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EXPRESS

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Year of Publication: 2004

Authors: Emre M et al.

Journal: New England Journal of Medicine

Citation: N Engl J Med 2004;351:2509-18

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

Content summarized and formatted by NeuroTrials.ai.

EXPRESS

(2004)

Objective

To evaluate the efficacy and safety of rivastigmine (3-12 mg/day) in patients with Parkinson's disease dementia

Study Summary

• 24-week RCT of rivastigmine vs placebo in 541 patients with PDD
• Rivastigmine improved ADAS-cog by 2.1 points vs 0.7-point worsening with placebo (P<0.001)
• Higher rates of nausea (29% vs 11%), vomiting (17% vs 2%), and tremor (10% vs 4%)

Intervention

Rivastigmine (Exelon) 3-12 mg/day orally vs placebo for 24 weeks

Inclusion Criteria

Age ≥50 years, PD per UK Brain Bank criteria, dementia onset ≥2 years after PD, MMSE 10-24

Study Design

Arms: Rivastigmine 3-12 mg/day vs Placebo (2:1 ratio)

Patients per Arm: Rivastigmine: 362; Placebo: 179

Outcome

• Primary: ADAS-cog +2.1 vs -0.7 points (P<0.001); ADCS-CGIC 3.8 vs 4.3 (P=0.007)
• Secondary: ADCS-ADL (P=0.02), NPI-10 (P=0.02), MMSE (P=0.03)

Bottom Line

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.).

Study Design

Study Type: Phase III, randomized, multicenter, double-blind, placebo-controlled trial (2:1 ratio)
Randomization: Yes
Blinding: Double-blind
Sample Size: 541
Follow-up: 24 weeks with assessments at baseline, week 16, and week 24
Centers: 76
Countries: Multinational

Primary Outcome

Definition: ADAS-cog change from baseline at 24 weeks

Control	Intervention	HR/OR	P-value
+0.7 points (worsening)	-2.1 points (improvement)	-	<0.001

Limitations & 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

Citation

N Engl J Med 2004;351:2509-18

EXPRESS

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Criticisms

Funding

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