BMJ 1999;318:633-640 ( 6 March )

Papers

Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial

Michael Rösler, head, ^a Ravi Anand, director, ^b Ana Cicin-Sain, international clinical adviser, ^c Serge Gauthier, director, ^d Yves Agid, director, ^e Peter Dal-Bianco, professor of neurology, ^f Hannes B Stähelin, head of gerontology, ^g Richard Hartman, clinical research manager, ^b Marguirguis Gharabawi, director, ^b on behalf of the B303 Exelon Study Group.

^a Sektion Gerontopsychiatric, Psychiatrische Universitätsklinik, Fuchsleinstrasse 15, D 97080 Würzburg, Germany, ^b CNS Clinical Research, Novartis Pharmaceuticals, 59 Route 10, East Hanover, NJ 07936, USA, ^c Novartis Pharma, Lichstrasse 35, 4002 Basel, Switzerland, ^d McGill Centre for Studies on Aging, 6825 LaSalle Blvd, Verdun, Quebec H4H 1R3, Canada, ^e Department of Neurology, Fédération de Neurologie and INSERM U 289, Hôpital Pitié Salpêtrière, 75013 Paris, France, ^f Universitätsklinik für Neurologie, Wahringer Gürtel 18-20, 1090 Vienna, Austria, ^g Geriatrische Universitätsklinik, Kantonsspital, 4031 Basel, Switzerland

Correspondence to: Professor Rösler roesler{at}rzbox.uni-wuerzburg.de

Objectives: To assess the effects of rivastigmine on the core domains of Alzheimer's disease.
Design: Prospective, randomised, multicentre, double blind, placebo controlled, parallel group trial. Patients received either placebo, 1-4 mg/day (lower dose) rivastigmine, or 6-12 mg/day (higher dose) rivastigmine. Doses were increased in one of two fixed dose ranges (1-4 mg/day or 6-12 mg/day) over the first 12 weeks with a subsequent assessment period of 14 weeks.
Setting: 45 centres in Europe and North America.
Participants: 725 patients with mild to moderately severe probable Alzheimer's disease diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.
Outcome measures: Cognitive subscale of the Alzheimer's disease assessment scale, rating on the clinician interview based impression of change incorporating caregiver information scale, and the progressive deterioration scale.
Results: At the end of the study cognitive function had deteriorated among those in the placebo group. Scores on the Alzheimer's disease assessment scale improved in patients in the higher dose group when compared with patients taking placebo (P<0.05). Significantly more patients in the higher dose group had improved by 4 points or more than had improved in the placebo group (24% (57/242) v 16% (39/238)). Global function as rated by the clinician interview scale had significantly improved among those in the higher dose group compared with those taking placebo (P<0.001), and significantly more patients in the higher dose group showed improvement than did in the placebo group (37% (80/219) v 20% (46/230)). Mean scores on the progressive deterioration scale improved from baseline in patients in the higher dose group but fell in the placebo group. Adverse events were predominantly gastrointestinal, of mild to moderate severity, transient, and occurred mainly during escalation of the dose. 23% (55/242) of those in the higher dose group, 7% (18/242) of those in the lower dose group, and 7% (16/239) of those in the placebo group discontinued treatment because of adverse events.
Conclusions: Rivastigmine is well tolerated and effective. It improves cognition, participation in activities of daily living, and global evaluation ratings in patients with mild to moderately severe Alzheimer's disease. This is the first treatment to show compelling evidence of efficacy in a predominantly European population.

Key messages In a 6 month trial rivastigmine was effective in treating the core cognitive and functional symptoms of patients with mild to moderate Alzheimer's disease Rivastigmine at doses of 6-12 mg/day produces clinically relevant and statistically significant improvements in cognitive and global assessments, and in activities of daily living The effects of rivastigmine are dose dependent Rivastigmine was well tolerated in this population of elderly patients

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