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CALM-PD Long-term

Long-term Effect of Initiating Pramipexole vs Levodopa in Early Parkinson Disease - CALM-PD Cohort Study

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Year of Publication: 2009

Authors: Parkinson Study Group CALM Cohort Investigators

Journal: Archives of Neurology

Citation: Arch Neurol. 2009;66(5):563-570

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

FieldControlInitial Pramipexole
InterventionLevodopa/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.
Duration6 years total follow-up6 years total follow-up

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Time-weighted average of self-reported disability (Schwab and England ADL Scale) at final visitPrimary82.5 (14.6)79.9 (16.2)0.19
Any dopaminergic complications (wearing off, on-off, or dyskinesias)Secondary68.4%50.0%OR 2.48 (1.39-4.44)0.002
DyskinesiasSecondary36.8%20.4%OR 2.56 (1.35-4.84)0.004
Wearing offSecondary58.8%44.4%OR 2.11 (1.19-3.71)0.01
FreezingSecondary26.2%34.7%OR 0.72 (0.39-1.35)0.30
UPDRS total score change from baselineSecondary0.5 (17.1)2.4 (17.4)0.11
Epworth Sleepiness Scale scoreAdverse8.6 (4.7)11.3 (5.8)<0.001
ESS ≥10 (excessive sleepiness)Adverse35.2%57.4%OR 0.39 (0.22-0.70)0.002
EdemaAdverse14.4%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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