MULTI-CENTER STUDY OF MINOCYCLINE IN ALS

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。目的：确定二甲胺四环素是否减缓ALS患者全身功能的进行性恶化。主要结局指标是服用米诺环素的患者与服用安慰剂的患者相比，通过ALSFRS-R检测功能的变化。次要结局指标是人工肌肉测试（MMT）、用力肺活量（FVC，预测百分比）、生活质量（QOL）和生存率的变化。研究计划：米诺环素的III期、多中心、随机、双盲安慰剂对照研究，400名受试者接受9个月的治疗。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，以确定每位患者的基线进展斜率，随后9个月的干预（米诺环素或安慰剂），以及11个月的额外生存随访，数据分析和准备出版物。在13个月的参与期间，受试者每月接受一次评估。随机化将在第4个月进行。在干预阶段的前3周（第5个月），受试者接受逐渐递增的剂量，在可耐受的情况下每天服用8片（400mg），并每周进行电话联系。随机化将在每个中心按中心、利鲁唑使用和发病部位（肢体无球、球有或无肢体）进行分层，以确保在整个试验过程中药物和安慰剂在每个分层中均匀分布。400名早期ALS患者（FVC大于或等于预测的75%，症状持续时间小于3年）将被纳入研究。主要结局指标是受试者内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）测量的疾病进展率的变化、肺功能（强迫肺活量下降的速度，预测的百分比）、生活质量（QOL）和生存率（死亡率与机械通气的开始）。在第4个月将受试者随机分为两组：在4个月的先导期后，第一组（200名受试者）在9个月的干预期内接受安慰剂（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和不良事件分析。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理解取得了进展，但ALS仍然是一种无法治愈的疾病。这是第一次对人类肌萎缩性侧索硬化症的药物进行研究，该药物同时具有抗细胞凋亡和抗炎作用。任何被证明能延缓人类ALS病程的化合物，无论是在临床上还是从了解运动神经元疾病的潜在生物学角度来看，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批准的唯一治疗这种疾病的药物，因为它的成本很高。米诺环素将为利鲁唑提供一种安全且更便宜的治疗选择。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.