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2.237 Ropinirole 24-hour prolonged release improves sleep disturbance, but does not increase daytime somnolence in patients with advanced Parkinson's disease when administered as adjunctive therapy
S108
Tuesday, 11 December 2007
2.237 Ropinirole 24-hour prolonged release improves sleep disturbance, but does not increase daytime somnolence in patients with advanced Parkinson’s disease when administered as adjunctive therapy S. Isaacson1° , F. Stocchi, N. Earl Raton, FL, USA
1 Boca
Objective: A new formulation, ropinirole 24-hour prolonged release, allows a simple, once-daily, dose-titration regimen with potential for enhanced compliance and tolerability in the treatment of Parkinson’s disease (PD). The effect of ropinirole 24-hour adjunctive therapy on sleep and daytime somnolence is presented. Method: The EASE-PD Adjunct study (protocol 101468/169) randomized patients with PD not optimally controlled with L-dopa to ropinirole 24-hour (n = 202) or placebo (n = 191), once daily, for 24 weeks. Initial dose was 2.0 mg/day, titrated to a maximum of 24.0 mg/day. At 8.0 mg/day and at each subsequent increase, L-dopa dose reduction was required. Secondary endpoints included change in PD Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS) total scores. Primary endpoint was mean change from baseline in awake time spent “off ” at Week 24 last observation carried forward (LOCF). Results: Baseline PDSS and ESS total scores were similar between treatment groups. At Week 24 LOCF, patients’ sleep, as measured by PDSS total score, was statistically significantly improved with ropinirole 24-hour versus placebo; adjusted mean change from baseline: 1.3 versus −3.3 (adjusted mean treatment difference [AMTD]: 4.7; 95% confidence interval [CI]: 0.8, 8.6; p = 0.0196). No statistically significant nor clinically relevant change in daytime somnolence was observed between ropinirole 24-hour and placebo, as measured by ESS total score, at Week 24 LOCF (AMTD: 0.3; 95% CI: −0.4, 1.1; p = 0.3692). At Week 24 LOCF, ropinirole 24-hour significantly reduced “off ” time, compared with placebo (AMTD: −1.7 hours; 95% CI: −2.3, −1.1; p < 0.0001). Mean (standard deviation) dose of ropinirole 24-hour at last visit was 18.8 (6.26) mg/day. Conclusion: Once-daily ropinirole 24-hour prolonged release leads to statistically significant improvements in sleep without increased ESSmeasured daytime somnolence, compared with placebo, in patients with PD not optimally controlled with L-dopa. 2.238 Ropinirole 24-hour prolonged-release adjunctive therapy improves cardinal symptoms in patients with advanced Parkinson’s disease not optimally controlled with L-dopa S. Isaacson1° , R. Pahwa, N. Earl Raton, FL, USA
1 Boca
Objective: Ropinirole 24-hour prolonged-release is a new formulation that provides a steady rate of absorption and reduces plasma level fluctuations (data on file). It offers a simple and convenient, once-daily treatment option in Parkinson’s disease (PD). This study evaluated the efficacy of adjunctive ropinirole 24-hour on the cardinal symptoms of PD in patients with PD not optimally controlled with L-dopa. Method: The EASE-PD Adjunct study (protocol 101468/169) randomized patients with advanced PD not optimally controlled with L-dopa to adjunctive ropinirole 24-hour (n = 202) or placebo (n = 191), once daily for 24 weeks. The initial dose was 2 mg/day, titrated to a maximum of 24 mg/day. At 8 mg/day and each subsequent dose increase, L-dopa dose reduction was required. Primary endpoint was mean change in daily “off ” time at Week 24 last observation carried forward (LOCF). Post-hoc analyses assessed mean changes from baseline in the tremor, rigidity and bradykinesia components of the Unified PD Rating Scale. Results: At Week 24 LOCF, significantly greater improvements were seen with ropinirole 24-hour, versus placebo, for change from baseline in tremor (adjusted mean treatment difference [AMTD]: −0.9; 95% CI: −1.3, −0.4; p = 0.0001), rigidity (AMTD: −0.9; 95% CI: −1.4, −0.4; p = 0.0003) and bradykinesia scores (AMTD: −1.8; 95% CI: −2.5, −1.0; p < 0.0001). Ropinirole 24-hour significantly reduced daily “off ” time,
versus placebo, at Week 2 (AMTD: −0.7 hours; 95% CI: −1.1, −0.2; p = 0.0029) and all visits through to Week 24 LOCF (AMTD: −1.7 hours; 95% CI: −2.3, −1.1; p < 0.0001). Mean (standard deviation) dose of ropinirole 24-hour at Week 24 LOCF was 18.8 (6.3) mg/day. Conclusion: Once-daily ropinirole 24-hour prolonged release significantly reduces “off ” time, versus placebo, and provides significant improvements in the cardinal symptoms of tremor, rigidity and bradykinesia in patients with advanced PD not optimally controlled with L-dopa.
2.239 Dose strength equivalence and dose proportionality demonstrated with ropinirole 24-hour prolonged release D. Vearer1° , D. Tompson United Kingdom
1 Harlow,
Objective: Evaluate dose proportionality and dose strength equivalence of ropinirole 24-hour prolonged release in patients with early Parkinson’s disease. Method: In an open-label, multicentre study (protocol 101468/165), patients received once-daily ropinirole 24-hour prolonged release at an initial dose of 2 mg/day, with weekly dose escalation of 2 mg up to 8 mg/day. To assess dose proportionality, steady-state pharmacokinetic evaluations were conducted at the 2, 4 and 8 mg dose levels. To assess steady-state dose strength equivalence, patients were randomized, at the 8 mg dose, to one of two once-daily treatment sequences: (1) ropinirole 24-hour 1 × 8 mg followed by 4× 2 mg; or (2) 4× 2 mg followed by 1 × 8 mg. To assess dose proportionality, estimated mean slopes and 90% CIs using the power model were constructed for AUC(0−24), Cmax and Cmin (primary endpoints). To assess dosage strength equivalence, point estimates and 90% CIs were constructed for AUC(0−24), Cmax and Cmin. Results: Dose proportionality was demonstrated for ropinirole 24-hour prolonged release based on estimated slopes for AUC(0−24) and Cmax, close to unity (1.07 and 1.05, respectively), and 90% CIs contained within dose-range-adjusted limits of 0.84−1.16. For Cmin, the slope was close to unity (1.04), but the upper end of the 90% CI fell marginally outside the pre-defined range. Dosage strength equivalence was demonstrated for Cmin, but for Cmax and AUC(0−24), the upper end of the 90% CI fell marginally outside the limit of 1.25. Bioequivalence was demonstrated for all three endpoints, however, when a single pharmacokinetic outlier was excluded from the statistical analysis. Conclusion: These data demonstrate that once-daily ropinirole 24-hour prolonged release provides a linear increase in systemic exposure to ropinirole over the tablet strength range of 2−8 mg. Patients taking multiple low strength tablets can switch to a single higher strength tablet and maintain similar systemic exposure.
2.240 Steady-state pharmacokinetics of ropinirole 24-hour prolonged release: Relative bioavailability and food effect in patients with Parkinson’s disease D. Vearer1° , D. Tompson United Kingdom
1 Harlow,
Objective: Assess the relative bioavailability of ropinirole 24-hour prolonged release (PR) and ropinirole immediate release (IR), and the effects of food using pharmacokinetic (PK) parameters in patients with Parkinson’s disease. Method: Protocol 101468/164 was an open-label, randomized, two-part study. Part A assessed relative bioavailability of steady-state ropinirole PR (8 mg once daily) versus ropinirole IR (2.5 mg three times daily). Patients were randomized to one of two treatment sequences (PR−IR or IR−PR) over two treatment periods; patients switched formulations at end of period 1. Part B evaluated effect of food intake on rate and extent of ropinirole PR absorption; patients receiving 8 mg ropinirole PR were compared in fed (high-fat breakfast 30mins before dosing) and fasted (overnight fast 10 hours) states. Blood samples for PK evaluation [AUC(0−24), Cmax,
Tuesday, 11 December 2007
2.237 Ropinirole 24-hour prolonged release improves sleep disturbance, but does not increase daytime somnolence in patients with advanced Parkinson’s disease when administered as adjunctive therapy S. Isaacson1° , F. Stocchi, N. Earl Raton, FL, USA
1 Boca
Objective: A new formulation, ropinirole 24-hour prolonged release, allows a simple, once-daily, dose-titration regimen with potential for enhanced compliance and tolerability in the treatment of Parkinson’s disease (PD). The effect of ropinirole 24-hour adjunctive therapy on sleep and daytime somnolence is presented. Method: The EASE-PD Adjunct study (protocol 101468/169) randomized patients with PD not optimally controlled with L-dopa to ropinirole 24-hour (n = 202) or placebo (n = 191), once daily, for 24 weeks. Initial dose was 2.0 mg/day, titrated to a maximum of 24.0 mg/day. At 8.0 mg/day and at each subsequent increase, L-dopa dose reduction was required. Secondary endpoints included change in PD Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS) total scores. Primary endpoint was mean change from baseline in awake time spent “off ” at Week 24 last observation carried forward (LOCF). Results: Baseline PDSS and ESS total scores were similar between treatment groups. At Week 24 LOCF, patients’ sleep, as measured by PDSS total score, was statistically significantly improved with ropinirole 24-hour versus placebo; adjusted mean change from baseline: 1.3 versus −3.3 (adjusted mean treatment difference [AMTD]: 4.7; 95% confidence interval [CI]: 0.8, 8.6; p = 0.0196). No statistically significant nor clinically relevant change in daytime somnolence was observed between ropinirole 24-hour and placebo, as measured by ESS total score, at Week 24 LOCF (AMTD: 0.3; 95% CI: −0.4, 1.1; p = 0.3692). At Week 24 LOCF, ropinirole 24-hour significantly reduced “off ” time, compared with placebo (AMTD: −1.7 hours; 95% CI: −2.3, −1.1; p < 0.0001). Mean (standard deviation) dose of ropinirole 24-hour at last visit was 18.8 (6.26) mg/day. Conclusion: Once-daily ropinirole 24-hour prolonged release leads to statistically significant improvements in sleep without increased ESSmeasured daytime somnolence, compared with placebo, in patients with PD not optimally controlled with L-dopa. 2.238 Ropinirole 24-hour prolonged-release adjunctive therapy improves cardinal symptoms in patients with advanced Parkinson’s disease not optimally controlled with L-dopa S. Isaacson1° , R. Pahwa, N. Earl Raton, FL, USA
1 Boca
Objective: Ropinirole 24-hour prolonged-release is a new formulation that provides a steady rate of absorption and reduces plasma level fluctuations (data on file). It offers a simple and convenient, once-daily treatment option in Parkinson’s disease (PD). This study evaluated the efficacy of adjunctive ropinirole 24-hour on the cardinal symptoms of PD in patients with PD not optimally controlled with L-dopa. Method: The EASE-PD Adjunct study (protocol 101468/169) randomized patients with advanced PD not optimally controlled with L-dopa to adjunctive ropinirole 24-hour (n = 202) or placebo (n = 191), once daily for 24 weeks. The initial dose was 2 mg/day, titrated to a maximum of 24 mg/day. At 8 mg/day and each subsequent dose increase, L-dopa dose reduction was required. Primary endpoint was mean change in daily “off ” time at Week 24 last observation carried forward (LOCF). Post-hoc analyses assessed mean changes from baseline in the tremor, rigidity and bradykinesia components of the Unified PD Rating Scale. Results: At Week 24 LOCF, significantly greater improvements were seen with ropinirole 24-hour, versus placebo, for change from baseline in tremor (adjusted mean treatment difference [AMTD]: −0.9; 95% CI: −1.3, −0.4; p = 0.0001), rigidity (AMTD: −0.9; 95% CI: −1.4, −0.4; p = 0.0003) and bradykinesia scores (AMTD: −1.8; 95% CI: −2.5, −1.0; p < 0.0001). Ropinirole 24-hour significantly reduced daily “off ” time,
versus placebo, at Week 2 (AMTD: −0.7 hours; 95% CI: −1.1, −0.2; p = 0.0029) and all visits through to Week 24 LOCF (AMTD: −1.7 hours; 95% CI: −2.3, −1.1; p < 0.0001). Mean (standard deviation) dose of ropinirole 24-hour at Week 24 LOCF was 18.8 (6.3) mg/day. Conclusion: Once-daily ropinirole 24-hour prolonged release significantly reduces “off ” time, versus placebo, and provides significant improvements in the cardinal symptoms of tremor, rigidity and bradykinesia in patients with advanced PD not optimally controlled with L-dopa.
2.239 Dose strength equivalence and dose proportionality demonstrated with ropinirole 24-hour prolonged release D. Vearer1° , D. Tompson United Kingdom
1 Harlow,
Objective: Evaluate dose proportionality and dose strength equivalence of ropinirole 24-hour prolonged release in patients with early Parkinson’s disease. Method: In an open-label, multicentre study (protocol 101468/165), patients received once-daily ropinirole 24-hour prolonged release at an initial dose of 2 mg/day, with weekly dose escalation of 2 mg up to 8 mg/day. To assess dose proportionality, steady-state pharmacokinetic evaluations were conducted at the 2, 4 and 8 mg dose levels. To assess steady-state dose strength equivalence, patients were randomized, at the 8 mg dose, to one of two once-daily treatment sequences: (1) ropinirole 24-hour 1 × 8 mg followed by 4× 2 mg; or (2) 4× 2 mg followed by 1 × 8 mg. To assess dose proportionality, estimated mean slopes and 90% CIs using the power model were constructed for AUC(0−24), Cmax and Cmin (primary endpoints). To assess dosage strength equivalence, point estimates and 90% CIs were constructed for AUC(0−24), Cmax and Cmin. Results: Dose proportionality was demonstrated for ropinirole 24-hour prolonged release based on estimated slopes for AUC(0−24) and Cmax, close to unity (1.07 and 1.05, respectively), and 90% CIs contained within dose-range-adjusted limits of 0.84−1.16. For Cmin, the slope was close to unity (1.04), but the upper end of the 90% CI fell marginally outside the pre-defined range. Dosage strength equivalence was demonstrated for Cmin, but for Cmax and AUC(0−24), the upper end of the 90% CI fell marginally outside the limit of 1.25. Bioequivalence was demonstrated for all three endpoints, however, when a single pharmacokinetic outlier was excluded from the statistical analysis. Conclusion: These data demonstrate that once-daily ropinirole 24-hour prolonged release provides a linear increase in systemic exposure to ropinirole over the tablet strength range of 2−8 mg. Patients taking multiple low strength tablets can switch to a single higher strength tablet and maintain similar systemic exposure.
2.240 Steady-state pharmacokinetics of ropinirole 24-hour prolonged release: Relative bioavailability and food effect in patients with Parkinson’s disease D. Vearer1° , D. Tompson United Kingdom
1 Harlow,
Objective: Assess the relative bioavailability of ropinirole 24-hour prolonged release (PR) and ropinirole immediate release (IR), and the effects of food using pharmacokinetic (PK) parameters in patients with Parkinson’s disease. Method: Protocol 101468/164 was an open-label, randomized, two-part study. Part A assessed relative bioavailability of steady-state ropinirole PR (8 mg once daily) versus ropinirole IR (2.5 mg three times daily). Patients were randomized to one of two treatment sequences (PR−IR or IR−PR) over two treatment periods; patients switched formulations at end of period 1. Part B evaluated effect of food intake on rate and extent of ropinirole PR absorption; patients receiving 8 mg ropinirole PR were compared in fed (high-fat breakfast 30mins before dosing) and fasted (overnight fast 10 hours) states. Blood samples for PK evaluation [AUC(0−24), Cmax,