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. The project will be a phase III, multicenter, IRB-approved, randomized, double-blind, placebo-controlled study of minocycline in 400 subjects with ALS treated for 9 months. The total length of the study is 48 months, including 24 months for recruitment, 4 months of serial monthly evaluations to determine baseline rates of deterioration for each subject, followed by 9 months on study medication and 11 months of survival follow-up, data analysis and preparation of publications. Subjects will undergo dose escalation during the first 3 weeks of the 9-month intervention period. The primary outcome measure is the change in slope of intr-subject ALSFRS-R scores. Secondary outcome measures include changes in disease progression rate as measured by manual muscle testing (MMT), pulmonary function (th rate of decline of forced vital capacity, precent 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; Gtoup 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. Subject will undergo serial monthly outpatient evaluations and analysis of laboratory and adverse events. The 9 month treatment period was chosen as sufficient to demonstrate effects of treatment in slowing the progression of ALS, and to ensure that the majority of subjects complete the study. A mixed linear effect model will be used to measure the drug effect for each endpoint.
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