The effectiveness of pramipexole dihydrochloride extended- release tablets in the treatment of Parkinson's disease was supported by clinical pharmacokinetic data [see Clinical Pharmacology (12.3)] and two randomized, double-blind, placebo- controlled, multicenter clinical trials in early and advanced Parkinson's disease. In both randomized studies, the Unified Parkinson's Disease Rating Scale (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 Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions and has a maximum (worst) score of 108.

Early Parkinson's Disease

The effectiveness of pramipexole dihydrochloride extended- release tablets in early Parkinson's disease 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 pramipexole dihydrochloride extended-release tablets, immediate-release pramipexole tablets, or placebo; those treated with pramipexole dihydrochloride extended-release tablets or immediate-release pramipexole 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 pramipexole dihydrochloride extended-release tablets versus placebo following 18 weeks of treatment.

At 18 weeks of treatment, the mean change from baseline UPDRS Parts II+III score was –8.1 points in patients receiving pramipexole dihydrochloride extended- release 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 pramipexole dihydrochloride extended-release tablets (3%) received levodopa rescue medication. At 18 weeks, the mean dose of pramipexole dihydrochloride extended- release tablets was 3 mg/day.

At 33-weeks, the adjusted mean improvement from baseline UPDRS Parts II+III score was –8.6 points in patients receiving pramipexole dihydrochloride extended- release tablets (n=213), compared to –3.8 points in patients receiving placebo (n=103).

At 18 and 33 weeks, the mean dose of pramipexole dihydrochloride extended- release tablets was approximately 3 mg/day. Twenty-two patients treated with placebo (21%) and 15 patients treated with pramipexole dihydrochloride extended-release tablets (7%) received levodopa rescue medication before the final assessment.

No differences in effectiveness based on age or gender were detected. Patients receiving MAOB-I, anticholinergics, or amantadine had responses similar to patients not receiving these drugs.

Advanced Parkinson's Disease

The effectiveness of pramipexole dihydrochloride extended- release tablets in advanced Parkinson's disease 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 pramipexole dihydrochloride extended- release tablets, immediate-release pramipexole tablets, or placebo; those treated with pramipexole dihydrochloride extended-release tablets or immediate- release pramipexole 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 pramipexole dihydrochloride extended- release tablets versus placebo following 18 weeks of treatment.

At 18 weeks of treatment, the adjusted mean improvement from baseline UPDRS Parts II+III score was –11.0 points in patients receiving pramipexole dihydrochloride extended- release 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 pramipexole dihydrochloride extended- release tablets and –1.4 hours for placebo (p=0.0199).

At 33-weeks the adjusted mean improvement from baseline UPDRS Parts II+III score was –11.1 points in patients receiving pramipexole dihydrochloride extended- release 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 pramipexole dihydrochloride extended- release tablets was 2.6 mg/day. At week 18, 4 patients (3%) in the placebo group and 14 patients (11%) in the pramipexole dihydrochloride extended- release tablets 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 (MAOB-I, amantadine or anticholinergics).