Efficacy
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).
Safety and efficacy measures were obtained at baseline, at weeks 2, 6, 16, and 24, and at a poststudy visit 2 weeks after the treatment period.
Figure 9.
German-Austrian trial: study design.
Of the 301 participating patients, 197 received entacapone (200 mg) and 104 received placebo with each scheduled carbidopa/levodopa or levodopa/benserazide dose for a 6-month treatment period. Patients were required to have stable levodopa regimens for at least 1 month prior to study treatment.
Safety outcome measures included adverse events, possible drug interactions, measurement of blood pressure and heart rate, ECG recording, and laboratory assessments.
Efficacy measures included UPDRS total, motor, and ADL scores, amount of awake time spent in the "On" and "Off" condition (as recorded in patient home diaries), global assessment of clinical condition, and total levodopa dose and dose frequency.
UPDRS ADL and motor scores and hours of daily "On" time were the primary efficacy measures; the other variables were secondary measures.
As this trial was originally planned as a safety study, no a priori sample size calculation was performed. Differences from baseline to week 24 were assessed and compared between the treatment groups for the total population and for the fluctuating population receiving 5 to 10 daily doses of entacapone, using an ITT-LOCF analysis.
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Safety
The overall safety of entacapone was good and comparable with the other phase 3 trials. A compilation of phase 3 clinical safety data is presented in the Safety section of this website.
Efficacy
While the trial was not powered to detect statistically significant differences between treatment groups, the results are consistent with and support the findings in the Nordic and North American trials.
UPDRS scores
Evaluations were performed while patients were in the "On" condition. At week 24, entacapone-treated patients experienced significant improvements in mean total UPDRS scores (P<0.05), and specifically in ADL and motor subscale scores (P<0.05 for each) from baseline, compared to placebo-treated patients (Table 5).3
ITT - last observation carried forward (LOCF) 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.
"On" time
Among entacapone-treated patients with "wearing-off," a trend was seen toward improvement in awake "On" time that was consistent with that seen in the Nordic and North American trials. At week 24, the mean awake "On" time in patients with "wearing-off" and receiving 5 to 10 doses of levodopa daily increased by about 1 hour in the entacapone group, compared to 0.5 hours in the placebo group (Fig 10). Similar results were obtained for the percentage of awake time "On," which at week 24 increased by 6.5% in entacapone-treated patients, compared to 3.5% in placebo-treated patients.
Figure 10.
The mean time spent in the "On" condition while awake,* in wearing-off patients participating in the German-Austrian trial.3
ITT-LOCF analysis (mean values shown) in patients who experience "wearing-off" receiving 5 to 10 doses of levodopa daily.
*As measured in a 24-hour day.
†P=NS, difference between treatment groups.
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"Off" time and levodopa dose
While not achieving statistical significance, the mean awake "Off" time at week 24 in patients with "wearing-off" and receiving 5 to 10 doses of levodopa daily decreased by 1.2 hours in the entacapone group, compared to a 0.6-hour decrease in the placebo group (P=0.07) (Fig 11).
Figure 11.
The mean time spent in the "Off" condition while awake,* in patients participating in the German-Austrian trial.3
ITT-LOCF analysis (mean values shown) in patients who experience "wearing-off" receiving 5 to 10 doses of levodopa daily.
*As measured in a 24-hour day.
†P=0.07, difference between treatment groups.
The mean daily levodopa dose decreased in entacapone-treated patients by about 6% and increased in placebo-treated patients by 0.7% (Fig 12). A statistically significant increase in the frequency of levodopa administration was observed in the placebo group (P<0.01), with about 15% of placebo-treated patients increasing their daily number of administrations, compared with 6% of entacapone-treated patients.3
Figure 12.
The mean daily levodopa dose for patients participating in the German-Austrian trial.3
ITT-LOCF analysis (mean values shown).
*P=NS, difference between treatment groups.
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