Ropinirole for the treatment of early Parkinson's disease

Levodopa (L-dopa) is considered the mainstay of treatment for Parkinson's disease. However, longterm use of L-dopa is limited by the development of motor fluctuations, dyskinesias, confusion, and hallucinations.^1-5 Motor fluctuations may be attributed to a combination of disease duration and severity and the duration of L-dopa therapy.⁶ In many patients, the response to L-dopa gradually declines after 3 years of therapy, regardless of the initial improvement or the severity of symptoms at the start of treatment.¹

Certain data suggest that oxidative metabolism and free radical generation may play an integral role in the pathogenesis of Parkinson's disease.⁷ One hypothesis is that the increased dopamine metabolism that results from L-dopa ingestion generates hydrogen peroxide and hydroxyl free radicals, which may contribute to further damage of an already compromised system.⁸ Thus, long-term treatment with L-dopa may actually accelerate the degeneration of dopaminergic neurons.^8,9

Because of the disabling side effects and the theoretical possibility of contribution to disease progression, many have advocated that L-dopa therapy be delayed in early Parkinson's disease until its use is necessitated by the presence of functional disability.^1,7,8,10,11 This has led to the investigation of alternate treatment strategies.^8,11,12

The utility of dopamine agonists, such as bromocriptine and pergolide, as monotherapy in early Parkinson's disease, has been explored in clinical trials.^13-18 However, many of these trials only included a small number of patients, were not well controlled, and provided inconsistent results. In addition, the ergoline-based agonists bromocriptine and pergolide have been associated, although rarely, with serious adverse effects, including pleural effusion, erythromelalgia, and pulmonary and retroperitoneal fibrosis.^16,19-21

Ropinirole, a nonergoline D₂-receptor agonist, is under investigation for the treatment of Parkinson's disease.²² In previous clinical trials, ropinirole demonstrated effective symptomatic reduction in patients with early Parkinson's disease and was generally well tolerated.¹⁷ In particular, the efficacy of ropinirole as monotherapy in early Parkinson's disease was explored by Brooks et al.¹⁷ in a double-blind, placebo-controlled, parallel-group trial. In this 12-week study, an improvement of at least 30% in the UPDRS motor score was achieved by significantly more patients who were treated with ropinirole than by patients who received placebo.¹⁷ The present study was undertaken to further assess the efficacy and safety of ropinirole in patients with early Parkinson's disease who were not receiving dopaminergic therapy.

Methods. This was a prospective, randomized, multicenter (25 sites), double-blind, placebo-controlled study of 6-months' duration in patients with early Parkinson's disease (Hoehn & Yahr stages I to III). All patients had motor symptoms of sufficient severity to warrant the introduction of dopaminergic therapy but had not received L-dopa or any dopaminergic agonist for more than 6 weeks prior to study entry. All other antiparkinsonian therapies, except selegiline, were discontinued at least 4 weeks prior to study entry. Patients entering the trial on selegiline were required to remain on a stable dose of selegiline for 4 weeks prior to study entry and for the duration of the study. Patients not receiving selegiline at the time of study entry were prohibited from receiving it during the study.

Exclusion criteria included the following: treatment with vasodilators, antiarrhythmics, digoxin, calcium channel blockers, angiotensin-converting enzyme inhibitors, or other antihypertensive agents (excluding diuretics); previous treatment with ropinirole; history of severe systemic disease, major psychosis, or dementia; history of severe dizziness or fainting; diastolic blood pressure ≥ 110 mm Hg; or recent history of alcoholism or drug dependence.

Written informed consent was obtained from all participants before study entry. On entry into the study, baseline demographic and clinical information(including medical history, physical examination, vital signs, laboratory tests, and ECG) was obtained. If qualified, patients were then entered into a 7-day placebo run-in period to assess compliance. Patients who were at least 80% compliant were allowed to continue in the study. Patients, stratified according to the concomitant use of selegiline, were randomized in a 1:1 ratio to receive either ropinirole or placebo.

The severity of Parkinson's disease symptoms was assessed using the UPDRS²³ at baseline and at weeks 4, 12, and 24. Patient visits were scheduled weekly for the first month, every other week for 2 months, and monthly thereafter for the duration of the study. Patients were evaluated at each visit using the Clinical Global Impression (CGI) scale. Routine serum chemistry, hematology, and urinalysis were performed during screening and at weeks 4, 12, and 24 of the study. ECG was performed at screening and at weeks 12 and 24, and a chest radiograph was taken at screening and at week 24.

All patients were started on 0.25 mg tid of study medication (ropinirole or an identical placebo [level 1]), which was titrated upward at weekly intervals until an optimal therapeutic response was achieved; patients were maintained at their optimal dose level for the remainder of the study. All patients were titrated up to a minimum dose of 1.5 mg tid and could receive a maximum dose of 8 mg tid. Patients were required to demonstrate at least 80% compliance with study medication.

Additional symptomatic therapy was permitted if a patient had first been titrated to the highest tolerated dose of study medication. Patients who required additional symptomatic therapy were started on open-label carbidopa/levodopa while continuing to receive blinded study medication for the remainder of the trial. No other symptomatic therapy was allowed.

Efficacy variables. The primary efficacy variable was defined as improvement in motor function as measured by the UPDRS motor examination. Secondary efficacy variables included the number (percentage) of patients with ≥ 30% reduction in the UPDRS motor score (responders), the number(percentage) of patients with scores of 1 (very much improved) or 2 (much improved) on the CGI global improvement item, and the number (percentage) of patients who did not experience sufficient symptomatic benefit, thereby requiring the initiation of L-dopa therapy.

Safety and tolerability. Safety and tolerability were assessed for all randomized patients by monitoring and reporting adverse experiences, vital signs, and clinical laboratory evaluations. All adverse experiences were coded from the WHO Adverse Reaction Terminology dictionary by body system and by preferred term.²⁴

Statistical analysis. A regression approach was used for analysis of improvement in motor score, based on the assumption that treatment effect was proportional to baseline score.²⁵ The fitted model was weighted by the square of the baseline score. This adjustment was made so that patients with more severe disease (i.e., higher baseline scores) contributed more to the analysis than did patients with less severe disease (i.e., lower baseline scores). Thus, an improvement in the UPDRS motor examination score from 60 to 30 carries more weight than a change from 6 to 3, although both changes represent a 50% improvement. A regression coefficient of 1.0 indicated similar baseline and endpoint scores during the study and no treatment effect, whereas a regression coefficient < 1 indicated an improvement. Percentage improvement (1 - regression coefficient× 100) was calculated from the regression coefficients. Thus, a regression coefficient of 0.7 can be interpreted as a 30% improvement.

Secondary efficacy variables were analyzed by logistic regression, and treatment differences are presented in the form of an odds ratio estimated from the fitted model and the corresponding 95% CI. Statistical significance was achieved if the 95% CI of the odds ratio did not include one. The overall incidence of adverse experiences in the two treatment groups were compared using Fisher's exact test.

Results. A total of 241 patients were randomized to receive study medication: 116 patients received ropinirole, and 125, placebo. Fifty percent of patients in the ropinirole treatment arm and 48.8% of patients in the placebo treatment arm received selegiline concomitantly. As expected, there were some differences between the selegiline and nonselegiline strata; in particular, duration of disease was shorter in the nonselegiline group. However, baseline demographic variables were comparable between the two treatment arms (table 1). A total of 57 patients (37 ropinirole and 20 placebo) in the intention-to-treat population were withdrawn before completing the 6-month study (Fisher's exact test, p = 0.004). Of the 57 patients withdrawn, 40 (27 ropinirole, 13 placebo) were withdrawn due to adverse experiences including intercurrent illness and disease progression.

The mean ± SD total daily dose of study medication at endpoint for the intention-to-treat population was 15.7 ± 8.3 mg per day in the ropinirole treatment arm and 19.7 ± 7.1 mg per day in the placebo treatment arm (maximum allowed = 24 mg/day). When examined by selegiline strata, the mean total daily dose of ropinirole at endpoint was 15.5 ± 8.3 mg/day for patients on selegiline and 15.8 ± 8.4 mg/day for patients not on selegiline. In the placebo treatment arm, the total daily dose was 20.0 ± 6.5 mg/day for the selegiline group and 19.2 ± 7.6 mg/day for the nonselegiline group.

Efficacy. The mean ± SD UPDRS motor examination score in all ropinirole-treated patients improved from 17.9 ± 8.8 at baseline to 13.4 ± 9.5 at endpoint. There was a statistically significant improvement of 24% in the UPDRS motor examination score in the ropinirole treatment arm compared with placebo as determined by weighted regression analysis (p < 0.001; figure 1). The placebo group experienced a 3% worsening in the UPDRS motor examination score(17.7 ± 9.5 at baseline to 17.9 ± 10.5 at endpoint). As shown in figure 1, results were similar in the patients receiving selegiline compared with patients not on selegiline.

Overall, a significantly greater percentage of patients in the ropinirole arm (47%) responded to treatment (≥ 30% reduction in UPDRS motor score) compared with the placebo arm (20%; odds ratio = 4.45 [95% CI:(2.26, 8.78)]; figure 2). Analysis of the separate strata reveals a statistically significant treatment effect in favor of ropinirole in the selegiline stratum (56% versus 14% [P = 0.008]). The treatment effect observed in the nonselegiline stratum was also favorable although not statistically significant (38% versus 25%).

At endpoint, 33% of ropinirole-treated patients were rated as very much improved or much improved from overall baseline condition on the CGI global improvement item compared with 12% in the placebo group. This difference was statistically significant (odds ratio = 4.06 [95% CI: (2.00, 8.22)];figure 3). There was no significant interaction between selegiline strata and treatment for this variable.

The proportion of patients who required L-dopa for additional symptomatic relief was also recorded during this study. By the end of the 6-month treatment period, only 11% of ropinirole-treated patients required L-dopa rescue compared with 29% of placebo-treated patients, a statistically significant treatment difference in favor of ropinirole (odds ratio = 0.30[95% CI: (0.14, 0.61)]; figure 4). There was no significant interaction between selegiline strata and treatment for this variable.

Safety and tolerability. Ropinirole was generally well tolerated. A total of 224 of the 241 enrolled patients (111 ropinirole, 113 placebo) reported one or more adverse experiences. A total of 40 patients (27 ropinirole, 13 placebo) withdrew from the study due to adverse experiences. Adverse experiences that occurred in ≥ 10% of patients and associated rates of withdrawal are presented in table 2. The most frequently reported adverse experience in both treatment arms was nausea, leading to withdrawal in eight (6.9%) ropinirole-treated patients and two(1.6%) patients who received placebo. When tracked by time of first occurrence during the study, nausea peaked during the initial titration(weeks 1 to 4) and declined in ropinirole-treated patients to a level similar to that of patients who received placebo by week 12 (figure 5, top).

Dizziness was the second most frequently reported adverse experience in both treatment arms, which led to withdrawal of five (4.3%) ropinirole-treated patients and two (1.6%) placebo-treated patients. When tracked by time of first occurrence during the study, dizziness was first reported with the initial titration, peaked during weeks 4 to 8 in the ropinirole treatment arm, and then declined (figure 5, bottom). No such pattern was observed in the placebo group. Somnolence was the other adverse effect more commonly found in the ropinirole-treated patients.

Neuropsychiatric adverse experiences were infrequent but included hallucinations in two ropinirole-treated patients and confusion in seven ropinirole-treated patients and in two patients who received placebo(table 3). One ropinirole-treated patient withdrew from the study due to hallucinations. No other adverse experience resulted in withdrawal of more than two patients from the study.

Discussion. The administration of ropinirole to patients in the early stages of Parkinson's disease resulted in significant improvement in motor function. Ropinirole significantly alleviated parkinsonian symptoms as documented by a 24% improvement in the UPDRS motor score. Furthermore, a significantly greater percentage of patients in the ropinirole treatment group met the criterion for response, defined as ≥ 30% reduction in UPDRS motor score, compared with the placebo group. This is especially noteworthy, because a 25% reduction in UPDRS motor score is considered to represent a clinically relevant improvement in patients with Parkinson's disease.²⁶ Ropinirole therapy also produced additional benefits as measured by the CGI global improvement item. Furthermore, significantly fewer patients receiving ropinirole (11%) required L-dopa for symptomatic relief compared with those receiving placebo (29%), during the 6-month treatment period.

Treatment with ropinirole was well tolerated in patients with early Parkinson's disease. Nausea and dizziness were the most common side effects, and these are the expected peripheral dopaminergic effects of dopamine agonists.^17,27,28 Although nausea occurred in 52.6% of ropinirole-treated patients, only 8 ropinirole patients(6.9%) withdrew because of nausea. Nausea and dizziness diminished with continued therapy with ropinirole, a finding consistent with clinical experience with dopaminergic agents in general.^4,17 Nausea associated with dopaminergic agents can generally be prevented by taking the medication with food and by initiating therapy at low doses followed by a gradual upward titration.^4,29 The incidence of neuropsychiatric adverse experiences in this study was low. Hallucinations were reported in two (1.7%) and confusion in seven (6%) ropinirole-treated patients. The low incidence of these events suggests there may be a potential tolerability advantage in using a dopamine agonist with a nonergoline structure.^27,28

A major advantage to the use of dopamine agonists in patients with early Parkinson's disease is that they may allow postponement of the introduction of L-dopa, potentially delaying the development of L-dopa motor response fluctuations while providing symptomatic improvement.^8,13,27,28 The motor response complications associated with long-term L-dopa therapy can be disabling and pose major management problems over the course of this chronic disease.^1-5,30 "Wearing off" phenomena, "on/off" fluctuations, and peak-dose dyskinesias have been reported in 28% to 84% of patients treated with L-dopa alone.³¹ When the ergoline-derived dopamine agonists, bromocriptine and pergolide, were examined as monotherapy in patients newly diagnosed with Parkinson's disease, introduction of L-dopa therapy could be delayed and fewer patients developed response fluctuations.^13,14,16,18

A 30-day study using an in vivo marmoset model of Parkinson's disease provides preclinical support for a lower propensity of ropinirole to induce dyskinesias. L-dopa, bromocriptine, and ropinirole all provided comparable symptomatic relief of the induced akinesia and motor disabilities, but L-dopa induced moderate-to-severe levels of dyskinesia by the end of the 30-day study. Dyskinesia scores for chronic bromocriptine and ropinirole administration were significantly lower (p < 0.01) than for L-dopa.³²

In summary, ropinirole provided effective symptomatic reduction in early Parkinson's disease patients and was generally well tolerated. Patients treated with ropinirole experienced a significant improvement in motor function compared with placebo, as measured by UPDRS motor score and the CGI improvement item. Ropinirole also demonstrated a favorable safety and tolerability profile. These results extend the findings of significant improvement in motor function reported by Brooks et al. in a double-blind, placebo-controlled, parallel-group trial of shorter duration.¹⁷ In the present study, only a small number of patients required additional symptomatic therapy with L-dopa. It seems reasonable, then, to consider the use of ropinirole as a L-dopa-sparing strategy for managing Parkinson's disease. The results of this study indicate that ropinirole is an effective therapeutic option for the treatment of early Parkinson's disease.

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