One is that researchers still have a lot to learn about what exactly goes wrong in progressive MS. After all, keep in mind that the diagnosis of any form of MS is still a clinical diagnosis, meaning the doctor (or “clinician”) must rely on signs and symptoms, bolstered by imaging or lab tests, to make a diagnosis. Another is that researchers are still working on establishing what biomarkers — or observable signs — indicate that a potential treatment has benefits. The two clinical trials described here are just two examples of progress being made in the study of progressive forms of MS and their treatment.
Choosing the Right Endpoints Makes a Difference
It’s been over three years since a paper I coauthored was published in The New England Journal of Medicine (NEJM), in August 2018. The paper summed up the results of an innovative study of a drug — ibudilast — for potential use as a disease-modifying therapy (DMT) for progressive forms of multiple sclerosis (MS). Individuals with both primary-progressive MS (PPMS) and secondary-progressive (SPMS) were enrolled in the trial. As the patient advocate on that study, it was important to me that we not only studied the medication in question but, as trials for progressive MS were relatively new, that we also lay out new primary endpoints to help researchers define success in MS trials. The standard endpoints for successful results in relapsing forms of MS — such as a reduced number of relapses — are not suitable for progressive trials. Instead, this trial focused on the rate of brain atrophy, or shrinkage. The study I contributed to concluded that “ibudilast was associated with slower progression of brain atrophy” but had a higher incidence of some side effects than placebo. A secondary analysis of the study, published in January 2021 in Neurology, concluded that “Ibudilast treatment was associated with a reduction in gray matter atrophy,” but it “was not associated with a reduction in new or enlarging T2 lesions or new T1 lesions.” (Both brain atrophy and lesions in the brain and spinal cord lead to MS symptoms.)
Novel Study Design Moves Research Along Faster
A study of a repurposed drug therapy — in this case, domperidone — for secondary-progressive MS was published in the journal Neurology in May 2021. The drug failed to meet the desired endpoint results, but the design of the study has many in the MS research world excited about that aspect of the study. This study used what is known as Simon’s 2-stage design. It’s a system of study review that allows investigators to stop the trial when “futility” is apparent. In other words, if the drug shows no benefit, stop the study. This type of trial study design is popular in the cancer research sphere, where many drugs proven safe and effective in one type of cancer are trialed in other cancers. According to Robert Fox, MD, who was the lead investigator in the NEJM study, and who coauthored an editorial about the Neurology study, “Simon design efficiently screens treatments using an initial futility study.” He also pointed out that this was the first time a Simon study was used in MS, saying, “Two-stage designs have been used in a handful of neurology trials, such as stroke and Parkinson’s disease; however, their usefulness in neurologic disorders remains relatively unknown.”
How Simon 2-Stage Design Differs From 3-Phase Studies
Drug trials start with a phase 1 study, in which a safe dose of the drug is established in a few dozen people. In phase 2, the medication is tried by up to several hundred people to see whether the drug has benefits that outweigh its side effects. In phase 3, the drug is tested on hundreds or thousands of volunteers for both benefits and side effects. But when studying treatments for progressive MS, the observed benefits needed to move from phase 2 to phase 3 can be difficult to lay out and observe. With the Simon 2-stage design, phase 2 is divided into phase 2a and 2b. If futility is apparent in 2a (meaning the drug does not produce the desired results), the study can be stopped, and we all move on. If the drug proves nonfutile (meaning it does appear beneficial), then phase 2b ensues. It may seem like an extra step, but in the end, it moves things along faster and more efficiently for researchers.
More and Faster ‘Nos’ Lead More Quickly to ‘Yes’
Just as the Apollo 13 mission — which had to be aborted after an oxygen tank exploded — was hailed in retrospect as a “successful failure” (for the experience gained in rescuing the crew), so, too, might this study’s failure to show the tested drug to be beneficial be counted as a success for leading to faster and earlier decisions on futility. Stopping work on a study that is not reaching its endpoints frees up investigators and research funding to move on to the next potentially disease-altering medication for those of us with progressive MS. So I toast the failure of this particular drug, because the design the investigators chose to use will help say “no” faster, and only by saying a good few “nos” will we get to the next “yes.” Wishing you and your family the best of health. Cheers, Trevis
