Efficacy and safety of tolcapone in levodopa‐treated Parkinson's disease patients with “wearing‐off” phenomenon: a multicentre, double‐blind, randomized, placebo‐controlled trial

To assess the effect of tolcapone added to levodopa plus benserazide or carbidopa on the “wearing-off” phenomenon in patients with Parkinson's disease, we undertook a double-blind, randomized, placebo-controlled, parallel-group study of tolcapone 50, 200, or 400 mg three times daily (t.i.d.) for 6 weeks in addition to levodopa therapy. We studied 154 parkinsonian patients, aged 40 years or more, who presented with the “wearing-off” phenomenon despite “optimal” antiparkinsonian therapy. The main outcome measures were “on”- and “off”-time, Investigator's Global Assessments, Subscales of the Unified Parkinson's Disease Rating Scale, changes in levodopa dosage, and safety and tolerability. Tolcapone was more effective than placebo in reducing the “wearing-off” phenomenon between baseline and week 6 at all three dosages. Tolcapone 200 mg t.i.d. increased “on”-time from 37.9% of the waking day to 50.8% (p < 0.01) and reduced “off”-time from 26.7% of the waking day to 16.4% (p < 0.05). Tolcapone treatment was generally well tolerated at all dosages. Initial exacerbation of adverse dopaminergic effects was controlled by levodopa dosage adjustment; at week 6, the mean total daily levodopa dosage had decreased by 80 mg, from 694 mg at baseline, in the tolcapone 200 mg t.i.d. group (p < 0.01). We conclude that the addition of tolcapone to levodopa plus a decarboxylase inhibitor effectively and safely reduces the “wearing-off” phenomenon in parkinsonian patients.