Clinical trials in the ALS syndrome: it is time for change

Abstract

Twenty-five\u2009years have passed since the first successful trial of riluzole in amyotrophic lateral sclerosis (ALS), a study that concluded that the drug had a modest effect in extending life expectancy.1 Since then, there have been a disturbingly large number of failed trials of other compounds.2 This negative experience has led to much discussion. For example, was patient selection too narrow or too broad?3 Were these trials adequately powered, the primary and secondary end points adequate and sufficiently sensitive and relevant?2 Had the patients studied had ALS for too long?2 Most of these studies used survival as the critical endpoint, usually with a suitable definition of ventilatory assistance as a surrogate endpoint.2 However, ALS is a heterogeneous syndromic disorder, due to multiple causative and modifying factors. Many different genetic factors confer susceptibility and there are likely dietary, exercise-related and other complex environmental factors leading to so-called ‘sporadic ALS’. The ALS syndrome shows remarkable variations in age of onset, site of onset, rate of progression and even in its clinical semiology, including a frequent association with frontotemporal dementia (FTD), itself of varying severity. Inevitably, the question arises as to whether trials be inclusive, involving all clinical variants or designed to test only a narrow question within this clinical range?3 Since ALS presents with different patterns of anterior brain degeneration, involving FTD and combinations of upper and lower motor neuron features, it is logical to include …