COMBINATION TRIAL IN ALS

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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.