In this trial, eligible male and female PD patients with stable motor disease, i.e. without disturbing motor fluctuations or dyskinesia according to the Movement Disorders Society-Unified Parkinson’s Disease-Rating Scale (MDS-UPDRS) Part IV over the age of 30 years suffering from NMS (measured on the basis of MDS-UPDRS I, including at least anxiety or pain) will be included. Eligibility will be assessed by inclusion and exclusion criteria (Table 1). To participate in the study, patients must have a score of at least ≥ 4 points on MDS-UPDRS Part 1 with ≥ 2 points in the item for anxiety or pain. Patients with disturbing impulse control disorders as defined per cut-off values of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale (QUIP-RS) will be excluded (Probst et al. 2014). Furthermore, PD patients with symptomatic orthostatic hypotension, sinus tachycardia, and chronic major psychiatric disorders will be excluded as these are possibly dangerous adverse reactions that may occur during the intake of nabilone. Patients with moderately or severely impaired liver function and/or chronic alcohol or drug abuse will be excluded from the trial because the primary route of elimination of nabilone is biliary. As this study is a pilot study, we decided to reduce bias as much as possible by applying these inclusion and exclusion criteria. Moreover, some of the exclusion criteria are applied for safety reasons such as exclusion of patients with severe depression, severe hallucinations, severe symptomatic orthostatic hypotension, severe cognitive impairment, or severe impulse control disorders.
Trial design and safety measures
The NMS-Nab Study is a mono-centric phase II, randomized, placebo-controlled, double-blind, parallel-group, enriched enrollment withdrawal study in patients with NMS in PD (Table 2). The study includes a screening period, followed by an open-label nabilone dose optimization period (phase 1) and a placebo-controlled, double-blind, parallel-group randomized withdrawal phase (phase 2). The trial includes a screening visit (SCR), one visit after dose titration (V − 1), a baseline visit (V 0) at the beginning of phase 2 for randomization, a termination visit (V 1) at the end of phase 2, and a safety follow-up visit (V-S) 2 weeks after discontinuation of the study drug or placebo. Eligible subjects, who have signed the informed consent form, will receive open-label nabilone starting with a dosage of 0.25 milligrams (mg) in the evening after the screening visit. During dose titration period, nabilone will be titrated in 0.25-mg increments one to four times daily until a maximum dosage of 1 mg twice daily. Regular phone calls with the study center will be performed every other day during titration phase. Dose adjustments during titration phase will be performed until the patient meets the criterion of a responder (Table 3). The Clinical Global Impression of Improvement Scale (CGI-I) was chosen as a responder criterion as it represents the overall status of the patient’s improvement/deterioration. It will be assessed with regard to non-motor features of the patients.
The open-label titration phase ends with an on-site visit (V − 1). Afterwards, patients should be on a stable nabilone dosage for at least 1 week before randomization. After at least 1 week of stable nabilone dosage, responders are randomized in a 1:1 ratio at the baseline visit (V 0) to receive either nabilone at the dosage reached during the titration phase or placebo for 4 weeks (phase 2). During the first week of the withdrawal phase, regular phone calls will be held every other day. During the open-label treatment period, dose adjustments may be performed if the CGI-I deteriorates. In this case, the patient will re-enter the titration phase of the trial.
After having finished the open-label period, a termination visit will be held and nabilone will be tapered in patients in 0.25-mg twice-daily decrements. Phone calls will be held every other day during dose-tapering phase. A phone call for safety purposes will be held after 5 days and a safety follow-up visit will be scheduled after 2 weeks of discontinuation from study drug (Fig. 1).
Hypotension, fatigue, and psychosis have been described as possible side effects of nabilone therapy. Besides, in addition to suicidal tendencies, these will also be examined as safety parameters in this study in all telephone calls and visits. Moreover, laboratory measures and an electrocardiogram will be performed at screening and termination visit to monitor possible tachycardia and laboratory abnormalities.
Randomization and unblinding
Randomization will take place in responders after up-titration of nabilone. Patients will be randomly assigned to the treatment with either placebo or nabilone at baseline in a 1:1 ratio. Randomization will be performed with a computer-generated randomization schedule provided by the Department of Medical Statistics of the Medical University of Innsbruck (MUI) in a blinded fashion for the study team and patients. The necessary medication kits are labelled with numbers according to the randomization list by the pharmaceutical company that provides the placebo and nabilone to ensure concealment. Patients will receive these kits in chronological order from blinded study team members at the baseline visit. No patient is allowed to be unblinded before the end of the trial, except for “emergencies”. Premature treatment unblinding will be performed via the emergency envelopes by a member of the study team after consultation with the principal investigator in case of an “emergency”. An “emergency” can be any event that is serious and related to the treatment in the investigator’s discretion or an event for which knowledge of the treatment group is crucial (i.e. pregnancy).
Administrative structure, data coordinating center, study center and recruitment
The NMS-Nab Study is performed at one clinical site, the Medical University of Innsbruck (MUI, Austria, urban and rural setting) which will be the sponsor of this trial. Trained members of the study team assess the outcome measurements using validated questionnaires and clinical routine parameters. The study team undertakes the administrative and regulatory function for this trial and has access to the final trial dataset. For all work involving data collection or management of subjects, the study center will adhere to the law as laid down in the European Regulation (EU) 2016/679 as well as to the national data protection law. The study team is supported by the Clinical Trial Center of the MUI which will perform monitoring and survey the randomization process. The safety data management is performed by Hans-Günther Knaus of the Department for Medical Genetics, Molecular and Clinical Pharmacology of the MUI. Data management and statistics is conducted by qualified members of the study team of the neurological study center Innsbruck. Recruitment will last to the point when 38 subjects have finished the double-blind phase of the trial.
Patients are seen in the outpatient department on-site or at the neurologic wards. For interested patients, a member of the qualified research team will explain the study purpose, goals, and requirements in an understandable manner and an institutional review board/independent ethics committee (IRB/IEC)-approved informed consent form will be handed to the patients considering participation. These patients will be followed up by a member of the study team.
Statistical rationale and outcomes
The primary and secondary efficacy criteria of this trial refer to the randomized, double-blind, placebo-controlled enriched enrollment randomized withdrawal phase of the study.
The primary efficacy criterion will be measured as the change of the MDS-UPDRS Part I between baseline (i.e. randomization) and week 4.
Since an interpolation of data will not be performed in case of a drop-out, the primary analysis is a per-protocol analysis. No interim analysis is planned. Secondary efficacy criteria will be measured as the change in the other clinical scales and questionnaires between baseline and week 4, except for the CGI-I measures, which will be singularly evaluated at week 4. The clinical scales include the other parts and single items of the MDS-UPDRS, the Non-Motor Symptoms Scale (NMSS), the Hospital anxiety and depression scale (HADS), the Parkinson’s Disease Questionnaire-39 (PDQ-39), the Montreal Cognitive Assessment (MoCA), the Epworth Sleepiness Scale (ESS), the Fatigue Severity Scale (FSS), the visual analog scale (VAS) of pain, the King’s Parkinson’s Disease Pain Scale (KPPS), and the QUIP-RS.
For the study’s primary efficacy and secondary efficacy objectives, mean changes from randomization to the 4-week follow-up in the nabilone and placebo groups will be analyzed separately within the two groups by Wilcoxon matched-pairs test and then compared between the two groups by Mann–Whitney U test. For all analyses, statistical significance will be set at the two-sided 5% level. Additionally, a sensitivity analysis will be performed for the primary efficacy or a key secondary efficacy variable, in case of differences in baseline characteristics at randomization (using Mann–Whitney U tests). Moreover, sensitivity to treatment will be assessed using effect sizes of the different outcome variables when using nabilone to treat non-motor symptoms in Parkinson’s disease. For CGI analyses, distributions of dichotomized ratings (amelioration, aggravation) in the nabilone and placebo groups at 4-week termination visit will be compared by Fisher exact test. The safety objectives of this study are to evaluate the safety and tolerability of nabilone in patients with PD between baseline and week 4 with reference to the number of subjects (%) who discontinue the study, the number of subjects (%) who discontinue the study due to an adverse event (AE), adverse events, serious adverse events (SAEs), clinical and laboratory assessments, assessments of vital signs including performance of active orthostatism, electrocardiogram (ECG) evaluation, patient’s compliance, patient’s prior and concomitant medication use, the hallucination item (1.2), the item for orthostatic hypotension (1.12), and the day-time sleepiness item (1.8) of the MDS-UPDRS, as well as the Columbia Suicide Severity Rating scale (C-SSRS). Distributions of AEs, SAEs, and suspected unexpected serious adverse reactions (SUSARs) in the nabilone and placebo groups at week 4 will be compared by Fisher exact test. Additionally, a descriptive analysis reporting all safety parameters mentioned above will be performed and displayed separately for the nabilone and placebo group.
To exclude that nabilone causes any negative effects on reaction time, attention span, and concentration, several tasks on an eye-tracker will be performed as an exploratory endpoint. Eye-tracking provides a fast and non-invasive method for various examinations. In this study, we will measure the reaction time using pro-saccade and anti-saccade tasks. Moreover, we will assess attention spans and the ability to concentrate using a customized pro- and anti-saccade task as well as a test involving task-switching. Mean changes from the screening visit to week 4 in error rates and reaction times in the nabilone and placebo group will be analyzed separately for the two groups by Wilcoxon matched-pairs test and then compared by Mann–Whitney U test.
Sample size and power calculation
This is a phase II randomized clinical trial that uses a complete enriched enrollment randomized withdrawal design to evaluate the effects of continuous nabilone therapy versus withdrawal to placebo in patients with PD suffering from NMS. This design has the advantage that the patient population enrolled is enriched by including only responders. Moreover, total exposure to placebo in this withdrawal design may be shorter than in a study with only a randomized treatment phase. The power calculation refers to the primary endpoint of the study, i.e. change of MDS-UPDRS Part I score from randomization to week 4 during the placebo-controlled, double-blind, parallel-group randomized withdrawal phase (i.e. phase 2 of the study). A total of 38 patients (19 in each group) will have 80% power to detect a probability of 0.231 that an observation in the treatment group is less than an observation in the placebo group using a Wilcoxon (Mann–Whitney) rank-sum test with a 0.050 two-sided significance level (Table 4). With this, a statistically significant difference in the change from randomization to week 4 in MDS-UPDRS Part I score between nabilone and placebo will be detected if the true difference is 2.5 points. In the absence of previous data, we empirically chose, as clinically meaningful, a 2.5-unit change from randomization to the week 4 visit (in phase 2). This sample size calculation assumes the standard deviation of the change to be 2.4 points from randomization to week 4 (Poewe et al. 2015). Assuming a drop-out rate of 25%, we plan to include around 48 patients with Parkinson’s disease in this trial. Importantly, although a sample size calculation is provided, this is an exploratory study evaluating different NMS domains. Therefore, corrections for multiple comparisons are not planned.
Permission for the conduct of the trial was received from the ethics committee of the MUI on 26 June 2017 (reference number: 1008/2017) and the Austrian regulatory authorities approved the study on the 15 September 2017. Two amendments to include an eye-tracking analysis as an exploratory endpoint in the study and to conform to the EU Data Protection Law 2018 have been approved by the ethics committee of the MUI and the regulatory authorities (Table 2). Patient recruitment was started in October 2017 and is still ongoing. The first patient was included in December 2017. The study was registered on ClinicalTrials.gov and Fox trial finder.
The results of this study will be published by study team members according to the principles of publication policy. There are no arrangements on publication issues with subsiding parties.