Efficacy, safety, and tolerability of pramipexole in untreated and levodopa-treated patients with Parkinson's disease. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Efficacy, safety, and tolerance of the non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson's disease: a double blind, placebo controlled, randomised, multicentre study.
To evaluate the efficacy and safety of the non-ergot dopamine agonist pramipexole in untreated and levodopa-treated Chinese patients with early or advanced Parkinson's disease.
                This randomized, double-blind, placebo-controlled, parallel-group study, which was conducted in Hong Kong and Taiwan, comprised a screening period of at least 1 week, a dose-escalation period of 7 weeks, and a maintenance period of 8 weeks (total duration of treatment: 15 weeks). During the dose-escalation period, the dose of pramipexole (or number of placebo tablets) was escalated in a blinded fashion according to a predetermined schedule to the optimum tolerated dose of pramipexole, administered three times a day (minimum dose=0.375 mg/day; maximum dose=4.5 mg/day). This dose was then maintained for the duration of the maintenance period. Efficacy was primarily assessed by the Unified Parkinson's Disease Rating Scale (UPDRS). Safety and tolerability were evaluated by treatment-emergent adverse event reports, clinical laboratory test results (blood chemistry, hematology, and urinalysis), vital signs, and electrocardiograms.
                Pramipexole was significantly more effective than placebo in reducing the total scores of the UPDRS Part II, Part III, and Parts II and III combined. Approximately 70% of both the placebo- and pramipexole-treated patients evaluated in this analysis were on levodopa. Regardless of levodopa use, the mean UPDRS total scores showed a consistently greater improvement in pramipexole patients than in placebo patients. Mean scores for pramipexole patients not on levodopa showed a greater improvement than did pramipexole patients on levodopa. The mean improvement for the pramipexole/no levodopa group relative to the placebo/no levodopa group at week 15 was 10.93 points (i.e., -14.43 points minus -3.50 points). The mean improvement for the pramipexole/levodopa group relative to the placebo/levodopa group at week 15 was 9.04 points (i.e., -10.26 points minus -1.22 points). Pramipexole was also superior to placebo as measured by improvement in the modified Hoehn and Yahr Scale and a reduction in the number of "off" hours for patients on concomitant levodopa therapy.
                Pramipexole is an effective and well-tolerated therapy, with or without concomitant levodopa, for Chinese patients with Parkinson's disease. The best way to initiate dopaminergic therapy for early Parkinson disease remains unclear.
                To compare initial treatment with pramipexole vs levodopa in early Parkinson disease, followed by levodopa supplementation, with respect to the development of dopaminergic motor complications, other adverse events, and functional and quality-of-life outcomes.
                Multicenter, parallel-group, double-blind, randomized controlled trial.
                Academic movement disorders clinics at 22 sites in the United States and Canada.
                Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997 and observed until August 2001.
                Subjects were randomly assigned to receive 0.5 mg of pramipexole 3 times per day with levodopa placebo (n = 151) or 25/100 mg of carbidopa/levodopa 3 times per day with pramipexole placebo (n = 150). Dosage was escalated during the first 10 weeks for patients with ongoing disability. Thereafter, investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability.
                Time to the first occurrence of dopaminergic complications: wearing off, dyskinesias, on-off fluctuations, and freezing; changes in the Unified Parkinson's Disease Rating Scale and quality-of-life scales; and adverse events.
                Initial pramipexole treatment resulted in a significant reduction in the risk of developing dyskinesias (24.5% vs 54%; hazard ratio, 0.37; 95% confidence interval [CI], 0.25-0.56; P<.001) and wearing off (47% vs 62.7%; hazard ratio, 0.68; 95% CI, 0.49-0.63; P =.02). Initial levodopa treatment resulted in a significant reduction in the risk of freezing (25.3% vs 37.1%; hazard ratio, 1.7; 95% CI, 1.11-2.59; P =.01). By 48 months, the occurrence of disabling dyskinesias was uncommon and did not significantly differ between the 2 groups. The mean improvement in the total Unified Parkinson's Disease Rating Scale score from baseline to 48 months was greater in the levodopa group than in the pramipexole group (2 +/- 15.4 points vs -3.2 +/- 17.3 points, P =.003). Somnolence (36% vs 21%, P =.005) and edema (42% vs 15%, P<.001) were more common in pramipexole-treated subjects than in levodopa-treated subjects. Mean changes in quality-of-life scores did not differ between the groups.
                Initial treatment with pramipexole resulted in lower incidences of dyskinesias and wearing off compared with initial treatment with levodopa. Initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and edema and provided for better symptomatic control, as measured by the Unified Parkinson's Disease Rating Scale, compared with initial treatment with pramipexole. Both options resulted in similar quality of life. Levodopa and pramipexole both appear to be reasonable options as initial dopaminergic therapy for Parkinson disease, but they are associated with different efficacy and adverse-effect profiles. Pramipexole, a non-ergot dopamine D2/D3 receptor agonist, was investigated as an add on drug in advanced parkinsonian patients with motor fluctuations to assess efficacy, safety, and tolerance.
                Seventy eight patients of either sex with advanced Parkinson's disease and treatment complications such as motor fluctuations were enrolled into a double blind, placebo controlled, randomised, multicentre study (phase II) and assigned to add on treatment with pramipexole (n=34) versus placebo (n=44) to a previously stabilised antiparkinsonian medication (7 week dose titration interval, 4 week maintenance period). The primary end point of efficacy was the change from baseline in the total score of the unified Parkinson's disease rating scale (UPDRS) in the on "period" (2 hours after intake of study medication). Safety and tolerability were assessed on the basis of adverse events, vital signs, laboratory measurements, and ECG recordings.
                There was a significant improvement of the pramipexole group in UPDRS total scores, subscores part II, III (activities of daily living and motor examination), and IV (complications of therapy). Mean UPDRS total score decreased by 37.3% under pramipexole compared with 12.2% under placebo (p<0.001). Patients under pramipexole reported an overall reduction in "off" periods of 12%--resulting in 1.7 more hours "on" time a day--compared with an increase in "off" periods of 2% under placebo. There were no unexpected safety results. The adverse event profile disclosed a high tolerability. The most important adverse events under pramipexole were fatigue, dyskinesia, and vivid dreams.
                Pramipexole administration is an efficacious and well tolerated add on therapy in patients with advanced Parkinson's disease with an improvement in activities of daily living, motor function, and treatment associated complications.
Pramipexole can be used to reduce off time, improve motor impairments and disability and reduce levodopa dose at the expense of increased dyskinetic adverse events. This conclusion is based on short and medium term trials (up to 24 weeks). Further trials are required to directly compare the newer with the older dopamine agonists.