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

Open AccessPublished:April 30, 2019DOI:https://doi.org/10.1016/j.jcf.2019.03.009

      Highlights

      • Ivacaftor was generally well tolerated in 2- to 5- year-olds up to 84 weeks in KLIMB
      • AST and/or ALT >3 × ULN occurred in 30% of children on ≥1 occasion
      • Sweat chloride improvements seen in KIWI were maintained through 84 weeks of KLIMB
      • Weight and BMI z score gains seen in KIWI were sustained but not further elevated
      • Improvements in pancreatic function seen in KIWI were maintained during 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.

      Keywords

      Abbreviations:

      ALT (alanine transaminase), AST (aspartate transaminase), BMI (body mass index), CF (cystic fibrosis), CFTR (cystic fibrosis transmembrane conductance regulator), IRT (immunoreactive trypsinogen), LFT (liver function test), MMRM (mixed-effect model for repeated measures), q12h (every 12 h), SD (standard deviation), SE (standard error), ULN (upper limit of normal)

      1. Introduction

      The pathophysiologic effects of cystic fibrosis (CF), including poor nutritional status and structural lung damage, typically begin in the first years of life [
      • Ranganathan S.C.
      • Hall G.L.
      • Sly P.D.
      • Stick S.M.
      • Douglas T.A.
      Australian Respiratory Early Surveillance Team for Cystic Fibrosis. Early lung disease in infants and pre-school children with cystic fibrosis: what have we learned and what should we do about it?.
      ]. Early intervention is known to be clinically beneficial [
      • Yen E.H.
      • Quinton H.
      • Borowitz D.
      Better nutritional status in early childhood is associated with improved clinical outcomes and survival in patients with cystic fibrosis.
      ,
      • VanDevanter D.R.
      • Kahle J.S.
      • O'Sullivan A.K.
      • Sikirica S.
      • Hodgkins P.S.
      Cystic fibrosis in young children: a review of disease manifestation, progression, and response to early treatment.
      ], and thus treatment with cystic fibrosis transmembrane conductance regulator (CFTR) modulators early in life could potentially improve long-term outcomes. To date, no studies have been conducted on prolonged use of CFTR modulators in children with CF who are younger than 6 years of age.
      Ivacaftor, a CFTR potentiator that enhances chloride transport by increasing the channel-open probability of CFTR at the cell surface [
      • Van Goor F.
      • Hadida S.
      • Grootenhuis P.D.
      • Burton B.
      • Cao D.
      • Neuberger T.
      • et al.
      Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770.
      ,
      • Van Goor F.
      • Yu H.
      • Burton B.
      • Hoffman B.J.
      Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function.
      ], has been shown to be safe and efficacious in patients aged 6 years and older with CF and specific CFTR mutations [
      • Ramsey B.W.
      • Davies J.
      • McElvaney N.G.
      • Tullis E.
      • Bell S.C.
      • Drevinek P.
      • et al.
      A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
      ,
      • Davies J.C.
      • Wainwright C.E.
      • Canny G.J.
      • Chilvers M.A.
      • Howenstine M.S.
      • Munck A.
      • et al.
      Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation.
      ,
      • De Boeck K.
      • Munck A.
      • Walker S.
      • Faro A.
      • Hiatt P.
      • Gilmartin G.
      • et al.
      Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation.
      ,
      • Rowe S.M.
      • Daines C.
      • Ringshausen F.C.
      • Kerem E.
      • Wilson J.
      • Tullis E.
      • et al.
      Tezacaftor–ivacaftor in residual-function heterozygotes with cystic fibrosis.
      ]. The 24-week, open-label, 2-part, phase 3 KIWI study demonstrated that the pharmacokinetics, safety, and efficacy of ivacaftor in children aged 2 to 5 years with CF and a CFTR gating mutation are generally similar to those seen in older patients [
      • Davies J.C.
      • Cunningham S.
      • Harris W.T.
      • Lapey A.
      • Regelmann W.E.
      • Sawicki G.S.
      • et al.
      Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.
      ]. Data from KIWI led to the approval of ivacaftor in the United States, European Union, Canada, and Australia for treatment of patients aged 2 years and older with CF and a CFTR gating/ivacaftor-responsive mutation.
      Here, we report results from KLIMB, an 84-week extension study of ivacaftor in children aged 2 to 5 years with CF and a CFTR gating mutation who completed the 24-week KIWI study. The primary outcome was long-term safety. Other outcomes included changes in sweat chloride, growth parameters, and measures of pancreatic function.

      2. Methods and materials

      2.1 Study design and participants

      KLIMB was an open-label extension study (ClinicalTrials.gov, number NCT01946412) in children who completed the 24-week, single-arm, open-label, phase 3 KIWI (part B) study of ivacaftor treatment [
      • Davies J.C.
      • Cunningham S.
      • Harris W.T.
      • Lapey A.
      • Regelmann W.E.
      • Sawicki G.S.
      • et al.
      Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.
      ]. Children eligible for KIWI were aged 2 to 5 years (median, 3.0 years), weighed 8 kg or more, and had a confirmed diagnosis of CF [
      • Farrell P.M.
      • White T.B.
      • Ren C.L.
      • Hempstead S.E.
      • Accurso F.
      • Derichs N.
      • et al.
      Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation.
      ] and a CFTR gating mutation (G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D) on at least 1 allele [
      • Davies J.C.
      • Cunningham S.
      • Harris W.T.
      • Lapey A.
      • Regelmann W.E.
      • Sawicki G.S.
      • et al.
      Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.
      ]. After completion of the study's design, the G970R mutation was discovered to be a class I splice mutation [
      • Seibert F.S.
      • Linsdell P.
      • Loo T.W.
      • Hanrahan J.W.
      • Riordan J.R.
      • Clarke D.M.
      Cytoplasmic loop three of cystic fibrosis transmembrane conductance regulator contributes to regulation of chloride channel activity.
      ]; none of the children in this study had this mutation. There was no interruption of ivacaftor treatment between KIWI and KLIMB. The primary outcome of KLIMB was long-term safety. Other outcomes included change from KIWI and KLIMB study baseline measurements in sweat chloride (assessed at clinic visits at day 1 and weeks 24, 48, 72, and 84) and weight, height, and body mass index (BMI; assessed at day 1 and weeks 12, 24, 36, 48, 60, 72, and 84). Exploratory endpoints included change from KIWI and KLIMB study baseline measurements in fecal elastase-1 (a measure of pancreatic exocrine function [
      • Borowitz D.
      • Baker S.S.
      • Duffy L.
      • Baker R.D.
      • Fitzpatrick L.
      • Gyamfi J.
      • et al.
      Use of fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis.
      ]), and percent predicted forced expiratory volume in 1 s (ppFEV1), all assessed at day 1 and weeks 12, 24, 36, 48, 60, 72, and 84. Immunoreactive trypsinogen (IRT; a serum-based marker of pancreatic insult) was assessed at day 1 and weeks 24, 48, 60, 72, and 84 [
      • Weintraub A.
      • Blau H.
      • Mussaffi H.
      • Picard E.
      • Bentur L.
      • Kerem E.
      • et al.
      Exocrine pancreatic function testing in patients with cystic fibrosis and pancreatic sufficiency: a correlation study.
      ]. Neither the site staff nor enrolled children received study-specific training in preschool lung function testing, nor were certification or over-reading conducted for spirometric assessments. Because acceptable spirometric data were only obtained in a small number of children in KIWI, these results are not presented.
      This study was conducted at 15 sites in the United States, United Kingdom, and Canada from December 2013 to December 2015. Children received weight-based ivacaftor as granules (Vertex Pharmaceuticals Incorporated, Boston, MA) every 12 h (q12h) at a dose of 50 mg q12h (weight < 14 kg) and 75 mg q12h (weight ≥ 14 kg). Children who turned 6 years of age during KLIMB received ivacaftor 150 mg q12h as tablets (Vertex Pharmaceuticals Incorporated, Boston, MA). Dose was adjusted as necessary based on weight at each study visit. Safety assessments consisted of adverse events primarily defined using Common Terminology Criteria for Adverse Events, version 4.0 [
      Common terminology criteria for adverse events (CTCAE) version 4.0: National Cancer Institute, Cancer Therapy Evaluation Program.
      ], clinical laboratory values, vital signs, 12-lead electrocardiogram readings, and physical and ophthalmological examinations. Standardized eye examinations were conducted by a licensed ophthalmologist at baseline and at specified intervals after dosing. Serious adverse events were defined per the International Conference on Harmonisation guidelines [
      Post-approval safety data management: definitions and standards for expedited reporting: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2003 [updated November 23].
      ].
      An independent ethics committee or institutional review board for each site approved the study protocol, and an independent data monitoring committee monitored study safety data. Written informed consent was obtained from each child's parent or legal guardian.

      2.2 Statistical analyses

      Safety and efficacy were assessed among all children who received at least 1 dose of ivacaftor in KLIMB. A mixed-effects model for repeated measures (MMRM) was used to analyze the absolute change from baseline in sweat chloride; height, weight, and BMI z scores; and fecal elastase-1 at each study visit. For IRT, as it was not normally distributed, the Wilcoxon Signed Rank Test was used. There was no adjustment for multiple comparisons in the analyses of absolute change from baseline in study endpoints due to the small sample size. All P values are nominal. Additional analyses performed using descriptive statistics and 95% CI for group comparisons are provided. Analyses were performed using SAS®, version 9.2 (Cary, NC).

      3. Results

      3.1 Study population

      Thirty-four children were enrolled in KIWI part B, and 33 (97%) completed the 24 weeks of treatment (Supplementary Fig. 1). All 33 who completed KIWI enrolled in KLIMB, with 28 (84.8%) completing the 84-week open-label treatment period. Of the 5 children who discontinued study drug before week 84, 2 switched to commercial ivacaftor, 1 had an adverse event (elevated alanine aminotransferase [ALT] >8 × upper limit of normal [ULN] and aspartate aminotransferase [AST] >3 × ULN), 1 had difficulty swallowing the ivacaftor 150-mg tablet, and 1 withdrew because of inability to tolerate further blood tests.

      3.2 Primary outcome: safety

      Adverse events are summarized in Table 1. All children reported at least 1 adverse event during the 84 weeks. The most common adverse events occurring in ≥30% of children were cough (72.7%), pyrexia (39.4%), vomiting (39.4%), and pulmonary exacerbation (30.3%), events that commonly occur in the pediatric CF population. Twenty-one serious adverse events occurred in 11 children. Serious adverse events considered related to ivacaftor were elevated ALT and AST levels that occurred in 2 children. One child had elevated ALT levels >8 × ULN and elevated AST levels >5 × ULN on the same day. The second had elevated ALT/AST levels >8 × ULN on the same day.
      Table 1Adverse events.
      Adverse events (AE), n (%)Overall

      (N = 33)
      Children with ≥1 adverse event33 (100)
      Treatment-emergent adverse events in ≥ 10% of children
      Cough24 (72.7)
      Pyrexia13 (39.4)
      Vomiting13 (39.4)
      Pulmonary exacerbation10 (30.3)
      Nasal congestion7 (21.2)
      Increased ALT7 (21.2)
      Increased AST6 (18.2)
      Otitis media6 (18.2)
      Rhinorrhea6 (18.2)
      Abdominal pain5 (15.2)
      Sinusitis5 (15.2)
      Viral upper respiratory tract infection5 (15.2)
      Viral gastroenteritis4 (12.1)
      Streptococcal pharyngitis4 (12.1)
      Rash4 (12.1)
      Serious adverse events (SAEs)
      Pulmonary exacerbation
      a Resulting hospitalization.
      6 (18.2)Patient # 1, 2, 5, 6, 7, 9
      ALT >8 × ULN
      b These were the same 2 children. An episode of transaminase >8 × ULN was observed in a total of 5 children (see Table 2); in only 2 cases did the investigator report the event as an SAE.
      2 (6.1)Patient # 10, 11
      AST >5 × ULN
      b These were the same 2 children. An episode of transaminase >8 × ULN was observed in a total of 5 children (see Table 2); in only 2 cases did the investigator report the event as an SAE.
      2 (6.1)Patient # 10, 11
      Pyrexia
      a Resulting hospitalization.
      2 (6.1)Patient # 3, 7
      Enterovirus infection
      a Resulting hospitalization.
      1 (3.0)Patient # 4
      Respiratory syncytial virus infection
      a Resulting hospitalization.
      1 (3.0)Patient # 1
      Staphylococcal infection
      a Resulting hospitalization.
      1 (3.0)Patient # 2
      Adenovirus test positive
      a Resulting hospitalization.
      1 (3.0)Patient # 3
      Dehydration
      a Resulting hospitalization.
      1 (3.0)Patient # 3
      Anoxic seizure
      a Resulting hospitalization.
      1 (3.0)Patient # 8
      ALT, alanine transaminase; AST, aspartate transaminase; ULN, upper limit of normal.
      a Resulting hospitalization.
      b These were the same 2 children. An episode of transaminase >8 × ULN was observed in a total of 5 children (see Table 2); in only 2 cases did the investigator report the event as an SAE.
      Elevated ALT and/or AST levels >3 × ULN were documented in 10 children (30%) during 84 weeks in KLIMB (Table 2). 4 of these 10 children also had transaminase elevations during KIWI, and a history of liver function test (LFT) elevations before enrollment in KIWI. In KLIMB, LFT elevations were reported as adverse events in 7 of the 10 children. Per protocol, treatment was interrupted in all 5 children who reported ALT and/or AST elevations >8 × ULN. Ivacaftor dosing was successfully resumed in 4 of the 5 children. One child permanently discontinued ivacaftor because of LFT elevations after ivacaftor was reinitiated.
      Table 2Summary of liver function test elevations during the 84-week KLIMB study.
      Maximum on-treatment ALT or AST (U/L), n (%)
      a 7 of the 10 total events were reported as AEs; 2 of the 5 events with ALT or AST >8  ×  ULN were reported as SAEs.
      N = 33
      >3 to ≤5 × ULN1 (3.0)
      >5 to ≤8 × ULN4 (12.1)
      >8 × ULN5 (15.2)
      ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.
      a 7 of the 10 total events were reported as AEs; 2 of the 5 events with ALT or AST >8  ×  ULN were reported as SAEs.
      Fig. 1 illustrates the prevalence of transaminase elevations over time during KLIMB. There was no evidence of increased prevalence of elevated transaminases with prolonged exposure to ivacaftor.
      Fig. 1
      Fig. 1Prevalence of elevated transaminase measurements over time in KLIMB, including proportion of children with ALT or AST elevations 3 × ULN and greater during the 84-week study. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BL, baseline; Ext, extension; ULN, upper limit of normal. a Data shown for children who enrolled in KLIMB.
      No abnormalities were detected on serial electrocardiograms. No meaningful changes in visual acuity from baseline occurred throughout the study. One child with a history of astigmatism developed a lens opacity at week 84 that was considered not visually significant and possibly related to ivacaftor. Drug withdrawal was not recommended.

      3.3 Secondary outcomes

      3.3.1 Sweat chloride

      Ivacaftor treatment during KIWI had led to a significant reduction in sweat chloride that was maintained over 24 weeks of treatment [
      • Davies J.C.
      • Cunningham S.
      • Harris W.T.
      • Lapey A.
      • Regelmann W.E.
      • Sawicki G.S.
      • et al.
      Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.
      ]. Continued treatment of these children with ivacaftor in KLIMB maintained this reduction in sweat chloride until the end of the study at week 84 (Fig. 2 and Table 3).
      Fig. 2
      Fig. 2Mean absolute change from KIWI baseline in (A) sweat chloride and (B) BMI z score and mean values for (C) fecal elastase-1 levels by visit. Means were calculated for each visit from the number of children contributing data at that time point. BL, baseline; Ext, extension; SE, standard error. a Data shown for all children who enrolled in KLIMB. Data for intermediate visits from KIWI are not shown for fecal elastase-1. P < .05. P < .01. P < .0001. All P values are for absolute change from KIWI baseline.
      Table 3Absolute change in secondary and tertiary endpoints at extension week 84.
      EndpointsMean absolute change at extension week 84 (95% CI)P value for mean absolute change from KIWI baseline
      a All P values are nominal.
      Secondary endpointsFrom KIWI baselineFrom KLIMB baseline
      Sweat chloride, mmol/L−54.7 (−65.4, −43.9)−8.5 (−18.9, 1.8)<.0001
      Tertiary endpoints
      BMI z score0.27 (0.04, 0.50)−0.08 (−0.31, 0.15).0229
      Weight z score0.20 (−0.05, 0.44)0.00 (−0.20, 0.20).1119
      Height z score0.12 (−0.06, 0.29)0.14 (0.00, 0.29).1800
      Fecal elastase-1, µg/g128.8 (45.7, 211.9)56.8 (−22.2, 135.8).0050
      Median absolute change (min,max) at extension week 84
      IRT, ng/mL−8.1 (−71.1, 21.9)1.0 (−16.4, 35.6).0103
      b From a Wilcoxon Signed Rank Test.
      BMI, body mass index; IRT, immunoreactive trypsinogen.
      a All P values are nominal.
      b From a Wilcoxon Signed Rank Test.

      3.3.2 Nutrition

      Improvements in weight z score (+0.2 [SD, 0.3]; P < .0001) and BMI z score (+0.4 [SD, 0.4]; P < .001) were observed during the initial 24-week KIWI study [
      • Davies J.C.
      • Cunningham S.
      • Harris W.T.
      • Lapey A.
      • Regelmann W.E.
      • Sawicki G.S.
      • et al.
      Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.
      ]. During the 84-week KLIMB extension, the weight z score from KIWI baseline was unchanged but the BMI z score continued to be significantly better than at KIWI baseline (0.27 [95% CI: 0.04, 0.50]; Table 3).

      3.4 Exploratory outcomes

      3.4.1 Pancreatic exocrine function

      In the KIWI study, mean fecal elastase-1 increased by 99.8 µg/g from baseline (SD, 138.4; P < .001). Additionally, 23% (P = .0504) had a fecal elastase-1 that improved to >200 µg/g, the cutoff value for pancreatic exocrine insufficiency. Improvements in fecal elastase-1 levels observed during KIWI were maintained during KLIMB (Fig. 2). At week 84, the mean (95% CI) absolute increase in fecal elastase-1 was 128.8 (45.7, 211.9) µg/g from KIWI baseline. During the 84-week open-label extension, fecal elastase-1 continued to increase, but the change from KLIMB baseline was not statistically significant (56.8 µg/g; 95% CI: −22.2, 135.8; Table 3). Seventeen children had paired fecal elastase-1 data at KIWI baseline and week 84 of KLIMB. At the start of the KIWI study, 1 of 17 (6%) children had fecal elastase-1 levels ≥200 µg/g. By week 84 of KLIMB, 6 of 17 (35%) children had fecal elastase-1 ≥ 200 µg/g.
      In KIWI, IRT levels decreased from baseline to week 24 by a mean of 20.7 ng/mL (SD, 24), suggesting reduced pancreatic inflammation/stress from KIWI study entry [
      • Davies J.C.
      • Cunningham S.
      • Harris W.T.
      • Lapey A.
      • Regelmann W.E.
      • Sawicki G.S.
      • et al.
      Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.
      ]. This decrease was maintained in KLIMB: at week 84, the mean (SD) absolute decrease from KIWI baseline was −15.9 (25.2) ng/mL. The median (range) absolute decrease from KIWI baseline was −8.1 ng/mL (−71.1, 21.9), with no significant change during the KLIMB extension (1.0 ng/mL; −16.4, 35.6).

      4. Discussion

      The results of this open-label extension study suggest that ivacaftor is generally well tolerated in children aged 2 to 5 years with CF and a gating mutation for up to 108 weeks. The safety profile was consistent with previous clinical trials of ivacaftor in children and adults. There were no clinical safety concerns identified in assessments of hematology laboratory parameters, vital signs, or electrocardiograms in this small sample.
      While there are limited data on the prevalence of LFT elevations in children with CF, studies indicate a natural propensity for transaminase elevations in children with CF in the first 2 to 3 years of life [
      • Lindblad A.
      • Glaumann H.
      • Strandvik B.
      Natural history of liver disease in cystic fibrosis.
      ,
      • Woodruff S.A.
      • Sontag M.K.
      • Accurso F.J.
      • Sokol R.J.
      • Narkewicz M.R.
      Prevalence of elevated liver enzymes in children with cystic fibrosis diagnosed by newborn screen.
      ]. Our findings on transaminase elevations seem to be consistent with the published data. Thirty percent of children aged 2 to 5 years in KLIMB had transaminase elevations >3 × ULN on at least 1 occasion across 84 weeks. Transaminase elevations were generally asymptomatic, did not require permanent treatment discontinuation except in 1 child, and occurred more often in children with a history of transaminase elevations prior to ivacaftor exposure and in KIWI. The lack of a placebo arm in this study makes interpretation of our results difficult, with uncertainty as to whether the prevalence of elevated transaminases reflects an effect of ivacaftor, ascertainment bias due to increased monitoring during a clinical trial, or the natural history of LFT elevations in this age group. This long-term extension study is important in demonstrating that the prevalence of LFT elevations did not appear to increase with the length of exposure to ivacaftor. However, it is recommended that LFTs be assessed before initiation of ivacaftor and monitored during treatment, particularly in children with a history of elevated transaminases.
      It is difficult to interpret the potential risk of the non-visually significant lens opacity seen in 1 patient at week 84 in association with astigmatism. Baseline assessment for lens opacities and periodic monitoring while on therapy is recommended.
      The improvements observed in sweat chloride concentrations during the 24-week KIWI study were maintained during this 84-week extension trial, demonstrating maintenance of improved CFTR function. Similarly, improvements in BMI z scores observed in KIWI were generally maintained in KLIMB, although without further improvement.
      The changes in the exploratory endpoints of fecal elastase-1 and serum IRT observed during KIWI were maintained during KLIMB, suggesting that early, effective CFTR modulation has the potential to delay deterioration in pancreatic function. Further support is lent to this hypothesis by the improvements in markers of pancreatic exocrine function (fecal elastase-1) and pancreatic insult (IRT, amylase, and lipase) reported recently in children 12 to <24 months treated with ivacaftor [
      • Rosenfeld M.
      • Wainwright C.E.
      • Higgins M.
      • Wang L.T.
      • McKee C.
      • Campbell D.
      • et al.
      Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study.
      ]. The mechanism by which ivacaftor might improve exocrine pancreatic function is unclear. In a recent study employing mouse models of Sjogren's syndrome and autoimmune pancreatitis, both of which involve decreased expression and mislocalization of CFTR in the pancreatic ducts, treatment with ivacaftor and a CFTR corrector rescued CFTR expression and localization, resulting in decreased acinar inflammation, fibrosis, and tissue damage [
      • Zeng M.
      • Szymczak M.
      • Ahuja M.
      • et al.
      Correction of ductal CFTR activity rescues acinar cell and pancreatic and salivary gland functions in mouse models of autoimmune disease.
      ]. These results (albeit not from a CF model) suggest that the effect of ivacaftor on the pancreas in infants and toddlers with CF may be mediated through restoration of ductal function, in turn improving acinar cell function and allowing some normalization of pancreatic secretions (enzymes, bicarbonate, fluid). In older children and adults, in whom ivacaftor does not improve fecal elastase, the improved nutritional status associated with ivacaftor appears to be the result of normalization of intestinal pH and CFTR-mediated bicarbonate secretion [
      • Gelfond D.
      • Heltshe S.
      • Ma C.
      • et al.
      Impact of CFTR modulation on intestinal pH, motility, and clinical outcomes in patients with cystic fibrosis and the G551D mutation clinical and translational.
      ] as well as decreased intestinal inflammation, resulting in improved absorption of fat [
      • Stallings V.
      • Sainath N.
      • Oberle M.
      • et al.
      Energy balance and mechanisms of weight gain with Ivacaftor treatment of cystic fibrosis gating mutations.
      ].
      The current study had several limitations. The age of the population and relative rarity of the CFTR gating mutations led to the decision to perform the original KIWI study as an open-label rather than a placebo-controlled trial. Because KLIMB was designed as a single-arm extension of this safety and pharmacokinetic trial, there was no placebo group. The lack of a control group limits our interpretation of both safety and therapeutic benefit. In addition, most participants had at least 1 G551D mutation, limiting our ability to assess the effects of ivacaftor treatment in persons with rarer gating mutations. The small sample size also limited our ability to detect rare adverse events. Finally, because of the challenge of obtaining accurate spirometry data from children aged 2 to 5 years [
      • Gaffin J.M.
      • Shotola N.L.
      • Martin T.R.
      • Phipatanakul W.
      Clinically useful spirometry in preschool-aged children: evaluation of the 2007 American Thoracic Society guidelines.
      ], very little acceptable spirometry data were collected, precluding our ability to analyze those data. Alternative lung function measures such as the lung clearance index from multiple-breath washout may also be considered in the future [
      • Horsley A.
      Lung clearance index in the assessment of airways disease.
      ].

      5. Conclusions

      This is the first study reporting long-term safety and efficacy of ivacaftor in children aged 2 to 5 years with a CFTR gating mutation. Ivacaftor was generally safe and well tolerated for up to 108 weeks. Increases in transaminases did not become more frequent with prolonged exposure to the drug. The reduction in sweat chloride concentration, growth benefits, and improvements in markers of pancreatic exocrine function observed during 24 weeks in KIWI were maintained for an additional 84 weeks in KLIMB.

      Funding

      This study was sponsored by Vertex Pharmaceuticals Incorporated. Medical writing and editorial support and coordination were funded by Vertex Pharmaceuticals Incorporated.

      Declaration of interest

      MR has received research grants and served as a consultant for Vertex Pharmaceuticals Incorporated, for which her institution received payment. SC has received fees paid by the UK Cystic Fibrosis Trust made to his institution for his contribution to the UKCFT Pharmacovigilance Programme. WTH reports grants from Vertex Pharmaceuticals, during the conduct of the study; grants from National Institutes of Health (NIH), grants from Cystic Fibrosis Foundation, and grants from Gilead Sciences outside the submitted work. WER and MC have served as site principal investigators for trials, institutions received fees from Vertex Pharmaceuticals Incorporated. GSS has received consulting fees from Vertex Pharmaceuticals Incorporated and his institution has received financial support from Vertex Pharmaceuticals Incorporated, Gilead Sciences, and Genentech. MH and ST are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. JC is a former employee of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. JCD has served on advisory boards, undertaken educational activities, and served as a national/site principal investigator for trials, for which her institution received fees from Vertex Pharmaceuticals Incorporated. AL and KWS have no declarations of interest.

      Acknowledgments

      The authors thank all the patients and their families for participating in the study. The authors also thank Linda T. Wang, MD, and Daniel Campbell, PhD, for their critical review of the manuscript. LTW and DC are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. The authors acknowledge the contributions of all KLIMB (VX11-770-109) study site investigators and coordinators: Frank Accurso, MD (Children's Hospital Colorado, Aurora, CO), Philip Black, MD (Children's Mercy Hospital, Kansas City, MO), Barbara Chatfield, MD (University of Utah Primary Children's Medical Center, Salt Lake City, UT), Theresa Laguna, MD (University of Minnesota, Minneapolis, MN), Gregory Montgomery, MD (Riley Hospital for Children at Indiana University Health, Indianapolis, IN), Howard Schmidt, MD (Virginia Commonwealth University Health Systems, Nelson Clinic, Richmond, VA), and Seth Walker, MD (The Emory Clinic Children's Healthcare of Atlanta at Egleston, Atlanta, GA) and acknowledge Andrew Fall, MBChB, and Debbie Miller from the NHS Lothian Children's Clinical Research Facility at the Royal Hospital for Sick Children, Edinburgh, Scotland; Katie Brand from the Child Health Research Unit at the University of Alabama at Birmingham; Melissa Richmond from the BC Children's Hospital, Vancouver, BC, Canada; and Rebecca Dobra, MBChB, and Sandra Scott, PhD, Royal Brompton and Harefield NHS Foundation Trust, London, UK. This project was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London . The views expressed in this publication are those of the authors and not necessarily those of the NHS, The National Institute for Health Research, or the Department of Health.
      Medical writing and editorial support were provided by Tejendra Patel, PharmD, an employee of Vertex Pharmaceuticals Incorporated and Stephanie Vadasz, PhD, of Ashfield Healthcare Communications, which received funding from Vertex Pharmaceuticals Incorporated.

      Appendix A. Supplementary data

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