- 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)
Research results: assessing safety, efficacy and pharmacokinetics
Part A
- 16 children completed treatment period
Assessments:
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
Assessments:
- 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:
- 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.