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
Condition: Mild Cognitive Impairment Due to Alzheimer's Disease
MeSH terms: Alzheimer Disease; Cognitive Dysfunction
Intervention: Pioglitazone; Pioglitazone placebo
Intervention description: Pioglitazone SR tablets; Pioglitazone placebo-matching tablets
Intervention MeSH terms: Pioglitazone
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 3494.0
Sex: All
Minimum age: 65 Years
Maximum age: 83 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Drug therapy

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.
    

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.