EDSS variability before randomization may limit treatment discovery in primary progressive MS

Genentech Inc., USA.
Multiple Sclerosis (Impact Factor: 4.82). 10/2012; 19(6). DOI: 10.1177/1352458512459685
Source: PubMed


Baseline Expanded Disability Status Scale (EDSS) is usually based on a single measurement. Here we evaluated whether using a baseline EDSS derived from two pre-treatment measurements improves the detection of progression events and the ability to demonstrate a therapeutic effect in delaying MS disability progression.

Real data from OLYMPUS, a phase II/III randomized, placebo-controlled trial of rituximab in patients with primary progressive multiple sclerosis (PPMS), as well as simulated data were analyzed. Several definitions of baseline EDSS were used to capture sustained disability progression (SDP) events. Variations in the EDSS were estimated by linear mixed-effect models.

Selecting the higher of two baseline EDSS scores lowered the number of SDP events in both treatment groups, so decreasing sensitivity, and reduced the number of false SDP events, so increasing specificity. Conversely, selecting the lower of two baseline scores increased sensitivity but decreased specificity. Increased power (~7% based on the simulation study) was observed when the average of screening and Week 0 EDSS scores was used for baseline.

Baseline EDSS derived from two pre-treatment EDSS measurements may enhance the ability of detecting a therapeutic effect in slowing disability progression in PPMS. This strategy could be implemented in future clinical trials of patients with MS.

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    • "In addition, the EDSS changes little over time in most patients, indicating low sensitivity for detecting treatmentrelated changes in disability during clinical trials (Rabadi and Vincent, 2013; Zhang et al., 2013), although administering two EDSS tests before treatment has been shown to improve the ability of the EDSS to detect such changes (Zhang et al., 2013). Substantial inter-operator variability in EDSS measurements has also been proposed as an important limitation of this test, with one group suggesting that a change in EDSS score of at least 1 unit (2 scale steps) is required to signify a reliable measurement of change in disability status (Noseworthy et al., 1990). "
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