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

NCT ID: NCT01931566

Last Updated: 2019-09-16

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 3494 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-01
• Study Completion Date: 2018-09-06

Brief Summary

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.

Detailed Description

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.

Conditions

Mild Cognitive Impairment Due to Alzheimer's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Low Risk Placebo

Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to low risk group for developing MCI-AD for up to 5 years.

Group Type: PLACEBO_COMPARATOR

Pioglitazone placebo

Intervention Type: DRUG

Pioglitazone placebo-matching tablets

High Risk Placebo

Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

Group Type: PLACEBO_COMPARATOR

Pioglitazone placebo

Intervention Type: DRUG

Pioglitazone placebo-matching tablets

High Risk Pioglitazone

Pioglitazone 0.8 mg, sustained release (SR) tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

Group Type: EXPERIMENTAL

Pioglitazone

Intervention Type: DRUG

Pioglitazone SR tablets

Interventions

Pioglitazone

Pioglitazone SR tablets

Intervention Type: DRUG

Pioglitazone placebo

Pioglitazone placebo-matching tablets

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 65 Years
• Maximum Eligible Age: 83 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Zinfandel Pharmaceuticals Inc.

INDUSTRY

Sponsor Role: collaborator

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Takeda

Locations

Phoenix, Arizona, United States

Sun City, Arizona, United States

Long Beach, California, United States

San Diego, California, United States

San Francisco, California, United States

Delray Beach, Florida, United States

Fort Myers, Florida, United States

Lady Lake, Florida, United States

Lake Worth, Florida, United States

Merritt Island, Florida, United States

Orlando, Florida, United States

Port Orange, Florida, United States

St. Petersburg, Florida, United States

Weston, Florida, United States

Atlanta, Georgia, United States

Decatur, Georgia, United States

Chicago, Illinois, United States

Elk Grove, Illinois, United States

Elk Grove Village, Illinois, United States

Iowa City, Iowa, United States

Farmington Hills, Michigan, United States

St Louis, Missouri, United States

Las Vegas, Nevada, United States

Marlton, New Jersey, United States

New York, New York, United States

Concord, North Carolina, United States

Durham, North Carolina, United States

Akron, Ohio, United States

Portland, Oregon, United States

Charleston, South Carolina, United States

Cordova, Tennessee, United States

Houston, Texas, United States

Salt Lake City, Utah, United States

Middleton, Wisconsin, United States

North Ryde, New South Wales, Australia

Southport, Queensland, Australia

West Heidelberg, Victoria, Australia

Nedlands, Western Australia, Australia

Stuttgart, Baden-Wurttemberg, Germany

Siegen, North Rhine-Westphalia, Germany

Halle, Saxony-Anhalt, Germany

Berlin, , Germany

Basel, , Switzerland

Exeter, Devon, United Kingdom

Plymouth, Devon, United Kingdom

Hammersmith, Greater London, United Kingdom

London, Greater London, United Kingdom

Manchester, Greater Manchester, United Kingdom

Salford, Greater Manchester, United Kingdom

Blackpool, Lancashire, United Kingdom

Isleworth, Middlesex, United Kingdom

Glasgow, Strathclyde, United Kingdom

Dundee, Tayside Region, United Kingdom

Perth, Tayside Region, United Kingdom

Bristol, , United Kingdom

Countries

United States; Australia; Germany; Switzerland; United Kingdom

References

Zou H, Luo S, Liu H, Lutz MW, Bennett DA, Plassman BL, Welsh-Bohmer KA. Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study. J Prev Alzheimers Dis. 2023;10(4):886-894. doi: 10.14283/jpad.2023.115.

Reference Type: DERIVED

PMID: 37874111 (View on PubMed)

Burns DK, Alexander RC, Welsh-Bohmer KA, Culp M, Chiang C, O'Neil J, Evans RM, Harrigan P, Plassman BL, Burke JR, Wu J, Lutz MW, Haneline S, Schwarz AJ, Schneider LS, Yaffe K, Saunders AM, Ratti E; TOMMORROW study investigators. Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer's disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2021 Jul;20(7):537-547. doi: 10.1016/S1474-4422(21)00043-0.

Reference Type: DERIVED

PMID: 34146512 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2012-003111-58

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1139-0355

Identifier Type: REGISTRY

Identifier Source: secondary_id

AD-4833/TOMM40_301

Identifier Type: -

Identifier Source: org_study_id