Effects of Rotigotine Transdermal Patch in Patients with Parkinson S Disease Presenting

Effects of rotigotine transdermal patch in patients with Parkinson’s disease presenting with nonmotor symptoms – results of a double-blind, randomised, placebo-controlled trial

Angelo Antonini, MD, PhD,1 Lars Bauer, MD,2 Elisabeth Dohin, MD,3 Wolfgang H. Oertel, MD, PhD,4 Olivier Rascol, MD, PhD,5 Heinz Reichmann, MD, PhD,6 Miriam Schmid,2 Pritibha Singh,2 Eduardo Tolosa, MD, PhD,7 K Ray Chaudhuri, MD, FRCP DSc,8

Parkinson and Movement Disorders Unit, IRCCS Hospital San Camillo, Venice, Italy
UCB Pharma, Monheim am Rhein, Germany
UCB Pharma, Paris, France
Department of Neurology, Philipps University, Marburg, Germany
Clinical Investigation Centre CIC1436, and Departments of Clinical Pharmacology and Neurosciences, INSERM and Toulouse University Hospital, Toulouse, France
Department of Neurology, University of Dresden, Dresden, Germany
Neurology Service, Hospital Clínic de Barcelona, Universitat de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain
National Parkinson Foundation International Centre of Excellence, King's College Hospital, Kings College and Kings Health Partners, London, UK

Corresponding author

Angelo Antonini, MD, PhD

Parkinson and Movement Disorders Unit, IRCCS Hospital San Camillo

Venice

Italy

Tel: +39041 2207554

Email:

Key words: Parkinson’s disease, nonmotor symptoms, nonmotor symptoms scale (NMSS), randomized-controlled trial

Word count: 3671 (including title page, abstract, references, legends)

Conflicts of interest

LB, ED and MS are employees of UCB Pharma and PS was an employee of UCB Pharma during the conduct of the study. AA has received funding from the Neureca Foundation, Gossweiler Foundation, Mundipharma, and from Italian National Research (project no.: RF-2009-1530177), and has received consultancy fees and honoraria for speaker related activities from AbbVie, UCB Pharma, Zambon, General Electric, Boston Scientific, and Mundipharma. WO has received fees from UCB Pharma during the conduct of the study for participation in advisory board meetings; fees for educational activities such lectures at conferences and participation in advisory board meetings from UCB Pharma and Mundipharma. OR has received fees from UCB Pharma during the conduct of the study for participation in advisory board meetings; research grants from Agence Nationale de la Recherche (ANR), CHU de Toulouse, France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, MJFox Foundation, Programme Hospitalier de Recherche Clinique, Boehringer Ingelheim, Lundbeck, TEVA and UCB Pharma; and personal fees from AbbVie, Britannia, Lilly France, Lundbeck, MDS, Servier, Teva, UCB Pharma, Merck, NeuroDerm, Osmotica and Zambon. HR has received fees for participated in advisory boards, given lectures for, and received research grants from AbbVie, Bial, Boehringer Ingelheim, Britannia, GSK, Lundbeck, Meda, Medtronic, Novartis, Orion, TEVA, and UCB Pharma. ET has received honoraria for consultancy from TEVA, Boehringer Ingelheim, UCB Pharma, Solvay and Lundbeck; research grants from Spaniard Network for research on neurodegenerative Disorders (CIBERNED) - instituto Carlos III, The Michael J Fox Foundation for Parkinson’s Research, and Fondo de Investigaciones Sanitarias de la Seguridad Social. KRC has received funding from Parkinson’s UK, NIHR, European Commission, as well as educational grants from UCB Pharma, Britannia, AbbVie and Medtronic; has received honorarium from UCB Pharma, Abbvie, Britannia, US Worldmeds, Mundipharma, Medtronic, Napp, Otsuka pharmaceuticals; and acted as a consultant for UCB Pharma, AbbVie, Britannia, Medtronic and Mundipharma.

Abstract

Background: Nonmotor symptoms (NMS) of Parkinson’s disease (PD) have a major impact on health-related quality of life. This was the first randomised-controlled trial to use the NMS Scale (NMSS) as a primary outcome to assess treatment effects on NMS in PD.

Methods: In this double-blind trial (NCT01300819), patients with PD and a total NMSS score ≥40 were randomised (2:1) to rotigotine or placebo, titrated over 1–7 weeks to optimal dose (≤8mg/24h for patients not receiving levodopa, ≤16mg/24h for patients receiving levodopa ), maintained for 12 weeks. Primary outcome: change in NMSS total score from baseline to end of maintenance. Secondary outcomes: the nine NMSS domains, Unified Parkinson's Disease Rating Scale (UPDRS) III (motor) and the 39-item Parkinson's Disease Questionnaire (PDQ-39).

Results: 283/349 (81.1%) randomised patients completed the trial; 211 rotigotine and 122 placebo were included in the full analysis set. NMSS total score decreased by 23 (rotigotine) and 19 (placebo) points; the treatment difference was not statistically significant (-3.58; 95% CI -8.43,1.26; P=0.147). Numerically greater than placebo improvements were detected in “mood/apathy” and “miscellaneous” NMSS domains (P<0.05). Treatment differences in UPDRS III (-2.60; -4.27,-0.92; P=0.002) and PDQ-39 (-2.79; -5.21,-0.37; P=0.024) favoured rotigotine. Adverse events reported more frequently with rotigotine were nausea, application site reactions, somnolence and headache.

Conclusions: Rotigotine improvement in the multi-domain NMSS total score was not superior to placebo. Different sensitivity of individual NMSS domains to dopaminergic therapy and large placebo effect may have contributed to these findings.

Introduction

In Parkinson disease (PD), together with the classic motor disability, patients complain about a number of nonmotor symptoms (NMS) [1-3]. The recognition of their diversity, prevalence and impact on patients’ health-related quality of life (HRQoL) has led to a significant shift in diagnostic and therapeutic approaches to the disease.

More than 90% of patients with PD suffer from NMS with individual patients complaining on average of five to six NMS [4]; they have a greater detrimental impact on HRQoL than motor symptoms [5] and are frequently under-reported and under-recognised [6, 7]. Furthermore, little is known about their progression, their response to dopaminergic medication and their occurrence as nonmotor fluctuations [8, 9].

The development of instruments for screening and evaluation of NMS, notably the NMS questionnaire (NMSQuest) and NMS scale (NMSS), represents an important step forward in the recognition of these disturbances, but they do not clearly establish the relationship with disease and the response to treatment [10-12]. The response of individual NMS to dopaminergic treatment may differ, as NMS may originate from multiple causative processes, underpinned by predominant involvement of non-dopaminergic circuits or even secondary to medications [13, 14].

Previous randomised studies have shown that if patients with discrete NMS such as depression or sleep problems are identified, dopamine agonists can provide greater benefit than placebo [15, 16]. However, this may not apply to other conditions like constipation or orthostatic hypotension that may even be worsened by dopaminergic therapy. The primary objective of the current trial was to determine the effects of the dopaminergic agent rotigotine on NMS in patients with PD with an NMSS score greater than 40. Secondary objectives were to compare the effects of rotigotine with those of placebo on the individual domains of the NMSS, motor symptoms and HRQoL.

Methods

Patients

Patients aged ≥18 years with a diagnosis of PD (Hoehn and Yahr [H&Y] stage I-IV), and a total NMSS score of at least 40 were recruited. The score of 40 was chosen as the entry criterion based on the mean NMSS score of patients in a previous rotigotine trial (RECOVER) [15]. Patients not receiving levodopa, as well as those receiving concomitant levodopa were included.

Permitted PD medications included anticholinergic agents, monoamine oxidase B (MAO-B) inhibitors, and amantadine, at stable dose for at least 28 days prior to baseline and maintained at that dose for the duration of the trial. CNS-acting agents (e.g. sedatives, hypnotics, selective serotonin reuptake inhibitors, anxiolytics, sleep-modifying medication) were also permitted as long as the dose had been stable for at least 28 days prior to baseline and were likely to remain stable during the trial. Patients receiving levodopa were required to be on a stable dose for at least 28 days before baseline; the dose could be decreased during titration, but had to remain stable during maintenance. Prohibited medication (or within 28 days prior to baseline) included alpha-methyl dopa, metoclopramide, reserpine, neuroleptics, MAO-A inhibitors, methylphenidate, amphetamine and other dopamine receptor agonists.

The study was conducted under the auspices of an Independent Ethics Committee, as defined in local regulations, the International Conference on Harmonisation and Good Clinical Practice requirements, in accordance with the ethical principles of the Declaration of Helsinki, and the local laws of the countries involved. Patients provided written, informed consent before study participation.

Trial design and procedures

This was a multicentre, double-blind, placebo-controlled, parallel-group trial conducted across 12 European countries (SP0976, NCT01300819). Patients were randomly assigned via an Interactive Voice Response System to either the rotigotine or placebo in a 2:1 ratio. Randomisation was stratified by site and use of concomitant levodopa. The trial consisted of screening, randomisation, titration, maintenance and de-escalation periods. Visits were scheduled at screening, baseline, every week during the titration period, and the start and end of 12-week maintenance (EoM). A final safety follow-up visit was scheduled 4 weeks after final patch removal. Patients started study medication at Visit 2 (baseline). Rotigotine and placebo were administered as once-daily patches of two different sizes (10 cm2 and 20 cm2) that were identical in appearance. Treatment was titrated over 1-7 weeks in weekly increments of 2 mg/24 h rotigotine or placebo and maintained for 12 weeks. Treatment started at 2 mg/24 h for patients not on concomitant levodopa or at 4 mg/24 h for patients on levodopa, and was titrated until either the optimal/maximum dose of trial medication was reached. The dose was regarded as optimal if both the investigator and the patient felt that the symptoms were adequately controlled. The maximum dose of rotigotine permitted was 8 mg/24h for patients not on levodopa and 16 mg/24h for those on levodopa. During titration, if an adverse event (AE) occurred that was thought to be the result of excessive dopaminergic stimulation, the dose was back-titrated to the previous dose, and the patient immediately began maintenance. At the EoM, patients de-escalated by 2 mg/24 h every other day.

NMS were assessed using the NMSS, a 30-item clinician-rated scale designed to assess the severity and frequency of nonmotor symptoms in patients with PD [11, 12]. The items are grouped into nine domains: “cardiovascular”, “sleep/fatigue”, “mood/apathy”, “perceptual problems/hallucinations”, “attention/memory”, “gastrointestinal tract”, “urinary”, “sexual function” and “miscellaneous” [11]. The NMSS was assessed at screening, baseline (Visit 2), start of maintenance (Visit 9) and EoM (Visit 10).

Motor symptoms and HRQoL were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III and the 39-item Parkinson’s disease questionnaire (PDQ-39), respectively, at baseline, and at the start and EoM.

Trial outcome measures

The primary efficacy outcome measure was change from baseline to EoM in total NMSS score, as observed. Secondary efficacy measures were changes from baseline to EoM in the individual domains of the NMSS, UPDRS Part III and PDQ-39, as observed. Safety variables were occurrence of treatment emergent adverse events (TEAEs) and changes in vital signs.

Statistical analysis

This trial was powered at 80% for a sample size of 333, with 222 patients for rotigotine and 111 for placebo. This sample size assumed an anticipated treatment difference between placebo and rotigotine
of -8.94 in the change in the total NMSS score with a standard deviation (SD) of 27.33. This calculation was based on efficacy data from the RECOVER trial where the NMSS was used as an exploratory measure.

The analysis of the primary variable was based on the full analysis set (FAS): all randomised, treated patients who had a baseline and at least one post-baseline measurement for the primary variable. Data are reported as observed. Analyses of the safety data was based on the safety set (SS): all patients receiving at least one dose of trial medication.

For the primary variable, an analysis of covariance (ANCOVA) was conducted to test for differences between the two arms, with the model including factors for the treatment assignment (main factor), geographic region of patients’ investigational centre, and PD stage (stratifying factors) and the baseline value of the total NMSS score as a covariate.

Testing for the secondary variables was also performed using an ANCOVA model; all p values presented for secondary variables are exploratory and do not infer statistical significance. No adjustments were made for multiplicity due to closed test procedure for primary efficacy variable. All statistical analyses were performed using SAS® Version 9.1.3.

Results

Patient disposition and baseline characteristics

From February 2011 to November 2012, 377 patients were recruited. Twenty-eight patients were not eligible for participation, leaving 349 patients; 125 randomised to placebo and 224 to rotigotine (Figure 1). Twenty-two patients in the placebo and 44 in the rotigotine groups failed to complete the trial; the most common reasons for discontinuation in both groups were AEs and withdrawal of consent. Overall, 122 (97.6%) patients in the placebo group and 211 (94.2%) in the rotigotine group met the FAS criteria; 180 patients (80.4%) assigned to rotigotine and 104 (83.2%) to placebo completed the maintenance period.

Demographic characteristics were similar in both treatment groups (Table 1). The median time since diagnosis of PD and range were 2.2 (0, 14.1) years in the placebo group and 2.8 (0, 20.6) years in the rotigotine group. Most patients were taking concomitant anti-Parkinson medication (84.8% in the placebo group and 90.6% in the rotigotine group). Moreover, the majority of patients were taking concomitant levodopa (66.4% of placebo treated, and 71.0% of rotigotine treated). The majority of patients were considered compliant (≥85% and <115%) during the treatment period.

Efficacy

The mean NMSS total and domain scores were comparable at the screening and baseline visits (Supplemental Table 1, online only). An improvement in the total NMSS score from baseline to the end of the 12-week maintenance period (primary efficacy variable) was observed in both arms (Figure 2). The mean decrease in the NMSS total score was approximately 23 points in the rotigotine group and 19 points in the placebo group. The treatment difference between placebo and rotigotine across all dose groups was -3.58 points (95% confidence interval [CI] -8.43, 1.26; P =0.147) and was not statistically significant.

The treatment difference between placebo and rotigotine among patients taking levodopa was -4.73 points (95% CI -10.75, 1.29; P=0.123). This was slightly numerically larger than that observed in the overall population (-4.73 points treatment difference in patients taking levodopa vs -3.58 points treatment difference in overall population). Among patients not taking levodopa, the treatment difference between placebo and rotigotine was -2.69 points (95% CI -10.88, 5.50; P=0.516).

A numerically greater change (indicating improvement) in two of the NMSS domains was observed among rotigotine-treated compared with placebo- treated patients: “mood/apathy” (P=0.047; exploratory analyses) and “miscellaneous” (P=0.043; exploratory analyses) (Table 2). In the “miscellaneous” domain, improvement in the individual NMSS item “excessive sweating” was the main response driver (Supplemental Table 2, online only).

At EoM, the change in UPDRS Part III score was greater in the rotigotine than in the placebo group (Figure 3). The change in PDQ-39 scores was also in favour of the rotigotine group (Figure 3).

Safety and tolerability

The mean duration of the exposure to study medication was similar for rotigotine- (111.8± 37.3 days) and placebo-treated patients (115.7 ± 36.6 days). At least one TEAE was reported by 48% of placebo- and 62·8% of rotigotine-treated patients. Drug-related TEAEs were reported by 26.4% and 44.4% of placebo- and rotigotine-treated patients, respectively. The most common TEAEs (>5%) that occurred more frequently in rotigotine treated patients were nausea, somnolence, headache and application site reactions. Conversely, fatigue occurred in a greater proportion of placebo-treated patients (Table 3).

Most TEAEs were mild or moderate in intensity. Severe TEAEs were reported in three placebo-treated patients (2.4%) and ten rotigotine-treated patients (4.5%). Serious TEAEs were reported by four placebo-treated patients (3.2%) and eight rotigotine-treated patients (3.6%). In the placebo group, 7.2% of the patients discontinued from the study due to TEAEs, while in the rotigotine group, 12.1% discontinued.

No clinically relevant changes or trends in the mean changes of vital signs and physical and neurological examinations from baseline were reported in either treatment group.

Discussion

In this randomised controlled trial, a marked improvement in NMSS was observed in both rotigotine and placebo-treated patients. The difference between the rotigotine- and placebo-treated groups was not statistically significant and the primary objective was not met.

The current trial was the first to use change in NMSS total score as the primary outcome measure; it was designed and conducted following observations that rotigotine was superior to placebo in improving NMSS total score (and the “sleep/fatigue” and “mood/apathy” domains) in patients with early-morning akinesia and sleep disturbances (RECOVER trial) [15]. In the randomised, placebo-controlled DEPRESS trial, treatment with pramipexole improved the Beck Depression Inventory) in PD patients suffering from depression [16]. Other studies have also found NMSS improvements in advanced PD patients with motor fluctuations following initiation of levodopa or apomorphine infusion, but they were open-label/non-interventional studies [17-20].

In the DEPRESS trial, patients were selected based on the presence of depression, while in RECOVER they were selected based on early-morning motor dysfunction, which is known to affect sleep; therefore, in both studies, clear target populations were enrolled [15, 16]. The current trial included a heterogeneous population of patients suffering from any type of NMS. Nonetheless, a greater than placebo effect was observed on the “mood/apathy” domain of the NMSS, similar to the improvement observed in the “mood/apathy” domain in the RECOVER trial [15] . The NMSS includes a wide variety of NMS; using the NMSS total score as the primary outcome, NMS such as gastrointestinal, cognitive, sleep and urinary disturbances, were measured as a unified symptom complex. As such, it is possible that the overall result may be ‘noisy’ given the heterogeneity of underlying causes, including PD-related dopaminergic and non-dopaminergic pathology and normal aging. Correspondingly, some symptoms may be more likely to respond to dopaminergic therapies than others; alternatively, the efficacy threshold may differ depending on the target nonmotor feature.