AD-4833/TOMM40_303 Extension Study of the Safety and Efficacy of Pioglitazone to Slow Cognitive Decline in Participants With Mild Cognitive Impairment Due to Alzheimer Disease

The drug being tested in this study is called pioglitazone. This study is designed to further
evaluate the safety and effectiveness of pioglitazone on cognitive function in participants
who have completed the AD-4833/TOMM40_301. This study will look at the effectiveness of
pioglitazone on cognitive decline in high-risk participants who have completed the
AD-4833/TOMM40_301 study with a diagnosis of mild cognitive impairment (MCI) due to
Alzheimer's Disease (AD).

The study is anticipated to enroll approximately 316 participants, but is dependent on how
many decide to continue treatment in an extension phase after completing the main (301)
study. Participants will continue to receive the same study medication they received during
the pivotal AD-4833/TOMM40_301 study, either:

- pioglitazone 0.8 mg tablets or

- placebo (this is a tablet that looks like the study drug but has no active ingredient).

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

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

Inclusion Criteria:

1. Completed the pivotal AD-4833/TOMM40_301 study with an adjudicated diagnosis of mild
cognitive impairment (MCI) due to Alzheimer's Disease (AD) without ongoing serious
adverse events (SAEs) from AD-4833/TOMM40_301.

2. Is male or female and is at least 65 years of age at the time of the Baseline Visit.

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

4. The participant or, when applicable, the participant's legally acceptable
representative signs and dates a written, informed consent form and any required
privacy authorization prior to the initiation of any study procedures.

5. Must be living independently or in nonmedical residential care.

6. Has a project partner able to separately consent on his/her own behalf and take part
in the study (with the intent to do so as long as the participant is enrolled),
providing information on the cognitive, functional, and behavioral status of the
participant and assisting with observation of adverse events (AEs) and monitoring of
study medication, if needed. Project partners participating in the pivotal
AD-4833/TOMM40_301 study are encouraged to participate in this extension study in this
capacity.

Exclusion Criteria:

1. Completed the pivotal AD-4833/TOMM40_301 study with an adjudicated diagnosis of AD
dementia.

2. Has a current diagnosis of significant psychiatric illness, per Diagnostic and
Statistical Manual of Mental Disorders, 4th Edition (including but not limited to
major depressive disorder, anxiety disorders) and is in an acute phase/episode, or the
participant has a current diagnosis or history of schizophrenia or bipolar disorder.

3. Has a glycosylated hemoglobin (HbA1c) >8% at the extension study Baseline Visit or
requires treatment with insulin, triple oral antidiabetic therapy or a peroxisome
proliferator-activated receptor gamma (PPAR-γ) agonist.

4. Has a clinically significant unstable illness, for example, hepatic impairment or
renal insufficiency, or cardiovascular, pulmonary, gastrointestinal (including s/p
gastric bypass surgery), endocrine, neurological, rheumatologic, immunologic,
infectious, skin and subcutaneous tissue disorders, or metabolic disturbance.

5. Is an immediate family member, study site employee, or is in a dependent relationship
with a study site employee who is involved in conduct of this study (eg, spouse,
pivotal, child, sibling) or may consent under duress.

6. Is required to take excluded medications.

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

8. Had any of the following values at the extension study Baseline Visit:

1. A serum total bilirubin value >15 x upper limit of normal (ULN).

2. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value
>2 x ULN.

3. Unexplained microscopic/macroscopic hematuria on 2 repeat examinations within 2
weeks.

9. Has a disease or takes medication that, in the opinion of the investigator, could
interfere with the assessments of safety, tolerability, or efficacy, or prevent the
participant from adequately participating in the study or continue for the anticipated
duration of the study.

10. Has received any investigational compound, with the exception of treatment during the
AD-4833/TOMM40_301 study, within 30 days prior to Baseline or 5 half-lives prior to
Baseline or is currently participating in another study that entails the
administration of an investigational or marketed drug, supplement, or intervention
including, but not limited to diet, exercise, lifestyle, or invasive procedure.

11. Has any cancer that has been in remission for less than 2 years from the extension
study Baseline Visit. Participants with basal cell or stage I squamous cell carcinoma
of the skin will be eligible. Participants with current diagnosis of bladder cancer
are not eligible irrespective of the remission status.

12. Has a current diagnosis of macular edema, degeneration or any maculopathy.

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