BACKGROUND:The best way to initiate dopaminergic therapy for early Parkinson disease remains unclear.OBJECTIVE: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.DESIGN:Multicenter, parallel-group, double-blind, randomized controlled trial.SETTING:Academic movement disorders clinics at 22 sites in the United States and Canada.PATIENTS: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.INTERVENTION: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.MAIN OUTCOME MEASURES: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.RESULTS: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.CONCLUSIONS: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.

We report on the development and results of preliminary psychometric testing of a disease specific health‐related quality of life (HRQoL) scale intended for use in individuals diagnosed with idiopathic Parkinson's disease (PD). Results from an initial qualitative study provided content for item development and scale construction of the Parkinson's disease quality of life scale (PDQUALIF). The 33‐item instrument includes seven domains: social/role function, self‐image/sexuality, sleep, outlook, physical function, independence, and urinary function, plus one item of Global HRQoL. Initial psychometric testing of the instrument was conducted in 233 outpatient clinic attendees with physician‐confirmed idiopathic PD. Factor structure, reliability and validity of the scale have been established in this cross‐sectional study. Continuing development of the PDQUALIF will be directed at enhancing the psychometric properties, establishing responsiveness and determining appropriateness in culturally diverse samples. © 2003 Movement Disorder Society

Background: Oral dopamine agonists are effective for treating early Parkinson's disease (PD). Rotigotine is a dopamine agonist delivered through a silicone-based transdermal patch that is replaced every 24 hours.Objectives: To assess the efficacy and safety of rotigotine in patients with PD not receiving dopaminergic medications.Design: Randomized, double-blind, placebo-controlled study.Patients: Two hundred forty-two patients with early PD.Intervention: Treatment with patches containing either 4.5, 9.0, 13.5, or 18.0 mg of rotigotine or placebo for 11 weeks.Main Outcome Measure; The change in the sum of the scores of the activities of daily living and motor components of the Unified Parkinson's Disease Rating Scale from baseline to the end of treatment.Results: There was a significant dose-related improvement in the motor and activities of daily living Unified Parkinson's Disease Rating Scale score between baseline and week 11 for the 13.5- and 18.0-mg groups compared with placebo (placebo, 0.3 +/- 7.7; 13.5-mg group, 5.1 +/- 7.0, P = .001; 18.0-mg group, 5.3 +/- 7.0, P < .001). Adverse experiences that occurred more commonly among subjects randomized to active treatment vs placebo included nausea, application site reactions, dizziness, insomnia, somnolence, vomiting, and fatigue.Conclusions: Rotigotine can be safely administered once daily transdermally and improves parkinsonian signs in patients with early PD.

Context Pramipexole and levodopa are effective medications to treat motor symptoms of early Parkinson disease (PD). In vitro and animal studies suggest that pramipexole may protect and that levodopa may either protect or damage dopamine neurons. Neuroimaging offers the potential of an objective biomarker of dopamine neuron degeneration in PD patients.Objective To compare rates of dopamine neuron degeneration after initial treatment with pramipexole or levodopa in early PD by means of dopamine transporter imaging using single-photon emission computed tomography (SPECT) with 2beta-carboxymethoxy-3beta(4-iodophenyl)tropane (beta-CIT) labeled with iodine 123.Design Substudy of a parallel-group, double-blind randomized clinical trial.Setting and Patients Eighty-two patients with early PD who were recruited at 17 clinical sites in the United States and Canada and required dopaminergic therapy to treat emerging disability, enrolled between November 1996 and August 1997.Interventions Patients were randomly assigned to receive pramipexole, 0.5 mg 3 times per day with levodopa placebo (n=42), or carbidopa/levodopa, 25/100 mg 3 times per day with pramipexole placebo (n=40). For patients with residual disability, the dosage was escalated during the first 10 weeks, and subsequently, open-label levodopa could be added. After 24 months of follow-up, the dosage of study drug could be further modified.Main Outcome Measures The primary outcome variable was the percentage change from baseline in striatal [I-123]beta-CIT uptake after 46 months. The percentage changes and absolute changes in striatal, putamen, and caudate [I-123]beta-CIT uptake after 22 and 34 months were also assessed. Clinical severity of PD was assessed using the Unified Parkinson Disease Rating Scale (UPDRS) 12 hours off anti-PD medications.Results Sequential SPECT imaging showed a decline in mean (SD) [I-123]beta-CIT striatal uptake from baseline of 10.3% (9.8%) at 22 months, 15.3% (12.8%) at 34 months, and 20.7% (14.4%) at 46 months-approximately 5.2% per year. The mean (SD) percentage loss in striatal [I-123] beta-CIT uptake from baseline was significantly reduced in the pramipexole group compared with the levodopa group: 7.1% (9.0%) vs 13.5% (9.6%) at 22 months (P=.004); 10.9% (11.8%) vs 19.6% (12.4%) at 34 months (P=.009); and 16.0% (13.3%) vs 25.5% (14.1%) at 46 months (P=.01). The percentage loss from baseline in striatal [I-123]beta-CIT uptake was correlated with the change from baseline in UPDRS at the 46-month evaluation (r=-0.40; P=.001).Conclusions Patients initially treated with pramipexole demonstrated a reduction in loss of striatal [I-123]beta-CIT uptake, a marker of dopamine neuron degeneration, compared with those initially treated with levodopa, during a 46-month period. These imaging data highlight the need to further compare imaging and clinical end points of PD progression in long-term studies.

CALM-PD (Comparison of the agonist pramipexole with levodopa on motor complications of Parkinson's disease) is a randomized, multicenter, double-blind, controlled clinical trial designed to compare the policy of initial treatment of pramipex ole with the policy of initial treatment with levodopa in early, symptomatic Parkinson's disease with regard to the development of dopamineragic motor complications. At 22 American and Canadian sites, 301 eligible subjects requiring antiparkinsonian therapy to treat emerging disability were enrolled in CALM-PD and randomized to (i) active pramipexole and placebo levodopa or (ii) placebo pramipexole and active levodopa. Subjects are being evaluated systematically at regular intervals during a 23.5-month period to determine if and when dopaminergic motor complications (wearing off, dyskinesias, "on-off " effects) occur. In addition, quality-of-life outcomes, economic outcomes, and functional imaging outcomes are being assessed in standard fashion with [I-123]beta-CIT and SPECT imaging throughout the trial. The study design contains many provisions to approximate routine clinical practice and to produce data about clinical effectiveness, tolerability, and cost to facilitate the evidence-based practice of neurology.

Tolcapone is a potent catechol-O-methyltransferase inhibitor that prolongs the plasma half-life of levodopa. This multicenter, double-blind, placebo-controlled study used two 10-hour clinical evaluations to compare the efficacy and safety of three doses of tolcapone (50, 200, and 400 mg tid) with placebo in patients with Parkinson's disease (PD) experiencing motor fluctuations from levodopa/carbidopa. One hundred fifty-one patients completed the study. Clinical evaluations lasting 10 hours were performed on day -1 and day 42 using United Parkinson's Disease Rating Scale motor subscale and "on/off" and dyskinesia assessments every 30 minutes. Tolcapone significantly reduced "off" time an average of 40% and increased total "on" time by about 25% at all dose levels, as compared to placebo treatment. Levodopa/carbidopa dosage and frequency were significantly reduced. Tolcapone was well tolerated, with patients experiencing typical dopaminergic side effects that could be reduced or eliminated by lowering levodopa/carbidopa dosages. Tolcapone was effective at prolonging the clinical benefit of levodopa and reducing total levodopa requirements in PD patients with motor fluctuations.

Context.-Monotherapy with dopamine agonists may be useful in early Parkinson disease.Objective.-To evaluate dose-response relationships for tolerability, safety, and efficacy of the synthetic dopamine agonist pramipexole.Design.-Multicenter, multidosage, parallel-group, double-blind, placebo-controlled, randomized clinical trial.Setting.-University or academically based movement disorder clinics.Patients.-A total of 264 patients with early Parkinson disease (PD) who were not requiring or receiving levodopa or other dopamine agonists were enrolled.Intervention.-Subjects were randomized to 1 of 5 treatment groups: pramipexole doses of 1.5 mg/d, 3.0 mg/d, 4.5 mg/d, and 6.0 mg/d, or matching placebo. A 6-week dosage escalation period was followed by a 4-week maintenance period and a 1-week period during which active treatment was withdrawn.Main Outcome Measures.-The primary measure of tolerability was the proportion of subjects completing the study on the assigned treatment. The primary measure of efficacy was the change from baseline to 10 weeks in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS).Results.-Pramipexole was generally safe and well tolerated in this 10-week study. The proportion of subjects completing the study on the originally assigned dosage was 98% for placebo and 81% for the 1.5-mg/d, 92% for the 3.0-mg/d, 78% for the 4.5-mg/d, and 67% for the 6.0-mg/d treatment groups. There was a trend toward increased frequency of adverse experiences, particularly somnolence, in the 6.0-mg/d group. After 10 weeks of treatment, pramipexole-treated subjects showed a 20% improvement in total UPDRS scores, with mean improvements in scores ranging from 5.9 to 7.0 units among active treatment groups, compared with 0.9 units for the placebo group (P<.005 for each comparison with placebo). There was also evidence that the treatment effects were more pronounced in subjects with worse UPDRS scores at baseline.Conclusions.-Pramipexole is safe and effective as short-term monotherapy in patients with early PD who are not receiving levodopa. Further study is warranted to determine the long-term impact of pramipexole on the progression of disability in PD and its value in comparison with levodopa therapy and other dopamine agonists.

Motor fluctuations associated with levodopa therapy are common problems encountered in the long-term treatment of Parkinson's disease (PD). Entacapone, a peripherally acting, reversible inhibitor of catechol-O-methyltransferase, slows the elimination of levodopa in humans by reducing the formation of 3-O-methyldopa. We conducted a placebo-controlled, double-blind, parallel-group, multicenter trial of entacapone in PD patients with motor fluctuations. Two hundred five patients were randomized to receive either entacapone 200 mg or matching placebo with each dose of levodopa and were followed for 24 weeks. The primary measure of efficacy was the change in percentage of ''on'' time (relief of parkinsonism) while awake, as recorded by subjects at home in diaries completed at 30-minute intervals. At baseline, patients averaged approximately 10 hours of ''on'' time per day while awake (60.5% ''on'' time), and entacapone treatment increased the percent ''on'' time by 5.0 percentage points. The effect of entacapone was more prominent in patients with a smaller percent ''on'' time (<55%) at baseline, and increased as the day wore on. Entacapone is effective at increasing the duration of response to levodopa and at relieving parkinsonism in patients experiencing motor fluctuations and was well tolerated during the 24 weeks of treatment.