Long-term safety of lumacaftor-ivacaftor in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a multicentre, phase 3, open-label, extension study.

BACKGROUND: A previous phase 3 study showed that lumacaftor-ivacaftor was generally safe and well tolerated over 24 weeks of treatment in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation. In this study, we aimed to assess the long-term safety of lumacaftor-ivacaftor in a rollover study of children who participated in this previous phase 3 study. METHODS: In this multicentre, phase 3, open-label, extension study (study 116; VX16-809-116), we assessed safety of lumacaftor-ivacaftor in children included in a previous multicentre, phase 3, open-label study (study 115; VX15-809-115). The study was done at 20 cystic fibrosis care centres in the USA and Canada. Children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation who completed 24 weeks of lumacaftor-ivacaftor treatment in study 115 received weight-based and age-based doses of oral lumacaftor-ivacaftor: children weighing less than 14 kg and aged younger than 6 years at study 116 screening received lumacaftor 100 mg-ivacaftor 125 mg every 12 h; children weighing 14 kg or more and aged younger than 6 years at screening received lumacaftor 150 mg-ivacaftor 188 mg every 12 h; and children aged 6 years or older received lumacaftor 200 mg-ivacaftor 250 mg every 12 h. Children received treatment for up to 96 weeks, equivalent to up to 120 weeks of treatment in total from the start of study 115 to completion of study 116. The primary endpoint was the safety and tolerability of the study drug in all participants who had received lumacaftor-ivacaftor for 24 weeks in study 115 and had received at least one dose in study 116. Secondary endpoints included change from baseline in study 115 at week 96 of study 116 in sweat chloride concentration, growth parameters, markers of pancreatic function, and lung clearance index (LCI) parameters in all children who received at least one dose of lumacaftor-ivacaftor in study 116. This study is registered with ClinicalTrials.gov, NCT03125395. FINDINGS: This extension study ran from May 12, 2017, to July 17, 2019. Of 60 participants enrolled and who received lumacaftor-ivacaftor in study 115, 57 (95%) were included in study 116 and continued to receive the study drug. A total of 47 (82%) of 57 participants completed 96 weeks of treatment. Most participants (56 [98%] of 57) had at least one adverse event during study 116, most of which were mild (19 [33%] participants) or moderate (29 [51%] participants) in severity. The most common adverse events were cough (47 [82%] participants), nasal congestion (25 [44%] participants), pyrexia (23 [40%] participants), rhinorrhoea (18 [32%] participants), and vomiting (17 [30%] participants). A total of 15 (26%) participants had at least one serious adverse event; most were consistent with underlying cystic fibrosis or common childhood illnesses. Respiratory adverse events occurred in five (9%) participants, none of which were serious or led to treatment discontinuation. Elevated aminotransferase concentrations, most of which were mild or moderate in severity, occurred in ten (18%) participants. Three (5%) participants discontinued treatment due to adverse events (two due to increased aminotransferase concentrations [one of whom had concurrent pancreatitis], considered as possibly related to study drug; and one due to gastritis and metabolic acidosis, considered unlikely to be related to study drug). No clinically significant abnormalities or changes were seen in electrocardiograms, vital signs, pulse oximetry, ophthalmological examinations, or spirometry assessments. Improvements in secondary endpoints observed in study 115 were generally maintained up to week 96 of study 116, including improvements in sweat chloride concentration (mean absolute change from study 115 baseline at week 96 of study 116 -29·6 mmol/L [95% CI -33·7 to -25·5]), an increase in growth parameters and pancreatic function, and stable lung function relative to baseline, as measured by the LCI. INTERPRETATION: Lumacaftor-ivacaftor was generally safe and well tolerated, and treatment effects were generally maintained for the duration of the extension study. These findings support the use of lumacaftor-ivacaftor for up to 120 weeks in young children with cystic fibrosis aged 2 years and older homozygous for the F508del-CFTR mutation. FUNDING: Vertex Pharmaceuticals Incorporated.

Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study.

BACKGROUND: The efficacy, safety, and tolerability of lumacaftor and ivacaftor are established in patients aged 6 years and older with cystic fibrosis, homozygous for the F508del-CFTR mutation. We assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of lumacaftor and ivacaftor in children aged 2-5 years. METHODS: In this multicentre, phase 3, open-label, two-part study, we enrolled children aged 2-5 years, weighing at least 8 kg at enrolment, with a confirmed diagnosis of cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children received lumacaftor 100 mg and ivacaftor 125 mg (bodyweight <14 kg) or lumacaftor 150 mg and ivacaftor 188 mg (bodyweight ≥14 kg) orally every 12 h for 15 days in part A (to assess pharmacokinetics and safety) and for 24 weeks in part B (to assess safety, pharmacokinetics, pharmacodynamics, and efficacy). Children could participate in part A, part B, or both. Children were enrolled into part A at five sites in the USA and into part B at 20 sites in North America (USA, 17 sites; Canada, three sites). The primary endpoints of the study were the pharmacokinetics (part A) and safety (part B) of lumacaftor and ivacaftor; all analyses were done in children who received at least one dose of lumacaftor and ivacaftor. Secondary endpoints in part A were safety and pharmacokinetics of the metabolites of lumacaftor and ivacaftor, and in part B included pharmacokinetics in children who received at least one dose of lumacaftor and ivacaftor and absolute changes from baseline in sweat chloride concentration, growth parameters, and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02797132. FINDINGS: The study was done from May 13, 2016, to Sept 8, 2017. 12 children enrolled in part A, 11 of whom completed the 15-day treatment period and enrolled in part B. 60 children enrolled in part B, 56 of whom completed the 24-week treatment period. Safety and pharmacokinetics were consistent with the well characterised safety profile of lumacaftor and ivacaftor. In part B, most children (59 [98%] of 60 children) had one or more treatment-emergent adverse events; most events were mild to moderate in severity. The most common adverse events were cough (38 [63%] of 60), vomiting (17 [28%]), pyrexia (17 [28%]), and rhinorrhoea (15 [25%]). Serious adverse events occurred in four children: infective pulmonary exacerbation of cystic fibrosis (n=2), gastroenteritis viral (n=1), and constipation (n=1). Three (5%) of 60 children discontinued treatment because of elevated serum aminotransferase concentrations. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function improved (fecal elastase-1 concentrations increased and serum immunoreactive trypsinogen concentrations decreased), and growth parameters increased at week 24. INTERPRETATION: Lumacaftor and ivacaftor were generally safe and well tolerated in children aged 2-5 years with cystic fibrosis for 24 weeks. Efficacy findings also suggest that early intervention with lumacaftor and ivacaftor has the potential to modify the course of disease. FUNDING: Vertex Pharmaceuticals Incorporated.

Increased adherence to CFF practice guidelines for pulmonary medications correlates with improved FEV1.

BACKGROUND: CFF practice guidelines recommend patients ≥age 6 use dornase alfa and hypertonic saline daily, and those ≥age 6 colonized with Pseudomonas aeruginosa use inhaled tobramycin and oral azithromycin to improve lung function and reduce pulmonary exacerbations. A decline in FEV1 was noted in our 2008 CF Center Report. We hypothesized that increasing adherence to prescribing guidelines for these pulmonary medications would improve mean FEV1. METHODS: This was a quality improvement project completed at a US CF center. CFF practice guidelines were reviewed with the center physicians. Patients were identified that were eligible to receive recommended therapies and it was determined whether they were prescribed the therapies. Baseline FEV1 data was collected. Adherence rates and FEV1 were followed quarterly for 1 year. Providers received a quarterly report card with adherence rates, mean FEV1 compared to colleagues, and a list of eligible patients that were not prescribed recommended therapies. RESULTS: Ninety-two patients were included. At baseline, the overall adherence rate was 59%. Overall adherence increased quarterly (P = < 0.001). Each quarter there was improvement in adherence to prescribing for each medication (P < 0.001). Except in quarter 1, FEV1 increased quarterly (P = 0.092). There was moderate correlation (r = 0.533) between improved adherence and improved FEV1. CONCLUSIONS: Educating clinicians about guidelines, providing feedback on adherence to guidelines, and monitoring prescribing patterns improves prescribing adherence. FEV1 showed improvement after months of sustained adherence, trending towards significance. Longer follow-up is necessary to determine if improved prescribing adherence translates into improved FEV1 or slows rate of decline in FEV1.