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

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.

SUBMITTER: Wong C

PROVIDER: S-EPMC8659356 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Wong Charis C Stavrou Maria M Elliott Elizabeth E Gregory Jenna M JM Leigh Nigel N Pinto Ashwin A AA Williams Timothy L TL Chataway Jeremy J Swingler Robert R Parmar Mahesh K B MKB Stallard Nigel N Weir Christopher J CJ Parker Richard A RA Chaouch Amina A Hamdalla Hisham H Ealing John J Gorrie George G Morrison Ian I Duncan Callum C Connelly Peter P Carod-Artal Francisco Javier FJ Davenport Richard R Reitboeck Pablo Garcia PG Radunovic Aleksandar A Srinivasan Venkataramanan V Preston Jenny J Mehta Arpan R AR Leighton Danielle D Glasmacher Stella S Beswick Emily E Williamson Jill J Stenson Amy A Weaver Christine C Newton Judith J Lyle Dawn D Dakin Rachel R Macleod Malcolm M Pal Suvankar S Chandran Siddharthan S

Brain communications 20211023 4

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 ...[more]

PMID: 34901853

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Project description:BackgroundAmyotrophic lateral sclerosis (ALS) is increasingly recognised as a multi-system disorder, presenting with common and impactful non-motor symptoms, such as neuropsychiatric symtpoms, cognitive and behavioural changes, pain, disordered sleep, fatigue and problematic saliva.Aim/hypothesisWe aimed to systematically review 25 years of ALS clinical trials data to identify if non-motor features were evaluated, in addition to the traditional measures of motor functioning and survival, and where evaluated to describe the instruments used to assess. We hypothesised that assessment of non-motor symptoms has been largely neglected in trial design and not evaluated with ALS-suitable instruments.MethodsWe reviewed clinical trials of investigative medicinal products in ALS, since the licensing of riluzole in 1994. Trial registry databases including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 16/09/2020. No language restrictions were applied.Results237 clinical trials, including over 29,222 participants, were investigated for their use of non-motor outcome measures. These trials evaluated neuropsychiatric symptoms (75, 32%), cognitive impairment (16, 6.8%), behavioural change (34, 14%), pain (55, 23%), sleep disturbances (12, 5%) and fatigue (18, 8%). Problematic saliva was assessed as part of composite ALS-FRS(R) scores in 184 trials (78%) but with no focus on this as an isolated symptom. 31 (13%) trials including 3585 participants did not include any assessment of non-motor symptoms.ConclusionsNon-motor symptoms such as neuropsychiatric, cognitive and behavioural changes, pain, disordered sleep, fatigue, and problematic saliva have not been consistently evaluated in trials for people with ALS. Where evaluated, non-symptoms were primarily assessed using instruments and impairment thresholds that are not adapted for people with ALS. Future trials should include non-motor symptom assessments to evaluate the additional potential therapeutic benefit of candidate drugs.Propsero registrationCRD42020223648.

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

Publications

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

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