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

NCT01931566 | Terminated Phase 3 Results DMC

• 3 other identifiers: AD-4833/TOMM40_3012012-003111-58U1111-1139-0355
• Study Type: interventional
• Target: 3,494
• Locations: 5 countries
• Sites: 55

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.

Conditions

Mild Cognitive Impairment Due to Alzheimer's Disease

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (2)

• Time to Diagnosis of Mild Cognitive Impairment Due to Alzheimer's Disease (MCI-AD) for Placebo-treated, High-risk, Non-Hispanic/Latino Caucasian Participants Versus Placebo-treated, Low-risk, Non-Hispanic/Latino Caucasian Participants

  The event definition for MCI-AD was the time in days from the randomization date to the date of the first of two consecutive scheduled visits at which a participant was assessed with a diagnosis of MCI due to AD confirmed by adjudication committee. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to the largest event time.

  Baseline to the end of study (approximately up to 5 years)

• Time to Diagnosis of MCI Due to AD for Pioglitazone-treated, High-risk, Non-Hispanic/Latino Caucasian Participants Versus Placebo-treated, High-risk, Non-Hispanic/Latino, Caucasian Participants

  The event definition for MCI-AD was the time in days from the randomization date to the date of the first of two consecutive scheduled visits at which a participant was assessed with a diagnosis of MCI due to AD confirmed by adjudication committee. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to the largest event time.

  Baseline to the end of study (approximately up to 5 years)

Secondary Outcomes (2)

• Change From Baseline for Cognitive Decline on Composite Score on the Cognitive Test Battery for Pioglitazone-treated Participants Versus Placebo-treated Participants in the High-risk Stratum

  Baseline and Month 48

• Change From Baseline in Instrumental Activities of Daily Living (Alzheimer's Disease Cooperative Study Activities of Daily Living - Prevention Instrument [ADCS ADL-PI]) Between Pioglitazone-treated and Placebo-treated Groups of the High-risk Stratum

  Baseline and Month 48

Study Arms (3)

Low Risk Placebo

PLACEBO COMPARATOR

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

Drug: Pioglitazone placebo

High Risk Placebo

PLACEBO COMPARATOR

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

Drug: Pioglitazone placebo

High Risk Pioglitazone

EXPERIMENTAL

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.

Drug: Pioglitazone

Interventions

Pioglitazone DRUG

Pioglitazone SR tablets

High Risk Pioglitazone

Pioglitazone placebo DRUG

Pioglitazone placebo-matching tablets

High Risk Placebo; Low Risk Placebo

Eligibility Criteria

• Age: 65 Years - 83 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Older Adult (65+)

You may qualify if:

• In the opinion of the investigator, participant is capable of understanding and complying with protocol requirements.
• Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
• 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.
• 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.
• Must score ≥25 on the Mini-Mental State Examination (MMSE) at the screening visit after the education and age adjustment.
• Is male or postmenopausal female between the ages of 65 and 83 years, inclusive, at time of the Screening visit.
• Has the ability and intention to participate in regular study visits, in the opinion of the Investigator.
• 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.

You may not qualify if:

• 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).
• 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.
• 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.
• 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.
• 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.
• Has a history of hypersensitivity or allergies to pioglitazone or related compounds.
• Is required to take excluded medications as specified in the Excluded Medications Section.
• Had any of the following values at the Baseline Visit (Visit 2):
• A serum total bilirubin value \>1.5× upper limit of normal (ULN).
• A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value \>2xULN.
• Unexplained microscopic/macroscopic hematuria on one repeat examinations within 2 weeks of the initial assessment.
• Is positive for either Hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV) antibodies at the Baseline Visit (Visit 2).
• 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.
• 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.
• 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.

Sponsors & Collaborators

• Takeda: lead
• Zinfandel Pharmaceuticals Inc.: collaborator

Study Sites (55)

Unknown Facility

Phoenix, Arizona, United States

Location

Unknown Facility

Sun City, Arizona, United States

Location

Unknown Facility

Long Beach, California, United States

Location

Unknown Facility

San Diego, California, United States

Location

Unknown Facility

San Francisco, California, United States

Location

Unknown Facility

Delray Beach, Florida, United States

Location

Unknown Facility

Fort Myers, Florida, United States

Location

Unknown Facility

Lady Lake, Florida, United States

Location

Unknown Facility

Lake Worth, Florida, United States

Location

Unknown Facility

Merritt Island, Florida, United States

Location

Unknown Facility

Orlando, Florida, United States

Location

Unknown Facility

Port Orange, Florida, United States

Location

Unknown Facility

St. Petersburg, Florida, United States

Location

Unknown Facility

Weston, Florida, United States

Location

Unknown Facility

Atlanta, Georgia, United States

Location

Unknown Facility

Decatur, Georgia, United States

Location

Unknown Facility

Chicago, Illinois, United States

Location

Unknown Facility

Elk Grove, Illinois, United States

Location

Unknown Facility

Elk Grove Village, Illinois, United States

Location

Unknown Facility

Iowa City, Iowa, United States

Location

Unknown Facility

Farmington Hills, Michigan, United States

Location

Unknown Facility

St Louis, Missouri, United States

Location

Unknown Facility

Las Vegas, Nevada, United States

Location

Unknown Facility

Marlton, New Jersey, United States

Location

Unknown Facility

New York, New York, United States

Location

Unknown Facility

Concord, North Carolina, United States

Location

Unknown Facility

Durham, North Carolina, United States

Location

Unknown Facility

Akron, Ohio, United States

Location

Unknown Facility

Portland, Oregon, United States

Location

Unknown Facility

Charleston, South Carolina, United States

Location

Unknown Facility

Cordova, Tennessee, United States

Location

Unknown Facility

Houston, Texas, United States

Location

Unknown Facility

Salt Lake City, Utah, United States

Location

Unknown Facility

Middleton, Wisconsin, United States

Location

Unknown Facility

North Ryde, New South Wales, Australia

Location

Unknown Facility

Southport, Queensland, Australia

Location

Unknown Facility

West Heidelberg, Victoria, Australia

Location

Unknown Facility

Nedlands, Western Australia, Australia

Location

Unknown Facility

Stuttgart, Baden-Wurttemberg, Germany

Location

Unknown Facility

Siegen, North Rhine-Westphalia, Germany

Location

Unknown Facility

Halle, Saxony-Anhalt, Germany

Location

Unknown Facility

Berlin, Germany

Location

Unknown Facility

Basel, Switzerland

Location

Unknown Facility

Exeter, Devon, United Kingdom

Location

Unknown Facility

Plymouth, Devon, United Kingdom

Location

Unknown Facility

Hammersmith, Greater London, United Kingdom

Location

Unknown Facility

London, Greater London, United Kingdom

Location

Unknown Facility

Manchester, Greater Manchester, United Kingdom

Location

Unknown Facility

Salford, Greater Manchester, United Kingdom

Location

Unknown Facility

Blackpool, Lancashire, United Kingdom

Location

Unknown Facility

Isleworth, Middlesex, United Kingdom

Location

Unknown Facility

Glasgow, Strathclyde, United Kingdom

Location

Unknown Facility

Dundee, Tayside Region, United Kingdom

Location

Unknown Facility

Perth, Tayside Region, United Kingdom

Location

Unknown Facility

Bristol, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 37874111 DERIVED

• 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.

  PMID: 34146512 DERIVED

MeSH Terms

Interventions

Pioglitazone

Intervention Hierarchy (Ancestors)

Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 26, 2013
• First Posted: August 29, 2013
• Study Start: August 1, 2013
• Primary Completion: July 24, 2018
• Study Completion: September 6, 2018
• Last Updated: September 16, 2019
• Results First Posted: August 14, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will share

Locations

US (34); DE (4); AU (4); CH (1); GB (12)