Study results show that treatment with riluzole did not slow the rate of brain atrophy and did not demonstrate a detectable neuroprotective effect in patients with early RRMS.
Copenhagen, Denmark — October 5, 2013 – Negative findings were reported for both clinical and imaging measures in a phase II randomized trial of riluzole in comparison to placebo in patients with very early multiple sclerosis (MS). Riluzole did not slow the rate of brain atrophy and did not demonstrate a detectable neuroprotective effect. All patients also received standard interferon treatment during the study.
Emmaneulle Waubant, MD, PhD, Professor of Neurology at the University of California in San Francisco, San Francisco, CA, presented negative results from a Phase II trial of riluzole on October 5 during the “Late Breaking News” session at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the 18th Annual Conference of Rehabilitation in MS.
Waubant explained the urgent need for agents having a neuroprotective effect during the early stages of MS, prior to the accumulation of permanent nerve damage that characterizes late-stage MS. Given the paucity of approved MS drugs with a neuroprotective benefit, it was decided to investigate riluzole, which is approved for the treatment of amyotrophic lateral sclerosis and thought to work by decreasing the levels of glutamate, thus protecting from nerve damage and decreasing neurodegeneration. Citing encouraging results from a small pilot study (Mult Scler. 2002 Dec;8(6):532-3.) that showed a slowing of the rate of cervical cord atrophy and the development of hypointense T1 brain lesions by magnetic resonance images (MRI) in patients with MS, Waubant and colleagues designed a randomized, double-blind, placebo-controlled phase II trial of riluzole as a neuroprotective agent in patients with early RRMS.
Patients in the trial were followed for up to three years; however, only nine patients overall stayed on study this long. The primary endpoint was change in brain volume, measured by SIENA; secondary endpoints included grey and white matter atrophy, recorded by SIENAX, and changes in MS functional composite (MSFC), peripapillary retinal nerve fiber layer thickness (RNFL), and Symbol Digit Modality Test (SDMT). “We decided that with this small cohort of patients we should get as many measurements as possible and to really make use of all data at all time points,” said Waubant.
The trial enrolled 43 subjects with early RRMS who had experienced the onset of MS within the prior year. Patients were randomized to receive either riluzole at 50 mg twice daily or placebo. All participants also received weekly interferon beta-1a treatment that began at study week three. Following randomization, it was noted that the 22 subjects in the riluzole treatment group were older (P=0.042), had higher normalized CSF volume (P=0.050), and lower normalized grey matter volume (P=0.14) at baseline than the 21 subjects in the placebo arm. Baseline characteristics were otherwise well balanced.
Normalized lesion volume was 7.56 in the riluzole group, compared with 4.01 in the placebo group (standard deviation ± 4.67; P=0.21). In the primary analysis, brain volume (SIENA) decreased each year in patients in the riluzole arm by a rate of 0.86% and by 0.49% in patients in the placebo arm, showing a greater decline with riluzole of 0.37% more per year (P= 0.065).
Although age did not seem to influence the rate of brain volume decline, the difference between treatment groups decreased to a rate of 0.26% lesions in the riluzole arm over placebo (P=0.22) when analyses were adjusted as preplanned for baseline normalized grey matter volume and baseline normalized lesion volume.
Secondary analyses showed no group differences for changes in normalized grey or white matter volume, MSFC, RNFL, or SDMT (P> 0.36). Riluzole subjects developed more new T2 lesions than placebo during the study (P=0.047). In answer to a question from the audience regarding whether Waubant had considered that riluzole might be deleterious to the patients, she responded that they did look into that and, referring to a graph, pointed out that the lines depicting the decline rates for riluzole and placebo over time were parallel. “It happened that the riluzole arm started out with more brain atrophy,” she said.
According to Waubant, “these data suggest that there was no effect in patients with very early RRMS on clinical and imaging outcome measures, but it cannot be ruled out that the study was too small and of too short a duration to detect an effect; nevertheless, if there had been a true effect it would have been mild.” She noted that there remained data analysis to be finished, in particular changes in peripapillary retinal nerve fiber layer thickness. “The lesson I learned from this study is to design trials that makes use of all recorded data and to adjust for key baseline differences between study arms,” she said.
This study was supported by a research grant funded by the National MS Society and free medication was provided by Biogen Idec and Sanofi-Aventis.