Results of the CSM-Protect trial show that a six-week course of riluzole as an adjunct to surgical decompression for moderate-severe degenerative cervical myelopathy (DCM) has “no significant benefit” to the primary outcome of mJOA and “interesting effects” on three predetermined secondary outcomes—VAS neck pain, ASIA motor score and the SF-36 physical function domain—which the investigators feel “need to be viewed as exploratory”.
Lead investigator Michael Fehlings (University of Toronto, Canada) recently presented these findings during the Best Paper session at the 2019 Global Spine Congress (GSC; 15–18 May, Toronto, Canada), concluding that the results also “confirm the significant improvement in neurological and functional outcomes with surgical decompression”.
Fehlings noted that a detailed analysis of the effect of riluzole on neurological complication (C5 palsy, deterioration of neurological function) is underway and that a longer duration (for example, three and six months) of riluzole “may warrant further study”.
He mentioned that he and his co-investigators suggest defining subsets of patients—such as those with neuropathic pain, who are at highest risk of perioperative neurological deterioration—who can potentially benefit the most from neuroprotective interventions.
Additionally, the development of more sensitive outcome measures (for gait and hand/arm function) is “needed”, as mJOA has “responsiveness limitations”. Overall, Fehlings and colleagues conclude that “the effect of riluzole in reducing pain in DCM is of clinical interest, is associated with improved SF-36 physical function, and merits further study”.
DCM is the leading cause of spinal cause impairment, and although surgical decompression improves function and QOL, Fehlings remarked that many patients are left with residual disability and there is a 7–11% risk of neurological deterioration after decompression. The investigators hypothesised that riluzole would enhance neurological recovery, attenuate neuropathic pain, and reduce perioperative neurological complications following surgical decompression for DCM.
Fehlings described the study as a multicentre, placebo-controlled, double-blinded, randomised trial, conducted in 16 sites across North America. Enrolment took place between March 2012 and June 2019, culminating in a study population of 300, all with moderate-to-severe symptomatic DCM (mJOA 8–14), no prior cervical spine surgery, and all undergoing elective spinal decompression. The participants were aged between 18 and 80.
Riluzole was given orally in 50mg doses every 12 hours for 14 days before surgery and continued for 28 days after surgery. For the control, a placebo was given on the same schedule. Outcomes were recorded at enrolment, on admission, and then after 35 days, six months, and one year. The primary outcome was change in mJOA (six months) and secondary outcomes were change in Nurick grade, neck disability index (NDI), SF-36, EQ-5D, ASIA motor and sensory scores, grip strength, and grip VAS (six months).
Patients were randomised 1:1 and subjects, physicians, and data collectors remained blinded to treatment allocation throughout randomisation and follow-up. The investigators note that to have 80% power to detect an effect size of 0.35 Cohen’s d (0.9–point of different in mJOA), a sample size of n=270 was needed.
In terms of statistical analysis, between-group comparisons of change in outcome scores from baseline were made using mixed-effects models for repeated measures; unstructured covariance matrix; fixed effects for treatment group (riluzole versus placebo), time (hospital admission, 35 days, six months, one year after surgery), and time-by-treatment interaction.
A total of 300 patients were randomised, and 290 underwent surgery, of which 141 received riluzole and 149 were allocated to the placebo group. The mean age of the cohort was 58±10.1 years, and there were 129 females (44.5%) in the group. The rate of follow-up was 90% at six months, and 79% at one year.
Sixty seven patients in the riluzole group experienced hypertension, compared to 63 in the placebo group. Diabetes occurred in 23 patients in the riluzole group, compared to 12 in the placebo group, and anxiety and depression symptoms were noted in 31 and 29 patients, respectively.
The investigators report no series drug-related adverse events, and no patient had to stop drug treatment. They found that at six months, surgery resulted in “significant improvement” in all outcomes, and the primary outcome analysis found improvement with surgery, but no additional benefit with riluzole.