Galantamine for Alzheimer's disease.

backgroundGalantamine (also called galanthamine, marketed as Reminyl (Janssen)) was isolated from several plants, including daffodil bulbs, but is now synthesized. Galantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor. It is also an allosteric modulator at nicotinic cholinergic receptor sites potentiating cholinergic nicotinic neurotransmission. A small number of early studies showed mild cognitive and global benefits for patients with Alzheimer's disease (AD), and recently several multicenter clinical trials have been published with positive findings. Galantamine has received regulatory approval in 29 counties: Argentina, Australia, Canada, Czechia, the European Union (except for The Netherlands), Iceland, Korea, Mexico, Norway, Poland, Singapore, South Africa, Switzerland, Thailand, and the United States.

objectivesThe objective of this overview is to assess the clinical effects of galantamine in patients with probable AD, and to investigate potential moderators of an effect. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 4 July 2001 using the terms galantamine and Reminyl. The Specialized Register at that time contained records from the following databases: CCTR/Central:April 2001 (issue 2); Medline: 1966 to June 2001; Embase: 1980 to April 2001; PsycLit: 1887 to April 2001; Cinahl: 1982 to March 2001; SIGLE (Grey Literature in Europe): 1980 to December 2000; ISTP (Index to Scientific and Technical Proceedings): to May 2000; INSIDE (BL database of Conference Proceedings and Journals): to June 2000; Aslib Index to Theses (UK and Ireland theses): 1970 to June 2001; Dissertation Abstract (USA): 1861 to June 2001; ADEAR (Alzheimer's Disease Clinical Trials Database): to June 2001; National Research Register (including the MRC Clinical Trials Directory): April 2001 (issue 2) Alzheimers Society Trials Database: to June 2001; Glaxo-Wellcome Trials Database: to June 2001; Centerwatch Trials Database: to December 2000. Published reviews were inspected for further sources. Additional information was collected from an unpublished investigational brochure for galantamine. SELECTION CRITERIA: Trials selected were randomized, double-blind, parallel-group, and unconfounded comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks in subjects with AD. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers and pooled where appropriate and possible. The pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Intention-to-treat and observed cases data were both reported, if the data were available to be reported. Outcomes of interest include the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), clinical global impression of change (CIBIC-plus or CGIC), Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL), Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI). Potential moderating variables of a treatment effect included trial duration and dose. MAIN

resultsSeven trials were identified that met criteria for entry, with six being Phase II or III industry-sponsored multicenter trials. Two were of 12 weeks duration; one of 13 weeks, one of 5 months; one of 29 weeks; and two of 6 months duration. Trials of 5 months or more were aggregated together in the analyses as '6 months.' Overall, galantamine showed significant treatment effects at daily doses of 16-32 mg/d for trials of 3- to 6-months duration. For global ratings, trials of 3 months duration with doses of 24-32mg/d (Odds Ratio (OR) 2.3; 95%CI 1.3 - 3.9) and 36mg/d (OR 3.3; 95%CI 1.2 - 9.3) were statistically significant in favor of treatment. For trials of 6 months duration (5-months to 29 weeks), only doses of 8mg/d failed to be statistically significant (16mg: OR 2.25; 95% CI 1.6 - 3.3; 24mg: OR 2.0; 95%CI 1.5 -2.5; 32mg: OR 1.9; 95%CI 1.4 - 2.5). For cognitive function over 6 months duration: at 16mg/d, improvements measured -3.3 points (k=1; 95%CI -4.4 - -2.1) on weighted mean difference on the ADAS-Cog scale; -3.5 points at 24mg/d (k=3; 95%CI -4.3 - -2.8), and -4.0 points at 32mg/d (k=2; 95%CI -5.0 - -3.0). The single 3 month trial with ADAS-Cog data also showed statistically significant improvement. Both observed cases (WMD 3.8; 95%CI 0.3 - 7.3) and intent to treat analyses using the Disability Assessment of Dementia scale gave statistically significant results in favor of treatment for daily doses of 32mg for 6 months duration (as did the single 3 month trial of 24-32mg/d treatment that used this scale) The small number of trials available for analysis, however, limited the power of subgroup analyses to detect differences. Galantamine consistently failed to show statistically significant treatment effects at doses of 8mg/day. Galantamine's adverse effects appear similar to those of other cholinesterase inhibitors, in that it tends to produce gastrointestinal effects acutely and with dosage increases. Overall, subjects treated with galantamine at doses of 24-32 mg/d were more likely to discontinue participation in most trials compared to subjects treated with lower doses or placebo, but in the one trial with a slower rate of titration the discontinuation rate was not significantly greater than placebo for the 16 mg/day dose. REVIEWER'S

conclusionsPatients in these trials were similar to those seen in earlier antidementia AD trials, and consisted primarily of mildly to moderately impaired outpatients. Galantamine's effects on more severely impaired subjects has not yet been assessed. Nevertheless, this review shows consistent positive effects for galantamine for trials of 3 months, 5 months and 6 months duration. In addition, although there was not a statistically significant dose-response effect, doses above 8mg/d were, for the most part, consistently statistically significant. Thus, there is evidence demonstrating efficacy for galantamine on global ratings, cognitive tests, assessments of ADLs and behavior. This magnitude for the cognitive effect is similar to other cholinesterase inhibitors including donepezil, rivastigmine, and tacrine. Galantamine's safety profile is similar to other cholinesterase inhibitors with respect to cholinergically mediated gastrointestinal symptoms. No information is available on adverse events that occurred less than 5% of the time. It appears that doses of 16 mg/d were best tolerated in the single trial where medication was titrated over 4 week periods, and because this dose showed statistically indistinguishable efficacy with higher doses, it is probably most preferable initially.