OBJECTIVE: To investigate the efficacy and safety of the ultra-high-dose micarb (25 mg and 50 mg intramuscularly twice weekly) group compared with the placebo group for the treatment of patients with amyotrophic lateral sclerosis (ALS). BACKGROUND: High-dose micarb has a neuroprotective effect against acromegaly neuropathy and was shown to increase compound muscle action potential in a clinical trial. METHODS: Patients with a diagnosis of definite, likely, or laboratory-supported likely ALS (373) according to El Escorial revised criteria were included in this study, except for those with an FVC less than 60% and a disease duration of more than 3 years. Patients were randomized to a placebo group, a Micropôle 25 mg group, and a 50 mg group, with intramuscular injections twice weekly for 182 weeks. The primary endpoints were event-free survival (time to death, TIPPV, or all-day NIPPV) and change in ALS Functional Rating Scale Revised (ALSFRS-R). RESULTS: Of 373 patients, 370 completed the study (N = 123 in the placebo group; N = 123 in the 50 mg group; N = 124 in the 25 mg group). At both endpoints, the two dose group comparisons (linear and saturation assumptions) were not statistically significant. Event-free survival was prolonged in a dose-dependent manner in ALS patients diagnosed within 12 months of onset (placebo group N = 48; 25 mg group N = 54; 50 mg group N = 42) (P = 0.010, risk ratio (95% CI) for the 25 mg, 50 mg groups 0.640 (0.377, 1.085), 0.498 (0.267, 0.929), respectively). 0.929), and the ALSFRS-R change was smaller in the treatment group (P=0.003) than in the placebo group. No adverse events of special concern were observed. DISCUSSION AND CONCLUSION: Diagnosis of ALS by the revised Escorial criteria is often delayed, but the newly revised Awaji criteria allow for early diagnosis. Patients are unlikely to benefit from ultra-high-dose mikepore treatment if the disease duration is more than 2 to 3 years.