CALM-PD
Pramipexole vs Levodopa as Initial Treatment for Parkinson Disease: A Randomized Controlled Trial
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, generalized and peripheral edema.
Major Points
- Pramipexole reduced risk of dopaminergic complications by 55% (HR 0.45, 95% CI 0.30-0.66, 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 (adjusted difference -5.0 [-7.6 to -2.4], P<.001) with parallel motor and ADL benefits
- Pramipexole associated with more somnolence (32.4% vs 17.3%, P=.003), hallucinations (9.3% vs 3.3%, P=.03), generalized edema (17.9% vs 8.0%, P=.01), and peripheral edema (14.6% vs 4.0%, P=.002)
- Quality of life scores favored levodopa at 23.5 months (PDQUALIF P=.006; sleep subscale P=.004; self-image/sexuality P=.02; EuroQol P=.06)
- No significant difference in striatal β-CIT decline at 23.5 months (pramipexole 20.0% [14.2%] vs levodopa 24.8% [14.4%]; n=39 per group; P=.15)
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
- Treatment with methylphenidate, cinnarizine, reserpine, amphetamine, or monoamine oxidase type A inhibitors in past 3 months
- Pramipexole treatment in past 4 months
- Neuroleptics, metoclopramide, alphamethyldopa, or flunarizine in past 6 months
- Unstable dosage of selegiline, amantadine, anticholinergic therapy, or other CNS-active therapies (eg, hypnotics, antidepressants, anxiolytics) in past 2 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 (50.7%) | 42/151 (27.8%) | 0.45 | <0.001 |
| Wearing off (hazard ratio) | Secondary | 57/150 (38.0%) | 36/151 (23.8%) | 0.57 | 0.01 |
| Dyskinesias (hazard ratio) | Secondary | 46/150 (30.7%) | 15/151 (9.9%) | 0.33 | <0.001 |
| On-off motor fluctuations (hazard ratio) | Secondary | 8/150 (5.3%) | 2/151 (1.3%) | 0.27 | 0.11 |
| Change in total UPDRS score from baseline to 23.5 months (adjusted difference, pramipexole minus levodopa) | Secondary | 9.2 (SD 10.8) improvement | 4.5 (SD 12.7) improvement | <0.001 | |
| Change in motor UPDRS score (adjusted difference) | Secondary | 7.3 (SD 8.6) improvement | 3.4 (SD 8.6) improvement | <0.001 | |
| Change in ADL UPDRS score (adjusted difference) | Secondary | 2.2 (SD 3.2) improvement | 1.1 (SD 4.5) improvement | 0.001 | |
| Change in mental UPDRS score (adjusted difference) | Secondary | -0.2 (SD 1.2) | 0.0 (SD 1.6) | 0.72 | |
| Need for supplemental levodopa (hazard ratio) | Secondary | 58/150 (39%) | 80/151 (53%) | 1.54 | 0.02 |
| PDQUALIF total quality-of-life score change at 23.5 months (favors levodopa) | Secondary | Higher (better) change score | Lower change score | 0.006 | |
| PDQUALIF sleep subscale at 23.5 months (favors levodopa) | Secondary | - | - | 0.004 | |
| PDQUALIF self-image/sexuality subscale at 23.5 months (favors levodopa) | Secondary | - | - | 0.02 | |
| EuroQol visual analog scale change at 23.5 months (trend favoring levodopa) | Secondary | - | - | 0.06 | |
| Striatal β-CIT uptake decline over 23.5 months (SPECT substudy) | Secondary | 24.8% (14.4%) decline; n=39 | 20.0% (14.2%) decline; n=39 | 0.15 | |
| 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 | |
| Peripheral edema | Adverse | 6/150 (4.0%) | 22/151 (14.6%) | 0.002 | |
| Nausea | Adverse | 55/150 (36.7%) | 55/151 (36.4%) | NS | |
| Falling asleep while driving | Adverse | 1 patient | 2 patients | ||
| Deaths | Adverse | 2 deaths (neither judged related to study drug) | 0 |
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 (primary); National Parkinson Foundation Center of Excellence; NIH Clinical Research Center grants RR00044 and RR01066 (University of Rochester and Massachusetts General Hospital, respectively)
Based on: CALM-PD (JAMA, 2000)
Authors: Parkinson Study Group
Citation: JAMA. 2000;284:1931-1938
Content summarized and formatted by NeuroTrials.ai.