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To investigate predictors of trial start-up times, high attrition, and poor protocol adherence in amyotrophic lateral sclerosis (ALS) trials.Retrospective analysis of start-up times, retention, and protocol adherence was performed on 5 clinical studies conducted by the Northeast ALS Consortium and 50 ALS clinical trials identified by PubMed search. Predictors of start-up times were estimated by accelerated failure time models with random effects. Predictors of retention and protocol deviations were estimated by mixed-model logistic regression.Median times for contract execution and institutional review board (IRB) approval were 105 days and 125 days, respectively. Contract execution was faster at sites with more ongoing trials (p = 0.005), and more full-time (p = 0.006) and experienced (p0.001) coordinators. IRB approval was faster at sites with more ongoing trials (p = 0.010) and larger ALS clinics (p = 0.038). Site activation after IRB approval was faster at sites with more full-time (p = 0.038) and experienced (p0.001) coordinators. Twenty-two percent of surviving participants withdrew before completing the trial. Better participant functional score at baseline was an independent predictor of trial completion (odds ratio 1.29, p = 0.002) and fewer protocol deviations (odds ratio 0.86, p = 0.030).Delays in IRB review contribute the most to prolonged trial start-up times, and these timelines are faster in sites with more experienced staff. Strategies to improve protocol adherence and participants' retention may include enrolling people at early disease stages.