Efficacy

MIRAPEX® Tablets

The effectiveness of MIRAPEX® Tablets in the treatment of Parkinson's disease (PD) was evaluated in a multinational drug development program consisting of seven randomized, controlled trials.¹ Three were conducted in patients with early PD who were not receiving concomitant levodopa, and four were conducted in patients with advanced PD who were receiving concomitant levodopa.¹ Among these seven studies, three studies provide the most persuasive evidence of MIRAPEX®'s effectiveness in the management of patients with PD who were and were not receiving concomitant levodopa.¹ Two of these three trials enrolled patients with early PD (not receiving levodopa), and one enrolled patients with advanced PD who were receiving maximally tolerated doses of levodopa.¹

In all studies, the Unified Parkinson's Disease Rating Scale (UPDRS), or one or more of its subparts, served as the primary outcome assessment measure. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), activities of daily living (part II), motor performance (part III), and complications of therapy (part IV). Part II of the UPDRS contains 13 questions relating to activities of daily living (ADL), which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II. It is designed to assess the severity of the cardinal motor findings in patients with PD (e.g., tremor, rigidity, bradykinesia, postural instability, etc), scored for different body regions, and has a maximum (worst) score of 108.¹

• Early PD

Patients were randomized to MIRAPEX® or placebo. Patients treated with MIRAPEX® had a starting daily dose of 0.375 mg and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) total score was 1.9 in the group receiving MIRAPEX® and -0.4 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.0 in the group receiving MIRAPEX® and -0.8 in the placebo group, a difference that was also statistically significant. A statistically significant difference between groups in favor of MIRAPEX® was seen beginning at week 2 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 3 of the UPDRS part III (maximum dose 1.5 mg/day).

In addition, another PD study (N=264) was a double-blind, placebo-controlled, parallel trial consisting of a 6-week dose-escalation period and a 4-week maintenance period.¹ Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but could not be on levodopa products. Patients were randomized to 1 of 4 fixed doses of MIRAPEX® (1.5 mg, 3.0 mg, 4.5 mg, or 6.0 mg per day) or placebo.¹ At the end of the 4-week maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.8 in the patients treated with MIRAPEX®, regardless of assigned dose group, and 0.3 in placebo-treated patients. The mean improvement from baseline on the UPDRS part III total score was 4.2 in patients treated with MIRAPEX® and 0.6 in placebo-treated patients.¹ No dose-response relationship was demonstrated. The between-treatment differences on both parts of the UPDRS were statistically significant in favor of MIRAPEX® for all doses.¹

• Advanced PD

Patients treated with MIRAPEX® had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses.¹ At selected times during the 6-month maintenance period, patients were asked to record the amount of "off," "on," or "on with dyskinesia" time per day for several sequential days.¹ At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 2.7 in the group treated with MIRAPEX® and 0.5 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.6 in the group treated with MIRAPEX® and 2.8 in the placebo group, a difference that was statistically significant.¹ A statistically significant difference between groups in favor of MIRAPEX® was seen at week 3 of the UPDRS part II (maximum dose 1.5 mg/day) and at week 2 of the UPDRS part III (maximum dose 0.75 mg/day). Dosage reduction of levodopa was allowed during this study if dyskinesia (or hallucinations) developed; levodopa dosage reduction occurred in 76% of patients treated with MIRAPEX® versus 54% of placebo patients. On average, the levodopa dose was reduced 27%.¹

• Restless Legs Syndrome

The efficacy of MIRAPEX® was evaluated in four placebo-controlled trials in approximately 1,000 patients with moderate to very severe Restless Legs Syndrome. ¹ Efficacy was demonstrated in controlled trials in patients treated for up to 12 weeks and sustained efficacy was shown over a period of 9 months. ¹ The efficacy of MIRAPEX® was maintained during open continuation trials lasting for up to 1 year. Longer term efficacy was evaluated in a placebo-controlled clinical trial. ¹ After 26 weeks of treatment, there was an adjusted mean reduction in IRLS total score of 13.7 and 11.1 points in the MIRAPEX® and placebo group, respectively, with a statistically significant (p = 0.008) mean treatment difference of -2.6. CGI-I responder rates (much improved, very much improved) were 50.3% (80/159) and 68.5% (111/162) for placebo and MIRAPEX®, respectively (p = 0.001), corresponding to a number needed to treat of 6 patients (95%CI: 3.5, 13.4).¹

MIRAPEX® Prolonged-Release (PR) tablets

The effectiveness of MIRAPEX® Prolonged-Release (PR) tablets in the treatment of PD was supported by clinical pharmacokinetic data and two randomized, double-blind, placebo-controlled, multicenter clinical trials in early and advanced PD. ¹ In both randomized studies, the UPDRS served as a primary outcome assessment measure. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and complications of therapy (Part IV). Part II of the UPDRS contains 13 questions related to activities of daily living, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings in patients with PD (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions and has a maximum (worst) score of 108. ²

• Early PD

The effectiveness of MIRAPEX® PR tablets in early PD patients (Hoehn & Yahr Stages I-III) who were not on levodopa therapy was established in a randomized, double-blind, placebo-controlled, 3-parallel-group clinical study. Patients were treated with MIRAPEX® PR tablets, immediate-release MIRAPEX® tablets, or placebo; those treated with MIRAPEX® PR tablets or IR MIRAPEX® tablets had a starting dose of 0.375 mg/day followed by a flexible up-titration, based on efficacy and tolerability, up to 4.5 mg/day. Levodopa was permitted during the study as rescue medication. Stable doses of concomitant MAO-B inhibitors, anticholinergics, or amantadine, individually or in combination, were allowed. The primary efficacy endpoint was the mean change from baseline in the UPDRS Parts II+III score for MIRAPEX® PR tablets versus placebo following 18 weeks of treatment.²

At 18 weeks of treatment, the mean change from baseline UPDRS Parts II+III score was -8.1 points in patients receiving MIRAPEX® PR tablets (n=102) and -5.1 points in patients receiving placebo (n=50), a difference that was statistically significant (p<0.03). Seven patients treated with placebo (14%) and 3 patients treated with MIRAPEX® PR tablets (3%) received levodopa rescue medication. At 18 weeks, the mean dose of MIRAPEX® PR was 3 mg/day. ²

At 33-weeks the adjusted mean improvement from baseline UPDRS Parts II+III score was -8.6 points in patients receiving MIRAPEX® PR tablets (n=213), compared to -3.8 points in patients receiving placebo (n=103). ²

At 18 and 33 weeks, the mean dose of MIRAPEX® PR tablets was approximately 3 mg/day. Twenty-two patients treated with placebo (21%) and 15 patients treated with MIRAPEX® PR tablets (7%) received levodopa rescue medication before the final assessment. No differences in effectiveness based on age or gender were detected. Patients receiving monoamine oxidase type B inhibitor, anticholinergics, or amantadine had responses similar to patients not receiving these drugs. ²

• Advanced PD

The effectiveness of MIRAPEX® PR tablets in advanced PD patients (Hoehn & Yahr Stages II-IV at ON time) who were on concomitant levodopa therapy (at an optimized dose) and who had motor fluctuations (at least 2 cumulative hours of OFF time per day) was established in a randomized, double-blind, placebo-controlled, 3-parallel group clinical study. Patients were treated with MIRAPEX® PR tablets, immediate-release MIRAPEX® tablets, or placebo; those treated with MIRAPEX® PR tablets or immediate-release MIRAPEX® tablets had a starting dose of 0.375 mg/day followed by a flexible up-titration over 7 weeks, based on efficacy and tolerability, up to 4.5 mg/day, followed by a 26 week maintenance period. Levodopa dosage reduction was permitted only in the case of dopaminergic adverse events. The primary efficacy endpoint was the adjusted mean change from baseline in the UPDRS Parts II+III score for MIRAPEX® PR tablets versus placebo following 18 weeks of treatment. ²

At 18 weeks of treatment, the adjusted mean improvement from baseline UPDRS Parts II+III score was -11.0 points in patients receiving MIRAPEX® PR tablets (n=161) and -6.1 points in patients receiving placebo (n=174), (p=0.0001). At week 18, the adjusted mean improvement from baseline in “off time” was -2.1 hours for PPX ER and -1.4 hours for placebo (p=0.0199). ²

At 33-weeks the adjusted mean improvement from baseline UPDRS Parts II+III score was –11.1 points in patients receiving MIRAPEX® PR tablets (n=117) and –6.8 points in patients receiving placebo (n=136) (p=0.0135). At both 18 and 33 weeks the mean daily dose of MIRAPEX® PR was 2.6 mg/day. At week 18, 4 patients (3%) in the placebo group and 14 patients (11%) in the PPX ER group had decreased their levodopa daily dose compared to baseline due to dopaminergic adverse events. No clinically relevant difference in effectiveness was observed in the sub-group analyses based on gender, age, race (White vs. Asian), or concomitant use of antiparkinsonian treatment (monoamine oxidase type B inhibitor, amantadine or anticholinergics). ²