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day in Japanese patients with Parkinson's disease
Parkinsonism and Related Disorders xxx (2017) 1e7
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Clinical evaluation of ropinirole controlled-release formulation at 18e24 mg/day in Japanese patients with Parkinson's disease Nobutaka Hattori, MD a, Kazuko Hasegawa, MD b, Katsuaki Sato, MSc c, *, Erika Mitsuyama, BSc c, Yotaro Numachi, MD c a
Department of Neurology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Department of Neurology, Sagamihara National Hospital, 18-1, Sakuradai, Minami-ku, Sagamihara, Kanagawa 252-0392, Japan Neurosciences Therapeutic Area Office, Medicines Development, Japan Development & Medical Affairs, GlaxoSmithKline K.K., GSK Bldg. 6-15, Sendagaya 4chome, Shibuya-ku, Tokyo 151-8566, Japan
b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 November 2016 Received in revised form 7 March 2017 Accepted 10 April 2017
Introduction: There has been no clinical data on Japanese patients with Parkinson's disease with which to examine whether motor symptoms improve and to assess the safety profile after the dose of ropinirole was increased in those who had not achieved an optimal response to the ropinirole immediate-release formulation 15 mg/day or the controlled-release (CR) formulation 16 mg/day. Methods: This was a multicenter, randomized, double-blind study, followed by an open-label, long-term study. Participants were randomized at a ratio of 3:1 to the high-dose ropinirole CR (18e24 mg/day) group or the maintenance ropinirole CR 16 mg/day group. Results: In the high-dose ropinirole CR group (N ¼ 61), the Japanese unified Parkinson's disease rating scale Part III total score at week 12 was significantly decreased compared with the baseline total score (4.8 ± 5.95, [95% CI, 6.3 to 3.2], p < 0.001). However, a comparable decrease was also observed in the maintenance ropinirole CR 16 mg/day group (N ¼ 20) (5.7 ± 5.18, [95% CI, 8.1 to 3.3]), with no statistically significant difference in the adjusted mean change between the high-dose and maintenance groups (0.5 [95% CI, 2.4 to 3.4]). Plasma drug concentrations increased at doses higher than 16 mg/day, but did not increase significantly in a dose-dependent manner at doses of 18e24 mg/day. No adverse events were found that would affect the known safety profile of ropinirole. Conclusion: This study did not demonstrate the difference in efficacy between the high-dose ropinirole CR group and the maintenance ropinirole CR group. Clinical trial registration: ClinicalTrials.gov identifier: NCT01929317. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Ropinirole controlled-release Randomized Double blind Pharmacokinetics Parkinson's disease
1. Introduction Ropinirole hydrochloride (JAN) developed by SmithKline Beecham, UK, (currently GlaxoSmithKline) is a non-ergot alkaloid dopamine receptor agonist that has selective affinity for the dopamine D2 receptor system. The ropinirole controlled-release (CR) formulation, which is an extended-release version of ropinirole hydrochloride, was approved in Japan for the treatment of Parkinson's disease in June 2012. In Japan, ropinirole CR can be administered to a maximum dose
* Corresponding author. E-mail addresses: [email protected] (N. Hattori), k-hasegawa@ sagamihara-hosp.gr.jp (K. Hasegawa), [email protected] (K. Sato), erika.2. [email protected] (E. Mitsuyama), [email protected] (Y. Numachi).
of 16 mg/day, which is deemed equivalent to a maximum dose of 15 mg/day for the preceding ropinirole immediate-release (IR) formulation. In other countries, however, both ropinirole CR and IR can be administered to a maximum dose of 24 mg/day [1e3], with differences in the approved dose between Japan and other countries. According to published reports of ropinirole hydrochloride administered at a maximum dose of 24 mg/day, ropinirole improved “wearing off” and dyskinesia [4], and delayed the need for stereotactic surgery or continuous apomorphine infusion [5]. Previous studies of ropinirole CR in Japan have shown that there are no clear ethnic differences in the pharmacokinetic profile between Japanese and non-Japanese patients with Parkinson's disease [Company internal document]. In the present study, therefore, the efficacy and safety of ropinirole CR administered at doses of 18e24 mg once daily were
http://dx.doi.org/10.1016/j.parkreldis.2017.04.005 1353-8020/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: N. Hattori, et al., Clinical evaluation of ropinirole controlled-release formulation at 18e24 mg/day in Japanese patients with Parkinson's disease, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.04.005
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evaluated in Japanese patients with Parkinson's disease who had not achieved an optimal response to ropinirole IR 15 mg/day or ropinirole CR 16 mg/day to determine whether a dose increase from 16 mg, the maximum daily dose of ropinirole CR approved for Parkinson's disease in Japan, to 24 mg, the equivalent approved in other countries, would yield additional clinical benefits or raise new safety concerns. In addition, the long-term safety was evaluated. Incidentally, there has been no comparison study between high-dose and standard-dose controlled formulation of the other dopamine agonists in Japanese or Asian population. 2. Methods 2.1. Ethics This was a multicenter study in Japanese patients with Parkinson's disease, conducted at 17 medical institutions from August 2013 to June 2015. The protocol, informed consent documents, and other aspects of this study requiring prior approval were reviewed and approved by the Institutional Review Board as specified in the “Good Clinical Practice (GCP) for Drugs.” The study was implemented in compliance with GCP. Furthermore, all applicable requirements for the protection of participants' privacy and the Declaration of Helsinki were adhered to by protecting participants' personal information and data. Written informed consent was obtained from all participants. 2.2. Trial design This was a multicenter, randomized, double-blind study followed by an open-label long-term study. It comprised a 4-weeks screening phase, 12-weeks dose increase effect verification phase, 1-week down titration phase 1, 39-weeks long-term phase, a 1- to 2-weeks down titration phase 2, and follow-up phase (1e4 weeks after the end of study treatment) (Supplemental Figure). The first 60 participants who completed the dose increase effect verification phase entered the down titration phase 1 and then the long-term phase. The remaining participants who completed the dose increase effect verification phase entered the down titration phase 2 and then completed the study. Participants were randomly assigned at a ratio of 3:1 to either the high-dose ropinirole CR group (18e24 mg/day) or maintenance ropinirole CR 16 mg/day group. Stratified randomization according to concomitant L-dopa (ropinirole monotherapy or L-dopa adjunct therapy) was used. The maintenance ropinirole CR 16 mg/day group was included in the study to confirm the efficacy and safety at the maximum dose (16 mg/day) approved in Japan in the same study. However, because a large sample size was required for a parallel-group comparison study to verify the superiority of high-dose ropinirole CR to the maintenance dose of 16 mg/day, the primary evaluation was a comparison before versus after the dose increase of ropinirole CR in the high-dose ropinirole CR group. 2.3. Study population Patients who met all of the following criteria were eligible for the study: those who were diagnosed with Parkinson's disease in stages I-IV on the modified Hoehn and Yahr scale during the “on” period; those who were receiving ropinirole IR 15 mg/day or CR 16 mg/day and had a unified Parkinson's disease rating scale (UPDRS) Part III total score (during “on”) of 10 or more at the start of screening; and those who were expected to show clinical improvement by increasing the dose of ropinirole CR (to 18e24 mg/ day). Participants receiving ropinirole monotherapy had never
received L-dopa, or had previously received L-dopa at doses up to 450 mg/day for up to 3 months in total and had been withdrawn from L-dopa for a minimum of 4 weeks prior to screening. Participants on L-dopa adjunct therapy had received L-dopa (up to 450 mg/day) for at least 4 weeks prior to screening. We were concerned that if L-dopa dosage was too high, it may difficult to obtain the effect of high-dose ropinirole CR compared to standard dose (16 mg). Therefore L-dopa dosage was limited up to 450 mg/ day. The following patients with Parkinson's disease were excluded from the study: those with advanced disease characterized by severe peak dose or biphasic dyskinesia, or unpredictable symptomatic fluctuations despite treatment with a stable dose of Ldopa; those with symptomatic orthostatic hypotension (e.g., dizziness, syncope); those with severe dementia as indicated by a UPDRS Part I, item 1 (intellectual function) score of 3 or 4; those with current or prior severe psychosis (e.g., schizophrenia, psychotic depression) as indicated by a UPDRS Part I, item 2 (thought disorder) or item 3 (depression) score of 3 or 4; and those who had previously received surgical treatment for Parkinson's disease (e.g., pallidectomy, deep brain stimulation). 2.4. Treatment During the screening phase, all participants received ropinirole CR 16 mg/day. Ropinirole CR (or placebo) was orally administered once daily at the same time each day, preferably in the morning for maximum benefit. 2.4.1. Dose increase effect verification phase (double-blind) The daily dose of ropinirole CR or placebo was adjusted to 18e24 mg by 2 mg/day at intervals of 1 week or longer from week 0 to week 7, depending on the clinical response/tolerance of each participant. After week 8, the participants received treatment at the same dose level for 4 consecutive weeks. 2.4.2. Long-term phase (open-label) To enter the long-term phase without disrupting the treatment assignment in the dose increase effect verification phase, the daily dose of ropinirole CR was reduced to 18e20 mg during the down titration phase 1 after the dose increase effect verification phase was completed. The long-term treatment with ropinirole CR was then started at a dose of 18 mg. The daily dose of ropinirole CR was increased to 18e24 mg by 2 mg/day at intervals of 1 week or longer, depending on the clinical response/tolerance of each participant. 2.5. Outcomes 2.5.1. Efficacy The primary endpoint was the change in the Japanese UPDRS Part III total score from week 0 to week 12 in the high-dose ropinirole CR group during the dose increase effect verification phase. The secondary endpoints were the UPDRS Part I, II, and IV total scores, modified Hoehn and Yahr severity, “on”/“off” time (only participants on L-dopa adjunct therapy), clinical global impressionimprovement(CGI-I) (7 grades from “very much improved” to “very much worse”), and proportion of participants remaining in the study. For the on/off time, participants were instructed to record in the diary the off time, on time, on time with troublesome dyskinesia, and asleep times over 2 days before a given day of evaluation. 2.5.2. Pharmacokinetics (PK) Plasma ropinirole concentrations were measured after administration of ropinirole CR at doses of 16e24 mg. Blood sampling for pharmacokinetics was conducted immediately before
Please cite this article in press as: N. Hattori, et al., Clinical evaluation of ropinirole controlled-release formulation at 18e24 mg/day in Japanese patients with Parkinson's disease, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.04.005
N. Hattori et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
administration in the morning at Week 0, about 2e4 h after administration at Week 1 or Week 2, and about 2e4 h after administration of maintenance dose at Week 12.
2.5.3. Safety The safety endpoints were adverse events, laboratory test values, electrocardiogram (12-lead ECG), and vital signs. All observed adverse events were coded using the medical dictionary for regulatory activities and summarized using the preferred term.
2.6. Statistical analysis A sample size of 60 participants was required for the high-dose ropinirole CR group. Based on the results of previous studies [6,7], it was assumed that the change from baseline in the UPDRS Part III total score at week 12 and its standard deviation would be 2.5 and 5.1, in the ropinirole CR monotherapy respectively, and 4.8 and 9.6, in the L-dopa adjunct therapy, respectively. Using a one-sample paired t-test at a significance level of 0.05 for the null hypothesis that the change in total score would be 0, a sample size of 60 participants would yield at least 95% power for both mono and adjunct therapies. A sample size of 20 participants was required for the maintenance ropinirole CR 16 mg/day group based on feasibility. Because major adverse events were reported in 5% or more of participants in a clinical study conducted in a country outside Japan [8], a sample size of 59 participants was deemed necessary to detect at least one adverse event, of which the incidence is 5%, with a probability of 95% or more, and to detect at least one adverse event, of which incidence is 10%, with a probability of 99% or more; therefore, a sample size of 60 participants was selected for the longterm phase. The primary efficacy analysis was performed using a paired ttest for the mean change in the UPDRS Part III total score from baseline to week 12 in the high-dose ropinirole CR group during the dose increase effect verification phase. The comparison used the full analysis set population and the last observation carried forward (LOCF) data. In the LOCF data, the last available data was used for the imputation for missing data at a planned visit. The imputation was conducted using the data within only the dose increase effect verification phase. The mean change from baseline in the UPDRS Part III total score after treatment and its 95% confidence interval (CI) are presented. An post-hoc analysis was performed for the change in the UPDRS Part III total score from baseline to week 12 in an exploratory manner using an analysis of covariance (ANCOVA) with the UPDRS Part III total score at week 0, L-dopa dose, and duration of treatment with ropinirole CR 16 mg or IR 15 mg as covariates, and the between-group difference and its 95% CI were calculated. The secondary efficacy analyses were comparisons between baseline and each visit. Secondary efficacy analyses for the dose increase effect verification phase were performed using the LOCF data. The analyses for long-term phase were performed using the observed case data. The point estimate of the difference between the high-dose ropinirole CR group and the maintenance ropinirole CR 16 mg/day group, and its two-sided 95% CI, was calculated. No statistical test was performed between the two treatment groups. The endpoints in the dose increase effect verification phase were summarized for each treatment group. The endpoints in the long-term phase, in which the dose of ropinirole CR was increased up to 24 mg/day in both treatment groups, were summarized for the study population.
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3. Results 3.1. Disposition of the study population The disposition of the study population is shown in Fig. 1. Slightly more participants in the high-dose ropinirole CR group were withdrawn from the study. Of subjects who completed the 12weeks dose increase effect verification phase, 62 subjects were enrolled in the open-label long term phase. After all participants completed the dose increase effect verification phase, these data were analyzed. The results showed no additional clinical benefit was derived from the dose increase in the high-dose ropinirole CR group, leading to the early termination of the entire study. This resulted in the premature withdrawal from the study of eight participants during the long-term phase. 3.2. Demographics and baseline characteristics The demographic and disease characteristics are shown in Table 1. The demographic characteristics of participants were comparable between the two treatment groups. In participants receiving L-dopa adjunct therapy, the duration of L-dopa therapy was approximately 8 months and slightly longer in the maintenance ropinirole CR 16 mg/day group, but the mean dose of L-dopa at week 0 was approximately 330 mg/day in both treatment groups. 3.3. Dosage In the high-dose ropinirole CR group, the mean daily dose was 23.1 mg at week 12. In the maintenance ropinirole CR 16 mg/day group, the mean daily dose was 16 mg through 12 weeks. The daily dose in the long-term phase was approximately 22 mg at week 52. 3.4. Efficacy results In the high-dose ropinirole CR group, the mean Japanese UPDRS Part III total score was 21.0 (95% CI, 19.0 to 23.0) at week 0. The mean change from week 0 to week 12 was 4.8 (95% CI, 6.3 to 3.2), which was a significant decrease from baseline (p < 0.001, paired t-test) on primary endpoint. In the maintenance ropinirole CR 16 mg/day group, the total score also decreased, with a change of 5.7 (95% CI, 8.1 to 3.3). An ANCOVA showed no statistically significant difference in the adjusted mean change of the UPDRS Part III total score, which was 0.5 (95% CI, 2.4 to 3.4) at week 12 between the high dose group and maintenance 16 mg/day group. Decreases up to week 12 are shown in the Supplemental Figure. The other efficacy results for the dose increase effect verification phase are shown in Table 2. All other efficacy results were comparable between both groups. The efficacy results in the long-term phase are shown in the Supplemental Table. 3.5. PK results Mean plasma drug concentrations following administration of ropinirole CR were higher at a dose of 24 mg/day than at a dose of 16 mg/day, but did not increase substantially in a dose-dependent manner from 18 to 24 mg/day (Supplemental Table). Because individual variability was large, there was no obvious increase in the mean plasma drug concentration as a whole, but in individual subjects it increased roughly in a dose-dependent manner. Hattori reported that plasma drug concentrations increased dosedependently from 2 to 16 mg/day in Japanese patients with Parkinson's disease who received ropinirole CR [9].
Please cite this article in press as: N. Hattori, et al., Clinical evaluation of ropinirole controlled-release formulation at 18e24 mg/day in Japanese patients with Parkinson's disease, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.04.005
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Fig. 1. Disposition of study population.
Table 1 Demographics and baseline characteristics. Ropinirole CR High-dose group (N ¼ 61)
Ropinirole CR 16 mg/day maintenance group (N ¼ 20)
Age (years) Sex, n (%)
65.5 ± 8.95 39 (64) 22 (36) 2 (3) 23 (38) 12 (20) 24 (39) 0 0.8 ± 1.34 5.4 ± 3.99 11.4 ± 7.66 21.0 ± 7.99 3.5 ± 2.31 5.74 ± 2.496 11.67 ± 2.881 10.91 ± 3.617
63.3 ± 12.42 11 (55) 9 (45) 0 8 (40) 2 (10) 9 (45) 1 (5) 0.9 ± 1.27 4.3 ± 2.99 13.1 ± 9.53 23.3 ± 10.07 3.9 ± 2.79 5.31 ± 2.280 12.85 ± 3.588 12.15 ± 4.007
Duration of PD (months) Age at onset of PD (years) Duration of L-dopa treatment (months) Baseline L-dopa dose (mg/day)
41.076 ± 28.0864 59.8 ± 14.75 e e
Female Male Modified Hoehn &Yahr stage, n (%) 1.5 2 2.5 3 4 UPDRS Part I score UPDRS Part II (“on”) score UPDRS Part II (“off”) score UPDRS Part III score UPDRS Part IV score Off time (h) On time (h) “On” time without troublesome dyskinesia (h)
Monotherapy subject (N ¼ 8) L-dopa adjunct subject (N ¼ 53) Monotherapy subject (N ¼ 2) L-dopa adjunct subject (N ¼ 18) 109.341 ± 64.2828 56.9 ± 9.84 61.308 ± 42.9648 328.3 ± 90.68
45.109 ± 27.9706 53.5 ± 10.61 e e
110.757 ± 65.4538 54.8 ± 11.79 69.740 ± 58.6246 330.6 ± 110.00
Values are expressed as mean ± SD, unless noted otherwise. CR, controlled release; PD, Parkinson's disease; UPDRS, Unified Parkinson's Disease Rating Scale.
3.6. Safety results Adverse events reported in the dose increase effect verification phase (week 0e12) and the long-term phase (week 13e52) are shown in Table 3. Adverse events reported in both these phases were similar.
In the dose increase effect verification phase, treatment-related adverse events that occurred in at least 3% of participants were somnolence (7%, 4/61 participants), nausea (5%, 3/61), dyskinesia, and sudden onset of sleep (3% each, 2/61) in the high-dose ropinirole CR group, and sudden onset of sleep (10%, 2/20), dyskinesia, somnolence, nausea, and peripheral edema (5% each, 1/20) in the
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Table 2 The efficacy results at week 12 in the dose increase effect verification phase.
Change from week 0 UPDRS Part I UPDRS Part II (When On) UPDRS Part II (When Off) UPDRS Part III UPDRS Part IV Off time (h) On time (h) On time without troublesome dyskinesia (h) 30% responder rate of UPDRS Part III Proportion of responders with score 1 or 2 on CGI-I
y
Ropinirole CR High-dose group (N ¼ 61)
Ropinirole CR 16 mg/day maintenance group (N ¼ 20)
0.1 ± 0.89 1.1 ± 3.61 1.4 ± 4.25 4.8 ± 5.95 0.1 ± 1.38 0.27 ± 2.781 0.07 ± 2.789 0.11 ± 2.968 44% (27/61) 37% (19/52)
0.1 ± 0.45 0.2 ± 2.64 1.3 ± 2.52 5.7 ± 5.18 0.1 ± 1.29 0.81 ± 1.953 0.79 ± 1.815 0.74 ± 1.733 35% (7/20) 32% (6/19)
Value are expressed as mean ± SD, unless noted otherwise. CR, controlled-release; UPDRS, Unified Parkinson's Disease Rating Scale; CGI-I, Clinical Global ImpressionImprovement. yScore 1 ¼ “very much improved”; 2 ¼ “much improved”.
Table 3 Adverse events in dose increase effect verification phase and long term phase (2 participants in each group). [Dose increase effect verification phase]
Preferred Term, n(%) Any event Nasopharyngitis Dyskinesia Somnolence Nausea Sudden onset of sleep Back pain Arthralgia Ligament sprain Pharyngitis
Ropinirole CR High-dose group
Ropinirole CR 16 mg/day maintenance group
(N ¼ 61)
(N ¼ 20)
32 2 3 4 3 2 3 2 2 2
(52) (3) (5) (7) (5) (3) (5) (3) (3) (3)
12 (60) 4 (20) 2 (10) 1 (5) 1 (5) 2 (10) 0 0 0 0
[Long term phase] Ropinirole CR (N ¼ 62)
Preferred Term, n(%) Any event Nasopharyngitis Constipation Sudden onset of sleep Back pain Dyskinesia Eczema Dizziness Nausea Vomiting Contusion Depression Hallucination Insomnia
maintenance ropinirole CR group. However, all these events are known as adverse reactions to ropinirole. During the study, no death occurred. Nine of non-fatal serious adverse events occurred in seven participants (ovarian cancer, myocardial infarction, pericarditis, inguinal hernia, atrial fibrillation, cerebral infarction, gastric cancer, fractured sacrum and uterine prolapsed), but none were considered related to the study treatment. No obvious changes were observed in any laboratory parameters or vital signs throughout the study period. The ECG results indicated that one participant in the maintenance ropinirole CR 16 mg/day group had clinically significant abnormal findings during the dose increase effect verification phase. This participant was withdrawn from the study due to atrial
46 5 5 4 4 3 3 2 2 2 2 2 2 2
(74) (8) (8) (6) (6) (5) (5) (3) (3) (3) (3) (3) (3) (3)
fibrillation, which was reported as an adverse event but was not considered related to the study treatment. During the long-term phase, one participant had clinically significant abnormal findings. For this participant, myocardial infarction and pericarditis were reported as serious adverse events, but were not considered related to the study treatment. 4. Discussion In the high-dose ropinirole CR group, the primary efficacy endpoint, that is, the change in the Japanese UPDRS Part III total score from week 0 to the dose increase effect verification phase at week 12, showed a statistically significant decrease. In the maintenance ropinirole CR 16 mg/day group, which was included in the
Please cite this article in press as: N. Hattori, et al., Clinical evaluation of ropinirole controlled-release formulation at 18e24 mg/day in Japanese patients with Parkinson's disease, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.04.005
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study as the reference group, the change in the primary efficacy endpoint from week 0e12 also showed a significant decrease. No obvious differences were observed in the primary or other efficacy endpoints between the high-dose ropinirole CR group and maintenance ropinirole CR 16 mg/day group. Because patients with Parkinson's disease who had not achieved an optimal response to ropinirole IR 15 mg/day or CR 16 mg/day were enrolled in the study, the change in the UPDRS Part III total score was expected to be 0 in the maintenance ropinirole CR 16 mg/day group. However, this total score significantly decreased in the maintenance ropinirole CR 16 mg/day group as well, presumably due to a stronger placebo effect than expected. The placebo effect is known to be substantial in patients with Parkinson's disease [10], and this effect may have been exaggerated in the maintenance ropinirole CR 16 mg/day group in the present study. According to reports by Miwa and by Goetz and colleagues, the placebo effect in patients with Parkinson's disease is not attributable to study design or variation in the study population, but is considered a disease-specific phenomenon, and it can occur irrespective of patient profile (age at baseline, gender, duration of Parkinson's disease, and modified Hoehn and Yahr severity), rather than exclusively in limited patients with certain factors [11,12]. Baseline characteristics of participants did not differ between the high-dose and maintenance ropinirole CR groups, indicating the placebo effect had likely occurred in the maintenance ropinirole CR 16 mg/day group. Furthermore, because the placebo effect is more apparent and persistent in patients already on active treatment [11], this effect may have been stronger in the patients in this study than in untreated patients with Parkinson's disease in previous clinical studies. The other possibility is that our study duration, i.e. 12 weeks of dose increase verification phase may have been too short to rule out strong placebo effects in the standard treatment group. Further, although the number of PD patients to be included may have been sufficient in the power analysis, the patients may have been too mildly affected in the high-dose ropinirole CR group. The controlled formulation has the advantage of continuous plasma levels throughout day and night. Thus, in future studies sleep quality could be another interesting secondary outcome parameter. Regarding safety, no new adverse events were found by higher dose than 16 mg/day in these Japanese patients. Our results were consistent with previous clinical trial which examined the effects of ropinirole up to 24 mg [6,7]. 4.1. Conclusion This study did not demonstrate the difference in efficacy between the high-dose ropinirole CR group and the maintenance dose ropinirole CR group. The possible reason is that the population was limited, such as patients who were limited the dose of L-dopa up to 450 mg/day or patients who were already on ropinirole CR or IR. Another possible reason was that the sample size was relatively small, with 80 participants overall but only 20 participants in the group receiving maintenance treatment with placebo in addition to ropinirole CR 16 mg. Although some patients need doses of ropinirole CR higher than 16 mg/day, the sample size of this study did not provide sufficient statistical power to conclude whether a dose increase would yield additional clinical benefits. The study provides clear observational data, but was underpowered and presents some unexplained results. Funding source Funding for this study was provided by GlaxoSmithKline (GSK) [Clinical study ID: ROP116991].
Conflicts of interest NH received honoraria as the coordinating investigator for this study from GSK. The site where KH worked participated in the study and has received research grants from GSK, and KH received honoraria for consulting services as a medical expert for this study from GSK. KS, EM, and YN are employees of GSK, and YN have stock of GSK. Authors' contribution All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. NH, KH and YN participated in the design of the study and interpretation of data, and reviewed the draft manuscript. KS participated in the design of the study and interpretation of data, and helped to draft the manuscript. EM participated in interpretation of data and drafted the manuscript. All authors critically reviewed and approved the final manuscript. Acknowledgments The authors thank the following principal investigators of this study: Takashi Kimura, Asahikawa Medical Center; Kazuto Yoshida, Japanese Red Cross Asahikawa Hospital; Masahiko Tomiyama, Aomori Prefectural Central Hospital; Takashi Abe, Abe Neurology Clinic; Kimiaki Utsugisawa, General Hanamaki Hospital; Tetsuya Maeda, Research Institute For Brain And Blood Vessels; Teruo Yokoyama, Sagamihara National Hospital; Shinichiro Ikebe, Ikebe Clinic; Tetsushi Atsumi, Atsumi Neurology Clinic; Naoki Atsuta, Nagoya University Hospital; Yoshihisa Tatsuoka, Tatsuoka Neurology Clinic; Hidemoto Saiki, Kitano Hospital; Takashi Naka, Higashiosaka City General Hospital; Yasuto Higashi, Himeji Central Hospital Clinic; Kazuo Toda, TODA Internal Medicine & Rehabilitation Clinic; Kenichi Kashihara, Okayama Kyokuto Hospital; Mitsutoshi Yamamoto, Takamatsu Neurology Clinic. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2017.04.005. References [1] R.L. Watts, K.E. Lyons, R. Pahwa, K. Sethi, M. Stern, R.A. Hauser, W. Olanow, A.M. Gray, B. Adams, N.L. Earl, On Behalf of 228 Study Investigators, Onset of dyskinesia with adjunct ropinirole prolonged-release or additional levodopa in early Parkinson's disease, Mov. Disord. 25 (2010) 858e866. [2] F. Stocchi, L. Giorgi, B. Hunter, A.H. Schapira, PREPARED: comparison of prolonged and immediate release ropinirole in advanced Parkinson's disease, Mov. Disord. 26 (2011) 1259e1265. [3] K. Ray Chaudhuri, P. Martinez-Martin, K.A. Rolfe, J. Cooper, C.B. Rockett, L. Giorgi, et al., Improvements in nocturnal symptoms with ropinirole prolonged release in patients with advanced Parkinson's disease, Eur. J. Neurol. 19 (2012) 105e113. [4] H. Reichmann, D. Angersbach, B. Buchwald, Practical experience on improving activities of daily living in Parkinson's patients treated with ropinirole. Results of a postmarketing surveillance study, Nervenarzt 76 (2005) 1239e1240, 1242e1245. [5] S. Cristina, R. Zangaglia, F. Mancini, E. Martignoni, G. Nappi, C. Pacchetti, Highdose ropinirole in advanced Parkinson's disease with severe dyskinesias, Clin. Neuropharmacol. 26 (2003) 146e150. [6] F. Stocchi, B.P. Hersh, B.L. Scott, P.A. Nausieda, L. Giorgi, On behalf of the EASEPD Monotherapy Study Investigators, Ropinirole 24-hour prolonged release and ropinirole immediate release in early Parkinson's disease: a randomized, double-blind, non-inferiority crossover study, Curr. Med. Res. Opin. 24 (2008) 2883e2895. [7] R. Pahwa, M.A. Stacy, S.A. Factor, K.E. Lyons, F. Stocchi, B.P. Hersh, L.W. Elmer, D.D. Truong, N.L. Earl, On behalf of the EASE-PD Adjunct Study Investigators, Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease, Neurology 68 (2007) 1108e1115.
Please cite this article in press as: N. Hattori, et al., Clinical evaluation of ropinirole controlled-release formulation at 18e24 mg/day in Japanese patients with Parkinson's disease, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.04.005
N. Hattori et al. / Parkinsonism and Related Disorders xxx (2017) 1e7 [8] C.W. Makumi, A. Asgharian, J. Ellis, S. Shaikh, T. Jimenez, S. VanMeter, Longterm, open-label, safety study of once-daily ropinirole extended/prolonged release in early and advanced Parkinson's disease, Int. J. Neurosci. 126 (2016) 30e38. [9] N. Hattori, K. Hasegawa, T. Sakamoto, Pharmacokinetics and effect of food after oral administration of prolonged-release tablets of ropinirole hydrochloride in Japanese patients with Parkinson's disease, J. Clin. Pharm. Ther. 37 (2012) 571e577.
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[10] L. Colloca, L. Lopiano, M. Lanotte, F. Benedetti, Overt versus covert treatment for pain, anxiety, and Parkinson's disease, Lancet Neurol. 3 (2004) 679e684. [11] H. Miwa, Placebo effect in Parkinson's disease, Brain Nerve 59 (2007) 139e146. [12] C.G. Goetz, J. Wuu, M.P. McDermott, C.H. Adler, S. Fahn, C.R. Freed, R.A. Hauser, W.C. Olanow, I. Shoulson, P.K. Tandon, , Parkinson Study Group, S. Leurgans, Placebo response in Parkinson's disease: comparisons among 11 trials covering medical and surgical interventions, Mov. Disord. 23 (2008) 690e699.
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Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Clinical evaluation of ropinirole controlled-release formulation at 18e24 mg/day in Japanese patients with Parkinson's disease Nobutaka Hattori, MD a, Kazuko Hasegawa, MD b, Katsuaki Sato, MSc c, *, Erika Mitsuyama, BSc c, Yotaro Numachi, MD c a
Department of Neurology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Department of Neurology, Sagamihara National Hospital, 18-1, Sakuradai, Minami-ku, Sagamihara, Kanagawa 252-0392, Japan Neurosciences Therapeutic Area Office, Medicines Development, Japan Development & Medical Affairs, GlaxoSmithKline K.K., GSK Bldg. 6-15, Sendagaya 4chome, Shibuya-ku, Tokyo 151-8566, Japan
b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 November 2016 Received in revised form 7 March 2017 Accepted 10 April 2017
Introduction: There has been no clinical data on Japanese patients with Parkinson's disease with which to examine whether motor symptoms improve and to assess the safety profile after the dose of ropinirole was increased in those who had not achieved an optimal response to the ropinirole immediate-release formulation 15 mg/day or the controlled-release (CR) formulation 16 mg/day. Methods: This was a multicenter, randomized, double-blind study, followed by an open-label, long-term study. Participants were randomized at a ratio of 3:1 to the high-dose ropinirole CR (18e24 mg/day) group or the maintenance ropinirole CR 16 mg/day group. Results: In the high-dose ropinirole CR group (N ¼ 61), the Japanese unified Parkinson's disease rating scale Part III total score at week 12 was significantly decreased compared with the baseline total score (4.8 ± 5.95, [95% CI, 6.3 to 3.2], p < 0.001). However, a comparable decrease was also observed in the maintenance ropinirole CR 16 mg/day group (N ¼ 20) (5.7 ± 5.18, [95% CI, 8.1 to 3.3]), with no statistically significant difference in the adjusted mean change between the high-dose and maintenance groups (0.5 [95% CI, 2.4 to 3.4]). Plasma drug concentrations increased at doses higher than 16 mg/day, but did not increase significantly in a dose-dependent manner at doses of 18e24 mg/day. No adverse events were found that would affect the known safety profile of ropinirole. Conclusion: This study did not demonstrate the difference in efficacy between the high-dose ropinirole CR group and the maintenance ropinirole CR group. Clinical trial registration: ClinicalTrials.gov identifier: NCT01929317. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Ropinirole controlled-release Randomized Double blind Pharmacokinetics Parkinson's disease
1. Introduction Ropinirole hydrochloride (JAN) developed by SmithKline Beecham, UK, (currently GlaxoSmithKline) is a non-ergot alkaloid dopamine receptor agonist that has selective affinity for the dopamine D2 receptor system. The ropinirole controlled-release (CR) formulation, which is an extended-release version of ropinirole hydrochloride, was approved in Japan for the treatment of Parkinson's disease in June 2012. In Japan, ropinirole CR can be administered to a maximum dose
* Corresponding author. E-mail addresses: [email protected] (N. Hattori), k-hasegawa@ sagamihara-hosp.gr.jp (K. Hasegawa), [email protected] (K. Sato), erika.2. [email protected] (E. Mitsuyama), [email protected] (Y. Numachi).
of 16 mg/day, which is deemed equivalent to a maximum dose of 15 mg/day for the preceding ropinirole immediate-release (IR) formulation. In other countries, however, both ropinirole CR and IR can be administered to a maximum dose of 24 mg/day [1e3], with differences in the approved dose between Japan and other countries. According to published reports of ropinirole hydrochloride administered at a maximum dose of 24 mg/day, ropinirole improved “wearing off” and dyskinesia [4], and delayed the need for stereotactic surgery or continuous apomorphine infusion [5]. Previous studies of ropinirole CR in Japan have shown that there are no clear ethnic differences in the pharmacokinetic profile between Japanese and non-Japanese patients with Parkinson's disease [Company internal document]. In the present study, therefore, the efficacy and safety of ropinirole CR administered at doses of 18e24 mg once daily were
http://dx.doi.org/10.1016/j.parkreldis.2017.04.005 1353-8020/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: N. Hattori, et al., Clinical evaluation of ropinirole controlled-release formulation at 18e24 mg/day in Japanese patients with Parkinson's disease, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.04.005
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N. Hattori et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
evaluated in Japanese patients with Parkinson's disease who had not achieved an optimal response to ropinirole IR 15 mg/day or ropinirole CR 16 mg/day to determine whether a dose increase from 16 mg, the maximum daily dose of ropinirole CR approved for Parkinson's disease in Japan, to 24 mg, the equivalent approved in other countries, would yield additional clinical benefits or raise new safety concerns. In addition, the long-term safety was evaluated. Incidentally, there has been no comparison study between high-dose and standard-dose controlled formulation of the other dopamine agonists in Japanese or Asian population. 2. Methods 2.1. Ethics This was a multicenter study in Japanese patients with Parkinson's disease, conducted at 17 medical institutions from August 2013 to June 2015. The protocol, informed consent documents, and other aspects of this study requiring prior approval were reviewed and approved by the Institutional Review Board as specified in the “Good Clinical Practice (GCP) for Drugs.” The study was implemented in compliance with GCP. Furthermore, all applicable requirements for the protection of participants' privacy and the Declaration of Helsinki were adhered to by protecting participants' personal information and data. Written informed consent was obtained from all participants. 2.2. Trial design This was a multicenter, randomized, double-blind study followed by an open-label long-term study. It comprised a 4-weeks screening phase, 12-weeks dose increase effect verification phase, 1-week down titration phase 1, 39-weeks long-term phase, a 1- to 2-weeks down titration phase 2, and follow-up phase (1e4 weeks after the end of study treatment) (Supplemental Figure). The first 60 participants who completed the dose increase effect verification phase entered the down titration phase 1 and then the long-term phase. The remaining participants who completed the dose increase effect verification phase entered the down titration phase 2 and then completed the study. Participants were randomly assigned at a ratio of 3:1 to either the high-dose ropinirole CR group (18e24 mg/day) or maintenance ropinirole CR 16 mg/day group. Stratified randomization according to concomitant L-dopa (ropinirole monotherapy or L-dopa adjunct therapy) was used. The maintenance ropinirole CR 16 mg/day group was included in the study to confirm the efficacy and safety at the maximum dose (16 mg/day) approved in Japan in the same study. However, because a large sample size was required for a parallel-group comparison study to verify the superiority of high-dose ropinirole CR to the maintenance dose of 16 mg/day, the primary evaluation was a comparison before versus after the dose increase of ropinirole CR in the high-dose ropinirole CR group. 2.3. Study population Patients who met all of the following criteria were eligible for the study: those who were diagnosed with Parkinson's disease in stages I-IV on the modified Hoehn and Yahr scale during the “on” period; those who were receiving ropinirole IR 15 mg/day or CR 16 mg/day and had a unified Parkinson's disease rating scale (UPDRS) Part III total score (during “on”) of 10 or more at the start of screening; and those who were expected to show clinical improvement by increasing the dose of ropinirole CR (to 18e24 mg/ day). Participants receiving ropinirole monotherapy had never
received L-dopa, or had previously received L-dopa at doses up to 450 mg/day for up to 3 months in total and had been withdrawn from L-dopa for a minimum of 4 weeks prior to screening. Participants on L-dopa adjunct therapy had received L-dopa (up to 450 mg/day) for at least 4 weeks prior to screening. We were concerned that if L-dopa dosage was too high, it may difficult to obtain the effect of high-dose ropinirole CR compared to standard dose (16 mg). Therefore L-dopa dosage was limited up to 450 mg/ day. The following patients with Parkinson's disease were excluded from the study: those with advanced disease characterized by severe peak dose or biphasic dyskinesia, or unpredictable symptomatic fluctuations despite treatment with a stable dose of Ldopa; those with symptomatic orthostatic hypotension (e.g., dizziness, syncope); those with severe dementia as indicated by a UPDRS Part I, item 1 (intellectual function) score of 3 or 4; those with current or prior severe psychosis (e.g., schizophrenia, psychotic depression) as indicated by a UPDRS Part I, item 2 (thought disorder) or item 3 (depression) score of 3 or 4; and those who had previously received surgical treatment for Parkinson's disease (e.g., pallidectomy, deep brain stimulation). 2.4. Treatment During the screening phase, all participants received ropinirole CR 16 mg/day. Ropinirole CR (or placebo) was orally administered once daily at the same time each day, preferably in the morning for maximum benefit. 2.4.1. Dose increase effect verification phase (double-blind) The daily dose of ropinirole CR or placebo was adjusted to 18e24 mg by 2 mg/day at intervals of 1 week or longer from week 0 to week 7, depending on the clinical response/tolerance of each participant. After week 8, the participants received treatment at the same dose level for 4 consecutive weeks. 2.4.2. Long-term phase (open-label) To enter the long-term phase without disrupting the treatment assignment in the dose increase effect verification phase, the daily dose of ropinirole CR was reduced to 18e20 mg during the down titration phase 1 after the dose increase effect verification phase was completed. The long-term treatment with ropinirole CR was then started at a dose of 18 mg. The daily dose of ropinirole CR was increased to 18e24 mg by 2 mg/day at intervals of 1 week or longer, depending on the clinical response/tolerance of each participant. 2.5. Outcomes 2.5.1. Efficacy The primary endpoint was the change in the Japanese UPDRS Part III total score from week 0 to week 12 in the high-dose ropinirole CR group during the dose increase effect verification phase. The secondary endpoints were the UPDRS Part I, II, and IV total scores, modified Hoehn and Yahr severity, “on”/“off” time (only participants on L-dopa adjunct therapy), clinical global impressionimprovement(CGI-I) (7 grades from “very much improved” to “very much worse”), and proportion of participants remaining in the study. For the on/off time, participants were instructed to record in the diary the off time, on time, on time with troublesome dyskinesia, and asleep times over 2 days before a given day of evaluation. 2.5.2. Pharmacokinetics (PK) Plasma ropinirole concentrations were measured after administration of ropinirole CR at doses of 16e24 mg. Blood sampling for pharmacokinetics was conducted immediately before
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N. Hattori et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
administration in the morning at Week 0, about 2e4 h after administration at Week 1 or Week 2, and about 2e4 h after administration of maintenance dose at Week 12.
2.5.3. Safety The safety endpoints were adverse events, laboratory test values, electrocardiogram (12-lead ECG), and vital signs. All observed adverse events were coded using the medical dictionary for regulatory activities and summarized using the preferred term.
2.6. Statistical analysis A sample size of 60 participants was required for the high-dose ropinirole CR group. Based on the results of previous studies [6,7], it was assumed that the change from baseline in the UPDRS Part III total score at week 12 and its standard deviation would be 2.5 and 5.1, in the ropinirole CR monotherapy respectively, and 4.8 and 9.6, in the L-dopa adjunct therapy, respectively. Using a one-sample paired t-test at a significance level of 0.05 for the null hypothesis that the change in total score would be 0, a sample size of 60 participants would yield at least 95% power for both mono and adjunct therapies. A sample size of 20 participants was required for the maintenance ropinirole CR 16 mg/day group based on feasibility. Because major adverse events were reported in 5% or more of participants in a clinical study conducted in a country outside Japan [8], a sample size of 59 participants was deemed necessary to detect at least one adverse event, of which the incidence is 5%, with a probability of 95% or more, and to detect at least one adverse event, of which incidence is 10%, with a probability of 99% or more; therefore, a sample size of 60 participants was selected for the longterm phase. The primary efficacy analysis was performed using a paired ttest for the mean change in the UPDRS Part III total score from baseline to week 12 in the high-dose ropinirole CR group during the dose increase effect verification phase. The comparison used the full analysis set population and the last observation carried forward (LOCF) data. In the LOCF data, the last available data was used for the imputation for missing data at a planned visit. The imputation was conducted using the data within only the dose increase effect verification phase. The mean change from baseline in the UPDRS Part III total score after treatment and its 95% confidence interval (CI) are presented. An post-hoc analysis was performed for the change in the UPDRS Part III total score from baseline to week 12 in an exploratory manner using an analysis of covariance (ANCOVA) with the UPDRS Part III total score at week 0, L-dopa dose, and duration of treatment with ropinirole CR 16 mg or IR 15 mg as covariates, and the between-group difference and its 95% CI were calculated. The secondary efficacy analyses were comparisons between baseline and each visit. Secondary efficacy analyses for the dose increase effect verification phase were performed using the LOCF data. The analyses for long-term phase were performed using the observed case data. The point estimate of the difference between the high-dose ropinirole CR group and the maintenance ropinirole CR 16 mg/day group, and its two-sided 95% CI, was calculated. No statistical test was performed between the two treatment groups. The endpoints in the dose increase effect verification phase were summarized for each treatment group. The endpoints in the long-term phase, in which the dose of ropinirole CR was increased up to 24 mg/day in both treatment groups, were summarized for the study population.
3
3. Results 3.1. Disposition of the study population The disposition of the study population is shown in Fig. 1. Slightly more participants in the high-dose ropinirole CR group were withdrawn from the study. Of subjects who completed the 12weeks dose increase effect verification phase, 62 subjects were enrolled in the open-label long term phase. After all participants completed the dose increase effect verification phase, these data were analyzed. The results showed no additional clinical benefit was derived from the dose increase in the high-dose ropinirole CR group, leading to the early termination of the entire study. This resulted in the premature withdrawal from the study of eight participants during the long-term phase. 3.2. Demographics and baseline characteristics The demographic and disease characteristics are shown in Table 1. The demographic characteristics of participants were comparable between the two treatment groups. In participants receiving L-dopa adjunct therapy, the duration of L-dopa therapy was approximately 8 months and slightly longer in the maintenance ropinirole CR 16 mg/day group, but the mean dose of L-dopa at week 0 was approximately 330 mg/day in both treatment groups. 3.3. Dosage In the high-dose ropinirole CR group, the mean daily dose was 23.1 mg at week 12. In the maintenance ropinirole CR 16 mg/day group, the mean daily dose was 16 mg through 12 weeks. The daily dose in the long-term phase was approximately 22 mg at week 52. 3.4. Efficacy results In the high-dose ropinirole CR group, the mean Japanese UPDRS Part III total score was 21.0 (95% CI, 19.0 to 23.0) at week 0. The mean change from week 0 to week 12 was 4.8 (95% CI, 6.3 to 3.2), which was a significant decrease from baseline (p < 0.001, paired t-test) on primary endpoint. In the maintenance ropinirole CR 16 mg/day group, the total score also decreased, with a change of 5.7 (95% CI, 8.1 to 3.3). An ANCOVA showed no statistically significant difference in the adjusted mean change of the UPDRS Part III total score, which was 0.5 (95% CI, 2.4 to 3.4) at week 12 between the high dose group and maintenance 16 mg/day group. Decreases up to week 12 are shown in the Supplemental Figure. The other efficacy results for the dose increase effect verification phase are shown in Table 2. All other efficacy results were comparable between both groups. The efficacy results in the long-term phase are shown in the Supplemental Table. 3.5. PK results Mean plasma drug concentrations following administration of ropinirole CR were higher at a dose of 24 mg/day than at a dose of 16 mg/day, but did not increase substantially in a dose-dependent manner from 18 to 24 mg/day (Supplemental Table). Because individual variability was large, there was no obvious increase in the mean plasma drug concentration as a whole, but in individual subjects it increased roughly in a dose-dependent manner. Hattori reported that plasma drug concentrations increased dosedependently from 2 to 16 mg/day in Japanese patients with Parkinson's disease who received ropinirole CR [9].
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N. Hattori et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
Fig. 1. Disposition of study population.
Table 1 Demographics and baseline characteristics. Ropinirole CR High-dose group (N ¼ 61)
Ropinirole CR 16 mg/day maintenance group (N ¼ 20)
Age (years) Sex, n (%)
65.5 ± 8.95 39 (64) 22 (36) 2 (3) 23 (38) 12 (20) 24 (39) 0 0.8 ± 1.34 5.4 ± 3.99 11.4 ± 7.66 21.0 ± 7.99 3.5 ± 2.31 5.74 ± 2.496 11.67 ± 2.881 10.91 ± 3.617
63.3 ± 12.42 11 (55) 9 (45) 0 8 (40) 2 (10) 9 (45) 1 (5) 0.9 ± 1.27 4.3 ± 2.99 13.1 ± 9.53 23.3 ± 10.07 3.9 ± 2.79 5.31 ± 2.280 12.85 ± 3.588 12.15 ± 4.007
Duration of PD (months) Age at onset of PD (years) Duration of L-dopa treatment (months) Baseline L-dopa dose (mg/day)
41.076 ± 28.0864 59.8 ± 14.75 e e
Female Male Modified Hoehn &Yahr stage, n (%) 1.5 2 2.5 3 4 UPDRS Part I score UPDRS Part II (“on”) score UPDRS Part II (“off”) score UPDRS Part III score UPDRS Part IV score Off time (h) On time (h) “On” time without troublesome dyskinesia (h)
Monotherapy subject (N ¼ 8) L-dopa adjunct subject (N ¼ 53) Monotherapy subject (N ¼ 2) L-dopa adjunct subject (N ¼ 18) 109.341 ± 64.2828 56.9 ± 9.84 61.308 ± 42.9648 328.3 ± 90.68
45.109 ± 27.9706 53.5 ± 10.61 e e
110.757 ± 65.4538 54.8 ± 11.79 69.740 ± 58.6246 330.6 ± 110.00
Values are expressed as mean ± SD, unless noted otherwise. CR, controlled release; PD, Parkinson's disease; UPDRS, Unified Parkinson's Disease Rating Scale.
3.6. Safety results Adverse events reported in the dose increase effect verification phase (week 0e12) and the long-term phase (week 13e52) are shown in Table 3. Adverse events reported in both these phases were similar.
In the dose increase effect verification phase, treatment-related adverse events that occurred in at least 3% of participants were somnolence (7%, 4/61 participants), nausea (5%, 3/61), dyskinesia, and sudden onset of sleep (3% each, 2/61) in the high-dose ropinirole CR group, and sudden onset of sleep (10%, 2/20), dyskinesia, somnolence, nausea, and peripheral edema (5% each, 1/20) in the
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Table 2 The efficacy results at week 12 in the dose increase effect verification phase.
Change from week 0 UPDRS Part I UPDRS Part II (When On) UPDRS Part II (When Off) UPDRS Part III UPDRS Part IV Off time (h) On time (h) On time without troublesome dyskinesia (h) 30% responder rate of UPDRS Part III Proportion of responders with score 1 or 2 on CGI-I
y
Ropinirole CR High-dose group (N ¼ 61)
Ropinirole CR 16 mg/day maintenance group (N ¼ 20)
0.1 ± 0.89 1.1 ± 3.61 1.4 ± 4.25 4.8 ± 5.95 0.1 ± 1.38 0.27 ± 2.781 0.07 ± 2.789 0.11 ± 2.968 44% (27/61) 37% (19/52)
0.1 ± 0.45 0.2 ± 2.64 1.3 ± 2.52 5.7 ± 5.18 0.1 ± 1.29 0.81 ± 1.953 0.79 ± 1.815 0.74 ± 1.733 35% (7/20) 32% (6/19)
Value are expressed as mean ± SD, unless noted otherwise. CR, controlled-release; UPDRS, Unified Parkinson's Disease Rating Scale; CGI-I, Clinical Global ImpressionImprovement. yScore 1 ¼ “very much improved”; 2 ¼ “much improved”.
Table 3 Adverse events in dose increase effect verification phase and long term phase (2 participants in each group). [Dose increase effect verification phase]
Preferred Term, n(%) Any event Nasopharyngitis Dyskinesia Somnolence Nausea Sudden onset of sleep Back pain Arthralgia Ligament sprain Pharyngitis
Ropinirole CR High-dose group
Ropinirole CR 16 mg/day maintenance group
(N ¼ 61)
(N ¼ 20)
32 2 3 4 3 2 3 2 2 2
(52) (3) (5) (7) (5) (3) (5) (3) (3) (3)
12 (60) 4 (20) 2 (10) 1 (5) 1 (5) 2 (10) 0 0 0 0
[Long term phase] Ropinirole CR (N ¼ 62)
Preferred Term, n(%) Any event Nasopharyngitis Constipation Sudden onset of sleep Back pain Dyskinesia Eczema Dizziness Nausea Vomiting Contusion Depression Hallucination Insomnia
maintenance ropinirole CR group. However, all these events are known as adverse reactions to ropinirole. During the study, no death occurred. Nine of non-fatal serious adverse events occurred in seven participants (ovarian cancer, myocardial infarction, pericarditis, inguinal hernia, atrial fibrillation, cerebral infarction, gastric cancer, fractured sacrum and uterine prolapsed), but none were considered related to the study treatment. No obvious changes were observed in any laboratory parameters or vital signs throughout the study period. The ECG results indicated that one participant in the maintenance ropinirole CR 16 mg/day group had clinically significant abnormal findings during the dose increase effect verification phase. This participant was withdrawn from the study due to atrial
46 5 5 4 4 3 3 2 2 2 2 2 2 2
(74) (8) (8) (6) (6) (5) (5) (3) (3) (3) (3) (3) (3) (3)
fibrillation, which was reported as an adverse event but was not considered related to the study treatment. During the long-term phase, one participant had clinically significant abnormal findings. For this participant, myocardial infarction and pericarditis were reported as serious adverse events, but were not considered related to the study treatment. 4. Discussion In the high-dose ropinirole CR group, the primary efficacy endpoint, that is, the change in the Japanese UPDRS Part III total score from week 0 to the dose increase effect verification phase at week 12, showed a statistically significant decrease. In the maintenance ropinirole CR 16 mg/day group, which was included in the
Please cite this article in press as: N. Hattori, et al., Clinical evaluation of ropinirole controlled-release formulation at 18e24 mg/day in Japanese patients with Parkinson's disease, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.04.005
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N. Hattori et al. / Parkinsonism and Related Disorders xxx (2017) 1e7
study as the reference group, the change in the primary efficacy endpoint from week 0e12 also showed a significant decrease. No obvious differences were observed in the primary or other efficacy endpoints between the high-dose ropinirole CR group and maintenance ropinirole CR 16 mg/day group. Because patients with Parkinson's disease who had not achieved an optimal response to ropinirole IR 15 mg/day or CR 16 mg/day were enrolled in the study, the change in the UPDRS Part III total score was expected to be 0 in the maintenance ropinirole CR 16 mg/day group. However, this total score significantly decreased in the maintenance ropinirole CR 16 mg/day group as well, presumably due to a stronger placebo effect than expected. The placebo effect is known to be substantial in patients with Parkinson's disease [10], and this effect may have been exaggerated in the maintenance ropinirole CR 16 mg/day group in the present study. According to reports by Miwa and by Goetz and colleagues, the placebo effect in patients with Parkinson's disease is not attributable to study design or variation in the study population, but is considered a disease-specific phenomenon, and it can occur irrespective of patient profile (age at baseline, gender, duration of Parkinson's disease, and modified Hoehn and Yahr severity), rather than exclusively in limited patients with certain factors [11,12]. Baseline characteristics of participants did not differ between the high-dose and maintenance ropinirole CR groups, indicating the placebo effect had likely occurred in the maintenance ropinirole CR 16 mg/day group. Furthermore, because the placebo effect is more apparent and persistent in patients already on active treatment [11], this effect may have been stronger in the patients in this study than in untreated patients with Parkinson's disease in previous clinical studies. The other possibility is that our study duration, i.e. 12 weeks of dose increase verification phase may have been too short to rule out strong placebo effects in the standard treatment group. Further, although the number of PD patients to be included may have been sufficient in the power analysis, the patients may have been too mildly affected in the high-dose ropinirole CR group. The controlled formulation has the advantage of continuous plasma levels throughout day and night. Thus, in future studies sleep quality could be another interesting secondary outcome parameter. Regarding safety, no new adverse events were found by higher dose than 16 mg/day in these Japanese patients. Our results were consistent with previous clinical trial which examined the effects of ropinirole up to 24 mg [6,7]. 4.1. Conclusion This study did not demonstrate the difference in efficacy between the high-dose ropinirole CR group and the maintenance dose ropinirole CR group. The possible reason is that the population was limited, such as patients who were limited the dose of L-dopa up to 450 mg/day or patients who were already on ropinirole CR or IR. Another possible reason was that the sample size was relatively small, with 80 participants overall but only 20 participants in the group receiving maintenance treatment with placebo in addition to ropinirole CR 16 mg. Although some patients need doses of ropinirole CR higher than 16 mg/day, the sample size of this study did not provide sufficient statistical power to conclude whether a dose increase would yield additional clinical benefits. The study provides clear observational data, but was underpowered and presents some unexplained results. Funding source Funding for this study was provided by GlaxoSmithKline (GSK) [Clinical study ID: ROP116991].
Conflicts of interest NH received honoraria as the coordinating investigator for this study from GSK. The site where KH worked participated in the study and has received research grants from GSK, and KH received honoraria for consulting services as a medical expert for this study from GSK. KS, EM, and YN are employees of GSK, and YN have stock of GSK. Authors' contribution All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. NH, KH and YN participated in the design of the study and interpretation of data, and reviewed the draft manuscript. KS participated in the design of the study and interpretation of data, and helped to draft the manuscript. EM participated in interpretation of data and drafted the manuscript. All authors critically reviewed and approved the final manuscript. Acknowledgments The authors thank the following principal investigators of this study: Takashi Kimura, Asahikawa Medical Center; Kazuto Yoshida, Japanese Red Cross Asahikawa Hospital; Masahiko Tomiyama, Aomori Prefectural Central Hospital; Takashi Abe, Abe Neurology Clinic; Kimiaki Utsugisawa, General Hanamaki Hospital; Tetsuya Maeda, Research Institute For Brain And Blood Vessels; Teruo Yokoyama, Sagamihara National Hospital; Shinichiro Ikebe, Ikebe Clinic; Tetsushi Atsumi, Atsumi Neurology Clinic; Naoki Atsuta, Nagoya University Hospital; Yoshihisa Tatsuoka, Tatsuoka Neurology Clinic; Hidemoto Saiki, Kitano Hospital; Takashi Naka, Higashiosaka City General Hospital; Yasuto Higashi, Himeji Central Hospital Clinic; Kazuo Toda, TODA Internal Medicine & Rehabilitation Clinic; Kenichi Kashihara, Okayama Kyokuto Hospital; Mitsutoshi Yamamoto, Takamatsu Neurology Clinic. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2017.04.005. References [1] R.L. Watts, K.E. Lyons, R. Pahwa, K. Sethi, M. Stern, R.A. Hauser, W. Olanow, A.M. Gray, B. Adams, N.L. Earl, On Behalf of 228 Study Investigators, Onset of dyskinesia with adjunct ropinirole prolonged-release or additional levodopa in early Parkinson's disease, Mov. Disord. 25 (2010) 858e866. [2] F. Stocchi, L. Giorgi, B. Hunter, A.H. Schapira, PREPARED: comparison of prolonged and immediate release ropinirole in advanced Parkinson's disease, Mov. Disord. 26 (2011) 1259e1265. [3] K. Ray Chaudhuri, P. Martinez-Martin, K.A. Rolfe, J. Cooper, C.B. Rockett, L. Giorgi, et al., Improvements in nocturnal symptoms with ropinirole prolonged release in patients with advanced Parkinson's disease, Eur. J. Neurol. 19 (2012) 105e113. [4] H. Reichmann, D. Angersbach, B. Buchwald, Practical experience on improving activities of daily living in Parkinson's patients treated with ropinirole. Results of a postmarketing surveillance study, Nervenarzt 76 (2005) 1239e1240, 1242e1245. [5] S. Cristina, R. Zangaglia, F. Mancini, E. Martignoni, G. Nappi, C. Pacchetti, Highdose ropinirole in advanced Parkinson's disease with severe dyskinesias, Clin. Neuropharmacol. 26 (2003) 146e150. [6] F. Stocchi, B.P. Hersh, B.L. Scott, P.A. Nausieda, L. Giorgi, On behalf of the EASEPD Monotherapy Study Investigators, Ropinirole 24-hour prolonged release and ropinirole immediate release in early Parkinson's disease: a randomized, double-blind, non-inferiority crossover study, Curr. Med. Res. Opin. 24 (2008) 2883e2895. [7] R. Pahwa, M.A. Stacy, S.A. Factor, K.E. Lyons, F. Stocchi, B.P. Hersh, L.W. Elmer, D.D. Truong, N.L. Earl, On behalf of the EASE-PD Adjunct Study Investigators, Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease, Neurology 68 (2007) 1108e1115.
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Please cite this article in press as: N. Hattori, et al., Clinical evaluation of ropinirole controlled-release formulation at 18e24 mg/day in Japanese patients with Parkinson's disease, Parkinsonism and Related Disorders (2017), http://dx.doi.org/10.1016/j.parkreldis.2017.04.005