A literature review evaluated phase 3 trials in patients with secondary progressive multiple sclerosis, including trials dating back to 1990, to establish the most important measures used.
A recent literature review concluded that primary outcome measures for patients with secondary progressive multiple sclerosis (SPMS) in phase 3 trials are time to confirmed disability at 3 months, and changes in Multiple Sclerosis Functional Composite (MSFC) score, as its variables may be more sensitive progressive disease changes. Appropriate secondary measures were identified as specific patient reported outcomes (PROs) and MRI measures related to brain parenchymal volume, which have recently been used in phase 3 trials.1
Corresponding author Tanuja Chitnis, MD, associate neurologist, Brigham and Women’s Hospital, and professor of neurology, Harvard Medical School, and colleagues performed a literature review of clinical trials since 1990, using the search terms SPMS and progressive MS, only including phase 3 trials studying patients with SPMS. Investigators concluded that the most successful of these trials ranged in length from 12 to 36 months, most frequently 24 months. Success trials had an average age range of 40.9 to 48.1 years, with unsuccessful trials including patients ranging in age from 42.7 to 52.3 years.
The most used outcome measure was the Expanded Disability Status Scale (EDSS), employed by 16 out of 17 trials, and time to confirmed disability at 3 months was the most frequently successful, as 3 out of 6 trials that used it as the primary outcome were positive. No positive trials were found when using time to confirmed disability at 6 months by EDSS, which was the second most used primary outcome, employed in 5 trials. Of the 2 trials that used mean change in EDSS from baseline at final evaluation, 1 was positive.
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Additional primary outcome measures included proportion of patients with disability improvement at 9 months and confirmed at 12 months by EDSS in an initial high-dose biotin trial (positive); time to at 4 months by EDSS (negative); and proportion of patients with disability by EDSS at 96 weeks (not positive).
When attempting to address disability worsening when transitioning to cane use in progressive patients, some trials used objective measures of the MSFC or a subcomponent, as the EDSS is not as capable of detecting worsening disability during this period of transition. In particular, the IMPACT trial evaluated baseline to 24-month change in the MSFC, with subset scores in the time 25-foot walk (T25FW), 9-hole peg test (9HPT), and pace auditory serial addition test (PASAT).2
The IMPACT trial saw changes in 9HPT and PASAT led to a positive primary outcome, but investigators noted its overall older participants that had low or no relapse rates prior to the trial with no effect on annualized relapse rate, which may indicate that affect as only on progression of independent relapse. IMPACT’s secondary outcome was time to at 3 months, which was negative, leading investigators to conclude that the variables associated with MSFC may be more sensitive to changes in the EDSS.
PROs were found to be promising for measuring progressive disease and suggested as the “best” option for future phase 3 trials for SPMS, although investigators were unable to confirm the most reliable, as some, namely the Health-Related Quality of Life inventory, clinical global impression scale, and the patient-assessed clinical global impression scale, have only been used once.
Investigators further concluded that using MRIs to observe progressive outcomes rather than lesions, looking at changes in brain parenchymal volume, using thalamic atrophy as a marker of progression, and SWI weighted MRI sequences should all be included in future trials. “Overall, there remains a need for development of new reliable clinical, biomarkers, and MRI measures of disability progression and improvement,” Chitnis et al wrote.
Uncertainty associated with SPMS diagnosis may have affected patient selection for trials and resultant success, Chitnis et al wrote. Additionally, trials prior to 2004 did not have the more standardized EDSS with NeuroStatus.
“Take-home points of this analysis suggest using changes to the composite MSFC or CDP at 3 months in future phase 3 trial design, with data suggesting MSFC is more sensitive to changes in progression,” Chitnis et al wrote. “This sensitivity to change may not be clinically relevant and the magnitude of these outcomes should be considered in implementing these medications in clinic.”