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6th International Congress of Parkinson's Disease and Movement Disorders June 13, 2000 Clinical trials in Parkinson's disease: new releases Pramipexol vs l-dopa in early Parkinson's disease: the randomized controlled CALM-PD trial I. Shoulson (Rochester, USA) We compared the option of initial treatments with pramipexole versus levodopa in patients with early Parkinson's disease (PD) in order to examine dopaminergic complications and other long-term consequences. Patients (N=301) who were at the point of requiring dopaminergic therapy were randomized in a double-blinded fashion to (1) active pramipexole or (2) active levodopa, and followed at 22 academic sites for 23.5 months. Provisions were made for adjustment of experimental therapy and the addition of open-label levodopa (week 11 to month 23.5) to treat continuing or emerging disability. The prespecified primary endpoint was the time to the first occurrence of any of three dopaminergic complications: wearing off, on-off effects, dyskinesias. b-CIT SPECT imaging of the dopamine transporter was carried out in a subgroup of subjects at baseline and 23 months later. At baseline, groups were balanced for age (mean 61 yrs) and mean total Unified Parkinson's Disease Rating Scale (UPDRS) scores (32 units). Twenty-eight percent (28%) of subjects assigned to initial pramipexole reached the primary endpoint compared with 51% in the levodopa group (hazard ratio 0.44, 95% CI 0.30-0.66, p < 0.0001). The proportion of subjects experiencing specific dopaminergic complications (pramipexole vs. levodopa; hazard ratios, 95% CI, p-value) were: wearing off (24% vs. 38%; 0.56, 0.36-0.87, p = 0.009), dyskinesias (10% vs. 31%, 0.32, 0.18-0.58, p = 0.0002), on-off effects (1% vs. 5%, 0.24, 0.05-1.13, p = 0.07). Forty-eight (48%) in the pramipexole group required supplemental levodopa compared with 36% in the levodopa group (hazard ratio 1.49, 95% CI 1.05-2.13, p = 0.03). The mean improvement in total UPDRS scores from baseline to 23.5 months was greater (p = 0.0002) in the levodopa group (31.1 to 21.9) than in the pramipexole group (32.5 to 28.1). The subgroup treated initially with pramipexole (N = 38) showed a 10.0% ± 7.1 annual decline in striatal b-CIT uptake compared with a 12.4% ± 7.2 annual decline in subjects (N=38) treated initially with levodopa (p = 0.15). Pramipexole delayed the onset of dopaminergic motor complications compared with levodopa therapy in patients with early PD. An extended controlled study of this cohort is underway to determine the longer-term impact of these initial dopaminergic treatments, including effects on safety, dopaminergic complications, UPDRS, functional status, economic outcomes, quality of life, and dopamine transporter neuroimaging.