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
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.
Showing the most recent 10 out of 600 publications
