PDF: Galantamine Raskind
(2000)Objective
Galantamine 24 mg/d and 32 mg/d — to evaluate efficacy and safety of a reversible, competitive cholinesterase inhibitor with nicotinic allosteric modulation in mild-to-moderate Alzheimer's disease.
Study Summary
• Global clinical impression (CIBIC-plus) and daily function (DAD scale) also favored both doses of galantamine (p<0.05), and cognitive/functional gains were maintained through 12 months at 24 mg/d in an open-label extension.
• Established galantamine as an effective and well-tolerated cholinesterase inhibitor option for AD, with no hepatotoxicity (a key advantage over tacrine) and tolerability improving over time.
Intervention
Galantamine escalated to 24 mg/d or 32 mg/d (via slow dose titration) versus placebo for 6 months (double-blind), followed by a 6-month open-label extension at 24 mg/d.
Inclusion Criteria
Adults with mild-to-moderate probable Alzheimer's disease (NINCDS-ADRDA criteria), MMSE 11-24.
Study Design
Arms: Galantamine 24 mg/d vs Galantamine 32 mg/d vs Placebo
Patients per Arm: 636 total randomized across the three arms
Outcome
• CIBIC-plus at 6 months: improved global clinical impression with both doses vs placebo (p<0.05)
• DAD at 6 months: favorable with galantamine
• At 12 months (24 mg open-label): ADAS-cog/11 and DAD unchanged from baseline — disease progression slowed
• APOE genotype did not modify response
• AEs predominantly GI (nausea, vomiting), decreased over time; no hepatotoxicity
Clinical Question
Does galantamine improve cognition, global function, and daily-living function in mild-to-moderate Alzheimer's disease?
Bottom Line
Galantamine 24 mg/d and 32 mg/d significantly improved cognition (ADAS-cog/11 by ~3.8-3.9 points vs placebo at 6 months, p<0.001) and global clinical impression (CIBIC-plus, p<0.05) in mild-to-moderate Alzheimer's disease. Benefit was maintained with 24 mg/d over 12 months, supporting galantamine as an effective ChEI option.
Major Points
- Phase 3, multicenter, randomized, double-blind, placebo-controlled trial with 6-month open-label extension (USA-1)
- 636 patients with mild-to-moderate probable AD (MMSE 11-24) randomized to placebo, galantamine 24 mg/d, or galantamine 32 mg/d
- Primary endpoints: ADAS-cog/11 and CIBIC-plus at 6 months
- Secondary: Disability Assessment for Dementia (DAD) scale
- Galantamine treatment effects at 6 months: -3.9 (24 mg) and -3.8 (32 mg) points on ADAS-cog/11 vs placebo; both p<0.001
- CIBIC-plus significantly better with both doses vs placebo (p<0.05)
- DAD favored galantamine over placebo
- Response not modified by APOE genotype
- Open-label extension at 24 mg/d for 6 additional months: ADAS-cog/11 and DAD unchanged from baseline — suggesting slowed decline
- AEs predominantly GI (nausea, vomiting), decreased in frequency with continued treatment
- No hepatotoxicity observed — a key advantage over tacrine
- Supported FDA approval of galantamine in 2001 for mild-to-moderate AD
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled with open-label extension
- Randomization
- Yes
- Blinding
- Double-blind (6-month core); open-label (6-month extension)
- Sample Size
- 636
- Follow-up
- 6 months double-blind + 6 months open-label
- Centers
- Multicenter, US
Primary Outcome
Definition: ADAS-cog/11 and CIBIC-plus at 6 months
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Decline in cognition with placebo | Improvement with galantamine 24 mg and 32 mg | - | p<0.001 for ADAS-cog (both doses); p<0.05 for CIBIC-plus |
Limitations & Criticisms
- 6-month primary follow-up short for a chronic progressive disease
- Open-label 6-month extension cannot assess placebo group's comparable trajectory
- No active comparator arm (e.g., donepezil)
- Modest absolute effect size (~4 points on ADAS-cog/11)
- Effect is symptomatic — disease-modification not demonstrated
- Extrapolation to severe AD not tested
Citation
Neurology 2000;54(12):2261-2268