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January 28, 2009
Letter to the Editor

Donepezil treatment of patients with MCI
A 48-week randomized, placebo-controlled trial

May 5, 2009 issue
72 (18) 1555-1561

Abstract

Background: Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms.
Methods: In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale–sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function.
Results: The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p ≤ 0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change–MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%).
Conclusions: Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment.

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REFERENCES

1.
Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol 2001;58:1985–1992.
2.
Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256:183–194.
3.
Rountree SD, Waring SC, Chan WC, Lupo PJ, Darby EJ, Doody RS. Importance of subtle amnestic and nonamnestic deficits in mild cognitive impairment: prognosis and conversion to dementia. Dement Geriatr Cogn Disord 2007;24:476–482.
4.
Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment: Alzheimer's Disease Cooperative Study Group. N Engl J Med 2005;352:2379–2388.
5.
Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer's disease. Arch Neurol 2001;58:397–405.
6.
Park KW, Pavlik VN, Rountree SD, Darby EJ, Doody RS. Is functional decline necessary for a diagnosis of Alzheimer's disease? Dement Geriatr Cogn Disord 2007;24:375–379.
7.
Farlow M, Anand R, Messina J Jr, Hartman R, Veach J. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease. Eur Neurol 2000;44:236–241.
8.
Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study. Lancet 2006;367:1057–1065.
9.
Black SE, Doody R, Li H, et al. Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology 2007;69:459–469.
10.
Raskind MA, Peskind ER, Wessel T, Yuan W, and the Galantamine USA-1 Study Group. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology 2000;54:2261–2268.
11.
Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. Donepezil Study Group: a 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Neurology 1998;50:136–145.
12.
Rogers SL, Friedhoff LT. Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: an interim analysis of the results of a US multicentre open label extension study. Eur Neuropsychopharmacol 1998;8:67–75.
13.
Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial [erratum in 2001;322:1456]. BMJ 1999;318:633–638.
14.
Tariot PN, Solomon PR, Morris JC, et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology 2000;54:2269–2276.
15.
Tariot PN, Cummings JL, Katz IR, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting. J Am Geriatr Soc 2001;49:1590–1599.
16.
Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489–495.
17.
Feldman HH, Ferris S, Winblad B, et al. Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. Lancet Neurol 2007;6:501–512.
18.
Winblad B, Gauthier S, Scinto L, et al. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology 2008;70:2024–2035.
19.
Salloway S, Ferris S, Kluger A, et al. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology 2004;63:651–657.
20.
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry 1984;141:1356–1364.
21.
Schneider LS, Olin JT, Doody RS, et al. Validity and reliability of the Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change: The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997;11 (suppl 2):S22–S32.
22.
Seltzer B, Zolnouni P, Nunez M, et al. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol 2004;61:1852–1856.
23.
Orgogozo JM, Small GW, Hammond G, Van Baelen B, Schwalen S. Effects of galantamine in patients with mild Alzheimer's disease. Curr Med Res Opin 2004;20:1815–1820.
24.
Benson AD, Slavin MJ, Tran TT, Petrella JR, Doraiswamy PM. Screening for early Alzheimer's disease: is there still a role for the Mini-Mental State Examination? Prim Care Companion J Clin Psychiatry 2005;7:62–69.
25.
Li M, Ng TP, Kua EH, Ko SM. Brief informant screening test for mild cognitive impairment and early Alzheimer's disease. Dement Geriatr Cogn Disord 2006;21:392–402.
26.
Hyman BT, Kromer LJ, Van Hoesen GW. Reinnervation of the hippocampal perforant pathway zone in Alzheimer's disease. Ann Neurol 1987;21:259–267.
27.
Geddes JW, Monaghan DT, Cotman CW, Lott IT, Kim RC, Chui HC. Plasticity of hippocampal circuitry in Alzheimer's disease. Science 1985;230:1179–1181.
28.
Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695–699.
29.
Feldman H, Gauthier S, Hecker J, et al. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease [erratum in 2001;57:2153]. Neurology 2001;57:613–620.
30.
Jelic V, Kivipelto M, Winblad B. Clinical trials in mild cognitive impairment: lessons for the future. J Neurol Neurosurg Psychiatry 2006;77:429–438.
31.
Thal LJ, Ferris SH, Kirby L, et al. A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment: Rofecoxib Protocol 078 Study Group. Neuropsychopharmacology 2005;30:1204–1215.
Letters to the Editor
15 June 2009
Reply from the author
Rachelle S. Doody, Baylor College of Medicine--Alzheimer's Disease and Memory Disorders Center

Dr. Crane correctly asserts that we utilized the LOCF for imputation of missing data in our trial. [1] Although there are concerns with every proposed method for dealing with missing data in clinical trials, an intention-to-treat analysis using LOCF was the common method used in anti-dementia trials when the statistical analysis plan for this study was written and reviewed by the FDA.

We reported a small and significant difference in Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-Cog) scores favoring donepezil, but stated that the dual primary outcome for efficacy was not reached. Two previous MCI trials reported drug placebo differences favoring donepezil on the ADAS-Cog at 6 months in one study and up to 36 months in another. [2,3] This would support the possibility that this difference may be "real." However, our study remains negative because the psychometric outcome (ADAS-Cog) was not validated by the co-primary global measure Clinical Dementia Rating Scale–sum of boxes.

Differential dropout is a concern in every AD treatment trial, and could promote a positive outcome if drug treated patients drop out earlier than placebo treated patients, especially if both groups decline from the start as depicted by Dr. Crane. The fact that both the donepezil and placebo groups improved over baseline mitigates the concern that degeneration in the placebo group alone could have yielded a positive treatment effect on this one measure.

Since most of the other outcome measures in our trial did not support a treatment effect and we have reported this as a negative study, the use of LOCF analysis is not a concern for our trial. This study adds to the existing evidence that MCI should not be routinely treated with anti-dementia drugs and raises the hypothesis that different outcome measures, as well as different study designs and methods of analysis, may be necessary for future MCI treatment trials.

References

2. Salloway S, Ferris S, Kluger A et al. Efficacy of donepezil in mild cognitive impairment Neurology 2004;63:651-657.

3. Petersen R, Vitamin E and donepezil for the treatment of mild cognitive impairment: Alzheimer's Disease Cooperative Study Group. NEJM 2005:352:2379-2388.

Disclosure: Dr. Doody has received personal compensation for serving on a scientific advisory board for Comentis, Elan, Wyeth, GlaxoSmithKline, Medivation, Myriad, Neurochem, Novartis, Pfizer, and Sonexa. She has served on editorial advisory boards for Alzheimer's Disease and Associated Disorders, Dementia and Geriatric Cognitive Disorders, and Alzheimer's Research & Therapy. She has received consultation fees from Abbott, Amgen, Astellas, Bristol Meyers Squibb, Dainippon, Debiopharm, Epix, Forest, MerckSerono, Noven, Ocera, Schering Plough and Varinel. She has received honoraria from Forest, Lundbeck and Pfizer. She has received research support from the Cynthia and George Mitchell Foundation, the JES Edwards Foundation, the NIH, Eisai, Pfizer, Elan, Wyeth, GlaxoSmithKline, and Myriad. She owns stock options in Medivation and Sonexa. She has provided expert consultation in one case for a firm representing Eisai.

15 June 2009
Donepezil treatment of patients with MCI. A 48-week randomized, placebo-controlled trial
Paul K. Crane, MD MPH, University of Washington

I read with some concern the report by Doody and colleagues [1] who describe results of a randomized controlled trial of donepezil in patients with mild cognitive impairment (MCI). The drug was generally well-tolerated but the active treatment group experienced greater and earlier drop-out than those assigned to placebo, mostly due to gastrointestinal side effects.

The investigators confronted the common problem of dealing with missing data that were disproportionate across the comparison groups. Their chosen approach was the last observation carried forward (LOCF) method. In this method, the last recorded values prior to drop-out are retained in the analysis at every time point subsequent to the last actual observation.

In progressive degenerative diseases, when the active treatment causes premature drop-out, the LOCF technique is biased in favor of the active treatment. Other things being equal, earlier observations should show better cognitive performance than later observations. In other words, the LOCF method stacks the deck in favor of the drug.

To illustrate, imagine a comparison of two groups of five people. The "active" treatment has no effect other than causing early drop-out. Everyone starts at a score of 10 points and declines 1 point every 2 months. No one in the placebo-assigned group drops out. In the "active" treatment group, one individual drops out at month 3, 5, 7, and 9, leaving only one person to complete the study period. If we use LOCF it appears at 48 weeks that the "active" treatment is 2.8 points better on average than the placebo treatment (Figure).

Approaches to missing data have been an important area of research in statistics and biostatistics over the past several decades. It is disappointing that papers are still published using biased techniques such as LOCF.

Reference

1. Doody RS, Ferris SH, Salloway S, et al. Donepezil treatment of patients with MCI. A 48-week randomized, placebo-controlled trial. Neurology 2009;72:1555-1561.

Figure

Figure. Effect of the last observation carried forward (LOCF) method for missing data in a hypothetical trial with no difference between "active" treatment and placebo other than earlier drop-out in the "active" treatment arm. The placebo group shows a decline from 10 points to 4 points, while the "active" treatment group appears to show a smaller decline, from 10 points to 6.8 points, even though the only impact of "active" treatment was causing drop-out.

Disclsoure: Dr. Crane has received grant support from the National Institutes of Health and from the Alzheimer's Association.

Information & Authors

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Published In

Neurology®
Volume 72Number 18May 5, 2009
Pages: 1555-1561
PubMed: 19176895

Publication History

Published online: January 28, 2009
Published in print: May 5, 2009

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Affiliations & Disclosures

R. S. Doody, MD, PhD
From the Alzheimer's Disease and Memory Disorders Center (R.S.D.), Baylor College of Medicine, Houston, TX; Alzheimer's Disease Center (S.H.F.), Silberstein Institute, New York University School of Medicine, New York, and Nathan Kline Institute, Orangeburg, NY; Memory and Aging Program (S.S.), Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI; Eisai Inc. (Y.S., A.K.M.), Woodcliff Lake, NJ; Pfizer Inc. (R.G., Y.X.), New York, NY; and PAREXEL (W.E.W.), Stamford, CT.
S. H. Ferris, PhD
From the Alzheimer's Disease and Memory Disorders Center (R.S.D.), Baylor College of Medicine, Houston, TX; Alzheimer's Disease Center (S.H.F.), Silberstein Institute, New York University School of Medicine, New York, and Nathan Kline Institute, Orangeburg, NY; Memory and Aging Program (S.S.), Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI; Eisai Inc. (Y.S., A.K.M.), Woodcliff Lake, NJ; Pfizer Inc. (R.G., Y.X.), New York, NY; and PAREXEL (W.E.W.), Stamford, CT.
S. Salloway, MD, MS
From the Alzheimer's Disease and Memory Disorders Center (R.S.D.), Baylor College of Medicine, Houston, TX; Alzheimer's Disease Center (S.H.F.), Silberstein Institute, New York University School of Medicine, New York, and Nathan Kline Institute, Orangeburg, NY; Memory and Aging Program (S.S.), Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI; Eisai Inc. (Y.S., A.K.M.), Woodcliff Lake, NJ; Pfizer Inc. (R.G., Y.X.), New York, NY; and PAREXEL (W.E.W.), Stamford, CT.
Y. Sun, PhD
From the Alzheimer's Disease and Memory Disorders Center (R.S.D.), Baylor College of Medicine, Houston, TX; Alzheimer's Disease Center (S.H.F.), Silberstein Institute, New York University School of Medicine, New York, and Nathan Kline Institute, Orangeburg, NY; Memory and Aging Program (S.S.), Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI; Eisai Inc. (Y.S., A.K.M.), Woodcliff Lake, NJ; Pfizer Inc. (R.G., Y.X.), New York, NY; and PAREXEL (W.E.W.), Stamford, CT.
R. Goldman, PhD
From the Alzheimer's Disease and Memory Disorders Center (R.S.D.), Baylor College of Medicine, Houston, TX; Alzheimer's Disease Center (S.H.F.), Silberstein Institute, New York University School of Medicine, New York, and Nathan Kline Institute, Orangeburg, NY; Memory and Aging Program (S.S.), Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI; Eisai Inc. (Y.S., A.K.M.), Woodcliff Lake, NJ; Pfizer Inc. (R.G., Y.X.), New York, NY; and PAREXEL (W.E.W.), Stamford, CT.
W. E. Watkins, MS
From the Alzheimer's Disease and Memory Disorders Center (R.S.D.), Baylor College of Medicine, Houston, TX; Alzheimer's Disease Center (S.H.F.), Silberstein Institute, New York University School of Medicine, New York, and Nathan Kline Institute, Orangeburg, NY; Memory and Aging Program (S.S.), Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI; Eisai Inc. (Y.S., A.K.M.), Woodcliff Lake, NJ; Pfizer Inc. (R.G., Y.X.), New York, NY; and PAREXEL (W.E.W.), Stamford, CT.
Y. Xu, PhD
From the Alzheimer's Disease and Memory Disorders Center (R.S.D.), Baylor College of Medicine, Houston, TX; Alzheimer's Disease Center (S.H.F.), Silberstein Institute, New York University School of Medicine, New York, and Nathan Kline Institute, Orangeburg, NY; Memory and Aging Program (S.S.), Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI; Eisai Inc. (Y.S., A.K.M.), Woodcliff Lake, NJ; Pfizer Inc. (R.G., Y.X.), New York, NY; and PAREXEL (W.E.W.), Stamford, CT.
A. K. Murthy, PharmD
From the Alzheimer's Disease and Memory Disorders Center (R.S.D.), Baylor College of Medicine, Houston, TX; Alzheimer's Disease Center (S.H.F.), Silberstein Institute, New York University School of Medicine, New York, and Nathan Kline Institute, Orangeburg, NY; Memory and Aging Program (S.S.), Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI; Eisai Inc. (Y.S., A.K.M.), Woodcliff Lake, NJ; Pfizer Inc. (R.G., Y.X.), New York, NY; and PAREXEL (W.E.W.), Stamford, CT.

Notes

Address correspondence and reprint requests to Dr. Rachelle S. Doody, Alzheimer's Disease Center, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030

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