Highlights
- •In randomized controlled trials that used the Lung Clearance Index as an outcome, there is a discordance between planned sample size required to observe statistically significant treatment effects and the magnitude of the treatment effects that are observed.
- •Large improvements in Lung Clearance Index for a few individuals can influence the interpretation of the effect size and may bias prospective sample size calculations.
- •Lung clearance index requires as little as 1/3 of the total sample size to detect equivalent changes with spirometry endpoints such as forced expiratory volume in 1 second (FEV1).
Abstract
Background
With the increasing availability of highly effective modulators for people living
with cystic fibrosis (CF), there is a need to re-design research studies to reflect
the changing epidemiology of the CF population. The lung clearance index (LCI), a
sensitive physiological measure of lung function, may be ideally suited as an endpoint
in the era of CF modulator therapies. In this study we describe study design considerations
for implementing LCI into interventional and observational research.
Methods
Simulations were used to estimate the required sample size to detect a range of treatment
effects for interventional studies (including cross-over trials) and to track lung
disease progression in observational studies.
Results
Using published treatment effects to inform the design of prospective studies can
lead to inefficient study designs. Large improvements in LCI for a few individuals
can skew results and can influence interpretations of treatment effects. Adjusting
for baseline LCI can help to improve the efficiency of a study. Compared to the forced
expiratory volume in 1 second (FEV1), analysis using LCI as an endpoint requires as little as one third of the total
sample size.
Conclusions
Planning of prospective studies that include LCI as an endpoint need to consider baseline
LCI and disease severity of the study population; whereas interpretation of results
needs to consider whether a few individuals skew the overall treatment effect.
Keywords
Abbreviations:
LCI (Lung Clearance Index)To read this article in full you will need to make a payment
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References
- Projecting the impact of delayed access to elexacaftor/tezacaftor/ivacaftor for people with cystic fibrosis.J Cyst Fibros. 2020; https://doi.org/10.1016/j.jcf.2020.07.017
- Cystic fibrosis drug trial design in the era of CFTR modulators associated with substantial clinical benefit: stakeholders’ consensus view.J Cyst Fibros. 2020; 19: 688-695https://doi.org/10.1016/j.jcf.2020.05.012
- The changing epidemiology and demography of cystic fibrosis.Presse Med. 2017; 46: e87-e95https://doi.org/10.1016/j.lpm.2017.04.012
- Lung clearance index in adults and children with cystic fibrosis.Chest. 2016; 150: 1323-1332https://doi.org/10.1016/j.chest.2016.06.029
- An overview of endpoints for cystic fibrosis clinical trials: one size does not fit all.Proc Am Thorac Soc. 2007; 4: 299-301https://doi.org/10.1513/pats.200611-178HT
- Physiologic endpoints for clinical studies for cystic fibrosis.J Cyst Fibros. 2016; 15: 416-423https://doi.org/10.1016/j.jcf.2016.05.014
- Innovating cystic fibrosis clinical trial designs in an era of successful standard of care therapies.Curr Opin Pulm Med. 2017; 23: 530-535https://doi.org/10.1016/j.physbeh.2017.03.040
- Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis.Thorax. 2004; 59: 1068-1073https://doi.org/10.1136/thx.2004.022590
- Reduced bacterial colony count of anaerobic bacteria is associated with a worsening in lung clearance index and inflammation in cystic fibrosis.PLoS ONE. 2015; 10https://doi.org/10.1371/journal.pone.0126980
- Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis.Thorax. 2008; 63: 135-140https://doi.org/10.1136/thx.2007.082628
- Lung clearance index at 4 years predicts subsequent lung function in children with cystic fibrosis.Am J Respir Crit Care Med. 2011; 183: 752-758https://doi.org/10.1164/rccm.200911-1646OC
- Lung clearance index is a repeatable and sensitive indicator of radiological changes in bronchiectasis.Am J Respir Crit Care Med. 2014; 189: 586-592https://doi.org/10.1164/rccm.201310-1747OC
- Lung clearance index: normal values, repeatability, and reproducibility in healthy children and adolescents.Pediatr Pulmonol. 2009; 44: 1180-1185https://doi.org/10.1002/ppul.21093
- Normative data for multiple breath washout outcomes in school-aged Caucasian children.Eur Respir J. 2020; 55https://doi.org/10.1183/13993003.01302-2019
- Lung clearance index: evidence for use in clinical trials in cystic fibrosis.J Cyst Fibros. 2014; 13: 123-138https://doi.org/10.1016/j.jcf.2013.09.005
- How small is big: sample size and skewness.Assessment. 2018; 25: 793-800https://doi.org/10.1177/1073191116669784
- Points to consider on adjustment for baseline covariates.2003 (London)
- The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis.Eur Respir J. 2011; 37: 806-812https://doi.org/10.1183/09031936.00072510
- A phase 3 open-label study of elexacaftor/tezacaftor/ivacaftor in children 6 through 11 years of age with cystic fibrosis and at least one F508del allele.Am J Respir Crit Care Med. 2021; 203: 1522-1532https://doi.org/10.1164/RCCM.202102-0509OC/SUPPL_FILE/DISCLOSURES.PDF
- Inter-test reproducibility of the lung clearance index measured by multiple breath washout.Eur Respir J. 2017; 50https://doi.org/10.1183/13993003.00433-2017
- Preschool multiple-breath washout testing an official American thoracic society technical statement.Am J Respir Crit Care Med. 2018; 197: e1-19https://doi.org/10.1164/rccm.201801-0074ST
- Lung clearance index to track acute respiratory events in school-age children with cystic fibrosis.Am J Respir Crit Care Med. 2020; https://doi.org/10.1164/rccm.202006-2433oc
- Is lung clearance index (LCI) affected by the severity of lung disease in CF?.J Pulm Respir Med. 2017; 07: 1-7https://doi.org/10.4172/2161-105x.1000392
- Inhaled hypertonic saline in preschool children with cystic fibrosis (SHIP): a multicentre, randomised, double-blind, placebo-controlled trial.Lancet Respir Med. 2019; 7: 802-809https://doi.org/10.1016/S2213-2600(19)30187-0
- Lung clearance index and steroid response in pediatric severe asthma.Pediatr Pulmonol. 2020; 55: 890-898https://doi.org/10.1002/ppul.24675
- A randomized controlled trial to evaluate the lung clearance index as an outcome measure for early phase studies in patients with cystic fibrosis.Respir Med. 2016; 112: 59-64https://doi.org/10.1016/j.rmed.2016.01.020
- Progression of lung disease in preschool patients with cystic fibrosis.Am J Respir Crit Care Med. 2017; 195: 1216-1225https://doi.org/10.1164/rccm.201610-2158OC
- Determinants of lung disease progression measured by lung clearance index in children with cystic fibrosis.Eur Respir J. 2021; 58https://doi.org/10.1183/13993003.03380-2020
- Longitudinal course of clinical lung clearance index in children with cystic fibrosis.Eur Respir J. 2020; (2002686)https://doi.org/10.1183/13993003.02686-2020
- Variability of lung clearance index in clinically stable cystic fibrosis lung disease in school age children.J Cyst Fibros. 2018; 17: 236-241https://doi.org/10.1016/j.jcf.2017.08.004
- Correction of sensor crosstalk error in Exhalyzer D multiple-breath washout device significantly impacts outcomes in children with cystic fibrosis.J Appl Physiol Respir Environ Exerc Physiol. 2021; 131: 1148-1156https://doi.org/10.1152/japplphysiol.00338.2021
- Impact of cross-sensitivity error correction on representative nitrogen-based multiple breath washout data from clinical trials.J Cyst Fibros. 2021; https://doi.org/10.1016/j.jcf.2021.08.033
- Integrating the multiple breath washout test into international multicentre trials.J Cyst Fibros. 2020; 19: 602-607https://doi.org/10.1016/j.jcf.2019.11.006
- Hypertonic saline improves the LCI in paediatric patients with CF with normal lung function.ThoraxThorax. 2010; 65: 379-383https://doi.org/10.1136/thx.2009.125831
- Lung clearance index as an outcome measure for clinical trials in young children with cystic fibrosis. A pilot study using inhaled hypertonic saline.Am J Respir Crit Care Med. 2013; 188: 456-460https://doi.org/10.1164/rccm.201302-0219OC
- Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial.Lancet Respir Med. 2013; 1: 630-638https://doi.org/10.1016/S2213-2600(13)70182-6
- Lung clearance index to monitor treatment response in pulmonary exacerbations in preschool children with cystic fibrosis Cystic fibrosis.Thorax. 2018; 73: 451-458https://doi.org/10.1136/thoraxjnl-2017-210979
- Withdrawal of dornase alfa increases ventilation inhomogeneity in children with cystic fibrosis.J Cyst Fibros. 2021; https://doi.org/10.1016/j.jcf.2021.02.004
Article info
Publication history
Published online: November 16, 2022
Accepted:
November 10,
2022
Received in revised form:
October 16,
2022
Received:
July 22,
2022
Publication stage
In Press Corrected ProofFootnotes
✰This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Identification
Copyright
© 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
