Abstract
Background: Ivacaftor has been previously assessed in patients with cystic fibrosis with Gly551Asp-CFTR or other gating mutations. We assessed ivacaftor in patients with Arg117His-CFTR, a residual function mutation. Methods: We did a 24-week, placebo-controlled, double-blind, randomised clinical trial, which enrolled 69 patients with cystic fibrosis aged 6 years and older with Arg117His-CFTR and percentage of predicted forced expiratory volume in 1 s (% predicted FEV1) of at least 40. We randomly assigned eligible patients (1:1) to receive placebo or ivacaftor 150 mg every 12 h for 24 weeks. Randomisation was stratified by age (6-11, 12-17, and ≥18 years) and % predicted FEV1 (<70, ≥70 to ≤90, and >90). The primary outcome was the absolute change from baseline in % predicted FEV1 through week 24. Secondary outcomes included safety and changes in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores. An open-label extension enrolled 65 of the patients after washout; after 12 weeks, we did an interim analysis. Findings: After 24 weeks, the treatment difference in mean absolute change in % predicted FEV1 between ivacaftor (n=34) and placebo (n=35) was 2.1 percentage points (95% CI -1.13 to 5.35; p=0.20). Ivacaftor treatment resulted in significant treatment differences in sweat chloride (-24.0 mmol/L, 95% CI -28.01 to -19.93; p<0.0001) and CFQ-R respiratory domain (8.4, 2.17 to 14.61; p=0.009). In prespecified subgroup analyses, % predicted FEV1 significantly improved with ivacaftor in patients aged 18 years or older (treatment difference vs placebo: 5.0 percentage points, 95% CI 1.15 to 8.78; p=0.01), but not in patients aged 6-11 years (-6.3 percentage points, -11.96 to -0.71; p=0.03). In the extension study, both placebo-to-ivacaftor and ivacaftor-to-ivacaftor groups showed % predicted FEV1 improvement (absolute change from post-washout baseline at week 12: placebo-to-ivacaftor, 5.0 percentage points [p=0.0005]; ivacaftor-to-ivacaftor, 6.0 percentage points [p=0.006]). We did not identify any new safety concerns. The studies are registered with ClinicalTrials.gov (the randomised, placebo-controlled study, number NCT01614457; the open-label extension study, number NCT01707290). Interpretation: Although this study did not show a significant improvement in % predicted FEV1, ivacaftor did significantly improve sweat chloride and CFQ-R respiratory domain scores and lung function in adult patients with Arg117His-CFTR, indicating that ivacaftor might benefit patients with Arg117His-CFTR who have established disease. Funding: Vertex Pharmaceuticals Incorporated.
| Original language | English |
|---|---|
| Pages (from-to) | 524-533 |
| Number of pages | 10 |
| Journal | The Lancet Respiratory Medicine |
| Volume | 3 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2015 |
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: A double-blind, randomised controlled trial'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: The Lancet Respiratory Medicine, Vol. 3, No. 7, 07.2015, p. 524-533.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation
T2 - A double-blind, randomised controlled trial
AU - On behalf of the VX11-770-110 (KONDUCT) Study Group
AU - Moss, Richard B.
AU - Flume, Patrick A.
AU - Elborn, J. Stuart
AU - Cooke, Jon
AU - Rowe, Steven M.
AU - McColley, Susanna A.
AU - Rubenstein, Ronald C.
AU - Higgins, Mark
N1 - Funding Information: Treatment with ivacaftor, an oral CFTR potentiator, did not significantly improve lung function across the entire study population, as measured by the absolute change from baseline in % predicted FEV 1 through week 24 in patients with cystic fibrosis and Arg117His-CFTR . However, significant changes were recorded in patient-reported respiratory symptoms, as measured by the CFQ-R respiratory domain, and CFTR function, as measured by sweat chloride concentrations. Prespecified subgroup analyses revealed a significant treatment effect based on patient age category, a randomisation stratification criterion. This is the first randomised, controlled study of a CFTR potentiator in patients with the Arg117His-CFTR mutation—a mutation associated with residual CFTR channel function and variable clinical consequence. The findings extend the in-vitro data showing ivacaftor potentiation of Arg117His-CFTR channels, 25 as well as individual case reports. 26,27 In adults with the Arg117His mutation, there was a significant treatment difference in FEV 1 ( table 2 ). In addition to lung function, adult patients reported a mean improvement in cystic fibrosis respiratory symptoms ( table 2 ), well in excess of the minimal clinically important difference established for this domain. 24 By contrast with adults, children aged 6–11 years who received ivacaftor had a reduction from baseline in FEV 1 compared with placebo ( table 2 ) and reported no positive respiratory symptom changes. The contrasting results in adults and children were not due to differences in drug exposure, and sweat chloride reductions were comparable in both groups ( table 2 ). Examination of intra-individual changes in FEV 1 for the children, including multiple pretreatment assessments, showed that lung function was generally stable throughout the study with the exception of one outlier who had a pulmonary exacerbation. The % predicted FEV 1 decreased in both age groups after ivacaftor washout and increased following re-initiation of treatment in the open-label period, which is consistent with on–off effects of an active drug. The Arg117His mutation is associated with variable disease that often presents in adult life. 15 Different lung function responses with ivacaftor based on age in patients with Arg117His-CFTR might be related mainly to baseline disease state. This hypothesis is supported by the high % predicted FEV 1 in children at baseline (95·8% in children vs 64·5% in adults), possibly establishing a ceiling effect for % predicted FEV 1 in the younger population. Analyses of subgroups based on other characteristics associated with baseline disease status showed non-significant trends towards greater response to ivacaftor in groups with more advanced disease or risk thereof (ie, lower baseline % predicted FEV 1 , Pseudomonas aeruginosa infection, and 5T intron 8 variant on the Arg117His -carrying allele). Previous studies have shown that older patients with Arg117His-CFTR are more likely to present with respiratory symptoms, including infection with cystic fibrosis pathogens, and have decreased FEV 1 compared with younger patients. Likewise, adult populations with Arg117His-CFTR are enriched for the 5T variant relative to young children, who are more likely to have been diagnosed by newborn screening. 28,29 Additionally, two (12%) patients aged 6–11 years had positive Pseudomonas aeruginosa cultures compared with 32 (64%) adults, and 9 (53%) 6–11 year olds were Arg117His-5T versus 38 (76%) adults. The effect size of ivacaftor treatment in this Arg117His population is smaller than seen in other ivacaftor-responsive mutation types, such as Gly551Asp-CFTR . 3,19 Intrinsic differences in the molecular defects associated with these mutations might be the cause. Although the Gly551Asp mutation specifically restricts CFTR channel opening (gating), the Arg117His mutation is multifaceted. Arg117His-CFTR has a primary defect in channel gating, but the reduction is less than with Gly551Asp . 30 In addition to reduced gating, Arg117His also slightly reduces channel conductance. Despite these multiple defects, Arg117His-CFTR is associated with residual CFTR chloride transport, and the population of patients with this mutation exhibits greater phenotypic variability compared with patients with other common cystic fibrosis causing mutations. 31 Intragenic variation of the CFTR haplotype is a major genetic modifier affecting cystic fibrosis disease phenotype. 32,33 Variation in the length of the poly-T tract of the intron 8 acceptor splice site is a well characterised intragenic modifier of Arg117His expression. Variation at this site results in an increased rate of exon 9 skipping that contributes to the partial penetrance recorded in people with an Arg117His-CFTR allele and increases disease risk in some individuals (ie, 5T variant). 6,34 In view of the phenotypic variability associated with the Arg117His mutation, some countries have moved to eliminate Arg117His from newborn screening panels, particularly countries with a high prevalence of the 7T variant in the population. 14 Although some patients with cystic fibrosis and Arg117His-7T have substantial clinical disease, many others have congenital bilateral absence of the vas deferens or are asymptomatic. 6,14,35 The establishment of alternative diagnoses, such as cystic fibrosis metabolic syndrome, for patients identified by newborn screening who do not meet cystic fibrosis diagnostic criteria (sweat chloride or clinical symptoms) is another approach to the challenge associated with this mutation for phenotypic prediction. 36 Even individuals with Arg117His-5T can have very different clinical courses, which are probably affected by various other intragenic and extragenic factors. 14,34,37,38 The many contributors to Arg117His-CFTR expression make it challenging to predict clinical responsiveness to CFTR modulation solely on the basis of the intron 8 poly-T variant. The mean baseline sweat chloride concentration of 70·5 mmol/L in the present study versus baseline values exceeding 100 mmol/L in Gly551Asp studies is consistent with the residual chloride transport associated with Arg117His-CFTR . Ivacaftor's mechanism of action increases CFTR channel gating and therefore addresses only one aspect of the molecular defects associated with Arg117His . It is consistent with that notion that the magnitude of sweat chloride change in this study (–24 mmol/L) was not as large as that recorded in studies in patients with Gly551Asp-CFTR ; nevertheless, as in those previous studies, ivacaftor treatment reduced sweat chloride concentrations below the diagnostic threshold for cystic fibrosis (60 mmol/L) in many patients. Unlike the Gly551Asp and most other gating mutations, the Arg117His lesion is located in the extracellular loops of the CFTR channel and might promote destabilisation of the channel open state. 39 Therefore, a molecular basis might also exist for the different magnitude of effect noted in response to CFTR potentiation between patients with the Arg117His mutation and those with Gly551Asp . These results emphasise some of the challenges of assessing standard cystic fibrosis endpoints in patients with residual CFTR function mutations. In addition to the difficulty in showing FEV 1 improvement in individuals with limited pulmonary impairment, exacerbations were infrequent and did not show a difference between treatment and placebo. Similarly, there was no improvement in body-mass index with treatment because 90% of the study population were pancreatic sufficient, with a normal body-mass index at baseline. However, the effect size recorded in the CFQ-R respiratory domain in this trial was comparable to that of Gly551Asp studies. Considering that patients with mutations such as Arg117His might not develop symptoms until later in life, quality of life instruments such as CFQ-R might prove more useful in these patients compared with younger patients. Ivacaftor was well tolerated throughout the 24 week study. The safety profile was similar to the placebo group and to that reported in previous ivacaftor clinical trials. 3,19 No new safety concerns were identified. Consistent with those previous trials, adverse events were generally mild or moderate. In summary, ivacaftor treatment improved CFTR function in individuals with cystic fibrosis and the Arg117His mutation, and significantly improved lung function in adults. Trends toward greater pulmonary effects in subgroups with more advanced or symptomatic disease, along with improvements in patient-reported respiratory symptoms and consistent on–off treatment effects, suggest that ivacaftor benefits many patients with Arg117His-CFTR , particularly those with established disease. Contributors RBM, PAF, JSE, SMR, SAM, and RCR were study investigators, enrolled patients, and collected the study data. RBM, PAF, JSE, JC, SMR, SAM, RCR, and MH contributed to the interpretation of the data. RBM, PAF, JSE, JC, SMR, SAM, RCR, and MH participated in the critical review and revision of the manuscript and granted final approval for submission. Declaration of interests No author received an honorarium or other form of financial support related to the development of this manuscript. RBM has served as an investigator on Vertex Pharmaceuticals Incorporated, PTC Therapeutics, and Nivalis Therapeutics clinical studies; has participated in advisory boards or as a consultant for Celtaxys, GlaxoSmithKline, Gilead, Novartis, ProQR, Asubio, Proteostasis Therapeutics, and Vertex Pharmaceuticals Incorporated; and has received research funding from Genentech and Cystic Fibrosis Foundation Therapeutics Incorporated. PAF has served as an investigator on Vertex Pharmaceuticals Incorporated clinical studies; has participated in advisory boards or as a consultant for Aptalis, Enanta, Gilead, Insmed, Vertex Pharmaceuticals Incorporated, Novartis, and Pharmaxis Ltd; and has received grant support from Aptalis, Gilead, Bayer Healthcare AG, Insmed, Novartis, Vertex Pharmaceuticals Incorporated, Pharmaxis Ltd, Boehringer Ingelheim, Savara Pharmaceuticals, KaloBios, and Cystic Fibrosis Foundation Therapeutics Incorporated. JSE has served as an investigator in Vertex Pharmaceuticals Incorporated clinical studies; has participated in advisory boards or as a consultant for Vertex Pharmaceuticals Incorporated, Novartis, Bayer, Actavis, and Boehringer Ingelheim; and has received grant support from Gilead and Novartis. JC is an employee of Vertex Pharmaceuticals (Europe) Ltd and owns stock or options in Vertex Pharmaceuticals Incorporated. SMR has served as an investigator on Vertex Pharmaceuticals Incorporated, Novartis, PTC Therapeutics, and Bayer clinical studies; and has received grant funding from the National Institutes of Health, Forest Research Institute, Cystic Fibrosis Foundation Therapeutics Incorporated, Bayer Healthcare, Novartis Research Institute, Galapagos, and the American Lung Association. SAM has served as an investigator on Vertex Pharmaceuticals Incorporated, PTC Therapeutics, Novartis, Savara Incorporated, AbbVie Incorporated, Aptalis Pharma US Incorporated, and Janssen Research & Development LLC studies; has served as a consultant for Vertex Pharmaceuticals Incorporated; and has received grant funding from Cystic Fibrosis Foundation Therapeutics Incorporated, and the National Institutes of Health. RCR has served as an investigator on Vertex Pharmaceuticals Incorporated, KaloBios, and Nivalis Therapeutics clinical studies; and has received personal fees from Sanofi-Chattem, Pharmaxis, Cystic Fibrosis Foundation Therapeutics Incorporated, Bristol-Myers Squibb, Guidepoint Global, Gerson Lehrman Group, Wells Fargo Advisors, and Health Strategies Group, outside of the submitted work. MH is an employee of Vertex Pharmaceuticals (Europe) Ltd and owns stock or options in Vertex Pharmaceuticals Incorporated. Acknowledgments This study was sponsored by Vertex Pharmaceuticals Incorporated. This research publication was also supported by the National Center for Research Resources of the National Institutes of Health (NIH) grant 1UL1 RR025744 to Stanford University; Northwestern University Clinical and Translational Research Institute NIH grant number UL1TR000150; the South Carolina Clinical & Translational Research Institute, with an academic home at the Medical University of South Carolina, by NIH grant number UL1TR000062; University of Alabama Center for Clinical and Translational Science grant number UL1 TR000165; The University of Pennsylvania/Children's Hospital of Philadelphia Clinical and Translational Science Awards Consortium grant numbers UL1RR024134 (National Center for Research Resources) and UL1TR000003 (National Center for Advancing Translational Sciences); and by the Northern Ireland Clinical Research Network (Respiratory Health) in Belfast Health and Social Care Trust. Medical writing and editorial support were funded by Vertex Pharmaceuticals Incorporated. The authors thank Barry Lubarsky for medical writing, editorial coordination, and support. Graphic design support was provided by Jonathan Kirk. Barry Lubarsky and Jonathan Kirk are employees of Vertex Pharmaceuticals Incorporated and own stock or options in that company. Editorial assistance was provided by Karen Stauffer of AlphaBioCom and by Bina J Patel of Peloton Advantage, and was funded by Vertex Pharmaceuticals Incorporated. Publisher Copyright: © 2015 Elsevier Ltd.
PY - 2015/7
Y1 - 2015/7
N2 - Background: Ivacaftor has been previously assessed in patients with cystic fibrosis with Gly551Asp-CFTR or other gating mutations. We assessed ivacaftor in patients with Arg117His-CFTR, a residual function mutation. Methods: We did a 24-week, placebo-controlled, double-blind, randomised clinical trial, which enrolled 69 patients with cystic fibrosis aged 6 years and older with Arg117His-CFTR and percentage of predicted forced expiratory volume in 1 s (% predicted FEV1) of at least 40. We randomly assigned eligible patients (1:1) to receive placebo or ivacaftor 150 mg every 12 h for 24 weeks. Randomisation was stratified by age (6-11, 12-17, and ≥18 years) and % predicted FEV1 (<70, ≥70 to ≤90, and >90). The primary outcome was the absolute change from baseline in % predicted FEV1 through week 24. Secondary outcomes included safety and changes in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores. An open-label extension enrolled 65 of the patients after washout; after 12 weeks, we did an interim analysis. Findings: After 24 weeks, the treatment difference in mean absolute change in % predicted FEV1 between ivacaftor (n=34) and placebo (n=35) was 2.1 percentage points (95% CI -1.13 to 5.35; p=0.20). Ivacaftor treatment resulted in significant treatment differences in sweat chloride (-24.0 mmol/L, 95% CI -28.01 to -19.93; p<0.0001) and CFQ-R respiratory domain (8.4, 2.17 to 14.61; p=0.009). In prespecified subgroup analyses, % predicted FEV1 significantly improved with ivacaftor in patients aged 18 years or older (treatment difference vs placebo: 5.0 percentage points, 95% CI 1.15 to 8.78; p=0.01), but not in patients aged 6-11 years (-6.3 percentage points, -11.96 to -0.71; p=0.03). In the extension study, both placebo-to-ivacaftor and ivacaftor-to-ivacaftor groups showed % predicted FEV1 improvement (absolute change from post-washout baseline at week 12: placebo-to-ivacaftor, 5.0 percentage points [p=0.0005]; ivacaftor-to-ivacaftor, 6.0 percentage points [p=0.006]). We did not identify any new safety concerns. The studies are registered with ClinicalTrials.gov (the randomised, placebo-controlled study, number NCT01614457; the open-label extension study, number NCT01707290). Interpretation: Although this study did not show a significant improvement in % predicted FEV1, ivacaftor did significantly improve sweat chloride and CFQ-R respiratory domain scores and lung function in adult patients with Arg117His-CFTR, indicating that ivacaftor might benefit patients with Arg117His-CFTR who have established disease. Funding: Vertex Pharmaceuticals Incorporated.
AB - Background: Ivacaftor has been previously assessed in patients with cystic fibrosis with Gly551Asp-CFTR or other gating mutations. We assessed ivacaftor in patients with Arg117His-CFTR, a residual function mutation. Methods: We did a 24-week, placebo-controlled, double-blind, randomised clinical trial, which enrolled 69 patients with cystic fibrosis aged 6 years and older with Arg117His-CFTR and percentage of predicted forced expiratory volume in 1 s (% predicted FEV1) of at least 40. We randomly assigned eligible patients (1:1) to receive placebo or ivacaftor 150 mg every 12 h for 24 weeks. Randomisation was stratified by age (6-11, 12-17, and ≥18 years) and % predicted FEV1 (<70, ≥70 to ≤90, and >90). The primary outcome was the absolute change from baseline in % predicted FEV1 through week 24. Secondary outcomes included safety and changes in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores. An open-label extension enrolled 65 of the patients after washout; after 12 weeks, we did an interim analysis. Findings: After 24 weeks, the treatment difference in mean absolute change in % predicted FEV1 between ivacaftor (n=34) and placebo (n=35) was 2.1 percentage points (95% CI -1.13 to 5.35; p=0.20). Ivacaftor treatment resulted in significant treatment differences in sweat chloride (-24.0 mmol/L, 95% CI -28.01 to -19.93; p<0.0001) and CFQ-R respiratory domain (8.4, 2.17 to 14.61; p=0.009). In prespecified subgroup analyses, % predicted FEV1 significantly improved with ivacaftor in patients aged 18 years or older (treatment difference vs placebo: 5.0 percentage points, 95% CI 1.15 to 8.78; p=0.01), but not in patients aged 6-11 years (-6.3 percentage points, -11.96 to -0.71; p=0.03). In the extension study, both placebo-to-ivacaftor and ivacaftor-to-ivacaftor groups showed % predicted FEV1 improvement (absolute change from post-washout baseline at week 12: placebo-to-ivacaftor, 5.0 percentage points [p=0.0005]; ivacaftor-to-ivacaftor, 6.0 percentage points [p=0.006]). We did not identify any new safety concerns. The studies are registered with ClinicalTrials.gov (the randomised, placebo-controlled study, number NCT01614457; the open-label extension study, number NCT01707290). Interpretation: Although this study did not show a significant improvement in % predicted FEV1, ivacaftor did significantly improve sweat chloride and CFQ-R respiratory domain scores and lung function in adult patients with Arg117His-CFTR, indicating that ivacaftor might benefit patients with Arg117His-CFTR who have established disease. Funding: Vertex Pharmaceuticals Incorporated.
UR - http://www.scopus.com/inward/record.url?scp=84943138352&partnerID=8YFLogxK
U2 - 10.1016/S2213-2600(15)00201-5
DO - 10.1016/S2213-2600(15)00201-5
M3 - Article
C2 - 26070913
AN - SCOPUS:84943138352
SN - 2213-2600
VL - 3
SP - 524
EP - 533
JO - The Lancet Respiratory Medicine
JF - The Lancet Respiratory Medicine
IS - 7
ER -