RANDOMIZED, PLACEBO-CONTROLLED STUDY OF TOLCAPONE IN PATIENTS WITH FLUCTUATING PARKINSON-DISEASE TREATED WITH LEVODOPA-CARBIDOPA

Objective: To assess the efficacy and tolerability of the catechol-O-m ethyltransferase inhibitor tolcapone in reducing ''off/on'' fluctuatio ns in levodopa-treated parkinsonian patients. Design: A randomized, do uble-blind, placebo-controlled, parallel-group study. Setting: Fifteen Parkinson disease clinics. Patients: Two hundred fifteen referred out patients with Parkinson disease who showed predictable end-of-dose mot or fluctuations that were not controlled by a stable levodopa-carbidop a (Sinemet) regimen of at least 4 weeks' duration. Interventions: In a ddition to their usual levodopa-carbidopa regimen, patients received p lacebo or tolcapone, 100 or 200 mg, 3 times daily orally for 6 weeks. Primary Outcome Measure: Change in daily off/on time. Results: Tolcapo ne, 100 and 200 mg 3 times daily, reduced off time by 2.0 and 2.5 hour s per day, respectively, and increased on time by 2.1 and 2.3 hours pe r day, respectively (P < .001 vs placebo). Investigators' global measu res of disease severity indicated that significantly more tolcapone-tr eated patients had reduced wearing off and symptom severity (P < .001 vs placebo). No significant change in quality-of-life measures occurre d. Clinical improvements occurred despite a reduction in total daily l evodopa dose of 185.5 mg (23%) in the tolcapone, 100 mg 3 times daily, group and 251.5 mg (29%) in the 200 mg 3 times daily group. Principal adverse events (mainly dyskinesia and nausea) were levodopa related, were not treatment limiting, and were seldom reported as reasons for w ithdrawal. The frequency of withdrawals because of adverse events was similar in all groups (3% to 7%). Conclusions: Tolcapone was well tole rated and substantially increased on time and reduced off time in pati ents with fluctuating Parkinson disease. Additionally, levodopa requir ements were significantly decreased.