Using the ALSFRS-R in multicentre clinical trials for amyotrophic lateral sclerosis: potential limitations in current standard operating procedures

Abstract Background Amyotrophic 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/hypothesis We 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. Methods We 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. Results 237 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. Conclusions Non-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 registration CRD42020223648.

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Current clinical trials in amyotrophic lateral sclerosis

Expert Opinion on Investigational Drugs ◽

10.1517/13543784.16.8.1197 ◽

2007 ◽

Vol 16 (8) ◽

pp. 1197-1207 ◽

Cited By ~ 23

Author(s):

Jaydeep M Bhatt ◽

Paul H Gordon

Keyword(s):

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Lateral Sclerosis

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Urate levels predict survival in amyotrophic lateral sclerosis: Analysis of the expanded Pooled Resource Open-Access ALS clinical trials database

Muscle & Nerve ◽

10.1002/mus.25950 ◽

2017 ◽

Vol 57 (3) ◽

pp. 430-434 ◽

Cited By ~ 14

Author(s):

Sabrina Paganoni ◽

Katharine Nicholson ◽

James Chan ◽

Amy Shui ◽

David Schoenfeld ◽

...

Keyword(s):

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Open Access ◽

Lateral Sclerosis

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Edaravone in Amyotrophic Lateral Sclerosis’Lessons from the Clinical Development Program and the Importance of a Strategic Clinical Trial Design

US Neurology ◽

10.17925/usn.2018.14.1.47 ◽

2018 ◽

Vol 14 (1) ◽

pp. 47 ◽

Cited By ~ 5

Author(s):

Said R Beydoun ◽

Jeffrey Rosenfeld

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Trial Design ◽

Development Program ◽

Clinical Trial Design ◽

Clinical Development ◽

Disease Heterogeneity ◽

Clinical Development Program ◽

Lateral Sclerosis

Edaravone significantly slows progression of amyotrophic lateral sclerosis (ALS), and is the first therapy to receive approval by the Food and Drug Administration (FDA) for the disease in 22 years. Approval of edaravone has marked a new chapter in pharmaceutical development since the key trial included a novel strategic clinical design involving cohort enrichment. In addition, approval was based on clinical trials that had a relatively small patient number and were performed outside of the US. Edaravone was developed through a series of clinical trials in Japan where it was determined that a well-defined subgroup of patients was required to reveal a treatment effect within the study period. Amyotrophic lateral sclerosis is associated with wide-ranging disease heterogeneity (both within the spectrum of ALS phenotypes as well as in the rate of progression). The patient cohort enrichment strategy aimed to address this heterogeneity and should now be considered as a viable, and perhaps preferred, trial design for future studies. Future research incorporating relevant biomarkers may help to better elucidate edaravone’s mechanism of action, pharmacodynamics, and subsequently ALS phenotypes that may preferentially benefit from treatment. In this review, we discuss the edaravone clinical development program, outline the strategic clinical trial design, and highlight important lessons for future trials.

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Plant-Derived Natural Compounds for the treatment of Amyotrophic Lateral Sclerosis: An Update

Current Neuropharmacology ◽

10.2174/1570159x19666210428120514 ◽

2021 ◽

Vol 19 ◽

Author(s):

Roohi Mohi-ud-din ◽

Reyaz Hassan Mir ◽

Abdul Jalil Shah ◽

Saba Sabreen ◽

Taha Umair Wani ◽

...

Keyword(s):

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Adverse Effects ◽

Therapeutic Strategies ◽

Structure Activity Relationships ◽

Complex Genetics ◽

Natural Agents ◽

Structure Activity ◽

Preclinical And Clinical Studies ◽

Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease (MND) that typically causes death within 3-5 years after diagnosis. Regardless of the substantial scientific knowledge accrued from more than a century ago, truly effective therapeutic strategies remain distant. Various conventional drugs are being used but are having several adverse effects. Objective/Aim: The current study aims to thoroughly review plant-derived compounds with well-defined ALS activities and their structure-activity relationships. Moreover, the review also focuses on complex genetics, clinical trials, and the use of natural products that might decrypt the future and novel therapeutics in ALS. Methods: The collection of data for the compilation of this review work was searched in PubMed Scopus, Google Scholar, and Science Direct. Results: Results showed that phytochemicals like-Ginkgolides, Protopanaxatriol, Genistein, epigallocatechingallate, resveratrol, cassoside, and others possess Amyotrophic lateral sclerosis (ALS) activity by various mechanisms. Conclusion: These plant-derived compounds may be considered as supplements to conventional (ALS). Moreover, further preclinical and clinical studies are required to understand the structure-activity relationships, metabolism, absorption, and mechanisms of plant-derived natural agents.

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Design and analysis of a clinical trial using previous trials as historical control

Clinical Trials ◽

10.1177/1740774519858914 ◽

2019 ◽

Vol 16 (5) ◽

pp. 531-538 ◽

Cited By ~ 6

Author(s):

David Alan Schoenfeld ◽

Dianne M Finkelstein ◽

Eric Macklin ◽

Neta Zach ◽

David L Ennist ◽

...

Keyword(s):

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Sample Size ◽

Standard Error ◽

Controlled Trial ◽

Sample Size Calculation ◽

Control Group ◽

Controlled Trials ◽

Number Of Patients ◽

Lateral Sclerosis

Background/AimsFor single arm trials, a treatment is evaluated by comparing an outcome estimate to historically reported outcome estimates. Such a historically controlled trial is often analyzed as if the estimates from previous trials were known without variation and there is no trial-to-trial variation in their estimands. We develop a test of treatment efficacy and sample size calculation for historically controlled trials that considers these sources of variation.MethodsWe fit a Bayesian hierarchical model, providing a sample from the posterior predictive distribution of the outcome estimand of a new trial, which, along with the standard error of the estimate, can be used to calculate the probability that the estimate exceeds a threshold. We then calculate criteria for statistical significance as a function of the standard error of the new trial and calculate sample size as a function of difference to be detected. We apply these methods to clinical trials for amyotrophic lateral sclerosis using data from the placebo groups of 16 trials.ResultsWe find that when attempting to detect the small to moderate effect sizes usually assumed in amyotrophic lateral sclerosis clinical trials, historically controlled trials would require a greater total number of patients than concurrently controlled trials, and only when an effect size is extraordinarily large is a historically controlled trial a reasonable alternative. We also show that utilizing patient level data for the prognostic covariates can reduce the sample size required for a historically controlled trial.ConclusionThis article quantifies when historically controlled trials would not provide any sample size advantage, despite dispensing with a control group.

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Standard Operating Procedures for Clinical Trials of the CESAR Central European Society for Anticancer Drug Research - EWIV

10.1159/isbn.978-3-318-01039-8 ◽

2003 ◽

Cited By ~ 1

Keyword(s):

Clinical Trials ◽

Anticancer Drug ◽

European Society ◽

Drug Research ◽

Standard Operating Procedures ◽

Central European ◽

Standard Operating

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Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

Journal of Neuromuscular Diseases ◽

10.3233/jnd-200531 ◽

2021 ◽

Vol 8 (1) ◽

pp. 25-38

Author(s):

Marisa Cappella ◽

Pierre-François Pradat ◽

Giorgia Querin ◽

Maria Grazia Biferi

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Muscular Atrophy ◽

Monogenic Disease ◽

Sporadic Als ◽

Pathological Mechanism ◽

Huge Impact ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease’s pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes clinical use of antisense oligonucleotides in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively.. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.

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