Identifying frailty in trials: an analysis of individual participant data from trials of novel pharmacological interventions

Hanlon, P. , Butterly, E., Lewsey, J. , Siebert, S. , Mair, F. S. and McAllister, D. A. (2020) Identifying frailty in trials: an analysis of individual participant data from trials of novel pharmacological interventions. BMC Medicine, 18, 309. (doi: 10.1186/s12916-020-01752-1) (PMID:33087107) (PMCID:PMC7579922)

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Abstract

Background: Frailty is common in clinical practice, but trials rarely report on participant frailty. Consequently, clinicians and guideline-developers assume frailty is largely absent from trials and have questioned the relevance of trial findings to frail people. Therefore, we examined frailty in phase 3/4 industry-sponsored clinical trials of pharmacological interventions for three exemplar conditions: type 2 diabetes mellitus (T2DM), rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD). Methods: We constructed a 40-item frailty index (FI) in 19 clinical trials (7 T2DM, 8 RA, 4 COPD, mean age 42–65 years) using individual-level participant data. Participants with a FI > 0.24 were considered ‘frail’. Baseline disease severity was assessed using HbA1c for T2DM, Disease Activity Score-28 (DAS28) for RA, and % predicted FEV1 for COPD. Using generalised gamma regression, we modelled FI on age, sex, and disease severity. In negative binomial regression, we modelled serious adverse event rates on FI and combined results for each index condition in a random-effects meta-analysis. Results: All trials included frail participants: prevalence 7–21% in T2DM trials, 33–73% in RA trials, and 15–22% in COPD trials. The 99th centile of the FI ranged between 0.35 and 0.45. Female sex was associated with higher FI in all trials. Increased disease severity was associated with higher FI in RA and COPD, but not T2DM. Frailty was associated with age in T2DM and RA trials, but not in COPD. Across all trials, and after adjusting for age, sex, and disease severity, higher FI predicted increased risk of serious adverse events; the pooled incidence rate ratios (per 0.1-point increase in FI scale) were 1.46 (95% CI 1.21–1.75), 1.45 (1.13–1.87), and 1.99 (1.43–2.76) for T2DM, RA, and COPD, respectively. Conclusion: The upper limit of frailty in trials is lower than has been described in the general population. However, mild to moderate frailty was common, suggesting trial data may be harnessed to inform disease management in people living with frailty. Participants with higher FI experienced more serious adverse events, suggesting screening for frailty in trial participants would enable identification of those that merit closer monitoring. Frailty is identifiable and prevalent among middle-aged and older participants in phase 3/4 drug trials and has clinically important safety implications.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McAllister, Professor David and Butterly, Dr Elaine and Hanlon, Dr Peter and Siebert, Professor Stefan and Lewsey, Professor Jim and Mair, Professor Frances
Authors: Hanlon, P., Butterly, E., Lewsey, J., Siebert, S., Mair, F. S., and McAllister, D. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > General Practice and Primary Care
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Health Economics and Health Technology Assessment
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Public Health
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:BMC Medicine
Publisher:BioMed Central
ISSN:1741-7015
ISSN (Online):1741-7015
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in BMC Medicine 18:309
Publisher Policy:Reproduced under a Creative Commons Licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
305232Understanding prevalence and impact of frailty in chronic illness and implications for clinical managementFrances MairMedical Research Council (MRC)MR/S021949/1HW - General Practice and Primary Care
173492Combining efficacy estimates from clinical trials with the natural history obtained from large routine healthcare databases to determine net overall treatment benefitsDavid McAllisterWellcome Trust (WELLCOTR)201492/Z/16/ZInstitute of Health & Wellbeing