Dataset Information

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5?years (KLIMB).

ABSTRACT: BACKGROUND:KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5?years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI. METHODS:Children received age- and weight-based ivacaftor dosages for 84?weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function. RESULTS:All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84?weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3?×?upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8?×?ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters. CONCLUSIONS:Ivacaftor was generally well tolerated for up to 108?weeks in children aged 2 to 5?years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24?weeks of treatment were maintained for up to an additional 84?weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.

SUBMITTER: Rosenfeld M

PROVIDER: S-EPMC6821553 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB).

Rosenfeld Margaret M Cunningham Steve S Harris William T WT Lapey Allen A Regelmann Warren E WE Sawicki Gregory S GS Southern Kevin W KW Chilvers Mark M Higgins Mark M Tian Simon S Cooke Jon J Davies Jane C JC

Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 20190430 6

<h4>Background</h4>KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI.<h4>Methods</h4>Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancr ...[more]

PMID: 31053538

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Project description:BackgroundIvacaftor has been shown to be a safe, effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation. We aimed to assess the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in children aged 2-5 years.MethodsIn the two-part KIWI study, we enrolled children aged 2-5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA, UK, and Canada. Participants received oral ivacaftor 50 mg (if bodyweight <14 kg) or 75 mg (if bodyweight ≥14 kg) every 12 h for 4 days in part A (to establish the short-term safety of doses for subsequent assessment in part B), and then for 24 weeks in part B (to assess safety and longer-term pharmacodynamics). Children could participate in both or just one part of the study. Primary outcomes were pharmacokinetics and safety, analysed in all patients who received at least one dose of ivacaftor. Secondary outcomes were absolute change from baseline in sweat chloride concentrations and bodyweight, body-mass index (BMI), and height Z scores, and pharmacokinetic parameter estimation of ivacaftor. This study is registered with ClinicalTrials.gov, number NCT01705145.FindingsBetween Jan 8, 2013, and March 1, 2013, nine patients were enrolled onto part A of the study, all of whom completed the 4 day treatment period, and eight of whom took part in part B. Between June 28, 2013, and Sept 26, 2013, 34 patients were enrolled in part B, 33 of whom completed the 24 week treatment period. All patients received at least one dose of ivacaftor. Results of ivacaftor pharmacokinetics suggested that exposure was similar to that reported in adults (median Cmin were 536 ng/mL for the 50 mg dose; 580 ng/mL for the 75 mg dose; median ivacaftor AUC values were 9840 ng × h/mL and 10 200 ng × h/mL, respectively). Common adverse events in part B included cough (in 19 [56%] of 34 patients) and vomiting (in ten [29%]). Five (15%) patients had liver function test (LFT) results that were more than eight times higher than the upper limit of normal, four of whom had study drug interrupted, and one of whom had study drug discontinued. Six (18%) of 34 patients had seven serious adverse events; a raised concentration of transaminases was the only serious adverse event regarded as related to ivacaftor and the only adverse event that resulted in study treatment discontinuation. At week 24, in patients for whom we had data, sweat chloride had changed from baseline by a mean of -46·9 mmol/L (SD 26·2, p<0·0001), weight Z score by 0·2 (0·3; p<0·0001), BMI Z score by 0·4 (0·4, p<0·0001), and height Z score by -0·01 (0·3; p=0·84).InterpretationIvacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-5 years with cystic fibrosis with a gating mutation followed up for 24 weeks, although the frequency of elevated LFTs suggests that monitoring should be frequent in young children, particularly those with a history of elevated LFTs. Results of an ongoing extension study assessing durability of these effects and longer-term safety are warranted.FundingVertex Pharmaceuticals Incorporated.

Project description:BackgroundIvacaftor is generally safe and effective in patients aged 2 years and older who have cystic fibrosis and specific CFTR mutations. We assessed its use in children aged 12 to <24 months.MethodsThe ARRIVAL study is a phase 3, single-arm, two-part, multicentre study. Eligible children were aged 12 to <24 months at enrolment and had a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele and could participate in one or both parts of the study. Children received 50 mg (bodyweight 7 to <14 kg) or 75 mg (bodyweight ≥14 to <25 kg) ivacaftor orally every 12 h. In study part A, children received ivacaftor for 3 days plus one morning. In study part B, children received 24 weeks of treatment. Children were enrolled into part A at seven sites in Australia (one site), the UK (one), and the USA (five) and into part B at 13 sites in Australia (two sites), Canada (one), the UK (three), and the USA (seven). Primary endpoints were pharmacokinetics (part A) and safety (parts A and B) in children who received at least one dose of ivacaftor. Secondary endpoints in part B were pharmacokinetics in children who received at least one dose of ivacaftor and absolute change from baseline in sweat chloride concentration. We also explored changes in growth parameters and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02725567.FindingsChildren aged 12 to <24 months were enrolled between Aug 25, 2016, and Nov 1, 2017. Seven children were enrolled in part A, of whom five received 50 mg and two received 75 mg ivacaftor. All completed treatment. Of 19 children enrolled in part B, including one from part A, all received 50 mg ivacaftor and 18 completed treatment (one withdrew because of difficulty with blood draws). All children received at least one dose of ivacaftor. Pharmacokinetics indicated exposure was similar to that in children aged 2 to <6 years and adults. No children discontinued because of adverse events or safety findings. In part A, three (43%) of seven children had treatment-emergent adverse events, all of which were mild and deemed not to be or unlikely to be related to ivacaftor. By 24 weeks in part B, treatment-emergent adverse events had been reported in 18 (95%) of 19 children, of which most were mild or moderate and the most frequent was cough (14 [74%] children). Two children in part B had four serious adverse events: one had constipation (possibly related to ivacaftor), distal intestinal obstruction syndrome, and eczema herpeticum, and one had persistent cough, all needing hospital admission. In five (28%) of 18 children aspartate or alanine aminotransferase concentrations rose to more than three times the upper limit of normal (to more than eight times in two children with concurrent infections). At week 24, the mean absolute change from baseline in sweat chloride concentration was -73·5 (SD 17·5) mmol/L. Growth parameters for age were normal at baseline and at week 24. At week 24, concentrations of faecal elastase-1 had increased and concentrations of immunoreactive trypsinogen had decreased from baseline. Mean serum lipase and amylase were raised at baseline and rapidly decreased after treatment was started.InterpretationIvacaftor was generally safe and well tolerated in children aged 12 to <24 months for up to 24 weeks and was associated with rapid and sustained reductions in sweat chloride concentrations. Improvements in biomarkers of pancreatic function suggest that ivacaftor preserves exocrine pancreatic function if started early. The study is continuing in infants younger than 12 months.FundingVertex Pharmaceuticals Incorporated.

Dataset Information

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5?years (KLIMB).

Publications

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB).

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Dataset Information

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5?years (KLIMB).

Publications

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB).