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Co-administration of ropinirole and domperidone during rapid dose escalation of the dopamine agonist
Parkinsonism & Related Disorders Parkinsonism and Related Disorders 4 (1998) 183–188
Co-administration of ropinirole and domperidone during rapid dose escalation of the dopamine agonist F. Stocchi a,*, A. Deste´e b a
Department of Neurological Science, University ‘‘la Sapienza’’ Roma and Neuromed, Pozzilli (IS), Rome, Italy b Clinique Neurologique, Centre Hospitalier Re´gional et Universitaire, 59037-Lille, France Received 27 April 1998; received in revised form 25 November 1998; accepted 1 December 1998
Abstract In patients naive to dopaminergic therapy, reducing the side-effects associated with dopamine agonist treatment will permit faster titration to effective therapeutic doses. The primary aim of this study was to compare the incidence of dopaminergic side-effects in parkinsonian patients undergoing fast titration with ropinirole under domperidone cover with that of patients undergoing slow titration with matched domperidone placebo. Patients in the former group experienced nausea on significantly fewer days than patients in the latter group. The fasttitration regimen with domperidone cover was well tolerated and allowed ropinirole to be introduced quickly. 䉷 1999 Published by Elsevier Science Ltd. All rights reserved. Keywords: Ropinirole; Dopamine agonist; Domperidone
1. Introduction Dopamine agonists were originally introduced for use as an adjunct to L-dopa in the later stages of Parkinson’s disease to supplement the effects of L-dopa and to smooth out motor fluctuations [1]. Now, these drugs are increasingly being used early in treatment, either alone or with a low dose of L-dopa [2–7]. The rationale for such treatment is to delay the introduction of L-dopa or reduce the dose required in an attempt to prevent or delay the onset of its long-term side-effects [3,5–10]. In patients who have not taken dopaminergic therapy before, the dopamine agonists must be titrated slowly to prevent adverse events (mainly peripheral dopaminergic effects of nausea and vomiting), but this means that treatment must be maintained for some time before an adequate therapeutic dose is reached. In addition, significant numbers of patients withdraw from treatment with dopamine agonists because of such early side-effects [1,11–13]. It is therefore important that the side-effects of these drugs are minimized, and titration to an effective dose is as fast as possible in order to promote patient compliance with treatment. Ropinirole is a novel non-ergoline dopamine agonist that has been introduced for use in early Parkinson’s disease
* Corresponding author. Tel.: ⫹3906 4991 4607; fax: ⫹3906 4440 790.
[14–17]. Overall, treatment with ropinirole is well tolerated. The most frequently reported dopaminergic adverse events arising from treatment with ropinirole are nausea, dizziness and vomiting [16]. The present study investigated whether ropinirole could be titrated more quickly than the standard schedule, without reducing tolerability, by prophylactic use of the peripheral dopamine antagonist domperidone [18]. Domperidone has been effectively used to block the undesirable peripheral side-effects of dopamine agonists [19,20], and pretreatment with domperidone does not alter ropinirole’s plasma pharmacokinetics [21]. Hence, three groups were compared: in two, ropinirole was titrated rapidly with and without domperidone cover, and in the third, ropinirole was titrated ‘slowly’ with no domperidone cover. ‘Fast’ titration took 21 days and ‘slow’ titration, 42 days. Ropinirole was titrated in each case to a dose of 7.5 mg/day. The slow schedule is the one usually used in clinical trials of ropinirole, and is as fast as that of the other dopamine agonists in general use. The primary comparison was between the groups receiving a fast titration of ropinirole under domperidone cover and the slow titration under placebo. The incidence of dopaminergic side-effects in these two groups was compared. The second fasttitration group was half the size of the other treatment groups and was included to measure the effect of fast titration of ropinirole on the incidence of dopaminergic side-effects.
1353-8020/99/$ - see front matter 䉷 1999 Published by Elsevier Science Ltd. All rights reserved. PII: S1353-802 0(98)00041-8
F. Stocchi, A. Deste´e / Parkinsonism and Related Disorders 4 (1998) 183–188
184
Table 1 The fast- and slow-titration schedules for ropinirole
Fast titration Daily dose (mg) Unit dose (mg)
Day of titration (dose until that day) 3 6 9
12
15
18
21
0.75 0.25
3.0 1.0
4.5 1.5
6 2.0
7.5 2.5
Slow titration Daily dose (mg) Unit dose (mg)
1.5 0.5
0.75 0.25
2.25 0.75
1.5 0.5
2. Materials and methods 2.1. Patients Patients were eligible for inclusion if they: had a diagnosis of Parkinson’s disease at Hoehn and Yahr stages I–III based on medical history and neurologic examination; were older than 30 years; and, if women, were of non-childbearing potential. Patients either had not previously received any dopaminergic treatments, or had received no more than six weeks’ treatment with a low or moderate dose of L-dopa or with a dopamine agonist. Such treatments were stopped for at least two weeks before screening. All patients gave their informed consent to take part in the study, which was conducted in accordance with the declaration of Helsinki, and the protocol was approved by local Ethics Committees in the trial centers. Patients were excluded if they had had systemic disease in the previous three months, psychosis or severe dementia, or postural hypotension. Excluded previous treatments were: any monoamine oxidase inhibitors except selegiline, any investigational new drug within the previous 30 days, or any previous exposure to ropinirole. Excluded concurrent treatments were: amantadine, anticholinergics and antiemetics. Treatment with selegiline, antidepressants and benzodiazepines was allowed provided these drugs were administered at a stable dose for at least two weeks before screening, and during the study.
2.2. Drug treatments Ropinirole was provided in identical tablets containing the following doses: 0.25, 0.50, 1.00 and 2.00 mg. Domperidone was supplied in capsules containing 10 mg of the drug. Matched placebo was provided for both these treatments. Both drugs were taken orally three times daily. Domperidone (or matched placebo) was taken 30 min before ropinirole, which was taken with or immediately after food. During the seven day run-in period, all patients took ropinirole placebo for seven days; those patients randomized to receive domperidone cover took placebo domperidone for three days, then domperidone for the next four days,
2.25 0.75
24
30
36
42
7.5 2.5
3.0 1.0
4.5 1.5
6 2.0
7.5 2.5
whereas the other patients continued to take placebo domperidone. At the end of the run-in period, ropinirole was introduced either by a fast- or slow-titration schedule, as detailed in Table 1. Each dose of ropinirole comprised two tablets; the contents of these two tablets amounted to the unit dose. Both patients and investigators were blinded to the use of domperidone and to the titration schedule for ropinirole. Open-label domperidone was also given to all patients to be used as rescue medication to relieve the symptoms of nausea. Patients were instructed to take a maximum of three tablets per day (30 mg) and not to take this therapy prophylactically. 2.3. Efficacy and safety assessments Patients were all issued with diaries in which they recorded daily whether they had experienced nausea (and its severity), vomiting, dizziness on standing, dizziness at any time, or heartburn. They also recorded the number of tablets of rescue domperidone taken. Patients were seen at the clinic each week for the first four weeks and then every two weeks, when diary information was collected, vital signs and adverse events were recorded, and a check on treatment compliance made (by tablet count). Reports of adverse events (apart from those recorded on the diary cards) were elicited by asking the neutral question ‘Do you feel different in any way since starting the new treatment?’. The primary efficacy parameter was the incidence of nausea during the 42-day titration period, which was recorded in patients’ diaries. Secondary efficacy parameters were: the percentage of days in the titration period on which patients experienced nausea, the incidence of moderate or severe nausea, the incidence of other dopaminergic sideeffects, and the percentage of days on which rescue domperidone treatment was taken. The main comparison was between the group that underwent a fast titration under domperidone cover and the one that underwent a slow titration with placebo. The efficacy of ropinirole was assessed using the Clinical Global Impression (CGI) and the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. The CGI was assessed at baseline and at all subsequent visits to the clinic.
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Table 2 Demographic characteristics of the patient groups
Number of patients Female/male (%) Mean age; years (range) Mean disease duration; years (range) Hoehn and Yahr stage; number (%) I I.5 II II.5 III
Treatment regimen (titration schedule ⫹ cover) Fast ⫹ domperidone Slow ⫹ placebo
Fast ⫹ placebo
53 25/28 (47.2/52.8) 61 (44–81) 2.7 (0.3–18.8)
51 23/28 (45.1/54.9) 64 (35–86) 2.2 (0.1–15.1)
24 11/13 (45.8/54.2) 64 (38–78) 4.5 (0.3–21.2)
6 11 22 13 1
8 (15.7) 14 (27.5) 13 (25.5) 13 (25.5) 3 (5.9)
3 (12.5) 7 (29.2) 6 (25.0) 4 (16.7) 4 (16.7)
(11.3) (20.8) (41.5) (24.5) (1.9)
The UPDRS motor score was recorded at baseline and on days 28, 56 and 84.
3. Results 3.1. Patient demographics
2.4. Statistical evaluation Formal efficacy comparisons were carried out only between the two main titration groups (fast titration with domperidone cover and slow titration under placebo). No formal testing was performed on the data for adverse experiences other than the dopaminergic effects. Logistic regression was used to detect between-group differences in dichotomous variables (e.g. incidence of nausea of any severity), assuming that the underlying distribution was binomial. Analysis of variance was used to detect differences in continuous variables. All statistical analyses were performed using the SAS statistical package (version 6.08).
A total of 128 patients were recruited to the trial from 20 centers in Italy, Belgium, France and the UK. These patients were randomized in a ratio of 2 : 2 : 1 to receive fast titration under domperidone cover, slow titration with placebo, or fast titration with placebo, respectively. The demographic characteristics of the patient groups are shown in Table 2. Slightly more men than women were recruited. The groups had a mean age range of 61–64 years. Most patients had a disease duration of 2–3 years and were at Hoehn and Yahr stage I.5–II.5. Patients in the group receiving fast titration and placebo cover had a somewhat longer disease duration, and a higher proportion of these patients were at Hoehn and Yahr stage III. None of the differences between the two groups of primary interest (i.e. patients undergoing fast titration under domperidone cover versus those undergoing slow titration with placebo cover) were significant; statistical analyses of differences between the third group and either of the other two groups were not performed. As usual in this type of patient population, a high proportion of patients (68%–79%) in each group were taking concomitant medications. The most common ones were those taken for cardiovascular and central nervous system disorders. The only medication taken by more than 10% of patients in any group was selegiline, which was taken by 25%–29% of patients in each group. Only a small number of patients had taken any prior dopaminergic therapy (7.5%–9.8% of each group). This treatment was most commonly apomorphine, which had been used in a challenge test to aid diagnosis of Parkinson’s disease [22,23]. 3.2. The incidence of nausea
Fig. 1. The percentage of patients in each treatment group reporting at least one incident of nausea during treatment.
The number of patients experiencing at least one incident of nausea during the titration periods was slightly lower in the fast-titration plus domperidone group than in the slowtitration group (45.3% compared with 54.9%, respectively, over days 1–42; Fig. 1). The highest incidence of nausea
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were similar for the groups undergoing fast titration with domperidone cover and slow titration with placebo. The incidences were markedly higher in patients who underwent fast titration of ropinirole without domperidone cover (Table 3). There were no significant differences between the main comparator groups, even for the incidence of ‘dizziness only on standing’, which was appreciably higher in the fast-titration group. 3.4. Efficacy of ropinirole
Fig. 2. The percentage of days during treatment on which patients in each treatment group reported any incident of nausea.
was experienced by patients undergoing fast titration without domperidone cover (58.3% over days 1–42). The odds ratio for a patient in the fast-titration plus domperidone group having nausea relative to the odds of a patient in the slow plus placebo group was less than one, indicating a difference between these two groups on this parameter. However, the 95% confidence intervals around the odds ratio includes one, indicating no statistically significant treatment effect. The percentage of patients experiencing moderate or severe nausea was also slightly lower in the fast-titration plus domperidone group than in the slow-titration group (30.2% compared with 37.3%, respectively, over days 1–42). In the fast-titration plus placebo group, the incidence was 33.3%. Patients in the group who underwent fast titration with domperidone cover experienced significantly fewer days with nausea than those undergoing slow titration (8.5% of days 1–42 vs. 19.2% of days, p 0.012) (Fig. 2). In addition, there was a significant difference between these groups in the percentage of the first 21 days on which domperidone rescue treatment was required. This difference was again in favour of the fast-titration under domperidone cover schedule (2.9% of days vs. 11.4%, p 0.002). 3.3. Other dopaminergic effects The incidences of dopaminergic effects other than nausea
Between 57% and 70% of the patients were found to be responders to ropinirole, according to the CGI measure of improvement, confirming the effectiveness of ropinirole in treating the symptoms of Parkinson’s disease. No large difference between the titration groups in response rate was apparent by day 21. By the end of the study (day 84), there did appear to be a slightly better response rate according to the CGI in the fast-titration plus domperidone group: 69.8% of patients showed an improvement from baseline compared with 56.9% of the slow-titration plus placebo group and 58.3% of the fast-titration plus placebo group. With the UPDRS motor score, the titration groups were well matched at baseline in this measure. By the end of the study (day 84), there was a mean percentage change from baseline of ⫺ 27.5% in the fast-titration plus domperidone group, ⫺ 30.1% in the slow-titration plus placebo group, and ⫺ 27.6% in the fast-titration plus placebo group. The respective percentages of patients with a reduction in score from baseline of at least 30%, were 33%, 35% and 37%. 3.5. Adverse experiences Similar proportions of patients in each group (35%–46%) experienced at least one adverse event. Investigators were not required to report as adverse events the dopaminergic effects that were recorded by patients in their diaries. Therefore, these do not feature among the most common adverse events shown in Table 4. The most common adverse event was somnolence, which had a higher incidence in the groups that underwent fast titration. Other events were similarly prevalent in all groups. Only seven patients withdrew because of adverse events. Three in the group receiving fast titration with placebo cover withdrew because of dopaminergic events: one withdrew because of postural hypotension, one because of nausea and vomiting, and one because of hallucinations. In the group receiving slow titration with
Table 3 The percentage of patients reporting dopaminergic side-effects (other than nausea) over 42 days of treatment
Symptom
Treatment regimen (titration schedule ⫹ cover) Fast ⫹ domperidone (n 53) Slow ⫹ placebo (n 51)
Fast ⫹ placebo (n 24)
Vomiting Dizziness only on standing Dizziness at any time Heartburn
17.0 28.3 24.5 20.8
29.2 33.3 33.3 37.5
17.7 17.7 23.5 21.6
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Table 4 The percentage of patients reporting the most common adverse events (those reported by more than 5% of patients) over 42 days of treatment
Adverse event
Treatment regimen (titration schedule ⫹ cover) Fast ⫹ domperidone (n 53) Slow ⫹ placebo (n 51)
Fast ⫹ placebo (n 24)
Somnolence Fatigue Nausea Headache
13.2 11.3 5.7 5.7
12.5 8.3 4.2 8.3
5.9 7.8 7.8 3.9
placebo cover, three patients withdrew: one withdrawal was because of breathlessness and palpitations, another because of leg edema, and the third for loss of consciousness. Only one patient withdrew from the group receiving fast titration under domperidone cover; this patient withdrew because of precordial pain. There were no clinically relevant changes in either vital signs or laboratory parameters.
4. Discussion Inclusion in this trial of the group that received fast titration of ropinirole under placebo cover showed that the rapid introduction of ropinirole is accompanied, as expected, by a relatively high level of dopaminergic side-effects – nausea, vomiting, dizziness and heartburn. In contrast, if this titration schedule is followed under domperidone cover, the incidences of nausea, vomiting and heartburn are reported at lower levels; these levels are also slightly lower than those experienced by patients undergoing the standard dose titration of ropinirole. This result concurs with those of two trials in which the effects of domperidone on the titration of bromocriptine were tested [19,20]. Both these trials showed that domperidone reduced these early peripheral side-effects of bromocriptine, so the dopamine agonist could be titrated faster and to a higher dose than usual. As shown in the trial of Agid et al. [20], domperidone appeared to be relatively ineffective in preventing postural hypotension caused by ropinirole. The incidence of this side-effect was appreciably higher in the fast-titration groups, which could suggest that postural dizziness is a centrally mediated effect of dopaminergic therapy, as it was not blocked by the peripherally active domperidone. However, these results were not supported by those of the efficacy evaluable population (all patients included in the intention-to-treat population who did not violate the study protocol), where the incidence of postural dizziness was similar in all titration groups, at approximately 18%. A slow dosing regimen may be preferable for patients at risk from this side-effect. The incidence of somnolence was also higher in the fast-titration groups compared with the slowtitration group, and may be an indication that this is a dopaminergically mediated experience, not controlled by peripheral dopaminergic antagonists. The overall incidences of nausea, assessed as the number of patients reporting at least one incident of nausea during
the titration period and the primary efficacy parameter, were not significantly different in the two main comparator groups. However, the number of days on which nausea occurred was significantly lower in the group undergoing fast titration with domperidone cover. This indicates that the persistence of this side-effect was lower in this group, which may have a beneficial impact on patient compliance with this medication. In conclusion, the results of this study indicate that a fast titration of ropinirole given as sole dopaminergic therapy to patients with early Parkinson’s disease is well tolerated when domperidone is given concurrently. Domperidone controlled the incidence of symptoms such as nausea, vomiting and heartburn to levels that were also produced by a standard dose titration of ropinirole, though somnolence and postural dizziness seemed to be more frequent with fast titration. Domperidone also appeared to reduce the persistence of the gastrointestinal side-effects. Thus, using a fast-titration schedule, ropinirole can be introduced quickly and after titration to the optimum regimen, domperidone can be discontinued in most patients. Further studies are needed to fully evaluate the benefits of using a fasttitration regimen. Acknowledgements Belgium: E. Baeck, P.P. de Deyn, J. Jacquy, M. van Orshoven; France: M. Ceccaldi, A. Deste´e, F. Durif, T. Tanugi, J.M. Warter; Italy: P. Lamberti, P. Nordera, M. Onofri, S. Ruggieri, F. Stocchi, F. Tamma, B. Tripaldelli; UK: G. Boddie, C. Clarke, H. Sagar, E. Spokes, P. Tidswell. References [1] Lieberman AN, Neophytides A, Leibowitz M, et al. Comparative efficacy of pergolide and bromocriptine in patients with advanced Parkinson’s disease. Advances in Neurology 1983;37:95–108. [2] Rascol A, Guiraud B, Montastruc JL, David J, Clanet M. Long-term reatment of Parkinson’s disease with bromocriptine. Journal of Neurology, Neurosurgery and Psychiatry 1979;42:143–150. [3] Stern GM, Lees AJ. Sustained bromocriptine therapy in 50 previously untreated patients with Parkinson’s disease. Advances in Neurology 1983;37:17–21. [4] Rinne UK. Dopamine agonists as primary treatment in Parkinson’s disease. Advances in Neurology 1986;45:519–523. [5] Rinne UK. Lisuride, a dopamine agonist in the treatment of early Parkinson’s disease. Neurology 1989;39:336–339.
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[6] Montastruc JL, Rascol O, Senard JM, Rascol A. A randomized controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson’s disease; a five year follow up. Journal of Neurology, Neurosurgery and Psychiatry 1994;57:1034–1038. [7] Nakanishi T, Iwata M, Goto I, et al. Nation-wide collaborative study on the long-term effects of bromocriptine in the treatment of parkinsonian patients. Final report. European Neurology 1992;32 (Suppl. 1):9–22. [8] Montastruc JL, Rascol O, Rascol A. A randomized controlled study of bromocriptine versus levodopa in previously untreated Parkinsonian patients: a 3 year follow-up. Journal of Neurology, Neurosurgery and Psychiatry 1989;52:773–775. [9] Yanagisawa N, Kanazawa I, Goto I, et al. Seven-year follow-up study of bromocriptine therapy for Parkinson’s disease. European Neurology 1994;34 (Suppl. 3):29–35. [10] Rinne UK. Early combination of bromocriptine and levodopa in the treatment of Parkinson’s disease: a 5-year follow-up. Neurology 1987;37:826–828. [11] Weil C. The safety of bromocriptine in long-term use: a review of the literature. Current Medical Research Opinion 1986;10:25– 51. [12] Langtry HD, Clissold SP. Pergolide: a review of its pharmacological properties and therapeutic potential in Parkinson’s disease. Drugs 1990;39:491–506. [13] Goetz CG, Tanner CM, Glantz RH, Klawans HL. Chronic agonist therapy for Parkinson’s disease: a 5-year study of bromocriptine and pergolide. Neurology 1985;35:749–751. [14] Korczyn AD, Brooks DJ, Brunt ER, Poewe WH, Rascol O, Stocchi F. On behalf of the 053 Study Group. Ropinirole versus bromocriptine in
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the treatment of early Parkinson’s disease: a 6-month interim report of a 3-year study, Movement Disorders, 13 (1998) 46–51. Rascol O, Brooks DJ, Brunt ER, Korczyn AD, Poewe WH, Stocchi F. On behalf of the 056 Study Group. Ropinirole in the treatment of early Parkinson’s disease: a 6-month interim report of a 5-year L-dopacontrolled study, Movement Disorders, 13 (1998) 39–45. Brooks DJ, Torjanski N, Burn DJ. Ropinirole in the symptomatic treatment of Parkinson’s disease. Journal of Neural Transmission 1995;45 (Suppl.):231–238. Adler CH, Sethi KD, Hauser RA, et al. Ropinirole for the treatment of early Parkinson’s disease. Neurology 1997;49:393–399. Corsini GU, Del Zompo M, Gessa GL, Margoni A. Therapeutic efficacy of apomorphine combined with an extracerebral inhibitor of dopamine receptors in Parkinson’s disease. Lancet 1979;i:954–956. Quinn N, Illas A, Lhermitte F, Agid Y. Bromocriptine and domperidone in the treatment of Parkinson’s disease. Neurology 1981;31:662–667. Agid Y, Pollak P, Bonnet AM, Signoret JL, Lhermitte F. Bromocriptine associated with a peripheral dopamine blocking agent in treatment of Parkinson’s disease, Lancet, March 17, 1979. de Mey C, Enterling D, Meineke I, Yeulet S. Interactions between domperidone and ropinirole, a novel dopamine D2-receptor agonist. British Journal of Clinical Pharmacology 1991;32:483–488. Gasser T, Schwarz J, Arnold G, Trenkwalder C, Oertel WH. Apomorphine test for dopaminergic responsiveness in patients with previously untreated Parkinson’s disease. Archives of Neurology 1992;49:1131–1134. Hughes AJ, Lees AJ, Stern GM. Challenge tests to predict the dopaminergic response in untreated Parkinson’s disease. Neurology 1991;41:1723–1725.
Co-administration of ropinirole and domperidone during rapid dose escalation of the dopamine agonist F. Stocchi a,*, A. Deste´e b a
Department of Neurological Science, University ‘‘la Sapienza’’ Roma and Neuromed, Pozzilli (IS), Rome, Italy b Clinique Neurologique, Centre Hospitalier Re´gional et Universitaire, 59037-Lille, France Received 27 April 1998; received in revised form 25 November 1998; accepted 1 December 1998
Abstract In patients naive to dopaminergic therapy, reducing the side-effects associated with dopamine agonist treatment will permit faster titration to effective therapeutic doses. The primary aim of this study was to compare the incidence of dopaminergic side-effects in parkinsonian patients undergoing fast titration with ropinirole under domperidone cover with that of patients undergoing slow titration with matched domperidone placebo. Patients in the former group experienced nausea on significantly fewer days than patients in the latter group. The fasttitration regimen with domperidone cover was well tolerated and allowed ropinirole to be introduced quickly. 䉷 1999 Published by Elsevier Science Ltd. All rights reserved. Keywords: Ropinirole; Dopamine agonist; Domperidone
1. Introduction Dopamine agonists were originally introduced for use as an adjunct to L-dopa in the later stages of Parkinson’s disease to supplement the effects of L-dopa and to smooth out motor fluctuations [1]. Now, these drugs are increasingly being used early in treatment, either alone or with a low dose of L-dopa [2–7]. The rationale for such treatment is to delay the introduction of L-dopa or reduce the dose required in an attempt to prevent or delay the onset of its long-term side-effects [3,5–10]. In patients who have not taken dopaminergic therapy before, the dopamine agonists must be titrated slowly to prevent adverse events (mainly peripheral dopaminergic effects of nausea and vomiting), but this means that treatment must be maintained for some time before an adequate therapeutic dose is reached. In addition, significant numbers of patients withdraw from treatment with dopamine agonists because of such early side-effects [1,11–13]. It is therefore important that the side-effects of these drugs are minimized, and titration to an effective dose is as fast as possible in order to promote patient compliance with treatment. Ropinirole is a novel non-ergoline dopamine agonist that has been introduced for use in early Parkinson’s disease
* Corresponding author. Tel.: ⫹3906 4991 4607; fax: ⫹3906 4440 790.
[14–17]. Overall, treatment with ropinirole is well tolerated. The most frequently reported dopaminergic adverse events arising from treatment with ropinirole are nausea, dizziness and vomiting [16]. The present study investigated whether ropinirole could be titrated more quickly than the standard schedule, without reducing tolerability, by prophylactic use of the peripheral dopamine antagonist domperidone [18]. Domperidone has been effectively used to block the undesirable peripheral side-effects of dopamine agonists [19,20], and pretreatment with domperidone does not alter ropinirole’s plasma pharmacokinetics [21]. Hence, three groups were compared: in two, ropinirole was titrated rapidly with and without domperidone cover, and in the third, ropinirole was titrated ‘slowly’ with no domperidone cover. ‘Fast’ titration took 21 days and ‘slow’ titration, 42 days. Ropinirole was titrated in each case to a dose of 7.5 mg/day. The slow schedule is the one usually used in clinical trials of ropinirole, and is as fast as that of the other dopamine agonists in general use. The primary comparison was between the groups receiving a fast titration of ropinirole under domperidone cover and the slow titration under placebo. The incidence of dopaminergic side-effects in these two groups was compared. The second fasttitration group was half the size of the other treatment groups and was included to measure the effect of fast titration of ropinirole on the incidence of dopaminergic side-effects.
1353-8020/99/$ - see front matter 䉷 1999 Published by Elsevier Science Ltd. All rights reserved. PII: S1353-802 0(98)00041-8
F. Stocchi, A. Deste´e / Parkinsonism and Related Disorders 4 (1998) 183–188
184
Table 1 The fast- and slow-titration schedules for ropinirole
Fast titration Daily dose (mg) Unit dose (mg)
Day of titration (dose until that day) 3 6 9
12
15
18
21
0.75 0.25
3.0 1.0
4.5 1.5
6 2.0
7.5 2.5
Slow titration Daily dose (mg) Unit dose (mg)
1.5 0.5
0.75 0.25
2.25 0.75
1.5 0.5
2. Materials and methods 2.1. Patients Patients were eligible for inclusion if they: had a diagnosis of Parkinson’s disease at Hoehn and Yahr stages I–III based on medical history and neurologic examination; were older than 30 years; and, if women, were of non-childbearing potential. Patients either had not previously received any dopaminergic treatments, or had received no more than six weeks’ treatment with a low or moderate dose of L-dopa or with a dopamine agonist. Such treatments were stopped for at least two weeks before screening. All patients gave their informed consent to take part in the study, which was conducted in accordance with the declaration of Helsinki, and the protocol was approved by local Ethics Committees in the trial centers. Patients were excluded if they had had systemic disease in the previous three months, psychosis or severe dementia, or postural hypotension. Excluded previous treatments were: any monoamine oxidase inhibitors except selegiline, any investigational new drug within the previous 30 days, or any previous exposure to ropinirole. Excluded concurrent treatments were: amantadine, anticholinergics and antiemetics. Treatment with selegiline, antidepressants and benzodiazepines was allowed provided these drugs were administered at a stable dose for at least two weeks before screening, and during the study.
2.2. Drug treatments Ropinirole was provided in identical tablets containing the following doses: 0.25, 0.50, 1.00 and 2.00 mg. Domperidone was supplied in capsules containing 10 mg of the drug. Matched placebo was provided for both these treatments. Both drugs were taken orally three times daily. Domperidone (or matched placebo) was taken 30 min before ropinirole, which was taken with or immediately after food. During the seven day run-in period, all patients took ropinirole placebo for seven days; those patients randomized to receive domperidone cover took placebo domperidone for three days, then domperidone for the next four days,
2.25 0.75
24
30
36
42
7.5 2.5
3.0 1.0
4.5 1.5
6 2.0
7.5 2.5
whereas the other patients continued to take placebo domperidone. At the end of the run-in period, ropinirole was introduced either by a fast- or slow-titration schedule, as detailed in Table 1. Each dose of ropinirole comprised two tablets; the contents of these two tablets amounted to the unit dose. Both patients and investigators were blinded to the use of domperidone and to the titration schedule for ropinirole. Open-label domperidone was also given to all patients to be used as rescue medication to relieve the symptoms of nausea. Patients were instructed to take a maximum of three tablets per day (30 mg) and not to take this therapy prophylactically. 2.3. Efficacy and safety assessments Patients were all issued with diaries in which they recorded daily whether they had experienced nausea (and its severity), vomiting, dizziness on standing, dizziness at any time, or heartburn. They also recorded the number of tablets of rescue domperidone taken. Patients were seen at the clinic each week for the first four weeks and then every two weeks, when diary information was collected, vital signs and adverse events were recorded, and a check on treatment compliance made (by tablet count). Reports of adverse events (apart from those recorded on the diary cards) were elicited by asking the neutral question ‘Do you feel different in any way since starting the new treatment?’. The primary efficacy parameter was the incidence of nausea during the 42-day titration period, which was recorded in patients’ diaries. Secondary efficacy parameters were: the percentage of days in the titration period on which patients experienced nausea, the incidence of moderate or severe nausea, the incidence of other dopaminergic sideeffects, and the percentage of days on which rescue domperidone treatment was taken. The main comparison was between the group that underwent a fast titration under domperidone cover and the one that underwent a slow titration with placebo. The efficacy of ropinirole was assessed using the Clinical Global Impression (CGI) and the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. The CGI was assessed at baseline and at all subsequent visits to the clinic.
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Table 2 Demographic characteristics of the patient groups
Number of patients Female/male (%) Mean age; years (range) Mean disease duration; years (range) Hoehn and Yahr stage; number (%) I I.5 II II.5 III
Treatment regimen (titration schedule ⫹ cover) Fast ⫹ domperidone Slow ⫹ placebo
Fast ⫹ placebo
53 25/28 (47.2/52.8) 61 (44–81) 2.7 (0.3–18.8)
51 23/28 (45.1/54.9) 64 (35–86) 2.2 (0.1–15.1)
24 11/13 (45.8/54.2) 64 (38–78) 4.5 (0.3–21.2)
6 11 22 13 1
8 (15.7) 14 (27.5) 13 (25.5) 13 (25.5) 3 (5.9)
3 (12.5) 7 (29.2) 6 (25.0) 4 (16.7) 4 (16.7)
(11.3) (20.8) (41.5) (24.5) (1.9)
The UPDRS motor score was recorded at baseline and on days 28, 56 and 84.
3. Results 3.1. Patient demographics
2.4. Statistical evaluation Formal efficacy comparisons were carried out only between the two main titration groups (fast titration with domperidone cover and slow titration under placebo). No formal testing was performed on the data for adverse experiences other than the dopaminergic effects. Logistic regression was used to detect between-group differences in dichotomous variables (e.g. incidence of nausea of any severity), assuming that the underlying distribution was binomial. Analysis of variance was used to detect differences in continuous variables. All statistical analyses were performed using the SAS statistical package (version 6.08).
A total of 128 patients were recruited to the trial from 20 centers in Italy, Belgium, France and the UK. These patients were randomized in a ratio of 2 : 2 : 1 to receive fast titration under domperidone cover, slow titration with placebo, or fast titration with placebo, respectively. The demographic characteristics of the patient groups are shown in Table 2. Slightly more men than women were recruited. The groups had a mean age range of 61–64 years. Most patients had a disease duration of 2–3 years and were at Hoehn and Yahr stage I.5–II.5. Patients in the group receiving fast titration and placebo cover had a somewhat longer disease duration, and a higher proportion of these patients were at Hoehn and Yahr stage III. None of the differences between the two groups of primary interest (i.e. patients undergoing fast titration under domperidone cover versus those undergoing slow titration with placebo cover) were significant; statistical analyses of differences between the third group and either of the other two groups were not performed. As usual in this type of patient population, a high proportion of patients (68%–79%) in each group were taking concomitant medications. The most common ones were those taken for cardiovascular and central nervous system disorders. The only medication taken by more than 10% of patients in any group was selegiline, which was taken by 25%–29% of patients in each group. Only a small number of patients had taken any prior dopaminergic therapy (7.5%–9.8% of each group). This treatment was most commonly apomorphine, which had been used in a challenge test to aid diagnosis of Parkinson’s disease [22,23]. 3.2. The incidence of nausea
Fig. 1. The percentage of patients in each treatment group reporting at least one incident of nausea during treatment.
The number of patients experiencing at least one incident of nausea during the titration periods was slightly lower in the fast-titration plus domperidone group than in the slowtitration group (45.3% compared with 54.9%, respectively, over days 1–42; Fig. 1). The highest incidence of nausea
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were similar for the groups undergoing fast titration with domperidone cover and slow titration with placebo. The incidences were markedly higher in patients who underwent fast titration of ropinirole without domperidone cover (Table 3). There were no significant differences between the main comparator groups, even for the incidence of ‘dizziness only on standing’, which was appreciably higher in the fast-titration group. 3.4. Efficacy of ropinirole
Fig. 2. The percentage of days during treatment on which patients in each treatment group reported any incident of nausea.
was experienced by patients undergoing fast titration without domperidone cover (58.3% over days 1–42). The odds ratio for a patient in the fast-titration plus domperidone group having nausea relative to the odds of a patient in the slow plus placebo group was less than one, indicating a difference between these two groups on this parameter. However, the 95% confidence intervals around the odds ratio includes one, indicating no statistically significant treatment effect. The percentage of patients experiencing moderate or severe nausea was also slightly lower in the fast-titration plus domperidone group than in the slow-titration group (30.2% compared with 37.3%, respectively, over days 1–42). In the fast-titration plus placebo group, the incidence was 33.3%. Patients in the group who underwent fast titration with domperidone cover experienced significantly fewer days with nausea than those undergoing slow titration (8.5% of days 1–42 vs. 19.2% of days, p 0.012) (Fig. 2). In addition, there was a significant difference between these groups in the percentage of the first 21 days on which domperidone rescue treatment was required. This difference was again in favour of the fast-titration under domperidone cover schedule (2.9% of days vs. 11.4%, p 0.002). 3.3. Other dopaminergic effects The incidences of dopaminergic effects other than nausea
Between 57% and 70% of the patients were found to be responders to ropinirole, according to the CGI measure of improvement, confirming the effectiveness of ropinirole in treating the symptoms of Parkinson’s disease. No large difference between the titration groups in response rate was apparent by day 21. By the end of the study (day 84), there did appear to be a slightly better response rate according to the CGI in the fast-titration plus domperidone group: 69.8% of patients showed an improvement from baseline compared with 56.9% of the slow-titration plus placebo group and 58.3% of the fast-titration plus placebo group. With the UPDRS motor score, the titration groups were well matched at baseline in this measure. By the end of the study (day 84), there was a mean percentage change from baseline of ⫺ 27.5% in the fast-titration plus domperidone group, ⫺ 30.1% in the slow-titration plus placebo group, and ⫺ 27.6% in the fast-titration plus placebo group. The respective percentages of patients with a reduction in score from baseline of at least 30%, were 33%, 35% and 37%. 3.5. Adverse experiences Similar proportions of patients in each group (35%–46%) experienced at least one adverse event. Investigators were not required to report as adverse events the dopaminergic effects that were recorded by patients in their diaries. Therefore, these do not feature among the most common adverse events shown in Table 4. The most common adverse event was somnolence, which had a higher incidence in the groups that underwent fast titration. Other events were similarly prevalent in all groups. Only seven patients withdrew because of adverse events. Three in the group receiving fast titration with placebo cover withdrew because of dopaminergic events: one withdrew because of postural hypotension, one because of nausea and vomiting, and one because of hallucinations. In the group receiving slow titration with
Table 3 The percentage of patients reporting dopaminergic side-effects (other than nausea) over 42 days of treatment
Symptom
Treatment regimen (titration schedule ⫹ cover) Fast ⫹ domperidone (n 53) Slow ⫹ placebo (n 51)
Fast ⫹ placebo (n 24)
Vomiting Dizziness only on standing Dizziness at any time Heartburn
17.0 28.3 24.5 20.8
29.2 33.3 33.3 37.5
17.7 17.7 23.5 21.6
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Table 4 The percentage of patients reporting the most common adverse events (those reported by more than 5% of patients) over 42 days of treatment
Adverse event
Treatment regimen (titration schedule ⫹ cover) Fast ⫹ domperidone (n 53) Slow ⫹ placebo (n 51)
Fast ⫹ placebo (n 24)
Somnolence Fatigue Nausea Headache
13.2 11.3 5.7 5.7
12.5 8.3 4.2 8.3
5.9 7.8 7.8 3.9
placebo cover, three patients withdrew: one withdrawal was because of breathlessness and palpitations, another because of leg edema, and the third for loss of consciousness. Only one patient withdrew from the group receiving fast titration under domperidone cover; this patient withdrew because of precordial pain. There were no clinically relevant changes in either vital signs or laboratory parameters.
4. Discussion Inclusion in this trial of the group that received fast titration of ropinirole under placebo cover showed that the rapid introduction of ropinirole is accompanied, as expected, by a relatively high level of dopaminergic side-effects – nausea, vomiting, dizziness and heartburn. In contrast, if this titration schedule is followed under domperidone cover, the incidences of nausea, vomiting and heartburn are reported at lower levels; these levels are also slightly lower than those experienced by patients undergoing the standard dose titration of ropinirole. This result concurs with those of two trials in which the effects of domperidone on the titration of bromocriptine were tested [19,20]. Both these trials showed that domperidone reduced these early peripheral side-effects of bromocriptine, so the dopamine agonist could be titrated faster and to a higher dose than usual. As shown in the trial of Agid et al. [20], domperidone appeared to be relatively ineffective in preventing postural hypotension caused by ropinirole. The incidence of this side-effect was appreciably higher in the fast-titration groups, which could suggest that postural dizziness is a centrally mediated effect of dopaminergic therapy, as it was not blocked by the peripherally active domperidone. However, these results were not supported by those of the efficacy evaluable population (all patients included in the intention-to-treat population who did not violate the study protocol), where the incidence of postural dizziness was similar in all titration groups, at approximately 18%. A slow dosing regimen may be preferable for patients at risk from this side-effect. The incidence of somnolence was also higher in the fast-titration groups compared with the slowtitration group, and may be an indication that this is a dopaminergically mediated experience, not controlled by peripheral dopaminergic antagonists. The overall incidences of nausea, assessed as the number of patients reporting at least one incident of nausea during
the titration period and the primary efficacy parameter, were not significantly different in the two main comparator groups. However, the number of days on which nausea occurred was significantly lower in the group undergoing fast titration with domperidone cover. This indicates that the persistence of this side-effect was lower in this group, which may have a beneficial impact on patient compliance with this medication. In conclusion, the results of this study indicate that a fast titration of ropinirole given as sole dopaminergic therapy to patients with early Parkinson’s disease is well tolerated when domperidone is given concurrently. Domperidone controlled the incidence of symptoms such as nausea, vomiting and heartburn to levels that were also produced by a standard dose titration of ropinirole, though somnolence and postural dizziness seemed to be more frequent with fast titration. Domperidone also appeared to reduce the persistence of the gastrointestinal side-effects. Thus, using a fast-titration schedule, ropinirole can be introduced quickly and after titration to the optimum regimen, domperidone can be discontinued in most patients. Further studies are needed to fully evaluate the benefits of using a fasttitration regimen. Acknowledgements Belgium: E. Baeck, P.P. de Deyn, J. Jacquy, M. van Orshoven; France: M. Ceccaldi, A. Deste´e, F. Durif, T. Tanugi, J.M. Warter; Italy: P. Lamberti, P. Nordera, M. Onofri, S. Ruggieri, F. Stocchi, F. Tamma, B. Tripaldelli; UK: G. Boddie, C. Clarke, H. Sagar, E. Spokes, P. Tidswell. References [1] Lieberman AN, Neophytides A, Leibowitz M, et al. Comparative efficacy of pergolide and bromocriptine in patients with advanced Parkinson’s disease. Advances in Neurology 1983;37:95–108. [2] Rascol A, Guiraud B, Montastruc JL, David J, Clanet M. Long-term reatment of Parkinson’s disease with bromocriptine. Journal of Neurology, Neurosurgery and Psychiatry 1979;42:143–150. [3] Stern GM, Lees AJ. Sustained bromocriptine therapy in 50 previously untreated patients with Parkinson’s disease. Advances in Neurology 1983;37:17–21. [4] Rinne UK. Dopamine agonists as primary treatment in Parkinson’s disease. Advances in Neurology 1986;45:519–523. [5] Rinne UK. Lisuride, a dopamine agonist in the treatment of early Parkinson’s disease. Neurology 1989;39:336–339.
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