scholarly journals Challenging the Established Order: Innovating Clinical Trials for Amyotrophic Lateral Sclerosis

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012545
Author(s):  
Ruben P.A. van Eijk ◽  
Stavros Nikolakopoulos ◽  
Kit C.B. Roes ◽  
Lindsay Kendall ◽  
Steve S. Han ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Design Stage ◽  
European Medicines Agency ◽  
Pivotal Phase ◽  
Disease Heterogeneity ◽  
Analytical Strategy ◽  
Design Modification ◽  
Use Of Resources ◽  
Lateral Sclerosis

Development of effective treatment for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology and methodological design challenges. Here we have evaluated two major themes in the design of pivotal, phase 3 clinical trials for ALS: (1) patient selection and (2) analytical strategy, and discussed potential solutions with the European Medicines Agency (EMA). Several design considerations were assessed using data from five placebo-controlled clinical trials (N = 988), four population-based cohorts (N = 5,100), and 2,436 placebo-allocated patients from the PRO-ACT database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework which naturally adapts the trial duration when inaccurate assumptions are made at the design stage such as the enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria and minimizing the exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve a blueprint for future clinical trials in this population.

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

US Neurology ◽  
2018 ◽  
Vol 14 (1) ◽  
pp. 47 ◽  
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.

scholarly journals Critical design considerations for time-to-event endpoints in amyotrophic lateral sclerosis clinical trials

2019 ◽  
pp. jnnp-2019-320998 ◽  
Author(s):  
Ruben P A van Eijk ◽  
Stavros Nikolakopoulos ◽  
Kit C B Roes ◽  
Bas M Middelkoop ◽  
Toby A Ferguson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Drug Use ◽  
Sample Size ◽  
Hazard Rate ◽  
Survival Models ◽  
Design Stage ◽  
Time To Event ◽  
Trial Duration ◽  
Lateral Sclerosis

BackgroundFunding and resources for low prevalent neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) are limited, and optimising their use is vital for efficient drug development. In this study, we review the design assumptions for pivotal ALS clinical trials with time-to-event endpoints and provide optimised settings for future trials.MethodsWe extracted design settings from 13 completed placebo-controlled trials. Optimal assumptions were estimated using parametric survival models in individual participant data (n=4991). Designs were compared in terms of sample size, trial duration, drug use and costs.ResultsPrevious trials overestimated the hazard rate by 18.9% (95% CI 3.4% to 34.5%, p=0.021). The median expected HR was 0.56 (range 0.33–0.66). Additionally, we found evidence for an increasing mean hazard rate over time (Weibull shape parameter of 2.03, 95% CI 1.93 to 2.15, p<0.001), which affects the design and planning of future clinical trials. Incorporating accrual time and assuming an increasing hazard rate at the design stage reduced sample size by 33.2% (95% CI 27.9 to 39.4), trial duration by 17.4% (95% CI 11.6 to 23.3), drug use by 14.3% (95% CI 9.6 to 19.0) and follow-up costs by 21.2% (95% CI 15.6 to 26.8).ConclusionsImplementing distributional knowledge and incorporating accrual at the design stage could achieve large gains in the efficiency of ALS clinical trials with time-to-event endpoints. We provide an open-source platform that helps investigators to make more accurate sample size calculations and optimise the use of their available resources.

scholarly journals A systematic review of non-motor symptom evaluation in clinical trials for amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Emily Beswick ◽  
Deborah Forbes ◽  
Zack Hassan ◽  
Charis Wong ◽  
Judith Newton ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Sleep Disturbances ◽  
Neuropsychiatric Symptoms ◽  
Behavioural Change ◽  
Motor Symptom ◽  
Motor Symptoms ◽  
Behavioural Changes ◽  
Non Motor Symptoms ◽  
Lateral Sclerosis

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.

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

2017 ◽  
Vol 57 (3) ◽  
pp. 430-434 ◽  
Author(s):  
Sabrina Paganoni ◽  
Katharine Nicholson ◽  
James Chan ◽  
Amy Shui ◽  
David Schoenfeld ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Open Access ◽  
Lateral Sclerosis

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

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.

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

2019 ◽  
Vol 16 (5) ◽  
pp. 531-538 ◽  
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.

scholarly journals The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1791
Author(s):  
Ana Bajc Česnik ◽  
Helena Motaln ◽  
Boris Rogelj
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Rna Binding ◽  
Neurodegenerative Disorder ◽  
Low Complexity ◽  
Wild Type ◽  
Disease Heterogeneity ◽  
Cytoplasmic Inclusions ◽  
The Impact ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder, characterized by cytoplasmic inclusions of RNA-binding protein TDP-43. Despite decades of research and identification of more than 50 genes associated with amyotrophic lateral sclerosis (ALS), the cause of TDP-43 translocation from the nucleus and its aggregation in the cytoplasm still remains unknown. Our study addressed the impact of selected ALS-associated genes on TDP-43 aggregation behavior in wild-type and aggregation prone TDP-43 in vitro cell models. These were developed by deleting TDP-43 nuclear localization signal and stepwise shortening its low-complexity region. The SH-SY5Y cells were co-transfected with the constructs of aggregation-prone TDP-43 and wild-type or mutant ALS-associated genes hnRNPA1, MATR3, VCP or UBQLN2. The investigated genes displayed a unique impact on TDP-43 aggregation, generating distinct types of cytoplasmic inclusions, similar to those already described as resembling prion strains, which could represent the basis for neurodegenerative disease heterogeneity.

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

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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