Innovating Clinical Trials for Amyotrophic Lateral Sclerosis

Abstract

Development of effective treatment for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology and methodological design challenges. Here we have evaluated two major themes in the design of pivotal, phase 3 clinical trials for ALS: (1) patient selection and (2) analytical strategy, and discussed potential solutions with the European Medicines Agency (EMA). Several design considerations were assessed using data from five placebo-controlled clinical trials (N = 988), four population-based cohorts (N = 5,100), and 2,436 placebo-allocated patients from the PRO-ACT database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework which naturally adapts the trial duration when inaccurate assumptions are made at the design stage such as the enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria and minimizing the exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve a blueprint for future clinical trials in this population.

Review of disease-modifying drug trials in amyotrophic lateral sclerosis

“…Clinical trials with highly selected subgroups are difficult to interpret in real-world settings, and the safety or effectiveness of a drug may be unknown for many patients. Eligibility criteria shape the prognosis of participating patients,28 impact on their possibility to complete the study29 and influence the generalisability of results. A consensus on eligibility criteria taking into account clinical, genetic and biomarker indicators may improve the design of future studies by assembling well-defined patient cohorts 27…”

“…Phenotypic and genetic heterogeneity of ALS have been documented, but it is not demonstrated how they would influence the conduct of clinical trials 39. Conversely, variables inherent to clinical trial design directly influence trial outcome 29…”

“…The use of composite end points does not provide advantages and post hoc analysis is a tangible source of bias when applied to traditional trial designs. Alternative designs may consider event-driven studies, where the trial has no fixed duration and the interim and final analyses are performed once the prespecified number of events is reached 29. The present review emphasises the importance of designing high-quality clinical trials with adequate generalisability potential.…”

Short structural variants as informative genetic markers for ALS disease risk and progression

“…Recently, the Treatment Research Initiative to Cure ALS (TRICALS) has brought the urgent need to reform ALS clinical trial design to the forefront of the literature [5,49]. In particular, the major concerns raised are related to the stringent patient selection criteria and analytical strategy of phase 3 clinical trials.…”

“…In particular, the major concerns raised are related to the stringent patient selection criteria and analytical strategy of phase 3 clinical trials. Van Eijk and Nikolakopoulos [49] highlight the use of patient risk profiles as a strategy to provide more informative selection criteria that will help to improved randomization, enable riskbased subgroup analyses, and increase the statistical power of clinical trials. Patient risk profiles are based on a multivariate analysis of several patient characteristics (i.e., age of onset, site of onset, vital capacity, diagnostic delay, ALSFRS etc.…”