背景:多发性硬化症(MS)是导致中青年残疾的主要原因,需要髓鞘修复疗法来减缓或潜在地逆转这种损伤。Bazedoxifene(BZA)是一种选择性雌激素受体调节剂,在一种新型的高通量无偏见筛选中被鉴定为其髓鞘再生潜力,其髓鞘再生作用在临床前模型中得到证实.
方法:这是一个单中心,双盲,随机化,控制,延迟启动的2期临床试验(NCT04002934)研究了BZA相对于安慰剂的髓鞘再生作用。复发缓解型MS的女性患者,年龄45-60岁(或>40,如果绝经后),和动态状态(包括EDSS0-6),将被招募到具有相同设计的两个手臂的临床试验中,除了“慢性视神经病变”组需要额外纳入先前视觉通路脱髓鞘的电生理证据标准。临床,电生理学,成像评估将在基线进行,3个月,和6个月。主要结果是MRI显示的髓磷脂水分数(MWF)在call体内的变化。次要结果是:视觉诱发电位(VEP)P100潜伏期,新的认知和活动的数字测量,和患者报告的结果。第三结果是:安全性和耐受性。
结论:BZA对髓鞘修复有很强的临床前作用,并且在普通人群中证明了治疗绝经后骨质疏松症的益处。一起,这些发现支持对MS女性进行RCT检测BZA的基本原理,评估已建立的神经影像学和神经视觉测量髓鞘修复。此外,验证新的数字工具可以提高对变化的敏感性,并为未来临床试验的持续时间和设计提供信息。
Multiple sclerosis (MS) is a major cause of disability in young and middle-aged people, and myelin repair therapies are needed to slow or potentially reverse this damage. Bazedoxifene (BZA) is a selective estrogen receptor modulator identified in a novel high-throughput unbiased screen for its remyelinating potential, and its remyelinating effects were demonstrated in pre-clinical models.
This is a single-center, double blind, randomized, controlled, delayed-start Phase 2 clinical trial (NCT04002934) investigating the remyelinating effects of BZA relative to placebo. Female patients with relapsing-remitting MS, aged 45-60 years (or > 40 if post-menopausal), and ambulatory status (EDSS 0-6 inclusive), will be recruited into a clinical trial with 2 arms of identical design, except that the \"Chronic Optic Neuropathy\" arm requires additional inclusion criteria of electrophysiological evidence of prior visual pathway demyelination. Clinical, electrophysiological, and imaging evaluations will occur at baseline, 3 months, and 6 months. The primary outcome is change in Myelin Water Fraction (MWF) on MRI within the corpus callosum. Secondary outcomes are: visual evoked potential (VEP) P100 latency, novel digital measures of cognition and activity, and patient reported outcomes. Tertiary outcomes are: safety and tolerability.
BZA has strong preclinical effects on myelin repair, and in the general population demonstrated benefits in treating postmenopausal osteoporosis. Together, these findings support the rationale for an RCT testing BZA in women with MS, evaluating established neuroimaging and neurovisual measures of myelin repair. Additionally, validating novel digital tools could increase sensitivity to change and inform the duration and design of future clinical trials.