Abstract
Objective: To compare the long-term efficacy and safety of ropinirole with bromocriptine over 3 years in patients with early PD with limited or no previous dopaminergic therapy.
Methods: In this prospective, double-blind, parallel-group study, 335 patients were randomized to 0.75 mg ropinirole or 1.25 mg bromocriptine titrated upward at weekly intervals—maximum permitted daily doses were 24 mg ropinirole, 40 mg bromocriptine.
Results: Approximately one third of patients in each group withdrew prematurely, mostly because of adverse experiences; 61/102 (60%) of ropinirole-treated and 59/112 (53%) of bromocriptine-treated patients completed the study on the dopamine agonist alone. Mean doses for all patients at completion were 12 mg (SD 6) ropinirole and 24 mg (SD 8) bromocriptine. Occurrence of adverse experiences in both groups was similar. Emergence of dyskinesias was low. Both treatments induced marked improvements in Unified Parkinson’s Disease Rating Scale activities of daily living (ADL, Part II) and motor (Part III) scores over the first 12 weeks, which were maintained during the study. After 3 years, patients in the ropinirole group had a mean improvement in motor score of 31% compared with 22% in the bromocriptine group (p = 0.086) and a significantly better ADL score (treatment difference 1.46 points, p = 0.029).
Conclusions: Both dopamine agonists are effective in the early treatment of a high proportion of PD patients; effectiveness persists for at least 3 years. Those who completed the study had a significantly better functional status on ropinirole than on bromocriptine.
Dopamine agonists were originally introduced for the treatment of patients with PD whose response to l-dopa therapy was deteriorating. Controlled studies have shown that dopamine agonists are also effective as monotherapy in early PD,1,2 although l-dopa is regularly added to such a regimen within about 5 years.3-6 Furthermore, a recent 6-month interim analysis7 of an ongoing 5-year study comparing l-dopa with ropinirole, a nonergoline dopamine agonist with high specificity for the D2-type receptor,8 suggested that although ropinirole was less effective than l-dopa in patients with more advanced PD, they had similar efficacy in less advanced disease.
Studies have also suggested that the occurrence of dyskinesias is lower in patients receiving bromocriptine, either as monotherapy or in combination with low dose l-dopa, compared with patients treated with l-dopa monotherapy from the outset.3,5,9,10 Other adverse effects such as nausea, hypotension, and psychiatric disturbances are associated with all dopaminergic agents, but they are more prevalent with dopamine agonists. However, there is a lack of double-blind, long-term studies to compare one dopamine agonist with another in early therapy. We performed a 3-year randomized, double-blind comparison of the efficacy and safety of ropinirole and bromocriptine in the treatment of early PD. The results of a planned 6-month interim analysis of this study have been published previously.11
Methods.
Patients.
Patients were eligible for entry into the study if they were 30 years of age or older and had early idiopathic PD (Hoehn and Yahr stages I–III) requiring dopaminergic therapy. l-Dopa or dopamine agonists could not have been administered for longer than 6 weeks, and any such treatment was to be discontinued at least 2 weeks before entry to the study. Treatment with selegiline, amantadine, or anticholinergics was permitted, provided that the dose remained constant or was not introduced for the first 6 months; randomization was stratified for selegiline use because this agent was widely used at the inception of the study and has mild symptomatic and putative neuroprotective effects. Patients were excluded from the study if they had severe systemic or psychiatric disease, a history of alcohol or drug dependence, severe dementia, or other clinically relevant abnormalities. Additionally, patients were ineligible if they had previously been treated with ropinirole or had contraindications to bromocriptine or other ergot alkaloids. Women of childbearing age were excluded unless they had undergone hysterectomy or surgical sterilization.
Written informed consent was obtained from all patients before entry to the study, which was performed according to the principles of the Declaration of Helsinki and approved by local ethics committees.
Study design.
The study was a 3-year randomized, double-blind trial performed at 37 centers in Europe, Israel, and South Africa between December 1992 and April 1997. After a 7-day run-in placebo treatment period, during which patients had to demonstrate compliance with medication, patients were randomly assigned in a 1:1 ratio to receive either ropinirole or bromocriptine.
Drug treatment.
Ropinirole and bromocriptine were supplied in tablet and capsule form, respectively, and a double-dummy technique was used to maintain study blinding. Patients took one tablet and one capsule three times daily with or immediately after meals. The initial total daily doses were 0.75 mg for ropinirole and 1.25 mg for bromocriptine. Dosing was flexible throughout the study and was initially titrated upward at weekly intervals according to the patient’s response and tolerance. There were 13 dose levels for titration for each drug, and the maximum permitted daily doses were 24 mg for ropinirole and 40 mg for bromocriptine. Open-label l-dopa with a decarboxylase inhibitor could be used as adjunct medication if a therapeutic response could not be maintained despite use of the highest tolerated dose of study medication; patients requiring supplementary l-dopa could continue to receive double-blind study medication. Domperidone could be used if necessary to control severe nausea, vomiting, or dizziness.
Assessments.
Patients visited the clinic at baseline, then every week during the first month of treatment, every 2 weeks for the next 2 months, monthly for the next 3 months, and every 2 months thereafter. Efficacy was assessed by means of the Unified Parkinson’s Disease Rating Scale (UPDRS), version 3.0,12,13 at baseline and after 4, 12, and 24 weeks and 12, 18, 24, 30, and 36 months.
Efficacy endpoints were defined as 1) mean Part II score—activities of daily living (ADL)—at completion of the study; 2) change in Part III—motor examination score; 3) the proportion of patients classed as “responders” (achieving at least a 30% decrease in motor score); and 4) the proportion of patients requiring supplementary l-dopa.
Safety was assessed by measuring vital signs and collecting information about adverse events at each clinic visit. Blood and urine samples were obtained at screening and after 4, 12, and 24 weeks’ treatment and every 6 months thereafter for standard hematologic and clinical chemistry tests.
Statistical analysis.
Differences in the occurrence of dichotomous variables were analyzed by logistic regression and presented in terms of odds ratios. Continuous variables were analyzed using analysis of covariance, assuming the underlying assumptions were met. The effect of noncorrelated baseline covariates (age, sex, Hoehn and Yahr stage, disease duration, age at disease onset, and age group [≤55, >55 years]) on the results was investigated. The effect of country and selegiline stratum was adjusted when appropriate, regardless of their significance.
Analysis of the percentage change from baseline in mean total motor examination score (UPDRS Part III) was found to violate assumptions underlying the analysis of variance. Therefore, an alternative “ratio” analysis was developed14 whereby the ratio of the score at completion to the score at baseline for each patient was plotted, and a regression coefficient calculated, adjusting for the baseline covariates. The regression coefficients for each treatment group were presented in terms of percentage improvement, using the following formula: 
The occurrences of neuropsychiatric adverse experiences and dyskinesias were analyzed using the chi-square test.
As carrying forward the last observation was not considered appropriate for this long-term study, all efficacy analyses were performed on the final 3-year observation. A limited data set consisting only of those who completed the study on monotherapy was analyzed separately, and the effect of selegiline strata on motor score in this limited data set was individually tabulated.
Results.
Patients.
Of the 354 patients who entered the study, 335 were randomized to treatment (figure 1). Of these, 168 were randomized to ropinirole and 167 to bromocriptine. Approximately two thirds of the patients recruited were in the nonselegiline strata (115/168 [68.5%] of the ropinirole group and 110/167 [65.9%] of the bromocriptine group). The demographic characteristics and PD history of the randomized patients are shown in table 1. Overall, the patients in the two groups were well matched.
Figure 1. Progress of patients through the study.
Demographic characteristics and PD history of randomized patients
A total of 214 patients completed the study, of whom 102 were in the ropinirole group. The most common reason for withdrawal was adverse events; 34/168 (20.2%) patients in the ropinirole group and 33/167 (19.8%) patients in the bromocriptine group withdrew because of one or more events. There was a higher occurrence of patients lost to follow-up or withdrawn owing to a protocol violation in the ropinirole group (21/168 [12.5%]; 9/167 [5.4%] in the bromocriptine group), which accounted for the higher withdrawal in this group (table 2). The mean duration of treatment for patients reaching the final 3-year visit was 149.2 weeks (SD 6.6) in the ropinirole group and 149.3 weeks (SD 7.1) in the bromocriptine group.
The disposition and numbers of patients in the study at different time points during the trial
Drug doses.
The mean dose of ropinirole increased to 10.3 mg (SD 5.4) after 48 weeks and to 11.1 mg (SD 5.5) after 96 weeks; the mean final dose in patients completing 3 years’ treatment was 12.0 mg (SD 5.6). The mean daily bromocriptine dose increased to 20.5 mg (SD 8.0) after 48 weeks, then 22.5 mg (SD 7.9) at 96 weeks and 24.1 mg (SD 8.2) at 3 years. Of those who completed the study to 3 years, 6/102 (5.8%) patients taking ropinirole and 9/112 (8.0%) taking bromocriptine were taking the maximum permitted doses. In those patients who did not require supplementary l-dopa, the mean doses of ropinirole and bromocriptine at completion were 10.1 mg (SD 4.8) and 22.5 mg (SD 8.4), respectively.
Use of supplementary l-dopa.
l-Dopa was added to the treatment regimen of 57/168 (33.9%) patients in the ropinirole group and 70/167 (41.9%) patients in the bromocriptine group during the study, a difference that was not statistically significant. Sixty-one (36.3%) of the 168 patients in the ropinirole group and 59/167 (35.3%) patients in the bromocriptine group completed the study without the requirement for l-dopa (see table 2). In both groups, younger patients were more likely to require l-dopa. The time to initiation of l-dopa was analyzed by a log-rank test that showed that the requirement for l-dopa was delayed in the ropinirole group relative to the bromocriptine group, but not by a statistically significant margin. At the time l-dopa was introduced, the mean dose of ropinirole was 12.7 mg (SD 6.2), that of bromocriptine was 23.6 mg (SD 7.4), and only 5 ropinirole- and 4 bromocriptine-treated patients were taking the maximum dose of the agonist. The mean initial dose of l-dopa was 223.1 mg (SD 163.2) in ropinirole-treated patients and 201.1 mg (SD 147.1) in the bromocriptine group.
Efficacy—all patients.
The changes in ADL and motor scores at each assessment throughout the study are illustrated in figures 2 and 3⇓. In both treatment groups, the greatest reduction in scores occurred during the first 6 months. Thereafter the scores were maintained at a generally constant level, apart from the ADL score in the bromocriptine group, which deteriorated. The patients’ baseline ADL scores and Hoehn and Yahr stage had significant influences on their endpoint ADL score, which was therefore adjusted for those covariates.
Figure 2. Mean (±SE) activities of daily living (ADL) score (Unified Parkinson’s Disease Rating Scale, Part II) in all patients over time.
Figure 3. Mean (±SE) motor score (Unified Parkinson’s Disease Rating Scale, Part III) in all patients over time.
At the end of the study, the mean ADL score was highly significantly better in the ropinirole group compared with the bromocriptine group. The mean endpoint motor score alone was also lower in the ropinirole group, and there was both a greater mean improvement from baseline in motor score and a greater proportion of responders in the ropinirole group compared with those on bromocriptine, although the differences did not reach significance (table 3).
Status at Year 3 of patients who completed the study
Efficacy—patients who did not require supplementary l-dopa.
In those patients who did not require supplementary l-dopa, the mean ADL score at the end of the study was significantly better in the ropinirole group. Additionally, there was both a greater mean improvement from baseline in motor score and a greater proportion of responders in the ropinirole group compared with those on bromocriptine.
In both treatment groups, a slightly greater proportion of patients who were taking concomitant selegiline completed the study without the requirement for l-dopa compared with those not on selegiline. In the bromocriptine group, there was a higher proportion of responders among those taking concomitant selegiline compared with those on bromocriptine alone. Conversely, the mean improvement in motor score was higher in the nonselegiline group. A similar inconsistency was seen in the ropinirole group (table 4).
Motor score status at Year 3 of nonselegiline-treated and selegiline-treated patients who completed the study without the requirement for l-dopa
Safety.
Dyskinesia, as assessed by the complications of therapy section (Part IV) of the UPDRS or reported as adverse events, developed in 13/168 (7.7%) patients in the ropinirole group and 12/167 (7.2%) bromocriptine-treated patients. There was no significant difference in the occurrence of dyskinesia between the two groups (p = 0.84, χ2 test). Of these patients, 6 (3.6%) in the ropinirole group and 5 (3.0%) in the bromocriptine group first exhibited dyskinesias after l-dopa was added.
Adverse effects that occurred in more than 10% of patients in either group are shown in table 5. With the exception of nausea, the occurrence of adverse events was similar in both groups. The most common adverse event in both groups was nausea; more so in the ropinirole group, which was also reflected in a greater use of domperidone in that group (32/168 [19.0%] for ropinirole versus 22/167 [13.2%] for bromocriptine). In the majority of patients, all of the most common adverse events including nausea were first reported during the initial 8 weeks of the trial.
Adverse events that occurred in more than 10% of patients in either group
Psychiatric adverse events were reported by 27/168 (16.1%) patients in the ropinirole group and 23/167 (13.8%) in the bromocriptine group. The most common of these were hallucinations, which affected 16/168 (9.5%) ropinirole- and 15/167 (9.0%) bromocriptine-treated patients, and confusion, which affected 13/168 (7.7%) and 9/167 (5.4%) patients, respectively. There was no significant difference in the occurrence of such events between the groups (p = 0.56, χ2 test).
There were few changes of clinical concern in vital signs, and no treatment differences were apparent. Orthostatic symptoms were reported by 16 patients receiving ropinirole and 22 receiving bromocriptine. There were no significant laboratory abnormalities reported as adverse events.
Few individual adverse events led to the withdrawal of more than three patients; those that did were nausea, vomiting, and hallucinations (table 6).
Adverse events leading to the withdrawal of more than three patients in either treatment group
Adverse events classified as serious according to the protocol-defined reporting criteria were recorded for 35/168 (20.8%) ropinirole patients and 50/167 (29.9%) bromocriptine patients. Those events that were reported for more than two patients in either treatment group are shown in table 7. Three ropinirole patients and seven bromocriptine patients died during the study, most commonly from cardiac failure.
Adverse events classified as serious* in more than two patients in either treatment group
Discussion.
The data presented here show that the superior efficacy of ropinirole that was initially observed in the 6-month interim analysis11 was maintained over the 3-year period, as demonstrated by the significant differences in terms of functional ability, using the ADL scores, regardless of whether l-dopa had been added. It was less clear what effect, if any, selegiline had on the patients’ outcome, as the majority of patients did not use this compound during the study. There were conflicting trends with and without selegiline seen in both motor score analyses and the l-dopa–use endpoints. This may have resulted from the unbalanced nature of the strata.
The study clearly demonstrated that both ropinirole and bromocriptine obviate the need for supplementary l-dopa treatment for a substantial period. It is interesting to compare this endpoint with the results from a similar double-blind study comparing l-dopa and cabergoline in early therapy,15 in which 18% of patients who were randomized to l-dopa and 38% of patients randomized to cabergoline had been given supplementary l-dopa by 1 year. In the current study, a total of 25/168 (14.8%) ropinirole patients and 31/167 (18.5%) bromocriptine patients had been given supplementary l-dopa by the same timepoint. During the entire study, the overall proportion of patients requiring l-dopa was lower in the ropinirole group (57/168 [33.9%]) than in the bromocriptine group (70/167 [41.9%]). Furthermore, it is noteworthy that 61/168 (36.3%) ropinirole-treated patients and 59/167 (35.3%) bromocriptine-treated patients completed the 3-year trial without requiring supplementary l-dopa.
Few patients exhibited emergent dyskinesias, and in half of the patients who did, this followed the introduction of l-dopa. As one of the reasons to start patients on monotherapy with a dopamine agonist rather than l-dopa is the possibility that this will prevent the development of dyskinesias, it is notable that emergent dyskinesias were rare on either agonist, but to answer this question we await the results of long-term studies.7,15
The tolerability of ropinirole in this study was comparable with that of bromocriptine. Although there was initially a higher occurrence of nausea in the ropinirole group, this rarely led to the withdrawal of a patient. A total of 4/168 (2.4%) ropinirole patients and 5/167 (3.0%) bromocriptine patients withdrew because of hallucinations; in a 6-month study performed in the United Kingdom, 5/134 (3.7%) patients receiving bromocriptine alone withdrew because of this psychiatric disturbance.16
The mean dose of bromocriptine used by patients in this study at 3 years (24 mg) was similar to that used by Bergamasco et al. (16 to 21 mg)17 and Hely et al. (29 to 31 mg)5 at the same timepoint in chronic dosing studies, but lower than the mean dose of 50 mg used by Montastruc et al.18 It is possible that some patients in the current study, particularly those initiated with supplementary l-dopa, may have tolerated titration to higher doses of both ropinirole and bromocriptine.
Ropinirole and bromocriptine are effective treatments for PD as over a third of the patients in each group completed the 3 years of treatment without the requirement for l-dopa. Patients who completed the study had significantly better functional status on ropinirole than on bromocriptine, regardless of whether l-dopa was used. Additionally, ropinirole is as well tolerated as bromocriptine.
Appendix
The 053 Study Group consisted of the following participants: Y. Agid (Paris, France); J. Aharon (Haifa, Israel); A. Albanese (Lausanne, Switzerland); A. Balogh (Budapest, Hungary); E. Brunt (Groningen, The Netherlands), N. Canal (Segrate, Italy); G. Caruso (Naples, Italy); P. Cras (Edegem, Belgium); J. Czopf (Pécs, Hungary); G. Dibo (Szeged, Hungary); K. Ditzler (Bad Krozingen, Germany); E. Einhaeupl (Berlin, Germany); A. Fazekas (Budapest, Hungary); G. Fénelon (Paris, France); E. Ferrari (Bari, Italy); D. Fuell (SmithKline Beecham Pharmaceuticals, Harlow, UK); D. Gardiner (SmithKline Beecham Pharmaceuticals, Harlow, UK); R. Gil (Poitiers, France); S. Honigman (Haifa, Israel); J. Keens (SmithKline Beecham Pharmaceuticals, Harlow, UK); B. Kies (Cape Town, South Africa); A. Korczyn (Tel-Aviv, Israel); J. Larsen (Stavanger, Norway); P. Maire (Aarau, Switzerland); A. Mesec (Ljubljana, Slovenia); C. Meyer (Baden, Switzerland); A. Muratorio (Pisa, Italy); Z. Nagy (Budapest, Hungary); J. Nuessner (Aachen, Germany); F. Piccoli (Palermo, Italy); W. Poewe (Innsbruck, Austria); E. Ringelstein (Münster, Germany); S. Ruggieri (Rome, Italy); I. Sagi (Miskolc, Hungary); E. Schumacher (Aachen, Germany); J. Szanto (Zalaegerszeg, Hungary); M. Tarczy (Budapest, Hungary); H. Teräväinen (Helsingfors, Finland); J-E. Vanderheyden (Montignies-le-Tilleul, Belgium); S. Vilming (Oslo, Norway); J. Warner (SmithKline Beecham Pharmaceuticals, Harlow, UK); R. Weiser (Swansea, UK).
Footnotes
- Received April 15, 1998.
- Accepted February 26, 1999.
References
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