Confirmed disability progression is often used as a study endpoint to predict progression, but a new report says its predictive value may be overblown.
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A new analysis suggests a common measure of multiple sclerosis (MS) progression may not be as meaningful as previously thought.
The report calls into question the use of confirmed disability progression (CDP) in clinical trials for MS, finding that while CDP at 24 months (CDP24) might initially appear to be predictive of subsequent disability accumulation, that predictive correlation does not hold up under scrutiny.
“Overall, we show that CDP24 progression provides limited predictive power regarding subsequent disability accumulation in participants with MS based on 3 different outcome measures,” wrote corresponding author Brian C. Healy, PhD, of Brigham and Women’s Hospital. “Alternative measures of disability provide more information regarding subsequent disease course.”
The study was published in Multiple Sclerosis Journal – Experimental, Translational, and Clinical.
The investigators began by explaining the difficulties of the standard measure of disability accumulation in MS, known as the Expanded Disability Status Scale (EDSS). They noted that the scale uses 7 functional system scores to quantify patient disability on an ordinal scale of 0-10.
“Given the ordinal nature of the EDSS, simple analysis of change scores can be challenging because a change in 1 unit reflects a different amount of disability accumulation depending on initial level of the scale, and the time between EDSS transitions varies based on initial EDSS level,” they said.
Many clinical trials attempt to account for the problem of EDSS scores by instead using CDP, which is defined by a patient achieving and maintaining a particular change in EDSS scores for 3 or 6 months. The change required to meet CDP depends on the patient’s initial EDSS score. For instance, a patient who has a baseline EDSS score of 0 will reach CDP if he or she maintains a change of at least 1.5 points for the specified time period. However, a patient with an EDSS score of at least 5.5 can reach CDP if he or she maintains just a half-point EDSS change over time.
Yet, while CDP is commonly used, Healy and colleagues said it is not yet clear how closely CDP actually correlates with long-term outcomes.
To study the question, the authors used the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women’s Hospital. They identified 1214 patients who had either relapsing-remitting MS or clinically isolated syndrome and EDSS scores of 5 or less. A total of 120 patients in the cohort experienced CDP24. The investigators used CDP to predict time to EDSS score 6 or to secondary progressive MS (SPMS). Those results seemed to affirm CDP.
“CDP was directionally associated with faster time to EDSS 6 in univariate analysis (HR = 1.61 [95% CI: 0.83, 3.13]),” they wrote.
However, when they adjusted for 24-month EDSS, the opposite finding occurred. CDP was directionally associated with slower time to EDSS 6 (adjusted HR = 0.65 [0.32, 1.28]).
“Models including CDP had worse fit statistics than those using EDSS scores without CDP,” Healy and colleagues said. “When models included clinical and magnetic resonance imaging measures, T2 lesion volume improved fit statistics.”
Results were similar for time to SPMS, though CDP24 was found to have a stronger association to SPMS than EDSS6, though the investigators said that could have to do with variance among physicians’ diagnoses due to the uncertain clinical definition of SPMS.
“Although CDP24 identifies patients who have experienced disability accumulation, our results may show that MS in patients who experience CDP24 may not be progressive, given the limited predictive information CDP24 provides in the presence of EDSS,” Healy and colleagues wrote.
They said other recent work suggests there are better measures of disease progression, such as the timed 25-foot walk or the 9-hole peg test.
Reference
Healy BC, Glanz BI, Swallow E, et al. Confirmed disability progression provides limited predictive information regarding future disease progression in multiple sclerosis. Mult Scler J Exp Transl Clin. 2021;7(2):2055217321999070. doi:10.1177/2055217321999070