Comparison Of King’s Clinical Staging In Multinational Amyotrophic Lateral Sclerosis Cohorts

Abstract

Background: Amyotrophic lateral sclerosis (ALS) shows considerable clinical heterogeneity, which affects clinical trials. A clinical staging system has been proposed for ALS with potential applications in patient care, research, trial design and health economic analyses. The King’s system consists of five stages. We have previously shown that progressive clinical stages were reached at predictable proportions through the disease course, but this needs to be validated in other independent samples. Objectives: We aimed to compare King’s clinical staging in ALS in four patient groups, located in different regions and countries and using different health care systems from the original study population in South London. Methods: Clinical data were extracted from two European phase 3 randomized controlled trials (MitoTarget and LiCALS) and from two databases predominately from the United States: the PRO-ACT Consortium Database and a database of patients from the PatientsLikeMe website. Clinical stage was estimated using an algorithm, and standardized time to each clinical stage was calculated in deceased patients. Results: 8,796 patients were included, of whom 1,959 had died by the end of follow-up. Stages occurred in the same order as in the original study for all cohorts. Median standardized times to stages (interquartile range) were Stage 2: 0.61 (0.47–0.75), Stage 3: 0.68 (0.56–0.81), Stage 4A: 0.82 (0.71–0.91), Stage 4B: 0.82 (0.69–0.92) and Stage 4 0.80 (0.67–0.91). Discussion: Timings for all stages were similar to those reported in the original study, except Stage 2 which occurred later in the clinical trial databases due to recruitment occurring after diagnosis.

Keywords:

• Prognosis
• King’s stage
• staging
• clinical trials
• survival
• prognostic

Acknowledgments

We thank all the participants involved in the study.

Declaration of interest

AAC reports consultancies or advisory boards for Amylyx, Apellis, Biogen, Brainstorm, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, and Wave Pharmaceuticals. At the time of study, PW was an employee of PatientsLikeMe. PW is employed by Wicks Digital Health Ltd, which has received funding from Ada Health, AstraZeneca, Baillie Gifford, Bold Health, Camoni, Compass Pathways, Coronna, EIT, Happify, HealthUnlocked, Inbeeo, Kheiron Medical, Sano Genetics, Self Care Catalysts, The Learning Corp, The Wellcome Trust, VeraSci, and Woebot. CAY is a Principal Investigator for Cytokinetics and receives speaker and consultancy fees from Biogen, Celgene, Cytokinetics, Genzyme, Janssen, Merck, Novartis, Orion, Roche and Teva. PJS is a consultant/Advisory Board member for Biogen, Benevolent AI, Quell Therapeutics, Aclipse Therapeutics and QurAlis.

Additional information

Funding

RB is an NIHR Academic Clinical Lecturer in Neurology at UCL and received funding from a Wellcome Trust Research Training Fellowship [107196/Z/14/Z] and the UCL Leonard Wolfson Experimental Neurology Center. AAK is funded by ALS Association Milton Safenowitz Research Fellowship [grant number22-PDF-609. DOI:10.52546/pc.gr.150909.], the Motor Neurone Disease Association (MNDA) Fellowship [Al Khleifat/Oct21/975-799], The Darby Rimmer Foundation, and The NIHR Maudsley Biomedical Research Center. PJS was supported as an NIHR Senior Investigator [NF-SI-0617-10077] and receives independent support from the Medical Research Council [MR/S004920/1], the Motor Neurone Disease Association, Life Arc and the EU Horizon 2020 programme. This study was supported by the NIHR Sheffield Biomedical Research Center [JS-BRC-1215-20017]. AAC is an NIHR Senior Investigator [NIHR202421]. This is an EU Joint Programme—Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the egis of JPND—www.jpnd.eu (United Kingdom, Medical Research Council [MR/L501529/1; MR/R024804/1] and Economic and Social Research Council [ES/L008238/1]) and through the Motor Neurone Disease Association, My Name’5 Doddie Foundation, and Alan Davidson Foundation. This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Center at South London and Maudsley NHS Foundation Trust and King’s College London.