Randomized trial of tolcapone versus pergolide as add-on to levodopa therapy in Parkinson's disease patients with motor fluctuations. Efficacy and tolerability of tolcapone compared with bromocriptine in levodopa-treated parkinsonian patients. Tolcapone Study Group.
In this 12-week, randomized, open-label, blinded-rater, parallel-group trial, the efficacy, safety, and tolerability of tolcapone and pergolide were compared in parkinsonian patients with a fluctuating response to levodopa. Patients received tolcapone 100 mg three times daily (t.i.d.), with a possible increase to 200 mg t.i.d., or pergolide titrated to a maximum dose of 5 mg/day by week 9 (mean final dose 2.2 mg/day). The trial involved 203 patients. Efficacy variables that decreased from baseline to week 12 with tolcapone and pergolide included "off" time (reduced by 2-3 hours/day), daily levodopa intake, sickness impact profile scores, Parkinson's disease questionnaire (PDQ)-39 scores, and Unified Parkinson's Disease Rating Scale (UPDRS) scores. Improvements in efficacy variables were similar with tolcapone and pergolide, with the exception of improvements in quality of life, which were significantly greater with tolcapone; the relative changes in PDQ-39 score at week 12 were -8.7 and -14.2 (P < 0.05) with pergolide and tolcapone, respectively. Improvements in the investigator's global assessment (IGA) of overall efficacy were recorded in 86% of tolcapone-treated patients and in 78% of pergolide-treated patients. The proportion of patients who withdrew because of adverse events was higher in the pergolide group (15%) than in the tolcapone group (5%). Confusion, hypotension, nausea, constipation, abdominal pain, and dyspepsia occurred more frequently with pergolide, whereas diarrhea and urine discoloration occurred more frequently with tolcapone. Tolcapone was better tolerated than pergolide (P < 0.01) according to the IGA of overall tolerability. We conclude that, in this 3-month study, both tolcapone and pergolide provided improvements in motor fluctuations and allowed reductions in levodopa intake when added to levodopa therapy; intent to treat analysis and a less than maximal dose of pergolide may have biased the results in favor of tolcapone. Tolcapone provided greater improvements in quality of fife, was better tolerated, and had a more favorable adverse-event profile than pergolide.
                Copyright 2001 Movement Disorder Society. The catechol-O-methyltransferase inhibitor tolcapone was compared with the dopamine agonist bromocriptine in an open-label, randomized trial involving 146 levodopa-treated parkinsonian patients with end-of-dose deterioration of efficacy. Tolcapone was given at a dosage of 200 mg three times daily; bromocriptine was titrated from 1.25 mg once daily at baseline to, at most, 10 mg three times daily by day 24 (mean final dose 22.4 mg/day). After 8 weeks, the tolcapone group had a significant reduction in daily levodopa dose compared with the bromocriptine group (p<0.05). No significant differences in the "on/off" time and motor disability were seen between the tolcapone and bromocriptine treatment groups. Bromocriptine induced more hallucinations, orthostatic hypotension, and nausea, whereas tolcapone therapy was associated with more muscle cramps and dystonia. These results suggest that when added to levodopa therapy, the two drugs have a different side effect profile, with the advantages for tolcapone being absence of titration and quicker efficacy.
The two trials comparing tolcapone with the dopamine agonists bromocriptine and pergolide were underpowered to detect clinically relevant differences between them. This is based on medium-term evidence. No evidence was found comparing entacapone with active comparators. Further larger and longer-term trials are required to compare tolcapone with entacapone and COMT inhibitor therapy with alternative adjuvant classes of drug in later Parkinson's disease such as dopamine agonists and monoamine oxidase inhibitors.