Claus F Vogelmeier1, Anne Fuhlbrigge2, Alexandra Jauhiainen3, Lieke E J M Scheepers3, Thomas Bengtsson4, Stefan Peterson4, Niklas Karlsson5, Tariq Sethi6, Nicholas Locantore7, Ruth Tal-Singer7, Stephen Rennard8, Malin Fagerås5, Carla A Da Silva9. 1. Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg, Germany, Member of the German Center for Lung Research (DZL). 2. Pulmonary Sciences and Critical Care, Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA. 3. AstraZeneca, BioPharma Early Biometrics and Statistical Innovation, Data Science & AI, BioPharmaceuticals R&D, Gothenburg, Sweden. 4. StatMind Statistical and Mathematical Modelling, Innovation and Design AB, Lund, Sweden. 5. AstraZeneca, BioPharmaceuticals Medical, Gothenburg, Sweden. 6. Emeritus Professor Respiratory Medicine, Kings College, London, UK; Galecto Biotech, London, UK. 7. GlaxoSmithKline R&D, Medical Innovation Value Evidence and Outcomes, Collegeville, PA, USA. 8. AstraZeneca, BioPharmaceuticals R&D, Cambridge, UK. 9. AstraZeneca, Early Respiratory & Immunology (R&I) Clinical Development, BioPharmaceuticals R&D, Gothenburg, Sweden. Electronic address: Carla.DaSilva@astrazeneca.com.
Abstract
BACKGROUND: Frequency of moderate and severe chronic obstructive pulmonary disease exacerbations is an important endpoint in clinical trials, but makes them large and lengthy when powered to evaluate it. We aimed to develop a composite endpoint (COPDCompEx) that could predict treatment effect on exacerbations, enabling the design of shorter early phase clinical trials requiring fewer patients. METHODS: In this post hoc analysis, data from 20 randomized controlled trials were used to develop and test COPDCompEx. Diary events were tested against predefined threshold values for peak expiratory flow, reliever medication use, and symptoms. A COPDCompEx event was defined as first occurrence of a diary event, a moderate or severe exacerbation, or a study dropout. Ratios of event frequency, treatment effect and future trial sample size were compared between COPDCompEx and moderate and severe exacerbations. FINDINGS: At 3 months, the proportion of patients experiencing COPDCompEx events increased over 3-fold versus exacerbations alone. All components contributed to COPDCompEx event rate. Treatment effects at 3 months were closely matched between COPDCompEx and exacerbations, and the large net gain in power substantially reduced the required sample size. INTERPRETATION: COPDCompEx may be used to predict treatment effect on moderate and severe exacerbations of chronic obstructive pulmonary disease. This may enable the design of shorter Phase 2 clinical trials requiring fewer patients when compared with current exacerbation studies, with exacerbations as a key Phase 3 endpoint. This would, therefore, allow more efficient decision-making with reduced burden and risk to study participants.
BACKGROUND: Frequency of moderate and severe chronic obstructive pulmonary disease exacerbations is an important endpoint in clinical trials, but makes them large and lengthy when powered to evaluate it. We aimed to develop a composite endpoint (COPDCompEx) that could predict treatment effect on exacerbations, enabling the design of shorter early phase clinical trials requiring fewer patients. METHODS: In this post hoc analysis, data from 20 randomized controlled trials were used to develop and test COPDCompEx. Diary events were tested against predefined threshold values for peak expiratory flow, reliever medication use, and symptoms. A COPDCompEx event was defined as first occurrence of a diary event, a moderate or severe exacerbation, or a study dropout. Ratios of event frequency, treatment effect and future trial sample size were compared between COPDCompEx and moderate and severe exacerbations. FINDINGS: At 3 months, the proportion of patients experiencing COPDCompEx events increased over 3-fold versus exacerbations alone. All components contributed to COPDCompEx event rate. Treatment effects at 3 months were closely matched between COPDCompEx and exacerbations, and the large net gain in power substantially reduced the required sample size. INTERPRETATION: COPDCompEx may be used to predict treatment effect on moderate and severe exacerbations of chronic obstructive pulmonary disease. This may enable the design of shorter Phase 2 clinical trials requiring fewer patients when compared with current exacerbation studies, with exacerbations as a key Phase 3 endpoint. This would, therefore, allow more efficient decision-making with reduced burden and risk to study participants.
Authors: Fernando J Martinez; Alvar Agusti; Bartolome R Celli; MeiLan K Han; James P Allinson; Surya P Bhatt; Peter Calverley; Sanjay H Chotirmall; Badrul Chowdhury; Patrick Darken; Carla A Da Silva; Gavin Donaldson; Paul Dorinsky; Mark Dransfield; Rosa Faner; David M Halpin; Paul Jones; Jerry A Krishnan; Nicholas Locantore; Fernando D Martinez; Hana Mullerova; David Price; Klaus F Rabe; Colin Reisner; Dave Singh; Jørgen Vestbo; Claus F Vogelmeier; Robert A Wise; Ruth Tal-Singer; Jadwiga A Wedzicha Journal: Am J Respir Crit Care Med Date: 2022-02-01 Impact factor: 21.405