Adler TFSGIII 1998.

Methods	Randomised double‐blind parallel group study. Patient randomisation numbers were generated in blocks of 6 for each centre by the sponsor's drug‐packaging department and incorporated into double‐blind labelling. These randomisation numbers were then assigned sequentially in each centre in the order in which the patients were enrolled. 15 centres, USA. Intention‐to‐treat analysis. Duration: 6 weeks
Participants	215 patients, 12 withdrew. 6 withdrew from placebo group, 5 due to adverse effects. 2 withdrew from the 100 mg entacapone group both due to adverse effects. 4 withdrew from 200 mg entacapone, 3 due to adverse events. 149 males. Mean 62 years, mean duration of disease 10.5 years. Mean H&Y can be calculated. Inclusion criteria: Patients were at least 30 years old, had at least 2 of the cardinal signs of idiopathic PD, had been treated with levodopa‐carbidopa for at least one year with clear clinical improvement. They were required to be taking at least 4 daily doses of levodopa‐carbidopa, or 3 doses if at least 2 were controlled release, and to show predictable end‐of‐dose wearing off that could not be eliminated by adjusting their existing antiparkinsonian medications. They had to be able to keep reliable diaries of 'off' and 'on' times. The minimal acceptable dose of carbidopa was 20 mg with each dose of levodopa or a total daily dose of 70 mg. Medications must have been stable 4 weeks prior to randomisation. Women had to be sterile or using effective contraception Exclusion criteria: Nonidiopathic Parkinson's disease or parkinsonian variants, sudden and unpredictable off/on fluctuations, or a diphasic pattern of dyskinesias. Treatment with centrally acting dopamine antagonists or MAO inhibitors (other than selegiline) within previous 2 months, drug or alcohol abuse within previous 2 years, psychotic illness or major depression within last 6 months, and any other clinically significant medical or neurological abnormalities.
Interventions	Patients received 200 mg tid tolcapone (n=74), 100 mg tid tolcapone (n=69) or placebo tid (n=72). The first dose was given with the first dose of levodopa‐carbidopa (either immediate‐release or controlled‐release formulations). The second and third doses were taken at 6‐hour intervals thereafter. Patients could also receive a stable regime of dopamine agonists, selegiline or other antiparkinsonian drugs.
Outcomes	Primary outcome: 'On' and 'Off' times Secondary outcomes: levodopa dose number of levodopa doses UPDRS ADL UPDRS motor (on) UPDRS total SIP physical SIP psychosocial IGA ‐ wearing off IGA ‐ symptom severity IGA ‐ overall efficacy Adverse events
Notes	TOLCAPONE
Risk of bias
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate