Figure 5.
North American trial: study design.

Patients and methods

There were no significant differences in demographics between the entacapone (n=103) and placebo (n=102) study groups. Over the 3 days prior to each study visit, patients recorded whether they were "On," "Off," or "asleep" at half-hour intervals over a 24-hour day. During each visit, response to study medication was evaluated through the change in the percentage of "On" time (periods relatively free of parkinsonian symptoms) while awake, which was the primary outcome measure for this study, and by secondary outcome measures.

Results

"On" time
During the stable treatment period, the mean proportion of awake time spent in the "On" condition in entacapone-treated patients increased by 11.2% (from 60.0% at baseline to 66.7%) (Fig 6). In contrast, in placebo-treated patients the mean proportion of awake time spent in the "On" condition increased only slightly, by 3.3% (from 60.8% at baseline to 62.8%). The difference in the change experienced by each study group was statistically significant (P<0.05).^{2, 3}

Entacapone withdrawal resulted in a decrease in the mean proportion of time spent in the "On" condition from stable treatment period values to near baseline values. The decrease experienced by entacapone-treated patients within 2 days of withdrawal was significant when compared to the change experienced by placebo-treated patients during this same period (P<0.01).²

Figure 6.
The change in the mean proportion of time spent in the "On" condition while awake,* in patients participating in the North American trial.^{2, 3}


ITT analysis-mean values shown.
*As measured in a 24-hour day.
†P<0.05, difference between treatment groups.
Additional data on file, Orion Corporation, Finland.

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"Off" time
During the stable treatment period, the mean awake "Off" time in entacapone-treated patients decreased by 1.2 hours (from 6.8 hours at baseline), compared to a 0.3 hour decrease in placebo-treated patients (from 6.6 hours at baseline) (Fig 7). This represents a 0.9 hour (13%) difference baseline (P<0.01).³

Figure 7.
The change in the mean number of hours spent in the "Off" condition while awake,* in patients participating in the North American trial.³

ITT analysis (mean ± SEM).
*As measured in a 24-hour day.
†P<0.01, difference between treatment groups.
Additional data on file, Orion Corporation, Finland.

UPDRS scores
Patient total and subscale UPDRS scores were assessed in both study groups at baseline and at week 24. Evaluations were performed while patients were "On," an average of 1.5 hours after a levodopa dose. Entacapone-treated patients experienced significant improvements in mean total UPDRS scores, as well as in part II (ADL) and part III (motor examination) subscale scores (P<0.05 for each) from baseline to week 24, in comparison with placebo-treated patients (Table 4).^{2, 3} As in the Nordic trial, the improvement seen in patients' ADL subscale scores has particular clinical significance, as these reflect a patient's ability to complete the essential tasks of day-to-day life. By 2 weeks postwithdrawal, entacapone-treated patients experienced a significant worsening in mean total UPDRS (P=0.004) and motor subscale (P=0.030) scores from week 24 values, in comparison to placebo-treated patients, indicating a deterioration of motor functional ability.²

ITT analysis.
UPDRS = Unified Parkinson's Disease Rating Scale; ADL = activities of daily living.
*Measured while patients were "On."
† P value, compared to placebo-treated group.

Levodopa dose
Patients recorded their daily levodopa dose for each of 3 days immediately prior to a study visit.² During the stable treatment period, the mean daily levodopa dose was reduced in entacapone-treated patients by about 12% (from 804 mg at baseline to 711 mg) to manage dopaminergic side effects, and increased in placebo-treated patients by about 3% (from 758 mg at baseline to 777 mg) (Fig 8). The difference in the change of daily levodopa dose between the 2 study groups was significant (P<0.001).³ By 2 weeks postwithdrawal, entacapone-treated patients required a mean increase in daily levodopa dose of approximately 80 mg from stable treatment period values to control motor symptoms.³

Figure 8.
The mean daily levodopa dose for patients participating in the North-American trial.^2,3

ITT analysis (mean ± SEM).
*P<0.001, difference between treatment groups.
Additional data on file, Orion Corporation, Finland.
Adapted with permission from Parkinson Study Group. Ann Neurol. 1997;42:747-755.²
© Lippincott Williams & Wilkins