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 (TOMMORROW)

• ClinicalTrials.gov Identifier: NCT01931566
• Recruitment Status: Terminated
• First Posted: August 29, 2013
• Results First Posted: August 14, 2019
• Last Update Posted: September 16, 2019
• Sponsor: Takeda
• Collaborator: Zinfandel Pharmaceuticals Inc.
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: August 26, 2013
• First Posted Date: August 29, 2013
• Results First Submitted Date: July 22, 2019
• Results First Posted Date: August 14, 2019
• Last Update Posted Date: September 16, 2019
• Actual Study Start Date: August 1, 2013
• Actual Primary Completion Date: July 24, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 22, 2019)

• 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 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.
• 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 [ Time Frame: Baseline to the end of study (approximately up to 5 years) ]
  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.

Original Primary Outcome Measures (submitted: August 26, 2013)

• Time to diagnosis of Mild Cognitive Impairment due to Alzheimer's Disease (MCI-AD) for biomarker risk algorithm qualification [ Time Frame: Baseline to end of study, anticipated to be about 5 years. ]
  A test from a Cox proportional hazards survival model will be used to compare data from non-Hispanic/Latino Caucasians in the (placebo-treated) low-risk group (ie, the combined placebo groups) with data from non-Hispanic/Latino Caucasians in the placebo-treated subjects in the high-risk group. The event in this analysis will be the diagnosis of cognitive impairment. If this test is significant at the 0.01 level, it can be concluded that the diagnostic prognostic test has differentiated between subjects at low and high risk of being diagnosed with cognitive impairment within 5 years of taking the test.
• Time to diagnosis of Mild Cognitive Impairment due to Alzheimer's Disease (MCI-AD) for pioglitazone-treated, non-Hispanic/Latino Caucasian subjects versus placebo-treated non-Hispanic/Latino, Caucasian subjects in the high-risk stratum. [ Time Frame: Baseline to end of study, anticipated to be about 5 years. ]
  A test from a Cox proportional hazards survival model will be used to compare data from non-Hispanic/Latino Caucasians in the (placebo-treated) low-risk group (ie, the combined placebo groups) with data from non-Hispanic/Latino Caucasians in the placebo-treated subjects in the high-risk group. The event in this analysis will be the diagnosis of cognitive impairment. If this test is significant at the 0.01 level, it can be concluded that the diagnostic prognostic test has differentiated between subjects at low and high risk of being diagnosed with cognitive impairment within 5 years of taking the test. If this test is significant at the 0.01 level, it can be concluded that active treatment has delayed the development of cognitive impairment within the 5-year period.

Current Secondary Outcome Measures (submitted: August 29, 2019)

• 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 [ Time Frame: Baseline and Month 48 ]
  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.
• 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 [ Time Frame: Baseline and Month 48 ]
  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.

Original Secondary Outcome Measures (submitted: August 26, 2013)

• Change from baseline in cognitive decline on composite score on the cognitive test battery [ Time Frame: Baseline and months 6, 12, 18, 24, 30, 36, 42 and 48 ]
  Composite scores will be derived from the test battery. Only the domains of episodic memory, executive function, language, and attention will be used for the composite score. To form the composite, z-scores will be calculated for each test, each z-score for the domain will be averaged, and then all relevant domains will be averaged to form the composite.
• Change from baseline in instrumental activities of daily living (Alzheimer's Disease Cooperative Study Activities of Daily Living - Prevention Instrument [ADCS ADL-PI]) [ Time Frame: Baseline and months 6, 12, 18, 24, 30, 36, 42 and 48 ]
  Self assessment of memory function will be obtained using the ADCS Prevention Instrument Project- Mail In Cognitive Function Screening Instrument. This is a 14-item self administered yes/no questionnaire to assess recent changes (over the last year) in cognition and functional activities which commonly are affected in the development of MCI.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Mild Cognitive Impairment Due to Alzheimer's Disease

Intervention

• Drug: Pioglitazone
  Pioglitazone SR tablets
• Drug: Pioglitazone placebo
  Pioglitazone placebo-matching tablets

Study Arms

• Placebo Comparator: 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.
  Intervention: Drug: Pioglitazone placebo
• Placebo Comparator: 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.
  Intervention: Drug: Pioglitazone placebo
• Experimental: 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.
  Intervention: Drug: Pioglitazone

• Publications *: 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 31, 2017): 3494
• Original Estimated Enrollment (submitted: August 26, 2013): 5800
• Actual Study Completion Date: September 6, 2018
• Actual Primary Completion Date: July 24, 2018 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 65 Years to 83 Years (Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Germany, Switzerland, United Kingdom, United States
• Removed Location Countries: Italy, Russian Federation

Administrative Information

• NCT Number: NCT01931566
• Other Study ID Numbers: AD-4833/TOMM40_301; 2012-003111-58 ( EudraCT Number ); U1111-1139-0355 ( Registry Identifier: WHO UTN )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: 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.

• Current Responsible Party: Takeda
• Original Responsible Party: Same as current
• Current Study Sponsor: Takeda
• Original Study Sponsor: Same as current
• Collaborators: Zinfandel Pharmaceuticals Inc.

Investigators

• Study Director: Medical Director; Takeda

• PRS Account: Takeda
• Verification Date: August 2019