Nabilone for non-motor symptoms of Parkinson’s disease: a randomized placebo-controlled, double-blind, parallel-group, enriched enrolment randomized withdrawal study (The NMS-Nab Study)

Abstract

Although open-label observations report a positive effect of cannabinoids on non-motor symptoms (NMS) in Parkinson’s disease (PD) patients, these effects remain to be investigated in a controlled trial for a broader use in NMS in PD patients. Therefore, we decided to design a proof-of-concept study to assess the synthetic cannabinoid nabilone for the treatment of NMS. We hypothesize that nabilone will improve NMS in patients with PD and have a favorable safety profile. The NMS-Nab Study is as a mono-centric phase II, randomized, placebo-controlled, double-blind, parallel-group, enriched enrollment withdrawal study. The primary efficacy criterion will be the change in Movement Disorders Society-Unified Parkinson’s Disease-Rating Scale Part I score between baseline (i.e. randomization) and week 4. A total of 38 patients 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 rank-sum test with a 0.050 two-sided significance level assuming a true difference of 2.5 points between nabilone and placebo in the primary outcome measure and a standard deviation of the change of 2.4 points. The reduction of harm through an ineffective treatment, the possibility of individualized dosing, the reduction of sample size, and the possible evaluation of the influence of the placebo effect on efficacy outcomes justify this design for a single-centered placebo-controlled investigator-initiated trial of nabilone. This study should be the basis for further evaluations of long-term efficacy and safety of the use of cannabinoids in PD patients.

Targeting the endocannabinoid system: a predictive, preventive, and personalized medicine-directed approach to the management of brain pathologies

“…Further, in a Web-based selfreported assessment (n = 595), 454 identified PD patients, who have consumed cannabis daily and for longer than 12 months, reported lower disability and fatigue, while 47.8% patients reported decline in intake of prescribed medicines since beginning of cannabis consumption [269]. These exciting early-stage clinical results showing a potential benefit of cannabinoids after PD will be further explored in the upcoming phase II, randomized, placebo-controlled, and doubleblind enriched enrollment withdrawal study (The NMS-Nab Study) [270]. In this study, 4-week outcomes will be assessed in 38 PD patients following administration of a synthetic cannabinoid, nabilone [270].…”

Non‐Motor Symptoms in Parkinson's Disease are Reduced by Nabilone

“…Patients with PD with symptomatic orthostatic hypotension, sinus tachycardia, and major psychiatric disorders were not allowed to participate in this study as they are more vulnerable to possible hazardous adverse reactions that may occur during nabilone intake. Patients with at least moderately impaired liver function and/or chronic alcohol or drug abuse were excluded (see related publication for full list of inclusion and exclusion criteria 18 ). The study was approved by the local ethics committee and the Austrian national regulatory authorities.…”

“…All procedures were performed in accordance with the 1964 Declaration of Helsinki and its later amendments. Details of the study design have been previously published 18 …”

“…Respective medication boxes with either nabilone or placebo were labeled consecutively (1–48) according to the randomization list to ensure concealment. Neither a member of the study team nor the participants were informed about treatment assignment 18 . The 4‐week, double‐blind, withdrawal phase ended with a termination visit from which the amount of the drug was tapered.…”

“…We aimed to enroll 48 patients to account for dropouts and include 19 patients per treatment group in the randomized trial phase, which was considered sufficient to detect a treatment difference of 2.5 points in the primary end point (standard deviation 2.4) with 80% power and a 2‐sided α‐level of 0.05 (Mann–Whitney U test; nQuery Advisor version 7) 18 . A descriptive analysis (χ 2 test for categorical variables, Mann‐Whitney U test for continuous variables) of demographic and clinical data at baseline was performed using the full dataset of all patients that have ever taken nabilone in this trial (n = 47).…”