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EfficacyThree long-term phase 3 clinical trials were conducted to demonstrate the efficacy and safety of entacapone as an adjunct to levodopa in Parkinson's disease patients. Two of these, the Nordic trial (NOMECOMT-Nordic Multicenter Study on Entacapone, the COMT Inhibitor)1 and the North American trial (SEESAW-Safety and Efficacy of Entacapone Study Assessing Wearing-Off),2 focused on the efficacy and safety of entacapone 200 mg as a complement to levodopa therapy in patients with Parkinson's disease exhibiting end-of-dose "wearing-off." The third trial, a German-Austrian study, focused primarily on the safety of entacapone treatment, although efficacy parameters were also assessed.
Nordic Multicenter Study on Entacapone
The experimental design of the Nordic trial (Fig 1) consisted of a 4-week run-in screening period, which allowed the stabilization of patients' antiparkinsonian medication prior to randomization,1 followed by a 24-week double-blind treatment period. Efficacy measures were obtained at baseline, and at weeks 2, 4, 8, 16, 24, and 26. The final assessment of efficacy parameters allowed an unblinded assessment of the effects of entacapone withdrawal.1
North American Study
The experimental design of the North American trial (Fig 5) was nearly identical to that of the Nordic trial. It began with a 4-week run-in screening period, which allowed the stabilization of patients' antiparkinsonian medication prior to randomization.2, 3 Patients were then randomized to receive either entacapone or placebo during the course of the study. Patients designated to receive entacapone were further randomized to receive either a 24- or 26-week course of treatment, followed respectively by either 4 or 2 weeks of placebo. Efficacy measures were obtained at baseline, and at weeks 2, 4, 8, 16, 24, 26, and 28. The variable duration of the treatment phase of this study allowed a staggered, blinded washout period for the evaluation of the effects of entacapone withdrawal.
German-Austrian Study
The German-Austrian trial was a multicenter, randomized, double-blind, placebo-controlled (2:1), phase 3 study assessing the safety of entacapone as a complement to levodopa therapy. Efficacy parameters were also measured. Patients who participated were not required to have been experiencing "wearing-off" (Data for section on file, Orion Corporation, Finland).
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Both the Nordic and North American trials were collaborative efforts involving multiple study centers. The Nordic trial involved 171 parkinsonian patients, and the North American trial involved 205 patients. Each trial was 6 months long and had a randomized, placebo-controlled, parallel-group, double-blind design.1, 2
Patients participating in the Nordic and North American studies were given either placebo or entacapone (200 mg) with each dose of levodopa and dopa decarboxylase (DDC) inhibitor (carbidopa or benserazide in the Nordic trial, carbidopa in the North American trial), up to 10 times per day. The 24-week treatment phase was followed by a 2- or 4-week withdrawal period.1, 2 In both trials, adjustments in levodopa dosage were permitted in the early portion of the treatment period (weeks 1 to 8), but levodopa dosage was held constant thereafter (weeks 8 to 24-the stable treatment period), unless clinical status mandated further changes. Sustained-release levodopa formulations were not allowed in either study. The efficacy measures for each study are shown in Table 1. Patients treated with amantadine, anticholinergics, selegiline, or dopamine agonists were eligible for participation in both the Nordic and North American studies; no significant interactions were observed between entacapone and these antiparkinsonian medications. Nonselective monoamine oxidase (MAO) inhibitors were not allowed in either study. A summary of the Nordic and North American trials is presented in Table 2.
AEs = adverse events; PRN = as needed; UPDRS = Unified Parkinson's Disease Rating Scale; ADL = activities of daily living.
*Stable treatment period values are the average of values measured at weeks 8, 16, and 24, by protocol-defined outcome measure.
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