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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01931566
Registration number
NCT01931566
Ethics application status
Date submitted
26/08/2013
Date registered
29/08/2013
Date last updated
16/09/2019
Titles & IDs
Public 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
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Scientific 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
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Secondary ID [1]
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2012-003111-58
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Secondary ID [2]
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AD-4833/TOMM40_301
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Universal Trial Number (UTN)
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Trial acronym
TOMMORROW
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Mild Cognitive Impairment Due to Alzheimer's Disease
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Condition category
Condition code
Neurological
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Alzheimer's disease
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Neurological
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Dementias
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Mental Health
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Other mental health disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Pioglitazone
Treatment: Drugs - Pioglitazone placebo
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.
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.
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.
Treatment: Drugs: Pioglitazone
Pioglitazone SR tablets
Treatment: Drugs: Pioglitazone placebo
Pioglitazone placebo-matching tablets
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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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
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline to the end of study (approximately up to 5 years)
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Primary outcome [2]
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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
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Assessment method [2]
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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.
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Timepoint [2]
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Baseline to the end of study (approximately up to 5 years)
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Secondary outcome [1]
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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
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline and Month 48
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Secondary outcome [2]
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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
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Assessment method [2]
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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.
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Timepoint [2]
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Baseline and Month 48
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Eligibility
Key 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.
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Minimum age
65
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Maximum age
83
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Sex
Both males and females
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Can healthy volunteers participate?
Yes
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Key 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-?) 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/08/2013
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
6/09/2018
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Sample size
Target
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Accrual to date
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Final
3494
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC,WA
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Recruitment hospital [1]
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- North Ryde
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Recruitment hospital [2]
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- Southport
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Recruitment hospital [3]
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- West Heidelberg
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Recruitment hospital [4]
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- Nedlands
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Recruitment postcode(s) [1]
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- North Ryde
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Recruitment postcode(s) [2]
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- Southport
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Recruitment postcode(s) [3]
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- West Heidelberg
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Recruitment postcode(s) [4]
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- Nedlands
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Recruitment outside Australia
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United States of America
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Arizona
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California
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Illinois
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Iowa
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Devon
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Bristol
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Takeda
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Address
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Other collaborator category [1]
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Commercial sector/Industry
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Name [1]
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Zinfandel Pharmaceuticals Inc.
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01931566
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
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Medical Director
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Address
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Takeda
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01931566
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