Fluoxetine, Riluzole or Amiloride No Benefit in Progressive MS

October 23, 2018

BERLIN — The first-ever multiarm phase 2 trial of different interventions for secondary progressive multiple sclerosis (MS) has shown no therapeutic benefit of any of the three drugs tested — fluoxetine (multiple brands), amiloride (multiple brands), or riluzole (Rilutek, Covis).

The results of the MS-SMART trial were presented at the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2018 by Jeremy Chataway, MD, Institute of Neurology, University College London, United Kingdom.

Chataway noted that the MS-SMART trial was an investigator-led project sponsored by University College London and funded by the UK Medical Research Council, the UK Multiple Sclerosis Society, and the US National Multiple Sclerosis Society.

He explained that the study had an innovative design in which several novel treatments were compared.

"This has the advantages of being efficient and cheaper than conducting three traditional clinical trials, as a shared control group can be used, more treatments can be tested with a limited set of patients, and it is more popular with patients, as there is more chance of being allocated to an active treatment," he said.

"Despite the disappointing results, the trial was successfully performed in a timely and economic fashion with excellent patient, clinician, and MS charities support and lays down a template for future work and to 'de-risk' phase 3 trials," Chataway concluded. "The results tell us a lot about the biological pathways in progressive MS. This will help researchers rule out and prioritize other drugs for future trials. By ruling out groups of drugs, we can identify which untried compounds hold the most promise for treating MS.

"MS-SMART has also shown, for the first time, that we can run effective multidrug trials for MS. This is like doing multiple phase 2 trials at the same time," he added.

Fifteen years of clinical trials have been condensed into 5 years in this trial, he pointed out.

"By being able to run more efficient trials that test many different drugs at the same time, this will also help us find treatments more quickly," Chataway said.

During the discussion period, other MS experts were enthusiastic about the trial despite its results.

Fred Lublin, MD, Mount Sinai Medical Center, New York City, described the study as having "a great innovative design," and Giancarlo Comi, MD, San Raffaele Scientific Institute at Vita-Salute, San Raffaele University, Milan, Italy, said: "This is a very important study — even negative trials provide important information."

The three drugs tested were chosen from a systematic review to identify oral putative neuroprotective drugs for secondary progressive MS.

Chataway reported that previous scientific studies had shown that the three drugs selected had potential mechanisms of neuroprotection.

"Fluoxetine stimulates glycogenolysis in astrocytes, boosting axonal metabolism against energy failure; amiloride acts as an acid-sensing ASICS1 ion channel blocker that reduces intracellular flow and accumulation of calcium; and riluzole inhibits toxic glutamate release and inactivates voltage-dependent sodium channels," he reported.

For the MS-SMART study, 445 patients with secondary progressive MS were randomly assigned to one of four arms: amiloride 5 mg twice daily; fluoxetine 20 mg twice daily; riluzole 50 mg twice daily; or placebo.

The mean age of the patients was 55 years, 67% were women, and 96% were white. The median duration of MS was 15 years, and the patients had had the secondary progressive form for a median of 6 years. The median Expanded Disability Status Scale (EDSS) score at baseline was 6.0.

Chataway said compliance was good, with 75% of patients completing the 2-year study.

The primary outcome was brain atrophy (change in brain volume) at 96 weeks. This did not differ between the four groups.

Table. Mean Percentage Brain Volume Change, 0 to 96 Weeks

Endpoint Fluoxetine Riluzole Amiloride Placebo
Mean percentage brain volume change, 0 - 96 weeks -1.42 -1.43 -1.25 -1.29
Difference vs placebo -0.12 -0.14 0.04
P value 0.86 0.77 1.00

 

There was also no difference in main secondary outcomes of number of new or enlarging T2 lesions at 96 weeks, change in EDSS scores, or any of the other clinical measures at 96 weeks.

Susan Kohlhaas, MD, director of research at the UK MS Society, one of the charities that funded the study, said: "We know this is extremely disappointing for people with progressive MS and everyone involved with the trial.

"However, we've learned a huge amount from this study, which will increase our chances of future success. We're now better placed to identify and rule out treatments that won't work and have demonstrated how to run faster, cheaper trials successfully — meaning we can test more potential drugs quicker."

34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2018. Abstract 324, presented October 12, 2018.

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