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Long-term Safety of Lumacaftor–Ivacaftor in Children Aged 2 to 5 Years with Cystic Fibrosis Homozygous for the F508del-CFTR Mutation


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Key takeaways

  • Children ages 2 to 5 who are homozygous for F508del-CFTR mutation were only recently able to receive modulator therapy.

  • Starting these treatments at a younger age could slow or even prevent some of the serious effects of CF.

  • The study found CFTR modulator lumacaftor-ivacaftor is safe and well-tolerated for up to 120 weeks for this population.


  • 44% of people with CF are homozygous for F508del-CFTR mutation
  • 20 CF care centers participated in extended study
  • 1st study of long-term lumacaftor–ivacaftor use in 2- to 5-year-olds with F508del-CFTR mutation

Research background: long-term CFTR modulator therapy in children

Cystic fibrosis (CF) is a progressive genetic disease that affects multiple systems in the body and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The F508del-CFTR mutation is the most common genetic mutation responsible for this disease.

CFTR modulator drug therapy has been found to improve health outcomes and quality of life for patients with CF. Lumacaftor-ivacaftor is the first combination CFTR modulator therapy approved to treat people with CF homozygous for the F508del-CFTR mutation.

A previous clinical trial (known as “study 115”), which assessed the effectiveness of lumacaftor-ivacaftor in children 2 to 5 years old with CF who are homozygous for the F508del-CFTR mutation, found the treatment to be safe and effective for up to 24 weeks.

An extension study (known as “study 116”) was led by Jordana Hoppe, MD, a pediatric pulmonologist in the Mike McMorris Cystic Fibrosis Research and Care Center at Children's Hospital Colorado. Researchers at 20 CF care centers in the U.S. and Canada investigated the safety and efficacy of longer-term (up to 120 weeks) lumacaftor-ivacaftor treatment in the same group of children.

Research methods: a rollover study of lumacaftor-ivacaftor in children


  • Evaluate safety and tolerability of long-term lumacaftor-ivacaftor between study 115 baseline and week 96 of study 116, based on:
    • Incidences of adverse events (respiratory, liver-related)
    • Changes in clinical laboratory values (serum chemistry, hematology, coagulation, urinalysis)
    • Electrocardiograms
    • Vital signs
    • Pulse oximetry
    • Ophthalmological examinations
    • Spirometry
  • Evaluate the pharmacodynamics of long-term lumacaftor-ivacaftor treatment, as shown by absolute changes in baseline for:
    • Sweat chloride concentration
    • Growth parameters
    • Markers of pancreatic function (fecal elastase-1 and immunoreactive trypsinogen concentrations)
  • Measures of pulmonary function (lung clearance index (LCI) 2•5% and LCI5.0
    • Microbiological cultures
    • Time to first pulmonary exacerbation
    • Number of pulmonary exacerbation events
    • Number of CF-related hospital admissions
  • Participants received weight- and age-based doses of oral lumacaftor-ivacaftor:
    • Children weighing less than 14 kg and who were younger than 6 years at study screening received lumacaftor 100 mg - ivacaftor 125 mg every 12 hours
    • Children weighing 14 kg or more and who were younger than 6 years at study screening received lumacaftor 150 mg - ivacaftor 188 mg every 12 hours
    • Children 6 years or older at study screening received lumacaftor 200 mg - ivacaftor 250 mg every 12 hours

Children were treated up to 96 weeks, equivalent to up to 120 weeks of treatment total from the start of study 115 to completion of this study. They attended a safety follow-up visit at 10 to 18 days after the final dose of the study drug, unless they had transitioned to commercially available lumacaftor-ivacaftor.

Research results: assessing adverse events

Fifty-seven (95%) of the 60 participants enrolled in study 115 were included in study 116 and received lumacaftor-ivacaftor treatment. The majority (82%) of participants completed the full 96 weeks. Results showed:

  • 56 of the 57 participants had at least one adverse event during the study:
  • Most common adverse events:
  • 26% of participants had at least one serious adverse event; most considered consistent with underlying CF or common childhood illness:
    • 11% infective pulmonary exacerbation of CF
    • 4% pneumonia
  • 9% of participants experienced a mild or moderate respiratory adverse event:
    • 5% dyspnea
    • 5% wheezing
    • 2% chest discomfort
    • 2% abnormal respiration
  • 9% had adverse events leading to treatment interruption
  • 5% discontinued treatment due to adverse events:
    • Two due to elevated aminotransferase concentrations (one had concurrent pancreatitis, one had gastritis and metabolic acidosis; both considered unrelated to study treatment)
    • One had serious adverse event of pancreatitis with increased liver function enzyme tests (possibly related to study drug)
    • One had adverse event of increased alanine aminotransferase and increased aspartate aminotransferase concentrations (possibly related to study drug)

Improvements in secondary endpoints

Improvements in secondary endpoints from study 115 generally maintained up to the full 96 weeks, and included:

  • Improvements in sweat chloride concentration
  • Increase in growth parameters and pancreatic function
  • Stable lung function relative to baseline as measured by LCI

Research discussion: improvements in key indicators of CF

To the researchers’ knowledge, this is the first study of long-term lumacaftor-ivacaftor use in 2- to 5-year-olds with the F508del-CFTR mutation, a group that accounts for the majority of CFTR modulator use in children under 5.

Researchers found lumacaftor-ivacaftor was generally safe and well-tolerated across the duration of both studies, consistent with previous findings in older children and adults.

Improvements in key indicators of CF


Incidence of adverse events

The incidence of respiratory adverse events in children 2 to 5 years old on lumacaftor-ivacaftor was generally lower than children 6 to 11 years old, tested in other studies. However, the incidence of adverse events in study 116 was higher for infectious pulmonary exacerbation of CF, nasopharyngitis and positive cultures for Staphylococcus aureus.

Study limitations include:

  • Open-label design and small sample size relative to studies in older populations and of non-rare genetic diseases
  • Absence of a direct comparator group

Research conclusion: long-term use in young children supported

Study findings support the long-term use of lumacaftor-ivacaftor for up to 120 weeks in children with CF age 2 years and older who are homozygous for the F508del-CFTR mutation.