title: Development of a Sensitive Outcome for Economical Drug Screening for Progressive Multiple Sclerosis Treatment.
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.
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
authors: Peter
authors: P
authors: Kosa
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
authors: Danish
authors: D
authors: Ghazali
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
authors: Makoto
authors: M
authors: Tanigawa
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Diseases and Stroke, National Institute of Health, Bethesda, MD, USA; Department of Mathematical Sciences, Montana State University, Bozeman, MT, USA.
authors: Chris
authors: C
authors: Barbour
authors: Neuroimmunology Clinic, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
authors: Irene
authors: I
authors: Cortese
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
authors: William
authors: W
authors: Kelley
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
authors: Blake
authors: B
authors: Snyder
authors: Neuroimmunology Clinic, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
authors: Joan
authors: J
authors: Ohayon
authors: Neuroimmunology Clinic, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
authors: Kaylan
authors: K
authors: Fenton
authors: EMG Section, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
authors: Tanya
authors: T
authors: Lehky
authors: Clinical Trials Unit, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
authors: Tianxia
authors: T
authors: Wu
authors: Department of Mathematical Sciences, Montana State University , Bozeman, MT , USA.
authors: Mark
authors: M
authors: Greenwood
authors: Neuroimmunology Clinic, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
authors: Govind
authors: G
authors: Nair
authors: Neuroimmunological Diseases Unit, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
authors: Bibiana
authors: B
authors: Bielekova
keywords: clinical trial; composite scale; disability scale; multiple sclerosis; outcome measure; progressive MS; quantitative MRI