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CALM-PD

Pramipexole vs Levodopa as Initial Treatment for Parkinson Disease: A Randomized Controlled Trial

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Year of Publication: 2000

Authors: Parkinson Study Group

Journal: JAMA

Citation: JAMA. 2000;284:1931-1938

Link: https://jamanetwork.com

Clinical Question

Does initial treatment with pramipexole reduce the development of dopaminergic motor complications compared to levodopa in early Parkinson disease?

Bottom Line

Initial pramipexole treatment resulted in significantly fewer dopaminergic motor complications (28%) compared with levodopa (51%) over 23.5 months, but levodopa provided greater improvement in UPDRS scores. Pramipexole was associated with more somnolence, hallucinations, and edema.

        Major Points
        Pramipexole reduced risk of dopaminergic complications by 55% (HR 0.45, P<.001)
Absolute risk reduction of 23% - NNT of 4-5 patients to prevent 1 dopaminergic complication
Levodopa group had greater improvement in total UPDRS (9.2 vs 4.5 points, P<.001)
Pramipexole associated with more somnolence (32.4% vs 17.3%, P=.003)
Quality of life scores favored levodopa at 23.5 months (PDQUALIF P=.006)
No significant difference in dopamine transporter decline on β-CIT imaging

      

Design

Study Type: Multicenter, parallel-group, double-blind, randomized controlled trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: October 1996 to August 1997

Follow-up Duration: 23.5 months

Centers: 22

Countries: United States, Canada

Sample Size: 301

Analysis: Intention-to-treat with Cox proportional hazards regression model stratified by enrolling investigator

Inclusion Criteria

Adults aged 30 years or older
Idiopathic Parkinson disease for fewer than 7 years
Required dopaminergic antiparkinsonian therapy at enrollment
Hoehn and Yahr stage I, II, or III

Exclusion Criteria

Levodopa or dopaminergic agonist use in 2 months prior to enrollment
History of previous dopaminergic complication
Atypical parkinsonian syndromes
Serious concurrent illness
Pramipexole treatment in past 4 months
Neuroleptics, metoclopramide, alphamethyldopa, or flunarizine in past 6 months

Arms

Field	Control	Pramipexole
Intervention	Carbidopa/levodopa 25/100 mg 3 times per day with pramipexole placebo. Dose escalation: 75/300 mg/day to 150/600 mg/day. Open-label supplementation permitted from week 11.	Pramipexole 0.5 mg 3 times per day with levodopa placebo. Dose escalation: 1.5 mg/day to 4.5 mg/day. Open-label carbidopa/levodopa permitted from week 11 for disability.
Duration	23.5 months	23.5 months

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Time from randomization until first occurrence of any of 3 dopaminergic complications: wearing off, dyskinesias, or on-off motor fluctuations	Primary	76/150 (51%)	42/151 (28%)	0.45	<0.001
Wearing off	Secondary	57/150 (38.0%)	36/151 (23.8%)	0.57	0.01
Dyskinesias	Secondary	46/150 (30.7%)	15/151 (9.9%)	0.33	<0.001
Change in total UPDRS score (baseline to 23.5 months)	Secondary	9.2 (SD 10.8) improvement	4.5 (SD 12.7) improvement		<0.001
Need for supplemental levodopa	Secondary	58/150 (39%)	80/151 (53%)	1.54	0.02
Somnolence	Adverse	26/150 (17.3%)	49/151 (32.4%)		0.003
Hallucinations	Adverse	5/150 (3.3%)	14/151 (9.3%)		0.03
Generalized edema	Adverse	12/150 (8.0%)	27/151 (17.9%)		0.01
Nausea	Adverse	55/150 (36.7%)	55/151 (36.4%)		NS
Falling asleep while driving	Adverse	1 patient	2 patients

Subgroup Analysis

Reduced risk of dopaminergic complications with pramipexole observed in each of four 6-month study periods: 0-6 months HR 0.46, 6-12 months HR 0.27, 12-18 months HR 0.56, 18-24 months HR 0.65

Criticisms

Pramipexole and levodopa dosing may not have been equivalent, potentially affecting comparison
53% of pramipexole patients required supplemental levodopa
Clinical significance of quality of life differences at 23.5 months unclear
Higher rate of somnolence with pramipexole raises safety concerns, especially regarding driving
No significant difference in dopamine transporter imaging despite hypothesis of neuroprotection

Funding

Pharmacia Corp; National Parkinson Foundation

Based on: CALM-PD (JAMA, 2000)

Authors: Parkinson Study Group

Citation: JAMA. 2000;284:1931-1938

Content summarized and formatted by NeuroTrials.ai.

CALM-PD

(2000)

Objective

To compare the development of dopaminergic motor complications after initial treatment of early Parkinson's disease with pramipexole vs levodopa.

Study Summary

• Initial pramipexole treatment resulted in significantly fewer motor complications (28%) compared with levodopa (51%) (HR 0.45, P<0.001)
• Levodopa produced greater improvement in total UPDRS (9.2 vs 4.5 points, P<0.001)
• Somnolence, hallucinations, and edema were more common with pramipexole; no difference in β-CIT striatal uptake decline

Intervention

Pramipexole up to 4.5 mg/day vs carbidopa/levodopa up to 600 mg/day for 23.5 months; open-label levodopa supplementation permitted from week 11

Inclusion Criteria

Adults >=30 years with idiopathic PD for <7 years requiring dopaminergic therapy, Hoehn and Yahr stage I-III, no prior dopaminergic complications

Study Design

Arms: Pramipexole (+ levodopa placebo), Levodopa (+ pramipexole placebo)

Patients per Arm: Pramipexole: 151, Levodopa: 150

Outcome

• Primary: Time to first dopaminergic complication: 28% vs 51% (HR 0.45, 95% CI 0.30-0.66, P<0.001)
• Dyskinesias: 9.9% vs 30.7% (HR 0.33, P<0.001)
• Wearing off: 23.8% vs 38.0% (HR 0.57, P=0.01)
• UPDRS improvement: 4.5 vs 9.2 points (P<0.001)

Bottom Line

Major Points

Pramipexole reduced risk of dopaminergic complications by 55% (HR 0.45, P<.001)
Absolute risk reduction of 23% - NNT of 4-5 patients to prevent 1 dopaminergic complication
Levodopa group had greater improvement in total UPDRS (9.2 vs 4.5 points, P<.001)
Pramipexole associated with more somnolence (32.4% vs 17.3%, P=.003)
Quality of life scores favored levodopa at 23.5 months (PDQUALIF P=.006)
No significant difference in dopamine transporter decline on β-CIT imaging

Study Design

Study Type: Multicenter, parallel-group, double-blind, randomized controlled trial
Randomization: Yes
Blinding: Double-blind
Sample Size: 301
Follow-up: 23.5 months
Centers: 22
Countries: United States, Canada

Primary Outcome

Definition: Time from randomization until first occurrence of any of 3 dopaminergic complications: wearing off, dyskinesias, or on-off motor fluctuations

Control	Intervention	HR/OR	P-value
76/150 (51%)	42/151 (28%)	0.45 (0.30-0.66)	<0.001

Limitations & Criticisms

Pramipexole and levodopa dosing may not have been equivalent, potentially affecting comparison
53% of pramipexole patients required supplemental levodopa
Clinical significance of quality of life differences at 23.5 months unclear
Higher rate of somnolence with pramipexole raises safety concerns, especially regarding driving
No significant difference in dopamine transporter imaging despite hypothesis of neuroprotection

Citation

JAMA. 2000;284:1931-1938

View Original Publication →

CALM-PD

Pramipexole vs Levodopa as Initial Treatment for Parkinson Disease: A Randomized Controlled Trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

Ask about CALM-PD