What is known about chronic inflammatory demyelinating polyradiculoneuropathy, a neurological disorder marked by by progressive weakness and impaired sensory function in the extremeties?
Oral fingolimod is no better than placebo for treating chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), according to results from a multinational randomized controlled trial (RCT).1 “There is no evidence from randomised controlled trials that any immunomodulatory treatments other than corticosteroids, intravenous or subcutaneous immunoglobulin, and plasma exchange are beneficial in CIDP,” wrote first author Richard Hughes, MD, of National Hospital for Neurology and Neurosurgery, London, UK, and colleagues.
CIDP refers to a group of rare neurological diseases that affect the peripheral nervous system. Although the cause has yet to be definitively established, CIDP is thought to result from an autoimmune process that causes the myelin sheath around nerves to degenerate, causing weakness, numbness and tingling of the extremities. In severe cases, CIDP can interfere with mobility.
Recommended first-line treatments for CIDP are generally effective and include corticosteroids or intravenous immunoglobulin (IVIg), and plasma exchange if these fail. However, not all patients respond adequately, and side effects as well as cost can limit their use. Other immunosuppressive and immunomodulatory agents are sometimes used in CIDP, but no formal evidence supports their efficacy.
Oral fingolimod is approved for treating relapsing-remitting multiple sclerosis, another inflammatory demyelinating disorder of the nervous system. Studies in rats have suggested that the drug may be a candidate for treating CIDP.
To test oral fingolimod in humans, researchers conducted a double-blind, randomized placebo-controlled trial in 48 neurology centers in Australia, Canada, Israel, Japan, the USA and nine countries in Europe between January 2013 and March 2016. Researchers randomized 106 participants who were already being treating with corticosteroids or IVIg to once daily fingolimod (0.5 mg, n=54) or placebo (n=52). Participants either discontinued IVIg treatment one day before receiving the study drug or underwent an eight-week steroid taper after randomization.
The primary endpoint was time to first worsening, defined as ≥ 1 point increase on the standardized Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale score.
In March 2016 the trial was stopped early for futility, after an interim analysis confirmed 44 worsening events. Participants had been on the study drug for a mean time of 9.0 months with oral fingolimod and 9.7 months with placebo.
Estimates showed that confirmed worsening of neurological symptoms was the same for fingolimod vs placebo (42% vs 43%, p=0.91). Further analyses showed that length of time to first worsening was also the same for both groups (HR 1.0, p=0·98).
Seventy-six percent (n=41) of participants on oral fingolimod experienced adverse events, compared to 85% (n=44) on placebo. Serious adverse events occurred in 17% (n=9) on fingolimod and 8% (n=4) on placebo.
The authors mentioned that abruptly stopping IVIg could have caused some patients to relapse, which may have affected results. In fact, the group that underwent a slow steroid taper did show better results with oral fingolomod than with placebo, but these did not reach statistical significance. However, the authors noted reluctance to draw conclusions based on small numbers of participants in the study.
Other limitations stem from the challenges of conducting an RCT in a rare disease like CIDP, which made it difficult to recruit sufficient numbers of participants. Investigators were also reluctant to discontinue active therapies known to be effective for a trial of a drug with unknown efficacy.
“Randomised controlled trials of new treatments in CIDP patients must overcome multiple methodological problems in this rare and heterogeneous disease for which there are known effective treatments,” the authors concluded.
Take home points
• Multinational RCT of oral fingolimod in the treatment of CIDP was stopped for futility when interim results showed worsening of symptoms was no different for oral fingolomod vs placebo
• Results highlight the challenges of conducting an RCT for new treatments of rare diseases like CIDP
1. Hughes R, Dalakas MC2, Merkies I, et al. Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): a double-blind, multicentre, randomised controlled trial. Lancet Neurol. 2018;17:689-698.