Improvement in exercise duration, lung function and well-being in G551D-cystic fibrosis patients

a double-blind, placebo-controlled, randomized, cross-over study with ivacaftor treatment

Deirdre Edgeworth, Dominic Keating, Matthew Ellis, Brenda Button, Elyssa Williams, Denise Clark, Audrey Tierney, Stephane Heritier, Tom Kotsimbos, John Wilson

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

Abstract

G551D, a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, results in impaired chloride channel function in cystic fibrosis (CF) with multiple end-organ manifestations. The effect of ivacaftor, a CFTR-potentiator, on exercise capacity in CF is unknown. Twenty G551D-CF patients were recruited to a single-centre, double-blind, placebo-controlled, 28-day crossover study of ivacaftor. Variables measured included percentage change from baseline (%Δ) of VO2max (maximal oxygen consumption, primary outcome) during cardiopulmonary exercise testing (CPET), relevant other CPET physiological variables, lung function, body mass index (BMI), sweat chloride and disease-specific health related quality of life (QOL) measures (CFQ-R and Alfred Wellness (AWEscore)). %ΔVO2max was unchanged compared with placebo as was %Δminute ventilation. However, %Δexercise time (mean 7.3, CI 0.5-14,1, P=0.0222) significantly increased as did %ΔFEV1 (11.7%, range 5.3-18.1, P<0·005) and %ΔBMI (1.2%, range 0.1-2.3, P=0·0393) whereas sweat chloride decreased (mean -43.4; range -55.5-18.1 mmol·l-1, P<0·005). Total and activity based domains in both CFQ-R and AWEscore also increased. A positive treatment effect on spirometry, BMI (increased), SCT (decreased) and total and activity based CF-specific QOL measures was expected. However, the lack of discernible improvement in VO2max and VE despite other positive changes including spirometric lung function and exercise time with a 28-day ivacaftor intervention suggests that ventilatory parameters are not the sole driver of change in exercise capacity in this study cohort. Investigation over a more prolonged period may delineate the potential interdependencies of the observed discordances over time.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov-NCT01937325.

Original languageEnglish
Pages (from-to)2037-2045
Number of pages9
JournalClinical Science
Volume131
Issue number15
DOIs
Publication statusPublished - 1 Aug 2017

Keywords

  • cystic fibrosis transmembrane conductance regulator
  • exercise
  • gene therapy

Cite this

@article{2efda8adb700474c95c9c5ee56a26404,
title = "Improvement in exercise duration, lung function and well-being in G551D-cystic fibrosis patients: a double-blind, placebo-controlled, randomized, cross-over study with ivacaftor treatment",
abstract = "G551D, a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, results in impaired chloride channel function in cystic fibrosis (CF) with multiple end-organ manifestations. The effect of ivacaftor, a CFTR-potentiator, on exercise capacity in CF is unknown. Twenty G551D-CF patients were recruited to a single-centre, double-blind, placebo-controlled, 28-day crossover study of ivacaftor. Variables measured included percentage change from baseline ({\%}Δ) of VO2max (maximal oxygen consumption, primary outcome) during cardiopulmonary exercise testing (CPET), relevant other CPET physiological variables, lung function, body mass index (BMI), sweat chloride and disease-specific health related quality of life (QOL) measures (CFQ-R and Alfred Wellness (AWEscore)). {\%}ΔVO2max was unchanged compared with placebo as was {\%}Δminute ventilation. However, {\%}Δexercise time (mean 7.3, CI 0.5-14,1, P=0.0222) significantly increased as did {\%}ΔFEV1 (11.7{\%}, range 5.3-18.1, P<0·005) and {\%}ΔBMI (1.2{\%}, range 0.1-2.3, P=0·0393) whereas sweat chloride decreased (mean -43.4; range -55.5-18.1 mmol·l-1, P<0·005). Total and activity based domains in both CFQ-R and AWEscore also increased. A positive treatment effect on spirometry, BMI (increased), SCT (decreased) and total and activity based CF-specific QOL measures was expected. However, the lack of discernible improvement in VO2max and VE despite other positive changes including spirometric lung function and exercise time with a 28-day ivacaftor intervention suggests that ventilatory parameters are not the sole driver of change in exercise capacity in this study cohort. Investigation over a more prolonged period may delineate the potential interdependencies of the observed discordances over time.TRIAL REGISTRATION NUMBER: ClinicalTrials.gov-NCT01937325.",
keywords = "cystic fibrosis transmembrane conductance regulator, exercise, gene therapy",
author = "Deirdre Edgeworth and Dominic Keating and Matthew Ellis and Brenda Button and Elyssa Williams and Denise Clark and Audrey Tierney and Stephane Heritier and Tom Kotsimbos and John Wilson",
year = "2017",
month = "8",
day = "1",
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language = "English",
volume = "131",
pages = "2037--2045",
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Improvement in exercise duration, lung function and well-being in G551D-cystic fibrosis patients : a double-blind, placebo-controlled, randomized, cross-over study with ivacaftor treatment. / Edgeworth, Deirdre; Keating, Dominic; Ellis, Matthew; Button, Brenda; Williams, Elyssa; Clark, Denise; Tierney, Audrey; Heritier, Stephane; Kotsimbos, Tom; Wilson, John.

In: Clinical Science, Vol. 131, No. 15, 01.08.2017, p. 2037-2045.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Improvement in exercise duration, lung function and well-being in G551D-cystic fibrosis patients

T2 - a double-blind, placebo-controlled, randomized, cross-over study with ivacaftor treatment

AU - Edgeworth, Deirdre

AU - Keating, Dominic

AU - Ellis, Matthew

AU - Button, Brenda

AU - Williams, Elyssa

AU - Clark, Denise

AU - Tierney, Audrey

AU - Heritier, Stephane

AU - Kotsimbos, Tom

AU - Wilson, John

PY - 2017/8/1

Y1 - 2017/8/1

N2 - G551D, a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, results in impaired chloride channel function in cystic fibrosis (CF) with multiple end-organ manifestations. The effect of ivacaftor, a CFTR-potentiator, on exercise capacity in CF is unknown. Twenty G551D-CF patients were recruited to a single-centre, double-blind, placebo-controlled, 28-day crossover study of ivacaftor. Variables measured included percentage change from baseline (%Δ) of VO2max (maximal oxygen consumption, primary outcome) during cardiopulmonary exercise testing (CPET), relevant other CPET physiological variables, lung function, body mass index (BMI), sweat chloride and disease-specific health related quality of life (QOL) measures (CFQ-R and Alfred Wellness (AWEscore)). %ΔVO2max was unchanged compared with placebo as was %Δminute ventilation. However, %Δexercise time (mean 7.3, CI 0.5-14,1, P=0.0222) significantly increased as did %ΔFEV1 (11.7%, range 5.3-18.1, P<0·005) and %ΔBMI (1.2%, range 0.1-2.3, P=0·0393) whereas sweat chloride decreased (mean -43.4; range -55.5-18.1 mmol·l-1, P<0·005). Total and activity based domains in both CFQ-R and AWEscore also increased. A positive treatment effect on spirometry, BMI (increased), SCT (decreased) and total and activity based CF-specific QOL measures was expected. However, the lack of discernible improvement in VO2max and VE despite other positive changes including spirometric lung function and exercise time with a 28-day ivacaftor intervention suggests that ventilatory parameters are not the sole driver of change in exercise capacity in this study cohort. Investigation over a more prolonged period may delineate the potential interdependencies of the observed discordances over time.TRIAL REGISTRATION NUMBER: ClinicalTrials.gov-NCT01937325.

AB - G551D, a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, results in impaired chloride channel function in cystic fibrosis (CF) with multiple end-organ manifestations. The effect of ivacaftor, a CFTR-potentiator, on exercise capacity in CF is unknown. Twenty G551D-CF patients were recruited to a single-centre, double-blind, placebo-controlled, 28-day crossover study of ivacaftor. Variables measured included percentage change from baseline (%Δ) of VO2max (maximal oxygen consumption, primary outcome) during cardiopulmonary exercise testing (CPET), relevant other CPET physiological variables, lung function, body mass index (BMI), sweat chloride and disease-specific health related quality of life (QOL) measures (CFQ-R and Alfred Wellness (AWEscore)). %ΔVO2max was unchanged compared with placebo as was %Δminute ventilation. However, %Δexercise time (mean 7.3, CI 0.5-14,1, P=0.0222) significantly increased as did %ΔFEV1 (11.7%, range 5.3-18.1, P<0·005) and %ΔBMI (1.2%, range 0.1-2.3, P=0·0393) whereas sweat chloride decreased (mean -43.4; range -55.5-18.1 mmol·l-1, P<0·005). Total and activity based domains in both CFQ-R and AWEscore also increased. A positive treatment effect on spirometry, BMI (increased), SCT (decreased) and total and activity based CF-specific QOL measures was expected. However, the lack of discernible improvement in VO2max and VE despite other positive changes including spirometric lung function and exercise time with a 28-day ivacaftor intervention suggests that ventilatory parameters are not the sole driver of change in exercise capacity in this study cohort. Investigation over a more prolonged period may delineate the potential interdependencies of the observed discordances over time.TRIAL REGISTRATION NUMBER: ClinicalTrials.gov-NCT01937325.

KW - cystic fibrosis transmembrane conductance regulator

KW - exercise

KW - gene therapy

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U2 - 10.1042/CS20170995

DO - 10.1042/CS20170995

M3 - Article

VL - 131

SP - 2037

EP - 2045

JO - Clinical Science and Molecular Medicine

JF - Clinical Science and Molecular Medicine

SN - 0009-9287

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