Nabiximols Shows Improved Symptomatic Spasticity Control in ALS

January 3, 2019

A proof-of-concept trial’s findings have shown that more clinical research into the potential neuroprotective effect of cannabinoids in slowing disease progression in motor neuron disease is warranted.

Giancarlo Comi, MD

Data from the phase 2 CANALS trial has shown that nabiximols (Sativex, GW Pharmaceuticals) may be able to help control the symptoms of spasticity in patients with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS).1

The proof-of-concept trial revealed that patients in the nabiximols group (n = 29) had a mean Modified Ashworth Scale (MAS) score improvement of 0.11 (standard deviation [SD], 0.48) compared to a deterioration of 0.16 (SD, 0.47) for those on placebo (adjusted effect estimate, -0.32; 95% CI, -0.57 to -0.069; P = .013).

Principal investigator Giancarlo Comi, MD, from the Department of Neurology and Institute of Experimental Neurology at the San Raffaele Scientific Institute, and colleagues wrote that despite nabiximols being licensed for symptomatic control of spasticity in multiple sclerosis in many countries, as well as the growing evidence recognizing cannabinoids as an option for many pain-related ailments, “further confirmatory phase 3 studies are warranted to confirm our findings, and more clinical research into the potential neuroprotective effect of cannabinoids in slowing disease progression in motor neuron disease is warranted.”

Additionally, the study findings showed a significant change in pain on the Numeric Rating Scale (NRS) for the nabiximols group. Those on the study drug showed a reduction of 0.97 (SD, 2.12) points compared to a reduction of 0.06 (SD, 1.47) for the placebo group (mean effect, 1.15; 95% CI, -2.10 to -0.21; P = 0.017).

As well, 55% (n = 16) of participants in the intervention group rated their global impression of change as improved, compared with 4 of 30 (13%) in the placebo group (P = .001 for overall between-group comparison). There were no significant differences between the caregivers’ (P = .163) or the neurologists’ (P = .080) global impression of change, with 72% and 86% of those in the nabiximols group stating their patent was at least stable or had improved compared to 60% and 66% in the placebo group, respectively.

The trial ultimately randomized 60 patients (59 were included in the final analysis, as a single patient was removed from the intervention group due to a protocol violation) to either the oromucosal nabiximols or placebo for 6 weeks. Study participants self-titrated during the first 14 treatment days according to a predefined escalation scheme of a maximum of 12 actuations per 24 hours, then maintained that dose for 4 weeks. Each 100 µL actuation of nabiximols contained 2.7-mg delta-9-tetrahydrocannabinol and 2.5-mg cannabidiol.

During the 4-week double-blind phase after dose titration, the mean number of daily actuations was 8.03 (SD, 2.9; range, 1 to 12) in the nabiximols group and 11.2 (SD, 1.4; range, 7 to 12) in the placebo group (P <.0001).

All patients in both groups who completed the double-blind phase were given the opportunity to enroll in a 6-week, open-label extension, which all but 2 patients did. All participants in the open-label phase received nabiximols, with a 2-week titration period for those placebo group followed by 4 weeks of fixed-dose treatment.

During the open-label phase, the mean daily number of actuations decreased significantly to 6.1 (SD, 3.4) for those previously on placebo (P <.0001). It did not change for those who were originally in the intervention group. MAS scores for the original placebo group improved after switching to nabiximols (mean change, -0.28; SD, 0.47). Comi and colleagues noted “a general improvement in efficacy outcome measures for the original placebo group.”

Additionally, the placebo participants’ global impression of change improved compared with those recorded during the double-blind phase, with 54% of 28 participants (n = 15) reporting improvements.

Overall, the nabiximols treatment was deemed well tolerated. In the double-blind phase, no participants permanently discontinued treatment. In total, 3 patients in the treatment group and 2 patients in the placebo group temporarily discontinued treatment due to adverse events (AEs). The mean duration of temporary discontinuation was 2.4 days (SD, 1.9; range, 1 to 5).

No serious AEs were recorded in either group, but 76% (n = 22) of participants in the intervention group and 27% (n = 8) in the placebo group had ≥1 all-cause AE, and 72% (n = 21) and 13% (n = 4), respectively, had ≥1 potentially treatment-related AE. In the nabiximols group, 24% (n = 7) had 13 investigator-judged potentially treatment-related AE of moderate severity, compared to 1 in the placebo group. The most common AEs potentially related to nabiximols were asthenia, somnolence, vertigo, and nausea.

In the open-label extension, 22 participants previously on placebo and 11 assigned to nabiximols throughout the study had ≥1 potentially treatment-related AE. There were 22 potentially treatment-related moderate or severe adverse events experienced by 11 participants, 9previously allocated to placebo and 2 to nabiximols. The most common AEs potentially related to nabiximols were asthenia, dizziness, somnolence, vertigo, muscle spasticity or rigidity, and dry mouth.

Comi and colleagues wrote that several trials have suggested that nabiximols and cannabinoids can efficaciously reduce spasticity in patients with MS, “which is consistent with our results.” Although, the authors noted troubles with the study’s use of the Ashworth Scale or its modified form, which they acknowledged has been used in previous positive studies of the efficacy of other antispastic treatments. Despite this, they wrote that “it lacked sensitivity in studies of cannabinoid efficacy in multiple-sclerosis-related spasticity, and thus spasticity numeric rating scale scores or visual analogue scales have been used in subsequent multiple sclerosis studies. The ideal objective measure of the highly complex symptom of spasticity does not exist.”

They wrote that despite its well-known limitations, the Ashworth Scale remains the best clinically validated measure of spasticity, though it “might not represent patients’ experience of spasticity.” They also noted that while self-reported measures might not faithfully represent the neurophysiological definition of spasticity, “patient-reported outcomes have a growing role in clinical trials, and significantly more patients in the nabiximols group than in the placebo group had a global impression of improvement.”

As well, Comi and colleagues wrote that “improvement in patients’ global impressions of change might reflect the multiple symptomatic effects of cannabinoids that could be beneficial to patients with amyotrophic lateral sclerosis.”

REFERENCE

1. Riva N, Mora G, Sorarù G, et al. Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. Published online December 13, 2018. doi: 10.1016/s1474-4422(18)30406-x.