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CompletedPhase 2Results posted

Effect of Insulin Sensitizer Metformin on AD Biomarkers

A Phase II Trial to Study the Effect of Metformin on AD Biomarkers: A Randomized Placebo Controlled Crossover Pilot Study of Metformin Effects on Cognitive, Physiological and Biochemical Biomarkers of MCI and Dementia Due to AD

Lead sponsor

University of Pennsylvania

Asset

Metformin

Listed sites

Recruiting sites

Enrollment

actual

Study population

Alzheimer’s disease, Vascular cognitive impairment / dementia

Key I/E criteria

•Amyloid biomarker required (PET/CSF)•MMSE ≥21

Primary endpoint

•ADAS-Cog

Footprint

Where this trial recruits

Site locations as reported to ClinicalTrials.gov. Site count is not enrollment count; per-site enrollment is not available from source.

Identifiers

Registered as

NCT IDNCT01965756

Org study IDUPenn-AHAF_A2012116

Timeline

Milestones

Study start2013-01 (month precision)

Study first posted2013-10-18estimated

Primary completion2015-12-22actual

Study completion2017-04actual (month precision)

Last update posted2017-09-21actual

Results first posted2017-09-21actual

Assets

Drug assets

Metformin

Study populations

Who this study enrolls

Alzheimer’s diseaseVascular cognitive impairment / dementia

Eligibility

Who can enroll

Minimum age55 Years

Maximum age80 Years

SexAll

Healthy volunteersNot accepted

Inclusion criteria

•• Ages 55-80.

-2 Sex distribution: male and female

-Diagnosis of MCI due to AD127 or early dementia due to AD128 with:

a)age 55 - 80,

b)complaint of cognitive decline,

c)abnormal performance on the Logical Memory subtest of the Wechsler Memory Scale,

d)MMSE > 21,

e)CDR 0.5-1,

f)positive topographic (MRI, FDG-PET) or molecular (CSF, amyloid imaging) biomarker consistent with AD, and

g)no history of diabetes or other exclusions.

-Fluent in English or Spanish

-Education >5, literate, and/or good working history that precludes consideration of mental retardation

-Visual and auditory acuity sufficient for neuropsychological testing and auditory evoked potential EEG

-Geriatric Depression Scale < 6

-Modified Hachinski Ischemic Score < 4

-No major health issues or diseases expected to interfere with the study

-Willing to complete all baseline assessments and study procedures

-Stable on all permitted medications for 8 weeks

-Not pregnant, lactating or of child-bearing potential (women must be >2 years post-menopausal or surgically sterile)

-No history of diabetes

-Fasting blood glucose <126 and/or HgbA1c < 6.4

-Study partner with frequent contact with patient willing to accompany patient to visits and complete partner study forms

-No contraindication to metformin

Exclusion criteria

•• Any CNS disease other than suspected incipient AD, such as clinical stroke, brain tumor, normal pressure hydrocephalus, brain tumor, multiple sclerosis, significant head trauma with persistent neurological of cognitive deficits or complaints, Parkinson's disease, frontotemporal dementia, or other neurodegenerative diseases

-Screening/baseline MRI scans with evidence of infarction or other focal lesions in critical memory structures that may be related to cognitive dysfunction

-Major active psychiatric illness (e.g., depression, bipolar disorder, obsessive compulsive disorder, schizophrenia) within the previous year

-History of alcohol or other substance abuse or dependence within the past two years

-Pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body or claustrophobia that would preclude MRI scanning

-History of past or current diabetes, pancreatic or liver disease, renal disease

-Any significant systemic illness or unstable medical condition that could affect compliance with study

-Laboratory abnormalities in B12, TFTs, RPR, Lyme or other common lab parameters that might contribute to cognition or participation in study

-Coagulopathy or anti-coagulant therapy (such as coumadin) increasing the risk for LP resulting in PT/PTT and INR within 1.5 standard deviations over the upper normal limit.

-Compromised renal function at screening as determined by creatinine clearance <30mL/min based on Cockcroft-Gault calculation

-Liver dysfunction at screening as evidenced by alanine transaminase (ALT/SGPT) values > 2X upper limit of normal or aspartate transaminase (AST/SGOT) values > 3X or total bilirubin > 2X.

-Has received acetylcholinesterase inhibitor and/or memantine and/or any other medicine that affects the central nervous system for less than 4 months or has less than 2 months stable therapy on these treatments by baseline visit.

-Current use of specified medications with psychoactive properties that deleteriously affect cognition (e.g., certain antidepressants, anticholinergics, anti-histamines, antipsychotics, sedative hypnotics, anxiolytics)

-Use of investigational agents one month prior to entry and for the duration of the trial

-Exceptions to these guidelines may be considered on a case-by-case basis at the discretion of the protocol director.

Endpoints (10)

What's being measured

Protocol endpoints and posted registry outcome measures, grouped into outcome categories. Composite endpoints show their component event types. Standard codes (LOINC, SNOMED CT) are shown where available.

Coverage by outcome category

Tau biomarkers

Global cognition

Amyloid biomarkers

Other (unclassified)

Global cognition

2 endpoints

Primary/protocol endpoint

Word List Memory Total - ADAS-cog

Time frame:16 weeks (total) - measured at baseline, week 8 (crossover), and week 16

ADAS-Cog

descriptive

Primary/registry result

Word List Memory Total - ADAS-cog

Time frame:16 weeks (total) - measured at baseline, week 8 (crossover), and week 16

ADAS-Cog

descriptive

Posted result

Group	Value (mean), Words recalled	Standard deviation
Metformin, Then PlaceboBaselinen=10 Participants	14.35	3.96
Week 8n=10 Participants	15.1	4.48
Week 16n=10 Participants	14.71	5.29
Placebo, Then MetforminBaselinen=10 Participants	14.7	3.33
Week 8n=10 Participants	14.67	3.74
Week 16n=10 Participants	15.5	5.72

Amyloid biomarkers

2 endpoints

Other/protocol endpoint

Cerebrospinal Fluid Amyloid Beta Concentration

Time frame:baseline and 8 weeks

concentration, descriptive

Other_pre_specified/registry result

Cerebrospinal Fluid Amyloid Beta Concentration

Time frame:baseline and 8 weeks

concentration, descriptive

Posted result

Group	Value (mean), pg/mL	Standard deviation
Metformin, Then PlaceboBaselinen=10 Participants	254.90	90.38
Week 8n=10 Participants	266.73	26.70
Placebo, Then MetforminBaselinen=10 Participants	409.01	145.46
Week 8n=10 Participants	424.45	117.39

Tau biomarkers

4 endpoints

Other/protocol endpoint

Cerebrospinal Fluid Total Tau Concentration

Time frame:baseline and 8 weeks

concentration, descriptive

Other/protocol endpoint

Cerebrospinal Fluid Phosphorylated Tau Concentration

Time frame:baseline and 8 weeks

concentration, descriptive

Other_pre_specified/registry result

Cerebrospinal Fluid Total Tau Concentration

Time frame:baseline and 8 weeks

concentration, descriptive

Posted result

Group	Value (mean), pg/mL	Standard deviation
Metformin, Then PlaceboBaselinen=10 Participants	554.05	217.29
Week 8n=10 Participants	588.53	180.02
Placebo, Then MetforminBaselinen=10 Participants	556.14	361.57
Week 8n=10 Participants	554.47	356.44

Other_pre_specified/registry result

Cerebrospinal Fluid Phosphorylated Tau Concentration

Time frame:baseline and 8 weeks

concentration, descriptive

Posted result

Group	Value (mean), pg/mL	Standard deviation
Metformin, Then PlaceboBaselinen=10 Participants	63.44	26.95
Week 8n=10 Participants	68.12	15.56
Placebo, Then MetforminBaselinen=10 Participants	64.62	23.94
Week 8n=10 Participants	64.10	26.17

Other (unclassified)

2 endpoints

Secondary/protocol endpoint/low confidence

Trails-B

Time frame:16 weeks- measured at baseline, week 8 (crossover), and week 16

descriptive

Secondary/registry result/low confidence

Trails-B

Time frame:16 weeks- measured at baseline, week 8 (crossover), and week 16

descriptive

Posted result

Group	Value (mean), Seconds	Standard deviation
Metformin, Then PlaceboBaselinen=10 Participants	164.28	101.22
Week 8n=10 Participants	164	95.72
Week 16n=10 Participants	170.5	99.99
Placebo, Then MetforminBaselinen=10 Participants	186.7	83.42
Week 8n=10 Participants	170.86	88.2
Week 16n=10 Participants	161.8	91.3

Publications (1)

Bibliography

Records linked to this trial through ClinicalTrials.gov references, PubMed NCT search, and curated study seeds. 'Canonical' marks design/result papers; others are registry references or candidates.

Registry references + supporting bibliography

Weinberg MS, He Y, Kivisakk P, Arnold SE, Das S. Effect of Metformin on Plasma and Cerebrospinal Fluid Biomarkers in Non-Diabetic Older Adults with Mild Cognitive Impairment Related to Alzheimer's Disease. J Alzheimers Dis. 2024;99(s2):S355-S365. doi: 10.3233/JAD-230899.
PMID38160357via DERIVED

Provenance

Sources

Trial identity, design, statusClinicalTrials.gov API v2

Snapshot dateJuly 21, 2026

Endpoint classificationDelfa ADRD endpoint taxonomy

Results tableClinicalTrials.gov results section

Trial facts come from public ClinicalTrials.gov records. Endpoint categories are Delfa's classification of those records, not a ClinicalTrials.gov field. All figures reflect the July 21, 2026 snapshot.