COPENHAGEN, Denmark — Results of a phase 2 randomized trial have failed to demonstrate any statistically significant effect of riluzole (Rilutek, Sanofi-Aventis) on the progression of brain atrophy among patients with early relapsing-remitting multiple sclerosis (MS).

There were no apparent benefits on imaging or clinical outcome measures, lead author Emmanuelle Waubant, MD, PhD, professor of neurology at the University of California, San Francisco, reported, and prior to adjustment, the effect of riluzole appeared negative relative to placebo.

"I was disappointed, but I knew there was that possibility because we're still trying to understand the better design, what's the best medication to try to treat patients with tissue loss," Dr. Waubant told Medscape Medical News. "And because it was a small study, it was more of a proof of concept, not only to test the medication but to come up with design strategies for future neuroprotection trials."

From that perspective, she said, "we learned tremendously, and now we have a lot of data to continue to analyze, to look for correlations between metrics. My goal with this set of data is to actually come up with possibly a surrogate, or 1 or 2 candidates that can be proposed as really good surrogate markers, so we can do shorter studies in the future for neuroprotection, because if you have to do 3-year studies for neuroprotection, it's going to take a long time to find drugs."

Dr. Waubant presented the results here at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Three Strategies

There are basically 3 strategies to address neuroprotection in MS, Dr. Waubant explained: studying it in primary or secondary progressive MS, in acute optic neuritis, and in early relapsing- remitting MS. The researchers chose this latter group to study "because these are the patients with the most tissue at risk to be lost," Dr. Waubant said.

Although it is not clear what is happening during the neurodegeneration seen in MS, it is thought there is an early reversible stage of tissue loss followed probably by a later stage that is irreversible, she said. There is likely some apoptosis and necrosis involved, and possibly some combination of excitoxicity, nonspecific toxic factors that may include oxidative stress, and deficits in neurotropic factors and their receptors, but which are the most important mechanisms is unclear.

For this study, they elected to use riluzole, a drug already approved for use in amyotrophic lateral sclerosis (ALS). Mechanisms of action with this drug include modulation of kainite and N-methyl-D-aspartate (NMDA) receptors, as well as activation of G protein–dependent pathways that induce neurotrophic factors promoting motor neuron survival.

Results of another small trial published in 2002 in 13 patients with primary progressive MS suggested some potential benefit on the primary endpoint of mean yearly change in the C2 area in a single crossover design, although there were no statistical comparisons of the 2 groups.

In the current study, the researchers randomly assigned 43 patients with clinically isolated syndrome or relapsing-remitting MS less than 1 year from disease onset, 22 to riluzole and 21 to placebo. For the first 3 months of the study, patients received only riluzole to make sure they could tolerate it, owing to the potential for liver toxicity. Thereafter, they received treatment with interferon beta-1a as well as the study drug for the duration of the trial.

The original design called for a 2-year follow-up, but additional imaging data released during the study suggested 3 years may be more instructive in terms of neuroprotection, so the protocol was amended for longer follow-up.

The primary endpoint was the percent brain volume change, measured with SIENA (structural image evaluation using normalization of atrophy). Secondary endpoints included normalized gray matter volume; normalized normal-appearing white matter volume, measured using SIENAX (the cross-sectional version of SIENA); the Multiple Sclerosis Functional Composite (MSFC) score; and a number of tertiary endpoints, including cognition, Expanded Disability Status Scale (EDSS), and low-contrast vision.

They were anxious to collect as much data as possible and make use to the extent possible of all of it, she said. "We used mixed-model regression analysis to compare the changes over time between the 2 groups, and that allowed us to account for the longitudinal nature of the data, and also make use of all of the data, including the patients who dropped out early from the study," Dr. Waubant noted.

Of the 22 patients randomly assigned to receive riluzole, 18 received the allocated intervention and 4 reduced the dose because of side effects possibly related to treatment. In the placebo group, 19 of 21 received the allocated treatment, and 4 reduced their regimen because of side effects.

Treating physicians could also switch from interferon beta-1a to another treatment for breakthrough disease activity; 2 patients in the riluzole group and 3 on placebo were switched during the study.

Twenty of the 22 riluzole patients completed 24 months of follow-up, and 9 were followed out to month 36. In the placebo group, 18 of 21 patients were followed to 24 months, and 13 to 36 months.

Their analysis showed that although baseline characteristics were "reasonably" well balanced, there were significant differences on 3 parameters: age, normalized cerebrospinal fluid (CSF) volume, and normalized gray matter volume. In addition, they tended to have more T2 bright lesions and a thinner retinal nerve fiber layer, "so unfortunately at baseline, the riluzole group was showing more severe signs of the disease," Dr. Waubant noted.

The primary analysis showed that in terms of monthly percent change in brain volume, there was -0.03% more progression in the riluzole group compared with placebo, which did not quite reach statistical significance.

On an annual basis, brain volume in the placebo group decreased at a rate of 0.49% per year, vs 0.86% with riluzole, a difference of 0.37% more brain volume loss per year between the 2 groups for those receiving the active treatment (95% confidence interval [CI], -0.78 to 0.024; P = .065).

They had preplanned to adjust their analysis for 1 or 2 baseline imbalances, which were not unexpected in a small trial. "So once we corrected for the imbalances in normalized gray matter volume and lesion volume, we saw that there was still a small difference in progression between the groups, but that difference was actually fairly attenuated after these adjustments," Dr. Waubant said.

The adjusted difference in brain volume loss was 0.26% more in the riluzole group vs placebo (95% CI, -0.057 to 0.014; P = .22).

They did not adjust for age per se at baseline because there are no data to suggest the rate of atrophy is affected by age, she noted. They did not see any significant differences either in secondary or tertiary endpoints.

In terms of safety, there were no serious adverse events in the study, and the adverse events seen were mild to moderate in severity. The only difference in effects was transient dizziness within half an hour of taking the medication, which was higher with riluzole (9 vs 5 events).

Six patients reported at least 1 side effect that was felt to be possibly related to study medication; 4 in the riluzole and 2 with placebo decreased the treatment regimen with the study drug, but only 5 of them actually decreased until study completion.

"I will conclude that based on these data, we were not able to detect an effect of riluzole in early relapsing-remitting MS on clinical and imaging outcome measures," Dr. Waubant said. "I have, though, to acknowledge that because of the sample size of the study and possibly also reasonably short duration, we can't rule out there was an effect."

The confidence intervals, however, suggest that if there is an effect, it is mild.

They will continue to analyze the large amount of data collected, including ongoing analyses of cortical thickness, diffusion tensor imaging, and spectroscopy, as well as "pretty comprehensive cognitive testing," she noted.

They are also studying correlations between imaging metrics and clinical outcomes, "with the hope that our study will actually be able to advance the field in terms of understanding what's more sensitive to detect changes over time." More of these data will be presented by Dr. Waubant at the upcoming American Neurological Association meeting next week.

Among other lessons from their study is that neuroprotection trials in MS are at least feasible, and the early stage of disease should not be "abandoned" in neuroprotection trials, she concluded. "You just have to make sure you treat with standard of care the patients to prevent exacerbations."

Nascent Field

After her presentation, session comoderator Fred Lublin, MD, Saunders Family Professor of Neurology and director of the Corrine Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center, New York City, queried Dr. Waubant about some of these other findings.

"This is a very nice study, and I think you've highlighted one of the very important issues and that's collecting lots of data, because this is a relatively nascent field for us," Dr. Lublin said. He asked whether their other analyses suggested any potential marker that might be more sensitive to change over time beyond brain volume.

The strongest correlation, she said, was between single-digit modality and SIENA measures, as well as a "reasonable correlation" between low-contrast vision and SIENA changes during that period.

"What was striking to us is that longitudinally, we were not able to detect any correlation between changes in percent brain volume and any of the components of the MSFC, which was interesting, and there was no correlation between normalized gray matter volume or normalized normal-appearing white matter with the clinical changes longitudinally," Dr. Waubant said. She added that all imaging metrics predicted clinical changes during the subsequent 3 years.

Another audience member asked whether they had considered if riluzole might have been in fact detrimental.

"Because the first data I saw were unadjusted data," she replied, "that's the first thing that came to my mind. It was actually a very interesting personal experience to see something that goes the way you don't expect it to go, and I probably would have been less anxious to see the adjusted analyses if it had been the reverse," Dr. Waubant added. In truth, though, investigators should always question whether the effects they see are real even if they appear beneficial and are adjusted for baseline differences, she said.

Because it was a small study, they could only adjust for a limited number of measures and so elected to use the main measures of atrophy and severity of disease. "Based on the data, I don't have the impression that there's a negative effect, but that's a very good question because there is a trial about to start in the UK with riluzole in secondary progressive MS, if I understand well, and that was one of my big concerns."

In an interview, Dr. Waubant added that she had hoped to present these data at ECTRIMS because the researchers associated with this new study were planning to be here. "I wanted to show them more data because I think it's important for them to see my entire set of data and decide for themselves whether they should move on with that drug or not."

This research was performed through a research grant funded by the National MS Society. Dr. Waubant reports that she has received honorarium from Roche, Sanofi-Aventis, and Genentech for 3 educational lectures and is on the advisory board for a trial of Novartis. She received free medication from Biogen Idec and Sanofi-Aventis for this trial. Sanofi-Aventis and Biogen Idec provided free riluzole, placebo, and interferon beta-1a. Dr. Waubant is also supported by the Nancy Davis Foundation, the National MS Society, and the National Institutes of Health.

29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Abstract 234. Presented October 5, 2013.


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