MULTI-CENTER STUDY OF MINOCYCLINE IN ALS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。目的：确定米诺环素是否减缓ALS患者的整体功能进行性恶化。主要结果测量是与服用安慰剂的患者相比，服用米诺环素的患者通过ALSFRS-R检测到的功能变化。次要结局指标为手动肌肉测试（MMT）、用力肺活量（FVC，预测百分比）、生活质量（QOL）和生存率的变化。 研究项目：米诺环素治疗400例受试者9个月的III期、多中心、随机、双盲、安慰剂对照研究。 方法：总研究长度为48个月：24个月用于患者招募，4个月的连续每月评估以确定每例患者的基线进展斜率，随后9个月的干预（二甲胺四环素或安慰剂），以及另外11个月的生存随访，数据分析和出版物的准备。受试者在13个月的参与期间接受每月评估。将在第4个月访视时进行随机化。在干预阶段的前3周（第5个月），受试者接受每天最多8片（400 mg）的递增剂量（如耐受），并每周进行电话联系。在每个中心内，将按中心、利鲁唑使用和发作部位（无延髓的肢体vs有或无肢体的延髓）对随机化进行分层，以确保整个试验期间药物和安慰剂在每个分层内均匀分布。将入组400例早期ALS患者（FVC大于或等于75%预测值，症状持续时间小于3年）。 主要结局指标是受试者内ALSFRS-R评分的斜率变化。次要结局指标包括通过手动肌肉测试（MMT）测量的疾病进展率变化、肺功能（用力肺活量下降率，预测百分比）、QOL和生存率（死亡率与开始机械通气相结合）。将有两个组，受试者在第4个月时随机分组：4个月导入期后，第1组（200例受试者）将接受安慰剂（与活性药物相同）;组2（200名受试者）将接受米诺环素，起始剂量为100 mg，每日两次，每周增加50 mg，每日两次，直至达到最大耐受剂量或200 mg，每日两次剂量达到。在3周剂量滴定期内，每周与受试者进行一次电话联系。研究药物将每4周一次分发。受试者将接受每月一次的连续门诊评价以及实验室和不良事件分析。 临床相关性：尽管最近在部分理解导致运动神经元变性的分子事件方面取得了进展，但ALS仍然是一种无法治愈的疾病。这是第一次在人类ALS中研究一种既能抗凋亡又能抗炎的药物。任何被证明可以减缓人类ALS进程的化合物，无论是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，都具有直接的重要性。此外，大约50%的ALS患者不服用利鲁唑，这是目前FDA批准的唯一用于这种疾病的药物，因为其成本高。米诺环素将提供一个安全和更便宜的治疗替代利鲁唑。此外，由于不同的作用机制，这些药物可能对疾病产生协同作用，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.