Biomarker Qualification for Risk of Mild Cognitive Impairment (MCI) Due to Alzheimer's Disease (AD) and Safety and Efficacy Evaluation of Pioglitazone in Delaying Its Onset

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

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.

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.

Inclusion Criteria:

1. In the opinion of the investigator, participant is capable of understanding and complying with protocol requirements.

2. Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

3. 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. Is cognitively normal at baseline, scoring as indicated for the following tests:

   • Clinical Dementia Rating (CDR)=0.
   • At least one memory test above -1.5 standard deviation (SD) of the demographically corrected normative mean.

5. Must score ≥25 on the Mini-Mental State Examination (MMSE) at the screening visit after the education and age adjustment.

6. Is male or postmenopausal female between the ages of 65 and 83 years, inclusive, at time of the Screening visit.

7. Has the ability and intention to participate in regular study visits, in the opinion of the Investigator.

8. Has a project partner who can separately 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 participant is enrolled) to provide information on the cognitive, functional, and behavioral status of the participant and to assist with monitoring of study medication, if needed.

Exclusion Criteria:

1. 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. 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 participant has a current diagnosis or history of schizophrenia or bipolar disorder.

3. Has a 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-γ) agonist. The participant should be on a stable antidiabetic regimen for at least 3 months prior to enrollment.

4. 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 HIV infection is considered exclusionary for this study.

5. 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. 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. Has a history of hypersensitivity or allergies to pioglitazone or related compounds.

8. Is required to take excluded medications as specified in the Excluded Medications Section.

9. Had any of the following values at the Baseline Visit (Visit 2):

   1. A serum total bilirubin value >1.5× upper limit of normal (ULN).
   2. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >2xULN.
   3. Unexplained microscopic/macroscopic hematuria on one repeat examinations within 2 weeks of the initial assessment.

10. Is positive for either Hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV) antibodies at the Baseline Visit (Visit 2).

11. 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 participant from adequately participating in the study or continue for the anticipated duration of the study.

12. 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.

13. Has a history of any cancer that has been in remission for less than 2 years from the Screening Visit. Participants with basal cell or stage I squamous cell carcinoma of the skin will be eligible. Participants with history of bladder cancer are not eligible irrespective of the remission status.

14. Has a history or current diagnosis of macular edema or macular degeneration.

15. If female, has a history of postmenopausal fractures with no or minimal trauma (eg, wrist, hip, lumbar or thoracic vertebral fracture).

16. Has a history or current diagnosis of congestive heart failure (CHF), New York Heart Association Class III-IV.

17. 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. Participant's Translocase of the Outer Mitochondrial Membrane 40 homolog (TOMM40) rs10524523 or apolipoprotein E (APOE) genotypes or APOE phenotype are known by the participant or the study staff participating in this study.