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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

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Summary

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 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 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.

Introduction

Cystic fibrosis is a chronic, genetic disease characterised by loss of lung function, poor nutritional status, pulmonary exacerbations, and respiratory failure.1 The disease is caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ion channel in the apical membrane of epithelial cells that conducts chloride ions and helps modulate bicarbonate ion transport.2, 3 Defective CFTR protein arises from mutations in the CFTR gene,4 the most common being the F508del mutation, for which approximately 38% of the global cystic fibrosis population is homozygous.5 The F508del-CFTR mutation affects processing and trafficking of the CFTR protein such that most is targeted for degradation before reaching the cell surface.6 F508del-CFTR protein expressed at the apical membrane is usually unstable and functionally defective.7, 8

Research in context

Evidence before this study

We searched PubMed on Feb 6, 2017, with the terms “ivacaftor” or “VX-770” and “lumacaftor” or “VX-809”, with no restrictions on publication date or language. We identified four relevant clinical studies: one combined report of two phase 3 trials in patients aged 12 years or older with cystic fibrosis and homozygous for F508del-CFTR (TRAFFIC and TRANSPORT); a phase 3 extension study of TRAFFIC and TRANSPORT (PROGRESS); and an open-label, phase 3 study in patients aged 6–11 years with cystic fibrosis and homozygous for F508del-CFTR. Lumacaftor and ivacaftor are modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. Combination therapy with lumacaftor and ivacaftor for 24 weeks in patients aged 12 years and older improved lung function and nutritional status, and decreased rates of pulmonary exacerbation, with an acceptable safety profile in the TRAFFIC and TRANSPORT trials. In the 96-week extension study (PROGRESS), the safety profile remained consistent, with benefits of lumacaftor and ivacaftor therapy being observed up to 120 weeks of treatment. Lumacaftor and ivacaftor treatment was also well tolerated over 24 weeks in younger patients with cystic fibrosis (aged 6–11 years) and homozygous for F508del-CFTR in an open-label, phase 3 study.

Added value of this study

In this phase 3, randomised, placebo-controlled trial (VX14-809-109), the efficacy of lumacaftor and ivacaftor combination therapy in patients aged 6–11 years with cystic fibrosis homozygous for the F508del-CFTR mutation was further assessed. Lung function in this paediatric population was measured by lung clearance index (LCI2·5), a sensitive measure of ventilation inhomogeneity, and spirometry (percent predicted forced expiratory volume in 1 s [ppFEV1]). Pharmacodynamic effect on CFTR function was established by assessment of sweat chloride concentration. LCI2·5 and sweat chloride concentration improved significantly (ie, decreased) in the lumacaftor and ivacaftor group versus the placebo group. A significant treatment difference favouring lumacaftor and ivacaftor over placebo was also observed for ppFEV1. The safety findings were consistent with those reported previously in young patients with cystic fibrosis homozygous for the F508del-CFTR mutation.

Implications of all the available evidence

Significant improvements in lung function with lumacaftor and ivacaftor treatment were seen when measured by absolute change from baseline in LCI2·5 relative to placebo treatment. Sweat chloride concentration also improved significantly (ie, decreased), thus providing a mechanistic CFTR biomarker of modulator efficacy. This phase 3 trial provides rigorous evidence for efficacy with lumacaftor and ivacaftor in the paediatric population at the early stages of disease and is among the first to use LCI2·5 as a primary endpoint.

Therapies directly targeting CFTR function have been developed, including ivacaftor, a CFTR potentiator that has been shown to increase channel open probability of mutant CFTR in vitro.9 Delivery of CFTR protein to the cell surface can be increased by lumacaftor, a CFTR corrector that improves the processing and trafficking of F508del-CFTR protein.10 Lumacaftor in combination with ivacaftor has greater effects than either agent alone, both in vitro and clinically in specific cystic fibrosis genotypes.9, 10, 11, 12 Combination treatment for 24 weeks improved lung function, reduced frequency of cystic fibrosis-related pulmonary exacerbations, and improved body-mass index (BMI) in two large phase 3 studies (TRAFFIC and TRANSPORT) in patients aged 12 years or older with cystic fibrosis and homozygous for F508del-CFTR.12 In an open-label phase 3 study,13 treatment with lumacaftor and ivacaftor was well tolerated over 24 weeks in patients aged 6–11 years homozygous for F508del-CFTR, with a safety profile similar to that seen in older patients. After treatment initiation, sweat chloride concentration rapidly decreased in the trial population of this study,13 returning to baseline after discontinuation of therapy. Although statistically significant improvements in percent predicted forced expiratory volume in 1 s (ppFEV1) were not observed in this population with generally preserved spirometric measures of lung function, ventilation inhomogeneity measured by the lung clearance index (LCI2·5; number of lung volume turnovers required to reach 2·5% of starting tracer gas concentration), BMI Z score, and quality of life measures improved significantly. It is not uncommon for patients in this age group to have normal spirometry,14 even when structural abnormalities can be observed with high-resolution computed tomography15 and hyperpolarised gas MRI16, 17 and LCI, which measures small airway disease, shows impaired ventilation.18, 19

We designed this phase 3 study to further investigate the efficacy and safety of lumacaftor in combination with ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for the F508del-CFTR mutation. LCI2·5 was chosen as the primary endpoint based on knowledge that it is a sensitive measure of lung function20 in this younger population.

Section snippets

Study design and participants

This phase 3, randomised, double-blind, placebo-controlled, parallel-group, multicentre study was done in patients aged 6–11 years with cystic fibrosis who were homozygous for the F508del-CFTR mutation (appendix). The study protocol, informed consent, and other necessary documents were approved by an independent ethics committee or institutional review board for each study site before initiation. This study was done in accordance with good clinical practice as described in the International

Results

Between July 23, 2015, and Sept 20, 2016, 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). 204 patients received at least one dose of study drug (103 lumacaftor and ivacaftor, 101 placebo; figure 1). 97 (94%) of 103 patients in the lumacaftor and ivacaftor group and 96 (95%) of 101 patients in the placebo group completed 24 weeks of treatment. Treatment discontinuation due to adverse events (respiration abnormal; elevated

Discussion

In this placebo-controlled study, combination lumacaftor and ivacaftor treatment decreased LCI2·5 and sweat chloride concentrations, maintained spirometric lung function, and was well tolerated in patients aged 6–11 years with cystic fibrosis homozygous for the F508del-CFTR mutation.

Patients receiving lumacaftor and ivacaftor had statistically significant improvement in LCI2·5 based on the average decrease from baseline across all study visits and a significant treatment effect versus placebo.

References (38)

  • J Walkowiak et al.

    Fecal elastase-1 cut-off levels in the assessment of exocrine pancreatic function in cystic fibrosis

    J Cyst Fibros

    (2002)
  • JC Davies et al.

    Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study

    Lancet Respir Med

    (2016)
  • HA Berger et al.

    Identification and regulation of the cystic fibrosis transmembrane conductance regulator-generated chloride channel

    J Clin Invest

    (1991)
  • JY Choi et al.

    Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis

    Nature

    (2001)
  • N Derichs

    Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

    Eur Respir Rev

    (2013)
  • Clinical and Functional Translation of CFTR (CFTR2), https://www.cftr2.org/index.php (accessed Feb 15,...
  • GL Lukacs et al.

    Conformational maturation of CFTR but not its mutant counterpart (delta F508) occurs in the endoplasmic reticulum and requires ATP

    EMBO J

    (1994)
  • F Van Goor et al.

    Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules

    Am J Physiol Lung Cell Mol Physiol

    (2006)
  • W Dalemans et al.

    Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation

    Nature

    (1991)
  • Cited by (0)

    Members of the investigator group are listed in the appendix

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