Children's Hospital Colorado
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CFTR Modulator Therapy for Young Children with Cystic Fibrosis


Edith Zemanick is pictured smiling in her headshot

Key takeaways

  • A large clinical trial demonstrated ETI was safe and effective for 6- to 11- year-olds with at least one copy of the F508del mutation in the CFTR gene.

  • The study found there were significant improvements in several clinically relevant parameters in this age range.

  • The FDA approved the drug combination to treat cystic fibrosis in patients as young as 6 in June 2021, allowing crucial clinical interventions to begin sooner.

CFTR modulator therapy in pediatrics

Highly effective cystic fibrosis transmembrane conductance regulator protein (CFTR) modulator drug therapy has been found to improve health outcomes and quality of life for patients with cystic fibrosis (CF) with one or two F508del-CFTR mutations. Previous studies showed the combined regimen of elexacaftor/tezacaftor/ivacaftor (ETI) is safe and efficacious for patients aged 12 years and older and more effective than the dual combination medication tezacaftor/ivacaftor.

The ETI regimen was theorized to be safe and effective in children under 12 years old with CF who have one F508del allele, based on outcomes from prior studies on CFTR modulators, but that had not been formally assessed prior to this study.

A study of elexacaftor, tezacaftor and ivacaftor in young children

This clinical trial evaluated the safety, efficacy and pharmacokinetics of ETI treatments in children 6 to 11 years old with CF and at least one F508del-CFTR allele with either a second F508del allele (F/F) or a second allele with minimal function (F/MF). Edith Zemanick, MD, pulmonologist in the Mike McMorris Cystic Fibrosis Research and Care Center at Children’s Hospital Colorado, was the lead author of the 24-week, multicenter, phase three, open-label study, which included two parts.

All patients stopped or remained off CFTR modulators for 28 or more days prior to their first-day visit.

Part A evaluated pharmacokinetics, safety and tolerability of ETI over a two-week treatment period. It was conducted at six U.S. sites from October 2018 to January 2019 with 16 children enrolled who received one or more doses of EIT at 50% of the adult daily dose.

  • Study goals:
    • Assess pharmacokinetic parameters of elexacaftor, tezacaftor and ivacaftor:
      • Maximum concentration, pre-dose concentration and area under concentration vs. time curve
      • Safety and tolerability as determined by adverse events, clinical laboratory values, electrocardiograms, vital signs and pulse oximetry

Part B evaluated pharmacokinetics, safety, tolerability and efficacy of ETI over the following 24-week treatment period. It was conducted at 21 sites in five countries from August 2019 to August 2020. Sixty-six children were enrolled who received one or more doses of ETI with dosing amounts based on weight. 

The study timeframe overlapped with the SARS-CoV-2 pandemic, so the study protocol was amended to incorporate in-home assessments and included:

  • Remote consent
  • Shipment of study drug to patient's home
  • Virtual study visits conducted by site personnel via teleconference
  • Home nursing visits for blood-draws
  • In-home assessments
  • Remote study site monitoring

ETI study goals

  • Primary: Safety and tolerability of ETI
    • Children who received more than one dose of ETI
  • Secondary:
    • Absolute change from baseline through week 24 in ppEV1 (using mixed effects model)
    • Sweat chloride concentration (using mixed effects model)
    • Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score (using mixed effects model)
    • Absolute change from baseline at week 24 in body mass index
    • Weight, height and corresponding for-age-z scores
    • Number of pulmonary exacerbations and CF-related hospitalizations through week 24
    • Pharmacokinetic parameters of ELX, TEZ and IVA
    • Absolute change from baseline through week 24 in lung clearance index (LCI2.5), using mixed effects model
  • Post hoc analysis conducted on proportion of patients achieving sweat chloride concentrations less than 60 mmol/L (the diagnostic cut-off for cystic fibrosis) and less than 30 mmol/L (similar values were seen in CF carriers or individuals without CF)

ETI study results assessing safety, efficacy and pharmacokinetics

Part A

Sixteen children completed treatment period.


Pharmacokinetics data confirmed that the study doses of ETI were appropriate with half the adult dose used for children less than 30kg and the full adult dose used for those 30 kg and over. Part B of the study also confirmed these findings.

Part B

  • 64 children completed the treatment period
    • Baseline characteristics:
      • 56.1% F/MF genotype
      • 43.9% F/F genotype
  • 2 children discontinued treatment
    • 1 adverse event of erythematous rash
    • 1 withdrawal of consent


  • Safety and pharmacokinetics:
    • 98.5% of children had adverse events, all considered consistent with manifestations of cystic fibrosis or common childhood infections
      • 54.5% mild
      • 42.4% moderate
      • 1 serious adverse event: concurrent events of rhinovirus infection, metapneumovirus infection and pneumonia (resolved with intravenous antibiotics)
      • Most common adverse events were:
        • Cough
        • Headache
        • Pyrexia
      • 10.6% of children had adverse events of transaminase elevations – all mild or moderate in severity
      • 24.2% of children had rash events, all mild or moderate in severity; one individual discontinued treatment due to rash
      • 2 children had adverse events related to creatine kinase
      • Mean change from baseline for systolic blood pressure ranged from -1.4mm Hg to 1.0 mm Hg; for diastolic blood pressure -0.3mm Hg to 1.0mm Hg
  • Overall efficacy:
    • ppFEV1 - mean absolute change from baseline of 10.2 percentage points, 95% confidence interval/7.9 to 12.6, with robust improvement noted as soon as 2 weeks after initiation
      • Similar improvements in F/MF and F/F genotype groups
    • CFQ-R – mean absolute change from baseline of 7.0 points, 95% confidence interval/4.7 to 9.2
      • Similar improvements in F/MF and F/F genotype groups
    • LCI2.5 – mean absolute change from baseline of -1.71 units, 95% confidence interval/-2.11 to -1.30
      • Similar improvements in F/MF and F/F genotype groups
    • Sweat chloride concentration – mean absolute change from baseline of -60.9 mmol/L, 95% confidence interval/-63.7 to -58.2
      • Greater decrease in F/F genotype group: baseline of -70.4 mmol/L, 95% confidence interval/-75.6 to -65.3 than the F/MF group: baseline of -55.1 mmol/L, 95% confidence interval/-59.0 to -51.2
      • More children with the F/F genotype had sweat chloride values below 60 mmol/L and below 30mmol/L following treatment compared to children with the F/M genotype.
    • BMI, BMI-for-age z-score, weight, weight-for-age z score and height increased without a plateau; height-for-age z score was maintained

Research discussion: Safety and efficacy of CFTR modulators in young children

Researchers found ETI treatments in children 6 to 11 years old with CF and at least one F508del-CFTR allele with F/MF or F/F genotypes to be generally safe and well-tolerated.

Since researchers expect ETI to be a long-term therapy for children with CF, the incidence of laboratory and clinical events that may occur during drug exposure must be well understood. The safety profile in children 6 to 11 years old was found to be consistent with the profile in patients 12 years and older.

Specific findings from this study include:

  • Children were found to have an incidence of elevated aminotransferase similar to incidence previously observed in patients 12 or more years old treated with ETI for 24 weeks and in children 6 to 11 years old treated with TEZ/IVA for 24 weeks.
  • Observed rashes were mild to moderate in severity and the vast majority were transient and resolved with continued drug treatment.
  • Pharmacokinetic and clinical evaluation confirmed appropriateness of a dose that is 50% of the adult daily dose of ETI for children 6 to 11 years old who are less than 30 kg and the full adult dose for those greater than 30 kg.
  • Children had higher mean baseline lung function and CFQ-R respiratory domain score than seen in phase three pivotal studies in adults and adolescents.
  • ETI treatment led to greater improvements in sweat chloride than those previously seen in adults and adolescents; children homozygous for F508del-CFTR had a greater decrease in sweat chloride than those with a single F508del-CFTR allele.

Study limitations include:

  • No placebo group so the incidence of safety events attributable to the underlying disease process was not determined
  • Small sample size limited ability to detect uncommon and rare adverse events
  • Participants from minority groups were less likely to be eligible because the F508del-CFTR mutation is less common in such populations

Research conclusion: ETI for young children safe and effective

Study results strongly support the use of ETI in children 6 through 11 years of age with more than one F508del-CFTR allele to provide effective treatment of CF at an early stage of disease when serious long-term complications may be avoided.

The efficacy and safety of ETI treatments in children are consistent with those reported in the randomized controlled phase three trials in adults and adolescents with CF and further confirm the ability of ETI to modulate a single F508del-CFTR allele in patients with CF.

Since the effects of CF often manifest in early childhood, it is crucial to initiate treatment as early as possible.

Update: In June 2021, three months after publication of the results of this clinical trial, the Food and Drug Administration approved ETI for use in this population of patients as young as 6 years old.