Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial

on behalf of the, VX14-809-109 investigator group, VX14-809-109 investigator group

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Abstract

Background Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6–11 years homozygous for F508del-CFTR. Methods In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV1) of 70 or more, and lung clearance index2·5 (LCI2·5) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs ≥25 kg) and ppFEV1 severity (<90 vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI2·5 from all on-treatment study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473. Findings Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was −1·09 units (95% CI −1·43 to −0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was −20·8 mmol/L (95% CI −23·4 to −18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV1 from all on-treatment study visits until week 24 was 2·4 (95% CI 0·4–4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group. Interpretation Treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI2·5 and ppFEV1, versus placebo in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR. The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor. Funding Vertex Pharmaceuticals.

Original languageEnglish (US)
Pages (from-to)557-567
Number of pages11
JournalThe Lancet Respiratory Medicine
Volume5
Issue number7
DOIs
StatePublished - Jul 2017

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Cystic Fibrosis Transmembrane Conductance Regulator
Cystic Fibrosis
Placebos
Safety
ivacaftor drug combination lumacaftor
Lung
Least-Squares Analysis
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR : a randomised, placebo-controlled phase 3 trial. / on behalf of the; VX14-809-109 investigator group; VX14-809-109 investigator group.

In: The Lancet Respiratory Medicine, Vol. 5, No. 7, 07.2017, p. 557-567.

Research output: Contribution to journalArticle

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title = "Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial",
abstract = "Background Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6–11 years homozygous for F508del-CFTR. Methods In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV1) of 70 or more, and lung clearance index2·5 (LCI2·5) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs ≥25 kg) and ppFEV1 severity (<90 vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI2·5 from all on-treatment study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473. Findings Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was −1·09 units (95{\%} CI −1·43 to −0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was −20·8 mmol/L (95{\%} CI −23·4 to −18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV1 from all on-treatment study visits until week 24 was 2·4 (95{\%} CI 0·4–4·4, p=0·0182). 196 (96{\%}) of 204 patients reported adverse events, most of which were mild (87 [43{\%}]) or moderate (98 [48{\%}]). Treatment was discontinued due to adverse events in three (3{\%}) of 103 patients in the lumacaftor and ivacaftor group and two (2{\%}) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13{\%}) of 103 patients in the lumacaftor and ivacaftor group and 11 (11{\%}) of 101 patients in the placebo group. Interpretation Treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI2·5 and ppFEV1, versus placebo in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR. The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor. Funding Vertex Pharmaceuticals.",
author = "{on behalf of the} and {VX14-809-109 investigator group} and {VX14-809-109 investigator group} and Felix Ratjen and Christopher Hug and Gautham Marigowda and Simon Tian and Xiaohong Huang and Sanja Stanojevic and Milla, {Carlos E.} and Robinson, {Paul D.} and David Waltz and Davies, {Jane C.} and Margaret Rosenfeld and Timothy Starner and George Retsch-Bogart and James Chmiel and David Orenstein and Carlos Milla and Ronald Rubenstein and Seth Walker and Alexandra Cornell and Fadi Asfour and Philip Black and Colombo, {John Louis} and Deborah Froh and Susanna McColley and Fadel Ruiz and Diana Quintero and Alicia Casey and Gary Mueller and Patrick Flume and Floyd Livingston and Michael Rock and Brian O'Sullivan and Howard Schmidt and Thomas Lahiri and John McNamara and Aaron Chidekel and Laura Sass and Thomas Keens and David Schaeffer and Melinda Solomon and Mark Chilvers and Larry Lands and Sibylle Junge and Matthias Griese and Doris Staab and Tacjana Pressler and {van Koningsburggen-Rietschel}, Silke and Lutz Naehrlich and Alastair Reid and Ian Balfour-Lynn",
year = "2017",
month = "7",
doi = "10.1016/S2213-2600(17)30215-1",
language = "English (US)",
volume = "5",
pages = "557--567",
journal = "The Lancet Respiratory Medicine",
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TY - JOUR

T1 - Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR

T2 - a randomised, placebo-controlled phase 3 trial

AU - on behalf of the

AU - VX14-809-109 investigator group

AU - VX14-809-109 investigator group

AU - Ratjen, Felix

AU - Hug, Christopher

AU - Marigowda, Gautham

AU - Tian, Simon

AU - Huang, Xiaohong

AU - Stanojevic, Sanja

AU - Milla, Carlos E.

AU - Robinson, Paul D.

AU - Waltz, David

AU - Davies, Jane C.

AU - Rosenfeld, Margaret

AU - Starner, Timothy

AU - Retsch-Bogart, George

AU - Chmiel, James

AU - Orenstein, David

AU - Milla, Carlos

AU - Rubenstein, Ronald

AU - Walker, Seth

AU - Cornell, Alexandra

AU - Asfour, Fadi

AU - Black, Philip

AU - Colombo, John Louis

AU - Froh, Deborah

AU - McColley, Susanna

AU - Ruiz, Fadel

AU - Quintero, Diana

AU - Casey, Alicia

AU - Mueller, Gary

AU - Flume, Patrick

AU - Livingston, Floyd

AU - Rock, Michael

AU - O'Sullivan, Brian

AU - Schmidt, Howard

AU - Lahiri, Thomas

AU - McNamara, John

AU - Chidekel, Aaron

AU - Sass, Laura

AU - Keens, Thomas

AU - Schaeffer, David

AU - Solomon, Melinda

AU - Chilvers, Mark

AU - Lands, Larry

AU - Junge, Sibylle

AU - Griese, Matthias

AU - Staab, Doris

AU - Pressler, Tacjana

AU - van Koningsburggen-Rietschel, Silke

AU - Naehrlich, Lutz

AU - Reid, Alastair

AU - Balfour-Lynn, Ian

PY - 2017/7

Y1 - 2017/7

N2 - Background Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6–11 years homozygous for F508del-CFTR. Methods In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV1) of 70 or more, and lung clearance index2·5 (LCI2·5) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs ≥25 kg) and ppFEV1 severity (<90 vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI2·5 from all on-treatment study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473. Findings Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was −1·09 units (95% CI −1·43 to −0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was −20·8 mmol/L (95% CI −23·4 to −18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV1 from all on-treatment study visits until week 24 was 2·4 (95% CI 0·4–4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group. Interpretation Treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI2·5 and ppFEV1, versus placebo in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR. The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor. Funding Vertex Pharmaceuticals.

AB - Background Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6–11 years homozygous for F508del-CFTR. Methods In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV1) of 70 or more, and lung clearance index2·5 (LCI2·5) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs ≥25 kg) and ppFEV1 severity (<90 vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI2·5 from all on-treatment study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473. Findings Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was −1·09 units (95% CI −1·43 to −0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was −20·8 mmol/L (95% CI −23·4 to −18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV1 from all on-treatment study visits until week 24 was 2·4 (95% CI 0·4–4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group. Interpretation Treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI2·5 and ppFEV1, versus placebo in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR. The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor. Funding Vertex Pharmaceuticals.

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U2 - 10.1016/S2213-2600(17)30215-1

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JF - The Lancet Respiratory Medicine

SN - 2213-2600

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