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

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

doi:10.1093/braincomms/fcab242

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

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

^*Corresponding author for this work

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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.

Original language	English
Article number	fcab242
Number of pages	16
Journal	Brain Communications
Volume	3
Issue number	4
DOIs	https://doi.org/10.1093/braincomms/fcab242
Publication status	Published - 1 Oct 2021

Bibliographical note

MND-SMART is funded by grants from MND Scotland, My Name’5 Doddie Foundation (DOD/14/15) and specific donations to the Euan MacDonald Centre. The Chandran lab is supported by the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. A.R.M. is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/R001162/1).

Keywords

amyotrophic lateral sclerosis
clinical trials
systematic review
methodology
perspective

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Wong, C., Stavrou, M., Elliott, E., Gregory, J., Leigh, N., Pinto, A. A., Williams, T. L., Chataway, J., Swingler, R., Parmar, M. K. B., Stallard, N., Weir, C. J., Parker, R. A., Chaouch, A., Hamdalla, H., Ealing, J., Gorrie, G., Morrison, I., Duncan, C. W., ... Macleod, M. R. (2021). Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective. Brain Communications, 3(4), Article fcab242. https://doi.org/10.1093/braincomms/fcab242

Wong, C, Stavrou, M, Elliott, E, Gregory, J, Leigh, N, Pinto, AA, Williams, TL, Chataway, J, Swingler, R, Parmar, MKB, Stallard, N, Weir, CJ, Parker, RA, Chaouch, A, Hamdalla, H, Ealing, J, Gorrie, G, Morrison, I, Duncan, CW, Connelly, P, Carod-Artal, FJ, Davenport, R, Reitboeck, PG, Radunovic, A, Srinivasan , V, Preston, J, Mehta, AR, Leighton, D, Glasmacher, S, Beswick, E, Williamson, J, Stenson, A, Weaver, C, Newton, J, Chandran, S, Dakin, R, Lyle, D, Pal, S & Macleod, MR 2021, 'Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective', Brain Communications, vol. 3, no. 4, fcab242. https://doi.org/10.1093/braincomms/fcab242

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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.",

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

Abstract

Bibliographical note

Keywords

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