Original Investigation |

Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease:  The TEAM-AD VA Cooperative Randomized Trial

Maurice W. Dysken, MD1; Mary Sano, PhD2; Sanjay Asthana, MD3; Julia E. Vertrees, PharmD, BCPP4; Muralidhar Pallaki, MD5,6; Maria Llorente, MD7; Susan Love, MA1; Gerard D. Schellenberg, PhD8; J. Riley McCarten, MD1; Julie Malphurs, PhD9; Susana Prieto, MD9; Peijun Chen, MD, MPH, PhD5,6; David J. Loreck, MD10,11; George Trapp, MD, JD12; Rajbir S. Bakshi, MD12; Jacobo E. Mintzer, MD13,14,15; Judith L. Heidebrink, MD16; Ana Vidal-Cardona, MD17; Lillian M. Arroyo, MD17; Angel R. Cruz, MD18; Sally Zachariah, MD18; Neil W. Kowall, MD19; Mohit P. Chopra, MD19; Suzanne Craft, PhD20,21; Stephen Thielke, MD20,21; Carolyn L. Turvey, PhD22,23; Catherine Woodman, MD22,23; Kimberly A. Monnell, MD24; Kimberly Gordon, MSN, RN, FNP-BC24; Julie Tomaska, PhD1; Yoav Segal, MD, PhD1; Peter N. Peduzzi, PhD25,26; Peter D. Guarino, MPH, PhD25,26
[+] Author Affiliations
1Minneapolis VA Health Care System, Minneapolis, Minnesota
2James J. Peters VA Medical Research Center, New York, New York
3William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin
4Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico
5Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio
6Case Western Reserve University School of Medicine, Cleveland, Ohio
7Washington DC VA Medical Center, Washington, DC
8University of Pennsylvania School of Medicine, Philadelphia
9Miami VA Healthcare System, Miami, Florida
10VA Maryland Healthcare System, Baltimore
11University of Maryland Medical School, Department of Psychiatry, Baltimore
12VA North Texas Health Care System, Dallas
13Ralph H. Johnson VA Medical Center, Charleston, South Carolina
14Department of Health Studies, Medical University of South Carolina, Charleston
15Roper St Francis Healthcare, Charleston, South Carolina
16VA Ann Arbor Healthcare System, Ann Arbor, Michigan
17VA Caribbean Healthcare System, San Juan, Puerto Rico
18Bay Pines VA Healthcare System, Bay Pines, Florida
19VA Boston Healthcare System, Boston, Massachusetts
20VA Puget Sound Health Care System, Seattle, Washington
21Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle
22Iowa City VA Medical Center, Iowa City, Iowa
23University of Iowa, Iowa City
24W. G. (Bill) Hefner VA Medical Center, Salisbury, North Carolina
25Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven
26Yale University School of Public Health, New Haven, Connecticut
JAMA. 2014;311(1):33-44. doi:10.1001/jama.2013.282834.
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Importance  Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD.

Objective  To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor.

Design, Setting, and Participants  Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers.

Interventions  Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152).

Main Outcomes and Measures  Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures.

Results  Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, −0.24 to 4.20; adjusted P = .40) than the placebo group’s decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of “infections or infestations,” with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants).

Conclusions and Relevance  Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden.

Trial Registration  clinicaltrials.gov Identifier: NCT00235716

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Figure 1.
Flow of Participants in the Study
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Figure 2.
Changes in Primary Outcome (ADCS-ADL Inventory Score) During the 4-Year Study Period, Compared With Baseline

In this between-group comparison, lower scores indicate worse functioning. Data are least squares means at each time point. Values have been adjusted for baseline scores as a fixed effect and the study site as a random effect. ADCS-ADL indicates Alzheimer’s Disease Cooperative Study/Activities of Daily Living; error bars, 95% CIs.

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Figure 3.
Changes in 4 Secondary Outcomes During the 4-Year Study Period, Compared With Baseline

Data are least squares means at each time point. Values have been adjusted for baseline scores as a fixed effect and the study site as a random effect. For between-group comparisons of scores on the the Mini-Mental State Examination (MMSE) (A), lower scores indicate worse functioning. For comparisons of the Alzheimer Disease Assessment Scale–Cognitive portion (ADAS-cog) (B), Neuropsychiatric Inventory (C), and the Caregiver Activity Survey (D), higher scores indicate worse functioning. Error bars indicate 95% CIs.

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Figure 4.
Dependence Scale Score Time-to-Event Analysis

The Dependence Scale assesses 6 levels of functional dependence. Time to event is the time to loss of 1 dependence level (increase in dependence). We used an interval-censored model assuming a Weibull distribution because the time of the event was known only at the end of a discrete interval of time (every 6 months).

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