Discussion
ALS
To estimate the treatment effect of PB and TURSO on survival in ALS in the absence of the placebo‐to‐active crossover that occurred in the OLE phase of the CENTAUR trial, we compared overall survival in those randomized to PB and TURSO with an external, PB and TURSO‐naïve control group from PRO‐ACT, the largest ALS clinical trials data set. Median overall survival was 10.39 months longer in those originally randomized to PB and TURSO in CENTAUR versus the external control group in this analysis, whereas the ITT analysis of the CENTAUR trial showed that median overall survival for PB and TURSO was 4.8 months longer versus placebo. The results of the current analysis align with a previous analysis using a rank‐preserving structural failure time model (RPSFTM), an advanced statistical method that adjusts overall survival for the effect of treatment crossover in the placebo group within a clinical trial incorporating a crossover design.Though less preferable than a concurrent, randomized control group given the potential for introducing bias, utilization of control data from an external database provides a treatment‐naïve comparator option for active treatment in clinical trials that allow for placebo‐to‐active crossover or completely exclude a concurrent placebo group based on ethical concerns.To minimize bias due to imbalance among nonrandomized cohorts or other trial variables, external controls should be as closely matched to the investigational cohort as possible.Propensity score matching has been proposed by the US Food and Drug Administration as a means of improving the quality of external control dataBecause data from clinical trials are generated in a controlled setting, the use of the PRO‐ACT data set in our analysis provided high‐quality external control data, in contrast to external data obtained from differing sources with varying data quality. Our analysis was also strengthened by the focus on survival, an objective end point that could be consistently and precisely measured in both analysis groups.Our analysis also did not account for potential between‐group differences in the frequency of initiating respiratory support or gastrostomy tube placement, both potentially life‐extending interventions in ALS, as this information is not comprehensively captured in the PRO‐ACT database. Similarly, neurofilament levels are not included in the PRO‐ACT database and could not be used as a covariate for propensity score matching in our analysis. However, the groups were matched based on other baseline covariates that have been previously identified as significant predictors of survival duration in ALS, including time since symptom onset, pre‐baseline ALSFRS‐R, and age and vital capacity at baseline. In addition, the matched cohorts included similar proportions of participants with bulbar‐onset ALS and riluzole use, additional factors that have been shown to predict survival duration.In conclusion, the results of this analysis align with prior analyses using statistical models adjusting for placebo‐to‐active crossover in CENTAUR and suggest a potentially greater survival benefit with PB and TURSO in ALS than seen on ITT analysis. The ongoing global Phase 3 PHOENIX trial (