MULTI-CENTER STUDY OF MINOCYCLINE IN ALS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。目的：确定米诺环素是否延缓ALS患者整体功能的进行性恶化。主要结果衡量标准是服用米诺环素的患者与服用安慰剂的患者相比，ALSFRS-R检测到的功能改变。次要结果指标是手动肌肉测试(MMT)、用力肺活量(FVC，预测百分比)、生活质量(QOL)和存活率的变化。研究计划：第三阶段，多中心、随机、双盲的米诺环素安慰剂对照试验，400名受试者治疗9个月。方法：总研究时间为48个月：24个月的患者招募，4个月的连续月度评估，以确定每个患者的基线进展斜率，然后是9个月的干预(米诺环素或安慰剂)，以及另外11个月的生存随访、数据分析和准备出版物。受试者在13个月的参与期间每月接受评估。随机化将在第4个月的访问中进行。在干预阶段的前3周(第5个月)，受试者在耐受性范围内每天接受最高8片(400毫克)的递增剂量，并每周进行电话联系。随机化将在每个中心内按中心、利鲁唑的使用和起病部位(无球部的四肢与有或无四肢的球部)分层，以确保药物和安慰剂在整个试验期间在每一层内均匀分布。400名早期ALS患者(预计FVC大于或等于75%，症状持续时间小于3年)将被纳入研究。主要的结果衡量标准是受试者内部ALSFRS-R分数斜率的变化。次要结果指标包括通过手动肌肉测试(MMT)测量的疾病进展率、肺功能(用力肺活量下降的百分比，预测的百分比)、生活质量和存活率(死亡率和开始机械呼吸)的变化。将有两组受试者在第4个月被随机分为两组：第1组(200名受试者)在4个月的先导期后，在第9个月干预期内接受安慰剂(与活性药物相同)；第2组(200名受试者)将接受米诺环素，从100毫克开始，每天两次，每周增加50毫克，每天两次，直到达到最大耐受量或每天两次200毫克。每周将在剂量滴定阶段的3周内与受试者进行电话联系。研究用药将每4周分发一次。受试者将接受每月一系列的门诊评估以及实验室和不良事件的分析。临床意义：尽管最近对导致运动神经元变性的分子事件的部分了解取得了进展，但ALS仍然是一种不治之症。这是在人类肌萎缩侧索硬化症中第一次对一种既具有抗细胞凋亡作用又具有抗炎作用的药物进行研究。任何被证明可以减缓人类肌萎缩侧索硬化症进程的化合物，无论在临床上还是从理解运动神经元疾病的潜在生物学的角度来看，都将具有直接的重要性。此外，大约50%的ALS患者没有服用利鲁唑，因为它是FDA目前批准的唯一一种治疗这种疾病的药物，因为它的成本很高。米诺环素将提供一种安全且成本较低的利鲁唑替代疗法。此外，由于作用机制的不同，这些药物可能会对这种疾病产生协同作用，并在未来的试验中进行测试。

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. OBJECTIVE: To determine if minocycline slows the progressive deterioration of global function in patients with ALS. Primary outcome measure is change in function as detected by the ALSFRS-R in those taking minocycline as compared to those taking placebo. The secondary outcome measures are changes in manual muscle testing (MMT), forced vital capacity (FVC, percent predicted), quality of life (QOL) and survival. RESEARCH PLAN: Phase III, multi-center, randomized, double-blind placebo-controlled study of minocycline in 400 subjects treated for 9 months. METHODS: The total study length is 48 months: Twenty-four months for patient recruitment, 4 months of serial monthly evaluations to determine baseline slopes of progression for each patient followed by 9 months of intervention (minocycline or placebo), and 11 additional months of survival follow-up, data analysis and preparation of publications. Subjects receive monthly evaluations during their 13 months of participation. Randomization will occur at the month 4 visit. During the first 3 weeks of the intervention phase (month 5) subjects receive an escalating dose of up to 8 pills (400 mg) per day as tolerated and have weekly phone contact. Randomization will be stratified by center, by riluzole use and by site of onset (limb with no bulbar vs. bulbar with or without limb) within each center to assure an even distribution of drug and placebo within each stratum throughout the trial. Four hundred patients with early ALS (FVC greater or equal to 75% predicted and symptom duration of less than 3 years) will be enrolled. The primary outcome measure is the change in slope of intra-subject ALSFRS-R scores. Secondary outcome measures include changes in disease progression rate as measured by manual muscle testing (MMT), pulmonary function (the rate of decline of forced vital capacity, percent 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; Group 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. Subjects will undergo serial monthly outpatient evaluations and analysis of laboratory and adverse events. CLINICAL RELEVANCE: Despite recent advances in partial understanding of molecular events leading to motor neuron degeneration, ALS remains an incurable disease. This is the first study in human ALS of a medication that acts as both an anti-apoptotic and anti-inflammatory agent. Any compound proven to slow the course of human ALS will be of immediate importance both clinically and from the perspective of understanding the underlying biology of motor neuron diseases. Additionally, approximately 50% of patients with ALS do not take riluzole, the only currently FDA approved drug for this disease, because of its high cost. Minocycline would provide a safe and less expensive treatment alternative to riluzole. Also, because of differing mechanisms of action, the drugs could have a synergistic effect upon the disease and be tested in future trials.