Metformin in Amnestic Mild Cognitive Impairment (MCI)

• ClinicalTrials.gov Identifier: NCT00620191
• Recruitment Status: Completed
• First Posted: February 21, 2008
• Results First Posted: October 23, 2020
• Last Update Posted: October 23, 2020
• Sponsor: Columbia University
• Collaborators: Institute for the Study of Aging (ISOA); National Institute on Aging (NIA)
• Information provided by (Responsible Party): José A. Luchsinger, Columbia University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Mild Cognitive Impairment
• Interventions: Drug: Metformin; Drug: Placebo
• Enrollment: 80

Participant Flow

Recruitment Details	Recruitment was completed in 32 months (2.5 subjects a month) [38]; 1426 subjects were screened by telephone and 331 were screened in person.
Pre-assignment Details	1426 screened by telephone and 1095 excluded; 331 deemed eligible for in-person screen; 224 of those were excluded; 87 met eligibility criteria, 7 declined randomization, 80 were randomized

Arm/Group Title	Placebo	Metformin
Arm/Group Description	placebo identical to metformin. placebo: placebo identical to metformin 2 tablets twice a day titrated from one table once a day	metformin 1000 mg twice a day metformin: metformin 1000 mg twice a day titrated from 500 mg once a day
Period Title: Overall Study
Started	40	40
3 Month Follow-up	39	39
6 Month Follow-up	38	36
9 Month Follow-up	37	34
Completed	33 [1]	32 [1]
Not Completed	7	8
[1] 12 month follow-up

Baseline Characteristics

Arm/Group Title		Placebo	Metformin	Total
Arm/Group Description		placebo identical to metformin. placebo: placebo identical to metformin 2 tablets twice a day titrated from one table once a day. Participants remained on the maximum number of tolerated tablets (0,1,2,3,4).	metformin 1000 mg twice a day metformin: metformin 1000 mg twice a day titrated from 500 mg once a day.Participants remained on the maximum number of tolerated tablets (0,1,2,3,4).	Total of all reporting groups
Overall Number of Baseline Participants		40	40	80
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	40 participants	40 participants	80 participants
		64.1 (7.9)	65.3 (7.0)	64.5 (7.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	40 participants	80 participants
	Female	24 60.0%	18 45.0%	42 52.5%
	Male	16 40.0%	22 55.0%	38 47.5%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	40 participants	80 participants
	Hispanic or Latino	13 32.5%	17 42.5%	30 37.5%
	Not Hispanic or Latino	27 67.5%	23 57.5%	50 62.5%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	40 participants	80 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	15 37.5%	11 27.5%	26 32.5%
	White	12 30.0%	12 30.0%	24 30.0%
	More than one race	13 32.5%	17 42.5%	30 37.5%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	40 participants	40 participants	80 participants
		40	40	80
APOE Epsilon 4 [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	40 participants	40 participants	80 participants
ApoE Epsilon 4 positive		11	10	21
ApoE epsilon 4 negative		29	30	59
		[1] Measure Description: homozygous or heterozygous for APOE Epsilon 4
Body Mass Index; Mean (Standard Deviation); Unit of measure: Kg/m⌃2
	Number Analyzed	40 participants	40 participants	80 participants
		31.3 (4.7)	30.9 (4.1)	31.1 (4.4)
Hemoglobin A1c; Mean (Standard Deviation); Unit of measure: Percent HbA1c
	Number Analyzed	40 participants	40 participants	80 participants
		6.1 (0.5)	6.1 (0.8)	6.1 (0.6)
Fasting insulin; Mean (Standard Deviation); Unit of measure: IU/dl
	Number Analyzed	40 participants	40 participants	80 participants
		13.4 (7.6)	16.3 (9.5)	14.7 (8.6)
Systolic blood pressure; Mean (Standard Deviation); Unit of measure: mmHg
	Number Analyzed	40 participants	40 participants	80 participants
		132.1 (12.4)	130.8 (10.9)	131.4 (11.6)
Total Cholesterol; Mean (Standard Deviation); Unit of measure: Mg/dl
	Number Analyzed	40 participants	40 participants	80 participants
		208.2 (46.7)	204.2 (43.6)	206.2 (44.9)
High Density lipoprotein; Mean (Standard Deviation); Unit of measure: Mg/dl
	Number Analyzed	40 participants	40 participants	80 participants
		58.3 (17.7)	51.5 (14.1)	54.8 (16.2)
Score of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) [1]; Mean (Standard Deviation); Unit of measure: Score
	Number Analyzed	40 participants	40 participants	80 participants
		14.6 (6.1)	12.0 (4.0)	13.3 (5.3)
		[1] Measure Description: The ADAS-cog is an aggregate for several cognitive tests intended to provide a global cognitive score and consists of 11 tasks. The tasks (and corresponding score range)) are Word Recall (0-10), Naming (0-4), Commands (0-5), Constructional Praxis (0-5) Ideational Praxis (0-5), Orientation (0-8), Word Recognition (0-12), Language (0-5), Word Finding Difficulty (0-5), and Remembering Test Instructions (1-5). The range of aggregate scores (sum of scores) is 1 to 69, with higher scores meaning worse cognitive performance.
Selective Reminding Test Total Recall score [1]; Mean (Standard Deviation); Unit of measure: Score
	Number Analyzed	40 participants	40 participants	80 participants
		36.1 (9.5)	34.2 (7.9)	35.2 (8.7)
		[1] Measure Description: The Selective Reminding Test measures verbal learning and delayed recall through a multiple-trial list-learning paradigm. Patients are presented aurally with a list of 12 words for trial 1 and are asked to recall as many as possible. For trials 2-6, there is a selective presentation of only those words not recalled on the previous trial. Trial 7 is similar to the other trials but is assessed after an 11-minute delay. The score for the selective reminding test is the unweighted average of seven individual study results (min=0 and max=84) Higher scores indicate a better cognitive performance.
Education in Years; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	40 participants	40 participants	80 participants
		13.1 (4.5)	13.8 (3.4)	13.4 (4.0)

Outcome Measures

1. Primary Outcome

Title	Change in Total Recall Score in the Selective Reminding Test
Description	The Selective Reminding Test measures verbal learning and delayed recall through a multiple-trial list-learning paradigm. Patients are presented aurally with a list of 12 words for trial 1 and are asked to recall as many as possible. For trials 2-6, there is a selective presentation of only those words not recalled on the previous trial. Trial 7 is similar to the other trials but is assessed after an 11-minute delay. The score for the selective reminding test is the unweighted average of seven individual study results (min=0 and max=84) Higher scores indicate a better cognitive performance. The total recall score from the first visit was subtracted from that of the last visit to calculate the change in score (total words recalled).
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Metformin
Arm/Group Description:	Placebo identical to metformin. placebo: placebo identical to metformin 2 tablets twice a day titrated from one tablet once a day. Participants remained on the highest tolerated dose (0,1,2,3,4 tablets).	Metformin 1000 mg twice a day metformin: metformin 1000 mg twice a day titrated from 500 mg once a day. Participants remained on the highest tolerated dose (0,1,2,3,4 tablets of 500 mg each).
Overall Number of Participants Analyzed	40	40
Mean (Standard Deviation); Unit of Measure: score on a scale
	5.7 (8.7)	9.4 (8.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Metformin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.05
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.7
	Parameter Dispersion	Type: Standard Deviation; Value: 1.92
	Estimation Comments	The difference is the value for the metformin arm minus the value for the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Metformin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.05
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	adjusted for baseline ADAS-Cog value
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.1
	Parameter Dispersion	Type: Standard Deviation; Value: 1.36
	Estimation Comments	The difference is the value for the metformin arm minus the value for the placebo arm.

2. Primary Outcome

Title	Change in Score of the Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog)
Description	The ADAS-cog is an aggregate for several cognitive tests intended to provide a global cognitive score and consists of 11 tasks. The tasks (and corresponding score range)) are Word Recall (0-10), Naming (0-4), Commands (0-5), Constructional Praxis (0-5) Ideational Praxis (0-5), Orientation (0-8), Word Recognition (0-12), Language (0-5), Word Finding Difficulty (0-5), and Remembering Test Instructions (1-5). The range of aggregate scores (sum of scores) is 1 to 69, with higher scores meaning worse cognitive performance. The change was calculated subtracting the baseline score from the final visit score.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Analyses used an intent to treat approach with last observation carried forward

Arm/Group Title	Placebo	Metformin
Arm/Group Description:	placebo identical to metformin. placebo: placebo identical to metformin 2 tablets twice a day titrated from one table once a day. Participants were maintained on the highest tolerated dose (0,1,2,3,4 tablets).	metformin 1000 mg twice a day metformin: metformin 1000 mg twice a day titrated from 500 mg once a day.Participants were maintained on the highest tolerated dose (0,1,2,3,4 tablets of 500 mg each).
Overall Number of Participants Analyzed	40	40
Mean (Standard Deviation); Unit of Measure: score
	-1.98 (5.5)	0.0 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Metformin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.06
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.98
	Parameter Dispersion	Type: Standard Deviation; Value: 1.01
	Estimation Comments	The difference is the value for the metformin arm minus the value for the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Metformin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.34
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	adjusted for baseline ADAS-Cog score.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.9
	Parameter Dispersion	Type: Standard Deviation; Value: 0.91
	Estimation Comments	The difference is the value for the metformin arm minus the value for the placebo arm.

3. Secondary Outcome

Title	Change in Relative Glucose Uptake (rCMRg) in the Posterior Cingulate-precuneus.
Description	Change in relative glucose uptake (rCMRgl) in the posterior cingulate-precuneus measured with subscale (ADAS-Cog) from brain [18]F-labeled 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET). The unit for rCMRgl is %. The results presented are absolute differences in rCMRgl, presented in % units; the change was calculated subtracting the baseline rCMRgl from the follow-up rCMRgl
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Out of 40 persons recruited in the imaging sub study, 33 underwent a 12 month scan (18 in the placebo group, 15 in the metformin group).

Arm/Group Title	Placebo	Metformin
Arm/Group Description:	Placebo identical to metformin. placebo: placebo identical to metformin 2 tablets twice a day titrated from one table once a day. Participants remained on the highest tolerated dose (0,1,2,3,4 tablets).	Metformin 1000 mg twice a day metformin: metformin 1000 mg twice a day titrated from 500 mg once a day. Participants remained on the highest tolerated dose (0,1,2,3,4 tablets of 500 mg each).
Overall Number of Participants Analyzed	18	15
Mean (Standard Deviation); Unit of Measure: percentage of rCMRgl
	0.0 (6.0)	2.0 (6.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Metformin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.36
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.0
	Parameter Dispersion	Type: Standard Deviation; Value: 2.14
	Estimation Comments	The difference is the value for the metformin arm minus the value for the placebo arm.

4. Other Pre-specified Outcome

Title	Change in Plasma Amyloid Beta-42
Description	Change in plasma Amyloid beta-42 from baseline to 12 months
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Metformin
Arm/Group Description:	placebo identical to metformin. placebo: placebo identical to metformin 2 tablets twice a day titrated from one table once a day. Participants remained on the highest tolerated dose (0,1,2,3,4 tablets).	metformin 1000 mg twice a day metformin: metformin 1000 mg twice a day titrated from 500 mg once a day.Participants remained on the highest tolerated dose (0,1,2,3,4 tablets of 500 mg each).
Overall Number of Participants Analyzed	40	40
Mean (Standard Deviation); Unit of Measure: pg/ml
	-4.40 (23.51)	0.69 (18.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Metformin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.34
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	5.09
	Parameter Dispersion	Type: Standard Deviation; Value: 4.73
	Estimation Comments	The difference is the value for the metformin arm minus the value for the placebo arm.

Adverse Events

Time Frame	12 months
Adverse Event Reporting Description	The adverse event data were collected during the 12 months of the duration of the trial
Arm/Group Title	Placebo		Metformin
Arm/Group Description	Matching placebo placebo: matching identical to metformin 2 tablets twice a day titrated from one table once a day		metformin 1000 mg twice a day metformin: metformin 1000 mg twice a day titrated from 500 mg once a day
All-Cause Mortality
	Placebo		Metformin
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Placebo		Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0.00%)		0/40 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Placebo		Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0.00%)		3/40 (7.50%)
Gastrointestinal disorders
Gastrointestinal symptoms †	0/40 (0.00%)	0	3/40 (7.50%)	3
† Indicates events were collected by systematic assessment

Limitations and Caveats

The pilot study had a small sample size and relatively short duration, both for the whole sample, and the imaging sub-sample

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Jose Luchsinger
• Organization: Columbia University Medical Center
• Phone: 212-3054730
• EMail: jal94@cumc.columbia.edu

Publications of Results:

Luchsinger JA, Perez T, Chang H, Mehta P, Steffener J, Pradabhan G, Ichise M, Manly J, Devanand DP, Bagiella E. Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. J Alzheimers Dis. 2016;51(2):501-14. doi: 10.3233/JAD-150493.

• Responsible Party: José A. Luchsinger, Columbia University
• ClinicalTrials.gov Identifier: NCT00620191
• Other Study ID Numbers: AAAC7231; R01AG026413 ( U.S. NIH Grant/Contract ); 270901 ( Other Grant/Funding Number: Alzheimer's Disease Drug Discovery Foundation )
• First Submitted: February 7, 2008
• First Posted: February 21, 2008
• Results First Submitted: June 8, 2015
• Results First Posted: October 23, 2020
• Last Update Posted: October 23, 2020