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

NCT00235716 | Completed Phase 3 Results DMC

• 1 other identifier: 546
• Study Type: interventional
• Target: 613
• Locations: 2 countries
• Sites: 14

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.

Conditions

Alzheimer's Disease

Keywords

Alzheimer's Disease; clinical trial; randomized controlled trial; alpha-tocopherol; vitamin E; Namenda; memantine

Outcome Measures

Primary Outcomes (5)

• Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline

  The primary outcome of the study was the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory. The ADCS/ADL Inventory is designed to assess functional abilities to perform activities of daily living in Alzheimer patients with a broad range of dementia severity. The total score ranges from 0 to 78 with higher scores indicating greater abilities. Outcome analysis is average least square means change from baseline.

  6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline

• Mini-Mental State Examination Change From Baseline

  The Mini-Mental State Examination (MMSE) briefly and objectively assess cognitive status in psychiatric patients with cognitive impairment. The MMSE questions are grouped into seven categories, each representing a different cognitive domain. The MMSE yields a total score that ranges from 0 for a patient who gives no correct response to a score of 30 for a patient who makes no errors. Outcome analysis is average least square means change from baseline.

  6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline

• Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline

  The Alzheimer's Disease Assessment Scale (ADAS) is a 21-item scale designed to assess the severity of cognitive and non-cognitive behavioral impairments in patients with Alzheimer's disease. The cognitive portion of the scale (ADAS-cog) consists of 11 items to assess memory, language, and praxis functions. The ADAS-cog total score ranges from 0 (no errors) to 70 (severe cognitive impairment). Outcome analysis is average least square means change from baseline.

  6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline

• Neuropsychiatric Inventory Change From Baseline

  The Neuropsychiatric Inventory (NPI) assesses psychological and behavioral problems in patients with dementia. For each of twelve domains, there are four scores: frequency, severity, total frequency x severity, and caregiver distress. The frequency x severity total scores from each domain are summed for an overall total score that ranges from 0 to 144. The total caregiver distress scores are also summed for an overall total caregiver distress score that ranges from 0 to 60. The secondary endpoint for the trial will be the overall frequency times severity total score. Outcome analysis is average least square means change from baseline.

  6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline

• Caregiver Activity Survey Change From Baseline

  The Caregiver Activity Survey (CAS) was developed to measure the time caregivers spend aiding Alzheimer patients with their day-to-day activities. The CAS consists of six items that ask for an estimate in hours and minutes of the time that the caregiver spent during the previous 24 hours performing these particular activities. The six CAS items are as follows: 1) communication with the person, 2) using transportation, 3) dressing, 4) eating, 5) looking after one's appearance, and 6) supervising the person. The more caregiving hours the worse the patient's functioning level. Outcome analysis is average least square means change from baseline.

  6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline

Secondary Outcomes (1)

• Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level)

  Every 6 months to a maximum of 4 years

Other Outcomes (1)

• All-cause Mortality

  up to 4 years

Study Arms (4)

Arm 1

EXPERIMENTAL

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

Drug: dl-alpha-tocopherol

Arm 2

EXPERIMENTAL

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

Drug: Memantine

Arm 3

EXPERIMENTAL

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

Drug: dl-alpha-tocopherol; Drug: Memantine

Arm 4

PLACEBO COMPARATOR

Matching placebos for dl-alpha-tocopherol and memantine

Drug: Placebo

Interventions

dl-alpha-tocopherol 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.

Also known as: Vitamin E

Arm 1

Memantine 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.

Also known as: Namenda (R)

Arm 2

Placebo DRUG

Matching placebos for dl-alpha-tocopherol and memantine.

Arm 4

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnoses of possible or probable Alzheimer's disease (NINCDS-ADRDA)
• 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
• Written informed consent from both the patient (or surrogate) and caregiver
• An MMSE score between 12 and 26 inclusive
• 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
• 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)

You may not qualify if:

• A non-Alzheimer primary dementia (e.g., vascular dementia, Lewy body dementia, fronto-temporal dementia, vitamin B-12 deficiency, hypothyroidism)
• Current major depression, delirium, alcohol or psychoactive substance abuse or dependency, schizophrenia, or delusional disorder as defined by DSM-IV
• Presence of any uncontrolled systemic illness that would interfere with participation in the study or a life expectancy of less than one year
• Pregnant or intention to become pregnant
• Enrollment in another interventional clinical trial
• Current prescription with more than one AChE inhibitor
• Current prescription for warfarin
• Use of vitamin E supplements in the past 2 weeks
• Use of memantine in the past 4 weeks or known intolerance
• Estimated creatinine clearance less than 5ml/min (Cockcroft-Gault formula)
• Use of amantadine in the past 2 weeks

Sponsors & Collaborators

• US Department of Veterans Affairs: lead
• Forest Laboratories: collaborator
• DSM Nutritional Products, Inc.: collaborator

Study Sites (14)

VA Medical Center, Bay Pines

Bay Pines, Florida, 33708, United States

Location

VA Medical Center, Miami

Miami, Florida, 33125, United States

Location

VA Medical Center, Iowa City

Iowa City, Iowa, 52246-2208, United States

Location

VA Maryland Health Care System, Baltimore

Baltimore, Maryland, 21201, United States

Location

VA Medical Center, Jamaica Plain Campus

Boston, Massachusetts, 02130, United States

Location

VA Ann Arbor Healthcare System

Ann Arbor, Michigan, 48113, United States

Location

VA Medical Center, Minneapolis

Minneapolis, Minnesota, 55417, United States

Location

Salisbury VAMC

Salisbury, North Carolina, 28144, United States

Location

VA Medical Center, Cleveland

Cleveland, Ohio, 44106, United States

Location

Ralph H Johnson VA Medical Center, Charleston

Charleston, South Carolina, 29401-5799, United States

Location

VA North Texas Health Care System, Dallas

Dallas, Texas, 75216, United States

Location

VA Puget Sound Health Care System, Seattle

Seattle, Washington, 98108, United States

Location

Wlliam S. Middleton Memorial Veterans Hospital, Madison

Madison, Wisconsin, 53705, United States

Location

VA Medical Center, San Juan

San Juan, 00921, Puerto Rico

Location

Related Publications (2)

• 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.

  PMID: 23583234 BACKGROUND

• 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.

  PMID: 24381967 RESULT

MeSH Terms

Conditions

Alzheimer Disease

Interventions

alpha-Tocopherol; Vitamin E; Memantine

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Tocopherols; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amantadine; Adamantane; Bridged-Ring Compounds; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Results Point of Contact

• Title: Peter Guarino, PhD, Director WH-CSPCC
• Organization: Dept. of Veterans Affairs Cooperative Stduies Program

peter.guarino@va.gov

203-932-5711

Study Officials

• Maurice Dysken

  Minneapolis Veterans Affairs Medical Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 6, 2005
• First Posted: October 10, 2005
• Study Start: August 1, 2007
• Primary Completion: September 1, 2012
• Study Completion: October 1, 2012
• Last Updated: July 23, 2014
• Results First Posted: January 29, 2014

Record last verified: 2014-07

Locations

PR (1); US (13)