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

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of pioglitazone at 24 months compared with placebo on cognitive decline in high-risk participants who have completed the AD-4833/TOMM40_301 study [NCT01931566] with an adjudicated diagnosis of mild cognitive impairment (MCI) due to Alzheimer's Disease (AD).

Detailed Description
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The drug being tested in this study is called pioglitazone. This study is designed to further evaluate the safety and effectiveness of pioglitazone on cognitive function in participants who have completed the AD-4833/TOMM40_301. This study will look at the effectiveness of pioglitazone on cognitive decline in high-risk participants who have completed the AD-4833/TOMM40_301 study with a diagnosis of mild cognitive impairment (MCI) due to Alzheimer's Disease (AD). The study enrolled 40 participants, but is dependent on how many decide to continue treatment in an extension phase after completing the main (301) study. Participants will continue to receive the same study medication they received during the pivotal AD-4833/TOMM40_301 study, either: Pioglitazone 0.8 mg tablets or Placebo (this is a tablet that looks like the study drug but has no active ingredient). All participants will be asked to take one tablet at the same time each day throughout the study. This multi-centre trial, like its precedent pivotal trial, will be conducted worldwide. The overall time to participate in this study is minimum 2 years and a maximum of 7 years depending on when participants roll over from the 301 study. Participants will make approximately 2 visits per year to the clinic, and will be contacted by telephone 3 months after each treatment visit for a follow-up assessment, and 2 weeks after the final visit.

Official Title
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A Blinded Long-term Extension Study to Evaluate the Safety and Efficacy of Pioglitazone (AD-4833 Sustained Release 0.8 mg Daily) to Slow the Progression of Cognitive Decline in Subjects Who Have Completed the AD-4833/TOMM40_301 Study With Diagnosis of Mild Cognitive Impairment Due to Alzheimer Disease

Conditions
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Mild Cognitive Impairment Due to Alzheimer's Disease

Intervention / Treatment
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* Drug: Pioglitazone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Is male or female and is at least 65 years of age at the time of the Baseline Visit. In the opinion of the investigator, is capable of understanding and complying with the protocol requirements. 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. Must be living independently or in nonmedical residential care. 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: Completed the pivotal AD-4833/TOMM40_301 study with an adjudicated diagnosis of AD dementia. 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. 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. 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. 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. Is required to take excluded medications. Has a history of hypersensitivity or allergies to pioglitazone or related compounds. Had any of the following values at the extension study Baseline Visit: A serum total bilirubin value >15 x upper limit of normal (ULN). A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >2 x ULN. Unexplained microscopic/macroscopic hematuria on 2 repeat examinations within 2 weeks. 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. 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. 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. Has a current diagnosis of macular edema, degeneration or any maculopathy. Has a history or current diagnosis of congestive heart failure (CHF), New York Heart Association class III-IV.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pioglitazone 0.8 mg<br>Pioglitazone 0.8 mg, tablets, orally, once, daily, for minimum of 2 years. | Drug: Pioglitazone<br>* Pioglitazone tablets<br>* Other names: AD-4833;|
| Placebo Comparator: Placebo<br>Pioglitazone placebo-matching tablets, orally, once, daily, for minimum of 2 years. | Drug: Placebo<br>* Pioglitazone placebo-matching tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Extension Study Baseline in Composite Score of a Broad Cognitive Test Battery at Month 24 | Composite scores were derived from the test battery. Each test in the battery falls into 1 of the following cognitive domains: Episodic Memory (California Verbal Learning Test - 2nd Edition [CVLT-II], Brief Visuospatial Memory Test - Revised [BVMT-R]), Executive Function (Trail Making Part B, Digit Span Backwards), Language (Animals, Lexical/Phonemic Fluency), Attention (Digit Span Forward, Trail Making Part A), and Visuospatial (Clock Drawing, BVMT-Copy). Only the domains of episodic memory, executive function, language, and attention were used for the calculation of composite score (i.e., Clock Drawing, BVMT-Copy, and the Multilingual Naming Test (MINT), which do not allow generation of standard z scores, were only used for diagnostic purposes and were excluded from the calculation of the composite score). To form the composite, z-scores were calculated for each test, each z-score for the domain were averaged, and then all relevant domains were averaged to form the composite. | Baseline and Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Diagnosis of Alzheimer's Disease (AD) Dementia |  | Day 1 and every 6 months (up to maximum of 36 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy