Effect of Insulin Sensitizer Metformin on AD Biomarkers

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT01965756
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 51
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory and other cognitive functions. It is the most common cause of dementia in older adults, affecting approximately 18 million people worldwide, including almost 500,000 in the Philadelphia tri-state area. After age 65, the incidence of AD rises exponentially, doubling every five years. By age 85, almost half of us will have AD. In 2030, as many as 7.7 million Americans could have AD, and by 2050 this number could rise to 11-16 million people. The annual cost of AD in the United States is about $200 billion. AD-related medical complications are among the most common causes of death in the elderly population. Despite these alarming statistics, a "cure" for AD may not be essential since delaying the onset of AD by just 5 years could have a profound impact on this disorder by reducing the incidence and cost of AD by 50% between now and 2050.

AD is difficult to recognize in its earliest stages, in which the principal complaint is typically an increase in episodes of forgetfulness. This stage is now commonly referred to as mild cognitive impairment (MCI). Neuroimaging and CSF biomarkers have demonstrated good accuracy in predicting which MCI patients later "convert" to AD and which tend to remain stable or revert to more normal cognition. The diagnosis of AD itself is made when increased loss of memory and other cognitive abilities (eg, language, praxis, and executive function) affect daily functioning. As the symptoms of dementia inevitably worsen, patients may become incapable of even basic activities such as feeding and dressing themselves. The disease course often spans more than a decade, creating a vast social and financial burden on society and extracting an immeasurable emotional toll on family members.

Clinical and preclinical evidence is accumulating that brain insulin resistance may play a role in the pathogenesis and/or progression of Alzheimer's disease and that ameliorating insulin action in the brain may benefit cognition symptomatically and modify disease pathology.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease; Vascular Dementia; Dementia; Memory Impairment	Drug: Metformin; Drug: Placebos	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: This pilot study used a randomized, double-blinded, placebo-controlled 16 week crossover design to examine the effects of metformin on biochemical, neurophysiological, and cognitive biomarkers of AD.This pilot study used a randomized, double-blinded, placebo-controlled 16 week crossover design to examine the effects of metformin on biochemical, neurophysiological, and cognitive biomarkers of AD.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: Dec 22, 2015
• Actual Study Completion Date: Apr 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin, Then Placebo Participants first received metformin for 8 weeks, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached. After 8 weeks, subjects were switched to matching placebo for an additional 8 weeks.	Drug: Metformin; Drug: Placebos
Experimental: Placebo, Then Metformin Participants first received placebo for 8 weeks. After 8 weeks, subjects were switched to metformin, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached.	Drug: Metformin; Drug: Placebos

Outcome Measures

Primary Outcome Measures

1. Word List Memory Total - ADAS-cog [16 weeks (total) - measured at baseline, week 8 (crossover), and week 16]

   Alzheimer's Disease Assessment Scale- Cognitive Sub scale (ADAS-COG). Three trials of 10 words each (30 words total)

Secondary Outcome Measures

1. Trails-B [16 weeks- measured at baseline, week 8 (crossover), and week 16]

   Standard Trails-B assessment, in which subject is asked to begin at Number 1 and draw a line to Letter A, then to Number 2, then to Letter B, then so forth until he/she reaches the END, without lifting their pencil. They should draw the line as fast as possible, and are timed (in seconds).

Other Outcome Measures

1. Cerebrospinal Fluid Amyloid Beta Concentration [baseline and 8 weeks]

2. Cerebrospinal Fluid Total Tau Concentration [baseline and 8 weeks]

3. Cerebrospinal Fluid Phosphorylated Tau Concentration [baseline and 8 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania, Penn Memory Center	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania

Investigators

• Principal Investigator: Steven E Arnold, MD, University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Penn Memory Center

Publications

None provided.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT01965756
• Other Study ID Numbers: UPenn-AHAF_A2012116
• First Posted: Oct 18, 2013
• Last Update Posted: Sep 21, 2017
• Last Verified: Aug 1, 2017

• Keywords provided by University of Pennsylvania: Alzheimer's Disease; Vascular Dementia; Dementia; Memory Impairment
• Additional relevant MeSH terms: Alzheimer Disease; Dementia; Dementia, Vascular; Metformin

Study Results

Participant Flow

Arm/Group Title	Metformin, Then Placebo (Treatment Sequence A, 0 to 16 Weeks)	Placebo, Then Metformin (Treatment Sequence B, 0 to 16 Weeks)
Arm/Group Description	Participants first received metformin for 8 weeks, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached. After 8 weeks, subjects were switched to matching placebo for an additional 8 weeks.	Participants first received placebo for 8 weeks. After 8 weeks, subjects were switched to metformin, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached.
Period Title: Overall Study
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Metformin, Then Placebo	Placebo, Then Metformin	Total
Arm/Group Description	Participants first received metformin for 8 weeks, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached. After 8 weeks, subjects were switched to matching placebo for an additional 8 weeks.	Participants first received placebo for 8 weeks. After 8 weeks, subjects were switched to metformin, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached.	Total of all reporting groups
Overall Participants	10	10	20
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	3 30%	2 20%	5 25%
>=65 years	7 70%	8 80%	15 75%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.1 (7.40)	71.1 (6.57)	70.1 (6.89)
Sex: Female, Male (Count of Participants)
Female	5 50%	4 40%	9 45%
Male	5 50%	6 60%	11 55%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 10%	0 0%	1 5%
Not Hispanic or Latino	9 90%	10 100%	19 95%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	10 100%	10 100%	20 100%
HbA1c (percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage]	5.5 (0.221)	5.37 (0.236)	5.44 (0.232)
Plasma Glucose (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	90.5 (8.77)	90.9 (14.1)	90.7 (11.4)
Clinical Dementia Rating - Global (Composite) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	0.5 (0)	0.8 (0.789)	0.658 (.579)

Outcome Measures

1. Primary Outcome

Title	Word List Memory Total - ADAS-cog
Description	Alzheimer's Disease Assessment Scale- Cognitive Sub scale (ADAS-COG). Three trials of 10 words each (30 words total)
Time Frame	16 weeks (total) - measured at baseline, week 8 (crossover), and week 16

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin, Then Placebo	Placebo, Then Metformin
Arm/Group Description	Participants first received metformin for 8 weeks, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached. After 8 weeks, subjects were switched to matching placebo for an additional 8 weeks.	Participants first received placebo for 8 weeks. After 8 weeks, subjects were switched to metformin for 8 weeks, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached.
Measure Participants	10	10
Baseline	14.35 (3.96)	14.7 (3.33)
Week 8	15.1 (4.48)	14.67 (3.74)
Week 16	14.71 (5.29)	15.5 (5.72)

2. Secondary Outcome

Title	Trails-B
Description	Standard Trails-B assessment, in which subject is asked to begin at Number 1 and draw a line to Letter A, then to Number 2, then to Letter B, then so forth until he/she reaches the END, without lifting their pencil. They should draw the line as fast as possible, and are timed (in seconds).
Time Frame	16 weeks- measured at baseline, week 8 (crossover), and week 16

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin, Then Placebo	Placebo, Then Metformin
Arm/Group Description	Participants first received metformin for 8 weeks, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached. After 8 weeks, subjects were switched to matching placebo for an additional 8 weeks. Participants first received placebo for 8 weeks. After 8 weeks, subjects were switched to metformin, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached.	Participants first received placebo for 8 weeks. After 8 weeks, subjects were switched to metformin for 8 weeks, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached.
Measure Participants	10	10
Baseline	164.28 (101.22)	186.7 (83.42)
Week 8	164 (95.72)	170.86 (88.2)
Week 16	170.5 (99.99)	161.8 (91.3)

3. Other Pre-specified Outcome

Title	Cerebrospinal Fluid Amyloid Beta Concentration
Time Frame	baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

CSF was only collected from all participants at baseline and again at week 8 (total of two lumbar punctures). This was pre-specified in the protocol, to ensure adequate tolerability for subjects (total of two lumbar punctures, rather than three). Thus, there is a maximum of 10 data points for each category: 10 for MET-->PBO, and 10 for PBO-->MET

Arm/Group Title	Metformin, Then Placebo	Placebo, Then Metformin
Arm/Group Description	Participants first received metformin for 8 weeks, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached. After 8 weeks, subjects were switched to matching placebo for an additional 8 weeks.	Participants first received placebo for 8 weeks. After 8 weeks, subjects were switched to metformin for 8 weeks, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached.
Measure Participants	10	10
Baseline	254.90 (90.38)	409.01 (145.46)
Week 8	266.73 (26.70)	424.45 (117.39)

4. Other Pre-specified Outcome

Title	Cerebrospinal Fluid Total Tau Concentration
Time Frame	baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

CSF was only collected from all participants at baseline and again at week 8 (total of two lumbar punctures). This was pre-specified in the protocol, to ensure adequate tolerability for subjects (total of two lumbar punctures, rather than three). Thus, there is a maximum of 10 data points for each category: 10 for MET-->PBO, and 10 for PBO-->MET

Arm/Group Title	Metformin, Then Placebo	Placebo, Then Metformin
Arm/Group Description	Participants first received metformin for 8 weeks, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached. After 8 weeks, subjects were switched to matching placebo for an additional 8 weeks. Metformin Placebos	Participants first received placebo for 8 weeks. After 8 weeks, subjects were switched to metformin, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached. Metformin Placebos
Measure Participants	10	10
Baseline	554.05 (217.29)	556.14 (361.57)
Week 8	588.53 (180.02)	554.47 (356.44)

5. Other Pre-specified Outcome

Title	Cerebrospinal Fluid Phosphorylated Tau Concentration
Time Frame	baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

CSF was only collected from all participants at baseline and again at week 8 (total of two lumbar punctures). This was pre-specified in the protocol, to ensure adequate tolerability for subjects (total of two lumbar punctures, rather than three). Thus, there is a maximum of 10 data points for each category: 10 for MET-->PBO, and 10 for PBO-->MET

Arm/Group Title	Metformin, Then Placebo	Placebo, Then Metformin
Arm/Group Description	Participants first received metformin for 8 weeks, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached. After 8 weeks, subjects were switched to matching placebo for an additional 8 weeks.	Participants first received placebo for 8 weeks. After 8 weeks, subjects were switched to metformin, according to the following dosing schedule: 500 mg by mouth daily for 1 week, then daily dose (in divided doses) increased by 500 mg per week until a maximum of 2000 mg/d (1000mg twice daily) was reached.
Measure Participants	10	10
Baseline	63.44 (26.95)	64.62 (23.94)
Week 8	68.12 (15.56)	64.10 (26.17)

Adverse Events

Time Frame	2 years, 5 months
Arm/Group Title	Metformin		Placebo
Arm/Group Description	This group includes subjects treated with metformin for the first 8 weeks of the study, as well as subjects treated with metformin during the second 8 weeks of the study.		This group includes subjects treated with placebo for the first 8 weeks of the study, as well as subjects treated with placebo during the second 8 weeks of the study.
All Cause Mortality
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Serious Adverse Events
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/20 (10%)		0/20 (0%)
Blood and lymphatic system disorders
Elevated plasma lactate level	2/20 (10%)	2	0/20 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.