.................................................................................................47
6.4
Premature Termination or Suspension of Study or Investigational Site.....................48
6.4.1
Criteria for Premature Termination or Suspension of the Study..........................48
6.4.2
Criteria for Premature Termination or Suspension of Investigational Sites .........48
6.4.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................48
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............50
7.1
Inclusion Criteria .....................................................................................................50
7.2
Exclusion Criteria ....................................................................................................50
7.3
Excluded Medications and Treatments.....................................................................52
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................54
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................56
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................57
8.1
Study Medication and Materials...............................................................................57
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................57
8.1.2
Storage...............................................................................................................57
8.1.3
Dose and Regimen .............................................................................................58
8.1.4
Overdose............................................................................................................58
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................58
8.3
Randomization Code Creation and Storage..............................................................59
8.4
Investigational Drug Blind Maintenance ..................................................................60
8.5
Unblinding Procedure..............................................................................................60
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................60
9.0
STUDY PLAN ..............................................................................................................63
9.1
Study Procedures.....................................................................................................63
9.1.1
Informed Consent Procedure..............................................................................63
9.1.2
Demographics, Medical History, and Medication History Procedure..................64
9.1.3
Physical Examination Procedure ........................................................................64
9.1.4
Weight, Height...................................................................................................64
9.1.5
Vital Sign Procedure..........................................................................................65
9.1.6
Documentation of Concomitant Medications......................................................65


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9.1.7
Documentation of Concurrent Medical Conditions.............................................65
9.1.8
Procedures for Clinical Laboratory Samples.......................................................65
9.1.9
Pregnancy ..........................................................................................................67
9.1.10 ECG Procedure..................................................................................................67
9.1.11 Genotyping ........................................................................................................67
9.1.12 Pharmacokinetic Sample Collection and Analysis ..............................................69
9.1.13 Documentation of Screen Failure and Baseline Failure.......................................71
9.1.14 Documentation of Randomization......................................................................71
9.1.15 Assessments.......................................................................................................72
9.1.16 Assessment of Suicidal Ideation and Behavior ...................................................76
9.1.17 Order of Assessments.........................................................................................77
9.1.18 Tester Monitoring Management Program...........................................................79
9.1.19 Tester Qualification and Certification.................................................................79
9.1.20 Health Economics and Outcomes Research Assessments ...................................79
9.1.21 Imaging..............................................................................................................79
9.1.22 Diet and Exercise Evaluation .............................................................................80
9.2
Monitoring Subject Treatment Compliance..............................................................80
9.3
Schedule of Observations and Procedures................................................................81
9.3.1
Screening...........................................................................................................81
9.3.2
Baseline .............................................................................................................81
9.3.3
Randomization...................................................................................................81
9.3.4
Treatment Phase.................................................................................................81
9.3.5
Unscheduled Visit..............................................................................................82
9.3.6
Final Visit or Early Termination.........................................................................82
9.3.7
Follow-up ..........................................................................................................82
9.3.8
Post Study Care..................................................................................................83
9.4
Biological Sample Retention and Destruction ..........................................................83
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................84
10.1
Definitions...............................................................................................................84
10.1.1 PTEs..................................................................................................................84
10.1.2 AEs....................................................................................................................84
10.1.3 Additional Points to Consider for PTEs and AEs................................................84
10.1.4 SAEs..................................................................................................................86
10.1.5 AESIs ................................................................................................................87


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10.1.6 Severity of PTEs and AEs..................................................................................87
10.1.7 Causality of AEs ................................................................................................88
10.1.8 Relationship to Study Procedures.......................................................................88
10.2
Procedures...............................................................................................................88
10.2.1 Collection and Reporting of AEs........................................................................88
10.2.2 Collection and Reporting of SAEs......................................................................91
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................92
10.3
Follow-up of SAEs ..................................................................................................92
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....92
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................94
11.1
Neuropsychology Advisory Board ...........................................................................94
11.2
Data Safety Monitoring Board .................................................................................94
11.3
Cognitive Impairment Adjudication Committee.......................................................94
12.0
DATA HANDLING AND RECORDKEEPING............................................................95
12.1
(e)CRFs ...................................................................................................................95
12.2
Record Retention .....................................................................................................95
13.0
STATISTICAL METHODS..........................................................................................97
13.1
Statistical and Analytical Plans ................................................................................97
13.1.1 Analysis Sets......................................................................................................97
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................97
13.1.3 Efficacy Analysis...............................................................................................97
13.1.4 Pharmacokinetic Analysis ..................................................................................99
13.1.5 Other Analysis ...................................................................................................99
13.1.6 Safety Analysis ..................................................................................................99
13.2
Futility Analysis and Criteria for Early Termination ..............................................100
13.3
Determination of Sample Size................................................................................101
13.4
Biomarker Qualification ........................................................................................103
14.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................104
14.1
Study-Site Monitoring Visits .................................................................................104
14.2
Protocol Deviations................................................................................................104
14.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................104
15.0
ETHICAL ASPECTS OF THE STUDY......................................................................105
15.1
IRB and/or IEC Approval ......................................................................................105
15.2
Subject Information, Informed Consent, and Subject Authorization .......................106


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15.3
Subject Confidentiality ..........................................................................................107
15.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................107
15.4.1 Publication and Disclosure...............................................................................107
15.4.2 Clinical Trial Registration................................................................................108
15.4.3 Clinical Trial Results Disclosure ......................................................................108
15.5
Insurance and Compensation for Injury..................................................................108
16.0
REFERENCES............................................................................................................109
LIST OF IN-TEXT TABLES
Table 4.a
Cognitive Test Battery**....................................................................................31
Table 4.b
Operationalized Criteria for MCI due to AD ......................................................32
Table 7.a
Excluded Medications and Treatments...............................................................53
Table 8.a
Sponsor-Supplied Drug......................................................................................58
Table 9.a
Clinical Laboratory Tests...................................................................................66
Table 9.b
Schedule for Pharmacokinetic Sample Collection...............................................70
Table 9.c
Order of Assessments.........................................................................................77
Table 10.a
Takeda Medically Significant AE List................................................................87
Table 13.a
Conversion Rate Estimates Based on Analysis of 3 Cohorts, Cognitive 
Impairment Incidence, and Observed TOMM40 rs10524523 Allele 
Frequencies......................................................................................................102
LIST OF IN-TEXT FIGURES
Figure 4.a
Age of Onset of Cognitive Impairment as a Function of TOMM40 
rs10524523 Genotype ........................................................................................28
Figure 6.a
Schematic of Study Design ................................................................................39
Figure 6.b
Subject Flow Chart ............................................................................................41
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures..........................................................................115
Appendix B
Responsibilities of the Investigator...................................................................120
Appendix C
Elements of the Subject Informed Consent.......................................................122
Appendix D
Investigator Consent to Use of Personal Information........................................125
Appendix E
Collection, Shipment, and Storage of Pharmacogenomic Samples (Separate 
from the risk stratification sample)...................................................................126


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Appendix F
Collection, Storage, and Shipment of Bioanalytical Samples............................127
Appendix G
Corrections to the MMSE based on Education and Age....................................129
Appendix H
A Sub Study To Evaluate the Effects of Pioglitazone on Whole and Regional 
Brain Volume over Time..................................................................................130
Appendix I
Operationalized Criteria for AD Dementia .......................................................132
Appendix J
Detailed Description of Amendments to Text...................................................135


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compound:
AD-4833
Title of Protocol: A Double Blind, Randomized, Placebo 
Controlled, Parallel Group Study to Simultaneously 
Qualify a Biomarker Algorithm for Prognosis of Risk of 
Developing Mild Cognitive Impairment due to 
Alzheimer’s Disease (MCI due to AD) and to Test the 
Safety and Efficacy of Pioglitazone (AD-4833 SR 0.8 mg 
QD) to Delay the Onset of MCI due to AD in Cognitively 
Normal Subjects
IND No.: 112,403
EudraCT No.:
2012-003111-58
Study Number: AD-4833/TOMM40_301
Phase: 3
Study Design:
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Eligible subjects will be 
stratified into high- and low-risk groups in terms of risk to develop mild cognitive impairment (MCI) due to 
Alzheimer disease (AD) over the next 5 years, based upon the results of a biomarker risk algorithm (comprised of 
TOMM40 rs10524523 genotype, apolipoprotein E [APOE] genotype, and age). High-risk subjects will be 
randomized to receive either pioglitazone or placebo. All subjects stratified to the low-risk stratum will be assigned
to receive placebo. The study duration will be the time needed to accumulate a total of 202 conversions to MCI due 
to AD diagnosis in the non-Hispanic/Latino Caucasian subjects within the high-risk stratum. The study will recruit 
internationally from large, diverse, community-based populations. Because the data used to develop the enrichment 
algorithm was collected in non-Hispanic/Latino Caucasian subjects only, the primary analyses of the study to 
compare the effects of pioglitazone versus placebo will be within the non-Hispanic/Latino Caucasian high-risk 
sub-group. Likewise, for the biomarker risk algorithm qualification, only the subjects within the 
non-Hispanic/Latino Caucasian high-risk sub-group will be included. In addition to their participation in the main 
Phase 3 study, approximately 300 cognitively normal elderly subjects will participate in a volumetric magnetic 
resonance imaging (vMRI) substudy at selected sites.
Primary Objectives:
For biomarker risk algorithm qualification:

To qualify the biomarker risk algorithm composed of TOMM40 rs10524523 genotype, APOE genotype, and 
age for prognosis of the risk of developing MCI due to AD within 5 years. 
For efficacy evaluation of pioglitazone:

To evaluate the efficacy of pioglitazone compared with placebo to delay the onset of MCI due to AD in 
cognitively-normal subjects who are at high-risk, as identified by the biomarker risk algorithm at enrollment,
for developing MCI due to AD within 5 years.
Key Secondary Objectives:

To evaluate the effect of pioglitazone compared with placebo on the progression of cognitive decline.

To evaluate the effect of pioglitazone compared with placebo on functional decline and instrumental activities 
of daily living.
Safety Objectives:

To evaluate long-term safety and tolerability of pioglitazone compared with placebo during the course of the 
treatment.


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Exploratory Objectives:
!
!
!
!
!
Subject Population: Open enrollment ages 65-83 (inclusive) male and female subjects who are cognitively normal.
Number of Subjects:
Approximately 3500 Subjects randomized. 
Number of Sites:
Estimated total: approximately 60 in North America, 
Europe, Australia
Dose Level(s):
AD-4833 sustained release (SR) 0.8 mg Tablet once daily
(QD)
Placebo QD
Route of Administration:
Oral
Duration of Treatment:
Estimate (event-driven study) is minimum 4 years 
(48 months)
Period of Evaluation:
Up to 125 day Screening period prior to 
Randomization
Minimum 4 year Double-Blind Treatment period
Main Criteria for Inclusion:
!
Male or postmenopausal female subject between 65 and 83 years of age, inclusive at the time of the screening 
visit. 
!
The subject must be cognitively normal at baseline, scoring as indicated for the following tests: 
–
Clinical Dementia Rating (CDR)=0.
–
At least one memory test above -1.5 SD of the demographically corrected normative mean.
!
The subject must score ≥25 on the Mini Mental Status Examination (MMSE) at the screening visit after the 
education and age adjustment referenced in Appendix G.
!
All subjects require a project partner who can separately complete an Acknowledgment Form on his/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.
!
The subject has the ability and intention to participate in regular study visits, in the opinion of the Investigator.
Main Criteria for Exclusion:
!
The subject has a current diagnosis or history of any type of cognitive impairment or dementia, or has a current 
diagnosis or history of neurological/psychiatric disorder or any other diagnosis that significantly affects 
cognitive performance (eg, mental retardation, organic mental disorder).
!
The subject has a current diagnosis of significant psychiatric illness, per the Diagnostic & Statistical Manual of 
Mental Disorders, 4th Edition - Text Revision (DSM-IV-TR) (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 
CCI


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schizophrenia or bipolar disorder.

The subject has glycosylated hemoglobin (HbA1c) >8.0% at the time of baseline or requires treatment with 
insulin, triple oral antidiabetic therapy or a peroxisome proliferator-activated receptor-gamma (PPAR) agonist. 
The subject should be on a stable antidiabetic regimen for at least 3 months prior to enrollment. 

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. 
History of human immunodeficiency virus (HIV) infection is considered exclusionary for this study.

The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse/dependence 
within 2 years prior to the Screening Visit.

The subject has a history or current diagnosis of macular edema or macular degeneration. 

If female, the subject has a history of postmenopausal fractures with no or minimal trauma (eg, wrist, hip, 
lumbar or thoracic vertebral fracture).

The subject has a history or current diagnosis of congestive heart failure (CHF), New York Heart Association 
Class III-IV.

The subject has been exposed to cognitive tests performed in this study within 6 months prior to the Screening 
Visit with the exception of the Mini-Mental State Examination (MMSE).

The subject’s TOMM40 rs10524523 or APOE genotypes or APOE phenotype are known by the subject or the 
study staff participating in this study.
Main Criteria for Evaluation and Analyses:
Efficacy:
The primary endpoint for the biomarker risk algorithm qualification:

Time to diagnosis of MCI due to AD for placebo-treated, high-risk subjects versus placebo-treated, low-risk 
subjects.
The primary endpoint for the efficacy evaluation of pioglitazone:

Time to diagnosis of MCI due to AD for pioglitazone-treated subjects versus placebo-treated subjects in the 
high-risk stratum.
Key Secondary endpoints for this study are:

Change from baseline for cognitive decline on composite score on the cognitive battery for pioglitazone-treated 
subjects versus placebo-treated subjects in the high-risk stratum.

Changes from baseline in instrumental activities of daily living (Alzheimer’s Disease Cooperative Study 
Activities of Daily Living - Prevention Instrument [ADCS ADL-PI]) between pioglitazone-treated and placebo-
treated groups of the high-risk stratum.
Statistical Considerations:
There are 2 independent null hypotheses in this protocol: 1) that there is no difference in conversion rate between the 
placebo-treated high-risk and low-risk groups, where risk is defined by the prognostic biomarker test and 2) that 
there is no difference in conversion rate between the high-risk active- and placebo-treated subjects. The alternate 
hypotheses are: 1) that there is a difference between the high- and low-risk groups treated with placebo, and 2) that 
there is a difference between placebo and active treatment in the high-risk group. Time to event analyses will be 
used to evaluate the conversion rates over time. The other secondary endpoints will be analyzed using 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 alpha = 0.01 level.


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Pharmacokinetic Analysis:
Sparse plasma samples from approximately 30% per region of study subjects will be collected to estimate 
population Pharmacokinetics (PK)/Pharmacodynamics (PD) of pioglitazone, random inter/intra-subject variability, 
random residual variability associated with PK and PD model parameters, and to identify sources of variability 
(continuous or categorical covariates) that may influence pioglitazone PK and PD profiles in study subjects. Once 
approximately 30% per region of study subjects have consented to the PK collection, future subjects will not have 
PK samples collected.
Sample Size Justification: The sample size for this study is based on the event-driven analysis that is planned for 
comparing treatment groups within the high-risk stratum. For the purposes of this study, it is assumed that the 
placebo-treated non-Hispanic/Latino Caucasian subjects in the high-risk stratum will have an event rate of 15% over 
5 years. With an expected improvement of a reduction in event rate of 40%, the target event rate for the active 
treatment group will be 9% over 5 years. Furthermore, the following specifications are used: alpha=0.01, a 2-sided 
statistical test based on survival analysis, power=90%, annual dropout rate of 12% (or cumulative dropout rate of 
47% over 5 years). In order to detect a difference of the specified magnitude (≥40% reduction in conversion rates 
over 5 years), at least 202 events must be observed during the course of the study in the non-Hispanic/Latino 
Caucasian subjects in the high risk stratum. Based on these assumptions and the fact that only non-Hispanic/Latino 
Caucasian subjects will be used for the primary analyses, a total of 2,346 non-Hispanic/Latino Caucasian subjects 
(1,173 on pioglitazone/1,173 on placebo) will be required in the high-risk stratum for randomization. 
All subjects screened into the study at the time of Amendment 5 will be allowed to enroll if they continue to meet all 
eligibility criteria. Therefore, the total number of subjects to be randomized is estimated at 3,500.


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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 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 Development Center, Inc. (TDC) 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
AD
Alzheimer disease
ADAPT
Alzheimer’s Disease Anti-inflammatory Prevention Trial
ADAS-cog
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
ADCS ADL-PI
Alzheimer’s Disease Cooperative Study Activities of Daily Living - Prevention 
Instrument
ADCS-CGIC-MCI
Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change – Mild 
Cognitive Impairment
ADCS-MCFSI
Alzheimer’s Disease Cooperative Study – Prevention Instrument Project – Mail-In 
Cognitive Function Screening Instrument
ADCS-RUI
Alzheimer’s Disease Cooperative Study - Resource Use Inventory
ADRC
Alzheimer’s Disease Research Center
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APOE
apolipoprotein E 
AST
aspartate aminotransferase
ATP
adenosine triphosphate
BOLD
blood oxygen level-dependent
BVMT-R
Brief Visuospatial Memory Test - Revised
CDR
Clinical Dementia Rating
CDR-SB
Clinical Dementia Rating – Sum of Boxes
CDT
Clock Drawing Test
CFR
Code of Federal Regulations
CI
confidence interval
CIAC
Cognitive Impairment Adjudication Committee
CGIC
Clinical Global Impression of Change
CHF
congestive heart failure
CMFV
Comprehensive Medical Follow-up Visit
CNS
central nervous system
CRO
contract research organization
C-SSRS
Columbia–Suicide Severity Rating Scale
CT
computerized axial tomography
CVLT-II
California Verbal Learning Test – 2nd Edition
CYP
cytochrome P-450
DNA
deoxyribonucleic acid
DSMB
data safety monitoring board


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DSM-IV-TR
Diagnostic & Statistical Manual of Mental Disorders, 4th Edition - Text Revision 
ECG
electrocardiogram
(e)CRF
(electronic) case report form 
EDC
electronic data capture
EoS
end of study
EMA
European Medicines Agency
EQ-5D
European Quality of life (includes single item measures of: mobility, self-care, usual
activities, pain/discomfort, and anxiety/depression)
EW
early withdrawal
FAS
full analysis set
FDA
Food and Drug Administration
fMRI
functional magnetic resonance imaging
GCP
Good Clinical Practice
GDS
Geriatric Depression Scale
GEMS
Ginkgo Evaluation of Memory Study
GGT
-glutamyl transferase
GWAS
genome wide association study 
HbA1c
glycosylated hemoglobin
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDPE
high density polyethylene
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IMP
investigational medicinal product
INR
international normalized ratio 
IQCODE
Informant Questionnaire on Cognitive Decline in the Elderly
IRB
institutional review board
IVD
in vitro diagnostic device
IVRS
interactive voice response system
IWRS
interactive web response system
K2EDTA
potassium ethylenediamine tetraacetic acid
L
long
LC-MS/MS
liquid chromatographic method with mass spectrometry detection
LD
linkage disequilibrium 
LFT
liver function test


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MACE
major adverse cardiac event
MAR
missing at random
MCI
mild cognitive impairment
Med ID
medication identification number
MedDRA
Medical Dictionary for Regulatory Activities
MetS
metabolic syndrome
MINT
Multilingual Naming Test
MMRM
mixed models repeated measures
MMSE
Mini-Mental State Examination 
MOA
mechanism of action
MRI
magnetic resonance imaging 
NIA
National Institute on Aging
NPI-Q
Neuropsychiatric Inventory Questionnaire
NPS
neuropsychiatric symptoms
NPV
negative predictive value
NSAID
non-steroidal anti-inflammatory drug
PD
pharmacodynamics
PGx
pharmacogenomics 
PK
pharmacokinetics
PPAR-
peroxisome proliferator-activated receptor-gamma
PPV
positive predictive value
PRO
patient reported outcome
PROACTIVE
PROspective pioglitAzone Clinical Trial In macroVascular Events
PTE
pretreatment event
PTH
parathyroid hormone
QD
once daily
rCBF
regional cerebral blood flow
RNA
ribonucleic acid
RPR
rapid plasma reagin
RU
resource utilization
S
short
SAE
serious adverse event
SAP
statistical analysis plan
SF-36
Short Form-36
SR
sustained release
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
T4
thyroxine
TMT
Trail Making Tests


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TOMM40
translocase of the outer mitochondrial membrane 40 homolog
TSH
thyroid-stimulating hormone
TZD
thiazolidinedione
ULN
upper limit of normal
VAS
visual analog scale
VL
very long
vMRI
volumetric magnetic resonance imaging
WAIS
Wechsler Adult Intelligence Scale
WHIMS
Women’s Health Initiative Memory Study
WHO
World Health Organization
3.4
Corporate Identification
TDC (Asia)
Takeda Development Center Asia Pte Ltd
TDC (Europe)
Takeda Development Centre (Europe) Ltd.
TDC (Americas)
Takeda Development Center Americas, Inc.
TDC
TDC (Asia), TDC (Europe) and/or TDC (Americas), as applicable
TPC
Takeda Pharmaceutical Company Limited
Takeda
Takeda Pharmaceutical Company Limited
TDC (Asia), TDC (Americas), TDC (Europe), and/or TPC, as applicable


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4.0
INTRODUCTION
4.1
Background
Pioglitazone hydrochloride is a member of a class of oral antidiabetic agents known as 
thiazolidinediones (TZDs) that are approved for the treatment of type 2 diabetes mellitus 
(T2DM). Pioglitazone is a potent and highly selective agonist of peroxisome 
proliferator-activated receptor-gamma (PPAR-), which is a ligand-activated transcription factor 
found in tissues sensitive to insulin action (including adipose tissue, skeletal muscle, liver, and 
the brain) [1]. The mechanism of action through which PPAR-agonists might affect Alzheimer 
disease (AD) pathophysiology is not established at this time; however, activated PPAR-
regulates a number of pathways implicated in the etiology of AD, and it has been shown that the 
drug crosses the blood brain barrier [1]. Numerous studies indicate that pioglitazone regulates 
glucose and lipid metabolism in neuronal cells [2,3], reduces or prevents neuroinflammation 
[4,5], has neuroprotective effects [6], and modulates mitochondrial biogenesis and function [7] 
and thus adenosine triphosphate (ATP) production. It is thought that mitochondrial dysfunction 
may play a chief role in the cerebral hypometabolism observed in AD and in subjects at risk to 
develop AD [8,9,11]. Roses et al have postulated that PPAR-agonists improve mitochondrial 
function in AD [12].
The effects of pioglitazone on mitochondrial structure and function and on stimulating neurite 
outgrowth have been suggested to occur at exposures well below the doses approved for T2DM. 
Pioglitazone at concentrations of 10 nM to 1 µM induces mitochondrial biogenesis and prevents 
glucose deprivation–induced neuronal death [7], and also stimulates neurite outgrowth in 
cultured neuronal cells [13]. Using a different neuronal cell line, Ghosh et al have also 
demonstrated similar effects on mitochondrial biogenesis with significantly higher 
concentrations of pioglitazone (10 to 20 µM, decreasing at 40 µM), which is greater than the 
serum levels achieved with doses used to treat T2DM [2]. Pioglitazone treatment significantly 
increased mitochondrial number and expression of factors involved in mitochondrial biogenesis, 
including PPAR-γ coactivator -1α and mitochondrial transcription factor [14].
Pioglitazone has been studied in randomized clinical studies as a treatment for subjects already 
exhibiting clinical symptoms of either mild cognitive impairment (MCI) or probable AD, with 
mixed results. Geldmacher et al conducted an 18-month, double-blind, placebo-controlled 
randomized trial to test long-term safety and tolerability of pioglitazone in a nondiabetic elderly 
population with AD [15]. Twenty-nine subjects were treated with pioglitazone titrated to 
45 mg/day (n=14; mean age = 74.9) or matching placebo (n=15; mean age = 67.0 years).
Subjects maintained treatment with cholinesterase inhibitors and could begin memantine therapy 
when it became available during the study. The primary outcome of this study was the frequency 
of adverse events (AEs), while secondary outcomes included measures of cognition, activities of 
daily living, neuropsychiatric symptoms (NPS), and global functioning. Pioglitazone was 
generally well tolerated in this pilot study, as no serious AEs (SAEs) or unanticipated AEs 


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occurred, while peripheral edema was the principal AE (28.6% in pioglitazone-treated subjects 
compared with 0% in placebo-treated subjects). No significant treatment effect was observed on 
exploratory analysis of clinical efficacy.
Sato et al conducted a 6-month, randomized, open-controlled pilot study of pioglitazone efficacy 
on cognition, regional cerebral blood flow (rCBF), and plasma A40 and A42 [16]. 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 [ADAS-cog]), Wechsler Memory 
Scale-revised logical memory-I) and rCBF at 6 months compared to baseline (Visit 2), while 
untreated subjects did not. Untreated subjects did, however, have increased plasma 
A40 /A42 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) [17]. 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 to 
controls, as evidenced by either improvement, stabilization, or lesser decline in performance on 
cognitive testing.
Pioglitazone is an appropriate therapeutic candidate for use in a study with cognitively normal 
subjects because it has an established safety profile even at doses considerably higher than the 
intended dose in the proposed phase 3 study. Over 8500 subjects with T2DM have been treated 
with pioglitazone in randomized, double-blind, controlled clinical studies, including 
2605 subjects with T2DM and macrovascular disease treated with pioglitazone in the 
PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE) clinical trial 
[18]. In these studies, over 6000 subjects have been treated with pioglitazone for 6 months or 
longer, over 4500 subjects have been treated with pioglitazone for one year or longer, and over 
3000 subjects have been treated with pioglitazone for at least 2 years. Common adverse events 
that occurred in these studies at an incidence rate of >5% and more frequently in pioglitazone 
(monotherapy) than in placebo treatment group were headache (9.1%), sinusitis (6.3%), myalgia 
(5.4%), and pharyngitis (5.1%).
The results of the PROACTIVE study showed that pioglitazone reduced the risk of secondary 
macrovascular events in a high-risk patient population with type 2 diabetes and established 
macrovascular disease. 
Since launch in the United States in July 1999, through 31 July 2014, the total patient-years of 
exposure to pioglitazone (monotherapy) globally is estimated to be approximately 26,682,746
[19]. Clinical experience has not identified differences in effectiveness or safety between the 


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elderly (≥65 years of age) and younger subjects, although small numbers of subjects ≥75 years of 
age limit this conclusion.
Few postmarketing reports of new-onset or worsening diabetic macular edema with decreased 
visual acuity have occurred with TZDs, including pioglitazone. Many of these patients reported 
concurrent peripheral edema. It is not known whether there is a direct association between 
pioglitazone and macular edema, but investigators should be alert to the possibility of macular 
edema. If study participants report disturbances in visual acuity (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), they will be evaluated by an ophthalmologist.
There have been postmarketing reports of bone fractures associated with the use of TZDs, 
including pioglitazone. The majority of the fractures occurred in women with most of the 
fractures involving upper and lower limbs of the body. Many cases lack any information about 
history or about risk factors for bone fractures. In cases where information was available, 
patients had a history of and multiple risk factors for fractures. 
Adverse events associated with pioglitazone, listed in the Warnings and Precautions section of
the Company Core Data Sheet [20], 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: congestive heart failure (CHF) and peripheral edema due to dose-
related fluid retention, hepatic failure, increased incidence of fractures in female population, 
hypoglycemia, macular edema, and bladder cancer. A detailed discussion of the safety profile of 
pioglitazone is provided in the investigator’s brochure.
4.2
Rationale for the Proposed Study
Zinfandel Pharmaceuticals, Inc. (Zinfandel) identified a genetic variant, translocase of the outer 
mitochondrial membrane 40 homolog (TOMM40) rs10524523, which appears to be prognostic 
of onset of cognitive decline within 5 years when combined with apolipoprotein E (APOE) 
genotype and age. The biomarker risk algorithm, which is the combination of TOMM40rs 
10524523 genotype, APOE and age, is used to categorize subjects as being either high-risk or 
low-risk to develop MCI due to AD within 5 years. 
Zinfandel and Takeda entered into a license agreement pursuant to which Takeda is the exclusive 
licensee of the biomarker risk algorithm, including its use in evaluating the efficacy of 
pioglitazone for delaying the onset of MCI due to AD in high-risk individuals identified on the 
basis of the biomarker risk algorithm.
It has been estimated that delaying AD onset by 1 or 2 years could decrease global disease 
burden in 2050 by 11.8 million or 22.8 million cases, respectively [21]. Coupled with the failure 
of multiple treatment trials that have been conducted over the past decade, the focus of AD 
clinical research has begun to shift to the pursuit of a prevention strategy for AD, as brain 


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pathology may be too advanced to allow effective treatment of clinical symptoms, or disease 
modification, once patients are diagnosed with AD dementia.
However, few AD primary prevention studies have been conducted to date, and their results have 
been disappointing. In large (>2,000 subjects), long-term (planned as ≥5 years), randomized 
clinical trials of ginkgo biloba extract (GuidAge [22] and Ginkgo Evaluation of Memory Study 
[GEMS] [23]), hormone replacement therapy in women (Women’s Health Initiative Memory 
Study [WHIMS] [24]), and non-steroidal anti-inflammatory drugs (NSAIDs) (Alzheimer’s 
Disease Anti-inflammatory Prevention Trial [ADAPT] [25]) none of the primary, disease 
prevention objectives were achieved. Each of these studies employed an enrichment strategy to 
enroll subjects perceived to be at increased risk of developing AD or cognitive impairment. 
GEMS targeted the very old (≥75) and did not exclude individuals with MCI or milder cognitive 
syndromes; ADAPT targeted subjects with Alzheimer-like dementia in a first degree relative; 
WHIMS targeted postmenopausal women; and GuidAge enrolled individuals who spontaneously 
complained of memory problems to their general practitioner.
Like previous studies, this phase 3 study, AD-4833/TOMM40_301, will employ a strategy to 
enrich for at-risk subjects, in this case, those who are at-risk for developing MCI due to AD. The 
enrichment strategy is provided by the biomarker risk algorithm. The trial, therefore, is designed 
to pursue two primary objectives independently yet simultaneously: 1) to prospectively qualify 
the risk algorithm comprised of TOMM40 rs10524523 genotype, APOE genotype, and age as a 
biomarker for prognosis of an individual’s risk of developing MCI due to AD in the next 5 years, 
and 2) to evaluate the efficacy of pioglitazone to delay the onset of MCI due to AD in 
cognitively normal subjects who are prognosed to be at high risk of developing MCI due to AD 
within 5 years. Subjects will be prospectively stratified into high-risk and low-risk groups on the 
basis of the risk algorithm and randomized to treatment with pioglitazone or placebo in the 
high-risk stratum or to placebo only in the low-risk stratum.
4.2.1
Genetic Risk Factors for AD
APOE epsilon genotype alone is neither sufficiently sensitive nor specific for clinical diagnosis 
of AD or prediction of age of onset of disease [26]. Roses et al have identified a second risk 
locus, in TOMM40, that provides greater resolution to the age of disease onset prediction, and 
for a greater proportion of the at-large population. Over a dozen genome wide association studies 
(GWAS) have confirmed the presence of a highly significant AD susceptibility locus within the 
TOMM40 gene, neighboring and in linkage disequilibrium (LD) with the well-known risk gene,
APOE. Due to the LD between the genes, the association signal within TOMM40 has been 
previously attributed to APOE and thus overlooked. 
In 2009, Roses et al. described the association between different lengths (short or S, long or L,
and very long or VL) of a polyT locus (ie, the rs10524523 locus) in TOMM40 with ages of AD 
onset [27]. A phylogenetic analysis of high resolution sequence data from the region containing 
APOE and TOMM40 revealed the relationships between different alleles of TOMM40 


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rs10524523 and the APOE epsilon alleles, APOE ε3 and APOE ε4, in non-Hispanic/Latino 
Caucasian subjects. Long alleles of TOMM40 rs10524523 were nearly always linked to APOE 
ε4 and associated with greater disease risk. In contrast, APOE ε3 (and APOE ε2) was linked to 
either short or very long TOMM40 rs10524523 alleles, with the short alleles associated with 
later disease onset and the very long alleles associated with earlier onset (mean onset ages of 
77 years versus 70 years, respectively) in a cohort of autopsy-confirmed AD patients carrying the 
APOE ε3/4 genotype. The association between APOE ε4 and risk of development of AD, or age 
of AD onset, first reported by Roses et al in 1993, has been replicated in many case-control and 
cohort studies. However, only ~ 25% of Caucasians carry an APOE ε4-containing genotype (2% 
are APOE ε4/4, 20% are APOE ε3/4, and 2% are APOE ε2/4); therefore, this allele is potentially 
informative for a minority of the at-risk population. Further, APOE ε4 carriage, alone, does not 
provide sufficient sensitivity, selectivity or predictive power to be used as a diagnostic or 
prognostic tool for AD [26,28]. While homozygosity for APOE ε4 is informative for AD risk 
prediction in the clinic, it is rare and therefore not widely useful [29,30]. Stratification of age of 
onset by TOMM40 rs10524523 genotypes provides information for >97% of the at-risk 
population, as it addresses age-dependent risk for carriers of APOE ε3, the most common allele, 
in addition to APOE ε4 (see Figure 4.a [31]). 


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Figure 4.a
Age of Onset of Cognitive Impairment as a Function of TOMM40 
rs10524523 Genotype
Figure 4.a illustrates that the previously measured age of onset distribution for APOE 
ε4/4 subjects is identical to the TOMM40 rs10524523 L-L genotype distribution. The APOE 
ε3/4 curve can be deconvoluted into two curves corresponding to the two different alleles of 
TOMM40 rs10524523, S and VL, that can be connected to APOE ε3 (and to APOE ε2 alleles). 
Three TOMM40 rs10524523 age of onset curves, S/S, S/VL, and VL/VL account for the APOE 
ε3/3 and APOE ε2/3 genotypes. In the entire data set used to develop this figure, only 5 of 
70 APOE ε2 allele carriers developed the clinical disease criteria and for the 5 individuals, this 
occurred after age 75 years on the three different curves (VL/VL, S/VL, and S/S). For the 
purpose of enrichment in this study, which will enroll subjects aged 65 to 83 years, inclusive, 
APOE ε2/2 and APOE ε2/3 carriers will be placed in the low risk stratum, while APOE 
ε2/4 subjects will be stratified to the high-risk stratum because these subjects also carry an APOE 
ε4 allele. Thus, TOMM40 rs10524523 and APOE genotypes may differentiate subjects at higher 
and lower age-dependent risk of developing MCI due to AD, and subsequently AD. 


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4.2.2
Pioglitazone
It has been suggested that PPAR-agonists could be effective in treating AD by regulating 
multiple pathogenic pathways in the central nervous system, including amyloid β homeostasis, 
insulin sensitivity, energy metabolism, lipid metabolism, and inflammation [32]. PPAR-
agonists are insulin-sensitizing agents that allow the body to use endogenous insulin efficiently, 
maintaining the normal physiological feedback mechanisms, and producing minimal 
hypoglycemia. There is ample documentation that glucose utilization is impaired in brain regions 
involved in cognition, including memory, in patients with AD. Indeed, it has been demonstrated 
that subjects at risk of developing AD exhibit impaired cerebral glucose metabolism decades 
before the typical ages of onset of late onset AD [33,34].
PPAR-agonists also play critical roles in energy metabolism due to their direct effects on 
mitochondrial function and ultimately ATP production and neuronal glucose utilization. 
Mitochondria may be key players in the cerebral hypometabolism observed in AD, as this 
organelle plays critical roles in energy metabolism, neuronal apoptosis and the maintenance of 
synapses. In AD-affected brain, the mitochondria have altered morphology, including an 
increased proportion of damaged mitochondria, altered distribution within neurons, and there is a 
decrease in the amounts of enzyme complexes that are essential for ATP production [35]. The 
effects of PPAR-agonists on mitochondria structure and function may be the basis of their 
beneficial effects on cognition, including memory, in AD subjects [12,36].
A paramount consideration for development of a preventive measure is its safety, set at a 
particularly high threshold given that the intended study population is cognitively normal. While 
some side effects may be acceptable to individuals already affected by the devastating symptoms 
of AD, only few, reversible, and minor adverse drug reactions would be acceptable to 
cognitively-normal individuals who may or may not decline to AD dementia. Ideally, an active 
pharmaceutical agent for a delay of MCI due to AD indication would be supported by extensive 
exposure data gathered through multiple years and in thousands of patients globally. While 
extensive drug exposure data exist for the two marketed TZDs, pioglitazone is widely considered 
to be safer than rosiglitazone. 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 [37]. The meta-analysis included 35 trials 
covering 22,131 patients, of whom 12,213 (55%) were randomized to pioglitazone and 9,918 
(45%) to the comparator. Overall, across all trials for pioglitazone, the estimated MACE (major 
adverse cardiovascular events, defined as cardiovascular death, stroke or myocardial infarction) 
risk was lower for pioglitazone compared to control (hazard ratio [HR]=0.80; 95% confidence 
interval [CI]=0.70-0.93). 


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4.2.3
Mild Cognitive Impairment due to Alzheimer’s Disease (MCI due to AD)
In 2011, a workgroup of the NIA and the Alzheimer’s Association (AA) published criteria 
developed to define the predementia symptomatic phase of Alzheimer’s disease, referred to as 
MCI due to AD [38]. The core clinical criteria recommended by the NIA/AA workgroup are 
applied in this study to define the primary endpoint event of MCI due to AD. It is important to 
underscore that the primary endpoint in this study is diagnosed using the NIA/AA core clinical 
criteria for this MCI phenotype without AD biomarker confirmation, since at this time no 
physical biomarker is validated, or qualified, for diagnosing MCI due to AD [39]. In addition, a 
recent population-based study confirms prior clinical studies, demonstrating that the 
development of clinical impairment is associated more with APOE genotype than with amyloid 
plaque deposition (ie, while amyloid deposition is modestly associated with cognitive 
performance in a population-based sample of cognitively normal older adults who carry at least 
one APOE ε4 allele, the relationship between amyloid and cognition is even less apparent in 
individuals without an APOE ε4) [40].
In clinical practice, the diagnosis of MCI due to AD, like AD dementia, cannot be made solely 
by laboratory or other tests, but requires the judgment of a clinician who takes into account 
clinical, cognitive, and functional criteria that define the syndrome. The clinical diagnosis, as 
defined by the NIA/AA in Albert et al., 2011 [38]:

Establishes clinical and cognitive criteria:
–
Cognitive concern reflecting a change in cognition reported by subject or informant or 
clinician (ie, historical or observed evidence of decline over time).
–
Objective evidence of impairment in one or more cognitive domains, typically including 
memory (ie, formal or bedside testing to establish level of cognitive function in multiple 
domains).
–
Preservation of independence in functional abilities.
–
Not demented.

Examines etiology of MCI consistent with AD pathophysiological process:
–
Rule out vascular, traumatic, medical causes of cognitive decline, where possible.
–
Provide evidence of longitudinal decline in cognition, when feasible.
–
Report history consistent with AD genetic factors, were relevant.
A cognitive test battery has been specifically constructed to help study Investigators identify 
individuals who are beginning to decline in their cognitive status and who can be accurately 
diagnosed with MCI due to AD. This test battery is summarized in the Table 4.a, and the 
individual instruments that comprise the battery are described in detail in Section 9.1.15.


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Table 4.a
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 (TMT) (Part B)
Wechsler Adult Intelligence Scale (WAIS)-III Digit Span Test – backwards span
Language
Multilingual Naming Test (MINT)*
Semantic Fluency (animals)
Lexical/phonemic fluency (F, A, and S)
Attention
WAIS-III Digit Span Test – forward span
TMT (Part A)
Visuospatial
Clock Drawing Test (CDT)*
Copy of BVMT figures*
* CDT, 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.
** There are 12 measures derived from 8 neuropsychological tests in the battery. The CVLT-II test involves 
2 primary measures (short delay recall, long delay recall); BVMT-R has 2 measures (copy and recall); Digit Span 
and Trails both have 2 measures (forward and backward span and Parts A and B, respectively). There is one total 
score for each test: CDT, MINT, semantic fluency and lexical fluency (F, A, and S).
Study Investigators will use this cognitive test battery to assess subjects’ cognitive status and will 
consider the results of this battery, in combination with the findings from other subject- and 
project partner-reported instruments of functional change and laboratory findings, to determine 
further subject flow within the study (ie, send case for adjudication or not).
For the purposes of this clinical trial, the clinical framework described by the NIA/AA [38] 
publication will be operationalized through the incorporation of objective cutoff points to 
provide the Investigator’s guidance for making a clinical diagnosis of MCI due to AD, as 
follows: 


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Table 4.b
Operationalized Criteria for MCI due to AD
Establish clinical and cognitive criteria

Clinical Dementia Rating (CDR) scale score of 0.5 AND one or more of the following:
–
Fails at least one of the two memory tests in the cognitive test battery (failure defined as an individual test 
score at or below -1.5 SD of the demographically corrected normative mean (a), and the score reflects a 
decline from baseline).
–
Fails at least 2 of the cognitive tests from at least 2 different cognitive domains, one of which must be 
memory (failure defined as an individual test score at or below -1.3 SD (10th percentile) of the 
demographically corrected normative mean, and the score reflects a decline from baseline).
Examine etiology of MCI consistent with AD pathophysiological process

Rule out vascular, traumatic, psychiatric, and other proximal medical causes of cognitive decline.

Continued evidence of cognitive impairment or continued decline on 6 month follow-up (ie, 2 consecutive study 
visits showing impairment). (b)
(a) Normative data will be available per language.
(b) It is not required that the two consecutive visits show an identical profile (ie, meeting any definition of MCI due 
to AD on two consecutive visits for a subject to be forwarded for adjudication).
The primary endpoint is met only on the second consecutive occurrence when the diagnosis of 
MCI due to AD is confirmed by the adjudication committee. The adjudicators will look at all the 
collective information sent by the investigative sites in order to confirm (or not) the diagnosis of 
MCI due to AD. Subjects who convert directly to an AD dementia diagnosis by the NIA/AA 
criteria [41] will also be considered toward the numerical count of events that determines the 
duration of the study.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
For biomarker risk algorithm qualification:
!
To qualify the biomarker risk algorithm composed of TOMM40 rs10524523 genotype, 
APOE genotype, and age for prognosis of the risk of developing MCI due to AD within 
5 years. 
For efficacy evaluation of pioglitazone:
!
To evaluate the efficacy of pioglitazone compared with placebo to delay the onset of MCI 
due to AD in cognitively-normal subjects who are at high-risk, as identified by the biomarker 
risk algorithm at enrollment, for developing MCI due to AD within 5 years.
5.1.2
Key Secondary Objectives
!
To evaluate the effect of pioglitazone compared with placebo on the progression of cognitive 
decline.
!
To evaluate the effect of pioglitazone compared with placebo on functional decline and 
instrumental activities of daily living.
5.1.3
Additional Objectives
5.1.3.1
Safety Objectives
!
To evaluate long-term safety and tolerability of pioglitazone compared with placebo during 
the course of the treatment.
5.1.3.2
Exploratory Objectives
!
!
!
!
 
!
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!
!
5.2
Endpoints
5.2.1
Primary Endpoints
For biomarker risk algorithm qualification:
Time to diagnosis of MCI due to AD for placebo-treated, high-risk, non-Hispanic/Latino 
Caucasian subjects versus placebo-treated, low-risk, non-Hispanic/Latino Caucasian subjects.
For efficacy evaluation of pioglitazone:
Time to diagnosis of MCI due to AD for pioglitazone-treated, non-Hispanic/Latino 
Caucasian subjects versus placebo-treated non-Hispanic/Latino, Caucasian subjects in the 
high-risk stratum.
5.2.2
Key Secondary Endpoints
!
Change from baseline for cognitive decline on composite score on the cognitive battery for 
pioglitazone-treated subjects versus placebo-treated subjects in the high-risk stratum.
!
Changes from baseline in instrumental activities of daily living (Alzheimer’s Disease 
Cooperative Study Activities of Daily Living - Prevention Instrument [ADCS ADL-PI]) 
between pioglitazone-treated and placebo-treated groups of the high-risk stratum.
5.2.3
Additional Endpoints 
5.2.3.1
Safety Assessments
!
Safety and tolerability: adverse events (including adverse events of special interest [AESIs]), 
vital signs, body weight, electrocardiogram (ECG), clinical laboratory data, and physical 
exam findings. 
5.2.3.2
Additional Endpoints
!
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!
!
!
!
!
!
!
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This phase 3 study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group
study designed to pursue two primary objectives independently yet simultaneously: (1) to qualify 
a biomarker risk algorithm composed of TOMM40 rs10524523 genotype, APOE genotype, and 
age for prognosis of the risk of developing MCI due to AD and (2) to evaluate the efficacy of 
pioglitazone (AD-4833 SR 0.8 mg once daily [QD)]) to delay the onset of MCI due to AD in 
cognitively normal subjects who are prognosed to be at high risk of developing MCI due to AD 
within 5 years.
The study duration will be the time needed to accumulate a total of 202 conversions in 
non-Hispanic/Latino Caucasian subjects within the high-risk stratum from normal cognition to a 
diagnosis of MCI due to AD, currently anticipated to be a minimum of 4 years. For the purposes 
of this study, a Caucasian subject will be defined as a person having origins in any of the original 
peoples of Europe, the Middle East, or North Africa. Hispanic/Latino will be defined as a person 
of Cuban, Mexican, Puerto Rican, South or Central American origin, regardless of race. The 
study will primarily recruit from large community-based populations.
The subjects must be cognitively normal as assessed first by performance on the MMSE at 
Screening, and then on the CDR scale and the Cognitive Test Battery (Sections 9.1.15.1 and 
9.1.15.2) at Baseline (Visit 2). The subject must be between the ages of 65 and 83 years, 
inclusive, at time of the Screening Visit. The subjects must have a project partner able to 
complete an Acknowledgement Form 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 is in the study.
Based on statistical requirement, a minimum of 2,793 subjects will be stratified into high- and 
low-risk (for the development of MCI due to AD over the next 5 years) groups based upon 
application of the biomarker risk algorithm. Subjects will be randomized via interactive web 
response system (IWRS) into this study as follows:

Non-Hispanic/Latino Caucasian subjects. A minimum of 2,660 subjects further divided into:
–
Approximately 2,346 subjects in the high-risk group (pioglitazone, n=1,173; placebo, 
n=1,173).
–
Approximately 314 subjects in the low-risk group: All subjects stratified to the low-risk 
stratum will also be randomized to maintain the stratification blind, but all subjects in this 
stratum will receive placebo. 

Non-Caucasian subjects and Hispanic/Latino Caucasian subjects. Subjects will be allocated 
to risk strata using the same algorithm as for the non-Hispanic/Latino Caucasian subjects. 


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Since all subjects screened at the time of Amendment 5 will be allowed to randomize if they 
continue to meet all eligibility criteria, it is estimated that approximately 3,500 will be 
randomized with the following groups:
!
Non-Hispanic/Latino Caucasian subjects. Estimated 3,330 subjects further divided into:
–
Approximately 2,940 subjects in the high-risk group (pioglitazone, n=1,470; placebo, 
n=1,470).
–
Approximately 394 subjects in the low-risk group: All subjects stratified to the low-risk 
stratum will also be randomized to maintain the stratification blind, but all subjects in this 
stratum will receive placebo. 
!
Non-Caucasian subjects and Hispanic/Latino Caucasian subjects. Subjects will be allocated 
to risk strata using the same algorithm as for the non-Hispanic/Latino Caucasian subjects 
(n=167). 
Because the data used to develop the biomarker risk algorithm was collected in
non-Hispanic/Latino Caucasian subjects only, biomarker qualification will be based upon
non-Hispanic/Latino Caucasian subjects in the placebo arm of the high-risk stratum compared to 
data from non-Hispanic/Latino Caucasian subjects in the low-risk stratum. Likewise, the primary 
analyses to evaluate the effects of pioglitazone versus placebo will be within the non-
Hispanic/Latino Caucasian high-risk sub-group. Data from non-Caucasian and Hispanic/Latino 
Caucasian subjects are expected to be limited and will be analyzed as exploratory data to 
An interactive response system will be used for central randomization. Stratification status and 
treatment assignment of all study participants will be double-blind. 
Subjects in the high-risk stratum will be randomized to pioglitazone and placebo in a 1:1 ratio. 
Subjects in the low-risk stratum will be randomized only to placebo.
Subjects will be instructed to take the first dose of study medication in the morning on the day 
following the randomization visit. It is recommended that the site may confirm first dose has 
occurred through a phone call.
A project partner will be required to participate with the subject in the study visits, including 
eligibility at Baseline (Visit 2) and follow-up. The project partner is a spouse, adult child, or 
other person familiar with the participant’s health and daily functioning for a minimum of two 
years prior to the Baseline Visit. Subjects and their project partners are expected to attend study 
visits every 6 months after randomization, for assessments of safety, efficacy, and treatment 
compliance. In addition, the subject will be contacted for telephone-based safety checks between 
visits. In-person participation of the project partner is required at Baseline (Visit 2), 
Comprehensive Medical Follow-up Visits (CMFV), and EoS Visits. In exceptional cases and 
with prior approval of the Sponsor, when in-person participation of the project partner is not 
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possible for a CMFV or the EoS/EW Visit, assessments may be performed during Home Visits 
or by telephone (see Section 6.2.4). While in-person participation is also strongly encouraged at 
all other study visits, telephone assessments for project partners will be acceptable in cases when 
in-person participation is not possible. If a comprehensive medical follow-up evaluation is 
needed (see Section 9.1.15) or if a safety issue is suspected, further evaluation of the subject may 
be required, which may include an unscheduled clinic visit. The project partner should attend 
unscheduled visits, whenever possible. If the original project partner is not able to continue 
participation in the study for any reason, he/she may be replaced by a different individual who 
also meets the criteria described above. The new project partner must sign the acknowledgement 
form prior to any of the project partner protocol directed procedures being performed.
Two sets of blood samples for deoxyribonucleic acid (DNA) will be collected during the course 
of this study:
1.
2.
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
* Non-Hispanic/Latino Caucasian, Hispanic/Latino Caucasian, and non-Caucasian subjects alike will be stratified 
into high- and low-risk strata using the same biomarker risk algorithm; however, target sample size for primary 
endpoint analyses refers to non-Hispanic/Latino Caucasian subjects only.
** As this is an event-driven study, double-blind treatment duration will depend on the time it takes for a total of 
202 conversions from cognitively normal status to MCI due to AD dementia to occur in the high-risk non-
Hispanic/Latino Caucasian population; conversions from cognitively normal status to AD will also be included in 
this total. Study visits to the testing center will take place every 6 months after the Randomization Visit.
6.2
Subject Flow based on Neuropsychological and Functional Assessments
6.2.1
Assessments at Screening Visit (Visit 1)
At this visit, after informed consent is given, subjects will be screened for any cognitive 
impairment using the MMSE. An MMSE score should be ≥25 after the education and age 
adjustment referenced in Appendix G for a subject to continue with additional procedures
(ie, blood draw for genotyping); failure to score at least 25 on the MMSE will make an 
individual ineligible for the study. All potential subjects passing the MMSE will have a risk 
stratification blood sample collected to determine their TOMM40 rs1054523 and APOE 
genotypes. After the results of risk stratification samples are available, those subjects who are 
still eligible to participate in the study will be asked to attend the Baseline visit (Visit 2), 
approximately14-18 days after the Screening Visit, unless additional time is required for subject 
to meet eligibility criteria (for example, subject requires stabilization of medications prior to the 


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Baseline Visit as per Table 7.a) which could occur up to 90 days after the Screening Visit. The 
results of the genotype blood test will not be shared with the subject or site. 
Sites may choose to conduct the Screening Visit procedures in the subject’s home, after 
appropriate review and approval by the Sponsor of the site’s procedures. This allowance only 
pertains to the Screening Visit.
6.2.2
Assessments at Baseline (Visit 2)
At this visit, in-person participation of both the subject and the project partner is mandatory. The 
project partner will be asked to sign an acknowledgement form. If the site has opted to use the 
split informed consent process, subject is required to sign the study entry informed consent at the 
Baseline Visit. Before being eligible for randomization, subjects’ cognitive status will be 
ascertained using the MMSE, cognitive test battery and the CDR. The cognitive test battery 
consists of the BVMT-R, CVLT-II, Semantic Fluency, Lexical/Phonemic Fluency, Digit span 
(forwards and backwards), MINT, TMT Parts A&B, and the CDT (see Section 9.1.15). At this 
Visit, the results of this assessment are intended to provide the baseline (ie, before study 
medication) values for each subject on the instruments. The scores from the neuropsychological 
instruments that are determined as potential triggers for an unscheduled visit/adjudication
described above will be converted to a common metric (z-score).
Subjects will be excluded at Baseline (Visit 2) if they meet one or both of the criteria below:

CDR scale score of >0. 

Fails both memory tests in the cognitive test battery (failure defined as an individual test 
score at or below -1.5 SD of the demographically corrected normative mean on CVLT-II 
LONG-delay Free Recall of the CVLT and BVMT-R Delayed Recall).
Also at Baseline (Visit 2), subject and partner-reported questionnaires will be administered as 
outlined in Appendix A. 
6.2.3
Assessments at Randomization (Visit 3)
After passing all eligibility criteria and after quality control has been performed on the cognitive 
battery test results, eligible subjects will return to the testing center for a Randomization Visit 
(Visit 3) within 35 days of the Baseline Visit (Visit 2). At this Visit, they will receive study 
medication and have a subject-optional blood sample drawn for PGx. 
6.2.4
Assessments after Randomization
Neuropsychological testing and functional assessments (described in Section 9.1.15) will be 
conducted at each scheduled visit using a broad cognitive test battery and functional 
measurements (including clinical judgment). Like the Baseline assessment, the scores from each 
cognitive test will be converted to a common metric (z-score). 


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The flow of subjects through the visits of this study after Randomization, and how the endpoint 
adjudication process fits into this flow, are illustrated in Figure 6.b and are described below. 
Figure 6.b
Subject Flow Chart


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Legend:
A: Subjects will be assessed by the site staff after every regularly scheduled Visit (3m, 6m, 9m, 12m)
B: Concern expressed about subject’s health to site between regularly scheduled study visits. Concern can be either the subject’s 
cognitive health or safety (other).
C: After randomization, at every regularly scheduled visit or between each visit, as applicable, the outcomes listed below will 
trigger further evaluation:
1. Pre-defined cut-off in cognitive tests:
a) Fails at least one of the two memory tests in the cognitive test battery (failure defined as an individual test 
score at or below -1.5 SD of the demographically corrected normative mean, and the score reflects a decline 
from baseline).
b) Fails at least 2 of the cognitive tests from at least 2 different cognitive domains, one of which must be 
memory (failure defined as an individual test score at or below -1.3 SD (10th percentile) of the 
demographically corrected normative mean, and the score reflects a decline from baseline)
2. Investigator’s clinical judgment of cognitive change and/or global deterioration in function based on the following:
a) Scores on subject-reported questionnaires (eg, ADCS-MCFSI; GDS).
b) Scores in project partner-reported questionnaires (eg, IQCODE, ADCS ADL-PI).
c) Subject or project partner expresses concern about the subject’s cognitive health to the Investigator or 
coordinator between regularly scheduled visits.
3. Cognitive impairment diagnosis from non-study clinician (with or without prescription of any cognitive-enhancing 
drug).
D: Comprehensive medical follow-up at an Unscheduled Visit (ie, a CMFV) may also be required if a subject or his/her project 
partner expresses their concern about his/her cognitive health to the Investigator or coordinator between regularly scheduled
study visits.
E: If a safety issue is suspected, further evaluation of the subject may be required, which may include an unscheduled visit. The 
Unscheduled visit can result in the Subject remaining in the study or study termination. 
F: CMFV. At the discretion of the investigator, the CMFV may be conducted on the same day as a regularly scheduled in-clinic 
visit (ie, Month 6 or Month 12 of any year) in situations when the CMFV conducted as an outcome of the previous scheduled 
office visit resulted in a MCI due to AD diagnosis and therefore the next scheduled visit will automatically result in the 
requirement to perform a CMFV, irrespective of a CMFV trigger being met.
G: If a PI diagnoses AD dementia even after the Cognitive Impairment Adjudication Committee (CIAC) report has determined 
that the subject does not meet criteria for MCI due to AD or for AD dementia, this will not count toward the total number of 
primary endpoint events.
H: Extension study is offered to subjects who have completed the current study having received an adjudicated diagnosis of MCI 
due to AD.
After randomization, at every regularly scheduled visit or between each visit, as applicable, the 
outcomes listed below will trigger further evaluation:
1. Pre-defined cut-off in cognitive tests:
a) Fails at least one of the two memory tests in the cognitive test battery (failure defined as 
an individual test score at or below -1.5 SD of the demographically corrected normative 
mean, and the score reflects a decline from baseline).
b) Fails at least 2 of the cognitive tests from at least 2 different cognitive domains, one of 
which must be memory (failure defined as an individual test score at or below -1.3 SD 
(10th percentile) of the demographically corrected normative mean, and the score reflects 
a decline from baseline).
2. Investigator’s clinical judgment of cognitive change and/or global deterioration in function 
based on the following:


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a) Scores on subject-reported questionnaires (eg, ADCS-MCFSI; GDS).
b) Scores in project partner-reported questionnaires (eg, IQCODE, ADCS ADL-PI).
c) Subject or project partner expresses concern about the subject’s cognitive health to the 
Investigator or coordinator between regularly scheduled visits.
3. Cognitive impairment diagnosis from non-study clinician (with or without prescription of 
any cognitive-enhancing drug).
Additional comprehensive medical follow-up assessments will be carried out for any subject who 
has any of the outcomes above; these assessments will require an Unscheduled Visit, which 
should take place within approximately 30 days of the routine study Visit when one of these 
triggers was met. A CMFV should not be conducted on the same day as a regularly scheduled in-
clinic visit (ie, Month 6 or Month 12 of any year), except in situations where the CMFV 
conducted as an outcome of the previous scheduled office visit resulted in an MCI due to AD 
diagnosis and therefore the next scheduled visit will automatically result in the requirement to 
perform a CMFV, irrespective of a CMFV trigger being met. In these cases, at the Investigator’s 
discretion, the CMFV assessments may be collected at the routine Month 6 or Month 12 Visit. 
Any assessments that are scheduled to be performed at both the routine visit and the CMFV do 
not need to be performed twice when combining visits in this way.
A comprehensive medical follow-up evaluation (which the subject’s project partner should make 
every effort to attend, if possible), triggered by any of the above, at minimum will include the 
following assessments (refer to Appendix A for a full list of assessments required to be 
performed at a CMFV):

Neurological examination (includes information from project partner).

CDR assessment.

NPI-Q completed by the project partner.

Standard blood chemistry and tests used in evaluating cognitively impaired and dementia 
subjects (eg, thyroid profile, Vitamin B12).

Cognitive Test Battery (only if beyond 3 months from last study visit; otherwise the 
neuropsychological outcome battery from the last visit would be used in the evaluation).

Magnetic resonance imaging (MRI) will be required at a subject’s second consecutive
comprehensive medical evaluation when other evaluation results corroborate a diagnosis of
MCI due to AD in the opinion of the investigator. (Note that this does not need to be the 
second consecutive investigator diagnosis of MCI due to AD, only the second consecutive 
CFMV.). This requirement does not preclude the conduct of an MRI on a for-cause basis or 
to support a potential diagnosis other than MCI due to AD, after discussion with the medical 
monitor. If an MRI scan has been performed for the study within 6 months of the CMFV, an 
additional MRI scan will not be required and the existing scan may be used. For subjects who 


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have contraindications for MRI procedure (such as unremovable ferromagnetic dental work, 
cardiac pacemakers, etc) a computerized axial tomography (CT) scan may be performed 
instead.
If a site determines that a subject and/or project partner are unable to return to the clinic for the 
CMFV within approximately 30 days of the routine study visit, or for the EoS/EW Visit, the 
following options will be permitted in order to collect the required assessments within the 
required timeframe:

Home Visit: with prior approval from Sponsor on a case-by-case basis, qualified site 
personnel may arrange a visit to the subject or project partner’s home in order to perform 
CMFV or EoS/EW assessments. If necessary (ie, confirmatory rule-out for MCI diagnosis at 
second of two consecutive CMFVs), the MRI scan will be performed on the subject in-clinic 
at the earliest opportunity.

Assessment via telephone: If the project partner is not able to return to the site for the CMFV 
or EoS/EW Visit, the site may, with prior approval of the Sponsor on a case-by-case basis, 
conduct the required assessments with the project partner via telephone call. The assessments 
must be carried out by appropriately qualified personnel in advance of the subject 
assessments and within a maximum of one day of the subject’s visit. Visit assessments of the 
subject will still be required in clinic.
After the comprehensive medical follow-up evaluation, the Investigator will consider the totality 
of information collected for the subject and make a clinical assessment which will determine 
subject flow within the study. The timing of sending a subject’s data to the adjudication 
committee after a first (of any potential two consecutive) CMFVs will depend on the 
Investigator’s clinical assessment. 

If an Investigator’s clinical assessment is that the subject is cognitively normal (ie, the 
comprehensive medical follow-up test results did not support the original trigger concern) or 
that the subject has a reversible cognitive impairment (eg, depression, hypothyroidism, 
vitamin B12 deficiency), the subject will continue with routine study visits, and the subject’s 
data will not be forwarded to the adjudication committee at this time. 

If an Investigator’s clinical assessment is that the subject meets criteria for an MCI due to 
AD diagnosis for the first time, the subject will also continue with routine study visits, and 
the subject’s data will not be forwarded to the adjudication committee at this time.

If an Investigator’s clinical assessment is dementia of any type or an irreversible cognitive 
impairment not associated with AD, the subject’s data will be forwarded to the adjudication 
committee immediately. 
At the next regularly-scheduled 6-month visit, the following outcomes can occur:

If the trigger criteria are not met at the regular 6-month visit and the subject was previously 
assessed as cognitively normal or as having reversible cognitive impairment, he/she will 


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continue with routine study visits, and his/her data will not be forwarded to the adjudication 
committee. 

If the trigger criteria are not met at the regular 6-month visit, the subject will still require 
comprehensive medical follow-up evaluation only if he/she met the MCI due to AD criteria 
at the previous CMFV. 

If the trigger criteria ARE met at the regular 6-month visit, the subject will require 
comprehensive medical follow-up evaluation. 
In cases where a second consecutive comprehensive medical follow-up evaluation is conducted, 
the Investigator will make another clinical assessment, but regardless of this outcome, the 
subject’s data will be forwarded to the adjudication committee at this time. 
When adjudication is required, all pertinent data from the subject will be shared with an 
adjudication committee, which will be blinded to the subject’s risk- and treatment-assignments. 
The adjudication process will result in one of three possible outcomes (listed below with relevant 
study dispositions): 
1. Meets Criteria for MCI due to AD (primary study endpoint)
Investigator will be asked to withdraw the subject from the study, the subject will be 
considered a study completer, will be scheduled for an EoS Visit, and will count toward the 
total number of events needed for the primary efficacy analysis. The visit at which the initial 
diagnosis was made will be considered the onset time for the primary endpoint. The subject 
will be offered the opportunity to continue treatment in an extension study. The 
operationalized criteria for MCI due to AD are defined in Table 4.b.
2. Meets Criteria for AD dementia [41].
If probable or possible AD dementia is confirmed, subject will be withdrawn from the study 
and considered a study completer. Subjects will be scheduled for an EoS Visit, and will count 
toward the total number of events needed for the primary efficacy analysis. Subjects will stop 
study treatment and be referred for appropriate standard of care. The operationalized criteria 
is defined in Appendix I.
3. Does not meet criteria for either MCI due to AD or for AD dementia. Subject disposition will 
be at the discretion of the Investigator and will be guided by the following possible 
outcomes:
a) Cognitively normal, MCI due to AD (first diagnosis), or reversible cognitive impairment: 
the subject will continue with routine study Visits.
b) AD dementia, irreversible cognitive impairment (other than MCI due to AD) or non-AD 
dementia: subject will be scheduled for an EoS Visit. (If a principal investigator [PI]
diagnoses AD dementia even after the CIAC report has determined that the subject does 


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not meet criteria for MCI due to AD or for AD dementia, this will not count toward the 
total number of primary endpoint events.)
6.3
Justification for Study Design, Dose, and Endpoints
6.3.1
Study Design
The design of this phase 3 study is one that allows for simultaneous co-development of a 
companion pharmacogenetic test with a therapeutic molecule. While similar studies to date have 
used enrichment strategies based on demographic and clinical risk factors (such as advanced age 
or family history), this study will be the first to use genetic information relevant to late-onset AD 
to enrich a “high-risk” population to increase statistical power for determining the therapeutic 
molecule’s ability to delay onset of cognitive impairment. This enrichment strategy will also 
allow for calculation of both the positive and negative predictive values of the prognostic marker 
and potentially provide a means for decreasing the duration of the trial. 
The therapeutic goal of this phase 3 study - to delay onset of MCI due to AD in cognitively 
normal subjects who are at risk for developing MCI due to AD within the next 5 years - reflects 
the recognition that AD is a continuous process with a clearly identifiable early symptomatic 
stage (MCI due to AD) that commonly occurs years before the onset of fully expressed dementia. 
As such: 1) the timeframe for a high-risk elderly individual to decline along the continuum that 
leads to detectable cognitive impairment is more realistic for a clinical trial than one that leads to 
diagnosed symptomatic AD dementia; and 2) MCI due to AD is a quantifiable construct 
indicative of early brain changes of the disease, and well-established, validated 
neuropsychological and functional instruments that are sensitive to these early changes can be 
used to detect it. 
This study is placebo-controlled, as reliable evaluation of treatments intended for the 
management of central nervous system disorders is not possible without the use of placebo. 
Comparison to placebo is also valuable for distinguishing disease manifestations from adverse 
reactions of the study compound. Furthermore, the use of placebo in subjects at high risk for 
developing MCI due to AD is justified given the lack of effective therapies available for the 
delay of onset of cognitive impairment, and subsequently AD dementia (ie, there is no active 
comparator).
Comparisons between high-risk subjects on placebo with those on active treatment will be used 
to evaluate the efficacy of pioglitazone to delay the onset of MCI due to AD, whereas 
comparison between high-risk subjects on placebo with low-risk subjects (all on placebo) will be 
used for the prospective qualification of the prognostic biomarker risk algorithm within the 
study. 


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6.3.2
Study Dose
Because studies for AD prevention require long treatment durations and large study populations, 
it is not practical to do typical phase 2 studies prior to initiating phase 3 studies. As such a phase 
2 program (including dose finding) was not conducted prior to the AD-4833/TOMM40_301 
study. Still, there are a number of preclinical studies that indicate that pioglitazone increases 
mitochondrial numbers, motility and function at very low doses (relative to doses used to treat 
T2DM) [7]. This effect on mitochondria is hypothesized to be the key mechanism of action 
(MOA) for pioglitazone’s ability to delay the onset of MCI due to AD. In addition to these 
preclinical studies, an imaging study (using functional magnetic resonance imaging [fMRI] was 
carried out in cognitively normal elderly subjects). From this study, it was ascertained that 
pioglitazone has central nervous system (CNS) effects at low doses and that there is a 
demonstrable blood oxygen level-dependent (BOLD) effect in the left hippocampus during an 
encoding task for episodic memory. This was a significant factor in dose selection because the 
intended AD-4833/TOMM40_301 study population is cognitively normal elderly adults, and the 
overall goal in dose selection was to minimize known dose-dependent adverse events 
(eg, edema) while ensuring that pioglitazone can still directly influence brain activity. Based on
the available literature and the results of the fMRI study, pioglitazone sustained release (SR) 0.8 
mg was selected for phase 3.
6.3.3
Study Endpoints
The cognitive test battery proposed in this study has been chosen to be sensitive to early deficits 
in cognition in the relevant ages and to minimize test-retest (practice or learning) effects that are 
particularly problematic in repeated measurements designs with cognitively normal individuals. 
Memory tests are particularly prone to this effect, which may then obscure measurable effects of 
medications on these domains of function. This study, however, employs a rigorous definition of 
memory impairment at Baseline and in defining MCI due to AD, as this practice has been shown 
to result in the highest positive predictive value for later AD outcome in clinical trials of MCI 
[43] and in a longitudinal study [44]. The assessment also includes measures of instrumental 
activities of daily living and depression, for determination of functional and mood changes to 
exclude differential diagnosis associated with impaired cognition. This information, when 
considered with the neuropsychological performance and other clinical variables, including a 
clinical diagnosis by the study PI, increases the specificity of the diagnosis of MCI due to AD.
This study acknowledges the importance of both cognitive and functional decline as key 
assessments in the earliest stage of the AD continuum and includes both of these recommended 
outcomes as key secondary endpoints. There are precedents for cognitive decline as a secondary 
endpoint from previous AD prevention studies. Three of the most recently conducted large-scale 
AD prevention studies (GuidAge, GEMS, and ADAPT) included cognitive decline as a 
secondary endpoint, while two of them (GuidAge, GEMS) also included functional decline or 
disability as a secondary endpoint. In addition, in the very early stages of the AD continuum, 
accelerated decline in multiple cognitive domains can be noted 5 to 6 years before Alzheimer’s 


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Dementia is diagnosed, whereas such decline is usually not observed in elderly individuals who 
do not eventually develop AD [45]. However, decline in functional abilities is often slower to 
develop in the early stages of AD and are usually more impactful after a person has already been 
diagnosed with MCI or AD. Albert et al, 2011 note that one of the core clinical criteria for the 
MCI due to AD diagnosis is preservation of independence in functional abilities, because while 
certain activities of daily living may take more time to execute as cognition begins to decline, 
individuals in this phase of the AD continuum can still usually perform instrumental activities of 
daily living (such as pay bills, drive, or prepare food) with minimal assistance [38]. Similarly, in 
a proposal to revise the definition of AD to include both predementia and dementia phases, 
Dubois et al, [46] describe “prodromal AD” as a stage where episodic memory deficits are 
present but do not affect instrumental activities of daily living.
6.4
Premature Termination or Suspension of Study or Investigational Site
6.4.1
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 data and safety monitoring board (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.

Study-specific criteria for terminating the study (eg, study meets predefined rule for futility) 
as described in Section 13.2, “Futility Analysis and Criteria for Early Termination”. 
6.4.2
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.
6.4.3
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 


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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 any test results, need to be confirmed prior to randomization. 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures.
3. The subject is able to physically perform the cognitive tests in the opinion of the investigator 
and is fluent in the language that tests will be administered.
4. The subjects must be cognitively normal at baseline, scoring as indicated for the following 
tests: 

CDR=0. 

At least one memory test above -1.5 SD of the demographically corrected normative 
mean.
5. The subject must score ≥25 on the MMSE at the screening visit after the education and age 
adjustment referenced in Appendix G.
6. The subject is male or postmenopausal female between the ages of 65 and 83 years, 
inclusive, at time of the Screening visit.
7. The subject has the ability and intention to participate in regular study visits, in the opinion 
of the Investigator.
8. The subject has a project partner able to complete an Acknowledgement Form on his/her own 
behalf and take part in the study (with the intent to do so as long as the subject is enrolled) to 
provide information on the cognitive, functional, and behavioral status of the subject and to 
assist with monitoring of study medication, if needed.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has a current diagnosis or history of any type of cognitive impairment or 
dementia, or has a current diagnosis or history of neurological/psychiatric disorder or any 
other diagnosis that significantly affects cognitive performance (eg, mental retardation, 
organic mental disorder).
2. The subject has a current diagnosis of significant psychiatric illness, per Diagnostic & 
Statistical Manual of Mental Disorders, 4th Edition - Text Revision (DSM-IV-TR) (or 


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35DSM-V when published) (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 glycosylated hemoglobin (HbA1c) >8.0% at the time of baseline or 
requires treatment with insulin, triple oral antidiabetic therapy or a PPAR-agonist. The 
subject should be on a stable antidiabetic regimen for at least 3 months prior to enrollment.
4. 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. History of human 
immunodeficiency virus (HIV) infection is considered exclusionary for this study.
5. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse/dependence within 2 years prior to the Screening Visit.
6. The subject is an immediate family member, testing center employee, or is in a dependent 
relationship with a testing center employee who is involved in conduct of this study 
(eg, spouse, parent, child, and sibling) or may consent under duress. 
7. The subject has a history of hypersensitivity or allergies to pioglitazone or related 
compounds.
8. The subject is required to take excluded medications as specified in the Excluded 
Medications Section (Section 7.3).
9. The subject had any of the following values at the Baseline Visit (Visit 2):
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 of the initial assessment.
10. The subject is positive for either Hepatitis B surface antigen (HBsAg) or anti-hepatitis C 
virus (HCV) antibodies at the Baseline Visit (Visit 2).
11. The subject has a condition 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.
12. The subject has received any investigational compound within 30 days prior to screening or 
5 half-lives prior to Screening or is currently participating in another study which entails the 
administration of an investigational or marketed drug, supplement or intervention including, 
but not limited to diet, exercise, lifestyle or invasive procedure.


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13. The subject has a history of any cancer that has been in remission for less than 2 years from 
the Screening Visit. Subjects with basal cell or stage I squamous cell carcinoma of the skin 
will be eligible. Subjects with history of bladder cancer are not eligible irrespective of the 
remission status.
14. The subject has a history or current diagnosis of macular edema or macular degeneration.
15. If female, the subject has a history of postmenopausal fractures with no or minimal trauma 
(eg, wrist, hip, lumbar or thoracic vertebral fracture).
16. The subject has a history or current diagnosis of CHF, New York Heart Association Class 
III-IV.
17. The subject has been exposed to the cognitive tests performed in this study within 6 months 
prior to the Screening Visit, with the exception of the MMSE.
18. The subject’s TOMM40 rs10524523 or APOE genotypes or APOE phenotype are known by 
the subject or the study staff participating in this study.
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. Table 7.a describes medications disallowed prior to Baseline
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 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] (eg. 
Adderal, Concerta, 
Dexedrine, modafanil)
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 Baseline
(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])
Antidepressants
Conditional, if stable dose at least 
3 months prior to Baseline
(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 Baseline 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
(Subject continues if condition met [a])
Benzodiazepines and non-
benzodiazepines sleep 
aides (zopiclone, 
eszopiclone, zolpidem)
Conditional, if stable dose at least 
3 months prior to Baseline
(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 Baseline
(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 Baseline
(Subject eligible if condition met)
Prohibited, if chronic use initiated 
(Subject must be discontinued)
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 Baseline Visit
During the Study
L-Dopa/carbidopa or any 
other Parkinson 
medication for the 
treatment of Parkinson 
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 Baseline
(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 Baseline
(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)
Pioglitazone or any other 
PPAR-agonist
Conditional, if prior use was stopped 
30 days or 5 half-lives – whichever is 
longer – prior to Baseline
(Subject eligible if condition met)
Prohibited, if initiated
(Subject must be discontinued)
Chemotherapy drugs (b)
No use in the past 2 years before the 
Baseline Visit
Prohibited, if initiated
(Subject must be discontinued)
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 followed 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 ([e]CRF) using the following categories. For screen 
or baseline failure subjects, refer to Section 9.1.13.
1. Pretreatment event (PTE) or adverse event (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 AESIs please refer to Section 10.2.1.3.


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2. Liver Function Test Abnormalities
Based on local country criteria, subjects in a clinical trial who experience ALT and/or AST
>3 ×ULN and total bilirubin >2xULN and satisfy the following two 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 48-72 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 x ULN.

ALT or AST >5 x ULN and persists for more than 2 weeks.

ALT or AST >3 x ULN in conjunction with elevated total bilirubin >2 x ULN or 
international normalized ratio (INR) >1.5.

ALT or AST >3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
3. Major protocol deviation. The discovery post-randomization 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.
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.
5. Voluntary withdrawal. The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the (electronic) case report form ([e]CRF).
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due to 
an AE or lack of efficacy should not be recorded in the “voluntary withdrawal” category).
6. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
7. Other.
Note: The specific reasons should be recorded in the “specify” field of the (e)CRF.


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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 EW 
Visit. Discontinued or withdrawn subjects will not be replaced.
Subjects who discontinue study medication prematurely should be contacted by the study site 
every 6 months until the conclusion of the study via telephone to assess the general well-being of 
the subject as well as to obtain any changes in medications related to cognitive health. In the 
event the subject is not able to be reached, the subject’s caregiver or primary care physician can 
be contacted to obtain this information.


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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 all or any of the drugs defined below. 
AD-4833 SR 0.8 mg Tablets and placebo will be provided in high density polyethylene (HDPE) 
bottles containing a desiccant. The active formulation contains drug substance and excipients and 
the placebo formulation contains excipients only. These tablets are for oral administration. 
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 HDPE bottle contains
100 tablets and a desiccant and has a child resistant cap. The bottles will be labeled with a 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 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 tablet placebo and AD-4833 SR 0.8 mg Tablet.
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.


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8.1.3
Dose and Regimen
This is a placebo-controlled, double-blind, parallel group study comparing AD-4833 SR 0.8 mg 
Tablet to Placebo. Subjects will be randomized in a blinded fashion to one of the following 
within the following two subject groups, Non-Hispanic/Latino Caucasian and Non-Caucasian or 
Hispanic/Latino Caucasian. 
Table 8.a describes the dose and tablet count that will be provided to each group.
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 adverse events) will be documented on an 
Overdose page of the (e)CRF, in order to capture this important safety information consistently 
in the database. Adverse events associated with an overdose will be documented on AE CRF(s) 
according to Section 10.0, PTEs and AEs.
Serious adverse events 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 IWRS at Screening to obtain the 
subject study number. The investigator or the investigator’s designee will utilize the IWRS to 
randomize each qualified subject into the study at Visit 3. During this contact, the investigator or 
designee will provide the necessary subject-identifying information, including the subject 
number assigned at screening.
The investigator or investigator’s designee will access the IWRS at each dispensing visit to 
obtain medication identification numbers (Med IDs) for up to two bottles containing 100 tablets 


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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. 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 
randomization 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 investigator must maintain records of all sponsor-supplied drug delivery to the site. The site 
will receive a confirmation email from the IWRS providing the Med ID’s 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. The investigator or designee will maintain records of site 
inventory, dispensation and use by each subject, and return of investigational medicinal product 
(IMP) to the sponsor or designee. Drug supplies will be counted and reconciled at the site before 
being returned to the sponsor or designee.
8.3
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule 
and will provide it to the IWRS vendor prior to the start of this study. All randomization 
information will be stored in a secured area, accessible only by authorized personnel.
Based on statistical requirement, a minimum of 2,793 subjects will be stratified into high- and 
low-risk groups (for the development of MCI due to AD over the next 5 years) based upon the 
results of the biomarker risk algorithm. Subjects will be randomized into this study as follows:

Non-Hispanic/Latino Caucasian subjects. Approximately 2,660 subjects further divided into:
–
Approximately 2,346 subjects in the high-risk group (pioglitazone n=1,173; placebo 
n=1,173).
–
Approximately 314 subjects in the low-risk group: All subjects stratified to the low-risk 
stratum will also be randomized to maintain the stratification blind, but all subjects in this 
stratum will receive placebo. 

Non-Caucasian and Hispanic/Latino Caucasian subjects: Subjects will be allocated to strata 
using the same algorithm as for the non-Hispanic/Latino Caucasian subjects.
Since all subjects screened at the time of Amendment 5 will be allowed to randomize if they 
continue to meet all eligibility criteria, it is estimated that approximately 3,500 will be 
randomized with the following groups:

Non-Hispanic/Latino Caucasian subjects. Estimated 3,330 subjects further divided into:
–
Approximately 2,940 subjects in the high-risk group (pioglitazone, n=1,470; placebo, 
n=1,470).


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–
Approximately 394 subjects in the low-risk group: All subjects stratified to the low-risk 
stratum will also be randomized to maintain the stratification blind, but all subjects in this 
stratum will receive placebo. 

Non-Caucasian subjects and Hispanic/Latino Caucasian subjects. Subjects will be allocated 
to risk strata using the same algorithm as for the non-Hispanic/Latino Caucasian subjects 
(n=167). 
It is anticipated that at least as many low-risk subjects will be available for screening as high-risk
subjects. Since only 314 low-risk subjects are needed, low-risk subjects who pass all other 
eligibility criteria and are eligible to enter the study will only be randomized into the study if the 
requirements for a pre-specified allocation scheme are met. This scheme is designed to ensure 
that low-risk subjects are enrolled throughout the whole duration of the study enrollment period 
and it is detailed in the IWRS specifications.
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 (e)CRF.
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 Tablets and AD-4833 Tablet placebo. 
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 Tablets and AD-4833 Tablet 
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.


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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 Tablet and AD-4833 Tablet placebo on a sponsor-approved drug accountability log or 
within IWRS. The following information will be recorded at a minimum: protocol number and 
title, name of investigator, site identifier and number, description of sponsor-supplied drugs, 
expiry or retest 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.
On expiry date notification from the sponsor or designee or IWRS, the site must complete if 
provided, 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 


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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. This consent will include the risk stratification 
sample collected to determine their TOMM40 rs10524523 and APOE genotypes. If sites prefer 
to split the ICF process at Visit 1 and Visit 2 into a screening informed consent and study entry 
informed consent and have IEC/IRB approval to do so, this is permitted.
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) will 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: HTTPS, 
FTPS and SSL. The vendor will store the recordings on a secure, password protected server. 
Recordings will be deleted one year after the last subject visit.
Pharmacogenomic Informed Consent Procedure
Informed consent pertaining to the PGx 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 PGx sample is independent of consent to the other aspects of the study. Combining 
the PGx sample informed consent within the main study informed consent form is permitted at 
sites, if Sponsor/IEC/IRB approval is received.
Project Partner Acknowledgement Form Procedure
The subjects must have a project partner able to complete an Acknowledgement Form 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 is in the study. The Project Partner Acknowledgement Form must be 


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obtained from the project 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 9.1.15.2. Should the project partner change during the course of the study, an 
Acknowledgement Form 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 to be obtained will include date of birth or age, sex, Hispanic/Latino
ethnicity, race as identified by the subject, years of education and academic degrees, 
bilingualism, years lived in the country/region, occupation, smoking status, and drinking habit of 
the subject at Screening Visit. 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 EoS/EW Visit.
Medical history, including family history of dementia and related conditions, to be obtained will 
include determining whether the subject has any significant conditions or diseases relevant to the 
disease under study that stopped at or prior to signing of informed consent. Ongoing conditions 
are considered concurrent medical conditions (see Section 9.1.7). Medical history will be 
collected at screening. Family history will be collected at the first 6 month visit and at the 
EoS/EW visit.
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 3 months prior to signing of informed consent.
9.1.3
Physical Examination Procedure
A baseline physical and neurological examination (defined as the pretreatment assessment at 
Baseline (Visit 2) 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 
Visit 2 (Baseline), each yearly visit (eg, month 12, 24, 36) of double-blind treatment, 
Unscheduled Visit, and EoS/EW Visit. Neurological examination will be performed at Visit 2 
(Baseline), every 6 month visit during double-blind treatment, Unscheduled Visit, and EoS/EW 
Visit.
9.1.4
Weight, Height 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. 
Height will be collected at Visit 2 (Baseline), each yearly visit (eg, month 12, 24, 36), and 
EoS/EW Visit in centimeters without decimal places. 


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Weight will be measured at Visit 2 (Baseline), every 6 month visit during double-blind 
treatment, and EoS/EW 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 will be measured at Visit 2 (Baseline), at each 6 month in clinic visit of double-blind 
treatment, unscheduled and at the EoS/EW 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, with the exception of the Visit 1 (Screening), 
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 (e)CRF.
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 16 mL, and the approximate total 
volume of blood for the study is 87 mL. Details of these procedures and required safety 
monitoring will be given in the laboratory manual. Table 9.a lists the laboratory tests that will be 
required by the protocol. 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 
Red blood cells
White blood cells count 
with differentials 
(Neutrophils, Eosinophils, 
Basophils, Lymphocytes, 
Monocytes)
Hemoglobin
Hematocrit
Platelets
HbA1c (b)
Alanine aminotransferase
Alkaline phosphatase
Aspartate aminotransferase
Total bilirubin
Direct bilirubin (a)
-Glutamyl transferase 
Total protein
Albumin
Creatinine
Blood urea nitrogen
Potassium
Sodium
Glucose
Calcium, parathyroid hormone (PTH)
Thyroid-stimulating hormone (TSH), free thyroxine 
(T4)
Vitamin B12, folate (c) 
Rapid plasma reagin (RPR) (c)
pH
Specific gravity
Protein
Glucose
Blood
Nitrite
Microscopic examination 
(Leucocytes, Erythrocytes, 
Casts)
Blood 
Hepatitis panel, including HBsAg and anti-HCV (b)
(a) Assess only if total bilirubin ≥2.0 mg/dL.
(b) To be done at Baseline only.
(c) At Baseline and as part of the comprehensive medical follow-up evaluation to rule out other causes of dementia.
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.
A separate contract laboratory will perform the TOMM40 rs10524523 and APOE genotyping. 
The result of the genotyping will remain blinded to the site, subject, and study team.
Should the subject be excluded from the study due to acute lab exclusions (eg, blood in urine) at 
Visit 2 that may resolve upon retesting, the subject is permitted to be retested within a window of 
2 weeks. Re-testing will only be allowed on safety lab data, not cognitive testing or at Visit 1 for 
the risk stratification sample. In this situation, sites should not enter that the subject baseline
failed into the electronic data capture (EDC) or IVRS until the retest results are completed and 
verified.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, -glutamyl transferase [GGT], and INR) should 
be performed within a maximum of 7 days and preferably within 48-72 hours after the 
abnormality was found.


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(Please refer to Section 7.4 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests 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 Liver Function Tests for reporting requirements).
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 (e)CRF from the subject’s ECG trace: heart rate, 
QT interval, QRS interval, and QT (corrected). ECG will be recorded at Visit 2 (Baseline), each 
yearly visit (eg, month 12, 24, 36) of double-blind treatment, and EoS/EW Visit.
9.1.11 Genotyping
9.1.11.1 Risk Stratification Samples (subject enrichment sample)
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9.1.11.2 Pharmacogenomics Samples
There is growing evidence that genetic variation may impact a subject’s response to therapy. 
Variable response to therapy may be due to genetic determinants that affect drug absorption, 
distribution, metabolism, and excretion, the molecular pathways of drug response, the disease 
etiology and/or the molecular subtype of the disease being treated, and disease progression 
(eg, conversion to MCI due to AD). Furthermore, and in accordance with regulatory guidance 
and white papers, PGx analyses using DNA and/or ribonucleic acid (RNA) collected from trial 
participants who provide separate consent may support investigation of any unexpected adverse 
events.
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.
CCI
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When sampling of whole blood for pharmacogenomic analysis occurs, every subject must sign 
informed consent/be consented in order to participate in the study.
The schedule for this DNA and RNA collection is found in the Study Schedule and identified as 
Safety/Efficacy PGx (DNA and RNA samples) – subject-optional. See Appendix E for directions 
on collecting, handling, and storing PGx samples. These samples are optional and should be 
collected from those subjects who provide independent consent to do so.
In the event of an unexpected adverse event or the observation of unusual response, DNA or 
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, GWAS 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 adsorption, 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 DNA sample and 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. As with the procedure for the risk stratification sample, PGx data from 
this sample will not be provided back to the investigator or the subject.
9.1.12 Pharmacokinetic Sample Collection and Analysis
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of study subjects have consented to the PK collection, future subjects will not have PK samples 
collected.
Blood sample collection times are listed in Table 9.b.
Subjects will be asked to take their medication at approximately 8:00 AM on the day before the 
scheduled PK blood draw and the day of the PK blood draw. Subjects will be asked to arrive at 
the clinic according to their assigned group’s time. However, if a patient arrives for a visit 
outside of their scheduled time period, the PK samples should still be collected. The time of 
study medication dosing and the drawing of blood samples are critical. For each of the blood 
sample collections, subjects will be asked to report the dates and times of their last dose of study 
medication prior to the blood sample collection; this information will be recorded on the 
appropriate (e)CRF. The exact time of the blood sample collections will also be recorded on the 
appropriate (e)CRF.
Table 9.b
Schedule for Pharmacokinetic Sample Collection
Group
Dosing Time 
(approximate)
Sample Collection
Sample Collection Time Postdose
Predose
1-1.5 hr
Start of visit
End of visit
1 (a)
8:00 AM
X
X
2 (b)
8:00 AM
X
X
3 (c)
8:00 AM
X
X
4 (d)
8:00 AM
X
X
(a) Subjects will arrive at the clinic prior to study drug administration.
(b) Subjects will arrive between 9 AM and noon, one PK sample will be taken at the beginning of the visit and one 
at the end of the visit.
(c) Subjects will arrive between noon and 3 PM, one PK sample will be taken at the beginning of the visit and one at 
the end of the visit.
(d) Subjects will arrive after 3 PM, one PK sample will be taken at the beginning of the visit and one at the end of 
the visit.
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9.1.12.1 Bioanalytical Methods
9.1.13 Documentation of Screen Failure and Baseline Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible at the Screening Visit or prior to the Baseline Visit, the 
investigator should complete the (e)CRF. The IWRS should be contacted as a notification of 
screen failure.
If the subject is found to be not eligible at the Baseline Visit or prior to the Randomization Visit, 
the Investigator should complete the (e)CRF. The IWRS should be contacted as a notification of 
baseline failure.
The primary reason for screen failure or baseline failure is recorded in the (e)CRF 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.
!
Study termination.
!
Other.
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.14 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable (e)CRF. The IWRS should be contacted as a 
notification of baseline failure.
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9.1.15 Assessments
9.1.15.1 Cognitive Test at Screening 
At the Screening Visit, subjects will be tested to determine if their cognitive status qualifies them 
for entry to the study. The screening instrument will be the MMSE [47]. The MMSE is a 
measurement of global cognitive function, includes 11 items that assess orientation to time and 
place, language, verbal registration, memory, and praxis. Scores on this instrument range from 
zero to 30, with lower scores indicating greater cognitive impairment. At the Screening Visit, 
MMSE scores should always be adjusted for education and age (Appendix G). Scores ≤24 after 
age and education adjustment are considered impaired. The MMSE will also be collected at the 
Baseline Visit, every 6 months after randomization (ie, each Study Visit), and at the EoS/EW
Visit.
9.1.15.2 Efficacy Assessments
Cognitive Tests in the Cognitive Test Battery
Neuropsychological testing will be conducted at Baseline (Visit 2) and each scheduled visit 
(every 6 months) using a broad cognitive test battery (Section 4.2.3). The battery will also be 
conducted as part of the comprehensive medical follow-up evaluation (at an Unscheduled Visit), 
if one of the triggers described in Section 6.2 is met and at the EoS/EW Visit, if either of these 
visits occur greater than 3 months after the previous regularly scheduled visit. The instruments 
used in the battery are all tools commonly used to evaluate AD in the clinical development 
setting. It is anticipated the cognitive battery will take approximately 60-90 minutes to 
administer at each applicable visit. Additional details regarding test administration will be 
provided in the Training Manual provided by the vendor selected by Takeda.

Brief Visuospatial Memory Test - Revised (BVMT-R [48]): One of the equivalent alternate 
forms of the BVMT-R is used to assess immediate and delayed nonverbal memory. The 
subject is presented with a card depicting six 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. Approximately 25 minutes after the initial presentation, the subject is asked to 
draw the designs again. Immediately thereafter, a yes/no recognition trial is administered. 
The use of alternate BVMT-R forms will be counterbalanced across visits. 

California Verbal Learning Test – Second Edition (CVLT-II [49]): (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 
four words from each of four 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 one trial. This second list contains 
words drawn from 2 semantic categories of List A (animals, vegetables) and two new 
categories (musical instruments, parts of a house). After presentation of List B, recall of 


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List A is assessed with free recall and cued recall procedures. Long term delayed recall and 
recognition memory of List A are tested 20 minutes later. Indices of learning include total 
number of words correctly recalled across Trials 1-5. 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 pre-determined counterbalance schedule.

Semantic Fluency [50]: Semantic fluency measures verbal production, semantic memory, and 
language. Participants are asked to name as many examples of animals as possible in one 
minute.

Lexical/Phonemic Fluency [50]: For lexical fluency, the participant is asked to produce as 
many words as possible that begin with a specified letter. Participants will have one minute 
to produce exemplars for each letter (F, A, and S). The number of words from each letter will 
be combined for a total score. Verbal fluency letters F, A, and S will vary across languages 
based upon the frequency of letters in the local language.

Wechsler Adult Intelligence Scale (WAIS)-III Digit Span Test [51]: The WAIS-III Digit 
Span subtest is used to assess auditory attention and working memory. Both forward and 
backward span will be assessed. The forward test consists of 8 pairs of number sequences 
and backward consists of 7 pairs that the tester reads aloud one at a time. After each sequence 
is read, the subject must repeat the digits back in the same (forward) or reverse (backward) 
order.

Visual naming test from the MINT, [52]. The MINT is a test of confrontation naming ability 
that was designed to measure this aspect of language in monolingual and 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. 
Normative data are available for normal older monolingual (English) and bilingual adults
(English/Spanish). Preliminary studies support its sensitivity to detecting mild naming 
deficits [52]. The test is comprised of 32 items that are presented to the participant in 
increasing order of difficulty. The maximum score is 1.

Trail Making Test (TMT) A & B [53]: 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 two categories in sequential order (1-A, 2-B, 3-C, and so on) and time to 
completion is recorded.

Brief Visuospatial Memory Test - Revised (BVMT-R) [48] constructional copy condition: 
Constructional praxis will be assessed using equivalent alternate forms of the BVMT-R. The 


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subject is presented with a card depicting six 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 
placement and accuracy of reproduction of the 6 figures.

Clock Drawing Test (CDT) [54]: The CDT is a test that taps elements of visuospatial 
analysis, planning, organization, and semantic knowledge. The scoring method evaluates the 
participant’s ability to reproduce three 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 three error subtypes, with higher scores indicating better performance 
[55].
Subject-Reported Outcome Questionnaires
In addition to the cognitive test battery, the following assessments will also be conducted at the 
time points stipulated in the Schedule of Study Procedures (Appendix A):

Self-Rating of Memory Functions: Self assessment of memory function will be obtained 
using the Alzheimer’s Disease Cooperative Study Prevention Instrument Project - Mail-In 
Cognitive Function Screening Instrument (ADCS-MCFSI) [42]: This is a 14-item self 
administered yes/no questionnaire to assess recent changes (over the last year) in cognition 
and functional activities which commonly are affected in the development of MCI.

Geriatric Depression Scale (GDS) [56]: This is a 15-item (short form) self-administered 
yes/no question test constructed for brief screening of depression in elderly persons.

Assessment of HRQoL will be done using the EQ-5D [57,58] measure from the EuroQOL 
Group, and the SF-36 [59]. These assessments will be completed by all subjects enrolled in 
the study.

Health care resource utilization during the study period will be measured by the Alzheimer’s 
Disease Cooperative Study - Resource Use Inventory (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. This questionnaire will be completed at Visit 2 (Baseline), 
every 6 month visit during double-blind treatment, Unscheduled Visit for comprehensive 
medical follow-up, and EoS/EW Visit. 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.
Project Partner-Reported Questionnaires

Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) [60]: The IQCODE 
is a 26-item questionnaire that asks the project partner about changes in an elderly person’s 
everyday cognitive function. The questionnaire aims to assess cognitive decline independent 


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of pre-morbid ability. Research revealed that it has high reliability, sensitivity, and 
specificity, and it is very useful in differentiating elderly suffering from dementia from those 
experiencing normal aging. This questionnaire will be completed at Visit 2 (Baseline), every 
6 month visit during double-blind treatment, and EoS/EW Visit.

Alzheimer’s Disease Cooperative Study Instrumental Activities of Daily Living – Prevention 
Instrument (ADCS ADL-PI) [61]: The ADCS ADL-PI is a functional measure that was 
specifically designed for standardized administration in long follow-up, AD prevention, 
clinical trials as a secondary outcome measure. It can be given in the format of an interview, 
either directly or by phone. Delay of onset and slowed progression therapy should show 
preserved or slower deterioration on activities of daily living. The ADCS ADL-PI is a 20-
item instrument that includes 15 ADL questions plus 5 vision, hearing, and mobility 
questions. This questionnaire will be completed at Visit 2 (Baseline), every 6 month visit 
during double-blind treatment, and EoS/EW Visit.

Neuropsychiatric Inventory Questionnaire (NPI-Q) [62]: The NPI-Q is a brief validated 
version of the standard NPI [63]. It is designed to assess NPS common in AD and related 
dementias. The NPI-Q is designed to be a self-administered and queries the presence of 
symptoms in each of 12 specific domains and is queried over the past 30 days: delusions, 
hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, 
apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, disturbances 
of sleep, and disturbances of appetite/eating. In special cases when Sponsor permission is 
given for the project partners to have the CMFV or EoS/EW Visit conducted by telephone, 
the questionnaire will no longer be self administered but will be conducted aurally over the 
telephone, more in keeping with the standard NPI, which was designed to be clinician 
administered with a query question (the items on the NPI-Q) followed by more detailed 
interviewing. The scale is constructed such that a screening question is asked for each 
symptom domain. If this item is endorsed, then specific follow up questions are asked to 
clarify the nature of the symptoms, their frequency, severity, degree of change from 
premorbid, and treatment. The NPS outcome variable is defined as either the presence or 
absence of a given NPS domain. The NPI can also be analyzed by dividing into absence of 
any NPS versus >1 NPS (NPI Total). NPI severity can also be calculated. The physician 
reviews the form and clarifies the nature and the presence of symptoms endorsed. This 
questionnaire will be completed at Visit 2 (Baseline), Unscheduled Visit, and EoS/EW Visit.
Investigator-Completed Questionnaire

Clinical Dementia Rating (CDR) [64]: The CDR is a clinician - completed structured 
interview with participant and project partner designed to assess an individual’s cognitive 
and functional performance in six areas for purposes of determining the severity of dementia 
symptoms. The six 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. Using an algorithm that takes into account the individual domain 


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scores, a total CDR score can be assigned. A CDR global score of 0 indicates normal 
function, whereas, a CDR global score of 0.5 indicates 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 six individual domain scores, resulting in a “sum of boxes”
(CDR-SB) score. This continuous measure, which will also be calculated for this study, 
allows a sensitive measure of cognitive and functional change in early AD progression [65].
The CDR will be completed at Visit 2 (Baseline), Unscheduled Visit, and EoS/EW Visit.

Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change – Mild 
Cognitive Impairment (ADCS-CGIC-MCI) [66]: This measure captures the clinician’s global 
impression of the subject. This measure will be completed at Visit 2 (Baseline), every 
6 month visit during double-blind treatment, Unscheduled Visit, and EoS/EW Visit.
9.1.16 Assessment of Suicidal Ideation and Behavior
The Columbia–Suicide Severity Rating Scale (C-SSRS; [67]) 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 subquestions 
assessing the severity. The tool is administered via interview with the subject. Different versions 
of the scale are available. In this study, “Baseline” version will be used at Visit 3 
(Randomization) and “Since last visit” version at all subsequent visits. 
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-SAEs in accordance with the standard 
adverse event reporting requirements (eg, if a pre-existing suicidal ideation recorded on the 
screening 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 (e)CRF, 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, ie, self-imposed cigarette burns, will be collected as 
non-SAEs.


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9.1.17 Order of Assessments 
Sites should make every attempt to adhere to the assessment schedule in Table 9.c. Should an 
interruption occur during the visit, the subject, and/or project partner, may return to the site 
within 2 weeks to complete the assessments. During the Baseline Visit only, sites may elect to 
administer the CDR prior to the Cognitive Test Battery to evaluate subject eligibility. 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 test results.
Table 9.c
Order of Assessments
Cognitive Test/Questionnaire
Visit
Assessor
MMSE
Visit 1, Visit 2, every 6 and 12 month 
visit after randomization, EoS/EW Visit
Certified tester
Cognitive Test Battery (completed in this 
order) 
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. CDT.
Visit 2, every 6 and 12 month visit after 
randomization, Unscheduled Visit, 
EoS/EW Visit
Certified tester
GDS
Visit 2, every 6 and 12 month visit after 
randomization, EoS/EW Visit
Study Subject
Footnotes are on last table page.


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Table 9.c
Order of Assessments (continued)
Cognitive Test/Questionnaire
Visit
Assessor
ADCS-MCFSI
Visit 2, every 6 and 12 month visit after 
randomization, EoS/EW Visit
Study Subject
EQ-5D
Visit 2, Unscheduled Visit, EoS/EW 
Visit
Study Subject
SF-36
Visit 2, Unscheduled Visit, EoS/EW 
Visit
Study Subject
IQCODE
Visit 2, every 6 and 12 month visit after 
randomization, EoS/EW Visit
Project Partner
ADCS ADL-PI
Visit 2, every 6 and 12 month visit after 
randomization, EoS/EW Visit
Trained Tester
NPI-Q
Visit 2, Unscheduled Visit, EoS/EW 
Visit
Project Partner
ADCS-RUI
Visit 2, every 6 and 12 month visit after 
randomization, Unscheduled Visit, 
EoS/EW Visit
Trained tester
CDR (a)
Visit 2, Unscheduled Visit, EoS/EW 
Visit
Investigator/ Sub-
Investigator (b)
ADCS-CGIC-MCI (c)
Visit 2, every 6 and 12 month visit after 
randomization, Unscheduled Visit, 
EoS/EW Visit
Trained tester (b)
AE Assessment
Visit 2, Visit 3, every 6 and 12 month 
visit after randomization, every 3 and 
9 month phone visit, Unscheduled 
Visit, EoS/EW Visit and follow up visit
Investigator/ Sub-
Investigator
C-SSRS
Visit 3, every 6 and 12 month visit after 
randomization, EoS/EW Visit, and 
follow up visit
Certified tester
(a) May be administered prior to the Cognitive Test Battery only during the baseline visit.
(b) Sites may utilize the same Investigator/Sub-Investigator tester administering the CDR for the ADCS-CGIC-MCI.
(c) May be administered in parallel with other assessments.
9.1.17.1 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 certified translations provided by TDC 
(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 (e)CRF.


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9.1.18 Tester Monitoring Management Program
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.
9.1.19 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 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. 
9.1.20 Health Economics and Outcomes Research Assessments
EQ-5D measure from the EuroQOL Group, and the SF-36 will not be used as a primary means to 
collect AEs. However, should the investigator become aware of a potential AE through the 
information collected with this instrument, proper follow-up with the patient for medical 
evaluation should be undertaken. Through this follow-up if it is determined that an AE not 
previously reported has been identified, normal reporting requirements should be applied. 
9.1.21 Imaging
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 collection of images in the 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 (e)CRF. Detailed instructions 
for the processing and shipping of images will be provided separately.


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For subjects who have contraindications for MRI procedure (such as unremovable ferromagnetic 
dental work, cardiac pacemakers, etc) a CT scan may be performed instead.
Imaging will be part of the comprehensive medical follow-up evaluation to rule out other causes 
of dementia and to provide supplemental information for an adjudicated clinical diagnosis of 
MCI due to AD during an Unscheduled Visit, as described in Section 6.2.4.
9.1.22 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 [68]. Although supplementation of a woman’s diet with these essential 
nutrients may be considered, recent guidance from the US Preventive Service Task Force 
(http://www.uspreventiveservicestaskforce.org/uspstf/uspsvitd.htm) has highlighted the uncertain 
risk/benefit balance of this approach. 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% 
[69]. Weight-bearing exercise can be as simple as brisk walking. Diet and exercise evaluation 
will be performed at Visit 2 (Baseline), every 6 month visit during double-blind treatment, and 
EoS/EW Visit.
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 (e)CRF. The 
project partner will also be asked to assess the subject’s compliance.
Subjects will be considered to be non-compliant with study medication if they miss >20% of 
doses required for the visit period, or take more than 100% of the doses for the required visit 
period. Non-compliance with study medication must be reported in the (e)CRF and subjects 
should be reminded of the importance of being compliant with dosing instructions. Any detected 
overdose must be reported on an Overdose page of the (e)CRF.
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.
During telephone visits that will occur yearly on the 3 month and 9 month interval, treatment 
compliance should be evaluated during the conversation.


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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
Screening 
Subjects will be screened (Visit 1) prior to Baseline (Visit 2). Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.13 for procedures for documenting screening failures. See Appendix A for list of 
procedures that will be performed and documented. It is anticipated the Screening visit will be 
about 45 minutes in length.
9.3.2
Baseline
Prior to the subjects returning to the site for the Baseline visit (Visit 2), the site will receive 
notification from IWRS to indicate if the Baseline visit should be scheduled based on the blinded 
risk assessment as determined by the screening visit. Baseline visit will take place prior to 
Randomization (Visit 3). Sites will complete a pre-randomization eligibility verification form for 
subjects who meet the baseline requirements. The form will be submitted to the CRO medical 
monitor for review and confirmation of inclusion/exclusion criteria. See Section 9.1.13 for 
procedures for documenting baseline failures. See Appendix A for list of procedures that will be 
performed and documented. It is anticipated the Baseline visit will be about 4 hours in length.
9.3.3
Randomization
Randomization will take place on Day 0 and no more than approximately 35 days after baseline. 
See Appendix A for list of procedures that will be performed and documented.
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IVRS/IWRS system, as described in 
Section 9.1.14. Subjects will be instructed on when to take the first dose of investigational drug 
as described in Section 6.1. The procedure for documenting Screening and Baseline failures is 
provided in Section 9.1.13. It is anticipated the Randomization visit will be about 45 minutes in 
length.
9.3.4
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.


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9.3.5
Unscheduled Visit
There are 2 types of Unscheduled Visits in this study: 1) Unscheduled Visits conducted to 
address any other emerging concerns, including safety, and 2) Unscheduled Visits conducted for 
Comprehensive Medical Follow-Up after a trigger relating to cognitive status has been met.
9.3.5.1
Unscheduled Visits for Other 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 (non-cognitive) concerns, the Investigator is expected to conduct whatever assessments are 
necessary to manage the needs of the subject appropriately. 
9.3.5.2
Comprehensive Medical Follow-Up
A Comprehensive Medical Follow-Up evaluation (which the subject’s project partner should 
make every effort to attend, if possible, or otherwise complete during a Home Visit or via 
telephone if appropriate), should be conducted within approximately 30 days of the trigger when 
one of the triggers described in Section 6.2.4 has been met. This type of Unscheduled Visit will 
include the assessments noted in Appendix A and Section 6.2.4. If appropriate, the CMFV 
assessments may be performed during the routine visit if the specific criteria specified in 
Section 6.2.4 are met. It is anticipated this visit will be about 5 to 6 hours in length, if an MRI is 
completed during the visit.
9.3.6
Final Visit or Early Termination
The Final visit will be performed once the total number of endpoints are reached, which is 
expected to occur four years after enrollment ends, or at the EoS/EW Visit for subjects who 
complete the study or withdraw before the total number of endpoints are reached. See 
Appendix A for a list of procedures that will be performed and documented.
For all subjects receiving study medication, the investigator must complete the EoS (e)CRF 
page.
Subjects who discontinue study medication prematurely should attempt to follow the procedures 
outlined in Section 7.5. It is anticipated the Final visit will be about 4 hours in length.
9.3.7
Follow-up
Subjects will be contacted for a Safety Follow-up call 2 weeks after the EoS/EW Visit. See 
Appendix A for list of procedures that will be performed and documented.
Follow-up will begin the first day after the EoS/EW Visit and will continue until 2 weeks later. 
Subjects will be contacted for a Safety Follow-up call, (follow up of any ongoing AEs, new 
events, new SAEs, and concomitant medications) 2 weeks after the EoS/EW Visit. Subjects who 
withdraw their consent should still be contacted for a Safety Follow-up call, but the contact 


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should only be recorded in the medical records (and not the (e)CRF), according to data 
protection regulations.
The Safety Follow-up call should not occur for those subjects who enter the long-term extension 
study (AD-4833/TOMM40_303).
9.3.8
Post Study Care
Subject to applicable laws and feasibility, access to the study medication may be available to 
individual subjects for whom no standard therapy exists, and the subject is at risk of significant 
morbidity or mortality. The investigator should contact the medical monitor to determine if 
access is possible.
Subjects who successfully complete this pivotal phase 3 (AD-4833/TOMM40_301) study and 
have reached the primary endpoint diagnosis of MCI due to AD may be considered for 
participation in the AD-4833/TOMM40_303 long-term extension study. The safety profile of 
long-term daily low-dose pioglitazone treatment in the elderly, as well as the efficacy of 
pioglitazone in slowing the progression of cognitive decline after diagnosis of MCI due to AD 
will continue to be evaluated in the long-term extension study.
9.4
Biological Sample Retention and Destruction 
In this study, specimens for PGx analysis will be collected as described in Section 9.1.11. After 
extraction and purification, the genetic material will be preserved and retained at 
 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.
“Stored samples” are defined as samples that are double coded (the samples are stripped of all 
personal identifying information but a key links the samples to the clinical data collected from 
the sample donor) and are used in the analysis of investigational drug, related drugs (comparator 
drug) and the disease state.
Subjects who consented and provided a PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time. Site should notify sponsor of 
consent withdrawal. 
CCI


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a 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 


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intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) 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.


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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 
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 (e)CRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page 
of the (e)CRF.
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.


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
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).
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 AESIs
An AESI (serious or non-serious) 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. AESIs are 
listed in section 10.2.1.3.
10.1.6 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.


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10.1.7 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.
10.1.8 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
(Study Visit 3) or until screen or 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 (Study Visit 3). Routine collection of AEs will continue until 2 weeks after 
completion or withdrawal from the study (safety 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. Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-
up for the purposes of the protocol.


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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 
(e)CRF, 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).

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 AESI Reporting 
The phase 3 efficacy and safety study will be conducted in cognitively normal elderly subjects. 
Pioglitazone appears to be safe and well tolerated in the elderly population, based on the 
available information from healthy volunteers and diabetics in Takeda-sponsored trials or from 
AD patients in Takeda-supported studies [15,16]. Based on the available safety information in 
the diabetic population, the following safety procedures will be implemented when specific 
AESIs 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 NYHA class III-IV will be excluded at 
screening. If a subject develops a new onset CHF or experiences deterioration of pre-existing 
condition 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. The diagnosis of 
CHF can be difficult. Many of the symptoms of heart failure are nondiscriminating and, 
therefore, of limited diagnostic value. Many of the signs of heart failure result from sodium 
and water retention and resolve quickly with diuretic therapy, ie, may be absent in patients 
receiving such treatment. Because the signs and symptoms of heart failure are so non-
specific, demonstration of an underlying cardiac cause using diagnostic tests (such as ECG, 
echocardiogram, chest X-ray, etc) is very important to the diagnosis of heart failure. For 


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events of heart failure, a CHF eCRF should be completed within 24 hours of the 
investigator’s awareness of the event.
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 be 
evaluated by an ophthalmologist. Subjects diagnosed with macular degeneration during the 
study will be followed up by an ophthalmologist and have retinal imaging (eg, Optic 
Coherence Tomography or Heidelberg Confocal Laser Doppler Imaging) performed at least 
every six months until study completion or early withdrawal to confirm that the condition is 
stable. 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 local
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 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 [68]. 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% [69]. 
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 


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will be excluded. All subjects will be screened 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 all subjects with the following AEs will be closely monitored using 
the following event categories [70].

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).

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 any subject is noted to have a hypoglycemic event, the hypoglycemia (e)CRF should be 
completed within 24 hours of the investigator’s awareness of the event.
All special interest AEs also have to be recorded as AEs in the (e)CRF. 
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 eCRF must be completed, in English, and electronically 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:


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
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.
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal Liver Function Tests 
When reviewing liver function tests (LFTs), 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 (e)CRF 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 (e)CRF 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 eCRF 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 (EMA), 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 


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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 IMP or that would be sufficient to consider changes in the IMPs 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
Neuropsychology Advisory Board
The selection of the neuropsychology instruments for the cognitive test battery, the relevant 
domains for testing, establishment of thresholds, and composite scores was defined by a 
neuropsychology advisory board that has been formed by Takeda/Zinfandel alliance. 
11.2
Data 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 adverse events of special interest. This group will include individuals with expertise in 
endocrinology, neuro-radiology, AD specialist, Cardiology and statistics.
Details of the independent DSMB are captured in a charter.
11.3
Cognitive Impairment Adjudication Committee
Adjudication to determine if a subject has reached the study endpoint event of MCI due to AD 
diagnosis will be carried out by independent experts who will review and adjudicate each event 
in a blinded fashion. Because AD dementia will also be considered a diagnostic event that will 
count toward the total number of events in AD-4833/TOMM40_301, the CIAC will also 
adjudicate potential occurrences of possible or probable AD dementia, as defined by the criteria 
described by McKhann et al., 2011 [41]. The adjudication of these events will be performed 
based on criteria outlined in the adjudication charter. The experts will adjudicate each event 
independently of each other. If the experts’ initial adjudications are not identical, they will 
review these cases together and come to a conclusion by unanimous consensus. Details of the 
adjudication procedure will be captured in an Adjudication Charter.


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary.
12.1
(e)CRFs 
Completed (e)CRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to (e)CRFs. The sponsor 
will make arrangements to train appropriate site staff in the use of the (e)CRF. These forms are
used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. (e)CRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the 
reason for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the (e)CRFs for completeness and accuracy and must sign 
and date the appropriate (e)CRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the (e)CRFs.
(e)CRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by study monitors. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the (e)CRFs. The 
completed (e)CRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor.
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 (e)CRFs, 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 


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8) until at least 2 years after the last approval of a marketing application for a specified drug 
indication being investigated or, if an application is not approved, until at least 2 years after the 
investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 Section 
4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the 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 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 blinded data review will be conducted prior to unblinding of the subjects’ treatment 
assignments. This review will assess the accuracy and completeness of the study database, 
subject evaluability, and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
All efficacy and safety variables will be analyzed using the full analysis set (FAS). The FAS will 
consist of all randomized subjects. The per-protocol population will be described in the SAP.
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
There are 2 independent null hypotheses in this protocol: (1) assumes that there is no difference 
in conversion rate between the placebo-treated high-risk and low-risk groups as defined by the 
prognostic biomarker test and (2) assumes that there is no difference in conversion rate between 
the high-risk active- and placebo-treated subjects. The alternate hypotheses are: (1) there is a 
difference between the high- and low-risk groups treated with placebo, and (2) there is a 
difference between placebo and active treatment in the high-risk group.
In order to test the first hypothesis, a test from a Cox proportional hazards survival model will be 
used to compare data from non-Hispanic/Latino Caucasians in the (placebo-treated) low-risk 
group (ie, the combined placebo groups) with data from non-Hispanic/Latino Caucasians in the 
placebo-treated subjects in the high-risk group. The event in this analysis will be the diagnosis of 
cognitive impairment. If this test is significant at the 0.01 level, it can be concluded that the 
diagnostic prognostic test has differentiated between subjects at low and high risk of being 
diagnosed with cognitive impairment within 5 years of taking the test.
A similar analysis will be used to compare the placebo- and active-treated non-Hispanic/Latino 
Caucasian subjects within the high-risk group. If this test is significant at the 0.01 level, it can be 
concluded that active treatment has delayed the development of cognitive impairment within the 
5-year period.
A secondary all-comers analysis will be done to compare the placebo and active-treated subjects 
within the high-risk group.


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All data collected in the study will be listed and summarized either by mean, SD, median, and 
range or by frequency tables, as appropriate to the data.
Time-to-event data will be analyzed using a Cox proportional hazard model, including an 
investigation of the effects of covariates (testing center, age, sex, etc). The incidence of MCI due 
to AD will also be compared using a chi-squared test and the difference in incidence will be 
reported along with 95% confidence intervals.
Following a significant finding for the primary efficacy endpoint, a sequential testing hierarchy 
will test the rate of cognitive decline endpoint first and then, if significant, proceed to testing the 
impairment of functional abilities using the functional impairment assessment ADCS ADL-PI As 
for the primary analysis, these key secondary endpoints will be tested at the alpha = 0.01 level. 
The analyses for these endpoints will be analysis of covariance (ANCOVA) for change from 
baseline using mixed models repeated measures (MMRM).
The other secondary endpoints will be analyzed using ANCOVA, 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 alpha = 0.01 level.
The primary endpoint in this study is event-based and subjects who discontinue from the study 
prior to having the event will be censored in the primary analysis. However, for completeness, 
follow-up information will be collected on as many subjects as possible, including the reason for 
discontinuation. For the continuous variables such as the composite scores, mixed models 
repeated measures using all available data will be used to evaluate changes over time. 
The rules for handling missing items from each of the scales are designed so that as much data as 
possible can be used in the analyses, yet with reliable information, 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. 
Composite scores will be derived from the test battery. Each test in the battery falls into one of 
the following cognitive domains: Episodic Memory (CVLT-II, BVMT-R), Executive Function 
(TMT Part B, Digit Span Backwards), Language (Animals, Lexical/Phonemic Fluency), 
Attention (Digit Span Forward, TMT Part A), and Visuospatial (CDT, BVMT-Copy). Only the 
domains of episodic memory, executive function, language, and attention will be used for the 
composite score (ie, CDT, 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 


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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 two tests for each domain, the composite can still be 
calculated if one test is missing. In the case of memory however, both tests are required to 
calculate the composite. 
There may still be missing values for the continuous variables and the analyses for continuous 
variables are based on a Missing at Random (MAR) 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.
Additional analyses may be done to assess the contribution of age, APOE genotype, and 
TOMM40 rs10524523 genotype to the risk assignment algorithm.
It is anticipated that approximately 20% of the subjects will be diabetic. Subgroup analyses for 
non-diabetic subjects and for diabetic subjects will be done to support the results of the primary 
analysis.
In addition to the primary analysis population, it is anticipated that approximately 5% as many 
subjects will be Hispanic/Latino and/or non-Caucasian. Additional analyses for Hispanic/Latino 
and/or non-Caucasian subjects and for all subjects will be done to support the results of the 
primary analysis. These analyses will be the same as those conducted for the primary subgroup 
of the Caucasian subjects in order to evaluate the biomarker effectiveness within this extra 
subpopulation and the efficacy for pioglitazone within high-risk non-Caucasian subjects.
13.1.4 Pharmacokinetic Analysis
Sparse plasma samples from approximately 30% per region of the study subjects will be 
collected to estimate population PK/PD of pioglitazone, random inter/intra-subject variability, 
random residual variability associated with PK and PD model parameters, and to identify sources 
of variability (continuous or categorical covariates) that may influence pioglitazone PK and PD 
profiles in study subjects.
13.1.5 Other Analysis
Any sensitivity or other analyses (eg, using additional covariates) will be described in the SAP.
13.1.6 Safety Analysis
AEs
AEs will be reported throughout the study.


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Treatment-emergent AEs are any new or worsened events that occurred after the first dose of 
study medication and within 30 days following discontinuation of study medication. 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 screening/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 
will be flagged and tabulated. Physical examination findings will also be summarized for each 
treatment group.
13.2
Futility Analysis and Criteria for Early Termination
Tracking of confirmed events of MCI due to AD, as adjudicated by the CIAC, will be done on an 
ongoing basis, in a blinded fashion. There will be two types of analyses conducted during the 
study to assess futility: an ‘operational futility analysis’ and an ‘efficacy futility analysis’. The 
study will be declared to be ‘operationally futile’ if the accrual of confirmed events is too slow to 
allow completion of the study in a feasible time frame. The timeframe for assessing operational 
futility is described in the SAP.
If operational futility is not declared, an analysis for futility for efficacy will be conducted once 
approximately 33% (66 out of 202) of the anticipated events (ie, conversions from cognitively 
normal status to adjudicated diagnosis of MCI due to AD, or to AD dementia) have occurred in 
the high-risk, Caucasian, non-Hispanic/Latino group. However, since the biomarker risk stratum 
information is blinded, the time of the futility analysis will be estimated using all subjects (both 
high-risk and low-risk) in the Caucasian, non-Hispanic/Latino group. Therefore, the efficacy 
futility analysis will occur when approximately 69 events have been confirmed through 
adjudication in the Caucasian, non-Hispanic/Latino group (including both high-risk and low-risk 
subjects). Note that no adjustment of the alpha level is required for an analysis for futility, and 
that for this study the results of the futility analysis will be considered to be non-binding with 
respect to efficacy for purposes of decision making around study continuation. 
If operational futility is declared, an early efficacy futility analysis (ie, prior to reaching 33% of 
anticipated events as described above) will be done as soon as practicable (ie, after all pertinent 
data for the futility analyses has been cleaned as per the specifications outlined in the Interim 
Database Lock Plan) and will be provided to the DSMB. This will not replace the efficacy 
futility analysis that is planned following the accrual of 33% of the anticipated events.
Further details of the operational and efficacy futility analyses are given in the SAP.
Because a review of unblinded data is involved, the DSMB will oversee this process. Once the 
total number of target events has been reached, the DSMB will be unblinded for a review of 


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actual treatment groups with respect to the primary efficacy endpoint (and potentially other 
analyses as described in the SAP, as applicable); this review would take place at the next 
regularly-scheduled DSMB meeting or at an ad hoc DSMB meeting. 
The primary futility analysis for efficacy will be conducted by the DSMB Statistician, based on 
the treatment effect within the high-risk, Caucasian, non-Hispanic/Latino group. The calculation 
is a test from a Cox proportional hazards survival model to evaluate a difference between the 
treatment groups (pioglitazone versus placebo) for the high-risk comparison at the time of the 
interim futility analysis. Additionally, Kaplan-Meier curves by treatment group (including low-
risk placebo) will be provided for the primary analysis population of non-Hispanic/Latino 
Caucasian subjects. If the primary futility analysis indicates futility, then the 
 Unblinded 
DSMB Statistician will provide an additional set of secondary futility analyses (described in the 
SAP). The DSMB could then recommend study continuation to completion for the targeted 
number of events or recommend (based on pre-specified criteria documented in the SAP) that the 
study be considered futile with respect to the primary efficacy endpoint, high-risk comparison. 
Immediately after the efficacy futility analysis data review meeting takes place (ie, either after an 
efficacy futility analysis following operational futility or the efficacy futility analysis following 
accrual of 33% of events), the DSMB recommendation regarding the continuation of the study 
will be promptly communicated to the DSMB Liaison. If the data indicate that study termination
should be considered, the DSMB Liaison will promptly convene an ad-hoc meeting within the 
Takeda/Zinfandel alliance senior management (ie, the Executive Committee) to further discuss 
the results of the futility analyses and make the final decision as to whether or not to terminate 
the study. In a similar manner to the DSMB, the Executive Committee will be unblinded to the 
results of the futility analyses, will keep all futility analysis results and discussions strictly 
confidential, and will have no involvement with the daily project activities of the study or study 
team.
If the alliance Executive Committee decides to terminate the study as a result of the futility 
analyses, this decision will be promptly communicated to all the stakeholders including the AD-
4833/TOMM40 project team, investigators, ethics committees, and regulatory agencies. Details 
of the stopping rules and analyses will be given in the DSMB Charter and in the SAP. 
13.3
Determination of Sample Size.
Background Information for Determining Sample Sizes
Using 73 years as the age at entry (+5 years = age 78), a conversion rate of around 18% over 
5 years can be expected (see Table 13.a). This is based on:
!
The TOMM40 rs10524523 allele frequencies from the Duke Alzheimer’s Disease Research 
Center (ADRC), Cache County, and Wisconsin cohorts.
!
The assessment of peer-reviewed published incident MCI in normal individuals.
!
The effect of APOE on the incidence of AD.
CCI


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Table 13.a
Conversion Rate Estimates Based on Analysis of 3 Cohorts, Cognitive 
Impairment Incidence, and Observed TOMM40 rs10524523 Allele 
Frequencies
TOMM40 
rs10524523 
Genotype
Duke 
Bryan 
ADRC 
Frequency
Wisconsin 
Frequency
Cache 
Frequency
Cohort 
Total 
Count
Age 78 (Proportion Converted)
Proportion
Number of 
Converted Subjects
L/L
0.05
0.04
0.02
189
0.53
100
VL/L
0.14
0.15
0.13
543
0.34
185
S/L
0.17
0.20
0.14
669
0.22
147
S/S
0.23
0.16
0.17
929
0.14
130
S/VL
0.31
0.31
0.36
1236
0.10
124
VL/VL
0.11
0.14
0.18
433
0.05
22
Total count = 3999
Total converted
708
Overall 
conversion rate
0.177
Taking into account the age ranges that will be enrolled in the phase 3 study, a 5-year conversion 
rate of 15% will be assumed for non-Hispanic/Latino Caucasian placebo subjects within the 
high-risk stratum identified by the enrichment process. Based on the expected 5-year conversion 
rate of 15%, the time-to-event was modeled using an exponential mathematical model for 
planning the study sample size.
Similarly, a 5-year conversion rate of 4% will be assumed for non-Hispanic/Latino Caucasian 
placebo subjects within the low-risk stratum. Thus, it is important to recognize that this summary 
of the data demonstrates nearly a four-fold enrichment of events over the population rate using 
the risk algorithm. 
Determination of Sample Size for the Phase 3 Study Based on the High-Risk Stratum
The sample size for this study is based on the event-driven analysis that is planned for comparing 
treatment groups within the high-risk stratum. For the purposes of this study, it is assumed that 
the placebo-treated non-Hispanic/Latino Caucasian subjects in the high-risk stratum will have an 
event rate of 15% over a 5-year period. This is more conservative than the 18% cited in the table, 
to assure adequate sample size. With an expected improvement of a reduction in event rate of 
40%, the target event rate for the active treatment group will be 9% over 5 years. Furthermore, 
the following specifications are used: alpha=0.01, a 2-sided statistical test based on survival 
analysis, power=90%, annual dropout rate of 12% (or cumulative dropout rate of 47% over 5 
years). In order to detect a difference of the specified magnitude (≥40% reduction in conversion 
rates over 5 years), at least 202 events must be observed during the course of the study in non-


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Hispanic/Latino Caucasian subjects (primary analysis). Based on these assumptions and the fact 
that only non-Hispanic/Latino Caucasian subjects will be used for the primary analyses, a total of 
2,346 non-Hispanic/Latino Caucasian subjects (1,173 on pioglitazone/1,173 on placebo) are 
required from the high-risk stratum for randomization. 
Sample Size for the Phase 3 Study Based On Qualifying the Test Used to Stratify Subjects
While using data from the results of risk stratification and not a comparison between randomized 
groups, the same analysis as specified for comparing the treatment groups within the high-risk 
stratum will also be used to compare the two placebo groups (high-risk placebo and low-risk 
placebo). Thus, assuming that the placebo-treated subjects in the low-risk stratum will have a 
conversion rate of 4% over a 5-year follow-up period, then approximately 314 non-Hispanic/
Latino Caucasian subjects identified as low-risk for the event are required in that stratum. While 
this number of subjects enrolled in the low-risk stratum will provide very high power (99% with 
alpha=0.01) to validate the enrichment algorithm with the assumed 5-year conversion rates (ie, 
15% vs. 4%).
13.4
Biomarker Qualification
At the end of this study, data from the analyses comparing high and low risk placebo groups will 
provide the data necessary to qualify the biomarker risk algorithm as a prognostic test and an 
important new tool for therapeutic decision making. Specifically, the high risk placebo group and 
low risk placebo group will provide the data needed to estimate the positive predictive value 
(PPV) and negative predictive value (NPV) of the biomarker risk algorithm. Kaplan Meier 
curves will be generated for TOMM40 rs10524523 and APOE genotypes and compared to 
previous results.
Receiver operating characteristic curves, hazard ratios and positive and negative predictive 
values will be reported for the performance of the biomarker risk algorithm. Specifically, 
calculations will be made of the time dependent positive (PPV[t]) and negative predictive values 
(NPV[t]), where PPV(t) is the proportion of subjects who are predicted to develop MCI due to 
AD during the 5 years who do develop MCI due to AD in the high risk group, and NPV(t) is the 
proportion of subjects predicted to be free of MCI due to AD at 5 years who are free of MCI due 
to AD at 5 years in the low risk group. 


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the (e)CRFs. Source documents are defined as original documents, data, and 
records. The investigator and institution guarantee access to source documents by the sponsor or 
its designee (CRO) 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 (e)CRFs 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, 
project partners) 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 United States (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 forms, 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 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 notification no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the 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.


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Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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 and project partner. 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.


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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.
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 [e]CRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.


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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.
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
REFERENCES
1. AD-4833/TOMM40 (pioglitazone hydrochloride/biomarker risk algorithm) IB-12, AD-
4833/TOMM40 (pioglitazone hydrochloride/biomarker risk algorithm) Investigator’s 
Brochure. Edition 12. Takeda Global Research & Development Center, Inc., 22 November 
2013.
2. Maeshiba Y, Kiyota Y, Yamashita K, Yoshimura Y, Motohashi M, Tanayama S. Disposition 
of the new antidiabetic agent pioglitazone in rats, dogs, and monkeys. Arzneimittelforschung 
1997;47:29-35. 
3. Ghosh S, Patel N, Rahn D, McAllister J, Sadeghi S, Horwitz G, Berry D, Wang KX, 
Swerdlow RH. The Thiazolidinedione Pioglitazone Alters Mitochondrial Function in Human 
Neuron-Like Cells. Mol Pharmacol 2007; 71:1695-702.
4. Jiang L-Y, Tang S-S, Wang X-Y, Liu L-P, Long Y, Hu M, Liao M-X, Ding Q-L, Hu W, Li 
J-C, et al. PPARγ Agonist Pioglitazone Reverses Memory Impairment and Biochemical 
Changes in a Mouse Model of Type 2 Diabetes Mellitus. CNS Neuroscience Therapeutics 
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61. Galasko D, Bennett DA, Sano M, Marson D, Kaye J, Edland SD; Alzheimer’s Disease 
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2012;11(3):241-9.


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Appendix A
Schedule of Study Procedures
Screen-
ing
Visit 1
Base-
line
Visit 2
Random-
ization
Visit 3
Double-Blind Treatment
Repeated yearly
Unscheduled 
-
CMFV 
(q) (v)
EoS / EW
Visit 
(b) (j)
Follow-up 
Visit 
(c)
Study Month:
-4
-1
0 (Day 0) 3 (a)
6
9 (a)
12
EoS/EW+0.5
Visit Window (t):
Max
Day
-125
Max
Day
-35
±2 
weeks
±2 
weeks
±2 
weeks
±2 
weeks
Within approx. 
30 days of 
trigger
Screening informed 
consent or Full study 
Informed consent
(Subject)(r)
X
Study entry informed 
consent (Subject)(r)
X
Informed consent (PGx)
X
Acknowledgement Form 
(Project partner)
X
Incl/Excl Criteria
X
X
X
Medical history
X
Demographic 
Information
X
X(p)
X(p)
X(i,p)
X(p)
Medication History
X
Family History
X (l)
X
Concurrent Conditions
X
Height
X
X
X
Body weight
X
X
X
X
Review of concurrent 
medications
X
X
X
X
X
X
X
X
X
Dispense study drug
X
X
X
Collect study drug
X
X
X
Compliance review
X
X
X
X
X
Contact IWRS
X
X
X
X
X
X
Genetics (blood samples)
TOMM40 rs10524523, 
APOE (Risk 
stratification)
X
Safety/efficacy PGx
(DNA and RNA 
samples) – subject-
optional
X(g, n)
X(n)
X(n)
Footnotes are on last table page.


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Appendix A
Schedule of Study Procedures (continued)
Screen-
ing
Visit 1
Base-
line
Visit 2
Random-
ization
Visit 3
Double-Blind Treatment
Repeated yearly
Unscheduled 
-
CMFV 
(q) (v)
EoS / EW
Visit 
(b) (j)
Follow-up 
Visit 
(c)
Study Month:
-4
-1
0 (Day 0)
3 (a)
6
9 (a)
12
EoS/EW+0.5
Visit Window (t):
Max
Day
-125
Max
Day
-35
±2 
weeks
±2 
weeks
±2 
weeks
±2 
weeks
Within 
approx. 30 
days of trigger
Safety
PTEs
X
X
AEs (including AESIs) 
(e)
X
X
X
X
X
X
X
X
Physical exam
X
X
X
X
Vital Signs
X
X
X
X
X
Neurological exam
X
X
X
X
X
12-lead 
Electrocardiogram
X
X
X
MRI (vMRI sub-study)
(Please refer to Appendix H)
MRI (ad hoc) (f)
X
Clinical chemistry,
hematology and 
urinalysis labs (m)
X
X
X
X
PK samples (o)
X
X
X
C-SSRS
X
X
X
X
X
Diet and Exercise 
Evaluation (k)
X
X
X
X
Efficacy
MMSE
X
X
X
X
X
Cognitive Test Battery 
(h)
X
X
X
X(i)
X(i)
Footnotes are on last table page.


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Appendix A
Schedule of Study Procedures (continued)
Screen-
ing
Visit 1
Base-
line
Visit 2
Random-
ization
Visit 3
Double-Blind Treatment
Repeated yearly
Unscheduled 
-
CMFV 
(q) (v)
EoS / EW
Visit 
(b) (j)
Follow-up 
Visit 
(c)
Study Month:
-4
-1
0 (Day 0)
3 (a)
6
9 (a)
12
EoS/EW+0.5
Visit Window (t):
Max
Day
-125
Max
Day
-35
±2 
weeks
±2 
weeks
±2 
weeks
±2 
weeks
Within 
approx. 30 
days of trigger
Efficacy (continued)
GDS
X
X
X
X(u)
ADCS-MCFSI
X
X
X
X(u)
EQ-5D
X
X
X(u)
SF-36
X
X
X(u)
IQCODE
X
X
X
X(u)
ADCS ADL-PI
X
X
X
X(u)
NPI-Q
X
X
X(u)
ADCS-RUI
X
X
X
X
X(u)
CDR
X
X
X(u)
ADCS-CGIC- MCI
X
X
X
X (u)
X(u)
Footnotes are on the following page.


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Excl=exclusion, Incl=inclusion.
(a) Telephone contact (should be every 3 months between the semi-annual clinic visits for the life of the study).
(b) EoS/EW Visit is an ad hoc visit that, for study completion, would take place as soon as possible after a regularly 
scheduled Study Visit, either after the CIAC has confirmed that the subject has reached the MCI due to AD primary 
endpoint event (or any other irreversible cognitive impairment or dementia) or after a subject has withdrawn 
prematurely from the study. In cases where the endpoint has been reached, the efficacy assessments will not need to 
be captured at this Visit.
(c) Subjects will have a safety follow-up call 2 weeks after completion or withdrawal. 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 in the [e]CRF), according to data protection regulations.
(d) footnote deleted
(e) Please refer to Section 10.2.1.3.
(f) As part of the comprehensive medical follow-up evaluation to rule out other causes of dementia and confirm the 
clinical diagnosis of MCI due to AD (See section 6.2.4). An MRI scan is not required to be performed if a study 
related MRI scan was collected within 6 months of the CMFV. For subjects who have contraindications for the MRI 
procedure (such as unremovable ferromagnetic dental work, cardiac pacemakers, etc) a CT scan can be done instead.
(g) DNA sample expected to be collected at this visit, but if necessary, may be collected at any visit after 
randomization.
(h) Sites should make every attempt complete the cognitive test battery in the order of outlined in Section 9.1.17.
(i) Cognitive Battery is completed at an Unscheduled Visit or EoS/EW Visit if the visit occurs greater than 3 months 
after the previous regularly scheduled visit.
(j) Subjects who discontinue study medication prematurely should be contacted by the study site every 6 months 
until the conclusion of the study via telephone to assess the general well being of the subject as well as to obtain any 
changes in medications related to cognitive health. In the event the subject is not able to be reached, the subject’s 
project partner or primary care physician can be contacted to obtain this information.
(k) female subjects only.
(l) Family history is captured at the first 6 month visit during year 1 of the study.
(m) Please refer to Table 9.a and lab manual for detailed test schedule.
(n) RNA sample to be collected at Day 0, Month 12 of Year 1, Year 2, Year 3, Year 4 and EoS.
(o) Greater detail is given below. Note: If subject has been off drug for 3 or more days prior to Unscheduled CMFV, 
or EoS/EW Visit, the PK samples should not be collected.
(p) A subject’s age will be collected at these post-Baseline study Visits only in countries that do not allow collection 
of a subject’s date of birth.
(q) Procedures for Unscheduled visits for CMFV includes the assessments marked, and should only be conducted 
after appropriate criteria are met as described in Section 6.2.4. Unscheduled visits for other concerns, including 
safety, the investigator is expected to conduct whatever assessments are necessary.
(r) If sites prefer to split the ICF process at Visit 1 and Visit 2 into a screening informed consent and study entry 
informed consent and have IEC/RIB approval to do so, this is permitted.
(s) ADCS-RUI should be administered every 6 months.
(t) Visit Window also applies to Project Partner assessments.
(u) These assessments only need to be administered at the applicable visit if it occurs greater than 3 months from the 
last administration of the particular assessment.
(v) At the Investigator’s discretion, CMFV assessments may be conducted at the routine Month 6 or Month 12 Visit
in situations where the CMFV conducted as an outcome of the previous scheduled office visit resulted in an MCI 
due to AD diagnosis. Refer to Section 6.2.4 for further detail.


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Schedule for Pharmacokinetic Sample Collection
Group
Dosing Time 
(approximate)
Sample Collection(a)
Sample Collection Time Post-Dose
Pre-Dose
1-1.5 hr
Start of visit
End of visit
1(b)
8:00 AM
X
X
2 (c)
8:00 AM
X
X
3 (d)
8:00 AM
X
X
4 (e)
8:00 AM
X
X
(a) Samples will be collected at each yearly visit, starting with the 12 month visit for all subjects who consent to 
have PK samples collected (approximately 30% within each region), Unscheduled Visit, and EoS/EW Visit.
(b) Subjects will arrive at the clinic prior to study drug administration.
(c) Subjects will arrive between 9 am and noon, one PK sample will be taken at the beginning of the visit and one at 
the end of the visit.
(d) Subjects will arrive between noon and 3 PM, one PK sample will be taken at the beginning of the visit and one at 
the end of the visit.
(e) Subjects will arrive after 3 PM, one PK sample will be taken at the beginning of the visit and one at the end of 
the visit.


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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 (non routine/non standard 
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 
(e)CRFs, 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.


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10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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.


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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 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 


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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.
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 (Separate 
from the risk stratification sample)
For instructions on shipping, both ambient and refrigerated, 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 
 
. Shipping information can be found in the pharmacogenomic lab manual.
Sample Storage
will store the DNA and 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.
CCI
CCI
CCI


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Appendix F
Collection, Storage, and Shipment of Bioanalytical Samples
Instructions for Processing of Plasma Samples for Pharmacokinetic Analysis of 
Pioglitazone
Shipping of Plasma Samples
The following instructions are recommended unless they differ from the site’s Standard 
Operation Procedures (SOPs) for labeling, packaging, or shipping of pharmacokinetic samples.
1. Biological samples (ie, plasma or urine) should be shipped on dry ice to prevent thawing 
during transit. Samples should be shipped only on Monday, Tuesday, or Wednesday, and at 
least 2 days prior to a national holiday, in order to minimize the possibility of samples in 
transit over a weekend or holiday. If duplicate samples are to be shipped, send SET 1 
samples and await confirmation of arrival before shipping the duplicate SET 2 samples.
2. Before shipping, make sure the sample tubes are tightly sealed. Separate each subject’s 
samples as follows:
3. Separate the duplicate SET 2 samples from the SET 1 samples.
a) Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc) containing 
additional absorbent material.
CCI


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b) Using a permanent marker, write the 4-digit randomization sequence number, sample 
matrix (ie, plasma), number of samples, and “SET 1” on each self-sealing bag.
c) Place the bags of individual subject’s samples into a larger plastic bag so that samples are 
double bagged. Duplicate SET 2 samples should be returned to the freezer for storage. 
Repeat steps 3 through 6 above when preparing duplicate samples for shipment, except 
self-sealing bags should be marked “SET 2.”
4. An inventory of individual samples should accompany each shipment and should include the 
Sponsor’s name (Takeda), study medication (pioglitazone), protocol number 
(AD-4833/TOMM40_301), investigator’s name, sample type (ie, plasma), subject 
randomization sequence number, collection day and time, and intended sample storage 
conditions. When duplicate SET 2 samples are being shipped, make a copy of the original 
SET 1 sample inventory and mark as “SET 2.” Place the inventory paperwork into a large 
self-sealing bag. SET 1 samples will be shipped first on dry ice, followed by shipment of 
duplicate SET 2 samples after SET 1 samples have been received by the analytical 
laboratory.
5. For sample packing, utilize dry ice generously (eg, 20-25 pounds per day of transit) to 
safeguard against longer than expected shipping times and delays. Use newspaper or other 
material to insulate the double-bagged samples from direct contact with the dry ice. Place the 
sample bundles into a styrofoam container (or other suitable container) and fill the excess 
space with dry ice slabs or ice pellets (preferably the latter). Make a note of the estimated 
weight of the dry ice used per shipping container.
6. Place the inventory paperwork (in a large self-sealing bag) on top of the dry ice in the 
styrofoam container. Place the lid on the styrofoam container and seal completely with 
strapping tape. Place the styrofoam container in a cardboard shipping carton and seal 
securely with strapping tape.
7. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).
8. Affix an address label to each shipping carton. Complete the address label as per the 
instructions in the laboratory manual.
9. Affix a carbon dioxide label on each carton, specifically:
Carbon Dioxide Solid UN-1845
Class 9 PKG GR III
Quantity _____________________
(fill in weight to nearest lb/kg and specify unit of measure used)
10. Affix 2 dry ice symbol labels on opposite sides of the carton. Mark KEEP FROZEN on each 
carton. Specify a return address and contact person on the carton.
11. Obtain the airway bill number and a receipt of shipment from the carrier.


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Appendix G
Corrections to the MMSE based on Education and Age
At the Screening Visit, the MMSE should be adjusted at the site by the following:

Low Education Strata: +1
Country
Low Education
(in years)
Australia
0-9
Germany
0-11
Switzerland
0-11
U.K.
0-10
U.S.
0-11

Old Age (76-83): +1


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Appendix H
A Sub Study To Evaluate the Effects of Pioglitazone on Whole and Regional 
Brain Volume over Time
Study Title
Assessment of pioglitazone effects on whole and regional brain volume in a sub-population of 
cognitively normal elderly subjects enrolled in a double blind, randomized, placebo controlled, 
parallel group study to simultaneously qualify a biomarker algorithm for prognosis of risk of 
developing mild cognitive impairment due to Alzheimer’s disease (MCI due to AD) and to test 
the safety and efficacy of pioglitazone (AD-4833 SR 0.8 mg QD) to delay the onset of MCI due 
to AD in cognitively normal subjects. 
Study Design
In addition to their participation in the main phase 3 study, approximately 300 cognitively 
normal elderly subjects will participate in a sub study at selected sites. Subjects will sign a 
separate informed consent form (ICF) in order to participate in this sub-study. Subjects who 
fulfill all inclusion criterion and none of the exclusion criteria for the sub-study will be selected 
in a double-blind fashion to represent a 5:4 randomization ratio between pioglitazone and 
placebo assignment. Subjects in this sub-study will be scanned to assess brain volume (vMRI). 
Serial brain MRI scans will be performed at baseline, 2 years, and EoS/EW (3 timepoints in 
total). If an MRI scan has been performed for the main study or the sub study within 6 months of 
a required timepoint, a separate MRI scan does not need to be performed.
Schedule of Additional Study Procedures for the Sub-Study
Screening
Visit 1
Baseline
Visit 2
Randomization
Visit 3
Double-Blind
Treatment
EoS/EW Visit
Study Month:
-4
-1
0 (Day 0)
24
Visit Window:
Max Day
-125
Max Day
-35
±2 weeks
Informed consent (a) 
X
X
Incl/Excl Criteria
X
X
X
vMRI scan (Brain Volume)
X
X (b)
X (b)
(a) All subjects should sign a separate informed consent to participate in the sub-study at either visit 1 or visit 2, must occur prior 
to any sub-study procedures taking place.
(b) This assessment only needs to be administered at this visit if it occurs greater than 6 months from the last administration for 
either the main study or the sub study.
Duration of Treatment
The total duration of the vMRI sub study will be the same duration as the main study.
Primary Objective
1. To evaluate changes in brain volume in subjects receiving pioglitazone versus subjects 
receiving placebo.


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Primary Endpoint
1. Changes from baseline in vMRI in whole brain and specific brain regions of interest at 
2 years and EoS/EW (in subjects enrolled in the sub study).
Inclusion / Exclusion Criterion
All inclusion/exclusion criteria specified in the main study will also apply to the sub-study. An 
additional exclusion criterion to the main study for the sub study is as follows: 
1. Subject has a contraindication to having MRI, for example because of ferromagnetic foreign 
bodies (eg, unremovable ferromagnetic dental work), medical devices such as aneurysm clips 
or cardiac pacemakers, or lead-based tattoos.
Sample Size 
This substudy is not designed or powered to assess any quantitative changes in the brain. Based 
on clinical judgment, a sample size of 300 subjects is believed to be sufficient to evaluate 
possible qualitative changes in the brain via vMRI.
IVRS/IWRS will be utilized to randomize subjects into this sub study in order to provide balance 
between high risk placebo and high risk pioglitazone. 
MRI protocol minimum standards
All MRI scans will be reviewed centrally at a designated imaging lab. All MRI scans will also be 
reviewed at the local labs for safety. 
Brain volumetric measurements will be done using T1-weighted MRI. Specific MRI parameters 
to be used in this study along with further instructions about the imaging will be detailed in the 
imaging procedure manual.


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Appendix I
Operationalized Criteria for AD Dementia
The endpoint of AD dementia requires that the criteria for dementia are fulfilled.
Dementia:
A.
Cognitive problems observed interfere with the individual’s ability to function at work or 
at usual activities; and 
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 (e.g. ADCS ADL-PI/-MCI; 
Clinical Dementia Rating Scale with informant; CGIC; IQCODE), 
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 (e.g. MMSE) or 
neuropsychological testing
E.
The cognitive or behavioral impairment involves a minimum of two 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: TMT; 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; CDT
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 (e.g. tools or utensils), or trouble 
with spatial awareness, dressing etc.
iv.
Language: Verbal fluency (FAS test), animal fluency, MiNT naming


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a.
Defined as newly acquired problems with either 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 [McKhann et al., 2011] 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 one of the following 
domains:
a.
Amnestic: Impaired new learning & memory, as evidenced in the clinician 
examination, history, or by impairment on at least one of the following 
subtests:
i. BVMT-R Delayed recall
ii. CVLT-II, short-delay, free recall
iii. CVLT-II, long-delay, free recall
b. Non-amnestic: Impairment on performance on at least one test of visuospatial 
ability, language, or executive function: TMT A, TMT B, Digit Span Total, 
MiNT, Semantic fluency, Lexical fluency, or CDT; or based on observation, 
or clinical history.


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5. Evidence of cognitive dysfunction in at least one 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 one of the following 
domains: Amnestic or Non-amnestic, as defined for Probable AD and
b. Evidence of cognitive dysfunction in one other domain from Amnestic or 
Non-amnestic 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 (e.g. sudden onset; pronounced 
aphasia etc), or insufficient historical detail or objective cognitive documentation 
of progressive decline.
_________________
1Impairment is guided by quantitative or qualitative aspects of an individual’s function, defined as either: 1) scores 
falling at least 1.5sd below demographically adjusted normative mean, OR 2) based on the clinical judgment of the 
site Neuropsychologist / Investigator that significant cognitive impairment has occurred and represents a significant 
overall change from the individual’s established premorbid level of function as measured at baseline of 301. 


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Appendix J
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment No. 5.
Page 3, Section 1.1, Contacts
Existing Text
Issue
North America Contact
European 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)
PPD


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Revised Text
Issue
North America Contact
European Contact 
Australia Contact
Serious 
adverse event 
and pregnancy
reporting
Medical 
Monitor
(medical 
advice on 
protocol, 
compound, an
medical 
management o
subjects)
Responsible 
Medical 
Officer 
(carries overall
responsibility 
for the conduct
of the study)
Rationale for Amendment
Study contacts have been updated in accordance with personnel changes.
PPD


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Page 4, Section 1.2, Approval
Existing Text
SIGNATURES
Revised text
SIGNATURES
Rationale for Amendment
Protocol signatories updated in accordance with personnel changes.
PPD
PPD


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Page 34, Section 5.2.3.2, Additional Endpoints
Existing Text

Changes from baseline in vMRI in whole brain and specific brain regions of interest at 
2 years, and 4 years or study termination.
Revised Text

Changes from baseline in volumetric magnetic resonance imaging (vMRI) in whole brain 
and specific brain regions of interest at 2 years and End of Study (EoS)/Early Withdrawal 
(EW).
Rational for Amendment
This endpoint has been updated to correctly reflect the planned timepoints for analysis.
Page 36-37, Section 6.1, Study Design
Existing Text
A project partner will be required to participate with the subject in the study visits, including 
eligibility at Baseline (Visit 2) and follow-up. The project partner is a spouse, adult child, or 
other person familiar with the participant’s health and daily functioning for a minimum of two 
years prior to the Baseline Visit. Subjects and their project partners are expected to attend study 
visits every 6 months after randomization, for assessments of safety, efficacy, and treatment 
compliance. In addition, the subject will be contacted for telephone-based safety checks between 
visits. In-person participation of the project partner is mandatory at Baseline (Visit 2), 
comprehensive medical follow-up, and End-of-Study Visits; while in-person participation is also 
strongly encouraged at all other study visits, telephone assessments for project partners will be 
acceptable in cases when in-person participation is not possible. If a comprehensive medical 
follow-up evaluation is needed (see Section 9.1.15) or if a safety issue is suspected, further 
evaluation of the subject may be required, which may include an unscheduled clinic visit. The 
project partner should attend unscheduled visits, whenever possible. If the original project 
partner is not able to continue participation in the study for any reason, he/she may be replaced 
by a different individual who also meets the criteria described above. The new project partner 
must sign the acknowledgement form prior to any of the project partner protocol directed 
procedures being performed.
Revised Text
A project partner will be required to participate with the subject in the study visits, including 
eligibility at Baseline (Visit 2) and follow-up. The project partner is a spouse, adult child, or 
other person familiar with the participant’s health and daily functioning for a minimum of two 
years prior to the Baseline Visit. Subjects and their project partners are expected to attend study 
visits every 6 months after randomization, for assessments of safety, efficacy, and treatment 
compliance. In addition, the subject will be contacted for telephone-based safety checks between 


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visits. In-person participation of the project partner is required at Baseline (Visit 2), 
Comprehensive Medical Follow-up Visits (CMFV), and EoS Visits. In exceptional cases and 
with prior approval of the Sponsor, when in-person participation of the project partner is 
not possible for a CMFV or the EoS/EW Visit, assessments may be performed during 
Home Visits or by telephone (see Section 6.2.4). While in-person participation is also strongly 
encouraged at all other study visits, telephone assessments for project partners will be acceptable 
in cases when in-person participation is not possible. If a comprehensive medical follow-up 
evaluation is needed (see Section 9.1.15) or if a safety issue is suspected, further evaluation of 
the subject may be required, which may include an unscheduled clinic visit. The project partner
should attend unscheduled visits, whenever possible. If the original project partner is not able to 
continue participation in the study for any reason, he/she may be replaced by a different 
individual who also meets the criteria described above. The new project partner must sign the 
acknowledgement form prior to any of the project partner protocol directed procedures being 
performed.
Rationale for Amendment
Revisions have been made to this section in accordance with changes made in section 6.2.4 of 
the Protocol to provide greater flexibility to sites in scheduling and conducting CMFVs and 
EoS/EW Visits, in order to ensure that critical data can be collected in circumstances when on-
site attendance of the project partner is not possible.
Page 42, Section 6.2.4, Assessments after Randomization, Figure 6.b, Subject Flow Chart
Existing Text
Legend
…
F: Comprehensive Medical Follow up Visit (CMFV). A CMFV should not be conducted on the 
same day as a regularly scheduled in-clinic visit (ie, Month 6 or Month 12 of any year).
Revised Text
Legend
…
F: CMFV. At the discretion of the investigator, the CMFV may be conducted on the same day 
as a regularly scheduled in-clinic visit (ie, Month 6 or Month 12 of any year) in situations when 
the CMFV conducted as an outcome of the previous scheduled office visit resulted in a 
MCI due to AD diagnosis and therefore the next scheduled visit will automatically result in 
the requirement to perform a CMFV, irrespective of a CMFV trigger being met.


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Rationale for Amendment
This change gives sites the ability to help ease subject burden by preventing the need for an 
additional visit in situations where it is known in advance that a CMFV will be required 
following a routine visit. 
Page 43-44, Section 6.2.4, Assessments after Randomization
Existing Text
Additional comprehensive medical follow-up assessments will be carried out for any subject who 
has any of the outcomes above; these assessments will require an Unscheduled Visit, which 
should take place within one month of the routine study Visit when one of these triggers was 
met. A comprehensive medical follow-up visit (CMFV) should not be conducted on the same day 
as a regularly scheduled in-clinic visit (ie, Month 6 or Month 12 of any year).
A comprehensive medical follow-up evaluation (which the subject’s project partner must attend), 
triggered by any of the above, will include:
c) Neurological examination (includes information from project partner).
4. CDR assessment.
5. NPI-Q completed by the project partner.
6. Standard blood chemistry and tests used in evaluating cognitively impaired and dementia 
subjects (eg, thyroid profile, Vitamin B12).
7. Cognitive Test Battery (only if beyond 3 months from last study visit; otherwise the 
neuropsychological outcome battery from the last visit would be used in the evaluation).
8. Magnetic resonance imaging (MRI) will be required at a subject’s second consecutive
comprehensive medical evaluation when other evaluation results corroborate a diagnosis of
MCI due to AD. This requirement does not preclude the conduct of an MRI on a for-cause 
basis or to support a potential diagnosis other than MCI due to AD, after discussion with the 
medical monitor. 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.
After the comprehensive medical follow-up evaluation, the Investigator will consider the totality 
of information collected for the subject and make a clinical assessment which will determine 
subject flow within the study. The timing of sending a subject’s data to the adjudication 
committee after a first (of any potential two consecutive) comprehensive medical follow-up Visits
will depend on the Investigator’s clinical assessment. 

If an Investigator’s clinical assessment is that the subject is cognitively normal (ie, the 
comprehensive medical follow-up test results did not support the original trigger concern) or 
that the subject has a reversible cognitive impairment (eg, depression, hypothyroidism, 


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vitamin B12 deficiency), the subject will continue with routine study Visits, and the subject’s 
data will not be forwarded to the adjudication committee at this time. 

Since an outcome of MCI due to AD will require two consecutive diagnoses by the 
investigator, if an Investigator’s clinical assessment is that the subject meets criteria for an 
MCI due to AD diagnosis for the first time, the subject will also continue with routine study 
Visits, and the subject’s data will not be forwarded to the adjudication committee at this 
time.

If an Investigator’s clinical assessment is dementia of any type or an irreversible cognitive 
impairment not associated with AD, the subject’s data will be forwarded to the adjudication 
committee immediately.
Revised Text
Additional comprehensive medical follow-up assessments will be carried out for any subject who 
has any of the outcomes above; these assessments will require an Unscheduled Visit, which 
should take place within approximately 30 days of the routine study Visit when one of these 
triggers was met. A CMFV should not be conducted on the same day as a regularly scheduled in-
clinic visit (ie, Month 6 or Month 12 of any year), except in situations where the CMFV 
conducted as an outcome of the previous scheduled office visit resulted in an MCI due to 
AD diagnosis and therefore the next scheduled visit will automatically result in the 
requirement to perform a CMFV, irrespective of a CMFV trigger being met. In these cases, 
at the Investigator’s discretion, the CMFV assessments may be collected at the routine 
Month 6 or Month 12 Visit. Any assessments that are scheduled to be performed at both 
the routine visit and the CMFV do not need to be performed twice when combining visits in 
this way.
A comprehensive medical follow-up evaluation (which the subject’s project partner should 
make every effort to attend, if possible), triggered by any of the above, at minimum will 
include the following assessments (refer to Appendix A for a full list of assessments 
required to be performed at a CMFV):

Neurological examination (includes information from project partner).

CDR assessment.

NPI-Q completed by the project partner.

Standard blood chemistry and tests used in evaluating cognitively impaired and dementia 
subjects (eg, thyroid profile, Vitamin B12).

Cognitive Test Battery (only if beyond 3 months from last study visit; otherwise the 
neuropsychological outcome battery from the last visit would be used in the evaluation).

Magnetic resonance imaging (MRI) will be required at a subject’s second consecutive
comprehensive medical evaluation when other evaluation results corroborate a diagnosis of


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MCI due to AD in the opinion of the investigator. (Note that this does not need to be the 
second consecutive investigator diagnosis of MCI due to AD, only the second 
consecutive CFMV.) This requirement does not preclude the conduct of an MRI on a for-
cause basis or to support a potential diagnosis other than MCI due to AD, after discussion 
with the medical monitor. If an MRI scan has been performed for the study within 6 
months of the CMFV, an additional MRI scan will not be required and the existing scan 
may be used. 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.
If a site determines that a subject and/or project partner are unable to return to the clinic 
for the CMFV within approximately 30 days of the routine study visit, or for the EoS/EW 
Visit, the following options will be permitted in order to collect the required assessments 
within that timeframe:

Home Visit: with prior approval from Sponsor on a case-by-case basis, qualified site 
personnel may arrange a visit to the subject or project partner’s home in order to 
perform CMFV or EoS/EW assessments. If necessary (ie, confirmatory rule-out for 
MCI diagnosis at second of two consecutive CMFVs), the MRI scan will be performed 
on the subject in-clinic at the earliest opportunity.

Assessment via telephone: If the project partner is not able to return to the site for the 
CMFV or the EoS/EW Visit, the site may, with prior approval of the Sponsor on a case-
by-case basis, conduct the required assessments with the project partner via telephone 
call. The assessments must be carried out by appropriately qualified personnel in 
advance of the subject assessments and within a maximum of one day of the subject’s 
visit. Visit assessments of the subject will still be required in clinic.
After the comprehensive medical follow-up evaluation, the Investigator will consider the totality 
of information collected for the subject and make a clinical assessment which will determine 
subject flow within the study. The timing of sending a subject’s data to the adjudication
committee after a first (of any potential two consecutive) CMFVs will depend on the 
Investigator’s clinical assessment. 

If an Investigator’s clinical assessment is that the subject is cognitively normal (ie, the 
comprehensive medical follow-up test results did not support the original trigger concern) or 
that the subject has a reversible cognitive impairment (eg, depression, hypothyroidism, 
vitamin B12 deficiency), the subject will continue with routine study visits, and the subject’s 
data will not be forwarded to the adjudication committee at this time. 

If an Investigator’s clinical assessment is that the subject meets criteria for an MCI due to 
AD diagnosis for the first time, the subject will also continue with routine study visits, and 
the subject’s data will not be forwarded to the adjudication committee at this time.


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
If an Investigator’s clinical assessment is dementia of any type or an irreversible cognitive 
impairment not associated with AD, the subject’s data will be forwarded to the adjudication 
committee immediately.
Rationale for Amendment
The timing of CMFVs has been softened from a hard window of 30 days to “approximately 30 
days” in recognition of the fact that it is sometimes challenging for sites and subjects to return to 
the site for the CMFV within this timeframe. The language has been revised to be consistent with 
other studies on the AD-4833/TOMM40 program. 
The ability to combine the CMFV with the routine Month 6 or Month 12 visit in cases where it is 
known in advance that a CMFV must be performed has been introduced to help ease subject 
burden and prevent the need for an additional visit where possible. 
Providing sites with the ability to perform selected assessments at a subject’s home or by 
telephone in exceptional circumstances has been included to help mitigate the risk of not 
collecting critical study data due to the challenges associated with conducting the study in an 
elderly population where subjects approaching endpoint are repeatedly triggering, requiring 
multiple additional visits that increases subject burden and may result in withdrawal due to study 
fatigue. 
Clarity has been provided to the assessments conducted during CMFVs. The required timing of 
MRI scans performed at CMFVs has been clarified and the requirement to perform multiple MRI 
scans within a short period of time, which adds to subject burden, has been removed.
Erroneous text stating that two consecutive diagnoses by the investigator are required to reach an 
outcome of MCI due to AD has been removed. Two consecutive diagnoses of MCI due to AD by 
the CIAC are required for the subject to meet endpoint and it is possible that these diagnoses 
differ from the investigator’s.
Page 56, Section 7.5, Procedures for Discontinuation or Withdrawal of a Subject
Existing Text
Subjects who discontinue study medication prematurely should be contacted by the study site 
every 6 months until the conclusion of the study via telephone to assess the general well-being of 
the subject as well as to obtain any changes in medications. In the event the subject is not able to 
be reached, the subject’s caregiver or primary care physician can be contacted to obtain this 
information.
Revised Text
Subjects who discontinue study medication prematurely should be contacted by the study site 
every 6 months until the conclusion of the study via telephone to assess the general well-being of 
the subject as well as to obtain any changes in medications related to cognitive health. In the 


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event the subject is not able to be reached, the subject’s caregiver or primary care physician can 
be contacted to obtain this information.
Rationale for Amendment
This revision more accurately describes the limited information that will be collected during 6 
monthly telephone follow-up calls for subjects who have discontinued study drug
Page 66, Section 9.1.8, Procedures for Clinical Laboratory Samples 
Existing Text
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)
Alanine aminotransferase
Alkaline phosphatase
Aspartate aminotransferase
Total bilirubin
Direct bilirubin (a)
-Glutamyl transferase 
Total protein
Albumin
Creatinine
Blood urea nitrogen
Potassium
Sodium
Glucose
Calcium, PTH
TSH, free T4 
Vitamin B12, folate (d) 
Rapid plasma reagin (RPR) (d)
pH
Specific gravity
Protein
Glucose
Blood
Nitrite
Blood 
Hepatitis panel, including HBsAg and anti-HCV (b)
(a) Assess only if total bilirubin ≥2.0 mg/dL.
(b) To be done at Baseline only.
(c) Microscopic examination (leucocytes, erythrocytes and casts) should be performed only if any of the urine 
evaluations are abnormal.
(d) At Baseline and as part of the comprehensive medical follow-up evaluation to rule out other causes of dementia.


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Revised Text
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry 
Urinalysis
Red blood cells
White blood cells count 
with differentials 
(Neutrophils, Eosinophils, 
Basophils, Lymphocytes,
Monocytes)
Hemoglobin
Hematocrit
Platelets
HbA1c (b)
Alanine aminotransferase
Alkaline phosphatase
Aspartate aminotransferase
Total bilirubin
Direct bilirubin (a)
-Glutamyl transferase 
Total protein
Albumin
Creatinine
Blood urea nitrogen
Potassium
Sodium
Glucose
Calcium, parathyroid hormone (PTH)
Thyroid-stimulating hormone (TSH), free thyroxine
(T4)
Vitamin B12, folate (c) 
Rapid plasma reagin (RPR) (c)
pH
Specific gravity
Protein
Glucose
Blood
Nitrite
Microscopic examination 
(Leucocytes, 
Erythrocytes, Casts)
Blood 
Hepatitis panel, including HBsAg and anti-HCV (b)
(a) Assess only if total bilirubin ≥2.0 mg/dL.
(b) To be done at Baseline only.
(c) At Baseline and as part of the comprehensive medical follow-up evaluation to rule out other causes of dementia.
Rationale for Amendment
Microscopic examinations will be performed on all samples at the initial assessment, rather than 
in response to findings on macroscopic examinations, in order to reduce burden to the subject by 
preventing the need for them to return to the site to provide another urine sample.
Page 75, Section 9.1.15.2, Efficacy Assessments 
Existing Text
Project Partner-Reported Questionnaires

Neuropsychiatric Inventory Questionnaire (NPI-Q) [62]: The NPI-Q is a brief validated 
version of the standard NPI [63]. It is designed to assess NPS common in AD and related 
dementias. The NPI-Q is designed to be a self-administered and queries the presence of 
symptoms in each of 12 specific domains and is queried over the past 30 days: delusions, 
hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, 
apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, disturbances 
of sleep, and disturbances of appetite/eating. The scale is constructed such that a screening 


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question is asked for each symptom domain. If this item is endorsed, then specific follow up 
questions are asked to clarify the nature of the symptoms, their frequency, severity, degree of 
change from premorbid, and treatment. The NPS outcome variable is defined as either the 
presence or absence of a given NPS domain. The NPI can also be analyzed by dividing into 
absence of any NPS versus >1 NPS (NPI Total). NPI severity can also be calculated. The 
physician reviews the form and clarifies the nature and the presence of symptoms endorsed. 
This questionnaire will be completed at Visit 2 (Baseline), Unscheduled Visit, and End of 
Study Visit/Early Withdrawal Visit.
Revised Text
Project Partner-Reported Questionnaires

Neuropsychiatric Inventory Questionnaire (NPI-Q) [62]: The NPI-Q is a brief validated 
version of the standard NPI [63]. It is designed to assess NPS common in AD and related 
dementias. The NPI-Q is designed to be a self-administered and queries the presence of 
symptoms in each of 12 specific domains and is queried over the past 30 days: delusions, 
hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, 
apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, disturbances
of sleep, and disturbances of appetite/eating. In special cases when Sponsor permission is 
given for the project partners to have the CMFV or EoS/EW Visit conducted by 
telephone, the questionnaire will no longer be self administered but will be conducted 
aurally over the telephone, more in keeping with the standard NPI, which was designed 
to be clinician administered with a query question (the items on the NPI-Q) followed by 
more detailed interviewing. The scale is constructed such that a screening question is asked 
for each symptom domain. If this item is endorsed, then specific follow up questions are 
asked to clarify the nature of the symptoms, their frequency, severity, degree of change from 
premorbid, and treatment. The NPS outcome variable is defined as either the presence or 
absence of a given NPS domain. The NPI can also be analyzed by dividing into absence of 
any NPS versus >1 NPS (NPI Total). NPI severity can also be calculated. The physician 
reviews the form and clarifies the nature and the presence of symptoms endorsed. This 
questionnaire will be completed at Visit 2 (Baseline), Unscheduled Visit, and EoS/EW Visit.
Rationale for Amendment
This revision explains how completion of the NPI-Q will differ in exceptional cases where the 
site is performing the CMFV or EoS/EW Visit assessments for the project partner via telephone.
Page 80, Section 9.2, Monitoring Treatment Compliance
Existing Text
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 (e)CRF. The 
project partner will also be asked to assess the subject’s compliance. 


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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.
Revised Text
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 (e)CRF. The 
project partner will also be asked to assess the subject’s compliance. 
Subjects will be considered to be non-compliant with study medication if they miss >20% 
of doses required for the visit period, or take more than 100% of the doses for the required 
visit period. Non-compliance with study medication must be reported in the (e)CRF and 
subjects should be reminded of the importance of being compliant with dosing instructions.
Any detected overdose must be reported on an Overdose page of the (e)CRF. 
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.
Rationale for Amendment
Formal limits on study drug treatment compliance have been added to ensure that all 
Investigators are consistently identifying and reporting cases of non-compliance with study 
medication.
Page 82, Section 9.3.5.2, Comprehensive Medical Follow-Up
Existing Text
A Comprehensive Medical Follow-Up evaluation (which the subject’s project partner must
attend), should be conducted within one month of the trigger when one of the triggers described 
in Section 6.2.4 has been met. This type of Unscheduled Visit will include the assessments noted 
in Appendix A and Section 6.2.4. It is anticipated this visit will be about 5 to 6 hours in length, if 
an MRI is completed during the visit.
Revised Text
A Comprehensive Medical Follow-Up evaluation (which the subject’s project partner should 
make every effort to attend, if possible, or otherwise complete during a Home Visit or via 
telephone if appropriate), should be conducted within approximately 30 days of the trigger 
when one of the triggers described in Section 6.2.4 has been met. This type of Unscheduled Visit 
will include the assessments noted in Appendix A and Section 6.2.4. If appropriate, the CMFV 
assessments may be performed during the routine visit if the specific criteria specified in 
Section 6.2.4 are met. It is anticipated this visit will be about 5 to 6 hours in length, if an MRI is 
completed during the visit.


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Rationale for Amendment
Additional options for performing CMFVs, as presented in Section 6.2.4, have been introduced 
in order to provide sites and subjects with flexibility in scheduling these visits to ensure that the 
procedures and assessments that are required are collected. 
Page 82, Section 9.3.6, Final Visit or Early Termination
Existing Text
The Final visit will be performed once the total number of endpoints are reached, which is 
expected to occur four years after enrollment ends, or at the Early Termination Visit. See 
Appendix A for a list of procedures that will be performed and documented.
For all subjects receiving study medication, the investigator must complete the End of Study
(e)CRF page.
Revised Text
The Final visit will be performed once the total number of endpoints are reached, which is 
expected to occur four years after enrollment ends, or at the EoS/EW Visit for subjects who 
complete the study or withdraw before the total number of endpoints are reached. See 
Appendix A for a list of procedures that will be performed and documented.
For all subjects receiving study medication, the investigator must complete the EoS (e)CRF 
page.
Rationale for Amendment
This section has been revised to clarify when the Final Visit will occur for all subjects, using 
nomenclature that is consistent with the rest of the protocol.
Page 90-91, Section 10.2.1.3, AESI Reporting
Existing Text
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 be 
evaluated by an ophthalmologist. 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 local standard of care.
2. …
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 


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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 [70].

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).

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 a subject is noted to have a hypoglycemic event, the hypoglycemia eCRF should be completed 
within 24 hours of the investigator’s awareness of the event.
Revised Text
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 be 
evaluated by an ophthalmologist. Subjects diagnosed with macular degeneration during 
the study will be followed up by an ophthalmologist and have retinal imaging (eg, Optic 
Coherence Tomography or Heidelberg Confocal Laser Doppler Imaging) performed at 
least every six months until study completion or early withdrawal to confirm that the 
condition is stable. 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 local standard of care.
3. …
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 


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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 all subjects with the following AEs will be closely monitored using 
the following event categories [70].

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).

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 any subject is noted to have a hypoglycemic event, the hypoglycemia (e)CRF should be 
completed within 24 hours of the investigator’s awareness of the event.
Rationale for Amendment
Revisions have been made to clarify that specific, ongoing follow-up is required for subjects 
diagnosed with macular degeneration during the study to ensure that there is no impact on their 
performance of the cognitive test battery due to worsening eyesight. 
Clarification also provided that hypoglycemic events must be reported as per the AESI guidance 
for any subjects participating in the study, not just those with T2DM or those taking insulin 
secretagogues in addition to study medication.
Page 100-101, Section 13.2, Futility Analysis and Criteria for Early Termination
Existing Text
An analysis for futility will be conducted once approximately 50% (101 out of 202) of the 
anticipated events (ie, conversions from cognitively normal status to adjudicated diagnosis of 
MCI due to AD, or to AD dementia) have occurred in the high-risk, Caucasian, non-
Hispanic/Latino group. However, since the biomarker risk stratum information is blinded, the 
time of the futility analysis will be estimated using all subjects (both high-risk and low-risk) in 
the Caucasian, non-Hispanic/Latino group. This will occur when approximately 106 events have 
been confirmed through adjudication in the Caucasian, non-Hispanic/Latino group (including 
both high-risk and low-risk subjects). This analysis will have two parts, performed 


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hierarchically: first, an analysis to determine futility based on lack of pioglitazone efficacy, and 
second, an analysis to determine futility based on the biomarker risk algorithm not having 
performed as expected to enrich the sample population. The second analysis is only conducted if 
futility is identified for the primary comparison within the high-risk, Caucasian, non-
Hispanic/Latino group. Because a review of unblinded data is involved, the DSMB will oversee 
this process. Note that no adjustment of the alpha level is required for an analysis for futility, and 
that for this study the results of the futility analysis will be considered to be non-binding with 
respect to efficacy for purposes of decision making around study continuation. 
Once the total number of target events has been reached, the DSMB will be unblinded for a 
review of actual treatment groups with respect to the primary efficacy endpoint only; this review 
would take place at the next regularly-scheduled DSMB meeting. 
The futility analysis will be conducted by the DSMB Statistician, based on the treatment effect 
within the high-risk, Caucasian, non-Hispanic/Latino group. The calculation is a test from a Cox 
proportional hazards survival model to evaluate a difference between the treatment groups 
(pioglitazone versus placebo) for the high-risk comparison at the time of the interim futility 
analysis. The DSMB could then recommend study continuation to completion for the targeted 
number of events or recommend (based on pre-specified criteria documented in the SAP) that the 
study be considered futile with respect to the primary efficacy endpoint, high-risk comparison. If 
futility is indicated for the high-risk primary efficacy endpoint comparison, then a futility 
analysis will be conducted for the biomarker comparison.
Immediately after the futility analysis data review meeting takes place, the DSMB 
recommendation regarding the continuation of the study will be promptly communicated to the 
DSMB Liaison. If the data indicate that study termination should be considered, the DSMB 
Liaison will promptly convene an ad-hoc meeting within the Takeda/Zinfandel alliance senior 
management to further discuss the results of the analysis with the DSMB and to make the final 
decision as to whether or not to terminate the study. If the alliance committee decides to 
terminate or modify the study as a result of the futility analysis, this decision will be promptly 
communicated to all the stakeholders including the AD-4833/TOMM40 project team, 
investigators, ethics committees, and regulatory agencies. Details of the stopping rules and 
analyses will be given in the DSMB Charter and in the SAP.
Revised Text
Tracking of confirmed events of MCI due to AD, as adjudicated by the CIAC, will be done 
on an ongoing basis, in a blinded fashion. There will be two types of analyses conducted 
during the study to assess futility: an ‘operational futility analysis’ and an ‘efficacy futility 
analysis’. The study will be declared to be ‘operationally futile’ if the accrual of confirmed 
events is too slow to allow completion of the study in a feasible time frame. The timeframe 
for assessing operational futility is described in the SAP.


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CONFIDENTIAL
If operational futility is not declared, an analysis for futility for efficacy will be conducted 
once approximately 33% (66 out of 202) of the anticipated events (ie, conversions from 
cognitively normal status to adjudicated diagnosis of MCI due to AD, or to AD dementia) have 
occurred in the high-risk, Caucasian, non-Hispanic/Latino group. However, since the biomarker 
risk stratum information is blinded, the time of the futility analysis will be estimated using all 
subjects (both high-risk and low-risk) in the Caucasian, non-Hispanic/Latino group. Therefore, 
the efficacy futility analysis will occur when approximately 69 events have been confirmed 
through adjudication in the Caucasian, non-Hispanic/Latino group (including both high-risk and 
low-risk subjects). Note that no adjustment of the alpha level is required for an analysis for 
futility, and that for this study the results of the futility analysis will be considered to be non-
binding with respect to efficacy for purposes of decision making around study continuation. 
If operational futility is declared, an early efficacy futility analysis (ie, prior to reaching 
33% of anticipated events as described above) will be done as soon as practicable (ie, after 
all pertinent data for the futility analyses has been cleaned as per the specifications outlined 
in the Interim Database Lock Plan) and will be provided to the DSMB. This will not 
replace the planned efficacy futility analysis that will occur following the accrual of 33% of 
the anticipated events.
Further details of the operational and efficacy futility analyses are given in the SAP.
Because a review of unblinded data is involved, the DSMB will oversee this process. Once 
the total number of target events has been reached, the DSMB will be unblinded for a review of 
actual treatment groups with respect to the primary efficacy endpoint (and potentially other 
analyses as described in the SAP, as applicable); this review would take place at the next 
regularly-scheduled DSMB meeting or at an ad hoc DSMB meeting.
The primary futility analysis for efficacy will be conducted by the DSMB Statistician, based on 
the treatment effect within the high-risk, Caucasian, non-Hispanic/Latino group. The calculation 
is a test from a Cox proportional hazards survival model to evaluate a difference between the 
treatment groups (pioglitazone versus placebo) for the high-risk comparison at the time of the 
interim futility analysis. Additionally, Kaplan-Meier curves by treatment group (including 
low-risk placebo) will be provided for the primary analysis population of non-
Hispanic/Latino Caucasian subjects. If the primary futility analysis indicates futility, then 
the 
 Unblinded DSMB Statistician will provide an additional set of secondary 
futility analyses (described in the SAP). The DSMB could then recommend study continuation 
to completion for the targeted number of events or recommend (based on pre-specified criteria 
documented in the SAP) that the study be considered futile with respect to the primary efficacy 
endpoint, high-risk comparison. 
Immediately after the efficacy futility analysis data review meeting takes place (ie, either after 
an efficacy futility analysis following operational futility or the efficacy futility analysis 
following accrual of 33% of events), the DSMB recommendation regarding the continuation of 
the study will be promptly communicated to the DSMB Liaison. If the data indicate that study 
CCI


AD-4833
Study No. AD-4833/TOMM40_301
Page 153 of 158
Protocol Incorporating Amendment No. 6
27 September 2016
CONFIDENTIAL
termination should be considered, the DSMB Liaison will promptly convene an ad-hoc meeting 
within the Takeda/Zinfandel alliance senior management (ie, the Executive Committee) to 
further discuss the results of the futility analyses and make the final decision as to whether or 
not to terminate the study. In a similar manner to the DSMB, the Executive Committee will 
be unblinded to the results of the futility analyses, will keep all futility analysis results and 
discussions strictly confidential, and will have no involvement with the daily project 
activities of the study or study team.
If the alliance Executive Committee decides to terminate the study as a result of the futility 
analyses, this decision will be promptly communicated to all the stakeholders including the AD-
4833/TOMM40 project team, investigators, ethics committees, and regulatory agencies. Details 
of the stopping rules and analyses will be given in the DSMB Charter and in the SAP.
Rationale for Amendment
Section updated following revisions to the planned futility analysis, including plans for a formal 
test of ‘operational futility’. The revisions will enable an earlier assessment of ‘efficacy futility’, 
protecting study subjects and the Sponsor from continuation of an ultimately futile study, whilst 
keeping the risk of a futility ‘false negative’ finding at an acceptably low probability. The 
inclusion of an assessment of operational futility will enable an assessment of whether the study 
can feasibly be completed within an acceptable timeframe, based on the accrual rate of 
adjudicated cases meeting the endpoint definition.


AD-4833
Study No. AD-4833/TOMM40_301
Page 154 of 158
Protocol Incorporating Amendment No. 6
27 September 2016
CONFIDENTIAL
Page 115-118, Appendix A, Schedule of Study Procedures
Existing Text
Screen-
ing
Visit 1
Base-
line
Visit 2
Random-
ization
Visit 3
Double-Blind Treatment
Repeated yearly
Unschedu
led -
Comprehe
nsive 
Medical 
Follow-up
(q)
End of Study 
(EoS)/Early 
Withdrawal (EW)
Visit (b) (j)
Follow-up 
Visit (c)
Study Month:
-4
-1
0 (Day 0) 3 (a)
6
9 (a)
12
EoS/EW+0.5
Visit Window (t):
Max
Day
-125
Max
Day
-35
±2 
weeks
±2 
weeks
±2 
weeks
±2 
weeks
Within 30 
days of 
trigger
Genetics (blood samples)
TOMM40 rs10524523, 
APOE (Risk 
stratification)
X
Safety/efficacy PGx
(DNA and RNA 
samples) – subject-
optional
X(g, n)
X(n)
(f) As part of the comprehensive medical follow-up evaluation to rule out other causes of dementia and confirm the 
clinical diagnosis of MCI due to AD (See section 6.2.4). For subjects who have contraindications for the MRI 
procedure (such as unremovable ferromagnetic dental work, cardiac pacemakers, etc) a CT scan can be done instead.
(j) Subjects who discontinue study medication prematurely should be contacted by the study site every 6 months 
until the conclusion of the study via telephone to assess the general well being of the subject as well as to obtain any 
changes in medications. In the event the subject is not able to be reached, the subject’s project partner or primary 
care physician can be contacted to obtain this information.
(n) RNA sample to be collected at Day 0, Month 12 of Year 1, Year 2, Year 3, Year 4, and Year 5.
(o) Greater detail is given below. Note: If subject has been off drug for 3 or more days prior to Unscheduled CMFU
Visit, End of Study Visit, or Early Withdrawal, the PK samples should not be collected.
(q) Procedures for Unscheduled visits for CMFV includes the assessments marked, and should only be conducted 
after appropriate trigger is met as described in Section 6.2.4. Unscheduled visits for other concerns, including safety, 
the investigator is expected to conduct whatever assessments are necessary.


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Study No. AD-4833/TOMM40_301
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CONFIDENTIAL
Revised Text
Screen-
ing
Visit 1
Base-
line
Visit 2
Random-
ization
Visit 3
Double-Blind Treatment
Repeated yearly
Unscheduled 
–
CMFV
(q) (v)
EoS/ EW
Visit 
(b) (j)
Follow-up 
Visit 
(c)
Study Month:
-4
-1
0 (Day 0) 3 (a)
6
9 (a)
12
EoS/EW+0.5
Visit Window (t):
Max
Day
-125
Max
Day
-35
±2 
weeks
±2 
weeks
±2 
weeks
±2 
weeks
Within 
approx. 30
days of trigger
Genetics (blood samples)
TOMM40 rs10524523, 
APOE (Risk 
stratification)
X
Safety/efficacy PGx
(DNA and RNA 
samples) – subject-
optional
X(g, n)
X(n)
X(n)
(f) As part of the comprehensive medical follow-up evaluation to rule out other causes of dementia and confirm the 
clinical diagnosis of MCI due to AD (See section 6.2.4). An MRI scan is not required to be performed if a study 
related MRI scan was collected within 6 months of the CMFV. For subjects who have contraindications for the 
MRI procedure (such as unremovable ferromagnetic dental work, cardiac pacemakers, etc) a CT scan can be done 
instead.
(j) Subjects who discontinue study medication prematurely should be contacted by the study site every 6 months 
until the conclusion of the study via telephone to assess the general well being of the subject as well as to obtain any 
changes in medications related to cognitive health. In the event the subject is not able to be reached, the subject’s 
project partner or primary care physician can be contacted to obtain this information.
(n) RNA sample to be collected at Day 0, Month 12 of Year 1, Year 2, Year 3, Year 4 and EoS.
(o) Greater detail is given below. Note: If subject has been off drug for 3 or more days prior to Unscheduled CMFV, 
or EOS/EW Visit, the PK samples should not be collected.
(q) Procedures for Unscheduled visits for CMFV includes the assessments marked, and should only be conducted 
after appropriate criteria are met as described in Section 6.2.4. Unscheduled visits for other concerns, including 
safety, the investigator is expected to conduct whatever assessments are necessary.
(v) At the Investigator’s discretion, CMFV assessments may be conducted at the routine Month 6 or Month 
12 Visit in situations where the CMFV conducted as an outcome of the previous scheduled office visit resulted 
in an MCI due to AD diagnosis. Refer to Section 6.2.4 for further detail.
Rationale for Amendment
Footnotes for Appendix A have been updated in line with revisions made elsewhere in the 
protocol. In addition, the acronym used for the Comprehensive Medical Follow-up Visit has 
been corrected in line with nomenclature used throughout the protocol. 


AD-4833
Study No. AD-4833/TOMM40_301
Page 156 of 158
Protocol Incorporating Amendment No. 6
27 September 2016
CONFIDENTIAL
Page 126, Appendix E, Collection, Shipment, and Storage of Pharmacogenomic Samples 
(Separate from the risk stratification sample)
Existing Text
RNA Sample Collection
One 2.5 mL whole blood sample for RNA extraction will be collected from each subject who 
consented to pharmacogenomic research. A sample will be collected at Day 0, Month 12 of Year 
1, Year 2, Year 3, Year 4 and Year 5 into a PAXgene tube.
Revised Text
RNA Sample Collection
One 2.5 mL whole blood sample for RNA extraction will be collected from each subject who 
consented to pharmacogenomic research. A sample will be collected at Day 0, Month 12 of Year 
1, Year 2, Year 3, Year 4 and EoS into a PAXgene tube.
Rationale for Amendment
Section 9.1.11.2 has always stated that RNA sample collection should occur at EoS since yearly 
RNA collection was introduced into the protocol in Amendment 2, however the visits at which 
collection should occur was incorrectly listed in Appendix E. Appendix E has been updated to 
ensure consistency within the protocol in the timing of RNA sample collection and to ensure that 
RNA samples are collected at EoS. 
Page 136, Appendix H, A Sub Study To Evaluate the Effects of Pioglitazone on Whole and 
Regional Brain Volume over Time
Existing Text
Study Design
In addition to their participation in the main phase 3 study, approximately 300 cognitively 
normal elderly subjects will participate in a sub study at selected sites. Subjects will sign a 
separate informed consent form (ICF) in order to participate in this sub-study. Subjects who 
fulfill all inclusion criterion and none of the exclusion criteria for the sub-study will be selected 
in a double-blind fashion to represent a 5:4 randomization ratio between pioglitazone and 
placebo assignment. Subjects in this sub-study will be scanned to assess brain volume (vMRI). 
Serial brain MRI scans will be performed at baseline, 2 years, and end of study/early termination
(3 timepoints in total).


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Study No. AD-4833/TOMM40_301
Page 157 of 158
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CONFIDENTIAL
Schedule of Additional Study Procedures for the Sub-Study
Screening
Visit 1
Baseline
Visit 2
Randomization
Visit 3
Double-Blind
Treatment
End of Study 
(EoS)/Early 
Withdrawal (EW)
Visit
Study Month:
-4
-1
0 (Day 0)
24
Visit Window:
Max Day
-125
Max Day
-35
±2 weeks
Informed consent (a) 
X
X
Incl/Excl Criteria
X
X
X
vMRI scan (Brain Volume)
X
X
X (b)
(a) All subjects should sign a separate informed consent to participate in the sub-study at either visit 1 or visit 2, must occur prior 
to any sub-study procedures taking place.
(b) This assessment only needs to be administered at this visit if it occurs greater than 6 months from the last administration.
Duration of Treatment
The total duration of the vMRI sub study will be the same duration as the main study.
Primary Objective
1. To evaluate changes in brain volume in subjects receiving pioglitazone versus subjects 
receiving placebo.
Primary Endpoint
1. Changes from baseline in vMRI in whole brain and specific brain regions of interest at 
2 years, and 4 years or study termination (in subjects enrolled in the sub study).
Revised Text 
Study Design
In addition to their participation in the main phase 3 study, approximately 300 cognitively 
normal elderly subjects will participate in a sub study at selected sites. Subjects will sign a 
separate informed consent form (ICF) in order to participate in this sub-study. Subjects who 
fulfill all inclusion criterion and none of the exclusion criteria for the sub-study will be selected 
in a double-blind fashion to represent a 5:4 randomization ratio between pioglitazone and 
placebo assignment. Subjects in this sub-study will be scanned to assess brain volume (vMRI). 
Serial brain MRI scans will be performed at baseline, 2 years, and EoS/EW (3 timepoints in 
total).


AD-4833
Study No. AD-4833/TOMM40_301
Page 158 of 158
Protocol Incorporating Amendment No. 6
27 September 2016
CONFIDENTIAL
Schedule of Additional Study Procedures for the Sub-Study
Screening
Visit 1
Baseline
Visit 2
Randomization
Visit 3
Double-Blind
Treatment
EoS/EW Visit
Study Month:
-4
-1
0 (Day 0)
24
Visit Window:
Max Day
-125
Max Day
-35
±2 weeks
Informed consent (a) 
X
X
Incl/Excl Criteria
X
X
X
vMRI scan (Brain Volume)
X
X (b)
X (b)
(a) All subjects should sign a separate informed consent to participate in the sub-study at either visit 1 or visit 2, must occur prior 
to any sub-study procedures taking place.
(b) This assessment only needs to be administered at this visit if it occurs greater than 6 months from the last administration for 
either the main study or the sub study.
Duration of Treatment
The total duration of the vMRI sub study will be the same duration as the main study.
Primary Objective
1. To evaluate changes in brain volume in subjects receiving pioglitazone versus subjects 
receiving placebo.
Primary Endpoint
1. Changes from baseline in vMRI in whole brain and specific brain regions of interest at 
2 years and EoS/EW (in subjects enrolled in the sub study). If an MRI scan has been 
performed for the main study or the sub study within 6 months of a required timepoint, 
a separate MRI scan does not need to be performed.
Rationale for Amendment
The text in this section has been revised to accurately reflect the timepoints at which analysis for 
this endpoint will occur using nomenclature that is consistent throughout the protocol. It has also 
been updated to clarify that MRI scans do not need to be performed if a scan has been collected 
for the study within 6 months or the required timepoint, to reduce subject burden in collecting 
additional MRI scans which are considered unnecessary.


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PPD

SAP_001.pdf: 


• 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 Double Blind, Randomized, Placebo Controlled, Parallel Group Study to 
Simultaneously Qualify a Biomarker Algorithm for Prognosis of Risk of Developing Mild 
Cognitive Impairment due to Alzheimer’s Disease (MCI due to AD) and to Test the Safety and 
Efficacy of Pioglitazone (AD-4833 SR 0.8 mg QD) to Delay the Onset of MCI due to AD in 
Cognitively Normal Subjects
NCT Number: NCT01931566
SAP Approve Date: 30 November 2017
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 (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


TAKEDA DEVELOPMENT CENTER
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: AD-4833/TOMM40_301
A Double Blind, Randomized, Placebo Controlled, Parallel Group Study to Simultaneously 
Qualify a Biomarker Algorithm for Prognosis of Risk of Developing Mild Cognitive 
Impairment due to Alzheimer’s Disease (MCI due to AD) and to Test the Safety and 
Efficacy of Pioglitazone (AD-4833 SR 0.8 mg QD) to Delay the Onset of MCI due to AD in 
Cognitively Normal Subjects
PHASE 3
Version: Amendment 1
Date: 30 November 2017
Prepared by: 
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.
PPD


AD-4833/TOMM40_301
Page 2 of 71
Statistical Analysis Plan, Amendment 1
30 November2017
CONFIDENTIAL
1.1
APPROVAL SIGNATURES
Study Title:
A Double Blind, Randomized, Placebo Controlled, Parallel Group Study to Simultaneously 
Qualify a Biomarker Algorithm for Prognosis of Risk of Developing Mild Cognitive 
Impairment due to Alzheimer’s Disease (MCI due to AD) and to Test the Safety and 
Efficacy of Pioglitazone (AD-4833 SR 0.8 mg QD) to Delay the Onset of MCI due to AD in 
Cognitively Normal Subjects
TDC Approvals
Date
Date
Date
Date
PPD


AD-4833/TOMM40_301
Page 3 of 71
Statistical Analysis Plan, Amendment 1
30 November2017
CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
APPROVAL SIGNATURES.....................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
SUMMARY OF CHANGES...........................................................................................9
5.0
INTRODUCTION.........................................................................................................11
6.0
OBJECTIVES AND STUDY DESIGN.........................................................................12
6.1
Primary Objectives ..................................................................................................12
6.2
Key Secondary Objectives .......................................................................................12
6.3
Additional Objectives ..............................................................................................12
6.3.1
Safety Objective.................................................................................................12
6.3.2
Exploratory Objectives.......................................................................................12
6.4
Study Design ...........................................................................................................13
7.0
ANALYSIS ENDPOINTS.............................................................................................17
7.1
Primary Endpoints ...................................................................................................17
7.2
Key Secondary Endpoints........................................................................................17
7.2.1
Additional Endpoints .........................................................................................17
8.0
DETERMINATION OF SAMPLE SIZE.......................................................................20
9.0
METHODS OF ANALYSIS AND PRESENTATION...................................................22
9.1
General Considerations............................................................................................22
9.1.1
Statistical Software ............................................................................................22
9.1.2
Summary Statistics and Precision.......................................................................22
9.1.3
Definition of Study Day and Study Visit Windows.............................................23
9.1.4
Grouping of Centers...........................................................................................24
9.2
Major Protocol Violations........................................................................................25
9.3
Analysis Sets ...........................................................................................................26
9.4
Disposition of Subjects ............................................................................................26
9.5
Demographic and Baseline Characteristics...............................................................27
9.6
Medical History and Concurrent Medical Conditions...............................................27
9.7
Medication History and Concomitant Medications...................................................28
9.8
Study Drug Exposure and Compliance.....................................................................29
9.9
Efficacy Analyses....................................................................................................30
9.9.1
Overview of Primary, Secondary, and Additional Variables...............................30
9.9.2
Task Completion, Irregular Procedure, and Missing Items on Rating Scales.......33


AD-4833/TOMM40_301
Page 4 of 71
Statistical Analysis Plan, Amendment 1
30 November2017
CONFIDENTIAL
9.9.3
Analysis of Primary Variable .............................................................................34
9.9.4
MCI Due to AD Event Description ....................................................................37
9.9.5
Sensitivity Analyses Using Alternative Event Definitions ..................................40
9.9.6
Analysis of Key Secondary Variables.................................................................41
9.9.7
Derivation of Cognitive Battery Composite Score..............................................42
9.9.8
Controlling Type I Error ....................................................................................43
9.9.9
Analysis of Additional Variables........................................................................43
9.9.10 Additional Biomarker Qualification Analyses ....................................................45
9.10
Analyses of Columbia-Suicide Severity Rating Scale (C-SSRS) ..............................47
9.11
Pharmacokinetic/Pharmacodynamic Analyses..........................................................48
9.12
Pharmacogenomic Analyses ....................................................................................48
9.13
Other Outcomes.......................................................................................................48
9.14
Safety Analysis........................................................................................................49
9.14.1 Adverse Events ..................................................................................................49
9.14.2 Clinical Laboratory Evaluations .........................................................................51
9.14.3 Vital Signs .........................................................................................................53
9.14.4 Physical Examinations .......................................................................................53
9.14.5 12-Lead ECGs ...................................................................................................53
9.14.6 Other Observations Related to Safety.................................................................53
9.15
Operational Futility Analysis ...................................................................................53
9.16
Efficacy Futility Analysis ........................................................................................54
9.16.1 Conditional Power for Futility for Efficacy ........................................................58
9.17
Changes in the Statistical Analysis Plan from the Protocol Analysis Plan.................58
10.0
REFERENCES..............................................................................................................59
LIST OF IN-TEXT TABLES
Table 8.a
Conversion Rate Estimates Based on Analysis of 3 Cohorts, Cognitive 
Impairment Incidence, and Observed TOMM40 rs10524523 Allele 
Frequencies........................................................................................................20
Table 9.a
Visit Windows ...................................................................................................23
Table 9.b
Primary, Secondary and Additional Variables ....................................................31
Table 9.c
Number of Missing Items on Scales with a Missing Value for Total Score.........34


AD-4833/TOMM40_301
Page 5 of 71
Statistical Analysis Plan, Amendment 1
30 November2017
CONFIDENTIAL
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................16
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................60
Appendix B
Criteria for Abnormal Changes from Baseline of Vital Signs..............................63
Appendix C
Criteria for Out-of-Range Values for the 12-Lead ECG Parameters....................64
Appendix D
Cognitive Test Battery .......................................................................................65
Appendix E
Detailed Description of Amendments to Text.....................................................66


AD-4833/TOMM40_301
Page 6 of 71
Statistical Analysis Plan, Amendment 1
30 November2017
CONFIDENTIAL
3.0
LIST OF ABBREVIATIONS
AA
Alzheimer’s Association
AD
Alzheimer’s Disease
ADAS-cog
Alzheimer’s Disease Assessment Scale-Cognitive Subscale
ADCS ADL-PI
Alzheimer’s Disease Cooperative Study Activities of Daily Living - Prevention Instrument
ADCS-CGIC-MCI
Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change – Mild 
Cognitive Impairment
ADRC
Alzheimer’s Disease Research Center
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
APOE
apolipoprotein E
ARIA
amyloid –related imaging abnormalities
AST
aspartate aminotransferase
BMI
body mass index
BPM
beats per minute
BUN
blood urea nitrogen
BVMT-R
Brief Visuospatial Memory Test - Revised
CDR
Clinical Dementia Rating
CDR-SB
Clinical Dementia Rating – Sum of Boxes
CDT
Clock Drawing Test
CGIC
Clinical Global Impression of Change
CI
confidence interval
CIAC
Cognitive Impairment Adjudication Committee
CMFV
Comprehensive Medical Follow-up Visit
CPH
Cox proportional hazards
CSR
Clinical Study Report
C-SSRS
Columbia–Suicide Severity Rating Scale
CVLT-II
California Verbal Learning Test – 2nd Edition
DNA
deoxyribonucleic acid
DSMB
Data Safety Monitoring Board
DSM-IV-TR
Diagnostic & Statistical Manual of Mental Disorders, 4th Edition - Text Revision
ECG
Electrocardiogram
(e)CRF
case report form (electronic)
EoS
end of study
EQ-5D
European Quality of life (includes single item measures of: mobility, self-care, usual
activities, pain/discomfort, and anxiety/depression)
EW
early withdrawal
FAS
full analysis set


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CONFIDENTIAL
GDS
Geriatric Depression Scale
GGT
-glutamyl transferase
HbA1c
glycosylated hemoglobin
ICH
International Conference on Harmonisation
IMP
investigational medicinal product
IQCODE
Informant Questionnaire on Cognitive Decline in the Elderly
IWRS
Interactive Web Response System
L
long
LDH
lactate dehydrogenase
LLN
lower limit of normal
MAR
missing at random
MCI
mild cognitive impairment
MedDRA
Medical Dictionary for Regulatory Activities
MINT
Multilingual Naming Test
mm Hg
millimeters of mercury
MMRM
mixed model for repeated measures
MMSE
Mini-Mental State Examination
NIA
National Institute on Aging
NPI-Q
Neuropsychiatric Inventory Questionnaire
NPS
neuropsychiatric symptoms
NPV
negative predictive value
PD
pharmacodynamics
PGx
pharmacogenomics
PK
pharmacokinetics
PPAR-
peroxisome proliferator-activated receptor-gamma
PPS
per-protocol analysis set
PPV
positive predictive value
PRO
patient-reported outcome
QD
once daily
RU
Resource Utilization
S
short
SAE
serious adverse event
SAP
statistical analysis plan
SDTM
Study Data Tabulation Model
SF-36
Short Form-36
SI
Systeme International
SOC
system organ class
TEAE
treatment-emergent adverse event
TOMM40
Translocase of the Outer Mitochondrial Membrane 40 homolog
ULN
upper limit of normal
VL
very long


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vMRI
volumetric magnetic resonance imaging
WHO
World Health Organization


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4.0
SUMMARY OF CHANGES
This section describes the changes in reference to the SAP Incorporating Amendment No. 1.
The primary purpose of this amendment is to revise the definition of the event time of a 
Cognitive Impairment Adjudication Committee (CIAC)CIAC confirmed event of MCI due to
AD and provide additional analyses for the efficacy futility analysis. The following is a summary 
of the changes made in the amendment. Detailed description of amendments to the text is 
presented in Appendix E.
1. The definition of the event time of a CIAC-adjudicated event of MCI due to AD has been 
revised as the time from a subject’s randomization date to the date of the first scheduled visit 
of the two consecutive scheduled visits at which that subject was assessed with a clinical 
diagnosis and determined as an primary endpoint event by CIAC using the data from 
scheduled visit and the triggered unscheduled comprehensive medical follow up visits.
Justification: This change will reflect the thinking that, in any subject dossier reviewed by the 
CIAC, the first scheduled visit is the first of the 4 visits considered by CIAC in their 
adjudication of primary endpoint event, and it represents the first time point of these 4 visits 
where clinical impairment or cognitive decline is first noted. This revised definition better 
reflects the concept of “time to onset” of the MCI due to AD – “onset” meaning start of 
symptoms that are confirmed as MCI due to AD (or AD dementia) by the CIAC.
2. The data collected at the EOS/EW visit is allowed to be used to determine the primary 
efficacy events of MCI due to AD.
Justification: the data collected at the EOS/EW is similar to those planned at the unscheduled 
CMFV.
3. The memory domain score derivation algorithm is revised so that at least one of the CVLT-II 
episodic memory tests (CVLT-II Short-delay free recall correct or CVLT-II Long-delay free 
recall correct) is required to be non-missing. The requirement of BMVT-R being non-
missing is removed. 
Justification: The BVMT-R can be missing for many reasons other than cognition (arthritis, 
motor issues, examiner error). The requirement of both BVMT and at least one CVLT-II to
be non-missing may cause valid data points to be omitted (such as subjects who complete 
CVLT only). The composite measure becomes uninformative without the memory domain; 
however, the CVLT alone can be used to calculate a memory domain.
4. Additional summaries and analyses are added to evaluate the biomarker qualification 
performance. Key secondary endpoints and additional variables (only at the domain and 
composite score levels) will be summarized and analyzed using the data from placebo 
subjects who are classified into low and high risk groups.
Justification: These analyses will be helpful for the evaluation of the biomarker qualification
performance and will be presented at the end of study.


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5. At the time of the efficacy futility analysis, if the conditional power is <30%, the following 
subgroup analyses will be performed on the primary efficacy endpoint: gender (male vs. 
female), APOE risk-status (low vs. high) and baseline MMSE (<=27 vs. >=28). A particular 
subgroup analysis (e.g. female) will be performed only when there are at least 20% of the 
total primary events in the subgroup. 
Justification: This addition is expected to be informative in the efficacy futility assessment 
when the conditional power based on the primary event is <30%.
6. At the time of the efficacy futility analysis, if the conditional power is <30%, the following 
subgroup summaries and MMRM analyses will be performed on the change from baseline in 
the composite score, CVLT-II Long and Short Delay Free Recall Correct, BVMT-R Delayed 
Recall and MMSE total score: gender (male vs. female), APOE risk-status (low vs. high) and 
baseline MMSE (<=27 vs. >=28). The subgroup analysis will be performed only when there 
are at least 400 subjects in a subgroup. 
Justification: This addition is expected to be informative in the efficacy futility assessment 
when the conditional power based on the primary event is <30%.
7. At the time of the efficacy futility analysis, if the conditional power is <30%, and the 
treatment effect on the change from baseline by visit in the composite score is statistically 
significant (p-value<0.05), a joint model of the time-to-event data and the longitudinal 
composite score data will be fitted to estimate the association between the composite score 
and hazard rate of MCI due to AD over time during the treatment period. Details of this 
model are presented in Section 9.16.
Justification: This addition is expected to be informative in the efficacy futility assessment 
when the conditional power based on the primary event is <30%.
8. At the time of the efficacy futility analysis, if the conditional power is between 10% (>10%) 
and 30% (<30%), the “progression” of the conditional power in terms of an increasing 
number of the events vs. total needed will be provided for the following information 
fractions: 10% (20 events), 20% (41 events) and 34% (69 events). The events will be selected 
based on the time of the occurrence of the event relative to the first dose.
Justification: When the evidence against the null hypothesis is accumulating, the conditional 
power should increase as the information fraction increases. However, if the CP does not 
change as the information fraction increases, it may be unlikely evidence against the null 
hypothesis is being accumulated. Essentially if CP remains flat across 10%, 20%, 30% of 
events, it makes it less likely we would reject the null hypothesis at end of study.


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5.0
INTRODUCTION
This document describes the statistical analyses to be performed and data presentations to be 
produced for this phase 3, randomized, double-blind, parallel-group, placebo-controlled study to 
simultaneously qualify a biomarker algorithm for prognosis of risk of developing mild cognitive 
impairment due to Alzheimer’s Disease (MCI due to AD) and to test the safety and efficacy of 
pioglitazone (AD-4833 SR 0.8 mg QD) to delay the onset of MCI due to AD in cognitively 
normal subjects.
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. This SAP was developed based on the International Conference on Harmonisation 
(ICH) E3 and E9 Guidelines and in reference to the following documents:

Protocol AD-4833/TOMM40_301 Amendment #1 dated 09 April 2013.

Protocol AD-4833/TOMM40_301 Amendment #2 dated 19 March 2014.

Protocol AD-4833/TOMM40_301 Amendment #3 dated 10 November 2014.

Protocol AD-4833/TOMM40_301 Amendment #4 (Local-Russia) dated 15 April 2015.

Protocol AD-4833/TOMM40_301 Amendment #5 dated 24 July 2015.
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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6.0
OBJECTIVES AND STUDY DESIGN
6.1
Primary Objectives
For biomarker risk algorithm qualification:
∀
To qualify the biomarker risk algorithm composed of TOMM40 rs10524523 genotype,
APOE genotype, and age for prognosis of the risk of developing MCI due to AD within
5 years.
For efficacy evaluation of pioglitazone:
∀
To evaluate the efficacy of pioglitazone compared with placebo to delay the onset of MCI
due to AD in cognitively-normal subjects who are at high-risk, as identified by the biomarker
risk algorithm at enrollment, for developing MCI due to AD within 5 years.
6.2
Key Secondary Objectives
∀
To evaluate the effect of pioglitazone compared with placebo on the progression of cognitive
decline.
∀
To evaluate the effect of pioglitazone compared with placebo on functional decline and
instrumental activities of daily living.
6.3
Additional Objectives
6.3.1
Safety Objective
∀
To evaluate long-term safety and tolerability of pioglitazone compared with placebo during
the course of the treatment.
6.3.2
Exploratory Objectives
∀
∀
∀
∀
∀
CCI


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∀
∀
6.4
Study Design
This phase 3 study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group
study designed to pursue two primary objectives independently yet simultaneously: (1) to qualify 
a biomarker risk algorithm composed of TOMM40 rs10524523 genotype, APOE genotype, and 
age for prognosis of the risk of developing MCI due to AD and (2) to evaluate the efficacy of 
pioglitazone (AD-4833 SR 0.8 mg once daily [QD]) to delay the onset of MCI due to AD in 
cognitively normal subjects who are prognosed to be at high risk of developing MCI due to AD 
within 5 years.
The study duration will be the time needed to accumulate a total of 202 conversions in 
non-Hispanic/Latino Caucasian subjects within the high-risk stratum from normal cognition to a 
diagnosis of MCI due to AD, currently anticipated to be a minimum of 4 years. For the purposes
of this study, a Caucasian subject will be defined as a person having origins in any of the original 
peoples of Europe, the Middle East, or North Africa. Hispanic/Latino will be defined as a person 
of Cuban, Mexican, Puerto Rican, South or Central American origin, regardless of race. The 
study will primarily recruit from large community-based populations.
The subjects must be cognitively normal as assessed first by performance on the MMSE at 
Screening, and then on the CDR scale and the Cognitive Test Battery (Sections 9.1.15.1 and 
9.1.15.2 of the protocol) at Baseline (Visit 2). The subject must be between the ages of 65 and 83 
years, inclusive, at time of the Screening Visit. The subjects must have a project partner able to 
complete an Acknowledgement Form 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 is in the study.
Based on statistical requirement, a minimum of 2,793 subjects will be stratified into high- and 
low-risk (for the development of MCI due to AD over the next 5 years) groups based upon 
application of the biomarker risk algorithm. Subjects will be randomized via interactive web 
response system (IWRS) into this study as follows:
∀
Non-Hispanic/Latino Caucasian subjects. A minimum of 2,660 subjects further divided into:
–
Approximately 2,346 subjects in the high-risk group (pioglitazone, n=1,173; placebo, 
n=1,173).
–
Approximately 314 subjects in the low-risk group: All subjects stratified to the low-risk 
stratum will also be randomized to maintain the stratification blind, but all subjects in this 
stratum will receive placebo.
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∀
Non-Caucasian subjects and Hispanic/Latino Caucasian subjects. Subjects will be allocated 
to risk strata using the same algorithm as for the non-Hispanic/Latino Caucasian subjects.
Since all subjects screened at the time of Amendment 5 will be allowed to randomize if they 
continue to meet all eligibility criteria, it is estimated that approximately 3,500 will be 
randomized with the following groups:
∀
Non-Hispanic/Latino Caucasian subjects. Estimated 3,330 subjects further divided into:
–
Approximately 2,940 subjects in the high-risk group (pioglitazone, n=1,470; placebo, 
n=1,470).
–
Approximately 394 subjects in the low-risk group: All subjects stratified to the low-risk 
stratum will also be randomized to maintain the stratification blind, but all subjects in this 
stratum will receive placebo.
∀
Non-Caucasian subjects and Hispanic/Latino Caucasian subjects. Subjects will be allocated 
to risk strata using the same algorithm as for the non-Hispanic/Latino Caucasian subjects 
(n=167).
Because the data used to develop the biomarker risk algorithm was collected in 
non-Hispanic/Latino Caucasian subjects only, biomarker qualification will be based upon 
non-Hispanic/Latino Caucasian subjects in the placebo arm of the high-risk stratum compared to 
data from non-Hispanic/Latino Caucasian subjects in the low-risk stratum. Likewise, the primary 
analyses to evaluate the effects of pioglitazone versus placebo will be within the non-
Hispanic/Latino Caucasian high-risk sub-group.
 
.
An interactive response system will be used for central randomization. Stratification status and 
treatment assignment of all study participants will be double-blind. The randomization will be 
stratified based on participation in the vMRI substudy (approximately 300 subjects). 
For subjects who are not participating in the vMRI substudy, subjects in the high-risk stratum 
will be randomized to pioglitazone and placebo in a 1:1 ratio. Subjects in the low-risk stratum 
will be randomized only to placebo.
For subjects who are participating in the vMRI substudy, subjects in the high-risk stratum will be 
randomized to pioglitazone and placebo in a 5:4 ratio. Subjects in the low-risk stratum will be 
randomized only to placebo.
It is estimated that at least 60% of subjects who present for screening will be low-risk as 
determined by the biomarker risk algorithm. Because the study requires many more high-risk 
subjects than low-risk subjects to be randomized into the study, a random rejection algorithm for 
low-risk subjects was implemented in the IWRS. The low-risk rejection algorithm is designed to 
lengthen the enrollment period for low-risk subjects in such a way that the ratio of high-risk to 
low-risk subjects randomized into the study is relatively stable over the entire enrollment period. 
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This will facilitate maintaining double-blinding of risk assignment for all subjects throughout the 
entire course of the study. Details of the low-risk random rejection algorithm are provided in the 
AD-4833/TOMM40_301 Study System Requirements document which was authored by the 
IWRS vendor, Bracket.
Subjects will be instructed to take the first dose of study medication in the morning on the day 
following the randomization visit.
A project partner will be required to participate with the subject in the study visits, including 
eligibility at Baseline (Visit 2) and follow-up. The project partner is a spouse, adult child, or 
other person familiar with the participant’s health and daily functioning for a minimum of two 
years prior to the Baseline Visit. Subjects and their project partners are expected to attend study 
visits every 6 months after randomization, for assessments of safety, efficacy, and treatment 
compliance. In addition, the subject will be contacted for telephone-based safety checks between 
visits. In-person participation of the project partner is mandatory at Baseline (Visit 2), 
comprehensive medical follow-up, and End-of-Study Visits; while in-person participation is also 
strongly encouraged at all other study visits, telephone assessments for project partners will be 
acceptable in cases when in-person participation is not possible. If a comprehensive medical 
follow-up evaluation is needed (see Section 9.1.15 of the protocol) or if a safety issue is 
suspected, further evaluation of the subject may be required, which may include an unscheduled 
clinic visit. The project partner should attend unscheduled visits, whenever possible. If the 
original project partner is not able to continue participation in the study for any reason, he/she 
may be replaced by a different individual who also meets the criteria described above. The new 
project partner must sign the acknowledgement form prior to any of the project partner protocol 
directed procedures being performed.
Two sets of blood samples for deoxyribonucleic acid (DNA) will be collected during the course 
of this study:
1.
2.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in
the protocol, Appendix A.
CCI


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Figure 6.a
Schematic of Study Design
* Non-Hispanic/Latino Caucasian, Hispanic/Latino Caucasian, and non-Caucasian subjects alike will be stratified 
into high- and low-risk strata using the same biomarker risk algorithm; however, target sample size for primary 
endpoint analyses refers to non-Hispanic/Latino Caucasian subjects only.
** As this is an event-driven study, double-blind treatment duration will depend on the time it takes for a total of 
202 conversions from cognitively normal status to MCI due to AD dementia to occur in the high-risk non-
Hispanic/Latino Caucasian population; conversions from cognitively normal status to AD will also be included in 
this total. Study visits to the testing center will take place every 6 months after the Randomization Visit.


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7.0
ANALYSIS ENDPOINTS
7.1
Primary Endpoints
For biomarker risk algorithm qualification:
Time to diagnosis of MCI due to AD for placebo-treated, high-risk, non-Hispanic/Latino 
Caucasian subjects versus placebo-treated, low-risk, non-Hispanic/Latino Caucasian subjects.
For efficacy evaluation of pioglitazone:
Time to diagnosis of MCI due to AD for pioglitazone-treated, non-Hispanic/Latino 
Caucasian subjects versus placebo-treated non-Hispanic/Latino, Caucasian subjects in the 
high-risk stratum.
7.2
Key Secondary Endpoints

Change from baseline to Year 4 for cognitive decline on composite score on the cognitive 
battery for pioglitazone-treated subjects versus placebo-treated subjects in the high-risk 
stratum.

Changes from baseline to Year 4 in instrumental activities of daily living (Alzheimer’s 
Disease Cooperative Study Activities of Daily Living - Prevention Instrument [ADCS 
ADL-PI]) between pioglitazone-treated and placebo-treated groups of the high-risk stratum.
7.2.1
Additional Endpoints 
7.2.1.1
Safety Assessments

Safety and tolerability: adverse events (including adverse events of special interest), vital 
signs, body weight, electrocardiogram (ECG), clinical laboratory data, and physical exam 
findings. 
7.2.1.2
Additional Endpoints

Change from baseline to all scheduled visits where the following is assessed (6-month visits 
and End-of-Study (EoS) / Early Withdrawal (EW)): cognitive decline on composite score on 
the cognitive battery for pioglitazone-treated subjects versus placebo-treated subjects in the 
high-risk stratum.
Change from baseline to all scheduled visits where the following is assessed (6-month visits and 
End-of-Study (EoS) / Early Withdrawal (EW)): cognitive decline on tests and domain scores 
within the cognitive battery (see Table 9.b) for pioglitazone-treated subjects versus placebo-
treated subjects in the high-risk stratum.

Changes from baseline to all scheduled visits where the following is assessed (6-month visits 
and EoS/EW): instrumental activities of daily living (Alzheimer’s Disease Cooperative Study 
Activities of Daily Living - Prevention Instrument [ADCS ADL-PI]) between pioglitazone-
treated and placebo-treated groups of the high-risk stratum.


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∀
∀
∀
∀
∀
∀
∀
∀
∀
∀
∀
∀
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∀
Although change-from-baseline endpoints will be assessed at all visits, the primary time frame 
for purposes of efficacy analysis is the change from baseline to Month 48 (Year 4).
CCI


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8.0
DETERMINATION OF SAMPLE SIZE
Background Information for Determining Sample Sizes
Using 73 years as the age at entry (+5 years = age 78), a conversion rate of around 18% over 
5 years can be expected (see Table 8.a). This is based on:

The TOMM40 rs10524523 allele frequencies from the Duke Alzheimer’s Disease Research 
Center (ADRC), Cache County, and Wisconsin cohorts.

The assessment of peer-reviewed published incident MCI in normal individuals.

The effect of APOE on the incidence of AD.
Table 8.a
Conversion Rate Estimates Based on Analysis of 3 Cohorts, Cognitive 
Impairment Incidence, and Observed TOMM40 rs10524523 Allele 
Frequencies
TOMM40 
rs10524523 
Genotype
Duke 
Bryan 
ADRC 
Frequency
Wisconsin 
Frequency
Cache 
Frequency
Cohort 
Total 
Count
Age 78 (Proportion Converted)
Proportion
Number of 
Converted Subjects
L/L
0.05
0.04
0.02
189
0.53
100
VL/L
0.14
0.15
0.13
543
0.34
185
S/L
0.17
0.20
0.14
669
0.22
147
S/S
0.23
0.16
0.17
929
0.14
130
S/VL
0.31
0.31
0.36
1236
0.10
124
VL/VL
0.11
0.14
0.18
433
0.05
22
Total count = 3999
Total converted
708
Overall 
conversion rate
0.177
Taking into account the age ranges that will be enrolled in the phase 3 study, a 5-year conversion 
rate of 15% will be assumed for non-Hispanic/Latino Caucasian placebo subjects within the 
high-risk stratum identified by the enrichment process. Based on the expected 5-year conversion 
rate of 15%, the time-to-event was modeled using an exponential mathematical model for 
planning the study sample size.
Similarly, a 5-year conversion rate of 4% will be assumed for non-Hispanic/Latino Caucasian 
placebo subjects within the low-risk stratum. Thus, it is important to recognize that this summary 
of the data demonstrates nearly a four-fold enrichment of events over the population rate using 
the risk algorithm. 


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Determination of Sample Size for the Phase 3 Study Based on the High-Risk Stratum
The sample size for this study is based on the event-driven analysis that is planned for comparing 
treatment groups within the high-risk stratum. For the purposes of this study, it is assumed that 
the placebo-treated non-Hispanic/Latino Caucasian subjects in the high-risk stratum will have an 
event rate of 15% over a 5-year period. This is more conservative than the 18% cited in the table, 
to assure adequate sample size. With a clinically meaningful improvement of a reduction in 
event rate of at least 40%, the target event rate for the active treatment group will be 9% over 5 
years. Furthermore, the following specifications are used: alpha=0.01, a 2-sided statistical test 
based on survival analysis, power=90%, annual dropout rate of 12% (or cumulative dropout rate 
of 47% over 5 years). In order to detect a difference of the specified magnitude (≥40% reduction 
in conversion rates over 5 years), at least 202 events must be observed during the course of the 
study in non-Hispanic/Latino Caucasian subjects (primary efficacy analysis). Based on these 
assumptions and the fact that only non-Hispanic/Latino Caucasian subjects will be used for the 
primary analyses, a total of 2,346 non-Hispanic/Latino Caucasian subjects (1,173 on 
pioglitazone/1,173 on placebo) should be enrolled from the high-risk stratum for randomization. 
Sample Size for the Phase 3 Study Based On Qualifying the Test Used to Stratify Subjects
While using data from the results of risk stratification and not a comparison between randomized 
groups, the same analysis as specified for comparing the treatment groups within the high-risk 
stratum will also be used to compare the two placebo groups (high-risk placebo and low-risk 
placebo). Thus, assuming that the placebo-treated subjects in the low-risk stratum will have a 
conversion rate of 4% over a 5-year follow-up period, then approximately 314 non-Hispanic/
Latino Caucasian subjects identified as low-risk for the event should be enrolled in that stratum. 
This number of subjects enrolled in the low-risk stratum will provide very high power (99% with 
alpha=0.01) to validate the enrichment algorithm with the assumed 5-year conversion rates (ie, 
15% vs. 4%).
Sample Size for the vMRI Substudy
This substudy is not designed or powered to assess any quantitative changes in the brain. Based 
on clinical judgment, a sample size of 300 subjects is believed to be sufficient to evaluate 
possible qualitative changes in the brain via vMRI.


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9.0
METHODS OF ANALYSIS AND PRESENTATION
9.1
General Considerations
9.1.1
Statistical Software
All statistical analyses will be performed using SAS® Version 9.1.3 or higher.
9.1.2
Summary Statistics and Precision
All tabulations of analysis results will include summaries for all three treatment groups: high-risk 
placebo, high-risk pioglitazone, and low-risk placebo.
Except when noted as otherwise, all confidence intervals (CIs), statistical tests, and resulting 
p-values will be reported as nominal 2-sided and will be assessed at the 5% significance level. 
No adjustments will be made for multiplicity except for primary efficacy and key secondary 
endpoints.
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 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.

Confidence intervals will be presented using the same number of reported decimal places as 
the parameters (eg, mean).
For categorical data, frequency counts and percentages will be presented. Percentages will be 
reported to 1 decimal place.
The data summaries will be accompanied by individual subject data listings sorted by treatment
(including low-risk placebo), study center and subject identifier. All data available from eCRFs 
will be listed. The actual day relative to the start of treatment will be determined and included in 
the listings.
Derived analysis datasets will be produced from SDTM data and laboratory data. This allows for 
convenient reviewing of the data as well as any necessary supplemental analyses. All data from 
the raw datasets will be included in the derived datasets. Derived dataset specifications will be 
developed to include the names and definitions of derived variables in the derived SAS datasets.


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9.1.3
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 corresponds to the randomization date. Other study days are defined relative to 
Study Day 1, the date of first double-blind study drug dose. 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.
For each visit, a window will be defined such that the lower and upper bounds of each window is 
generally the midpoint between 2 consecutive study visits. The visit windows and applicable 
study day ranges are presented below in Table 9.a.
Table 9.a
Visit Windows
Nominal Visit 
Month
Nominal Visit 
Day
vMRI
Height, ECG, Chemistry and 
Hematology, PK, RU, 
DNA/RNA, PE
All Other 
Variables (c)
Baseline
-36 to -1 (a)
≤-1
≤ -1 (b)
≤ -1
6
183
2—273
12
365
2—547
274—456
18
548
457—638
24
731
639—821
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 (d)
2009
≥1370
≥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, date of first dose of dose of double-blind study drug is 
scheduled for the day after randomization. Exemptions were granted on a case-by-case basis for subjects who had a 
screening-to-randomization time frame greater than the 35-day window planned per the protocol.
(b) No baseline assessment for PK samples.
(c) CDR and NPI-Q are collected only at Baseline (Visit 2), unscheduled visits (eg, comprehensive medical follow-
up visits) and End of Study / Early Withdrawal.
(d) The planned study duration of 5.5 years is approximate, since this is an event-driven trial.
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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In general, the baseline value for a variable is defined as the last observation prior to the first 
dose of double-blind study medication (visit date ≤ first dose date), including the screening 
value, if necessary.
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 efficacy and 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. (Note: This efficacy data window only applies to determining which 
data are included/excluded from the summary statistics and formal statistical analysis tables for a 
given efficacy endpoint. All events of MCI due to AD (or AD dementia) as determined by the 
adjudication committee will be included in the time-to-event analyses, without regard to the date 
of last dose of double-blind study medication.)
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. For efficacy listings, 
windowed visits will also be shown on the listings.
9.1.4
Grouping of Centers
Pooling of small sites will be done (if necessary) to form centers for purposes of analysis.
Before unblinding the study, sites that are considered small (<40 subjects) will be pooled with 
geographically similar sites to minimize artifacts in the statistical analyses from imbalances in 
subject counts within the sites.
Starting with the smallest center, center(s) with fewer than 40 subjects randomized will be 
pooled into the nearest center. The pooling will start first within each country; if it is still small, 
other countries within the same geographical region (for example, US, Europe, Rest of World) 
will also be considered. The pooled centers within a region which still have fewer than 
40 subjects will be kept as they are and will not be pooled with centers in other regions.
The pooling of the centers will be reviewed and approved by the clinical and statistical team for 
agreement, and will then be used in the appropriate analyses once the database has been locked 
and unblinded.


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Quality issues were detected at site 5055; therefore, data collected exclusively at that site will be 
excluded for purposes of efficacy analyses.
Because of the smaller number of events available at the time of the efficacy futility analysis, 
pooling will be done for the efficacy futility analysis using a smaller number of pooled centers, 
based on country/sovereign state, as shown below.

US

UK

Australia

Switzerland/Germany
9.2
Major Protocol Violations
All subjects with major protocol violations will be identified prior to unblinding, and will be 
listed by study center and subject number.
Subjects with the following major protocol violations will be excluded from the per-protocol set 
(PPS) defined in Section 9.3:

Age outside of the range 65 to 83, inclusive, at the screening visit.

CDR Global Score > 0 at Baseline.

MMSE ≤24 at the screening visit (after adjusting for education and age as described in 
Appendix G of the protocol).

Subject does not have at least one memory test above -1.5 SD of the demographically 
corrected normative mean at Baseline.

At Baseline, the subject has a current diagnosis or history of any type of cognitive 
impairment or dementia, or has a current diagnosis or history of neurological/psychiatric 
disorder or any other diagnosis that significantly affects cognitive performance (eg, mental 
retardation, organic mental disorder).

At Baseline, the subject has a current diagnosis of significant psychiatric illness, per 
Diagnostic & Statistical Manual of Mental Disorders, 4th Edition - Text Revision (DSM-IV-
TR) (or DSM-V when published) (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 (HbA1c) >8.0% at the time of baseline or 
requires treatment with insulin, triple oral antidiabetic therapy or a PPAR-agonist. The 
subject should be on a stable antidiabetic regimen for at least 3 months prior to enrollment.

The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse/dependence within 2 years prior to the Screening Visit.


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
Low study drug compliance (<80%).

Double-blind study medication exposure less than 6 months ([last dose date – first dose date 
+1/30.5] <6).

Subject switched treatment during study.

Randomized treatment different from actual treatment received.

Incorrect risk stratum assignment used for randomization.

Subject unblinded prematurely.
The above list may be revised and any additional major protocol violations (eg, related to 
prohibited concomitant medications) will be identified by the study team prior to final study 
unblinding.
9.3
Analysis Sets
The safety analysis set will include all subjects who were randomized and received at least 1 
dose of double-blind study medication. In safety summaries, subjects will be analyzed according 
to the treatment they 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 two most 
common treatments are used with equal frequency, then the randomized treatment will be used 
as the actual treatment.
The full analysis set (FAS) will include all subjects who were randomized, received at least 
one dose of study drug, and had at least one valid post-baseline value for assessment of primary 
efficacy. In FAS efficacy summaries, subjects will be analyzed by the treatment to which they 
were randomized.
The per-protocol analysis set (PPS) will include all FAS subjects who had no major protocol 
violations. In PPS efficacy summaries, subjects will be analyzed by the treatment to which they 
were randomized.
9.4
Disposition of Subjects
A subject disposition summary presented by treatment group and overall will be provided. The 
categories will include all subjects who were randomized, subjects who were not treated, 
subjects who discontinued from the study categorized by reason, and subjects who completed the 
study. Post-randomization discontinuation reasons include pretreatment event or adverse event, 
major protocol deviations, lost to follow-up, lack of efficacy, voluntary withdrawal, study 
termination, pregnancy, and other. A listing will be presented to describe study treatment, date of 
first dose, date of last dose, date of completion or early withdrawal, and the reason for early 
discontinuation for each subject.
A summary of screening failures and listings of inclusion/exclusion criteria responses for 
subjects with violations will also be provided.


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9.5
Demographic and Baseline Characteristics
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.
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, occupation, smoking status, drinking habit of the subject at Screening 
Visit, height, weight, body mass index (BMI), family history of dementia and related conditions, 
APOE genotype, TOMM40 genotype, risk status as identified by the biomarker risk algorithm, 
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 all 
randomized subjects.
Baseline values for selected efficacy parameters (cognitive battery composite score, ADCS 
ADL-PI) will also be presented for each treatment group and overall based on all randomized 
subjects.
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 Visit 2 (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.
For continuous variables, the number of non-missing values and the mean, median, SD, 
minimum and maximum based on the raw scores uncorrected for demographic modifiers (ie, 
age, gender, education) 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.
9.6
Medical History and Concurrent Medical Conditions
Medical history refers to significant conditions/diseases that stopped at or prior to Screening 
(time of informed consent). Concurrent medical conditions are those significant ongoing 
conditions/diseases present at Screening (time of informed consent). Family history of dementia 
and related conditions will be collected at the first 6 month visit and at the End of Study/Early 
Withdrawal visit.
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) latest version and will be summarized by treatment group 
and overall using System Organ Class (SOC) and MedDRA preferred term. The table will 
include number and percentages of subjects and will be sorted in alphabetical order by system 


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organ class and sorted by decreasing frequency order by preferred term. A subject will only be 
counted once within a particular class even if he/she has multiple conditions/symptoms. 
Summaries will be based on all randomized subjects.
All medical history and concurrent medical condition data will be listed by treatment, study 
center and subject number. The listing will contain subject identifier, whether there was any 
significant medical history or concurrent condition, and include system organ class, preferred 
term and details of the medical history or condition.
9.7
Medication History and Concomitant Medications
The medication history and concomitant medications are defined as follows:

Medication history refers to the medication that the study subjects stopped taking within 3 
months prior to the Screening Visit (ie, stop date < first screening visit date).

Concomitant medication is defined as medication that the study subjects continued taking or 
took from Screening through end of study:
–
Concomitant medication that started and stopped prior to baseline (ie, stop date ≥ first 
screening visit date, and stop date < first dose date).
–
Concomitant medication that started prior to and was ongoing at baseline (ie, start date 
< first dose date, and stop date > first dose date).
–
Concomitant medication that started after baseline but before or at last dose (ie, start date 
≥first dose date, and start date ≤ last dose date).
–
Concomitant medication taken during the study (ie, start date ≤ last dose date, and stop 
date ≥ first dose date.
–
If start date and stop date are missing, medication will be assumed to occur both prior and 
concomitantly.
Medication history and concomitant medications will be coded using the latest version of the 
World Health Organization (WHO) Drug Dictionary and summarized by giving the number and 
percentage of subjects by preferred term within each therapeutic class, with therapeutic class and 
medications in each class sorted in order of decreasing frequency. The number of subjects with 
medications in each reported therapeutic class will also be presented. If a subject reports taking 
2 drugs belonging to the same class, he/she will only be counted once within that class. 
Summaries of medication history and concomitant medication will be based on all randomized 
subjects.
All prior and concomitant medications will be listed by treatment, study center and subject 
number. The listings will contain subject identifier, WHO Drug preferred term and reported 
term, dose, unit, frequency, route, start date, end date, whether the medication was ongoing, 
whether the medication as given to treat a pretreatment event/adverse event, and reason for use.


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9.8
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).
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 to <48 months (1258 to 1440 days).

48 to <54 months (1441 to 1622 days).

54 to <60 months (1623 to 1805 days).

60 to <66 months (1806 to 1987 days).

66 months ≥1988 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.


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9.9 Efficacy Analyses
Except as otherwise noted, the analyses and summaries will be based on the FAS.
All primary and key secondary efficacy analyses and summaries will be presented separately for 
the following groups of subjects:

Non-Hispanic/Latino Caucasian subjects.

Hispanic/Latino and/or non-Caucasian subjects.

All subjects.
All primary, secondary, additional, and other outcomes variables listed below will be presented 
by treatment group using descriptive statistics by visit (including change-from-baseline for 
continuous variables) and presented in efficacy listings.
9.9.1
Overview of Primary, Secondary, and Additional Variables
The primary, secondary and additional variables for this study are presented in Table 9.b. While 
most of the variables in the table are technically discrete, the variable type column indicates how 
the variables will be considered for purposes of analysis.


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Table 9.b
Primary, Secondary and Additional Variables
Parameter
Description
Range
Variable Type 
MCI_TIME
Time to event of MCI due to AD
N/A
Time-to-event
MMSE
Total of all items correct
0-32
Continuous
MMSEi
MMSE single item i
0-5
Categorical
BVMT_T1
# of elements recalled, Trial 1 (0-12 possible)
0-12
Continuous
BVMT_T2
# of elements recalled, Trial 2 (0-12 possible)
0-12
Continuous
BVMT_T3
# of elements recalled, Trial 3 (0-12 possible)
0-12
Continuous
BVMT_TOT
Total # of elements recalled, Trials 1-3
0-36
Continuous
BVMT_DEL
Total # of elements recalled after a delay (25-minute delay)
0-12
Continuous
BVMT_HIT
Total # of target elements correctly recognized
0-6
Continuous
BVMT_FP
Total # of foils incorrectly endorsed
0-6
Continuous
BVMTDISC
Total target elements correctly recognized relative to Total 
false positives
-6 to 6
Continuous
BVMTCOPY
Total # of elements copied correctly
0-12
Continuous
DIGIT_F
Total items correct, Digit Span Forward
0-16
Continuous
DIGIT_B
Total items correct, Digit Span Backward
0-14
Continuous
DIGITTOT
Total Forward + Back
0-30
Continuous
TRAILSAS
# of seconds to complete all items, Trails A
0-300
Continuous
TRAILSAE
Errors (number of errors committed during the test) 
0-5
Continuous
TRAILSBS
# of seconds to complete all items, Trails B
0-300
Continuous
TRAILSBE
Errors (number of errors committed during the test) 
0-15
Continuous
MINT
Total correct, MiNT
0-32
Continuous
SEMFLU
Number of exemplars generated in 1 minute (up to 
max=100)
0-100
Continuous
LEXFLU
Number of exemplars generated total for F, A, and S (up to 
max 267)
0-267
Continuous
LEX_F
Number of exemplars generated in 1 minute (up to 
max=89)
0-89
Continuous
LEX_A
Number of exemplars generated in 1 minute (up to 
max=89)
0-89
Continuous
LEX_S
Number of exemplars generated in 1 minute (up to 
max=89)
0-89
Continuous
CLOCK
Number of elements correct (eg, clock face, hands, number 
placement), Clock Drawing Test
0-10
Continuous
CVLT_T1
# of words (out of 16), recalled 1st trial
0-16
Continuous
CVLT_T2
# of words (out of 16), recalled 2nd trial
0-16
Continuous
CVLT_T3
# of words (out of 16), recalled 3rd trial
0-16
Continuous
CVLT_T4
# of words (out of 16), recalled 4th trial
0-16
Continuous
CVLT_T5
# of words (out of 16), recalled 5th trial
0-16
Continuous
CVLT_TOT
# of words recalled (16/trial), trials 1-5
0-80
Continuous


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Table 9.b
Primary, Secondary and Additional Variables (continued)
Parameter
Description
Range
Variable Type 
CVLT_TB
# of words (out of 16), recalled, intrusion trial B
0-16
Continuous
CVLTSDEL
# of words (out of 16), recalled, short delay
0-16
Continuous
CVLTLDEL
# of words (out of 16), recalled, long (20 min) delay
0-16
Continuous
CVLTINTR
False positive, words recalled
0-50
Continuous
CVLT_REP
Total words repeated
0-28
Continuous
CVLTHITS
Total target words correctly recognized from recognition 
list
0-16
Continuous
CVLT_FP
Total foil words incorrectly recognized form recognition 
list
0-32
Continuous
OVERALL
Composite Score (mean of cognitive battery domain 
scores)
N/A
Continuous
EPISODIC
Mean of cognitive battery Memory domain scores
N/A
Continuous
EXECUTIV
Mean of cognitive battery Executive Function domain 
scores
N/A
Continuous
LANGUAGE
Mean of cognitive battery Language domain scores
N/A
Continuous
ATTENTN
Mean of cognitive battery Attention domain scores
N/A
Continuous
GDSSC
GDS Short-Form total score
0-15
Continuous
GDSi
GDS single item i
0-1
Binary
ADCSTOT
ADCS MCFSI total score
0-14
Continuous
ADCSi
ADCS MCFSI single item i
N/A
Categorical
EQ5DINDX
EQ-5D index utility score
0-1
Continuous
EQ5D_VAS
EQ-5D VAS score
0-100
Continuous
EQ5Di
EQ-5D single item i
1-3
Categorical
SF36_PCS
SF-36 Physical Component Summary score
0-100
Continuous
SF36_PCT
SF-36 Physical Component Summary T score
N/A
Continuous
SF36_PCR
SF-36 Physical Component Summary Reliability 
Consistency Index score
0-100
Continuous
SF36_MCS
SF-36 Mental Component Summary score
0-100
Continuous
SF36_MCT
SF-36 Mental Component Summary T score
N/A
Continuous
SF36_MCR
SF-36 Mental Component Summary Reliability 
Consistency Index score
0-100
Continuous
SF36_V
SF-36 Vitality domain T score
0-100
Continuous
SF36_P
SF-36 Physical Functioning domain T score
0-100
Continuous
SF36_B
SF-36 Bodily Pain domain T score
0-100
Continuous
SF36_G
SF-36 General Health Perceptions domain T score
0-100
Continuous
SF36_PRF
SF-36 Physical Role Functioning domain T score
0-100
Continuous
SF36_E
SF-36 Emotional Role Functioning domain T score
0-100
Continuous
SF36_S
SF-36 Social Role Functioning domain T score
0-100
Continuous
SF36_M
SF-36 Mental Health domain T score
0-100
Continuous
SF36i
SF-36 single item i
1-5
Categorical
IQTOT
IQCODE overall mean score
1-5
Continuous
IQi
IQCODE single item i
1-5
Categorical
ADLTOT
ADCS ADL-PI ADL total score
0-45
Continuous
PHYTOT
ADCS ADL-PI Physical Function total score
0-5
Continuous


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Table 9.b
Primary, Secondary and Additional Variables (continued)
Parameter
Description
Range
Variable Type 
ADLQi
ADCS ADL single item i
0-3
Categorical
NPIQ_SEV
NPI-Q Total Severity score
0-36
Continuous
NPIQ_CD
NPI-Q Total Caregiver Distress score
0-60
Continuous
NPIQi
NPI-Q single item i
0-5
Categorical
CGIC_TOT
ADCS-CGIC-MCI total score
1-7
Categorical
CGIC_COG
ADCS-CGIC-MCI cognition score
1-7
Categorical
CGIC_BHV
ADCS-CGIC-MCI behavior score
1-7
Categorical
CGICFUNC
ADCS-CGIC-MCI functional abilities score
1-7
Categorical
CDR01GS
CDR Global Score
0-3
Continuous
CDR01SB
CDR Sum of Boxes
0-18
Continuous
CDR0102
CDR orientation domain score
0-3
Continuous
CDR0101
CDR memory domain score
0-3
Continuous
CDR0103
CDR judgment and problem-solving domain score
0-3
Continuous
CDR0105
CDR home and hobbies domain
0-3
Continuous
CDR0104
CDR community affairs domain score
0-3
Continuous
CDR0106
CDR personal care domain score
0-3
Continuous
C-SSRSi
C-SSRS single item i
N/A
Categorical
LHIP_ATR
Left Hippocampal Atrophy
N/A
Continuous
RHIP_ATR
Right Hippocampal Atrophy
N/A
Continuous
WHLB_ATR
Whole Brain Atrophy
N/A
Continuous
VNTENLRG
Ventricle Enlargement
N/A
Continuous
9.9.2
Task Completion, Irregular Procedure, and Missing Items on Rating Scales
The rules for handling missing items from each of the scales are designed so that as much data as 
possible can be used in the analyses, yet with reliable information, 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.
For some reasons, subjects may not complete the tasks / tests as requested, or subjects used 
irregular procedure and/or questionable effort. In such cases, the data may be considered 
unreliable and/or invalid. For baseline and follow-up assessments, the scoring of the following 
cognitive test instruments, including the assignment of missing value codes, will rely on the 
NeuroCog Trials expert judgment, and will be clearly indicated in the dataset: MMSE, CVLT-II, 
BVMT-R, Digit Span tests, Trail Making Tests, MiNT, Semantic and Lexical Fluency tests, and 
Clock Drawing Test.


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The criteria for triggering possible cases for adjudication are provided in the appendix of the 
CIAC Charter. If values for a particular test are: ‘999’ (not administered due to Cognitive 
Impairment) or ‘992’ (Refusal), then the test is considered to be failed. This failure will be 
treated in the same manner as any other 'failed test' in regards to the triggering algorithm. If 
values for a particular test are: ‘991’ (is missing due to physical/sensory reason) or ‘994’ (‘other’ 
reason), then the test is treated as missing and as a non-failure.
The following tests which are collected at an item level in the eCRF will be prorated whenever a 
sufficient percentage of data is non-missing: GDS Short-Form total score, ADCS MCFSI total 
score, IQCODE Overall mean score, ADCS ADL-PI ADL total score, ADCS ADL-PI Physical 
Function total score, NPI-Q Total Severity score, and NPI-Q Total Caregiver Distress score.
The general rule when individual items are missing from the multiple-item assessments specified 
in Table 9.c below is as follows: The total score will be calculated using a SAS function 
ROUND, as ROUND[(sum of nonmissing items)×(total number of items)/(number of 
nonmissing items)]. (The IQCODE Overall mean score is a mean of the item-level values and so 
will remain unchanged when proration is valid and will be set to missing when prorating is not 
valid.) If more than 20% of the items are missing, the total score will be set to missing. The 
implications of this rule are indicated in Table 9.c for each rating scale. The resulting calculated 
total scores will be used in all analyses.
Table 9.c
Number of Missing Items on Scales with a Missing Value for Total Score
Parameter
Number of Missing Items
GDS Short-Form total score
≥4 
ADCS MCFSI total score
≥3
IQCODE Overall mean score
≥6
ADCS ADL-PI ADL total score
≥4
ADCS ADL-PI Physical Function total score
≥2
NPI-Q Total Severity score
≥3
NPI-Q Total Caregiver Distress score
≥3
9.9.3
Analysis of Primary Variable
There are 2 independent null hypotheses in this protocol: (1) assumes that there is no difference 
in conversion rate between the placebo-treated high-risk and low-risk groups as defined by the 
prognostic biomarker risk algorithm and (2) assumes that there is no difference in conversion 
rate between the high-risk active- and placebo-treated subjects. The alternate hypotheses are: 
(1) there is a difference between the high- and low-risk groups treated with placebo, and (2) there 
is a difference between placebo and active treatment in the high-risk group.
A futility analysis will be conducted for this study (see Section 9.15).


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9.9.3.1
Primary biomarker risk assignment algorithm analysis
In order to test the first hypothesis, a test from a Cox proportional hazards survival model will be 
used to compare data from non-Hispanic/Latino Caucasian subjects in the (placebo-treated) low-
risk group (ie, the combined placebo groups) with data from non-Hispanic/Latino Caucasian 
subjects in the placebo-treated subjects in the high-risk group. The event in this analysis will be 
an adjudicated event of MCI due to AD (see Section 9.9.4 below). If this test is significant at the 
0.01 level, it can be concluded that the diagnostic prognostic test has differentiated between 
subjects at low and high risk of being diagnosed with MCI due to AD within 5 years of taking 
the test.
An exact partial likelihood function will be constructed to fit the Cox proportional hazards 
(CPH) model to accommodate events with the same times to the event. The robust sandwich 
estimate for the covariance matrix from the CPH model will be used. The analysis of the primary 
biomarker comparison will be conducted using the FAS and a CPH model of MCI due to AD 
events with a factor for biomarker risk assignment and including center, gender, and education as 
covariates. (Except as otherwise noted, education will be treated as a continuous variable and 
measured in years for purposes of statistical modeling.)
Parameter estimates, 2-sided 99% CIs, and appropriate p-values for the hazard ratios obtained 
from the CPH model will be computed to test the null hypothesis of equality of the hazard 
functions between high-risk placebo and low-risk placebo.
Assessment of the proportional hazards assumption for risk assignment category will be 
assessed. Plots of Schoenfeld residuals obtained from the CPH models that fit the primary 
MCI-to-AD endpoint versus ordered time of events along with a smoothing spline will be used to 
evaluate the proportional hazards assumption for risk assignment category. Systematic 
departures from a horizontal line are indicative of meaningfully non-proportional hazards. 
Diagnostic checks will be presented in CSR Appendix 16.1.9.
9.9.3.2
Primary efficacy analysis
A similar analysis process as described above for the primary biomarker risk algorithm analysis 
will be used to compare the placebo- and active-treated non-Hispanic/Latino Caucasian subjects 
within the high-risk group (ie, using a similar CPH model with covariates of center, gender, and 
education and an additional covariate of age but using a factor of high-risk treatment group 
instead of biomarker risk assignment). If this test is significant at the 0.01 level, it can be 
concluded that active treatment has delayed the development of mild cognitive impairment due 
to AD.
An exact partial likelihood function will be constructed to fit the Cox proportional hazards 
(CPH) model to accommodate events with the same times to the event. The robust sandwich 
estimate for the covariance matrix from the CPH model will be used. The analysis of the primary 
efficacy comparison will be conducted using the FAS and a CPH model of MCI due to AD 
events with a factor for treatment and including center, gender, education, and age as covariates.


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Parameter estimates, 2-sided 99% CIs, and appropriate p-values for the hazard ratios obtained 
from the CPH model will be computed to test the null hypothesis of equality of the hazard 
functions between the high-risk pioglitazone and high-risk placebo treatment groups.
Assessment of the proportional hazards assumption for treatment group will be assessed. Plots of 
Schoenfeld residuals obtained from the CPH models that fit the primary MCI-to-AD endpoint 
versus ordered time of events along with a smoothing spline will be used to evaluate the 
proportional hazards assumption for treatment group. Systematic departures from a horizontal 
line are indicative of meaningfully non-proportional hazards. Diagnostic checks will be 
presented in CSR Appendix 16.1.9.
9.9.3.3
Supportive Nonparametric Interval-Censoring Analyses
Alternative methods of analysis may be considered should some of the underlying model 
assumptions seem inappropriate (eg, non-proportional hazards). The reasons for any changes to 
the planned approach and methods will be fully documented.
Most survival analysis methods, including the CPH model, work best when the true event date is 
known for each and every event which occurs during a study (eg, right censoring). For complex 
events such as MCI due to AD, generally the true event date is unknown and is only detected at a 
subsequent visit (ie, interval censoring).
Primary high-risk placebo versus low-risk placebo biomarker analysis
As a sensitivity analysis to the above primary biomarker risk assignment analysis, a 
nonparametric analysis which accounts for interval censoring by using a weighted generalized 
log-rank test, stratified by gender, will be done using SAS PROC ICLIFETEST with the option 
WEIGHT=FINKELSTEIN (which corresponds to a proportional hazards assumption).
Primary high-risk pioglitazone versus placebo efficacy analysis
As above, alternative methods of analysis may be considered if some of the underlying CPH 
model assumptions are violated; and a similar nonparametric sensitivity analysis using SAS 
PROC ICLIFETEST will be done to account for interval censoring and its possible effect on the 
results of the primary efficacy analysis. 
9.9.3.4
Supportive Log-rank Sensitivity Analyses
Primary high-risk placebo versus low-risk placebo biomarker analysis
As a sensitivity analysis to the above primary biomarker risk assignment analysis, a log-rank test, 
stratified by gender, will be done using SAS PROC LIFETEST.
Primary high-risk pioglitazone versus placebo efficacy analysis
A similar log-rank sensitivity analysis as described above for the primary biomarker risk 
assignment analysis will be used to compare the placebo- and active-treated non-Hispanic/Latino 
Caucasian subjects within the high-risk group (ie, stratified by gender, but using a factor of high-
risk treatment group instead of biomarker risk assignment category).


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9.9.3.5
Supportive PPS and subgroup analyses
If more than 5% of total subjects in the FAS high-risk, non-Hispanic/Latino Caucasian subjects 
have major protocol violations, the primary efficacy analysis will also be performed based on the 
PPS.
Similarly, if more than 5% of total subjects in the FAS placebo (both high-risk and low-risk), 
non-Hispanic/Latino Caucasian subjects have major protocol violations, the primary biomarker 
analysis will also be performed based on the PPS.
For the primary efficacy variable (for both the primary efficacy comparison and for the primary 
biomarker comparison), subgroup analyses by:
∀
age at randomization (<75, #75)
∀
gender (female, male)
∀
baseline diabetic status (non-diabetic: baseline HbA1c <6.5%, diabetic: baseline HbA1c 
#6.5%)
∀
race/ethnicity (Hispanic/Latino and/or non-Caucasian, all subjects)
∀
baseline NPI-Q Apathy/Indifference Score (no symptoms; mild, moderate, or severe 
symptoms)
∀
regulatory geographic region (North America: US; Europe: UK, Germany, Switzerland; Rest 
of World: Australia)
∀
geographic region based on language (English, German)
∀
baseline statin use (based on the Standardized Drug Groupings maintained by Uppsala 
Monitoring Centre, sponsors of the WHO Drug dictionaries)
and other variables, if necessary, will be performed. Analysis results for subgroups containing 
less than 20% of the total subjects in the primary efficacy analysis population should be 
interpreted especially cautiously. The treatment groups will be compared within each subgroup. 
 
9.9.4
MCI Due to AD Event Description
In clinical practice, the diagnosis of MCI due to AD, like AD dementia, cannot be made solely 
by laboratory or other tests, but requires the judgment of a clinician who takes into account 
clinical, cognitive, and functional criteria that define the syndrome. The clinical diagnosis, as 
defined by the National Institute on Aging (NIA) and Alzheimer’s Association (AA) in Albert et 
al., 2011 (reference given in protocol):
∀
Establishes clinical and cognitive criteria:
–
Cognitive concern reflecting a change in cognition reported by subject or informant or 
clinician (ie, historical or observed evidence of decline over time).
CCI


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–
Objective evidence of impairment in one or more cognitive domains, typically including 
memory (ie, formal or bedside testing to establish level of cognitive function in multiple 
domains).
–
Preservation of independence in functional abilities.
–
Not demented.

Examines etiology of MCI consistent with AD pathophysiological process:
–
Rule out vascular, traumatic, medical causes of cognitive decline, where possible.
–
Provide evidence of longitudinal decline in cognition, when feasible.
–
Report history consistent with AD genetic factors, were relevant.
A cognitive test battery has been specifically constructed to help study Investigators identify 
individuals who are beginning to decline in their cognitive status and who can be accurately 
diagnosed with MCI due to AD. This test battery is summarized in the Appendix D, and the 
individual instruments that comprise the battery are described in detail in Section 9.1.15 of the 
protocol.
Study Investigators use this cognitive test battery to assess subjects’ cognitive status and 
consider the results of this battery, in combination with the findings from other subject- and 
project partner-reported instruments of functional change and laboratory findings, to determine 
diagnosis and further subject flow within the study (ie, send case for adjudication or not).
For the purposes of this clinical trial, the clinical framework described by the NIA/AA 
publication was operationalized through the incorporation of objective cutoff points to provide 
the Investigator’s guidance for making the clinical diagnosis of MCI due to AD, as
Follows (Table 4.a in the protocol):
Operationalized Criteria for MCI due to AD
Establish clinical and cognitive criteria

Clinical Dementia Rating (CDR) scale score of 0.5 AND one or more of the following:
–
Fails at least one of the two memory tests in the cognitive test battery (failure defined as 
an individual test score at or below -1.5 SD of the demographically corrected normative 
mean (a), and the score reflects a change from baseline).
–
Fails 2 or more of the 12 measures in the cognitive test battery, representing separate 
cognitive domains.
–
(Failure is defined as an individual test score at or below -1.3 SD (10th percentile) of the 
demographically corrected normative mean, and the score reflects a change from 
baseline).


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Examine etiology of MCI consistent with AD pathophysiological process

Rule out vascular, traumatic, psychiatric, and other proximal medical causes of cognitive 
decline.

Continued evidence of cognitive impairment or continued decline on 6 month follow-up (ie, 
2 consecutive study visits showing impairment). (b)
--------------------------------------------------------------------
(a) Normative data will be available per language.
(b) It is not required that the two consecutive visits show an identical profile (ie, meeting any definition of MCI due 
to AD on two consecutive visits is acceptable for a subject to be forwarded for adjudication). Note that the two 
consecutive visits must contain non-missing determinations of MCI due to AD status in order to contribute to the 
determination of an adjudicated event of MCI due to AD.
The criteria for triggering possible cases for adjudication are provided in the appendix of the 
CIAC Charter. For purposes of triggering possible cases, the choice of tests to assess the 
cognitive domains differs slightly from the table in Appendix D. In particular, the Executive 
Function domain is assessed using Trail Making Test Part B and digit span total (rather than digit 
span backwards). And the attention domain consists only of Trail Making Test Part A (and does 
not include digit span forward).
The CVLT-II memory test consists of 3 measures, two of which are important for purposes of 
triggering and for calculation of the composite score: Short-Delay Free Recall and Long-Delay 
Free Recall. Of those two CVLT-II measures, only Long-Delay Free Recall is used for 
inclusion/exclusion. For post-baseline visits, failure on either of the two measures indicates 
failure on the CVLT-II test.
As described in the protocol, at each scheduled visit after randomization (ie, every 6 months), 
outcomes indicating possible MCI or AD will trigger further evaluation at an unscheduled 
comprehensive medical follow-up visit which should take place within one month of the routine 
scheduled visit when one of the triggering outcomes was met. The CDR, which is not taken at 
regularly scheduled post-randomization visits, is one of the procedures which is completed at the 
unscheduled comprehensive medical follow-up visit.
The primary endpoint is met only on the second consecutive occurrence when the diagnosis of 
MCI due to AD is confirmed by the adjudication committee. The adjudicators will look at all the 
collective information sent by the investigative sites in order to confirm (or not) the diagnosis of 
MCI due to AD. Subjects who convert directly to an AD dementia diagnosis by the NIA/AA 
criteria (reference given in protocol) will also be considered toward the numerical count of 
events that determines the duration of the study.
Note that data collected at the EoS/EW visit will also contribute to the determination of primary 
efficacy events of MCI due to AD. Further details about the definition of an event of MCI Due to 
AD and the adjudication process are provided in the protocol and the CIAC Charter.


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Event Times and Censoring Times
For purposes of analysis, the event time of a CIAC confirmed event of MCI due to AD is the 
time from the randomization date to the date of the first scheduled visit of the two consecutive 
scheduled visits at which a subject was assessed with a clinical diagnosis and determined as 
an primary endpoint event by CIAC using the data from scheduled visit and the triggered 
unscheduled comprehensive medical follow up visits.
For subjects whose first and only clinical assessment of MCI due to AD (or AD itself)
corresponds to their last visit during the study (e.g., due to subject dropout) and determined by 
CIAC as an primary endpoint event, the event time of a CIAC confirmed event of MCI due to 
AD is the time from the randomization date to the date of the scheduled visit.
A subject who does not have an event of MCI due to AD (including AD itself) will be censored 
for that event at the date of last visit at which a case of MCI due to AD could have been assessed 
(i.e., the last regularly scheduled visit at which the cognitive battery was assessed or the last 
unscheduled comprehensive medical follow-up visit at which the CDR was assessed, whichever 
is later). For subjects who discontinue from the study prior to their first assessment of the 
cognitive battery or CDR, the date of last contact will be used as the censoring time. At the time 
of the futility analysis, a subject who has not discontinued from the study and has not had an 
event of MCI due to AD (or AD) will be censored for that event at the date of the last visit at 
which a case of MCI due to AD could have been assessed prior to the futility analysis clinical 
database cut date (ie, the last regularly scheduled visit at which the cognitive battery was 
assessed or the last unscheduled comprehensive medical follow-up visit at which the CDR was 
assessed prior to the futility analysis clinical database cut date, whichever is later).
For subjects who die during the trial, the date of death is considered a censoring time for the 
event of MCI due to AD (rather than as a component of the event of MCI due to AD itself).
9.9.5
Sensitivity Analyses Using Alternative Event Definitions
As sensitivity analyses for the primary biomarker and primary efficacy analyses, analogous 
analyses as described in Sections 9.9.3.1 and 9.9.3.2 will be done using the following revised 
definitions related to an event of MCI due to AD:

Revised Event Time Definition: For purposes of analysis, the revised event time of a CIAC 
confirmed event of MCI due to AD is the time from either:
–
(1) the randomization date to the date of the first unscheduled comprehensive medical 
follow-up visit which was triggered by the first of the two consecutive scheduled visits at 
which a subject was assessed with a diagnosis of MCI due to AD (or AD itself) by the 
CIAC; or
–
(2) the randomization date to the date of the unscheduled comprehensive medical 
follow-up visit which was triggered by the subject’s last scheduled visit during the study 
because the subject was assessed (for the first and only time) with a diagnosis of MCI due 
to AD (or AD itself) by the CIAC.


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The revised event time definition above changes the event time so that it is based on the date of 
the first unscheduled visit date at which a case of MCI due to AD was determined by CIAC 
(since CDR data isn’t collected at scheduled visits).
9.9.6
Analysis of Key Secondary Variables
The change from baseline in cognitive battery composite score will be analyzed as a continuous 
variable by study visit using MMRM (mixed model for repeated measures) analysis of 
covariance with treatment, gender, center, visit, and treatment-by-visit interaction as fixed, 
categorical effects and education, age, baseline composite score, and baseline composite score-
by-visit as continuous, fixed covariates. The effect at each time point for each treatment is 
allowed to vary freely, and an unstructured covariance matrix will be used to model the within-
subject errors. The Kenward-Roger approximation will be used to estimate denominator degrees 
of freedom. Based on a Missing at Random (MAR), this analysis will be performed using 
observed case data only.
The SAS code for the MMRM analysis will be as follows:
Proc mixed data=all;
–
class visit treat center gender subject;
–
model Change = Baseline Baseline*visit treat center gender education age visit visit*treat 
/solution ddfm=KenwardRoger;
–
repeated visit/subject=subject type=UN;
–
lsmeans visit*treat / cl pdiff.
In the above model, Baseline is the baseline value and Change is the change from baseline value.
Similarly, the change from baseline in ADCS ADL-PI ADL total score will be analyzed as a 
continuous variable by study visit using MMRM, where the ADCS ADL-PI ADL total score 
Baseline, gender, education, and age will be used as the covariate adjustments in the MMRM.
Key secondary endpoints will be analyzed (including reporting mean differences, CIs, and 
p-values) using the FAS subjects in the primary efficacy population (high-risk, non-
Hispanic/Latino subjects) using a 0.01 significance level.
Although change-from-baseline endpoints will be assessed at all visits, the primary time frame 
for purposes of efficacy analysis is the change from baseline to Month 48 (Year 4).
Missing data from this study will be reviewed carefully to evaluate any patterns in this study. 
Also, as a sensitivity analysis, pattern mixture models using standard SAS STAT procedures will 
be performed for the key secondary endpoints to address the possibility of missing data not at 
random. 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 will be imputed based on the available data from 
control subjects and using PROC MI methodology for imputation of monotone missing data 


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patterns to impute the outcome variables at consecutive visits in a sequential (chain) manner. The 
number of imputed datasets will be 100.
Alternative methods of analysis (eg, using a transformation of the response variable or by using 
generalized estimating equations in SAS PROC GLIMMIX or PROC GENMOD) may be 
considered prior to unblinding should some of the underlying model assumptions (eg, normality) 
seem severely violated. The reasons for any changes to the planned approach and methods will 
be fully documented.
9.9.7
Derivation of Cognitive Battery Composite Score
The cognitive test battery by domain is described in Appendix D. To form the composite score, 
z-scores will be calculated for each test listed below.
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
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 the CVLT-II 
episodic memory tests is required to calculate the composite (i.e., CVLT-II Short-delay free 
recall correct 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.
The z-scores will only be used for the analyses and summaries of endpoints which are derived 
using multiple components (eg, the composite score and domain scores). All other endpoints will 
be analyzed and summarized using raw scores.


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9.9.8
Controlling Type I Error
To control the two-sided type I error over all the efficacy endpoints that are intended to support 
potential claims, the primary and key efficacy endpoints will be tested in the following 
sequential order at significance level 0.01; as soon as an efficacy endpoint test is non-significant 
at alpha=0.01, the testing procedure stops for all subsequent endpoints:

Time to diagnosis of MCI due to AD for pioglitazone-treated, non-Hispanic/Latino 
Caucasian subjects versus placebo-treated non-Hispanic/Latino, Caucasian subjects in the 
high-risk stratum.

Change from baseline to Year 4 for cognitive decline on composite score on the cognitive 
battery for pioglitazone-treated, non-Hispanic/Latino Caucasian subjects versus placebo-
treated non-Hispanic/Latino, Caucasian subjects in the high-risk stratum.

Changes from baseline to Year 4 in instrumental activities of daily living (Alzheimer’s 
Disease Cooperative Study Activities of Daily Living - Prevention Instrument 
[ADCS-ADL-PI]) for pioglitazone-treated, non-Hispanic/Latino Caucasian subjects versus 
placebo-treated non-Hispanic/Latino, Caucasian subjects in the high-risk stratum.
9.9.9
Analysis of Additional Variables
Except where otherwise noted, summaries and analyses for additional variables will be done 
using the FAS subjects in primary efficacy analysis population (high-risk, non-Hispanic/Latino 
subjects). Except for analyses involving the primary and key secondary endpoints, all other 
analyses (ie, analyses of additional variables) will be done using a significance level of 0.05.
The incidence of MCI due to AD will also be compared using a chi-squared test, and the 
difference in incidence will be reported along with 95% confidence intervals.
Relatively few cases of AD are anticipated. The incidence AD will be compared using a chi-
squared test, and the difference in incidence will be reported along with 95% confidence 
intervals. Cases of AD will be described in the listings.
For continuous endpoints which are collected at multiple scheduled visits, change from baseline 
will be analyzed by study visit using MMRM analysis of covariance.
Although change-from-baseline endpoints will be assessed at all visits, the primary time frame 
for purposes of efficacy analysis is the change from baseline to Month 48 (Year 4).
The change from baseline variables for the BVMT-R test (BVMT_T1, BVMT_T2, BVMT_T3,
BVMT_TOT, BVMT_DEL, and BVMT_COPY) will each be analyzed as a continuous variable 
by study visit using an MMRM model similar to the ones described above for the key secondary 
variables.
The change from baseline variables for the Trail Making Tests (Trails A time and Trails B time) 
and WAIS-III digit span tests (forward span, backward span, and total) will each be analyzed as 
a continuous variable by study visit using an MMRM model similar to the ones described above 
for the key secondary variables.


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For the variables BVMT_HIT, BVMT_FP, and BVMTDISC, TRAILSAE, and TRAILSBE, 
counts and percentages of each possible value will be tabulated and summary statistics (n, mean, 
SD, median, minimum, and maximum) will be given by treatment group (including low-risk 
placebo) for the actual values and change-from-baseline values for each visit and EoS/EW.
The change from baseline variables for the MINT, semantic and lexical fluency test variables 
(SEMFLU, LEXFLU, LEX_F, LEX_A, and LEX_S), and Clock Drawing Test will each be 
analyzed as a continuous variable by study visit using an MMRM model similar to the ones 
described above for the key secondary variables.
The change from baseline variables for the CVLT-II test (CVLT_T1, CVLT_T2, CVLT_T3, 
CVLT_T4, CVLT_T5, CVLT_TOT, CVLT_TB, CVLTSDEL, CVLTLDEL, CVLTINTR, 
CVLT_REP, CVLTHITS, and CVLT_FP) will each be analyzed as a continuous variable by 
study visit using an MMRM model similar to the ones described above for the key secondary 
variables.
The change from baseline variables for the cognitive battery domain scores (memory, executive 
function, language, and attention) will each be analyzed as a continuous variable by study visit 
using an MMRM model similar to the ones described above for the key secondary variables.
The change from baseline variables for GDS Total score, ADCS MCFSI total score, IQCODE 
Overall mean score, and ADCS ADL-PI Physical Function total score will each be analyzed as a 
continuous variable by study visit using an MMRM model similar to the ones described above 
for the key secondary variables.
The ADCS-CGIC-MCI total, cognition, behavior, and functional ability scores will each be 
analyzed as continuous variables by study visit using a MMRM models similar to the ones 
described above for the key secondary variables (using the appropriate corresponding 
ADCS-CGIC-MCI baseline score). In addition, each of these 4 ADCS-CGIC-MCI variables will 
be analyzed at the last visit using the Cochran-Mantel-Haenszel test and stratifying by center.
The MMSE total score is scheduled to be collected at 6-month visits and EoS/EW. Summary 
statistics will be used to present MMSE total score and change from baseline in MMSE total 
score at EoS/EW.
The CDR and NPI-Q are scheduled to be collected at baseline and EoS/EW. The CDR Global 
Score and domain scores will be presented using shift tables from baseline to EoS/EW. Summary 
statistics will be used to present CDR-SB and change from baseline in CDR-SB at EoS/EW. In 
addition, each of the 6 CDR domain scores at Baseline and at each time point when MCI due to 
AD was diagnosed will be included in the listings.
For each of the NPI-Q variables Total Severity Score and Caregiver Distress Score, the change 
from baseline in NPI-Q from baseline to EoS/EW will be analyzed using an ANCOVA model 
analogous to the model for the key secondary endpoints. The following SAS code will be used 
for the ANCOVA analysis:

Proc mixed data=all;

class treat center gender;


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
model Change= Baseline treat center gender education age;

lsmeans treat / cl pdiff;
In the above model, baseline is the baseline value and Change is the change from baseline value.
Volumetric MRI (vMRI) variables were collected in a substudy of approximately 300 subjects. 
These volumetric MRI atrophy and enlargement endpoints are calculated with sophisticated 
algorithms that derive the change in the brain by registering each of the follow-up time points 
against the baseline and calculating algorithmically the change (ie, this is not determined by 
calculating the volume at baseline and then independently calculating the volume at a given post-
baseline visit and then subtracting).The vMRI variables left hippocampal atrophy, right 
hippocampal atrophy, whole brain atrophy, and ventricular enlargement will each be analyzed as 
continuous variables by study visit using a ANCOVA models similar to the ones described above 
for the NPI-Q variables. The appropriate baseline variable (ie, left hippocampal volume, right 
hippocampal volume, whole brain volume, or ventricular volume), as well as intracranial 
volume, will be used as covariates in each these models.
For each efficacy variable for which MMRM analysis of covariance analyses will be done, 
summary statistics (n, mean, SD, median, minimum, and maximum) by treatment group 
(including low-risk placebo) will be given for the actual values and change-from-baseline values 
for each visit and EoS/EW. 
For the single-item variables MMSEi, GDSi, ADCSi, EQ5Di, SF36i, IQi, ADLQi, and NPIQi, the 
counts and percentages of each possible value will be tabulated by treatment group (including 
low-risk placebo) for each visit and EoS/EW. For single-item variables which have a meaningful 
numerical score, summary statistics (n, mean, SD, median, minimum, and maximum) by 
treatment group (including low-risk placebo) will be given for the actual values and change-
from-baseline values for each visit and EoS/EW.
MRIs will be done as part of the comprehensive medical follow-up evaluation to rule out other 
causes of dementia and confirm the clinical diagnosis of MCI due to AD (see Section 6.2.4 of the 
protocol). For subjects who have contraindications for the MRI procedure (such as unremovable 
ferromagnetic dental work, cardiac pacemakers, etc) a CT scan can be done instead. The possible 
categories for the interpretation results are: Within Normal Limits; Abnormal, Not Clinical 
Significant; and Abnormal, Clinical Significant. The last available MRI/CT scan interpretation 
results for each subject will be summarized by treatment group, and all MRI/CT scan 
interpretation results will be presented in the listings.
Except for time-to-event analyses and the summary of MRI interpretation results, unscheduled 
visit values will be excluded from the summaries and analyses but will be included in the end-of-
text CSR listings.
9.9.10 Additional Biomarker Qualification Analyses
At the end of this study, data from the analyses comparing high and low risk placebo groups will 
provide the data necessary to qualify the biomarker risk algorithm as a prognostic test and an 
important new tool for therapeutic decision making. Specifically, the high risk placebo group and 


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low risk placebo group will provide the data needed to estimate the positive predictive value 
(PPV) and negative predictive value (NPV) of the biomarker risk algorithm. Kaplan-Meier 
curves by treatment group (including low-risk placebo) will be generated for TOMM40 
rs10524523 and APOE genotypes and compared to previous results.
Positive and negative predictive values will be reported for the performance of the biomarker 
risk algorithm. Specifically, calculations will be made of the PPV and NPV at Years 1, 2, 3, 4 
and End of Study / Early Withdrawal (for subjects who were in the study at least 4 years), where 
PPV(t) is the proportion of subjects who are predicted to develop MCI due to AD during the 5 
years who do develop MCI due to AD by time t in the high-risk group, and NPV(t) is the 
proportion of subjects predicted to be free of MCI due to AD at 5 years who are free of MCI due 
to AD at time t in the low-risk group.
Comparison of Performance Characteristics
The following additional analyses will be done to assess the contribution of age, APOE 
genotype, and TOMM40 rs10524523 genotype to the biomarker risk algorithm.
Because the biomarker risk algorithm uses multiple criteria for assigning the risk status (ie, 
APOE genotype, TOMM40 ‘523 genotype, and Age), a number of analyses will be conducted to 
delineate which characteristics of the algorithm contributed to the success of the risk assignment. 
These analyses will evaluate the efficacy of the risk assignment for different aspects of the 
biomarker risk algorithm. Parts (a) and (b) below both use CPH time-to-event model analogous 
to the primary biomarker high-risk pioglitazone versus low-risk pioglitazone analysis model 
described in Section 9.9.3.
a.
Time-to-event analyses using alternative possible risk-assignment methods:

MCI Biomarker Risk Assignment Algorithm using APOE genotype, TOMM40 
‘523 genotype, and Age (ie, using the primary biomarker CPH analysis described 
in Section 9.9.3).

Use Age alone with the following cutoff value:
–
≥76 years (This is the TOMM40 S/VL genotype age threshold for high-
risk from the biomarker risk algorithm.)
This analysis could demonstrate the value of the MCI biomarker risk algorithm 
over a doctor using age only to assess risk for cognitively normal patients.

Use Age and APOE as follows:
–
High-risk: Age ≥ 76 years or carriage of the APOE ε4 allele.
–
Low-risk: Age less than 76 years and non-carriage of APOE ε4 allele.
b. Time-to-event analyses using alternative forms of the biomarker risk algorithm 
variables as follows: 

Age (continuous).


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
APOE risk-status (Low, High – where High denotes carriage of at least one 
APOE ε4 allele).

TOMM40 ‘523 risk status (Low, Indeterminate, High – where Low corresponds 
to VL/VL; Indeterminate corresponds to S/VL, S/S, S/L; and High corresponds to 
L/VL or L/L).
The following sets of the above variables will be added to the primary biomarker 
comparison CPH model described in Section 9.9.3 so that assessment of the 
contribution of each variable to assigning a risk category relative to the biomarker 
risk algorithm risk classification can be made.

Age.

APOE risk status.

TOMM40 ‘523 risk status.

Age, APOE risk status.

Age, TOMM40 ‘523 risk status.

APOE risk status, TOMM40 ‘523 risk status.

Age, APOE risk status, TOMM40 ‘523 risk status.
Analysis of Key Secondary2ndary Endpoints and Additional Variables in Placebo Subjects
The summaries and analyses described for the key secondary endpoints and additional 
continuous variables (at the domain and composite score levels only) (Section 9.9.6 and Section 
9.9.9.) will also be performed using high and low risk placebo groups. The summaries will be 
presented by high and low risk placebo groups. The analyses will include the risk factor as a
fixed factor (high vs. low risk). Other covariates (age, baseline, pooled center, gender and years 
of education) will be included.
9.10
Analyses of Columbia-Suicide Severity Rating Scale (C-SSRS)
The following summaries will be presented for C-SSRS scale:

Descriptive statistics by study visit.

Number of subjects with positive reports at baseline and during treatment.

A shift-table to demonstrate changes from baseline in C-SSRS scores during treatment.
A subject will be summarized as having a positive report at baseline if the subject reported any 
of the following suicidal ideation or behavior:

Active suicidal ideation with some intent to act, without specific plan.

Active suicidal ideation with specific plan and intent.

Any actual suicide attempt.


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∀
Any interrupted suicide attempt.
∀
Any aborted suicide attempt.
∀
Any preparatory acts or behavior.
A subject will be summarized as having a positive report during treatment if the subject reported 
any of the following suicidal ideation or behavior:
∀
Active suicidal ideation with some intent to act, without specific plan.
∀
Active suicidal ideation with specific plan and intent.
∀
Any actual suicide attempt.
∀
Any interrupted suicide attempt.
∀
Any aborted suicide attempt.
∀
Any preparatory acts or behavior.
∀
Completed suicide.
9.11
Pharmacokinetic/Pharmacodynamic Analyses
A Population Pharmacokinetic Analysis Plan will be prepared prior to the population PK 
analyses. This plan will describe the underlying hypotheses, the population PK analysis set, and 
the statistical methods to be used.
9.12
Pharmacogenomic Analyses
A separate pharmacogenomic analysis plan will be prepared prior to unblinding of the 
pharmacogenomic data and the subsequent exploratory pharmacogenomic analysis.
 
9.13
Other Outcomes
The change from baseline variables for the EQ-5D index utility score and VAS scores, SF-36 
Physical Component and Mental Component summary T scores, and the 8 SF-36 domain T 
scores will each be analyzed as a continuous variable by study visit using an MMRM model 
similar to the ones described above for the key secondary variables. (The Physical Component 
and Mental Component summary scores and reliability consistency index scores will be included 
in the derived datasets, but analyses for these variables will not be presented in the CSR; they 
may be provided in the future in a separate report.)
For the following endpoints (corresponding to the analysis method for the key secondary 
endpoints), subgroup/responder analyses by MCI event status (ie, subject had confirmed a MCI 
due to AD event during the study, subject did not have confirmed MCI due to AD event during 
the study) will be done (using the corresponding measurements at the time of the MCI due to AD 
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event or using the last non-missing measurements for subject who did not have an MCI due to 
AD event during the study:

Change in HRQoL (European Quality of life scale [Euro-Qol EQ-5D] health utility and VAS 
scores, and Short Form-36 [SF-36] Mental and Physical component scores).
Responder analyses involve subgroups which are defined using post-baseline data and so need to 
be interpreted cautiously. Analysis results for subgroups containing less than 20% of the total 
subjects in the primary efficacy analysis population should be interpreted especially cautiously. 
The treatment groups will be compared within each subgroup. Additional exploratory analyses 
examining subgroup effect and treatment-by-subgroup interaction may be performed.
Data will be collected to allow evaluation of the impact of pioglitazone on health care resource 
utilization (RU) in individuals at high risk of developing MCI due to AD, to be used in future 
pharmacoeconomic evaluation of pioglitazone. (These analyses will not be presented in the CSR, 
but may be provided in the future in a separate report.)
9.14
Safety Analysis
Safety summaries will be based on the safety set. Safety summaries will include descriptive 
statistics for values, changes, and incidence of events for all treatment groups combined in 
addition to summary by treatment group. Conventions for the definition of baseline values and 
visit windowing are provided in Section 9.1.3. Missing safety data will not be imputed.
9.14.1 Adverse Events
All adverse events will be coded using the latest version of MedDRA. In this dictionary, each 
verbatim term is coded to a lower level term, and then mapped to a preferred MedDRA term, 
which is then mapped to an SOC. All adverse events will be included in the data listings but only 
treatment-emergent adverse events will be included in the summary tables.
A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that 
occurs after receiving study drug (AE start date ≥ first dose date) and within 30 days after 
receiving the last dose of study drug (AE start date – last dose date ≤30). A TEAE may also be a 
pretreatment adverse event or a concurrent medical condition diagnosed prior to the date of first 
dose of study drug that increases in severity after the start of dosing. Adverse events data with 
onset occurring more than 30 days after last dose of study drug (AE start date – last dose date 
>30) will be listed, but not included in the summary tables. Adverse events with missing onset 
dates will be summarized regardless of severity and relationship to study medication.
Serious adverse events (SAEs) with onset that occurs after receiving study drug (AE start date 
≥first dose date) and within 30 days after receiving the last dose of study drug (AE start 
date - last dose date ≤30) will be summarized.
At the adverse event level, the summary tables will present the number of subjects reporting each 
of these MedDRA events, ie, the number of subjects reporting one or more events which map to 
the given MedDRA term.


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At the SOC level, the summary tables will present the number of subjects reporting one or more 
events that map to the given SOC. That is, the number of subjects reported at the SOC level will 
be less than or equal to the sum of the subject counts across all adverse events within that SOC.
In selected summaries (TEAEs overview, and TEAEs by SOC and preferred term), adverse 
events will be summarized by the number of events reported in addition to the number and 
percentage of subjects with events.
For the summary of TEAEs by SOC, preferred term and maximum intensity, if a subject 
experiences more than one episode of a particular coded adverse event, the subject will be 
counted only once by the maximum intensity of the episode (preferred term). Similarly, if a 
subject has more than one adverse event within an SOC, the subject will be counted only once by 
the maximum intensity in that SOC. Adverse events with missing severity will be classified as 
having the highest severity.
TEAEs classified in the eCRF as related to the study medication will also be summarized by 
preferred term and SOC. If a subject experiences more than one episode of a particular coded 
adverse event, the subject will be counted only once by the most related report for the preferred 
term. Similarly, if a subject has more than one adverse event within an SOC, the subject will be 
counted only once by the most related report in that SOC. Adverse events with missing 
relationship will be classified as being related to study drug.
The following summaries will be presented:

Overview of TEAEs during the study - number and percentage of subjects, number of events.

TEAEs by SOC and preferred term - number and percentage of subjects, number of events.

TEAEs by SOC and preferred term by gender (male and female) - number and percentage of 
subjects, number of events.

TEAEs by SOC and preferred term by age group (<75, 75) - number and percentage of 
subjects, number of events.

TEAEs by SOC - number and percentage of subjects.

TEAEs by preferred term - number and percentage of subjects.

Intensity of TEAEs by SOC and preferred term - number and percentage of subjects.

Drug-related TEAEs by SOC and preferred term - number and percentage of subjects, 
number of events.

TEAEs leading to study discontinuation by SOC and preferred term - number and percentage 
of subjects, number of events.

Treatment-emergent SAEs by SOC and preferred term - number and percentage of subjects, 
number of events.


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
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 - number and percentage of 
subjects, number of events.

Adverse Events of Special Interest using the following categories defined in the protocol:
–
Congestive Heart Failure.
–
Macular Edema.
–
Hepatic Effects.
–
Bone Fractures.
–
Bladder Cancer.
–
Hypoglycemic Events.
SOCs will be sorted by alphabetical order. Within an SOC, adverse events will be sorted in 
descending order of total number of subjects with preferred term among all the treatment groups.
Subjects mappings will be provided for TEAEs, TEAEs leading to study drug discontinuation, 
and serious TEAEs.
All adverse events will be listed by treatment, study center, subject number and onset date of the 
adverse event. The listing will contain: subject identifier, age, gender, body weight, race, adverse 
event (preferred term and reported term), SOC, onset date, end date or whether the event was 
ongoing, duration, type (pretreatment event, adverse event) frequency (intermittent, continuous), 
intensity (mild, moderate or severe), related to study procedure (yes/no; if yes, specify), 
relationship to study drug (not related, related), action taken concerning study drug (drug 
withdrawn, dose not changed, unknown, not applicable, or dose interrupted), the outcome 
(recovered/resolved, recovering/resolving, not recovered/not resolved, recovered with sequelae, 
fatal, or unknown), increased liver function tests (yes, no), whether the adverse event was an 
SAE, and whether the event was an adverse event of special interest (AESI).
Listings for TEAEs leading to study discontinuation, SAEs, deaths, and AEs of special interest 
will also be presented. A description of the AESIs for this study are provided in Section 10.2.1.3 
of the protocol and consist of the following categories: congestive heart failure, macular edema, 
hepatic effects, bone fractures, bladder cancer, and hypoglycemia. 
9.14.2 Clinical Laboratory Evaluations
The following clinical laboratory parameters will be summarized:

Serum chemistry including alanine aminotransferase (ALT), alkaline phosphatase, aspartate 
aminotransferase (AST), total bilirubin, GGT, total protein, albumin, creatinine, blood urea 
nitrogen (BUN), potassium, sodium, glucose, calcium, vitamin B12, folate, parathyroid 
hormone (PTH), thyroid stimulating hormone (TSH), and free thyroxine (free T4). (Direct 
bilirubin will be assessed only if total bilirubin ≥2.0 mg/dL. Vitamin B12, folate, and RPR is 


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collected only at Baseline and as part of the comprehensive medical follow-up evaluation to 
rule out other causes of dementia).

Hematology including red blood cells, white blood cells, neutrophils, eosinophils, basophils, 
lymphocytes, monocytes, hemoglobin, hematocrit, platelets, and HbA1c. (HbA1c is collected 
only at Baseline.)

Urinalysis including pH, specific gravity, glucose, and nitrite. (Protein and blood values will 
not be summarized but will be included in the listings.)
For each laboratory parameter, the following will be displayed for each scheduled time point
(each visit and end of study).

Summary statistics (n, mean, SD, median, minimum, and maximum) 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. 
For these tables each subject will be categorized as low, normal, or high for the baseline 
value and low, normal, or high for each post-Baseline time point, according to the central 
laboratory reference ranges. The number of subjects in each of the combinations of shifts will 
be presented.

Markedly abnormal values for laboratory parameters, as defined in Appendix A, will be 
summarized by treatment group and overall. The number and percentage of subjects with 
MAV values observed post-Baseline in each of the applicable laboratory parameters will be 
presented.

Number and percentage of subjects with elevated liver enzyme lab values will be presented 
using the criteria described in the protocol.
Subject mappings will be provided for markedly abnormal lab values and elevated liver enzyme 
lab values.
A listing of all laboratory data will be provided. Laboratory data outside of the normal reference 
range will be flagged on the listing along with values meeting MAV criteria. The listing 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 regain (RPR) will not be summarized but 
will be listed.
The following listings of information from the liver function test eCRF pages will be presented: 
Study drug interruption, signs and symptoms, event history, test results and reports, and 
additional comments.
When lab values are recorded in the form of “<x” or “>y”, “x” will be used for “<x” and “y” will 
be used for “>y” in the MAV summary tables. However, these values will be displayed as is 
when the individual subject data listings are presented.
Summaries and listings of laboratory data will be presented, as appropriate, in Systeme 
International (SI) and conventional units.


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9.14.3 Vital Signs
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 B.
9.14.4 Physical Examinations
All physical examination findings will be listed by treatment, study center and subject number. 
The following variables will be listed: subject identifier, age, gender, study visit, visit date, body 
system, whether there was an abnormality, and, a description of the abnormality.
9.14.5 12-Lead ECGs
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 double-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 C.
9.14.6 Other Observations Related to Safety
Not applicable.
9.15
Operational Futility Analysis
Tracking of confirmed events of MCI due to AD will be done on an ongoing basis, in a blinded 
fashion. A confirmed event of MCI due to AD requires two consecutive cases of MCI due to AD 
corresponding to two consecutive 6-month visits as adjudicated by the CIAC. The study will be 
declared to be “operationally futile” if the accrual of confirmed events is too slow to allow 
completion of the study in a feasible time frame.
Under the assumptions of the study, a projection has been made of when the target of 202 
confirmed events (in the primary efficacy analysis population) of high-risk, non-Hispanic/Latino 
Caucasian subjects) will be achieved, as well as a corresponding last-subject-out (LSO) date.
The first assessment of operational futility will be done in April 2017. A maximum delay of up 
to 1 year in LSO is acceptable at the time of the first operational futility. If the projected LSO 
delay is 1 year or less at the time of operational futility, then the study will be considered as 
non-futile with respect to operational futility and will continue unchanged.


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If the projected delay in LSO is greater than 1 year at the time of the first operational futility 
assessment, then a review of subjects with one case of MCI due to AD will be done to see 
whether or not it is feasible that within the next 6 months enough confirmed events of MCI due 
to AD are likely to accrue such that the delay in projected LSO date is less than or equal to 1 
year: If not, then the study will be declared to be “operationally futile”.
If the first operational futility assessment in April 2017 indicates a projected delay in LSO of 
greater than 1 year but a review of subjects currently being tracked as part of the adjudication 
process indicates the study is not operationally futile, then a second assessment of operational 
futility will be done in October 2017, using decision rules analogous to those used for the first 
operational futility analysis. If the second assessment of operational futility is passed 
successfully (ie, is non-futile), no further assessments of operational futility are planned.
If operational futility is declared, then an early efficacy futility analysis (ie, prior to reaching 
33% of planned events as described in Section 9.16 below) will be done as soon as practicable 
(ie, after all pertinent data for the futility analyses has been 100% cleaned and locked in the 
clinical database) and will be provided to the DSMB. 
In the event of an early efficacy futility analysis triggered by a declaration of operational futility, 
the calculated value of conditional power (described below) will be provided to the DSMB: If 
the conditional power value of the primary efficacy futility analysis is ≤30%, then the DSMB 
will recommend that the study is futile with respect to efficacy; if the conditional power value is 
>30%, then the DSMB may consider recommending that the trial is non-futile with respect to 
efficacy. The DSMB will then present their conclusions to the Executive Committee, who will 
decide whether or not the trial will be stopped for futility. (Note that any interim analyses will 
only be used to assess futility: No claim of efficacy will be made based on any interim analysis 
results in this study.)
9.16
Efficacy Futility Analysis
An analysis for futility for efficacy will be conducted once approximately 33% (66 out of 202) of 
the anticipated events (ie, conversions from cognitively normal status to adjudicated diagnosis of 
MCI due to AD, or to AD dementia) have occurred in the high-risk, Caucasian, non-
Hispanic/Latino group. However, since the biomarker risk stratum information is blinded, the 
time of the futility analysis will be estimated using all subjects (both high-risk and low-risk) in 
the Caucasian, non-Hispanic/Latino group. Therefore, the efficacy futility analysis will occur 
when approximately 69 events have been confirmed through adjudication in the Caucasian, non-
Hispanic/Latino group (including both high-risk and low-risk subjects). Note that no adjustment 
of the alpha level is required for an analysis for futility, and that for this study the results of the 
futility analysis will be considered to be non-binding with respect to efficacy for purposes of 
decision making around study continuation.
Because a review of unblinded data is involved, the DSMB will oversee this process.
Once the total number of target events for the futility analysis has been reached, the DSMB will 
be unblinded for a review of actual treatment groups with respect to the primary efficacy 


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endpoint (and potentially other analyses described below, as applicable); this review could take 
place at the next regularly-scheduled DSMB meeting, or at an ad hoc DSMB meeting.
The primary futility analysis will be conducted by the 
 Unblinded DSMB Statistician, 
based on the treatment effect within the high-risk, Caucasian, non-Hispanic/Latino group. The 
calculation is a test from a Cox proportional hazards survival model to evaluate a difference 
between the treatment groups (pioglitazone versus placebo) for the high-risk comparison at the 
time of the interim futility analysis. Additionally, Kaplan-Meier curves by treatment group 
(including low-risk placebo) will be provided for the primary analysis population of non-
Hispanic/Latino Caucasian subjects. If the primary futility analysis indicates futility, then the 
 Unblinded DSMB Statistician will provide an additional set of secondary futility 
analyses (described below). The DSMB could then recommend study continuation to completion 
for the targeted number of events or recommend (based on pre-specified criteria documented in 
the SAP) that the study be considered futile with respect to the primary efficacy endpoint, high-
risk comparison.
Immediately after the futility analysis data review meeting takes place, the DSMB 
recommendation regarding the continuation of the study will be promptly communicated to the 
DSMB Liaison. If the data indicate that study termination should be considered, the DSMB 
Liaison will promptly convene an ad-hoc meeting within the Takeda/Zinfandel alliance senior 
management (ie, the Executive Committee) to further discuss the results of the futility analyses 
and make the final decision as to whether or not to terminate the study. In a similar manner to the 
DSMB, the Executive Committee will be unblinded to the results of the futility analyses, will 
keep all futility analysis results and discussions strictly confidential, and will have no 
involvement with the daily project activities of the study or study team.
If the alliance Executive Committee decides to terminate the study as a result of the futility 
analyses, this decision will be promptly communicated to all the stakeholders including the 
AD-4833/TOMM40 project team, investigators, ethics committees, and regulatory agencies.
Specifics of the ublinded analyses to the DSMB (and to the Executive Committee, if applicable) 
are described below. The futility analysis will have two parts, to be assessed in a hierarchical 
manner:
∀
First, an unblinded analysis to determine futility based on lack of pioglitazone efficacy with 
respect to the primary efficacy endpoint will be provided to the DSMB.
∀
Second, if the conditional power value is >30% (see Section 9.16.1), then the DSMB will 
make a recommendation to the Executive Committee that the study is non-futile with respect 
to efficacy. In this case, the study will continue unchanged, and the Executive Committee 
will remain blinded.
–
If the conditional power value is ≤30%, then the DSMB will receive the additional planned 
unblinded analyses (described below) from the 
 Unblinded Statistician.
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∃
MMRM analyses by visit (including all visits for which at least 50% of the subjects have 
non-missing values) based on the composite score key secondary endpoint related to 
changes from baseline in cognition.
∃
MMRM analyses by visit (including all visits for which at least 50% of the subjects have 
non-missing values) based the following components of the composite score key 
secondary endpoint.
∀
CVLT-II Long-Delay Free Recall
∀
CVLT-II Short-Delay Free Recall
∀
BVMT-R Delayed Recall
∃
MMRM analyses by visit (including all visits for which at least 50% of the subjects have 
non-missing values) for MMSE total score.
∃
Summary statistics by visit for all of the above-described CLVT-II, BVMT-R, CDR-SB, 
and MMSE total score continuous endpoints for all visits. For CDR-SB, visit will be 
derived using visit window defined in Section9.1.3.
∃
–
For the longitudinal model, a linear trajectory model (SPM1L) will be used to model the 
change in the continuous efficacy endpoint over time. This model is chosen because the 
futility analysis is likely at an early stage of the disease development and treatment effect. 
Treatment and treatment*time will be included to evaluate the effect of treatment on the 
progression of the continuous efficacy endpoint. Values of the continuous endpoint will 
be used as the response in the model. Baseline value will be coded as the response at time 
0. Other covariates (age, years of education, gender, and pooled center) that are included 
in the MMRM model for the change from baseline in the composite score will also be 
included in the longitudinal model.
–
For the hazard rate model, number of intervals for the piecewise constant baseline hazard 
function will be selected using AICSurv|Long [Ref. 2]. Treatment effect on the hazard 
function will be evaluated by including treatment as a fixed factor. Other covariates (age, 
years of education, gender, and pooled center) included in the primary CPH model will 
also be included. Conditional power will be calculated using the value of the t statistic for 
testing the treatment effect on the hazard rate.
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∃
Following subgroup analyses on the primary efficacy endpoint will be performed when 
there are at least 20% of the total primary efficacy events in the futility analysis in a 
subgroup: 
∀
Gender (male vs. female)
∀
APOE risk-status (Low, High – where High denotes carriage of at least one APOE ε4 
allele)
∀
Baseline MMSE (<=27 vs. >=28)
∃
Following subgroup summaries and MMRM analyses on the change from baseline in the 
composite score, CVLT-II Long and Short Delay Free Recall, BVMT-R Delayed Recall 
and MMSE total score will be performed when there are at least 400 subjects in a 
subgroup:
∀
Gender (male vs. female)
∀
APOE risk-status (Low, High – where High denotes carriage of at least one APOE ε4 
allele)
∀
Baseline MMSE (<=27 vs. >=28)
∃
If the conditional power value is >10% but <30%, “progression” of the conditional power 
in terms of an increasing number of the events vs. total needed will be provided for the 
following information fractions:10% (20 events), 20% (41 events) and 34% (69 events)
will be provided. The events will be selected based on the time of the occurrence of the 
event relative to the first dose. When the evidence against the null hypothesis is
accumulating, the conditional power should increase as the information fraction 
increases; however, if the CP does not change as the information fraction increases, it 
may be unlikely evidence against the null hypothesis is being accumulated. Essentially if 
CP remains flat across 10%, 20%, 30% of events, it makes it less likely that the null 
hypothesis would be rejected the null hypothesis at end of study.
–
For each of the conditional power calculation in this analysis, at each cut-off day, 
subjects with confirmed event or censored on or prior to the cut-off day, time-to-event 
definition will follow the time to the primary event definition. Subjects with confirmed 
event after the cut-off day will be censored at the last scheduled or unscheduled visit date 
prior to the cut-off day. Subjects censored after the cut-off day, time-to-event is censored 
on the cut-off day.
–
Any additional ad hoc analyses requested by the Executive Committee (which will be 
generated and provided by the 
 Unblinded Statistician).
The above list of additional planned unblinded analyses may be revised by the Executive 
Committee.
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The DSMB will meet, discuss, and decide on a formal recommendation to the Executive 
Committee regarding continuation of the study with respect to efficacy. Subsequently, the 
Executive Committee will decide whether or not to stop the trial with respect to efficacy.
In all possible scenarios, the DSMB will clearly document for the Executive Committee whether 
or not the study appears to be futile, or non-futile, with respect to the conditional power threshold 
(described below) specified for the primary efficacy analysis.
9.16.1 Conditional Power for Futility for Efficacy
Any conditional power (CP) is the probability of rejecting a tested null hypothesis at the final 
analysis, given the interim data and a particular assumption about the population treatment 
effect. For the futility analysis to be performed in this study after 66 events of MCI due to AD in 
the high-risk, non-Hispanic/Latino Caucasian study population, rejecting the null hypothesis of 
no treatment effect with respect to the primary efficacy endpoint at the final analysis is 
equivalent to the event {Z(1) ≤-2.576}, and the assumption about the treatment effect is that the 
population hazard ratio equals the sample hazard ratio observed at the time of this futility 
analysis. The CP is therefore calculated as
CP(t) = Φ[-(Z(t)/t
1/2 
+ 2.576)/(1-t)
1/2
]
where Z(t) is the Wald statistic at information time t computed from the CPH model and Φ is the 
standard normal cumulative distribution function. If the CP(t) ≤30%, the study may be deemed 
futile for demonstrating the superiority of pioglitazone to placebo for the primary efficacy 
endpoint of time to MCI due to AD at the final analysis after 202 adjudicated events in the high-
risk, non-Hispanic/Latino Caucasian study population.
In the above, a z-value of -2.576 corresponds to a one-sided significance level of 0.005; and t 
will be equal to the number of events in the high-risk, non-Hispanic/Latino Caucasian primary 
efficacy study population divided by 202.
9.17
Changes in the Statistical Analysis Plan from the Protocol Analysis Plan 
The study protocol states that academic degrees at baseline will be listed and summarized by 
treatment group and overall. Information about academic degrees is not collected directly in the 
eCRF and so won’t be presented in the CSR.


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10.0
REFERENCES
1. A Double Blind, Randomized, Placebo Controlled, Parallel Group Study to Simultaneously 
Qualify a Biomarker Algorithm for Prognosis of Risk of Developing Mild Cognitive 
Impairment due to Alzheimer’s Disease (MCI due to AD) and to Test the Safety and Efficacy 
of Pioglitazone (AD-4833 SR 0.8 mg QD) to Delay the Onset of MCI due to AD in 
Cognitively Normal Subjects, Takeda Development Center Inc., Protocol No. AD-
4833/TOMM40_301, Amendment #3, dated 10 November 2014.
2. Zhang D, et al., JMFit: A SAS Macro for Joint Models of Longitudinal and Survivial Data. 
Journal of Statistical Software, 2016 July; 71(3)


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Appendix A
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 B
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 C
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 D
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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Appendix E
Detailed Description of Amendments to Text
This section describes changes in reference to SAP incorporating Amendment No. 1.
Page 2 Section 1.1 Approval Signatures
Existing Text
TDC Approvals
Date
Date
Date
Date
Revised Text
Date
Date
PPD
PPD


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CONFIDENTIAL
Date
Date
Rational for Amendment
SAP signatories updated in accordance with personnel changes.
Page 37, Section 8.9.4, MCI Due to AD Event Description
Existing Text
–
Note that data collected at the EoS/EW visit will not contribute to the determine of primary 
efficacy events of MCI due to AD.
–
Revised Text
–
Note that data collected at the EoS/EW visit will also contribute to the determination of 
primary efficacy events of MCI due to AD.
–
Rational for Amendment
The data collected at the EOS/EW is similar to those planned at unscheduled CMFV visit.
Page 38, Section 8.9.4, MCI Due to AD Event Description
Existing Text
–
For purposes of analysis, the event time of a CIAC confirmed event of MCI due to AD is the 
time from the randomization date to the date of the first unscheduled comprehensive medical 
follow-up visit (i.e., corresponding to when the CDR was collected) which was triggered by 
the first of the two consecutive scheduled visits at which a subject was assessed with a 
diagnosis of MCI due to AD (or AD itself) by the CIAC.
–
Revised Text
–
For purposes of analysis, the event time of a CIAC confirmed event of MCI due to AD is the 
time from the randomization date to the date of the first scheduled visit of the two 
consecutive scheduled visits at which a subject was assessed with a clinical diagnosis 
and determined as an primary endpoint event by CIAC using the data from scheduled 
visit and the triggered unscheduled comprehensive medical follow up visits. 
–
For subjects whose first and only clinical assessment of MCI due to AD (or AD itself) 
corresponds to their last visit during the study (e.g., due to subject dropout) and 
determined by CIAC as an primary endpoint event, the event time of a CIAC 
confirmed event of MCI due to AD is the time from the randomization date to the date 
of the scheduled visit.
PPD


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–
Rational for Amendment
–
This change will reflect the thinking that, in any subject dossier reviewed by the CIAC, 
the first scheduled visit is the first of the 4 visits considered by CIAC in their adjudication 
of primary endpoint event, and it represents the first time point of these 4 visits where 
clinical impairment or cognitive decline is first noted. This revised definition better 
reflects the concept of “time to onset” of the MCI due to AD – “onset” meaning start of 
symptoms that are confirmed as MCI due to AD (or AD dementia) by the CIAC.
Page 38, Section 8.9.5, Sensitivity Analyses Using Alternative Event Definitions
Existing Text

Revised Event Definition: For purposes of analysis, the revised event time of a CIAC 
confirmed event of MCI due to AD is the time from either:
–
the randomization date to the date of the first unscheduled comprehensive medical 
follow-up visit which was triggered by the first of the two consecutive scheduled visits at 
which a subject was assessed with a diagnosis of MCI due to AD (or AD itself) by the 
CIAC; or
–
the randomization date to the date of the unscheduled comprehensive medical follow-
up visit which was triggered by the subject’s last scheduled visit during the study 
because the subject was assessed (for the first and only time) with a diagnosis of MCI due 
to AD (or AD itself) by the CIAC.
The revised event definition above expands the definition of MCI due to AD to include 
subjects whose first diagnosis of MCI due to AD corresponds to their last visit during the 
study (eg, due to subject dropout).

Revised Event Time: For purposes of analysis, the revised event time of a CIAC confirmed 
event of MCI due to AD is the time from either:
–
the randomization date to the date of the first scheduled visit of the two consecutive 
scheduled visits at which a subject was assessed with a diagnosis of MCI due to AD (or 
AD itself) by the CIAC; or
–
the randomization date to the date of the subject’s last scheduled visit during the study 
because the subject as assessed (for the first and only time) with a diagnosis of MCI due 
to AD by the CIAC.
The revised event time definition above changes the event time so that it is based on the date 
of the first scheduled visit date at which a case of MCI due to AD was suspected (since CDR 
data isn’t collected at scheduled visits).
–
Revised Text

Revised Event Time Definition: For purposes of analysis, the revised event time of a CIAC 
confirmed event of MCI due to AD is the time from either:


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
the randomization date to the date of the first unscheduled comprehensive medical 
follow-up visit which was triggered by the first of the two consecutive scheduled visits at 
which a subject was assessed with a diagnosis of MCI due to AD (or AD itself) by the 
CIAC; or

the randomization date to the date of the unscheduled comprehensive medical follow-
up visit which was triggered by the subject’s last scheduled visit during the study 
because the subject was assessed (for the first and only time) with a diagnosis of MCI due 
to AD (or AD itself) by the CIAC.
The revised event time definition above changes the event time so that it is based on 
the date of the first unscheduled visit date at which a case of MCI due to AD was 
confirmed by CIAC (since CDR data isn’t collected at scheduled visits).
–
Rational for Amendment
–
This change will keep the alternative definition of time to MCI due to AD onset as from 
the time of randomization to the 1st unscheduled CMFV visit in the sensitivity analyses.
Page 40, Section 8.9.7, Derivation of Cognitive Battery Composite Score
Existing Text

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).
–
Revised Text

One exception is the case of memory domain, where at least one subtest from the CVLT-II 
episodic memory tests is required to calculate the composite (i.e., CVLT-II Short-delay 
free recall correct or CVLT-II Long-delay free recall correct must be non-missing).
–
Rational for Amendment
–
The BVMT-R can be missing for many reasons other than cognition (arthritis, motor 
issues, examiner error). The requirement of both BVMT and at least one CVLT-II to be 
non-missing may cause valid data points to be omitted (such as subjects who complete 
CVLT only). The composite measure becomes uninformative without the memory 
domain; however, the CVLT alone can be used to calculate a memory domain.
–
Page 44, Section 8.9.10, Additional Biomarker Qualification Analyses
Existing Text

N/A
–
Revised Text


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∀
Analysis of Key Secondary Endpoints and Additional Variables in Placebo Subjects
The summaries and analyses described for the key secondary endpoints and additional 
continuous variables (at the domain and composite score levels only) (Section 9.9.6 and 
Section 9.9.9) will also be performed using high and low risk placebo groups. The 
summaries will be presented by high and low risk placebo groups. The analyses will 
include the risk factor as a fixed factor (high vs. low risk). Other covariates (age, 
baseline, pooled center, gender and years of education) will be included.
–
Rational for Amendment
–
It is expected that these analyses will be helpful for the evaluation of the biomarker 
qualification performance. These analyses will be presented at the end of study.
–
Page 54, Section 8.16, Efficacy Futility Analysis
Existing Text
∀
Summary statistics by visit for all of the above-described CLVT-II, BVMT-R, CDR-SB, and 
MMSE total score continuous endpoints for all visits.
–
Revised Text
∀
Summary statistics by visit for all of the above-described CLVT-II, BVMT-R, CDR-SB, and 
MMSE total score continuous endpoints for all visits. For CDR-SB, visit will be derived 
using visit window defined in Section 9.1.3.
∀
For the longitudinal model, a linear trajectory model (SPM1L) will be used to model 
the change in the continuous efficacy endpoint over time. This model is chosen because 
the futility analysis is likely at an early stage of the disease development and treatment 
effect. Treatment and treatment*time will be included to evaluate the effect of 
treatment on the progression of the continuous efficacy endpoint. Values of the 
continuous endpoint will be used as the response in the model. Baseline value will be 
coded as the response at time 0. Other covariates (age, years of education, gender, and 
pooled center) that are included in the MMRM model for the change from baseline in
the composite score will also be included in the longitudinal model.
For the hazard rate model, number of intervals for the piecewise constant baseline 
hazard function will be selected using AICSurv|Long [Ref. 2]. Treatment effect on the 
hazard function will be evaluated by including treatment as a fixed factor. Other 
CCI


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covariates (age, years of education, gender, and pooled center) included in the primary 
CPH model will also be included. Conditional power will be calculated using the value 
of the t statistic for testing the treatment effect on the hazard rate.

Following subgroup analyses on the primary efficacy endpoint will be performed when 
there are at least 20% of the total primary efficacy events in the futility analysis in a 
subgroup: 

Gender (male vs. female)

APOE risk-status (Low, High – where High denotes carriage of at least one 
APOE ε4 allele)

Baseline MMSE (<=27 vs. >=28) 

Following subgroup summaries and MMRM analyses on the change from baseline in 
the composite score, CVLT-II Long and Short Delay Free Recall, BVMT-R Delayed 
Recall and MMSE total score will be performed when there are at least 400 subjects in 
a subgroup: 

Gender (male vs. female)

APOE risk-status (Low, High – where High denotes carriage of at least one 
APOE ε4 allele)

Baseline MMSE (<=27 vs. >=28) 

If the conditional power value is >10% but <30%, “progression” of the conditional 
power in terms of an increasing number of the events vs. total needed will be provided 
for the following information fractions:10% (20 events), 20% (41 events) and 34% (69 
events) will be provided. The events will be selected based on the time of the occurrence 
of the event relative to the first dose. When the evidence against the null hypothesis is 
accumulating, the conditional power should increase as the information fraction 
increases; however, if the CP does not change as the information fraction increases, it 
may be unlikely evidence against the null hypothesis is being accumulated. Essentially if 
CP remains flat across 10%, 20%, 30% of events, it makes it less likely that the null 
hypothesis would be rejected the null hypothesis at end of study.
For each of the conditional power calculation in this analysis, at each cut-off day, 
subjects with confirmed event or censored on or prior to the cut-off day, time-to-event 
definition will follow the time to the primary event definition. Subjects with confirmed 
event after the cut-off day will be censored at the last scheduled or unscheduled visit 
date prior to the cut-off day. Subjects censored after the cut-off day, time-to-event is 
censored on the cut-off day.
–
Rational for Amendment
–
These additional analyses may be informative in the efficacy futility assessment when the 
conditional power based on the primary event is <30%.


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