Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective.

Charis Wong,Nigel Stallard,Dawn Lyle,Nigel Leigh,John Ealing,Richard Davenport,Amy Stenson,Venkataramanan Srinivasan,Elizabeth Elliott,Jeremy Chataway,Jenna M Gregory,Pablo Garcia Reitboeck,Rachel Dakin,Suvankar Pal,Jenny Preston,Robert Swingler,Amina Chaouch,Ian Morrison,Hisham Hamdalla,Siddharthan Chandran,Francisco Javier Carod-Artal,Judith Newton,Malcolm Macleod,Peter Connelly,Maria Stavrou,Danielle Leighton,George Gorrie,Christine Weaver,Emily Beswick,Callum W Duncan ,Christopher Weir ,Arpan R Mehta ,Ashwin Pinto ,J Williamson ,Timothy Williams ,Aleksandar Radunović ,Stella Glasmacher ,Mahesh Parmar ,Richard Parker

doi:10.1093/braincomms/fcab242

Abstract

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease-modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of Phase II, Phase II/III and Phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15 000 people with amyotrophic lateral sclerosis. About 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis.

Highlights

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease with a median survival of 2-3 years.[1]
To review sample size considerations including recruitment and retention, we summarised trials for completed trials with efficacy-based primary outcome measures according to number of study arms, number of participants recruited, number of participants recruited per arm, withdrawal rates and reasons for withdrawal
To determine the approximate proportion of people with ALS (pwALS) participating in clinical trials, we evaluated reported recruitment data for trials identified in our systematic search and compared this to ALS

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease with a median survival of 2-3 years.[1] While there has been some progress in non-pharmacological interventions such as noninvasive ventilation and gastrostomy, and symptomatic pharmacological treatments in ALS,[2] trials in the last 25 years have largely failed to identify effective disease-modifying drugs. Riluzole, approved in 1995, is the only globally licensed disease-modifying drug and prolongs survival by just 2-3 months on average.[3] Edaravone has been approved in some countries including United States, Canada, Japan and South Korea following a positive trial in a highly selected population.[4] AMX0035. (sodium phenylbutyrate-Taursodiol), masitinib and methylcobalamin have recently emerged as promising candidates following trials in subsets of people with ALS (pwALS).[5,6,7,8] evidence for generalisable and substantial effects on survival for edaravone, AMX0035, masitinib and methylcobalamin is limited

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Conclusion