Kosa Peter, Ghazali Danish, Tanigawa Makoto, Barbour Chris, Cortese Irene, Kelley William, Snyder Blake, Ohayon Joan, Fenton Kaylan, Lehky Tanya, Wu Tianxia, Greenwood Mark, Nair Govind, Bielekova Bibiana
Neuroimmunological Diseases Unit, National Institute of Neurological Diseases and Stroke, National Institute of Health , Bethesda, MD , USA.
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.
Front Neurol. 2016 Aug 15;7:131. doi: 10.3389/fneur.2016.00131. eCollection 2016.
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.
进展性多发性硬化症（MS）的治疗进展一直非常缓慢。基于磁共振成像（MRI）对比增强病变在复发缓解型MS药物研发中所起的变革性作用，我们认为缺乏敏感的疗效指标是进展性MS新疗法开发的最大障碍。本研究的目的是在进展性MS试验的实际情况下比较58个前瞻性获得的候选疗效指标，以选择并验证表现最佳的指标。适应性设计的IPPoMS（ClinicalTrials.gov #NCT00950248）和RIVITaLISe（ClinicalTrials.gov #NCT01212094）II期试验的1年预处理期，通过比较8项临床指标、1项电生理指标、1项光学相干断层扫描指标、7项MRI体积指标、9项定量T1 MRI指标和32项扩散张量成像MRI指标，来确定后续盲法治疗阶段的主要疗效指标。在预定分析中，15项指标在1年期间显示出显著进展（Δ），其中7项在两个独立队列中得到验证。经验证的MRI指标与临床量表的相关性有限，信噪比（SNR）相对较差，并且健康受试者与中度至重度残疾的MS患者之间记录到重叠值。临床测量指标的相关性更好，尽管每个指标反映的残疾领域略有不同。因此，我们使用机器学习技术，开发了一种综合权重调整后的残疾评分（CombiWISE），它整合了四个临床量表：扩展残疾状态量表（EDSS）、斯克里普斯神经学评分量表、25英尺步行试验和9孔插针试验。CombiWISE的表现优于所有临床量表（Δ = 9.10%；p = 0.0003）和所有MRI指标。CombiWISE在健康受试者和残疾MS患者之间未记录到重叠值，具有高SNR，并且在对98例进展性MS患者的纵向评估以及303例未治疗受试者的横断面队列中预测了EDSS的变化。EDSS的1分变化平均对应CombiWISE的7.50分变化，标准误差为0.10。新的经过验证的临床疗效指标CombiWISE优于目前广泛使用的MRI脑萎缩指标，并且与传统用于监管批准的量表EDSS相比，在检测进展性MS临床恶化方面的敏感性提高了一倍多。
