Mild Cognitive Impairment Due to Alzheimer's Disease
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to evaluate the effect of pioglitazone at 24 months compared with placebo on cognitive decline in high-risk participants who have completed the AD-4833/TOMM40\_301 study \[NCT01931566\] with an adjudicated diagnosis of mild cognitive impairment (MCI) due to Alzheimer's Disease (AD).
Detailed description
The drug being tested in this study is called pioglitazone. This study is designed to further evaluate the safety and effectiveness of pioglitazone on cognitive function in participants who have completed the AD-4833/TOMM40\_301. This study will look at the effectiveness of pioglitazone on cognitive decline in high-risk participants who have completed the AD-4833/TOMM40\_301 study with a diagnosis of mild cognitive impairment (MCI) due to Alzheimer's Disease (AD). The study enrolled 40 participants, but is dependent on how many decide to continue treatment in an extension phase after completing the main (301) study. Participants will continue to receive the same study medication they received during the pivotal AD-4833/TOMM40\_301 study, either: * Pioglitazone 0.8 mg tablets or * Placebo (this is a tablet that looks like the study drug but has no active ingredient). All participants will be asked to take one tablet at the same time each day throughout the study. This multi-centre trial, like its precedent pivotal trial, will be conducted worldwide. The overall time to participate in this study is minimum 2 years and a maximum of 7 years depending on when participants roll over from the 301 study. Participants will make approximately 2 visits per year 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.
Interventions
DRUGPioglitazone
Pioglitazone tablets
DRUGPlacebo
Pioglitazone placebo-matching tablets
Sponsors
Takeda
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Completed the pivotal AD-4833/TOMM40\_301 study with an adjudicated diagnosis of mild cognitive impairment (MCI) due to Alzheimer's Disease (AD) without ongoing serious adverse events (SAEs) from AD-4833/TOMM40\_301. 2. Is male or female and is at least 65 years of age at the time of the Baseline Visit. 3. In the opinion of the investigator, is capable of understanding and complying with the protocol requirements. 4. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. 5. Must be living independently or in nonmedical residential care. 6. 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), providing information on the cognitive, functional, and behavioral status of the participant and assisting with observation of adverse events (AEs) and monitoring of study medication, if needed. Project partners participating in the pivotal AD-4833/TOMM40\_301 study are encouraged to participate in this extension study in this capacity.
Exclusion criteria
1. Completed the pivotal AD-4833/TOMM40\_301 study with an adjudicated diagnosis of AD dementia. 2. Has a current diagnosis of significant psychiatric illness, per Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (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% at the extension study Baseline Visit or requires treatment with insulin, triple oral antidiabetic therapy or a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist. 4. Has a clinically significant unstable illness, for example, hepatic impairment or renal insufficiency, or cardiovascular, pulmonary, gastrointestinal (including s/p gastric bypass surgery), endocrine, neurological, rheumatologic, immunologic, infectious, skin and subcutaneous tissue disorders, or metabolic disturbance. 5. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, pivotal, child, sibling) or may consent under duress. 6. Is required to take excluded medications. 7. Has a history of hypersensitivity or allergies to pioglitazone or related compounds. 8. Had any of the following values at the extension study Baseline Visit: 1. A serum total bilirubin value \>15 x upper limit of normal (ULN). 2. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value \>2 x ULN. 3. Unexplained microscopic/macroscopic hematuria on 2 repeat examinations within 2 weeks. 9. Has a disease 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. 10. Has received any investigational compound, with the exception of treatment during the AD-4833/TOMM40\_301 study, within 30 days prior to Baseline or 5 half-lives prior to Baseline or is currently participating in another study that entails the administration of an investigational or marketed drug, supplement, or intervention including, but not limited to diet, exercise, lifestyle, or invasive procedure. 11. Has any cancer that has been in remission for less than 2 years from the extension study Baseline Visit. Participants with basal cell or stage I squamous cell carcinoma of the skin will be eligible. Participants with current diagnosis of bladder cancer are not eligible irrespective of the remission status. 12. Has a current diagnosis of macular edema, degeneration or any maculopathy. 13. Has a history or current diagnosis of congestive heart failure (CHF), New York Heart Association class III-IV.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Extension Study Baseline in Composite Score of a Broad Cognitive Test Battery at Month 24 | Baseline and Month 24 | Composite scores were derived from the test battery. Each test in the battery falls into 1 of the following cognitive domains: Episodic Memory (California Verbal Learning Test - 2nd Edition \[CVLT-II\], Brief Visuospatial Memory Test - Revised \[BVMT-R\]), Executive Function (Trail Making Part B, Digit Span Backwards), Language (Animals, Lexical/Phonemic Fluency), Attention (Digit Span Forward, Trail Making Part A), and Visuospatial (Clock Drawing, BVMT-Copy). Only the domains of episodic memory, executive function, language, and attention were used for the calculation of composite score (i.e., Clock Drawing, BVMT-Copy, and the Multilingual Naming Test (MINT), which do not allow generation of standard z scores, were only used for diagnostic purposes and were excluded from the calculation of the composite score). To form the composite, z-scores were calculated for each test, each z-score for the domain were averaged, and then all relevant domains were averaged to form the composite. |
Secondary
| Measure | Time frame |
|---|---|
| Time to Diagnosis of Alzheimer's Disease (AD) Dementia | Day 1 and every 6 months (up to maximum of 36 months) |
Countries
Australia, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 3 investigative sites in Australia, United Kingdom and United States from 12 Feb 2015 to 08 May 2018.
Pre-assignment details
Participants with who have completed the pivotal AD-4833/TOMM40\_301 (NCT01931566) study with an adjudicated diagnosis of mild cognitive impairment (MCI) due to Alzheimer's Disease (AD) were enrolled to pioglitazone (0.8 mg sustained release tablet) or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Low Risk Placebo Pioglitazone placebo-matching tablets, orally, once daily, for 10 months to participants assigned to low risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40\_301). | 3 |
| High Risk Placebo Pioglitazone placebo-matching tablets, orally, once daily, for minimum of 3 years to participants assigned to high risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40\_301). | 18 |
| High Risk Pioglitazone Pioglitazone 0.8 mg tablets, orally, once daily for 3 years to participants assigned to high risk group for developing MCI- AD within the next five years in previous study (AD-4833/TOMM40\_301). | 19 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Major Protocol Deviation | 0 | 1 | 0 |
| Overall Study | Pretreatment Event/Adverse Event | 0 | 1 | 0 |
| Overall Study | Reason not Specified | 1 | 1 | 0 |
| Overall Study | Study Termination | 0 | 11 | 14 |
| Overall Study | Voluntary Withdrawal | 2 | 4 | 5 |
Baseline characteristics
| Characteristic | Total | High Risk Pioglitazone | High Risk Placebo | Low Risk Placebo |
|---|---|---|---|---|
| Ability to Communicate in Primary Language Not At All | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ability to Communicate in Primary Language Very Well | 39 Participants | 19 Participants | 17 Participants | 3 Participants |
| Age, Continuous | 78.2 years STANDARD_DEVIATION 4.27 | 78.1 years STANDARD_DEVIATION 4.42 | 78.9 years STANDARD_DEVIATION 3.98 | 74.7 years STANDARD_DEVIATION 4.73 |
| Alcohol Classification Participant Has Never Drunk | 7 Participants | 3 Participants | 3 Participants | 1 Participants |
| Alcohol Classification Participant is a Current Drinker | 32 Participants | 15 Participants | 15 Participants | 2 Participants |
| Alcohol Classification Participant is an Ex-drinker | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Baseline Statin Use No | 22 Participants | 11 Participants | 9 Participants | 2 Participants |
| Baseline Statin Use Yes | 18 Participants | 8 Participants | 9 Participants | 1 Participants |
| Body Mass Index (BMI) | 26.16 kg/m^2 STANDARD_DEVIATION 3.218 | 25.68 kg/m^2 STANDARD_DEVIATION 3.653 | 26.49 kg/m^2 STANDARD_DEVIATION 2.769 | 27.27 kg/m^2 STANDARD_DEVIATION 3.412 |
| Diabetic Status Diabetic | 6 Participants | 3 Participants | 3 Participants | 0 Participants |
| Diabetic Status Non-Diabetic | 34 Participants | 16 Participants | 15 Participants | 3 Participants |
| Does Participant Speak More Than Two Languages No | 39 Participants | 19 Participants | 17 Participants | 3 Participants |
| Does Participant Speak More Than Two Languages Yes | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Height | 167.9 cm STANDARD_DEVIATION 10.81 | 166.8 cm STANDARD_DEVIATION 11.73 | 168.7 cm STANDARD_DEVIATION 10.85 | 169.7 cm STANDARD_DEVIATION 4.16 |
| If Participant Speaks Second Language, Ability to Very Well Communicate in Second Language | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Primary Language English | 37 Participants | 19 Participants | 16 Participants | 2 Participants |
| Primary Language Other | 3 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic/Latino and/or non-Caucasian | 4 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Non-Hispanic/Latino Caucasian | 36 Participants | 17 Participants | 17 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 37 Participants | 18 Participants | 17 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 39 Participants | 18 Participants | 18 Participants | 3 Participants |
| Region of Enrollment Australia | 7 Participants | 2 Participants | 5 Participants | 0 Participants |
| Region of Enrollment United Kingdom | 5 Participants | 2 Participants | 2 Participants | 1 Participants |
| Region of Enrollment United States | 28 Participants | 15 Participants | 11 Participants | 2 Participants |
| Sex: Female, Male Female | 16 Participants | 10 Participants | 5 Participants | 1 Participants |
| Sex: Female, Male Male | 24 Participants | 9 Participants | 13 Participants | 2 Participants |
| Smoking Classification Participant Has Never Smoked | 18 Participants | 9 Participants | 7 Participants | 2 Participants |
| Smoking Classification Participant is an Ex-smoker | 22 Participants | 10 Participants | 11 Participants | 1 Participants |
| Weight | 74.32 kg STANDARD_DEVIATION 14.224 | 72.11 kg STANDARD_DEVIATION 15.685 | 76.00 kg STANDARD_DEVIATION 13.719 | 78.20 kg STANDARD_DEVIATION 6.053 |
| Years Lived in Country/Region for 10 Years or More | 40 Participants | 19 Participants | 18 Participants | 3 Participants |
| Years of Education | 14.9 years STANDARD_DEVIATION 3.54 | 14.9 years STANDARD_DEVIATION 3.67 | 14.8 years STANDARD_DEVIATION 3.59 | 15.0 years STANDARD_DEVIATION 3.61 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 18 | 0 / 19 |
| other Total, other adverse events | 1 / 3 | 10 / 18 | 12 / 19 |
| serious Total, serious adverse events | 0 / 3 | 4 / 18 | 3 / 19 |
Outcome results
Primary
Change From Extension Study Baseline in Composite Score of a Broad Cognitive Test Battery at Month 24
Composite scores were derived from the test battery. Each test in the battery falls into 1 of the following cognitive domains: Episodic Memory (California Verbal Learning Test - 2nd Edition \[CVLT-II\], Brief Visuospatial Memory Test - Revised \[BVMT-R\]), Executive Function (Trail Making Part B, Digit Span Backwards), Language (Animals, Lexical/Phonemic Fluency), Attention (Digit Span Forward, Trail Making Part A), and Visuospatial (Clock Drawing, BVMT-Copy). Only the domains of episodic memory, executive function, language, and attention were used for the calculation of composite score (i.e., Clock Drawing, BVMT-Copy, and the Multilingual Naming Test (MINT), which do not allow generation of standard z scores, were only used for diagnostic purposes and were excluded from the calculation of the composite score). To form the composite, z-scores were calculated for each test, each z-score for the domain were averaged, and then all relevant domains were averaged to form the composite.
Time frame: Baseline and Month 24
Population: As the study was early terminated, there were limited number of enrolled participants and insufficient treatment duration, therefore, data was not collected for this outcome measure.
Secondary
Time to Diagnosis of Alzheimer's Disease (AD) Dementia
Time frame: Day 1 and every 6 months (up to maximum of 36 months)
Population: As the study was early terminated, there were limited number of enrolled participants and insufficient treatment duration, therefore, data was not collected for this outcome measure.