Disability Outcome Measures in Phase III Clinical Trials in Multiple Sclerosis

The current evaluation highlights the wide range of endpoints that have been used to evaluate disability in phase III clinical trials in MS, particularly in progressive forms of the disease. As one might expect, disability measures were assessed as both primary and secondary endpoints in progressive MS trials, whereas the primary endpoint in most RRMS trials was based on the relapse rate. While entirely rational, this in itself presents a challenge in assessing treatment differences in disability progression in RRMS as trials are powered to detect differences in primary, but not secondary, endpoints. Trials including relapsing and progressive MS phenotypes have either relapses or disability progression as the primary endpoint, although one ongoing study has a composite endpoint (absence of relapses and an increase in EDSS ≤ 1) [NCT02937285].

Based on the current analysis, it is difficult to discern any evolution over time in the primary or secondary disability outcome measures used in these trials. As found in the previous review by Lavery et al. [20], sustained EDSS worsening, particularly over 3 months, is widely used and was included as an endpoint in almost all of the trials identified, including those that are ongoing. This is interesting as it has been shown that short-term changes in EDSS do not correctly identify patients with truly irreversible disability progression. For example, in a trial of 929 patients with RRMS or clinically isolated syndrome, sustained progression was maintained (over a mean follow-up of 45 months) in fewer than 50% of those meeting the initial criteria for EDSS progression (mainly over 6 months) [62]. In another trial, which included data from over 16,000 patients, approximately 70% of patients with EDSS worsening over 3 or 6 months had sustained disability over 5 years; this increased to 80 and 89% when the criteria were changed to EDSS worsening over 12 and 24 months, respectively [63]. In this context, it is interesting that in the CONCERTO trial [64], one of the endpoints was the EDSS progression over 9 months, the longest time period reported in any of the trials included in the current evaluation. Although the issue of using short-term EDSS changes is particularly pertinent to relapsing MS (in view of the potential confounding effects of transient, relapse-related neurological impairment), it is also recognised that the EDSS has limited ability to detect clinically relevant disability progression in progressive MS [65]. In a recent analysis of data from the placebo arm of the PROMiSe trial, which was conducted in patients with primary progressive MS [49], sustained (3-month) worsening of the EDSS was less sensitive to disability progression than sustained (3-month) changes in the T25FW (≥ 20% increase) or composite measures (EDSS or T25FW; EDSS or 9HPT [≥ 20% increase]; EDSS, T25FW or 9HPT). The authors concluded that T25FW or composite measures should be considered as the primary endpoint for future studies of new disease-modifying therapies [66].

Despite its limitations, the EDSS is the only disability outcome measure currently advocated by the European Medicines Agency (EMA) for trials in MS [67]. More specifically, the EMA advises that the mean change in EDSS score from baseline is not appropriate and that sustained worsening of a relevant magnitude over a prespecified timeframe should be used. This undoubtedly explains, at least in part, the persistent use of sustained EDSS worsening over 3 or 6 months in the trials identified as part of the current evaluation. However, the EMA does acknowledge that there is a need for alternative measures (see below for information on the Multiple Sclerosis Outcome Assessments Consortium [68, 69]), and research in this area has been active for many years. The MSFC was first introduced almost 20 years ago to address some of the limitations of the EDSS [17], and a recent meta-analysis has shown it to be more sensitive than the EDSS for detecting progression of MS [70]. The MSFC was included in over half (9/16) of the phase III RRMS trials identified in the current evaluation, although it was a primary endpoint in only one [43]. Perhaps surprisingly, the MSFC was used in only 5/20 phase III trials (25%) in progressive MS. Two factors that may have limited the use of the MSFC are lack of clarity (until relatively recently, at least [15, 16]) on the magnitude of clinically significant changes for the three component tests [12] and patients’ dislike of the PASAT (used to assess cognition) [15, 16]. The major issue is probably the lack of acceptance by regulatory agencies, which is most likely driven by the poor clinical interpretability of the overall score [12]. Other approaches taken to improve on disability assessment include development of the EDSS-Plus, which includes the EDSS and the 9HPT and T25FW [71], and use of a roving versus fixed reference value [72].

Among the trials identified in the current evaluation, some included secondary outcomes to assess manual dexterity and cognition, aspects of disability progression that are not evaluated by the EDSS. Some also included separate measures of ambulation, one of the most valued functions for patients with MS [15]. Although the data obtained for these endpoints are informative, as discussed above, trials are designed and specifically powered to detect statistical treatment differences in primary endpoints, but not necessarily in secondary endpoints.

Other pertinent observations include the use, in some trials, of composite endpoints to assess disability progression. These include a single composite score of five component measures [44], as well as endpoints for which patients only had to satisfy one of two or more criteria to be classified as progressors (e.g. increase in EDSS score or ≥ 20% worsening on the 9HPT) [46, 54]. Interestingly, when testing the EDSS-Plus (see above), it was observed that defining progression on at least one of three components (EDSS, T25FW or 9HPT) identified 60% of patients as progressors, compared with 25, 42 and 34%, respectively, when using the individual tests alone [71].

The inclusion of endpoints to evaluate disability improvement is also pivotal as it marks the start of a shift in the goals for treating MS, from limiting disability progression to reversing it, using not only agents aimed at halting disease activity but also interventions intended to repair and remyelinate [73]. However, use of the EDSS to assess disability improvement is subject to the same limitations as its use to assess disability progression, and discussions regarding more appropriate endpoints to measure improvement have already started [74]. Another advance in the assessment of disability in MS is the possibility of measuring physical activity and ambulation remotely [75, 76]. The feasibility of remote evaluation of cognitive and patient-reported outcomes in MS has also been assessed [77‐79].

One of the potential limitations of the current evaluation was the use of PubMed to identify phase III MS trials, thus relying on inclusion of the term ‘phase 3’ (or ‘phase III’) in the abstract or Medical Subject Heading (MeSH) terms; however, the bibliographies of review articles on the treatment of MS were also screened to address this. Another limitation, in the context of assessing the evolution of disability outcome measures over time, is that it was not possible to ascertain the start date for all of the trials in progressive MS. The evaluation was therefore conducted according to the trial publication date, which may not truly reflect the chronology of the trials. Nevertheless, it gives a general overview of disability-related outcomes assessed in phase III trials, adding to that provided by Lavery et al. in trials of RRMS [20], and providing useful information on progressive MS trials conducted over the last 20 years.

The need for improved disability outcome measures is recognised by the wider MS community. The international MS Outcome Assessments Consortium was set up to develop a tool set for use in MS clinical trials that can detect the benefit of potential treatments that slow or reverse progressive disability, and is recognised as a primary outcome measure by regulatory authorities [68, 69, 80]. The consortium, which includes representatives from academic institutions, pharmaceutical companies, the EMA, US FDA and National Institutes for Health, recently published four papers reviewing the evidence for the validity of four outcome measures: the T25FW, the 9HPT, the Symbol Digit Modalities Test (SDMT) and the Low-Contrast Visual Acuity Test (LCVA), suggesting that these scales will be included in the final tool set [15, 16, 81, 82]. These scales assess ambulation, manual dexterity, cognition and vision, respectively, as impairments to these functions represent core symptoms in MS [81]. The SDMT was selected to measure cognition rather than the PASAT (which is part of the MSFC) as it has shown superior reliability and sensitivity and greater patient acceptability [82]. With regard to visual function, which is not captured by the MSFC, LCVA was selected as it captures visual loss not identified using high-contrast visual acuity tests [81]. The four manuscripts also include information on the magnitude of clinically meaningful changes (T25FW, ≥ 20%; 9HPT, ≥ 20%; SDMT, ≥ 4 points or ≥ 10%; LCVA, ≥ 7%) based on published data [15, 16, 81, 82].