Clinical trial NCT02284906: 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
Official title: A Blinded Long-term Extension Study to Evaluate the Safety and Efficacy of Pioglitazone (AD-4833 Sustained Release 0.8 mg Daily) to Slow the Progression of Cognitive Decline in Subjects Who Have Completed the AD-4833/TOMM40_301 Study With Diagnosis of Mild Cognitive Impairment Due to Alzheimer Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Mild Cognitive Impairment Due to Alzheimer's Disease
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2014-11-06
Enrollment: 40
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

The study enrolled 40 participants, but is dependent on how many decide to continue treatment in an extension phase after completing the main (301) study. Participants will continue to receive the same study medication they received during the pivotal AD-4833/TOMM40_301 study, either:

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

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

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

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Extension Study Baseline in Composite Score of a Broad Cognitive Test Battery at Month 24
timeFrame: Baseline and Month 24
Secondary outcomes:
measure: Time to Diagnosis of Alzheimer's Disease (AD) Dementia
timeFrame: Day 1 and every 6 months (up to maximum of 36 months)
Other outcomes:
Locations:
city: Phoenix
country: United States
state: Arizona
city: Sun City
country: United States
state: Arizona
city: San Diego
country: United States
state: California
city: Delray Beach
country: United States
state: Florida
city: Fort Myers
country: United States
state: Florida
city: Lake Worth
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state: Florida
city: Melbourne
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state: Florida
city: Merritt Island
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state: Florida
city: Port Orange
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state: Florida
city: Saint Petersburg
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state: Florida
city: Weston
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state: Florida
city: Atlanta
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state: Georgia
city: Decatur
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state: Georgia
city: Chicago
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state: Illinois
city: Elk Grove Village
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state: Illinois
city: Elk Grove
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state: Illinois
city: Iowa City
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state: Iowa
city: Saint Louis
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state: Missouri
city: Las Vegas
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state: Nevada
city: Marlton
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state: New Jersey
city: New York
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state: New York
city: Concord
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state: North Carolina
city: Durham
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state: North Carolina
city: Akron
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state: Ohio
city: Charleston
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state: South Carolina
city: Houston
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state: Texas
city: Salt Lake City
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state: Utah
city: Middleton
country: United States
state: Wisconsin
city: North Ryde
country: Australia
state: New South Wales
city: Southport
country: Australia
state: Queensland
city: Heidelberg West
country: Australia
state: Victoria
city: Nedlands
country: Australia
state: Western Australia
city: Basel
country: Switzerland
city: Bristol
country: United Kingdom
state: Avon
city: Exeter
country: United Kingdom
state: Devon
city: Plymouth
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state: Devon
city: Hammersmith
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state: Greater London
city: London
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state: Greater London
city: Manchester
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state: Greater Manchester
city: Blackpool
country: United Kingdom
state: Lancashire
city: Isleworth
country: United Kingdom
state: Middlesex
city: Glasgow
country: United Kingdom
state: Strathclyde
city: Perth
country: United Kingdom
state: Tayside Region
Study officials:
affiliation: Takeda
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References: