EXPRESS
Clinical Question
To evaluate the efficacy and safety of rivastigmine in patients with dementia associated with Parkinson's disease
Bottom Line
Pramipexole ER (extended-release, once daily) was noninferior to pramipexole IR (immediate-release, three times daily) for UPDRS Part II+III improvement in early PD (-7.5 vs -7.4 points; difference -0.1; 95% CI -1.6 to 1.5). Both superior to placebo (-3.4). Similar adverse event profiles. 539 patients, 76 centers. Published Neurology 2010.
Major Points
- ER noninferior to IR: UPDRS II+III -7.5 vs -7.4 (diff -0.1; 95% CI -1.6 to 1.5). Predefined margin ±3.0.
- Both superior to placebo: -7.5/-7.4 vs -3.4 (P<0.0001 for both).
- 539 patients with early PD (Hoehn & Yahr ≤3). 18-week, double-blind, double-dummy.
- ER dose: 0.375-4.5 mg once daily. IR dose: 0.125-1.5 mg TID. 7-week titration.
- CGI-I responder rate: ER 72.3% vs IR 68.4% vs placebo 51.4%.
- AEs similar: somnolence ~11% all active, nausea ~14%, dizziness ~8%.
- Convenience advantage: once-daily dosing with equivalent efficacy and safety.
- 76 centers across 12 countries. Boehringer Ingelheim sponsored.
- Supports switch from IR to ER pramipexole for patient convenience.
- Published Neurology 2010 (Hauser et al.).
Design
Study Type: Phase III, randomized, multicenter, double-blind, placebo-controlled trial (2:1 ratio)
Randomization: 1
Blinding: Double-blind
Enrollment Period: 24 weeks
Follow-up Duration: 24 weeks with assessments at baseline, week 16, and week 24
Centers: 76
Countries: Multinational
Sample Size: 541
Inclusion Criteria
- Age ≥50 years
- PD per UK Brain Bank criteria
- DSM-IV dementia onset ≥2 years after PD
- MMSE 10-24
- caregiver contact ≥3 days/week
Exclusion Criteria
- Primary neurodegenerative disorder other than PD
- other causes of dementia
- major depression
- uncontrolled seizures
- cholinesterase inhibitor use within 4 weeks
Arms
| Field | Rivastigmine 3-12 mg/day | Control |
|---|---|---|
| Intervention | Rivastigmine 3-12 mg/day (mean achieved 8.6 mg/day) | Matching placebo |
| Duration | 24 weeks with assessments at baseline, week 16, and week 24 | 24 weeks with assessments at baseline, week 16, and week 24 |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| ADAS-cog change from baseline at 24 weeks | Primary | +0.7 points (worsening) | -2.1 points (improvement) | 2.9 | <0.001 |
| ADCS-CGIC (global impression) | Secondary | 4.3 | 3.8 | 0.007 | |
| ADCS-ADL (daily living) | Secondary | 0.02 | |||
| NPI-10 (neuropsychiatric) | Secondary | 0.02 | |||
| MMSE | Secondary | 0.03 | |||
| Verbal fluency (D-KEFS) | Secondary | <0.001 | |||
| Nausea | Adverse | 11% | 29% | ||
| Vomiting | Adverse | 2% | 17% | ||
| Tremor worsening | Adverse | 4% | 10% | ||
| Dizziness | Adverse | 1% | 6% |
Criticisms
- 2:1 randomization may introduce bias
- high dropout rate (27% vs 18%)
- LOCF imputation may overestimate effect
- modest effect sizes
- short duration
- industry-sponsored
Funding
Novartis Pharmaceuticals
Based on: EXPRESS (New England Journal of Medicine, 2004)
Authors: Emre M et al.
Citation: N Engl J Med 2004;351:2509-18
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