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Mild Cognitive Impairment Due to Alzheimer's DiseasePhase 3TOMMORROWNCT01931566

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

A Phase 3 study testing Pioglitazone in people with Mild Cognitive Impairment Due to Alzheimer's Disease, run by Takeda at 55 sites in 5 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 65 to 83 yearsHealthy volunteers can take part
What is being tested?
Pioglitazone
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
3,494 participants
Where
55 sitesin 5 countries
Study dates
1 Aug 2013to 6 Sep 2018
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 65 to 83 years
  • All sexes
  • Healthy volunteers accepted
  • Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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 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.
  • 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.
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  • 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.
  • Has a history or current diagnosis of macular edema or macular degeneration.
  • If female, has a history of postmenopausal fractures with no or minimal trauma (eg, wrist, hip, lumbar or thoracic vertebral fracture).
  • Has a history or current diagnosis of congestive heart failure (CHF), New York Heart Association Class III-IV.
  • 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.
  • 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.

Trial locations and contacts

55 sites in 5 countries.

55 sites in 5 countries

United States34 sites

  • Study site

    Akron, Ohio

  • Study site

    Atlanta, Georgia

  • Study site

    Charleston, South Carolina

  • Study site

    Chicago, Illinois

  • Study site

    Concord, North Carolina

  • Study site

    Cordova, Tennessee

  • Study site

    Decatur, Georgia

  • Study site

    Delray Beach, Florida

  • Study site

    Durham, North Carolina

  • Study site

    Elk Grove, Illinois

  • Study site

    Elk Grove Village, Illinois

  • Study site

    Farmington Hills, Michigan

  • Study site

    Fort Myers, Florida

  • Study site

    Houston, Texas

  • Study site

    Iowa City, Iowa

  • Study site

    Lady Lake, Florida

  • Study site

    Lake Worth, Florida

  • Study site

    Las Vegas, Nevada

  • Study site

    Long Beach, California

  • Study site

    Marlton, New Jersey

  • Study site

    Merritt Island, Florida

  • Study site

    Middleton, Wisconsin

  • Study site

    New York, New York

  • Study site

    Orlando, Florida

  • Study site

    Phoenix, Arizona

  • Study site

    Port Orange, Florida

  • Study site

    Portland, Oregon

  • Study site

    Salt Lake City, Utah

  • Study site

    San Diego, California

  • Study site

    San Francisco, California

  • Study site

    St Louis, Missouri

  • Study site

    St. Petersburg, Florida

  • Study site

    Sun City, Arizona

  • Study site

    Weston, Florida

Other trials in United States

United Kingdom12 sites

  • Study site

    Blackpool, Lancashire

  • Study site

    Bristol

  • Study site

    Dundee, Tayside Region

  • Study site

    Exeter, Devon

  • Study site

    Glasgow, Strathclyde

  • Study site

    Hammersmith, Greater London

  • Study site

    Isleworth, Middlesex

  • Study site

    London, Greater London

  • Study site

    Manchester, Greater Manchester

  • Study site

    Perth, Tayside Region

  • Study site

    Plymouth, Devon

  • Study site

    Salford, Greater Manchester

Other trials in United Kingdom

Australia4 sites

  • Study site

    Nedlands, Western Australia

  • Study site

    North Ryde, New South Wales

  • Study site

    Southport, Queensland

  • Study site

    West Heidelberg, Victoria

Other trials in Australia

Germany4 sites

  • Study site

    Berlin

  • Study site

    Halle, Saxony-Anhalt

  • Study site

    Siegen, North Rhine-Westphalia

  • Study site

    Stuttgart, Baden-Wurttemberg

Other trials in Germany

Switzerland1 site

  • Study site

    Basel

Other trials in Switzerland

About this study

Official title: A Double Blind, Randomized, Placebo Controlled, Parallel Group Study to Simultaneously Qualify a Biomarker Algorithm for Prognosis of Risk of Developing Mild Cognitive Impairment Due to Alzheimer's Disease (MCI Due to AD) and to Test the Safety and Efficacy of Pioglitazone (AD-4833 SR 0.8 mg QD) to Delay the Onset of MCI Due to AD in Cognitively Normal Subjects

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.

Read the 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.

Being tested
Pioglitazone, Pioglitazone placebo
Keywords
Drug therapy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PioglitazoneDrug

    Pioglitazone SR tablets

  • Pioglitazone placeboDrug

    Pioglitazone placebo-matching tablets

Study groups in NCT01931566
Study groupRoleWhat they receive
Low Risk PlaceboPlacebo comparatorPioglitazone placebo-matching tablets, orally, once daily to participants assigned to low risk group for developing MCI-AD for up to 5 years.
Receives: Drug: Pioglitazone placebo
High Risk PlaceboPlacebo comparatorPioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.
Receives: Drug: Pioglitazone placebo
High Risk PioglitazoneExperimentalPioglitazone 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.
Receives: Drug: Pioglitazone

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

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

  2. 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.

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

Secondary outcomes (2)

  1. 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

    Composite scores derived from the test battery. Domains of Episodic Memory [California Verbal Learning Test-2nd Edition (CVLT-II), Brief Visuospatial Memory Test-Revised (BVMT-R)]; Executive Function [Trail Making Test (TMT) (Part B), Wechsler Adult Intelligence Scale (WAIS)-III Digit Span Test-backwards span]; Language [Multilingual Naming Test (MiNT), Semantic Fluency (animals), Lexical/phonemic fluency (F, A, and S in English; D, S, and F in German)]; and Attention [WAIS-III Digit Span Test-forward span, TMT (Part A)] used for composite score. 12 measures were derived from 8 neuropsychological tests. CVLT-II test involved 2 primary measures (short, long delay recall); BVMT-R had 2 measures (copy and recall); Digit Span and Trail both had 2 measures (forward and backward span and Parts A and B). There was 1 total score for each test: CDT, MINT, semantic and lexical fluency. Total score ranged from -1.222 to 1.707 at baseline, a higher composite score indicated better cognition.

    Measured: Baseline and Month 48

  2. 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

    The ADCS ADL-PI is a functional measure that was specifically designed for standardized administration over long duration clinical studies to prevent AD. The ADCS ADL-PI is a 20-item instrument that included 15 ADL questions, which were scored as 1 (with a lot of difficulty), 2 (with some difficulty), or 3 (as well as usually, with no difficulty), plus 5 vision, hearing, and mobility questions, which were scored from 0 (no) to 1 (yes). ADL Total ranged from 0 to 45, and lower scores indicated greater disability.

    Measured: Baseline and Month 48

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Aug 2013 (estimated)
  2. Study start1 Aug 2013
  3. Primary completion24 Jul 2018
  4. Study completion6 Sep 2018

Why it stopped: Lack of efficacy of the drug; no safety concern

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
3,494 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01931566
Sponsor's protocol ID
AD-4833/TOMM40_301
Other IDs
2012-003111-58, U1111-1139-0355
Acronym
TOMMORROW
Status last verified
Aug 2019
First submitted
26 Aug 2013
Last updated
16 Sep 2019
Data monitoring committee
Yes
Individual data sharing
Yes: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com 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.

Publications

  • 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.

    PubMed 37874111

  • 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.

    PubMed 34146512

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Pioglitazone in people with Mild Cognitive Impairment Due to Alzheimer's Disease, run by Takeda at 55 sites in 5 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 16 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 55 sites in United States, United Kingdom, Australia, Germany, Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 14 Aug 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (time frame: Baseline to the end of study (approximately up to 5 years)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01931566, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Sep 2019.

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