PHASE II STUDY OF HU23F2G IN ACUTE EXCERBATIONS OF MULTIPLE SCLEROSIS

多中心研究计划共纳入188例患者。 在招募后，患者将被随机分配到四个治疗组之一：安慰剂、甲泼尼龙1克，每天IV持续3天、Hu23F2G 1 mg/kg IV或Hu23F2G 2 mg/kg IV。受试者将在治疗后随访1年，以评估与急性加重（第0天至第90天）以及后续病程（第91天至第365天）相关的早期变化。 将通过神经系统检查表测量对治疗的临床反应，其中得出三个数值评分：Scripps评分、功能系统（FS）总和和改良扩展残疾状态量表（EDSS）。 主要终点为第0天至第90天Scripps评分的变化。 选择Scripps评分作为主要结局指标，因为我们假设它对急性加重环境的变化比其他两个评分更敏感。第0天至第90天FS和EDSS总和的变化将作为次要终点。 将在给药前和第5天进行脑部MRI检查。 第0天至第5天MRI检测到的异常程度变化将作为次要终点。 由于糖皮质激素补救治疗可用于被认为分配治疗失败的患者，因此至糖皮质激素补救治疗的时间将是次要终点。 将通过确定至下一次急性加重的时间和第365天的EDSS来评估治疗后一年内的临床病程;这些参数也将是次要终点。 Hu23F2G在实验性变态反应性脑脊髓炎（EAE）的非人灵长类动物模型中的体外生物活性和体内功效支持在MS治疗中的潜在应用。MS的急性加重组分将根据本方案进行研究。基本原理是EAE模型与神经功能缺损急性发作和中枢神经系统（CNS）新发病变相关，这些事件类似于急性MS加重。在急性加重的情况下，通常提供的治疗是三到五天的皮质类固醇。 该治疗持续时间与1期研究中单次IV给药1至2 mg/kg Hu23F2G后观察到的最大药效学效应的持续时间相当。由于皮质类固醇疗法目前用于许多患有急性加重的患者，因此在本研究中，将Hu23 F2 G治疗的效果与标准皮质类固醇方案沿着安慰剂进行比较。 皮质类固醇治疗也将适用于被认为分配治疗失败的患者。

A total of 188 patients are planned for the multi-center study. Upon enrollment, patients will be randomly assigned to one of four treatment group: placebo, methylprednisolone 1 gram IV daily for 3 days, Hu23F2G 1 mg/kg IV, or Hu23F2G 2 mg/kg IV. The subjects will be followed for one year after treatment in order to assess the early changes related to the acute exacerbation (Day 0 to Day 90) as well as the subsequent course (Day 91 to Day 365). The clinical response to treatment will be measured by a neurologic examination form which three numerical scores are derived: the Scripps score, the sum of the Functional System (FS), and modified Expanded Disability Status Scale (EDSS). The primary endpoint will be the change in Scripps score form Day 0 through Day 90. The Scripps score was selected as the primary outcome measure because we hypothesize that it will be more sensitive to change in the setting of an acute exacerbation than the other two scores. The change in the sum of the FS and EDSS form Day 0 through Day 90 will be secondary endpoints. MRI of the brain will be obtained prior to treatment and on Day 5. The change in the extent of abnormalities detected on the MRI form Day 0 to Day 5 will be a secondary endpoint. Since corticosteroid rescue will be available for patients deemed to have failed the assigned treatment, the time to corticosteroid rescue will be a secondary endpoint. The clinical course over the year following treatment will be assessed by determining the time to the next exacerbation and the EDSS on Day 365; these parameters will also be secondary endpoints. The in vitro biologic activity and in vivo efficacy of Hu23F2G in a nonhuman primate model of experimental allergic encephalomyelitis (EAE) support a potential application in the treatment of MS. The acute exacerbation component of MS will be studied under this protocol. The rationale is that the EAE model is associated with acute onset of neurologic deficits and new lesions in the central nervous system (CNS), events that are analogous to the acute MS exacerbation. In the acute exacerbation setting, a treatment commonly offered is three to five days of corticosteroids. This treatment duration is comparable to the duration of maximal pharmacodynamic effects observed after a single IV dose of 1 to 2 mg/kg of Hu23F2G in Phase 1 studies. Since corticosteroids therapy is currently used for many patients with acute exacerbations, in this study the effects of Hu23F2G treatment will be compared to a standard corticosteroid regimen along with placebo. Corticosteroid therapy will also be available for patients deemed to have failed the assigned treatment.