The clinical trial design is extremely complex in neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). The clinical and pathological heterogeneity of ALS has made therapeutic targets difficult to identify, increasing the variability in endpoints. Nowadays, the most effective interventions in ALS are multidisciplinary clinics and non-invasive ventilation, which can significantly improve quality of life and prolong survival. In terms of disease-modifying treatment, riluzole is widely accepted to have some value but since its first successful trial 25 years ago, more than 40 clinical trials have failed to identify a molecule with a major impact on ALS outcome.

In the December issue of JNNP, van Eijk and colleagues systematically reviewed the design assumptions for ALS clinical trials with time-to-event endpoints and provide optimized settings for future trials. Using a strict statistical methodology, this novel reanalysis of data from 13 completed placebo-controlled trials compared designs in terms of sample size, trial duration, drug use and costs. In summary, the authors found that the mean hazard rate (HR) for the endpoint of death (the usual measure adopted in ALS clinical trials) was overestimated by approximately 20%. In addition, the median expected HR increased over time, mainly as a result of increasing ventilator hazard, which clearly affects the design and planning of future trials. Taking these factors into account, sample size could be reduced by 33%, trial duration by 17%, drug use by 14% and trial costs by 21%. Finally, an open-source platform to help researchers in clinical trials design was also provided.

The findings of this JNNP article crucially provide valuable insights into the design of future clinical trials in ALS. Importantly, the searching of strong disease-modifying treatments should also aim to optimize (i) the use of representative ALS animal models for drug discovery and selection, (ii) the trial inclusion criteria for ALS phenotypes, and (iii) the use of surrogate biomarker for disease progression. This article also introduces the possibility that potentially useful molecules may have been excluded from the ALS armamentarium in past trials that were not well designed, which may even justify their retrial. Nevertheless, there is universal agreement across the neurological and scientific community that as funds and resources for rare neurological conditions are limited, trial optimization is vital for efficient drug development.

Read more at https://jnnp.bmj.com/content/90/12/1331