COMBINATION TRIAL IN ALS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这是一项药物启动的II期随机双盲对照试验，采用简单有效的设计。 我们将招募多达120名ALS患者（每组60名）（FVC ≥ 60%预测值，症状持续时间少于5年）。 患者将被随机分为两组：米诺环素（100 mg BID）/肌酐（10 g BID）或塞来昔布（400 mg BID）/肌酐（10 g BID）。 将按中心和疾病进展率对随机化进行分层，以确保整个试验期间各分层内治疗分配的均匀分布。 在第一个汇总完成6个月后，如果两组之间的平均差异足够大（定义为0.. 75倍SD）;将选择诱导ALSFRS-R平均变化较小的组合。 如果一个组合提供了组间平均变化20%的改善，则该停止规则将以67%的概率在一个汇总中结束试验。 否则，将额外随机分配60例患者。 最多将入组两个汇总（120例患者）。 我们估计4个月的招募期为60例患者，每个样本库需要10个月才能完成。 如果试验需要两个样本池，则需要大约20个月的时间才能完成。 即使两种组合都没有真正将ALSFRS-R的下降降低20%，选择程序仍将以更高的概率选择更好的组合。 将与近期临床试验的自然史数据库进行比较，以确定所选组合是否不劣于安慰剂（无效性比较）。 受试者将符合埃尔埃斯科里亚的可能、实验室支持的很可能、很可能或明确ALS标准。 他们将在6个月的参与期间接受每月评估。 随机化将在基线访视时进行，并将按中心和基线疾病进展率分层，以确保整个试验期间各组内受试者的均匀分布。 如果一种联合治疗证明具有上级疗效且非无效，则本研究的数据将用于设计和实施所选药物联合治疗的III期安慰剂对照试验。

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. This is an investigator-initiated, phase II, randomized, double-blind, controlled trial, which uses a simple and efficient design. We will employ up to 120 patients with ALS (60 per group) (FVC greater or equal to 60% predicted and symptom duration of less than 5 years). Patients will be randomized in pools of 60 to one of two arms: minocycline (100 mg BID)/creatinine (10g BID) or celecoxib (400 mg BID)/creatinine (10 g BID). Randomization will be stratified by center, and by disease rate of progression to assure an even distribution of treatment assignment within each stratum throughout the trial. After the first pool completes 6 monnths, the trial is stopped if the mean difference between the two arms is adequately large (defined as 0..75 times the SD); the combination inducing the smaller mean change in ALSFRS-R will be selected. If a combination provides 20% improvement in the mean change between groups, this stopping rule will conclude the trial in one pool with 67% probability. Otherwise, an additional 60 patients will be randomized. A maximum of two pools (120 patients) will be enrolled. We estimate a 4-month recruitment period 60 patients, requiring `10 months to complete each pool. Should the trial need two pools, it will take approximately 20 months to complete. Even if neither combination truly reduces the decline in ALSFRS-R by 20%, the selection procedure will still select the better combination with higher probability. Comparison to a natural history database from a recent clinical trial will be made to determine whether the selected combination is no worse than placebo (futility comparison). Subjects will meet El Escorial criteria for possible, laboratory supported probable, probable or definite ALS. They will receive monthly evaluations during their 6 months of participation. Randomization will occur at the baseline visit, and will be stratified by Center and by baseline rate of disease progression to assure an even distribution of subjects within each group throughout the trial. If one combination proves superior and non-futile, the data from this study will be used to design and implement a phase III placebo controlled trial of the selected drug combination.