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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 safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02284906
Recruitment Status : Terminated (Lack of efficacy of the drug; no safety concern)
First Posted : November 6, 2014
Results First Posted : July 2, 2019
Last Update Posted : July 2, 2019
Information provided by (Responsible Party):

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).

Condition or disease Intervention/treatment Phase
Mild Cognitive Impairment Due to Alzheimer's Disease Drug: Pioglitazone Drug: Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : February 12, 2015
Actual Primary Completion Date : January 31, 2018
Actual Study Completion Date : May 8, 2018

Arm Intervention/treatment
Experimental: Pioglitazone 0.8 mg
Pioglitazone 0.8 mg, tablets, orally, once, daily, for minimum of 2 years.
Drug: Pioglitazone
Pioglitazone tablets
Other Name: AD-4833

Placebo Comparator: Placebo
Pioglitazone placebo-matching tablets, orally, once, daily, for minimum of 2 years.
Drug: Placebo
Pioglitazone placebo-matching tablets

Primary Outcome Measures :
  1. Change From Extension Study Baseline in Composite Score of a Broad Cognitive Test Battery at Month 24 [ Time Frame: Baseline and 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.

Secondary Outcome Measures :
  1. Time to Diagnosis of Alzheimer's Disease (AD) Dementia [ Time Frame: Day 1 and every 6 months (up to maximum of 36 months) ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02284906

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United States, Arizona
Phoenix, Arizona, United States, 85006
Sun City, Arizona, United States, 85351
United States, California
San Diego, California, United States, 92103
United States, Florida
Delray Beach, Florida, United States, 33445
Fort Myers, Florida, United States, 33912
Lake Worth, Florida, United States, 33449
Melbourne, Florida, United States, 32940
Merritt Island, Florida, United States, 32952
Port Orange, Florida, United States, 32127
Saint Petersburg, Florida, United States, 33709
Weston, Florida, United States, 33331
United States, Georgia
Atlanta, Georgia, United States, 30329
Decatur, Georgia, United States, 30033
United States, Illinois
Chicago, Illinois, United States, 60640
Elk Grove Village, Illinois, United States, 60007
Elk Grove, Illinois, United States, 60007
United States, Iowa
Iowa City, Iowa, United States, 52242
United States, Missouri
Saint Louis, Missouri, United States, 63141
United States, Nevada
Las Vegas, Nevada, United States, 89106
United States, New Jersey
Marlton, New Jersey, United States, 08053
United States, New York
New York, New York, United States, 10019
United States, North Carolina
Concord, North Carolina, United States, 28025
Durham, North Carolina, United States, 27705
United States, Ohio
Akron, Ohio, United States, 44320
United States, South Carolina
Charleston, South Carolina, United States, 29401
United States, Texas
Houston, Texas, United States, 77030
United States, Utah
Salt Lake City, Utah, United States, 84107
United States, Wisconsin
Middleton, Wisconsin, United States, 53562
Australia, New South Wales
North Ryde, New South Wales, Australia, 2113
Australia, Queensland
Southport, Queensland, Australia, 4215
Australia, Victoria
Heidelberg West, Victoria, Australia, 3081
Australia, Western Australia
Nedlands, Western Australia, Australia, 6009
Basel, Switzerland, CH-4012
United Kingdom
Bristol, Avon, United Kingdom, BS16 1LE
Exeter, Devon, United Kingdom, EX2 5DW
Plymouth, Devon, United Kingdom, PL6 8DH
Hammersmith, Greater London, United Kingdom, W6 8RF
London, Greater London, United Kingdom, EC1M 6BQ
Manchester, Greater Manchester, United Kingdom, M13 9NQ
Blackpool, Lancashire, United Kingdom, FY2 0JH
Isleworth, Middlesex, United Kingdom, TW7 6FY
Glasgow, Strathclyde, United Kingdom, G20 0XA
Perth, Tayside Region, United Kingdom, PH2 7BH
Sponsors and Collaborators
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Study Director: Medical Director Clinical Science Takeda
  Study Documents (Full-Text)

Documents provided by Takeda:
Statistical Analysis Plan  [PDF] September 14, 2018
Study Protocol  [PDF] January 19, 2016

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Responsible Party: Takeda Identifier: NCT02284906    
Other Study ID Numbers: AD-4833/TOMM40_303
U1111-1154-9637 ( Registry Identifier: WHO )
2013-004984-30 ( EudraCT Number )
First Posted: November 6, 2014    Key Record Dates
Results First Posted: July 2, 2019
Last Update Posted: July 2, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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Studies a U.S. FDA-regulated Drug Product: Yes
Keywords provided by Takeda:
Drug therapy
Additional relevant MeSH terms:
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Alzheimer Disease
Cognitive Dysfunction
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Hypoglycemic Agents
Physiological Effects of Drugs