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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Takeda
Sponsor:
Collaborator:
Zinfandel Pharmaceuticals
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT01931566
First received: August 26, 2013
Last updated: May 26, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Mild Cognitive Impairment Due to Alzheimer's Disease
Drug: Pioglitazone
Drug: Pioglitazone placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 0.8 SR mg QD) to Delay the Onset of MCI Due to AD in Cognitively Normal Subjects

Resource links provided by NLM:


Further study details as provided by Takeda:

Primary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 5800
Study Start Date: August 2013
Estimated Study Completion Date: April 2019
Estimated Primary Completion Date: April 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pioglitazone
Pioglitazone tablets, orally, once daily for up to 5 years.
Drug: Pioglitazone
Low-Dose Pioglitazone tablets
Placebo Comparator: Placebo
Pioglitazone placebo-matching tablets, orally, once daily for up to 5 years.
Drug: Pioglitazone placebo
Pioglitazone placebo-matching tablets

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 idenfitied by the biomarker in the non-Hispanic/Latino Caucasian participants. In addition, approximately 300 cognitively normal elderly participants will participate in an Amyloid-Related Imaging Abnormalities (ARIA) substudy at selected sites. In the ARIA substudy, high-risk participants will be randomized (5:4) to receive either pioglitazone or placebo.

This multi-centre trial will be conducted worldwide. The study will enroll approximately 5800 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.

  Eligibility

Ages Eligible for Study:   65 Years to 83 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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 stanard 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 able to separately consent 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.
  9. Female participants must agree to take daily supplements of vitamin D (minimum 800 International Units [IU] daily) and calcium (minimum 1000 mg daily) for the duration of the treatment period, unless medically contraindicated.

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, endocrine, neurological, rheumatologic, immunologic, infectious, skin and subcutaneous tissue disorders, or metabolic disturbance.
  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 two repeat examinations within 2 weeks.
  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 interfer 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, degeneration or any maculopathy.
  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.
  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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01931566

Contacts
Contact: Takeda Study Registration Call Center 800-778-2860 medicalinformation@tpna.com

  Show 42 Study Locations
Sponsors and Collaborators
Takeda
Zinfandel Pharmaceuticals
Investigators
Study Director: Medical Director Takeda
  More Information

No publications provided

Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01931566     History of Changes
Other Study ID Numbers: AD-4833/TOMM40_301, 2012-003111-58, U1111-1139-0355
Study First Received: August 26, 2013
Last Updated: May 26, 2014
Health Authority: United States: Food and Drug Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Italy: The Italian Medicines Agency
Germany: Federal Institute for Drugs and Medical Devices
Switzerland: Swiss Agency for Therapeutic Products
Russia: Pharmacological Committee, Ministry of Health
Australia: Therapeutic Goods Administration

Keywords provided by Takeda:
Drug therapy

Additional relevant MeSH terms:
Alzheimer Disease
Mild Cognitive Impairment
Cognition Disorders
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Pioglitazone
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 16, 2014