CALM-PD Long-term
Long-term Effect of Initiating Pramipexole vs Levodopa in Early Parkinson Disease - CALM-PD Cohort Study
Clinical Question
Does initial treatment with pramipexole vs levodopa in early Parkinson disease result in different long-term outcomes in disability, motor complications, and quality of life after 6 years?
Bottom Line
After 6 years, initial pramipexole and initial levodopa strategies (both followed by open-label levodopa use) resulted in similar self-reported disability. Persistent differences favored initial pramipexole for lower rates of motor complications (dyskinesias, wearing off), but initial levodopa had less severe somnolence and edema.
Major Points
- Extended follow-up study of CALM-PD trial participants for mean 6.0 years after randomization
- 222 of original 301 subjects (73.8%) enrolled in cohort study
- By 6 years, >90% of patients in both groups received levodopa therapy regardless of initial assignment
- More than 80% of those initially on pramipexole were still taking a dopamine agonist
- Primary outcome: similar self-reported disability (S/E ADL Scale) between groups (79.9 vs 82.5, P=0.19)
- Dopaminergic motor complications significantly more common with initial levodopa (68.4% vs 50.0%, P=0.002)
- Dyskinesias more common in initial levodopa group (36.8% vs 20.4%, P=0.004)
- Wearing off more frequent with initial levodopa (58.8% vs 44.4%, P=0.01)
- Significantly higher daytime sleepiness with initial pramipexole (ESS 11.3 vs 8.6, P<0.001)
- More edema with initial pramipexole (27.1% vs 14.4%, P=0.04)
- No differences in quality of life, depression, or cognitive outcomes
Design
Study Type: Extended open-label follow-up of randomized controlled trial
Randomization: 1
Blinding: Open-label extension after initial 4-year blinded phase
Enrollment Period: CALM Cohort: April 2002 to January 2004 (original: October 1996 to August 1997)
Follow-up Duration: Mean 6.0 (0.2) years from original randomization
Centers: 22
Countries: United States, Canada
Sample Size: 222
Analysis: Propensity score adjustment; ANCOVA for continuous outcomes; logistic regression for dichotomous outcomes
Inclusion Criteria
- Patients with early Parkinson disease (idiopathic PD for less than 7 years)
- Required dopaminergic antiparkinsonian therapy at time of original enrollment
- Previously enrolled in CALM-PD trial
- Consented to extended follow-up in CALM Cohort study
Exclusion Criteria
- Had taken levodopa or dopaminergic agonist in 2 months prior to original CALM-PD enrollment
- Did not consent to extended follow-up
- Died before cohort enrollment
Arms
| Field | Control | Initial Pramipexole |
|---|---|---|
| Intervention | Levodopa/carbidopa titrated to 300-600 mg/day. Open-label levodopa or other medications permitted for emerging disability. | Pramipexole titrated to 1.5-4.5 mg/day. Open-label levodopa or other medications permitted for emerging disability. |
| Duration | 6 years total follow-up | 6 years total follow-up |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Time-weighted average of self-reported disability (Schwab and England ADL Scale) at final visit | Primary | 82.5 (14.6) | 79.9 (16.2) | 0.19 | |
| Any dopaminergic complications (wearing off, on-off, or dyskinesias) | Secondary | 68.4% | 50.0% | OR 2.48 (1.39-4.44) | 0.002 |
| Dyskinesias | Secondary | 36.8% | 20.4% | OR 2.56 (1.35-4.84) | 0.004 |
| Wearing off | Secondary | 58.8% | 44.4% | OR 2.11 (1.19-3.71) | 0.01 |
| Freezing | Secondary | 26.2% | 34.7% | OR 0.72 (0.39-1.35) | 0.30 |
| UPDRS total score change from baseline | Secondary | 0.5 (17.1) | 2.4 (17.4) | 0.11 | |
| Epworth Sleepiness Scale score | Adverse | 8.6 (4.7) | 11.3 (5.8) | <0.001 | |
| ESS ≥10 (excessive sleepiness) | Adverse | 35.2% | 57.4% | OR 0.39 (0.22-0.70) | 0.002 |
| Edema | Adverse | 14.4% | 27.1% | OR 0.48 (0.24-0.98) | 0.04 |
Subgroup Analysis
Propensity score adjustment performed. Patients who did not enter cohort were older, had more severe disease, and worse quality of life.
Criticisms
- Only 73.8% of original CALM-PD participants enrolled in extended follow-up
- Open-label design after 4-year blinded phase may introduce bias
- Treatment crossover permitted (>90% of both groups receiving levodopa by final visit)
- Initial levodopa group unable to add dopamine agonist during initial blinded phase - design artifact
- No baseline Epworth Sleepiness Scale scores from original trial
- Compulsive behaviors not assessed
- Higher amantadine use in initial levodopa group may have modified dyskinesia severity
Funding
Pharmacia Corp and Boehringer Ingelheim
Based on: CALM-PD Long-term (Archives of Neurology, 2009)
Authors: Parkinson Study Group CALM Cohort Investigators
Citation: Arch Neurol. 2009;66(5):563-570
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