A Randomized, Clinical Trial of Vitamin E and Memantine in Alzheimer's Disease

NCT ID: NCT00235716

Last Updated: 2014-07-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 613 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-08-31
• Study Completion Date: 2012-10-31

Brief Summary

The purpose of this study is to determine whether alpha-tocopherol, memantine (Namenda), or the combination will significantly delay clinical progression in mild to moderately demented patients with Alzheimer's disease compared to placebo.

Detailed Description

Abstract: Alzheimer's disease (AD), a neurodegenerative disorder resulting in cognitive loss, behavioral problems, and functional decline, is characterized by well-established and well-known neuropathological changes in the brain. Cognitive deficits and behavioral symptoms are thought to be due to cholinergic neuronal degeneration and loss associated with oxidative stress and inflammatory responses.

Current therapeutic strategies include efforts to

1. enhance cholinergic neuronal function,

2. promote neuroprotective effects, and

3. block pathologic activity of excessive glutamate with a moderate-affinity NMDA antagonist.

A combination of pharmacological therapies directed at simultaneously improving neuronal function and neuroprotection would presumably be more effective than either treatment alone.

To test this hypothesis, this study will examine the efficacy of drug treatment with a combination of

1. any of three FDA approved cholinesterase inhibitors that facilitates central acetylcholine neurotransmission (donepezil, rivastigmine, galantamine);

2. alpha-tocopherol, a fat soluble vitamin that has been shown to slow the rate of progression of AD, presumably through neuroprotective mechanism that reduces oxidative stress; and

3. memantine, a moderate-affinity NMDA antagonist that blocks excessive stimulation of NMDA receptors by glutamate. CSP#546 will be a double-blind, placebo-controlled, randomized, clinical trial to assess the efficacy of adding alpha-tocopherol, memantine, and the combination for the treatment of functional decline in mild-to-moderately demented patients with Alzheimer's disease (MMSE 12-26) who are currently taking an acetylcholinesterase inhibitor (AchEI).

Eligible Veterans will be randomly assigned to either

1. 2,000 IU/d of alpha-tocopherol plus memantine placebo,

2. 20 mg/d of memantine (Namenda) plus alpha-tocopherol placebo,

3. 2,000 IU/d of alpha-tocopherol plus 20 mg/d of memantine, or

4. alpha-tocopherol placebo plus memantine placebo.

The primary outcome for the study will be progression of AD as measured by the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) inventory. The ADCS/ADL inventory is an established outcome measure that was designed to assess functional capacity over a broad range of dementia severity and to be sensitive in measuring dementia progression. Secondary outcome measures will include the following five instruments: Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) (cognition), MMSE (cognition), The Dependence Scale (function), Neuropsychiatric Inventory (NPI) (behavior), and Caregiver Activity Survey (CAS) (caregiver time). Outcomes and safety assessments will be obtained at baseline and every six months. The target sample size for the trial will be 620 patients (210 per treatment arm). This sample size will provide 90% power to detect a 4-point mean treatment difference in the ADCS/ADL inventory by the end of the average follow-up period, adjusted for losses. The effects to be detected are modest and translate into a 17.7% reduction in the annual rate of decline with each therapy given alone, and if the effects are additive, an approximate 35% reduction for combined therapy. These effects are equivalent to slowing the rate of progression of the disease by nearly 6 months for monotherapy and 12 months for combined therapy. To achieve the target sample size, Veterans will be recruited over a 3-year period with an estimated minimum follow-up of 1 year and a maximum of 4 years. A total of 10 to 15 VA sites will be established to enroll an average of one Veteran every 2 weeks. CSP#546 is designed to assess both a clinically and economically important treatment effect. If the study definitely determined that alpha-tocopherol, memantine, or the combination delays the progression of AD, the study would be tremendously valuable in reducing the financial and emotional costs of the disease in the VA and U.S. as a whole.

Conditions

Alzheimer's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Arm 1

2,000 IU per day of dl-alpha-tocopherol plus placebo for memantine

Group Type: EXPERIMENTAL

dl-alpha-tocopherol

Intervention Type: DRUG

Alpha-tocopherol will be given as an oral dose of 1000 IU twice a day (morning and evening). The form of vitamin E that will be used in this study will be hard gel capsules of dl-alpha-tocopheryl acetate ("synthetic") vitamin E.

Arm 2

20 mg per day of memantine plus placebo for dl-alpha-tocopherol

Group Type: EXPERIMENTAL

Memantine

Intervention Type: DRUG

A moderate-affinity NMDA antagonist. Memantine will be titrated over four weeks to a maintenance dose of 10 mg twice a day. During week 1 patients will take one 5-mg memantine tablet in the morning. During week 2 patients will take one 5-mg memantine tablet in the morning and one in the evening. During week 3 patients will take two 5-mg memantine tablets in the morning and one 5-mg tablet in the evening. Beginning with week 4, participants will take four 5-mg tablets daily, two in the morning and two in the evening.

Arm 3

Combination of 2,000 IU per day of dl-alpha-tocopherol and 20 mg per day of memantine

Group Type: EXPERIMENTAL

dl-alpha-tocopherol

Intervention Type: DRUG

Alpha-tocopherol will be given as an oral dose of 1000 IU twice a day (morning and evening). The form of vitamin E that will be used in this study will be hard gel capsules of dl-alpha-tocopheryl acetate ("synthetic") vitamin E.

Memantine

Intervention Type: DRUG

A moderate-affinity NMDA antagonist. Memantine will be titrated over four weeks to a maintenance dose of 10 mg twice a day. During week 1 patients will take one 5-mg memantine tablet in the morning. During week 2 patients will take one 5-mg memantine tablet in the morning and one in the evening. During week 3 patients will take two 5-mg memantine tablets in the morning and one 5-mg tablet in the evening. Beginning with week 4, participants will take four 5-mg tablets daily, two in the morning and two in the evening.

Arm 4

Matching placebos for dl-alpha-tocopherol and memantine

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Matching placebos for dl-alpha-tocopherol and memantine.

Interventions

dl-alpha-tocopherol

Alpha-tocopherol will be given as an oral dose of 1000 IU twice a day (morning and evening). The form of vitamin E that will be used in this study will be hard gel capsules of dl-alpha-tocopheryl acetate ("synthetic") vitamin E.

Intervention Type: DRUG

Memantine

A moderate-affinity NMDA antagonist. Memantine will be titrated over four weeks to a maintenance dose of 10 mg twice a day. During week 1 patients will take one 5-mg memantine tablet in the morning. During week 2 patients will take one 5-mg memantine tablet in the morning and one in the evening. During week 3 patients will take two 5-mg memantine tablets in the morning and one 5-mg tablet in the evening. Beginning with week 4, participants will take four 5-mg tablets daily, two in the morning and two in the evening.

Intervention Type: DRUG

dl-alpha-tocopherol

Alpha-tocopherol will be given as an oral dose of 1000 IU twice a day (morning and evening). The form of vitamin E that will be used in this study will be hard gel capsules of dl-alpha-tocopheryl acetate ("synthetic") vitamin E.

Intervention Type: DRUG

Memantine

A moderate-affinity NMDA antagonist. Memantine will be titrated over four weeks to a maintenance dose of 10 mg twice a day. During week 1 patients will take one 5-mg memantine tablet in the morning. During week 2 patients will take one 5-mg memantine tablet in the morning and one in the evening. During week 3 patients will take two 5-mg memantine tablets in the morning and one 5-mg tablet in the evening. Beginning with week 4, participants will take four 5-mg tablets daily, two in the morning and two in the evening.

Intervention Type: DRUG

Placebo

Matching placebos for dl-alpha-tocopherol and memantine.

Intervention Type: DRUG

Other Intervention Names

Vitamin E; Namenda (R); Vitamin E; Namenda (R)

Eligibility Criteria

Inclusion Criteria

1. Diagnoses of possible or probable Alzheimer's disease (NINCDS-ADRDA)

2. Presence of a caregiver (friend or relative) who can assume responsibility for medication compliance, can accompany the patient to all visits, and rate patient's condition

3. Written informed consent from both the patient (or surrogate) and caregiver

4. An MMSE score between 12 and 26 inclusive

5. Administration of a maintenance dosage of donepezil (5-10mg/d), rivastigmine (6-12mg/d) or rivastigmine (Exelon) patch (4.6 mg or 9.5 mg), galantamine or galantamine ER (16-24mg/d) for a minimum of 4 weeks prior to randomization

6. Agreement not to take vitamin E supplements and/or memantine outside of the study (daily multivitamin is permitted containing up to 100 IU alpha-tocopherol)

Exclusion Criteria

1. A non-Alzheimer primary dementia (e.g., vascular dementia, Lewy body dementia, fronto-temporal dementia, vitamin B-12 deficiency, hypothyroidism)

2. Current major depression, delirium, alcohol or psychoactive substance abuse or dependency, schizophrenia, or delusional disorder as defined by DSM-IV

3. Presence of any uncontrolled systemic illness that would interfere with participation in the study or a life expectancy of less than one year

4. Pregnant or intention to become pregnant

5. Enrollment in another interventional clinical trial

6. Current prescription with more than one AChE inhibitor

7. Current prescription for warfarin

8. Use of vitamin E supplements in the past 2 weeks

9. Use of memantine in the past 4 weeks or known intolerance

10. Estimated creatinine clearance less than 5ml/min (Cockcroft-Gault formula)

11. Use of amantadine in the past 2 weeks

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Forest Laboratories

INDUSTRY

Sponsor Role: collaborator

DSM Nutritional Products, Inc.

INDUSTRY

Sponsor Role: collaborator

US Department of Veterans Affairs

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Maurice Dysken

Role: STUDY_CHAIR

Minneapolis Veterans Affairs Medical Center

Locations

VA Medical Center, Bay Pines

Bay Pines, Florida, United States

VA Medical Center, Miami

Miami, Florida, United States

VA Medical Center, Iowa City

Iowa City, Iowa, United States

VA Maryland Health Care System, Baltimore

Baltimore, Maryland, United States

VA Medical Center, Jamaica Plain Campus

Boston, Massachusetts, United States

VA Ann Arbor Healthcare System

Ann Arbor, Michigan, United States

VA Medical Center, Minneapolis

Minneapolis, Minnesota, United States

Salisbury VAMC

Salisbury, North Carolina, United States

VA Medical Center, Cleveland

Cleveland, Ohio, United States

Ralph H Johnson VA Medical Center, Charleston

Charleston, South Carolina, United States

VA North Texas Health Care System, Dallas

Dallas, Texas, United States

VA Puget Sound Health Care System, Seattle

Seattle, Washington, United States

Wlliam S. Middleton Memorial Veterans Hospital, Madison

Madison, Wisconsin, United States

VA Medical Center, San Juan

San Juan, , Puerto Rico

Countries

United States; Puerto Rico

References

Dysken MW, Guarino PD, Vertrees JE, Asthana S, Sano M, Llorente M, Pallaki M, Love S, Schellenberg GD, McCarten JR, Malphurs J, Prieto S, Chen P, Loreck DJ, Carney S, Trapp G, Bakshi RS, Mintzer JE, Heidebrink JL, Vidal-Cardona A, Arroyo LM, Cruz AR, Kowall NW, Chopra MP, Craft S, Thielke S, Turvey CL, Woodman C, Monnell KA, Gordon K, Tomaska J, Vatassery G. Vitamin E and memantine in Alzheimer's disease: clinical trial methods and baseline data. Alzheimers Dement. 2014 Jan;10(1):36-44. doi: 10.1016/j.jalz.2013.01.014. Epub 2013 Apr 11.

Reference Type: BACKGROUND

PMID: 23583234 (View on PubMed)

Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, Love S, Schellenberg GD, McCarten JR, Malphurs J, Prieto S, Chen P, Loreck DJ, Trapp G, Bakshi RS, Mintzer JE, Heidebrink JL, Vidal-Cardona A, Arroyo LM, Cruz AR, Zachariah S, Kowall NW, Chopra MP, Craft S, Thielke S, Turvey CL, Woodman C, Monnell KA, Gordon K, Tomaska J, Segal Y, Peduzzi PN, Guarino PD. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014 Jan 1;311(1):33-44. doi: 10.1001/jama.2013.282834.

Reference Type: RESULT

PMID: 24381967 (View on PubMed)

Other Identifiers

546

Identifier Type: -

Identifier Source: org_study_id