Study 1 (Flexible-Dose Trial)

The effectiveness of ropinirole extended-release tablets as adjunctive therapy to L-dopa in patients with Parkinson’s disease was established in a 24-week, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose, clinical trial in 393 patients (Hoehn & Yahr criteria Stages II-IV) who were not adequately controlled by L-dopa therapy. Patients were allowed to be on concomitant selegiline, amantadine, anticholinergics, and catechol-O-methyltransferase inhibitors provided the doses were stable for at least 4 weeks prior to screening and throughout the trial. The primary efficacy endpoint evaluated was the mean change from baseline in total awake time spent “off”.

Patients in this trial had a mean disease duration of 8.6 years, had a mean duration of exposure to L-dopa of 6.5 years, had experienced a minimum of 3 hours’ awake time “off” with a baseline average of approximately 7 hours’ awake time “off”, and had a mean baseline UPDRS motor score of approximately 30 points. The mean baseline dose of L-dopa was 824 mg/day in the group receiving ropinirole extended-release tablets and 776 mg/day in the placebo group. Patients initiated treatment at 2 mg/day for 1 week, followed by increases of 2 mg/day at weekly intervals, to a minimum dose of 6 mg/day. The following week, the total daily dose of ropinirole extended-release tablets could be further increased (based upon therapeutic response and tolerability) to 8 mg/day. Once a daily dose of 8 mg/day was reached, the background L-dopa dosage was reduced. Thereafter, the daily dose could be increased by up to 4 mg/day approximately every 2 weeks until an optimal dose was achieved (based upon therapeutic response and tolerability). The mean dose of ropinirole extended-release tablets at the end of Week 24 was 18.8 mg/day. Dose titrations were based upon the degree of symptom control, planned L-dopa dosage reduction, and/or tolerability. The maximum allowed daily dosage for ropinirole extended-release tablets was 24 mg/day.

The primary efficacy endpoint was mean change from baseline in total awake time spent “off” at Week 24. At baseline, the mean total awake time spent “off” was approximately 7 hours in each treatment group. At Week 24, the total awake time spent “off”, on average, had decreased by approximately 2 hours in the group receiving ropinirole extended-release tablets and by approximately one-half hour in the placebo group. The adjusted mean difference in total awake time spent “off” between ropinirole extended-release tablets and placebo was -1.7 hours, which was statistically significant (analysis of covariance [ANCOVA], P<0.0001). Results for this endpoint, showing the statistical superiority of ropinirole extended-release tablets over placebo, are presented in Table 5.

Table 5. Change from Baseline in Total Awake Time Spent “Off” (Primary Efficacy Endpoint) at Week 24 (Study 1)

The difference between groups in favor of ropinirole extended-release tablets, with regard to a decrease in total “off” hours, was primarily related to an increase in total “on” hours without troublesome dyskinesia. Patients treated with ropinirole extended-release tablets had a mean reduction in L-dopa dose of 278 mg/day (34%), while patients treated with placebo had a mean reduction of 164 mg/day (21%). In patients who reduced their L-dopa dose, reduction was sustained in 93% of patients treated with ropinirole extended-release tablets and in 72% of patients treated with placebo (P<0.001).

Study 2 (Fixed-Dose, Dose-Response Trial)

A double-blind, placebo-controlled, fixed-dose, parallel-group trial evaluated the dose response of ropinirole extended-release tablets as adjunctive therapy to L-dopa in 352 randomized patients with advanced Parkinson’s disease (Hoehn & Yahr criteria Stages II-IV) over a total dosing period of 18 weeks. Patients initiated treatment with placebo or ropinirole extended-release tablets at 2 mg/day for 1 week, and increased to a target dose of 4, 8, 12, 16, or 24 mg/day over a 13-week up-titration period. The dose remained stable over an additional 4-week maintenance period, followed by a 1-week down-titration period. The L-dopa dose was kept constant during the study, if possible. The primary efficacy endpoint was the mean change from baseline in total awake time spent “off” at Week 4 of the maintenance period with daily doses of 4, 8, 12, 16, and 24 mg compared with placebo. The primary statistical analysis of the primary efficacy endpoint was Mixed Model Repeated Measures (MMRM).

At baseline, the mean “off” time ranged from 5.6 to 6.5 hours across groups on ropinirole extended-release tablets and placebo. Table 6 shows the results for the primary efficacy endpoint. The greatest treatment difference (ropinirole extended-release tablets – PLACEBO) for the primary efficacy endpoint was observed with the 8-mg dose; however, higher doses were not shown to provide additional benefit.

Table 6. Change from Baseline in Total Awake Time Spent “Off” (Primary Efficacy Endpoint) at the End of the Maintenance Period (Study 2)