MINOCYCLINE STUDY IN ALS PATIENTS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。该项目将是一项III期、多中心、irb批准、随机、双盲、安慰剂对照的二甲胺四环素研究，在400名ALS患者中治疗9个月。研究的总时间为48个月，包括24个月的招募，4个月的连续月度评估，以确定每个受试者的基线恶化率，随后9个月的研究药物治疗和11个月的生存随访，数据分析和准备出版物。受试者将在9个月干预期的前3周接受剂量递增。主要结局指标是受试者间ALSFRS-R评分斜率的变化。次要结局指标包括通过手工肌肉测试（MMT）测量的疾病进展率、肺功能（强迫肺活量下降率，预测百分比）、生活质量和生存率（死亡率合并机械通气）的变化。在第4个月随机分为两组：在4个月的先导期后；组1（200名受试者）在9个月的干预期内给予安慰剂（与活性药物相同）；第2组（200名受试者）接受米诺环素治疗，起始剂量为100mg，每日两次，然后每周增加50mg，每日两次，直至达到最大耐受剂量或200mg，每日两次。在剂量滴定阶段的3周内，每周与受试者进行电话联系。研究药物将每4周分发一次。受试者将接受连续的每月门诊评估和实验室及不良事件分析。选择9个月的治疗期是为了充分证明治疗在减缓ALS进展方面的效果，并确保大多数受试者完成研究。将使用混合线性效应模型来测量每个终点的药物效应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The project will be a phase III, multicenter, IRB-approved, randomized, double-blind, placebo-controlled study of minocycline in 400 subjects with ALS treated for 9 months. The total length of the study is 48 months, including 24 months for recruitment, 4 months of serial monthly evaluations to determine baseline rates of deterioration for each subject, followed by 9 months on study medication and 11 months of survival follow-up, data analysis and preparation of publications. Subjects will undergo dose escalation during the first 3 weeks of the 9-month intervention period. The primary outcome measure is the change in slope of intr-subject ALSFRS-R scores. Secondary outcome measures include changes in disease progression rate as measured by manual muscle testing (MMT), pulmonary function (th rate of decline of forced vital capacity, precent predicted), QOL and survival (mortality combined with initiation of mechanical ventilation). There will be two arms with subjects randomized at month 4: after the 4 month lead in period; Group 1 (200 subjects) will receive placebo (identical to active drug) during the 9 month intervention period; Gtoup 2 (200 subjects) will receive minocycline starting at 100 mg twice daily and increasing each week by 50 mg twice daily until maximum tolerated dose or 200 mg twice daily dose is reached. Weekly phone contact will be made with subjects during the 3 weeks of the dose titration phase. The study medication will be dispensed every 4 weeks. Subject will undergo serial monthly outpatient evaluations and analysis of laboratory and adverse events. The 9 month treatment period was chosen as sufficient to demonstrate effects of treatment in slowing the progression of ALS, and to ensure that the majority of subjects complete the study. A mixed linear effect model will be used to measure the drug effect for each endpoint.