Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations

Although levodopa combined with a dopa decarboxylase (DDC) inhibitor is currently the mainstay and most effective treatment of PD, it is not considered to be pharmacokinetically or pharmacodynamically ideal.^1,2 Furthermore, long-term levodopa treatment is accompanied by an increasing frequency of levodopa-related fluctuations in disability.^3,4 These fluctuations may be related partly to oscillations in plasma levodopa concentrations,^1,2 which could be stabilized by preventing the metabolism of levodopa. Currently, when the peripheral decarboxylation of levodopa is blocked with a DDC inhibitor, the enzyme catechol-O-methyltransferase (COMT) compensates by degrading levodopa into 3-O-methyldopa (3-OMD).^5,6 Only a small proportion of the levodopa is metabolized by COMT in the brain. Thus, by blocking COMT in the gastrointestinal tract and in the periphery, more levodopa will eventually reach the striatum to be decarboxylated into dopamine.^5,6 This was confirmed in PET studies that demonstrated that COMT inhibition with entacapone increases the availability of fluorodopa-a levodopa analog-for decarboxylation in the brain.^7-9

It was not until the late 1980s that a second generation of highly potent, selective, orally active nitrocatechol-structured COMT inhibitors was developed.^5,6 One of the most promising is the peripherally acting COMT inhibitor entacapone.¹⁰ The absorption of entacapone is rapid and it has a short half-life of approximately 0.5 hours (β-phase) and 2 to 3 hours (γ-phase) after oral administration.¹¹ The pharmacokinetics of entacapone are similar for PD patients and healthy volunteers.^11-14 Entacapone and levodopa have similar pharmacokinetic profiles and thus entacapone is coadministered with each levodopa dose.

When used concomitantly with levodopa/DDC inhibitor treatment regimes, entacapone increases the area under the concentration-time curve of levodopa, prolongs its half-life of elimination, and delays the fall in plasma levodopa without influencing the peak plasma levodopa concentration (C_max) or the time when the maximum concentration is reached (t_max).^5,12-19 Short-term studies of as long as 2 months incorporating single and multiple levodopa doses have demonstrated that entacapone prolongs the therapeutic response to levodopa significantly in parkinsonian patients with motor fluctuations.^13,14,16-19

To elucidate further the efficacy of entacapone in the treatment of PD we report a 6-month, double-blind, randomized, placebo-controlled, long-term study in which entacapone was used as an adjunct to levodopa in PD patients with end-of-dose deteriorations.

Patients and methods. Patients. A total of 171 patients with PD entered the study. Of these, 152 patients completed the entire course of the study: 77 in the entacapone group and 75 in the placebo group. The study was conducted in 16 neurologic departments in the Nordic countries. The patients were given oral and written information, and they gave their written consent. Ethics committees approved the study protocol according to national regulations. The study followed the guidelines of the amended Declaration of Helsinki.

The inclusion criteria were as follows: levodopa-responsive patients with idiopathic PD with motor fluctuations of the end-of-dose type (wearing-off phenomenon) as judged by clinical history and examination, Hoehn and Yahr stage between 1.5 to 4.0 according to the modified scale (defined in "on" phase), and average "on" time after each single dose of levodopa less than 4 hours. Patients taking 4 to 10 daily doses of standard levodopa as either levodopa/carbidopa or levodopa/benserazide preparations could be included. Controlled-release levodopa preparations were not permitted. Patients treated with amantadine, anticholinergics, selegiline, or dopamine agonists in addition to levodopa were eligible.

Demographic data of the patients and some characteristics of PD are presented in table 1. The mean duration of PD and of levodopa therapy was slightly longer (p < 0.05) in the placebo group than in the entacapone group. These differences should not have any clinical significance.

Methods. This study had a parallel-group, randomized, double-blind design. The patients took either entacapone or placebo for 6 months (24 weeks). The study comprised six study visits (at the 0-, 2-, 4-, 8-, 16-, and 24-week time points) and a poststudy visit 2 weeks after withdrawal of the study medication.

After the patients were screened for the study, their antiparkinsonian medications (both levodopa and other antiparkinsonian drugs) were optimized individually at a level at which they were required to remain for at least 4 weeks before randomization. Entacapone 200 mg or identical placebo tablets were given in combination with each scheduled levodopa/DDC inhibitor dose (4 to 10 doses daily). The levodopa dose was adjusted during the study as considered clinically necessary, primarily by decreasing or increasing the dose and secondarily by changing the dosing interval; although, as much as possible, it was to be unchanged at the last three time points (weeks 8, 16, and 24).

Patients completed a home diary for 5 days before each study visit that was reviewed at the visit by the investigator. For the initial 2 diary days, the duration of the effect of the first morning levodopa dose was recorded. During the last 3 days of the diary-recording periods the patients recorded whether they were "on," "off," or "in bed" at half-hour intervals (covering the 18-hour period from 06:00 to 24:00 hours). The "on" time could be described as a period when the patient was relatively free of parkinsonian symptoms (e.g., mobile or capable of moving with relative ease and independence). The "off" time could be described as a period when the patient experienced increased parkinsonian symptoms (e.g., immobility or inability to move with ease). The total Unified Parkinson's Disease Rating Scale (UPDRS) score, and the global evaluation, were assessed at baseline and at the end of the study (week 24).

At each study visit the motor part (part III) of the UPDRS and daily fluctuations in disability were assessed. In addition, patients were asked to assess verbally the duration of benefit from a single daily levodopa dose. The total daily levodopa dose and the number of daily doses, and changes in other medications, were also recorded at each visit. During the study, adverse events, blood pressure, heart rate, and electrocardiograms (ECGs) were recorded and blood samples taken for safety evaluation (hematology, biochemistry, and urinalysis). Compliance was assessed by tablet count in all patients, and in 11 of the 16 centers by measurement of plasma 3-OMD concentrations in 58 entacapone-treated patients and in 59 placebo-treated patients.

The efficacy parameters and levodopa dosing were monitored in an unblinded fashion 2 weeks after the study medications were withdrawn. Home diaries were completed during the 5 days preceding the poststudy visit.

Evaluations. The primary efficacy parameters were mean daily "on" time and the duration of "on" time after the first morning levodopa dose, as derived from the home diaries.

Secondary efficacy parameters were daily "off" time, the patients' self-estimation of the average benefit from a single daily levodopa dose, the different parts of the UPDRS evaluated by the investigators before noon when the patients were "best on" (1.5 to 1.8 hours after intake of the last levodopa dose), daily fluctuations in disability evaluation (results not shown), and an evaluation of global score by both the patient and the investigator (on a 9-point scale).

Statistics. All randomized patients were included in the intent-to-treat (ITT) analyses. The main analyses were ITT by last observation carried forward. In instances when patients discontinued the study prematurely, before week 4, the baseline was carried forward. Efficacy evaluation was based on observations recorded from the last three study visits while the patients were taking medication (weeks 8, 16, and 24). For continuous variables, the entacapone group was compared with the placebo group with ANCOVA using the baseline as a covariate. For categoric variables, the Cochran-Mantel-Haenszel test was used. Bonferroni adjustment was applied in multiple comparisons. A two-way significance level of 5% was considered to be statistically significant. Variables based on home diaries, average duration of benefit from a single levodopa dose, daily levodopa dose and dosing frequency, and part III of the UPDRS were analyzed as the mean of the last three visits (weeks 8, 16, and 24). Comparison of entacapone and placebo treatments with respect to other parts of the UPDRS were analyzed at baseline and during week 24, as were differences in global evaluation. The withdrawal effect was evaluated by comparing the poststudy visit (week 26) with the last study visit (week 24).

Results. Therapeutic responses. The mean "on" time measured from home diaries increased by 1.2 hours more (13%) in the entacapone group than in the placebo group (table 2, figure 1). This intergroup difference was highly significant statistically (p < 0.001). Correspondingly, the mean "off" time decreased by 1.3 hours more (-22%) in the entacapone group than in the placebo group (see table 2). This intergroup difference was also highly significant statistically (p < 0.001).

The mean duration of the beneficial effect following the first morning levodopa dose as recorded in the home diaries (see table 2) was 0.24 hours greater in the entacapone group than in the placebo group (p < 0.05). The mean benefit of a single levodopa dose during the day, as evaluated by the patient, increased by 0.4 hours during the treatment with entacapone (see table 2; figure 2). Because there was no change in the placebo group, the intergroup difference was highly significant statistically (p < 0.001). When the change in daily "on" time was compared with the benefit of a single levodopa dose, there was a significant correlation in the entacapone group (p < 0.05, r = 0.26).

During the study period, the UPDRS subscores for parts II (activity of daily living; p < 0.01) and III (motor disability; p < 0.05) decreased slightly more in the entacapone group than in the placebo group. There was no intergroup difference in the UPDRS subscore for part I (mentation, behavior, and mood; see table 2). The global evaluation was in favor of entacapone, both when performed by the patient and the investigator, but only the investigator's evaluation was significant statistically.

The levodopa dose was reduced in approximately 50% of patients in the entacapone group and in approximately 10% in the placebo group during the study. The mean daily levodopa dose (see table 2) was decreased by 12% in the entacapone group, whereas it was slightly increased (2%) in the placebo group. The intergroup difference of 102 mg was statistically significant (p < 0.001). Similarly, a significant reduction (p < 0.01) in the number of daily levodopa doses was attained in the entacapone group when compared with the placebo group (see table 2).

Withdrawal responses. Two weeks after the withdrawal of entacapone the "on" time decreased to a mean duration approximating the baseline, which was statistically significant (p < 0.001; see figure 1). The withdrawal of entacapone was reflected also as similar significant losses in other efficacy variables and as an increase in the daily levodopa dose (see table 2).

Adverse events. The most frequent adverse events are presented in table 3. Six patients withdrew prematurely from the entacapone group because of adverse events (7%): three because of diarrhea, one because of nausea and leg pain, one because of a feeling of intoxication, and one because of pericarditis. Five patients withdrew prematurely from the placebo group because of adverse events (6%): one because of abdominal pain, one because of anxiety and mental exhaustion, one because of hyperkinesia, one because of chest pain, and one because of many nonspecific symptoms and signs. Otherwise, incidences of dopaminergic adverse events, such as the worsening of dyskinesias and nausea, were more frequent in the entacapone group than in the placebo group. At baseline, dyskinesias occurred in 67% of patients in the entacapone group and in 64% of patients in the placebo group. When the dose of levodopa was reduced during the study, the occurrence of dyskinesias was the same at the end of the study as in the beginning. Disabling or painful dyskinesias were not increased. The frequency of reported gastrointestinal adverse events was greater in the entacapone group; the most common were diarrhea and abdominal pain. Nine patients in the entacapone group and one in the placebo group reported discoloration of their urine.

Safety. Entacapone treatment did not affect notably any of the laboratory safety parameters used in this study. No clinically significant intergroup differences were detected in supine or standing systolic or diastolic blood pressures or heart rates. No changes in the ECG conduction times were recorded. No drug interactions were observed.

Plasma 3-OMD. Entacapone decreased the mean plasma 3-OMD level by about 55%-a change that was consistent during the treatment period. During the same time period this parameter described a small upward trend (22%) in the placebo group. The intergroup difference was highly significant statistically (p < 0.001). During the 2-week period following withdrawal of study medication, the plasma 3-OMD levels of patients treated previously with entacapone increased significantly (p < 0.01), almost reaching the baseline.

Discussion. This long-term, 6-month, double-blind study evaluated the efficiency of entacapone as adjuvant therapy for parkinsonian patients with end-of-dose deterioration. The results demonstrated the clinically significant beneficial effect of entacapone as an extender and enhancer of the levodopa responses of these patients. The results from this study support the findings from previously conducted short-term entacapone studies that incorporated single-dose to 2-month treatment periods.^13,14,16-19

In many of the single-dose and short-term studies,^13,14,17-19 frequent scoring of parkinsonian signs and symptoms was used as the outcome measure in the levodopa test. In a 1-month cross-over study, a home diary recording of "on" and "off" time was also used to evaluate the therapeutic effect, in addition to the levodopa test.¹⁶ There was a good correlation between these two methods of evaluation. Furthermore, this study demonstrated that in long-term studies with large numbers of patients and examinations, the home diary-recording method is useful and appropriate for the primary outcome measurement of therapeutic responses.

Parkinsonian patients who have levodopa-related end-of-dose failure are cognizant of the average beneficial duration of a levodopa dose. They are also able to relate accurately their detection of increasing associated parkinsonian symptoms, typical of the wearing-off phenomenon, on the beneficial therapeutic response. In this study, therefore, a patient's self-estimation of duration of average benefit from a daily levodopa dose was used as an efficacy parameter. The evaluation of our results by this method demonstrated that the entacapone-induced increase in "on" time was comparable with that derived from home diary recordings.

By using these different evaluation methods, the results of this study demonstrated that long-term treatment with entacapone as an adjuvant to levodopa therapy resulted in a clinically significant increase in "on" time, and a corresponding reduction in "off" time, whereas no change was evident in patients taking placebo. The well-being of the patients also improved, as shown by a statistically significant improvement in activities of daily living score (UPDRS, part II) in the entacapone group. This beneficial effect of entacapone was almost completely lost during the withdrawal period, thus emphasizing the relevance of the therapeutic value of entacapone. Almost identical results were obtained in an independently conducted 6-month study of similar design.²⁰ Similar results have been obtained with tolcapone, another COMT inhibitor, in two 6-week^21,22 and in one 3-month study.²³

Because of efficacy requirements it is typical that during long-term treatment there is a need to increase slowly the daily dosage of levodopa. Not unexpectedly this tendency was found in our study for patients receiving placebo treatment. This contrasted markedly with the significant reductions in both total daily levodopa dosage and the number of daily doses of levodopa required by entacapone-treated patients. This is in accordance with the evidence derived from short-term usage of entacapone.^13,14,16-18

Pharmacokinetic¹⁵ and PET^7-9 studies have demonstrated that COMT inhibition with entacapone increases significantly the availability of levodopa in the striatum. This establishes a foundation not only for the prolongation of the therapeutic response during coadministration of entacapone and levodopa, but also for an increase in dyskinesias.

Dyskinesias and other dopaminergic adverse events were increased to a greater extent with entacapone than with placebo treatment. These symptoms, which usually took place within days to weeks after the addition of entacapone to the treatment regimen, could be ameliorated by reducing the levodopa dose. Thus, entacapone was relatively well tolerated during this 6-month treatment period, which again concurs with results from previous short-term studies.^13,14,16-18

In this double-blind, placebo-controlled, long-term study, entacapone was demonstrated to be an effective extender of the effect of levodopa. The home diary data clearly described a significant increase in "on" time, and a corresponding reduction in "off" time. These changes are considered to be of clinical benefit to this population of patients with levodopa-related end-of-dose failure. All these positive changes occurred irrespective of the reduction of mean daily levodopa intake.

Acknowledgment

The authors thank Brian Watson, CBiol, MiBiol, for linguistic review of this text.

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