PDF: Rivastigmine Rosler
(1999)Objective
Rivastigmine 1-4 mg/day (lower dose) or 6-12 mg/day (higher dose) — novel pseudo-irreversible brain-selective acetylcholinesterase inhibitor — evaluated over 26 weeks in mild-to-moderate Alzheimer's disease.
Study Summary
• Global function (CIBIC-plus): 37% improved on high-dose vs 20% placebo (p<0.001); 29% had ≥10% improvement on progressive deterioration scale vs 19% placebo (p<0.01).
• MMSE stabilized with high-dose rivastigmine while placebo declined (-0.47); high-dose improved 0.21 points (p<0.05).
• Low-dose rivastigmine (1-4 mg/day) was not significantly different from placebo.
• Cholinergic GI AEs (nausea 50%, vomiting 34%, diarrhea 17%) during dose titration drove 23% discontinuation in high-dose arm.
• First large European ChEI trial, supporting FDA approval (2000); later transdermal patch reduced GI AE burden.
Intervention
Rivastigmine 1-4 mg/day (lower dose) or 6-12 mg/day (higher dose) administered orally with weekly dose escalation during weeks 1-12 and maintenance dose weeks 13-26, or matching placebo. Forced titration to target dose range.
Inclusion Criteria
Adults 50-85 years with probable Alzheimer's disease (DSM-IV + NINCDS-ADRDA criteria), MMSE 10-26, responsible caregiver, at 45 centers in Austria, France, Germany, Switzerland, and North America.
Study Design
Arms: Placebo vs Rivastigmine 1-4 mg/day (lower) vs Rivastigmine 6-12 mg/day (higher)
Patients per Arm: Placebo 239; Lower-dose 243; Higher-dose 243 (N=725)
Outcome
• Responders (≥4-point ADAS-cog improvement): higher-dose 24% vs placebo 16% ITT (p<0.1); 29% vs 19% observed cases (p<0.05)
• CIBIC-plus improvement: higher-dose 37% (80/219) vs placebo 20% (46/230); p<0.001
• Progressive deterioration scale: 29% higher-dose improved ≥10% vs 19% placebo (p<0.01 ITT)
• MMSE: higher-dose +0.21 vs placebo -0.47 (p<0.05); high-dose AE discontinuation 23% vs placebo 7%
Bottom Line
In 725 patients with mild-to-moderate AD at 45 European and North American centers, rivastigmine 6-12 mg/day over 26 weeks significantly improved ADAS-cog (diff 1.6 points vs placebo), CIBIC-plus (37% vs 20% improved; p<0.001), and progressive deterioration scale vs placebo; lower dose 1-4 mg/day was not effective. 23% discontinued for AEs (vs 7% placebo), primarily GI cholinergic effects during dose escalation. Established rivastigmine as an effective ChEI for AD — FDA approved 2000, now widely used via oral and transdermal patch.
Major Points
- Phase 3 multicenter randomized double-blind placebo-controlled trial at 45 centers in Europe and North America (B303 ADENA, Rosler BMJ 1999)
- N=725 adults 50-85 with probable AD (DSM-IV + NINCDS-ADRDA), MMSE 10-26
- Three arms: placebo, rivastigmine 1-4 mg/day (lower), rivastigmine 6-12 mg/day (higher); 12-week forced titration + 14-week maintenance
- Primary endpoint: ADAS-cog (cognitive subscale) change from baseline to week 26
- ADAS-cog: higher-dose +1.17 vs placebo -1.41 (observed cases); ~2.4-point difference; p<0.001
- Lower-dose (1-4 mg/day) was not significantly different from placebo
- CIBIC-plus global improvement: 37% higher-dose vs 20% placebo; p<0.001
- Progressive Deterioration Scale (ADL): 29% higher-dose improved ≥10% vs 19% placebo; p<0.01
- MMSE: higher-dose +0.21 vs placebo -0.47 decline; p<0.05
- Cholinergic GI AEs common on high-dose: nausea 50%, vomiting 34%, diarrhea 17%, anorexia 14%
- 23% discontinued for AEs on high-dose vs 7% placebo; mostly during forced titration
- Supported FDA approval of rivastigmine (Exelon) for mild-to-moderate AD in 2000; transdermal patch 2007 reduced GI burden
Study Design
- Study Type
- Phase 3 multicenter randomized double-blind placebo-controlled parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 725
- Follow-up
- 26 weeks (12-week forced titration + 14-week maintenance)
Primary Outcome
Definition: Change in ADAS-cog (cognitive subscale) from baseline to week 26
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| -1.34 to -1.45 (decline) across analyses | +0.26 to +1.17 (stable/improved) with higher-dose | - (Varied by analysis type) | p<0.001 higher-dose vs placebo; lower-dose not significant |
Limitations & Criticisms
- Forced dose escalation (mandatory titration within fixed period) did not reflect clinical practice — slower individualized titration reduces AE burden
- 26-week duration relatively short; long-term progression still occurred (rivastigmine delays, does not halt, decline)
- High discontinuation rate (33%) in high-dose arm limits completer-only analyses; ITT still favorable
- No comparison with donepezil or tacrine — head-to-head ChEI comparisons came later and were generally non-inferior
- Effect magnitude is modest clinically (~3-6 month delay in decline); patient/family expectations must be calibrated
- Older ADAS-cog threshold for response (≥4 points) debated as clinically meaningful; newer trials use different benchmarks