Trial Outcomes & Findings for AD-4833/TOMM40_303 Extension Study of the Safety and Efficacy of Pioglitazone to Slow Cognitive Decline in Participants With Mild Cognitive Impairment Due to Alzheimer Disease (NCT NCT02284906)

Last Updated: 2019-07-02

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

40 participants

Primary outcome timeframe

Baseline and Month 24

Results posted on

2019-07-02

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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).	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).	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).
Overall Study STARTED	3	18	19
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	3	18	19

Reasons for withdrawal

Reasons for withdrawal
Measure	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).	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).	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).
Overall Study Pretreatment Event/Adverse Event	0	1	0
Overall Study Major Protocol Deviation	0	1	0
Overall Study Voluntary Withdrawal	2	4	5
Overall Study Study Termination	0	11	14
Overall Study Reason not Specified	1	1	0

Baseline Characteristics

Analysis was performed only on participants who were able to speak second language.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Low Risk Placebo n=3 Participants 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).	High Risk Placebo n=18 Participants 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).	High Risk Pioglitazone n=19 Participants 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).	Total n=40 Participants Total of all reporting groups
Race/Ethnicity, Customized Black or African American	0 Participants n=3 Participants	0 Participants n=18 Participants	1 Participants n=19 Participants	1 Participants n=40 Participants
Race/Ethnicity, Customized White	3 Participants n=3 Participants	18 Participants n=18 Participants	18 Participants n=19 Participants	39 Participants n=40 Participants
Race/Ethnicity, Customized Non-Hispanic/Latino Caucasian	2 Participants n=3 Participants	17 Participants n=18 Participants	17 Participants n=19 Participants	36 Participants n=40 Participants
Race/Ethnicity, Customized Hispanic/Latino and/or non-Caucasian	1 Participants n=3 Participants	1 Participants n=18 Participants	2 Participants n=19 Participants	4 Participants n=40 Participants
Region of Enrollment United States	2 Participants n=3 Participants	11 Participants n=18 Participants	15 Participants n=19 Participants	28 Participants n=40 Participants
Age, Continuous	74.7 years STANDARD_DEVIATION 4.73 • n=3 Participants	78.9 years STANDARD_DEVIATION 3.98 • n=18 Participants	78.1 years STANDARD_DEVIATION 4.42 • n=19 Participants	78.2 years STANDARD_DEVIATION 4.27 • n=40 Participants
Sex: Female, Male Female	1 Participants n=3 Participants	5 Participants n=18 Participants	10 Participants n=19 Participants	16 Participants n=40 Participants
Sex: Female, Male Male	2 Participants n=3 Participants	13 Participants n=18 Participants	9 Participants n=19 Participants	24 Participants n=40 Participants
Race/Ethnicity, Customized Hispanic or Latino	1 Participants n=3 Participants	1 Participants n=18 Participants	1 Participants n=19 Participants	3 Participants n=40 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	2 Participants n=3 Participants	17 Participants n=18 Participants	18 Participants n=19 Participants	37 Participants n=40 Participants
Region of Enrollment United Kingdom	1 Participants n=3 Participants	2 Participants n=18 Participants	2 Participants n=19 Participants	5 Participants n=40 Participants
Region of Enrollment Australia	0 Participants n=3 Participants	5 Participants n=18 Participants	2 Participants n=19 Participants	7 Participants n=40 Participants
Height	169.7 cm STANDARD_DEVIATION 4.16 • n=3 Participants	168.7 cm STANDARD_DEVIATION 10.85 • n=18 Participants	166.8 cm STANDARD_DEVIATION 11.73 • n=19 Participants	167.9 cm STANDARD_DEVIATION 10.81 • n=40 Participants
Weight	78.20 kg STANDARD_DEVIATION 6.053 • n=3 Participants	76.00 kg STANDARD_DEVIATION 13.719 • n=18 Participants	72.11 kg STANDARD_DEVIATION 15.685 • n=19 Participants	74.32 kg STANDARD_DEVIATION 14.224 • n=40 Participants
Body Mass Index (BMI)	27.27 kg/m^2 STANDARD_DEVIATION 3.412 • n=3 Participants	26.49 kg/m^2 STANDARD_DEVIATION 2.769 • n=18 Participants	25.68 kg/m^2 STANDARD_DEVIATION 3.653 • n=19 Participants	26.16 kg/m^2 STANDARD_DEVIATION 3.218 • n=40 Participants
Smoking Classification Participant Has Never Smoked	2 Participants n=3 Participants	7 Participants n=18 Participants	9 Participants n=19 Participants	18 Participants n=40 Participants
Smoking Classification Participant is an Ex-smoker	1 Participants n=3 Participants	11 Participants n=18 Participants	10 Participants n=19 Participants	22 Participants n=40 Participants
Alcohol Classification Participant Has Never Drunk	1 Participants n=3 Participants	3 Participants n=18 Participants	3 Participants n=19 Participants	7 Participants n=40 Participants
Alcohol Classification Participant is a Current Drinker	2 Participants n=3 Participants	15 Participants n=18 Participants	15 Participants n=19 Participants	32 Participants n=40 Participants
Alcohol Classification Participant is an Ex-drinker	0 Participants n=3 Participants	0 Participants n=18 Participants	1 Participants n=19 Participants	1 Participants n=40 Participants
Years of Education	15.0 years STANDARD_DEVIATION 3.61 • n=3 Participants	14.8 years STANDARD_DEVIATION 3.59 • n=18 Participants	14.9 years STANDARD_DEVIATION 3.67 • n=19 Participants	14.9 years STANDARD_DEVIATION 3.54 • n=40 Participants
Years Lived in Country/Region for 10 Years or More	3 Participants n=3 Participants	18 Participants n=18 Participants	19 Participants n=19 Participants	40 Participants n=40 Participants
Primary Language English	2 Participants n=3 Participants	16 Participants n=18 Participants	19 Participants n=19 Participants	37 Participants n=40 Participants
Primary Language Other	1 Participants n=3 Participants	2 Participants n=18 Participants	0 Participants n=19 Participants	3 Participants n=40 Participants
Ability to Communicate in Primary Language Not At All	0 Participants n=3 Participants	1 Participants n=18 Participants	0 Participants n=19 Participants	1 Participants n=40 Participants
Ability to Communicate in Primary Language Very Well	3 Participants n=3 Participants	17 Participants n=18 Participants	19 Participants n=19 Participants	39 Participants n=40 Participants
If Participant Speaks Second Language, Ability to Very Well Communicate in Second Language	0 Participants Analysis was performed only on participants who were able to speak second language.	1 Participants n=18 Participants • Analysis was performed only on participants who were able to speak second language.	0 Participants Analysis was performed only on participants who were able to speak second language.	1 Participants n=18 Participants • Analysis was performed only on participants who were able to speak second language.
Does Participant Speak More Than Two Languages Yes	0 Participants n=3 Participants	1 Participants n=18 Participants	0 Participants n=19 Participants	1 Participants n=40 Participants
Does Participant Speak More Than Two Languages No	3 Participants n=3 Participants	17 Participants n=18 Participants	19 Participants n=19 Participants	39 Participants n=40 Participants
Diabetic Status Diabetic	0 Participants n=3 Participants	3 Participants n=18 Participants	3 Participants n=19 Participants	6 Participants n=40 Participants
Diabetic Status Non-Diabetic	3 Participants n=3 Participants	15 Participants n=18 Participants	16 Participants n=19 Participants	34 Participants n=40 Participants
Baseline Statin Use Yes	1 Participants n=3 Participants	9 Participants n=18 Participants	8 Participants n=19 Participants	18 Participants n=40 Participants
Baseline Statin Use No	2 Participants n=3 Participants	9 Participants n=18 Participants	11 Participants n=19 Participants	22 Participants n=40 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

Adverse Events

Low Risk Placebo

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

High Risk Placebo

Serious events: 4 serious events

Other events: 10 other events

Deaths: 0 deaths

High Risk Pioglitazone

Serious events: 3 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Low Risk Placebo n=3 participants at risk 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).	High Risk Placebo n=18 participants at risk 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).	High Risk Pioglitazone n=19 participants at risk 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).
Cardiac disorders Cardiac failure congestive	0.00% 0/3 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.6% 1/18 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Myocardial infarction	0.00% 0/3 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.6% 1/18 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Eye disorders Retinal artery occlusion	0.00% 0/3 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/18 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Non-cardiac chest pain	0.00% 0/3 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.6% 1/18 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/3 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/18 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/3 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/18 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Laceration	0.00% 0/3 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.6% 1/18 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/3 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.6% 1/18 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer metastatic	0.00% 0/3 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.6% 1/18 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/19 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.00% 0/3 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/18 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 1/19 • Up to 30 days after receiving the last dose of study drug (approximately up to 1113 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Other adverse events

Additional Information

Medical Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Publication restrictions are in place

Restriction type: OTHER