The efficacy and tolerability of entacapone was investigated in a randomized, 
double-blind, placebo-controlled, 3-month study of 162 patients with Parkinson's 
disease (PD) treated with levodopa and a dopamine agonist and experiencing 
wearing-off motor fluctuations. Patients were randomized in a 3 : 2 ratio to 
entacapone 200 mg or placebo, administered with each dose of levodopa. Efficacy 
was judged on the improvement of "on" and "off" time while awake (Patient Diary 
and UPDRS part IV Item 39), Investigators' Global Assessment, the SF-36 Health 
Survey, and changes in levodopa dosages. Patients were monitored for adverse 
events, laboratory safety and vital signs throughout the study. Improvements in 
"on" time as assessed using patient diary data showed a trend in favour of 
entacapone, however these did not reach statistical significance. "Off" time 
while awake (UPDRS part IV Item 39) showed an improvement of at least one 
category in 36% of entacapone-treated patients, compared with 22% in the control 
group (p = 0.0038). The proportion of patients showing an improvement at the 
Investigators' Global Assessment was significantly higher (p = 0.0006) in the 
entacapone-treated group of patients. Also, the proportion of patients with a 
reduction in their daily levodopa dose was significantly higher (p = 0.02) in 
the entacapone group (28%) compared with placebo (13%). As expected, the most 
frequent adverse events were dopamine-mediated (dyskinesia: entacapone 31% 
versus placebo 13%), and harmless urinary discoloration. The modest increase in 
dyskinesias could be readily managed by levodopa down-adjustment, and, at study 
end there was no significant difference for the UPDRS "overall dyskinesia score" 
between entacapone and placebo. In conclusion, although the primary efficacy 
variable did not reach statistical significance, the present results demonstrate 
that entacapone provides additional antiparkinsonian benefits to levodopa 
therapy and is well tolerated in levodopa-treated PD patients experiencing 
wearing-off motor fluctuations despite adjunct dopamine agonist therapy.