Tailoring patients’ enrollment in ALS clinical trials: the effect of disease duration and vital capacity cutoffs

Abstract

Objective: To evaluate how Amyotrophic Lateral Sclerosis (ALS) patients’ mortality rates change, based on different levels of forced vital capacity (FVC) and disease duration, providing a scheme of mortality rates of a real population of ALS patients to improve the design of future RCTs. Methods: One random spirometry for each ALS patient was selected during four time intervals from disease onset: (1) ≤12 months; (2) ≤18 months; (3) ≤24 months; (4) ≤36 months. Date of spirometry corresponded to date of trial entry, while time interval onset-spirometry to disease duration at enrollment. Mortality rates from inclusion were computed at different time intervals. Based on progression rates, patients were stratified in slow, intermediate and fast progressors. Survival from recruitment was calculated depending on FVC, disease duration and progression rate. Results: We included 659 patients in group 1, 888 in group 2, 1019 in group 3 and 1102 in group 4. Mortality rates were higher in each group at reducing the FVC cutoff used for recruitment (p < 0.001). Median survival decreased when lowering FVC and disease duration cutoffs (p < 0.001); a higher median disease progression rate of included patients led to lower median survival from recruitment. The proportion of recruited fast progressors raised when shortening disease duration and lowering FVC cutoff. Conclusions: This is a simple model for setting eligibility criteria, based on mortality rates of patients depending on FVC and disease duration, to select the best population for RCTs, tailored to trials’ primary endpoints and duration.

Keywords:

• Amyotrophic lateral sclerosis
• randomized clinical trials
• forced vital capacity
• eligibility criteria

Acknowledgements

Our special thanks also to our colleagues Dr Giuseppe Tabbia, Dr Marco Michele Bardessono, Paola Calvi, Dr Fulvia Ribolla, Dr Luana Focaraccio, Dr Elena Rindone, Dr Michela Bellocchia, Dr Cinzia Ferrero, Dr Ennio Mantellini, Dr Biagio Polla, Dr Lorenzo Appendini, Dr Alessandro Mastinu, Andrea Tagliabue, and Sandro Longu for their valuable collaboration in ALS patients management. The sponsor organizations had no role in data collections and analysis and did not participate to writing and approving the manuscript. The information reported in the manuscript has never been reported elsewhere.

Author contributions

Study concept and design: Maria Claudia Torrieri, Umberto Manera, Gabriele Mora, Letizia Mazzini, Cristina Moglia, Andrea Calvo, Adriano Chiò. Data analysis: Maria Claudia Torrieri and Umberto Manera. Data interpretation: Maria Claudia Torrieri, Umberto Manera, Gabriele Mora, Antonio Canosa, Rosario Vasta, Alessio Mattei, Letizia Mazzini, Cristina Moglia, Andrea Calvo, Adriano Chiò. Acquisition of data: all coauthors. Original draft preparation: Maria Claudia Torrieri and Umberto Manera. Review and editing: Gabriele Mora, Antonio Canosa, Rosario Vasta, Giuseppe Fuda, Paolina Salamone, Maurizio Grassano, Paolo Cugnasco, Nicola Launaro, Fabiola De Marchi, Alessio Mattei, Letizia Mazzini, Cristina Moglia, Andrea Calvo, Adriano Chiò. Supervision: Gabriele Mora, Cristina Moglia, Andrea Calvo, Adriano Chiò. Administrative, technical or material support: Antonio Canosa, Rosario Vasta, Giuseppe Fuda, Paolina Salamone, Maurizio Grassano, Paolo Cugnasco, Fabiola De Marchi, Alessio Mattei, Letizia Mazzini.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Data availability statement

Data will be available upon request by interested researchers.

Additional information

Funding

Professor Calvo has received research grant from Cytokinetics. Prof Chiò serves on scientific advisory boards for Mitsubishi Tanabe, Roche, Biogen, Denali Pharma, AC Immune, and Cytokinetics.This work was in part supported by the Italian Ministry of Health [Ministero della Salute, Ricerca Sanatoria Finalizzata, grant RF-2016-02362405], the European Commission’s Health Seventh Framework Programme [FP7/2007-2013 under grant agreement 259867], the Italian Ministry of Education, University and Research [Progetti di Ricerca di Rilevante Interesse Nazionale, PRIN, grant 2017SNW5MB], the Joint Programme – Neurodegenerative Disease Research (ALS-Care, Strength and Brain-Mend projects), granted by Italian Ministry of Education, University and Research. This study was performed under the Department of Excellence grant of the Italian Ministry of Education, University and Research to the ‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, Italy.