Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS): Protocol and Study Design

Abstract

Objectives: To identify putative biomarkers that may serve as quantifiable, biological, nonclinical measures of the pharmacodynamic effect of edaravone in amyotrophic lateral sclerosis (ALS) and to report real-world treatment outcomes.

Methods: This is a prospective, observational, longitudinal, multicenter (up to 40 sites) US study (Clinicaltrials.gov; NCT04259255) with at least 200 patients with ALS who will receive edaravone for 24 weeks (6 cycles; Food and Drug Administration-approved regimen). All participants must either be treatment naive for edaravone or be more than 1 month without receiving any edaravone dose before screening. Biomarker quantification and other assessments will be performed at baseline (before cycle 1) and during cycles 1, 3, and 6. Selected biomarkers of oxidative stress, inflammation, neuronal injury and death, and muscle injury, as well as biomarker discovery panels (EpiSwitch and SOMAscan), will be evaluated and, when feasible, compared with biobanked samples. Clinical efficacy assessments will include the ALS Functional Rating Scale-Revised, King's clinical staging, ALS Assessment Questionnaire-40, Appel ALS Score (Rating Scale), slow vital capacity, hand-held dynamometry and grip strength, and time to specified states of disease progression or death. DNA samples will also be collected for potential genomic evaluation. The predicted rates of progression and survival, and their potential correlations with biomarkers, will be evaluated. Adverse events related to the study will be reported.

Results: The study is estimated to be completed in 2022 with an interim analysis planned.

Conclusions: Findings may help to further the understanding of the pharmacodynamic effect of edaravone, including changes in biomarkers, in response to treatment.

© 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Study Design

aTime between screening/baseline to day 1 of cycle 1 may take approximately 4–12 weeks for insurance approval. bVisit 2 should occur 0–2 days before starting edaravone treatment. For visits while the patient is on drug, target the visit to occur 1–5 days before stopping their infusions for that cycle. For visits while the patient is off drug, target the visit to occur 0–4 days before beginning their next edaravone cycle. cThe Appel ALS Score and hand-held dynamometry and hand grip strength testing will be assessed at specific sites only. dVital signs include systolic and diastolic pressure in mm Hg, respiratory rate/minute, heart rate/minute, temperature, and weight. Height will be assessed at screening/baseline only. eClinical labs to be completed at these visits. fWhole blood collection for DNA whole-genome sequencing can be collected following consent at the screening/baseline visit or any subsequent study visit. gOnly adverse events that occur after signing of the consent form and that are directly related to study procedures will be recorded. ALS = amyotrophic lateral sclerosis; ALSAQ-40 = ALS Assessment Questionnaire-40; ALSFRS-R = ALS Functional Rating Scale–Revised.

Figure 2. Data and Biomarker Workflow

MGH NCRI = Massachusetts General Hospital Neurological Clinical Research Institute; NYGC = New York Genome Center; UAB = University of Alabama at Birmingham.