Abstract
Therapeutic advance in progressive multiple sclerosis (MS) has been very slow. Based on the transformative role magnetic resonance imaging (MRI) contrast-enhancing lesions had on drug development for relapsing-remitting MS, we consider the lack of sensitive outcomes to be the greatest barrier for developing new treatments for progressive MS. The purpose of this study was to compare 58 prospectively acquired candidate outcomes in the real-world situation of progressive MS trials to select and validate the best-performing outcome. The 1-year pre-treatment period of adaptively designed IPPoMS (ClinicalTrials.gov #NCT00950248) and RIVITaLISe (ClinicalTrials.gov #NCT01212094) Phase II trials served to determine the primary outcome for the subsequent blinded treatment phase by comparing 8 clinical, 1 electrophysiological, 1 optical coherence tomography, 7 MRI volumetric, 9 quantitative T1 MRI, and 32 diffusion tensor imaging MRI outcomes. Fifteen outcomes demonstrated significant progression over 1 year (Δ) in the predetermined analysis and seven out of these were validated in two independent cohorts. Validated MRI outcomes had limited correlations with clinical scales, relatively poor signal-to-noise ratios (SNR) and recorded overlapping values between healthy subjects and MS patients with moderate-severe disability. Clinical measures correlated better, even though each reflects a somewhat different disability domain. Therefore, using machine-learning techniques, we developed a combinatorial weight-adjusted disability score (CombiWISE) that integrates four clinical scales: expanded disability status scale (EDSS), Scripps neurological rating scale, 25 foot walk and 9 hole peg test. CombiWISE outperformed all clinical scales (Δ = 9.10%; p = 0.0003) and all MRI outcomes. CombiWISE recorded no overlapping values between healthy subjects and disabled MS patients, had high SNR, and predicted changes in EDSS in a longitudinal assessment of 98 progressive MS patients and in a cross-sectional cohort of 303 untreated subjects. One point change in EDSS corresponds on average to 7.50 point change in CombiWISE with a standard error of 0.10. The novel validated clinical outcome, CombiWISE, outperforms the current broadly utilized MRI brain atrophy outcome and more than doubles sensitivity in detecting clinical deterioration in progressive MS in comparison to the scale traditionally used for regulatory approval, EDSS.
Highlights
Therapeutic progress in relapsing-remitting multiple sclerosis (RRMS) has been facilitated by the recognition that contrastenhancing lesions (CELs) on brain magnetic resonance imaging (MRI) can serve as a predictive marker of multiple sclerosis (MS) relapses
While at any given time, multiple candidate therapies are available, the present bottleneck resides in the inability to screen them in small, but adequately powered, Phase II trials that can correctly predict efficacy on FDA-accepted clinical endpoint utilized for Phase III trials
This study provides a comprehensive comparison of outcomes in the same patient group(s) within a real-world situation of Phase II clinical trials
Summary
Therapeutic progress in relapsing-remitting multiple sclerosis (RRMS) has been facilitated by the recognition that contrastenhancing lesions (CELs) on brain magnetic resonance imaging (MRI) can serve as a predictive marker of multiple sclerosis (MS) relapses. Utilizing this outcome allowed rapid, inexpensive screening of candidate agents. In contrast to RRMS, therapeutic development for progressive MS patients, who have few CELs and MS relapses, has been extremely slow These patients relentlessly accumulate neurological disability, albeit at a pace that requires observation of hundreds of patients for a minimum of 2–3 years to reliably detect moderate (30–50%) therapeutic effects using the expanded disability status scale (EDSS) [1]. We integrated systematic comparisons of clinical, electrophysiological, optical coherence tomography (OCT) and a large number of qMRI measures as an adaptive part of the IPPoMS (double-blind, placebo-controlled Phase I/II clinical trial of Idebenone in patients with Primary Progressive Multiple Sclerosis; NCT00950248) and RIVITaLISe (Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low-Inflammatory Secondary Progressive Multiple Sclerosis; NCT01212094) clinical trials and present the results
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