Multiarm Trial Fails at SPMS Treatment, But Shows New Way Forward for Studies
A clinical trial testing Midamor (amiloride), Prozac (fluoxetine), and riluzole in people with secondary progressive multiple sclerosis (SPMS) failed to find a treatment benefit for any of the medications.
Despite these negative results, this study demonstrates the feasibility of testing multiple potential treatments in the same trial, which could allow for future trials that are more quick and efficient than traditional single-treatment studies.
The results were published in the journal The Lancet Neurology, in the study “Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial.”
Randomized clinical trials typically compare the safety and/or effectiveness of a single medication to a placebo. This means that substantial resources — including personnel, equipment, time, and trial participants themselves — are necessary in order to test a single potential treatment.
Oncology research has pioneered the use of multiarm clinical trials, or trials with one placebo group and multiple different treatment groups. Although this strategy requires more resources than a single-arm trial, on a per-medication basis, it cuts down on overall resources required. This multiarm strategy has never before been applied in the context of neurodegenerative diseases.
The Phase 2 MS-SMART clinical trial (NCT01910259) tested the safety and efficacy of Midamor, Prozac, and riluzole in people with SPMS at 13 clinical neuroscience centers in the U.K. These three medications are all approved for other conditions, and they were chosen for this trial because previous data suggested they could promote the growth of axons (neuronal projections that are damaged in MS) and reduce the development of new brain lesions.
The study reports results from 393 participants who were randomly assigned to one of four groups — each of the three treatments and a placebo. The Prozac group had 96 patients, while the other three groups had 99 patients each. Trial participants had a mean age of 55, and about two-thirds were female. All enrolled were not using a disease-modifying therapy, and their Expanded Disability Status Scale (EDSS) scores ranged from 4.0 to 6.5, indicating notable to significant disability. They were treated for 96 weeks (about two years).
To ensure trial integrity, all three treatments and the placebo were delivered as identical pills.
The main efficacy measure was the change in brain volume from the trial’s start to its end, “which is the standard primary outcome in phase 2 trials in progressive multiple sclerosis,” the researchers wrote.
After 96 weeks, no significant differences in brain volume were between any of the treatment and placebo groups. Most secondary endpoints, such as the time to first relapse, also showed no significant differences between treatments and placebo.
“Secondary outcomes accord with insufficient evidence of therapeutic effect,” the researchers wrote.
Prozac treatment resulted in significant improvements in two secondary endpoints: brain volume change after 24 weeks, and the occurrence of new or enlarging T2 lesions (which represent damage to the brain). However, these results “should be interpreted with caution” as “these outcomes were secondary outcomes and the number of participants developing new or enlarging T2 lesion was, overall, low,” the team noted.
No new safety concerns related to the studied treatments were identified. There were three deaths during the study, but none were deemed related to treatments given.
Taken together, these “results do not support the effectiveness of amiloride, fluoxetine, and riluzole in reducing disease progression for secondary progressive multiple sclerosis, and they indicate that exclusive targeting of axonal pathobiology is an inadequate strategy to achieve neuroprotection in progressive disease,” the researchers concluded.
“Sadly, the results came back negative,” Ferran Prados, PhD, a professor at Universitat Oberta de Catalunya in Spain and a study co-author, said in a press release. “The disease continues to be more aggressive than any available treatment. We must trudge forward.”
Nonetheless, the team stressed that the fact that the trial analyzed three treatments simultaneously and provided meaningful results is a promising step forward for MS clinical trials in general.
“We have shown that a multiarm approach can be used successfully to expedite drug discovery in patients with progressive multiple sclerosis,” the researchers wrote. “Such trial designs will be highly relevant to future therapeutic development in brain medicine in general.”
The multiarm approach “had never been tested on treatments for neurodegenerative diseases,” Prados added. “It has created an entirely new paradigm in which lowered costs make trials more viable. We’re witnessing the future of clinical testing.”