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Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries

Open AccessPublished:June 10, 2019DOI:https://doi.org/10.1016/j.jcf.2019.05.015

      Highlights

      • Analyses of 2 independent CF registries support disease modification with ivacaftor.
      • Ivacaftor-treated patients have better-preserved lung function vs comparators.
      • Patients treated with ivacaftor for up to 5 years have lower risk of exacerbations.
      • Favorable trends in CFRD, P. aeruginosa with ivacaftor treatment (vs comparators).

      Abstract

      Background

      Ivacaftor is the first in a class of drugs, CFTR modulators, that target the underlying defect in cystic fibrosis (CF). This long-term observational safety study evaluated CF disease progression in patients treated with ivacaftor in a real-world setting for up to 5 years.

      Methods

      Data from existing US and UK CF patient registries were used to assess longitudinal patterns in lung function, nutritional status, pulmonary exacerbations and hospitalizations, CF-related diabetes (CFRD), and Pseudomonas aeruginosa in ivacaftor-treated vs untreated comparator cohorts matched by age, sex, and disease severity.

      Results

      US analyses included 635 ivacaftor-treated patients and 1874 comparators followed for 5 years from year 1 of market availability (2012–2016). Evaluation of outcome patterns from pretreatment baseline (2011) through year 5 (2016), showed that relative to comparators, ivacaftor-treated patients had better preserved lung function (mean change in percent predicted FEV1, −0.7 percentage points with ivacaftor vs −8.3 percentage points in comparators) and improved nutritional status (mean body mass index change +2.4 kg/m2 with ivacaftor vs +1.6 kg/m2 in comparators). US patients treated with ivacaftor had significantly lower frequencies of exacerbations and hospitalizations in each of the 5 years of follow-up relative to pretreatment baseline and comparators. Favorable trends in CFRD and P. aeruginosa prevalence were also observed. Findings from the smaller UK registry were directionally similar to and consistent with US findings.

      Conclusions

      This observational study represents the largest longitudinal analysis of patients treated with ivacaftor in a real-world setting. The findings support disease modification by CFTR modulation with ivacaftor.

      Keywords

      Abbreviations:

      BMI (body mass index), CF (cystic fibrosis), CFFPR (Cystic Fibrosis Foundation Patient Registry), CFR (Cystic Fibrosis Registry), CFRD (cystic fibrosis–related diabetes), CFTR (cystic fibrosis transmembrane conductance regulator), IVA (ivacaftor), LTFU (lost to follow-up), P. aeruginosa (Pseudomonas aeruginosa), PEx (pulmonary exacerbations), ppFEV1 (percent predicted forced expiratory volume in 1 s), RR (relative risk)

      1. Introduction

      Cystic fibrosis (CF) is a progressive, multisystem disease caused by a loss of cystic fibrosis transmembrane conductance regulator (CFTR) protein quantity and/or function due to mutations in the CFTR gene. Lung function decline is a hallmark of the clinical course of CF and the major cause of mortality. Pulmonary exacerbations (PEx) are associated with loss of lung function, hospitalizations, and reduced quality of life [
      • Goss C.H.
      • Burns J.L.
      Exacerbations in cystic fibrosis. 1: epidemiology and pathogenesis.
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      • Liou T.G.
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      Predictive 5-year survivorship model of cystic fibrosis.
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      • Britto M.T.
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      • Tsevat J.
      • Wilmott R.W.
      Impact of recent pulmonary exacerbations on quality of life in patients with cystic fibrosis.
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      • Konstan M.W.
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      • Silva S.J.
      • et al.
      Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis.
      ]. Many patients experience chronic lung infections, with Pseudomonas aeruginosa being one of the major pathogens [
      • O'Sullivan B.P.
      • Freedman S.D.
      Cystic fibrosis.
      ,
      • Mayer-Hamblett N.
      • Kloster M.
      • Rosenfeld M.
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      • Emerson J.
      • et al.
      Impact of sustained eradication of new Pseudomonas aeruginosa infection on long-term outcomes in cystic fibrosis.
      ,
      • Sanders D.B.
      • Bittner R.C.
      • Rosenfeld M.
      • Hoffman L.R.
      • Redding G.J.
      • Goss C.H.
      Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation.
      ]. Additionally, progressive pancreatic damage over time leads to exocrine pancreatic insufficiency associated with poor nutritional status and growth, as well as endocrine pancreatic dysfunction associated with development of CF-related diabetes (CFRD) later in life [
      • O'Sullivan B.P.
      • Freedman S.D.
      Cystic fibrosis.
      ].
      CFTR modulators, such as ivacaftor, provide a novel therapeutic approach by targeting the underlying cause of CF. Ivacaftor facilitates increased chloride transport by potentiating the channel open–probability (or gating) of the CFTR protein at the epithelial cell surface [
      • Yu H.
      • Burton B.
      • Huang C.J.
      • Worley J.
      • Cao D.
      • Johnson Jr., J.P.
      • et al.
      Ivacaftor potentiation of multiple CFTR channels with gating mutations.
      ]. In clinical studies, patients treated with ivacaftor demonstrated sustained improvements in CFTR function and corresponding substantial, sustained improvements in lung function, PEx, respiratory symptoms, and weight gain [
      • 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.
      • Sheridan H.
      • Bell N.
      • Cunningham S.
      • Davis S.D.
      • Elborn J.S.
      • et al.
      Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial.
      ,
      • 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.
      ,
      • Moss R.B.
      • Flume P.A.
      • Elborn J.S.
      • Cooke J.
      • Rowe S.M.
      • McColley S.A.
      • et al.
      Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial.
      ,
      • 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.
      ].
      Following marketing authorization of ivacaftor in 2012 in the US, an observational study using real-world data from the US Cystic Fibrosis Foundation Patient Registry (CFFPR) and the UK Cystic Fibrosis Registry (CFR) was initiated to evaluate the long-term safety of ivacaftor and disease progression in ivacaftor-treated patients. The study was designed as a post-authorization safety surveillance study to fulfill a post-marketing commitment to the European Medicines Agency and is disclosed on the European Union electronic Register of Post-Authorization Studies (EUPAS4270). The study included 5 annual cross-sectional safety analyses of all patients with a record of ivacaftor treatment each year, as well as longitudinal disease progression analyses in the subset of patients treated continuously from the first year of market availability through study completion. The study has been completed, and the findings of the annual cross-sectional safety analyses have been presented and discussed elsewhere [
      • Bessonova L.
      • Volkova N.
      • Higgins M.
      • Bengtsson L.
      • Tian S.
      • Simard C.
      • et al.
      Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor.
      ,
      • Volkova N.
      • Evans J.
      • Higgins M.
      • Campbell D.
      • Tian S.
      • Simard C.
      • et al.
      Disease progression in patients with CF treated with ivacaftor: analyses of real-world data from the US and UK CF registries.
      ]. These cross-sectional analyses showed no new safety concerns, lower risks of death and organ transplants among ivacaftor-treated patients, and a favorable impact of ivacaftor treatment on exacerbations and other markers of disease.
      In this paper, we present findings of the disease progression analyses, focusing on evaluation of longitudinal patterns in lung function, nutritional status, PEx, hospitalizations, and prevalence of CFRD and P. aeruginosa for up to 5 years following approval of ivacaftor. Whereas previous analyses from this study focused on cross-sectional evaluation of single-year data in each registry [
      • Bessonova L.
      • Volkova N.
      • Higgins M.
      • Bengtsson L.
      • Tian S.
      • Simard C.
      • et al.
      Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor.
      ], this report describes longitudinal evaluations of patterns in disease progression outcomes over time, from the first year of commercial availability through 2016.

      2. Methods

      2.1 Data sources

      Existing US and UK registries of patients with CF are two of the largest national CF disease registries worldwide and were used as data sources for all analyses presented in this paper. The US CFFPR collects data across >120 CFF-accredited care centers, representing approximately 84% of all US patients with CF; in 2016, 29,497 patients were included [
      • Knapp E.A.
      • Fink A.K.
      • Goss C.H.
      • Sewall A.
      • Ostrenga J.
      • Dowd C.
      • et al.
      The Cystic Fibrosis Foundation patient registry. Design and methods of a national observational disease registry.
      ,
      • Cystic Fibrosis Foundation
      Cystic Fibrosis Foundation patient registry 2016 annual data report.
      ]. The UK CFR included 10,461 patients across 32 pediatric and 28 adult CF care centers in England, Scotland, Wales, and Northern Ireland (>99% coverage of the UK CF population) in 2016 [
      • Taylor-Robinson D.
      • Archangelidi O.
      • Carr S.B.
      • Cosgriff R.
      • Gunn E.
      • Keogh R.H.
      • et al.
      Data resource profile: the UK cystic Fibrosis registry.
      ,
      • Cystic Fibrosis Trust
      UK Cystic fibrosis registry 2016 annual data report.
      ]. Both registries use an online application for entry of pertinent data related to patients and their medical care by staff at CF care centers, providing a unique opportunity to evaluate long-term effects of novel therapies in the real-world setting [
      • Knapp E.A.
      • Fink A.K.
      • Goss C.H.
      • Sewall A.
      • Ostrenga J.
      • Dowd C.
      • et al.
      The Cystic Fibrosis Foundation patient registry. Design and methods of a national observational disease registry.
      ,
      • Taylor-Robinson D.
      • Archangelidi O.
      • Carr S.B.
      • Cosgriff R.
      • Gunn E.
      • Keogh R.H.
      • et al.
      Data resource profile: the UK cystic Fibrosis registry.
      ].

      2.2 Study cohorts

      Ivacaftor cohorts included all patients with a record of ivacaftor use during the first calendar year of market availability (2012 in the US and 2013 in the UK) who were followed prospectively and were still on treatment, alive, and not lost to follow-up and had not received lung transplant as of 2016 (year 5 of market availability in the US and year 4 of market availability in the UK). To reflect the real-world use of the therapy, no inclusion/exclusion criteria based on patient age or genotype were applied to the ivacaftor cohorts. However, because ivacaftor was initially approved for use in patients aged ≥6 years with ≥1 copy of a G551D mutation, the majority of patients in the ivacaftor cohorts were expected to be of this age and genotype.
      Comparator cohorts included patients without ivacaftor use during the first year of market availability who were followed prospectively and were still alive and not lost to follow-up, had not received a lung transplant, and did not initiate any CFTR modulator treatment as of 2016. These comparators were matched with ivacaftor cohort patients by age, sex, and disease severity as assessed by genotype in an approximately 5 to 1 ratio. Because of the high uptake of ivacaftor in the indicated populations, it was not feasible to identify comparators of the same genotype. However, the matching algorithm ensured that ivacaftor-treated patients and comparator patients had genotypes resulting in similar disease severity. Both mutant alleles were matched; for example, ivacaftor-treated patients with a G551D mutation on one allele and a class II mutation on the second allele could be matched with untreated patients who had an F508del mutation on one allele and a class II mutation on the second, based on research indicating that CF disease phenotypes are comparable between patients with class III mutations, such as G551D, and class II mutations [
      • McKone E.F.
      • Emerson S.S.
      • Edwards K.L.
      • Aitken M.L.
      Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study.
      ,
      • Sawicki G.S.
      • McKone E.F.
      • Millar S.J.
      • Pasta D.J.
      • Konstan M.W.
      • Lubarsky B.
      • et al.
      Patients with cystic fibrosis and a G551D or homozygous F508del mutation: similar lung function decline.
      ].

      2.3 Disease progression endpoints

      Clinical signs of CF disease progression evaluated in this study and presented here include lung function as assessed by percent predicted forced expiratory volume in 1 s (ppFEV1), body mass index (BMI), PEx (defined as episodes requiring intravenous antibiotic use at home or in the hospital), hospitalizations (US, for any reason; UK, for intravenous antibiotic therapy only), CFRD status (present or absent, as recorded in the registries), and presence of the clinically important bacterial pathogen P. aeruginosa (US, ≥1 positive sputum culture within a 12-month period; UK, presence of ≥3 positive cultures within a 12-month period).

      2.4 Data analysis

      The evaluation of CF disease progression was based on a comparison of longitudinal patterns in clinical signs of disease progression between the ivacaftor and the comparator cohorts. Separate analyses were conducted for each registry (ie, no pooled analyses were conducted) due to the differences in data capture.
      The year prior to market availability of ivacaftor was considered “baseline” (2011 in the US and 2012 in the UK). The first year of market availability of ivacaftor was considered the “cohort entry year” (2012 in the US and 2013 in the UK).
      Analyses of lung function and nutritional status included calculating summary statistics (mean and 95% CIs) for ppFEV1 and BMI in the baseline year and in each follow-up year through 2016 in ivacaftor and comparator cohorts in each registry. Additionally, mean change in ppFEV1 and BMI from the baseline year was calculated for each follow-up year through 2016 in all patients with nonmissing assessments at baseline and follow-up. Lung function analyses were stratified by age (<12, 12 to <18, ≥18 years) and baseline ppFEV1 (<70 and ≥70). In the US patients, the ppFEV1 value for each year was defined as average of the best available values for each quarter in that year; in the UK patients, the annual assessment ppFEV1 value was used. BMI analyses were stratified by age (<18 and ≥18 years); BMI percentile was evaluated for patients aged <18 years. Survival analyses using life-table methodology were also performed.
      Proportions of patients with ≥1 PEx, and ≥1 hospitalization were calculated for the baseline year and each follow-up year through 2016 in the ivacaftor and comparator cohorts in each registry. These annual proportions were compared between ivacaftor and comparator cohorts by calculating relative risks (RRs) and 95% CIs based on normal approximation. Similarly, proportions of patients with CFRD and with P. aeruginosa were tabulated for the baseline year and each analysis year in the ivacaftor and comparator cohorts in each registry; RRs and 95% CIs were calculated for between-cohort comparisons. Differences between cohorts were considered statistically significant if the 95% CI for the RR did not include 1.

      3. Results

      3.1 Cohorts and demographics

      During the first year of ivacaftor availability in the US (2012), 805 patients who had a record of ivacaftor use were matched with 3815 untreated comparators. Matching achieved good balance between the 2012 US ivacaftor and comparator cohorts on values of mean age at baseline (19.6 vs 19.1 years in the ivacaftor vs comparator cohorts) and pretreatment baseline ppFEV1 (78.8 vs 78.0, respectively). >90% of patients in the 2012 US ivacaftor cohort had ≥1 copy of G551D (class III mutation). After the exclusion of patients who died, were lost to follow-up, changed their CFTR modulator treatment regimen, or received transplants during 5 years of follow-up (Fig. 1A ), the 2016 ivacaftor cohort included 635 patients (78.9% of the initial 2012 cohort), while the 2016 comparator cohort included 1874 patients (49.1% of the initial 2012 cohort). The considerable attrition of the US comparator cohort over the course of 5 years was primarily driven by the exclusion of patients with a new record of lumacaftor and ivacaftor combination therapy beginning in 2015, when it became commercially available in the US. Because these excluded comparator patients tended to have more severe lung disease, comparator patients remaining in the cohort through 2016 had less severe lung function impairment at baseline (mean ppFEV1, 81.7 vs 79.0) than ivacaftor cohort patients (Table 1).
      Fig. 1
      Fig. 1Ivacaftor and comparator disease progression cohorts for the 2016 analysis. (A) Patients in the US. (B) Patients in the UK. CF, cystic fibrosis; CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; IVA, ivacaftor; LTFU, lost to follow-up.
      Fig. 1
      Fig. 1Ivacaftor and comparator disease progression cohorts for the 2016 analysis. (A) Patients in the US. (B) Patients in the UK. CF, cystic fibrosis; CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; IVA, ivacaftor; LTFU, lost to follow-up.
      Table 1Patient characteristics of US and UK ivacaftor-treated and untreated comparator cohorts.
      CharacteristicUS CFFPRUK CFR
      IvacaftorComparatorIvacaftorComparator
      (n = 635)(n = 1874)(n = 247)(n = 1230)
      Mean age in 2016 (SD), years23.8 (11.6)22.7 (11.6)24.8 (11.2)24.0 (10.9)
      Age in 2016, n (%)
       <12 years84 (13.2)319 (17.0)26 (10.5)157 (12.8)
       12 to <18 years163 (25.7)482 (25.7)50 (20.2)254 (20.7)
       ≥18 years388 (61.1)1073 (57.3)171 (69.2)819 (66.6)
      Male sex, n (%)307 (48.3)959 (51.2)134 (54.3)642 (52.2)
      Class I-III genotype, n (%)
      In the US, 1662 of 1874 comparators (88.7%) had a class I-II genotype. In the UK, 1162 of 1230 comparators (94.5%) had a class I-II genotype.
      609 (95.9)1689 (90.1)235 (95.1)1162 (94.5)
      Mean baseline
      Baseline is defined as 2011 for the US CFFPR and 2012 for the UK CFR.
      ppFEV1 (SD)
      79.0 (25.3)81.7 (23.7)73.0 (23.6)73.4 (22.4)
      Baseline
      Baseline is defined as 2011 for the US CFFPR and 2012 for the UK CFR.
      ppFEV1, n (%)
       <4038 (6.0)66 (3.5)26 (10.5)93 (7.6)
       40 to <70146 (23.0)351 (18.7)69 (27.9)388 (31.5)
       ≥70393 (61.9)1184 (63.2)132 (53.4)646 (52.5)
       Unknown/missing58 (9.1)273 (14.6)20 (8.1)103 (8.4)
      PEx at baseline,
      Baseline is defined as 2011 for the US CFFPR and 2012 for the UK CFR.
      n (%)
      230 (37.5)592 (33.1)133 (53.8)556 (45.2)
      Hospitalizations at baseline,
      Baseline is defined as 2011 for the US CFFPR and 2012 for the UK CFR.
      n (%)
      232 (37.8)644 (36.0)116 (47.0)505 (41.1)
      Medications at baseline, %
       Chronic antibiotics
      In the US CFFPR, chronic antibiotics were defined as any of the following: tobramycin-based medications for inhalation, other inhaled aminoglycosides (eg, gentamicin, amikacin), colistin, aztreonam (inhaled), chronic oral macrolide antibiotics, and other oral antibiotics. In the UK CFR, chronic antibiotics were defined as any of the following: chronic oral antibiotics, chronic oral antibiotics (macrolide), inhaled antibiotics, and inhaled dry powder antibiotics.
      75.166.669.266.8
       Bronchodilators89.087.151.855.0
       Corticosteroids
      In both the US CFFPR and UK CFR, corticosteroids were defined to include oral corticosteroids, inhaled corticosteroids, and inhaled corticosteroids in combination with a bronchodilator.
      55.452.951.448.2
       Dornase alfa83.977.355.557.7
       Hypertonic saline52.950.921.123.1
      CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; PEx, pulmonary exacerbation; ppFEV1, percent predicted forced expiratory volume in 1 s.
      a In the US, 1662 of 1874 comparators (88.7%) had a class I-II genotype. In the UK, 1162 of 1230 comparators (94.5%) had a class I-II genotype.
      b Baseline is defined as 2011 for the US CFFPR and 2012 for the UK CFR.
      c In the US CFFPR, chronic antibiotics were defined as any of the following: tobramycin-based medications for inhalation, other inhaled aminoglycosides (eg, gentamicin, amikacin), colistin, aztreonam (inhaled), chronic oral macrolide antibiotics, and other oral antibiotics. In the UK CFR, chronic antibiotics were defined as any of the following: chronic oral antibiotics, chronic oral antibiotics (macrolide), inhaled antibiotics, and inhaled dry powder antibiotics.
      d In both the US CFFPR and UK CFR, corticosteroids were defined to include oral corticosteroids, inhaled corticosteroids, and inhaled corticosteroids in combination with a bronchodilator.
      Potential bias resulting from differential attrition of older US comparator patients with more severe lung function impairment, disadvantaging the ivacaftor cohort, should be considered when interpreting results of the disease progression analyses. For instance, the effect of ivacaftor on lung function and PEx is likely to be underestimated relative to comparators in the US analyses.
      In the UK analysis, 293 patients with a record of ivacaftor use in the first year of market availability (2013) were matched with 1433 comparators. After the exclusion of patients who died, were lost to follow-up, changed their CFTR modulator treatment regimen, or received transplants during the 4 years of follow-up (Fig. 1B), the 2016 ivacaftor cohort included 247 patients, and the comparator cohort included 1230 patients, representing 84.3% and 85.8% of the initial 2013 cohorts, respectively. The composition of both cohorts over time in the UK remained relatively stable; the exclusions appeared to be nondifferential as supported by the fact that after 4 years of follow-up, ivacaftor and comparator cohorts remained well balanced in terms of age, sex, and pretreatment ppFEV1 (Table 1).
      Interpretation of the survival analyses results is limited due to the relatively small patient populations and low number of deaths overall (17 and 8 deaths over the entire study duration in the ivacaftor cohorts in the US and UK, respectively; Fig. 1). However, overall, in the US these analyses showed a statistically significantly higher probability of survival and of remaining transplant free over the course of 5 years among ivacaftor-treated patients than among comparators. Similarly, there was a trend toward higher probability of survival and of remaining transplant free over the course of 4  years among ivacaftor-treated patients in the UK, although the differences were not statistically significant (data not shown).

      3.2 Lung function

      The US analyses showed better preserved lung function in patients treated with ivacaftor for up to 5 years vs comparators (Fig. 2A ). On average, among patients with nonmissing measurements in both the baseline year (2011) and 2016, the ppFEV1 decreased over the course of 5 years by 0.7 percentage points (95% CI: −1.6, 0.2) in ivacaftor-treated patients compared with 8.3 percentage points (95% CI: −9.0, −7.7) in comparators.
      Fig. 2
      Fig. 2Lung function over time in (A) US patients and (B) UK patients. For each year, mean observed ppFEV1 values are shown for patients with nonmissing lung function data. * Listed n values are the numbers of patients with nonmissing ppFEV1 data for the indicated year. CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; ppFEV1, percent predicted forced expiratory volume in 1 s.
      Similarly, the UK analyses showed better preserved lung function in patients treated with ivacaftor for up to 4 years relative to comparators (Fig. 2B). Among patients with measurements available in both 2012 and 2016, the ppFEV1 improved by 4.9 percentage points (95% CI: 3.30, 6.56) in ivacaftor-treated patients and decreased by 4.3 percentage points (95% CI: −5.06, −3.44) in comparators.
      The pattern of better-preserved lung function in ivacaftor-treated vs comparator patients was consistent within all age and baseline lung function strata in both registries (Supplementary Data).

      3.3 Nutritional status

      In the US analyses, among patients with BMI measurements available in both 2011 and 2016, mean BMI increased by 2.4 kg/m2 in the ivacaftor cohort and by 1.6 kg/m2 in the comparator cohort. Similarly, in the UK analyses, among patients with BMI measurements available in both 2012 and 2016, BMI increased on average by 1.9 kg/m2 in the ivacaftor cohort and by 0.9 kg/m2 in the comparator cohort. These improvements in nutritional status in ivacaftor-treated patients relative to comparator patients were seen in both pediatric and adult patients in both registries (Table 2).
      Table 2Nutritional status over time, by age at baseline.
      US CFFPR
      All Ages: BMI, kg/m2<18 Years: BMI Percentile≥18 Years: BMI, kg/m2
      Ivacaftor (n = 635)Comparator (n = 1874)Ivacaftor (n = 247)Comparator (n = 801)Ivacaftor (n = 388)Comparator (n = 1073)
      Baseline (2011)
      n
      Nonmissing value within an analysis year.
      61017682377563721008
      Mean20.320.053.354.522.422.2
      (95% CI)(20.0, 20.6)(19.8, 20.2)(50.0, 56.6)(52.8, 56.2)(22.0, 22.7)(22.0, 22.4)
      2016
      n
      Nonmissing value within an analysis year.
      63318712478013881071
      Mean22.721.659.851.223.722.9
      (95% CI)(22.4, 23.0)(21.4, 21.8)(56.2, 63.3)(49.4, 53.0)(23.3, 24.1)(22.7, 23.1)
      2016 change from baseline
      n
      Nonmissing value within the baseline year and 2016.
      60817662377563721007
      Mean+2.4+1.6+6.0−3.4+1.3+0.7
      (95% CI)(2.1, 2.6)(1.5, 1.7)(3.2, 8.9)(−4.9, −2.0)(1.1, 1.6)(0.5, 0.8)
      UK CFR
      All Ages: BMI, kg/m2<18 Years: BMI Percentile≥18 Years: BMI, kg/m2
      Ivacaftor (n = 247)Comparator (n = 1230)Ivacaftor (n = 102)Comparator (n = 547)Ivacaftor (n = 145)Comparator (n = 683)
      Baseline (2012)
      n
      Nonmissing value within an analysis year.
      246120889464144668
      Mean20.620.543.351.222.722.4
      (95% CI)(20.1, 21.1)(20.3, 20.7)(37.7, 49.0)(48.7, 53.6)(22.2, 23.3)(22.1, 22.7)
      2016
      n
      Nonmissing value within an analysis year.
      244122281426142679
      Mean22.421.454.649.923.922.6
      (95% CI)(21.9, 22.9)(21.2, 21.7)(48.0, 61.1)(47.1, 52.7)(23.3, 24.4)(22.3, 22.9)
      2016 change from baseline
      n
      Nonmissing value within the baseline year and 2016.
      243120081421141664
      Mean+1.9+0.9+10.0−1.0+1.2+0.2
      (95% CI)(1.6, 2.1)(0.8, 1.0)(4.9, 15.0)(−3.2, 1.1)(0.9, 1.6)(0.0, 0.4)
      BMI, body mass index; CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry.
      a Nonmissing value within an analysis year.
      b Nonmissing value within the baseline year and 2016.

      3.4 Pulmonary exacerbations and hospitalizations

      In both registries, the analyses showed significant and consistent reductions in the annual frequencies of PEx among patients treated with ivacaftor during follow-up relative to untreated comparators and relative to baseline values.
      In the US analyses, from 2011 (baseline) to 2016, the proportion of patients having ≥1 PEx decreased in the ivacaftor cohort from 37.5% to 25.7%, while in the comparator cohort, it increased from 33.1% to 44.0% (Fig. 3A ). The results of the UK data analyses were similar (Fig. 3B). An analysis of the average number of PEx events per patient per year showed trends that were consistent with other PEx analyses (Supplementary Data).
      Fig. 3
      Fig. 3Proportion of patients with PEx over time in (A) US patients and (B) UK patients. CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; PEx, pulmonary exacerbations; RR, relative risk.
      Similarly, there were significant and consistent reductions in the annual frequencies of hospitalizations in ivacaftor-treated patients during follow-up relative to untreated comparators and relative to baseline values in both registries (Figs. 4A and B ).
      Fig. 4
      Fig. 4Proportion of patients with hospitalizations over time. (A) For US patients, hospitalizations for any reason are shown. (B) For UK patients, hospitalizations due to PEx are shown. CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; PEx, pulmonary exacerbations; RR, relative risk.

      3.5 CFRD

      Evaluation of patterns in CFRD prevalence among the ivacaftor-treated vs comparator patients suggested favorable trends in both registries. In the US analyses, the increase in the prevalence of CFRD was lower in the ivacaftor cohort than the comparator cohort (by 12.1 vs 18.3 percentage points); similarly in the UK analyses, the increase in the prevalence of CFRD was lower in the ivacaftor cohort than in the comparator cohort (Fig. 5A and B ).
      Fig. 5
      Fig. 5Prevalence of CFRD over time in (A) US patients and (B) UK patients. CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; CFRD, cystic fibrosis–related diabetes; RR, relative risk.

      3.6 Pseudomonas aeruginosa

      The prevalence of one of the most common CF pulmonary pathogens, P. aeruginosa, increased numerically over time in untreated comparators and decreased in ivacaftor-treated patients in both registries (Fig. 6A and B ).
      Fig. 6
      Fig. 6Prevalence of Pseudomonas aeruginosa over time in (A) US patients and (B) UK patients. CFFPR, Cystic Fibrosis Foundation Patient Registry; CFR, Cystic Fibrosis Registry; P. aeruginosa, Pseudomonas aeruginosa; RR, relative risk.

      4. Discussion

      Extensive data from clinical and post-marketing studies in different patient populations have demonstrated that ivacaftor slows CF disease progression. The data presented in this paper further support that ivacaftor is disease-modifying therapy, consistent with the mechanism of action addressing the underlying defect in CF.
      Previously, randomized, controlled, Phase 3 studies (STRIVE [NCT00909532] and ENVISION [NCT00909727]) showed that ivacaftor improved lung function, respiratory symptoms, and nutritional status in patients with CF [
      • 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.
      ]. In the follow-up PERSIST study (NCT01117012), the clinical benefits of ivacaftor were shown to be sustained for up to 144 weeks of treatment [
      • McKone E.F.
      • Borowitz D.
      • Drevinek P.
      • Griese M.
      • Konstan M.W.
      • Wainwright C.
      • et al.
      Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST).
      ]. Comparison of ivacaftor-treated patients enrolled in these clinical studies with a propensity-matched untreated comparator cohort obtained from the CFFPR estimated that the rate of lung function decline slowed by approximately 50% over a 3-year analysis period [
      • Sawicki G.S.
      • McKone E.F.
      • Pasta D.J.
      • Millar S.J.
      • Wagener J.S.
      • Johnson C.A.
      • et al.
      Sustained benefit from ivacaftor demonstrated by combining clinical trial and cystic fibrosis patient registry data.
      ].
      The potential of ivacaftor to slow disease progression was also suggested by a number of smaller real-world studies across geographies, including the US [
      • Heltshe S.L.
      • Rowe S.M.
      • Skalland M.
      • Baines A.
      • Jain M.
      GOAL investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Ivacaftor-treated patients with cystic fibrosis derive long-term benefit despite no short-term clinical improvement.
      ], Ireland [
      • Ronan N.J.
      • Einarsson G.G.
      • Twomey M.
      • Mooney D.
      • Mullane D.
      • NiChroinin M.
      • et al.
      CORK study in cystic fibrosis: sustained improvements in ultra-low-dose chest CT scores after CFTR modulation with ivacaftor.
      ,
      • Kirwan L.
      • Fletcher G.
      • Harrington M.
      • Jeleniewska P.
      • Zhou S.
      • Casserly B.
      • et al.
      Longitudinal trends in real-world outcomes following initiation of ivacaftor: a cohort study from the Cystic Fibrosis Registry of Ireland.
      ], France [
      • Hubert D.
      • Dehillotte C.
      • Munck A.
      • David V.
      • Baek J.
      • Mely L.
      • et al.
      Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2 years of treatment with ivacaftor in a real-world setting.
      ,
      • Hubert D.
      • Fajac I.
      • Munck A.
      • Marguet C.
      • Benichou J.
      • Payen-Champenois C.
      • et al.
      Clinical effectiveness from the first interim analysis of the BRIO study: an observational study of cystic fibrosis patients treated with ivacaftor in France.
      ], and the UK [
      • Newsome S.J.
      • Keogh R.H.
      • Daniel R.M.
      CF-EpiNet. The effects of 3-year ivacaftor use on lung function and intravenous days seen in UK CF registry data.
      ], all of which consistently demonstrated improvements in ppFEV1 and PEx.
      Our findings from much larger patient cohorts in the US and the UK followed for up to 5 years show sustained favorable effects of ivacaftor therapy on disease progression. The results are consistent with the findings observed in the earlier studies [
      • Heltshe S.L.
      • Rowe S.M.
      • Skalland M.
      • Baines A.
      • Jain M.
      GOAL investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Ivacaftor-treated patients with cystic fibrosis derive long-term benefit despite no short-term clinical improvement.
      ,
      • Ronan N.J.
      • Einarsson G.G.
      • Twomey M.
      • Mooney D.
      • Mullane D.
      • NiChroinin M.
      • et al.
      CORK study in cystic fibrosis: sustained improvements in ultra-low-dose chest CT scores after CFTR modulation with ivacaftor.
      ,
      • Kirwan L.
      • Fletcher G.
      • Harrington M.
      • Jeleniewska P.
      • Zhou S.
      • Casserly B.
      • et al.
      Longitudinal trends in real-world outcomes following initiation of ivacaftor: a cohort study from the Cystic Fibrosis Registry of Ireland.
      ,
      • Hubert D.
      • Dehillotte C.
      • Munck A.
      • David V.
      • Baek J.
      • Mely L.
      • et al.
      Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2 years of treatment with ivacaftor in a real-world setting.
      ,
      • Hubert D.
      • Fajac I.
      • Munck A.
      • Marguet C.
      • Benichou J.
      • Payen-Champenois C.
      • et al.
      Clinical effectiveness from the first interim analysis of the BRIO study: an observational study of cystic fibrosis patients treated with ivacaftor in France.
      ,
      • Newsome S.J.
      • Keogh R.H.
      • Daniel R.M.
      CF-EpiNet. The effects of 3-year ivacaftor use on lung function and intravenous days seen in UK CF registry data.
      ] and provide additional support that ivacaftor modifies the course of disease in patients with CF.
      Progressive loss of lung function is one of the primary drivers of mortality [
      • Liou T.G.
      • Adler F.R.
      • Fitzsimmons S.C.
      • Cahill B.C.
      • Hibbs J.R.
      • Marshall B.C.
      Predictive 5-year survivorship model of cystic fibrosis.
      ,
      • Sanders D.B.
      • Bittner R.C.
      • Rosenfeld M.
      • Hoffman L.R.
      • Redding G.J.
      • Goss C.H.
      Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation.
      ]. In our analyses, ivacaftor-treated patients had better-preserved lung function in the long term compared with untreated comparators in both registries. A certain degree of lung function decline over time in the aging ivacaftor-treated patient population as observed in our study is expected due to the progressive nature of CF [
      • O'Sullivan B.P.
      • Freedman S.D.
      Cystic fibrosis.
      ] and should be interpreted in the context of untreated patients. In our analyses, lung function in the cohort of US patients treated with ivacaftor for 5 years was only slightly below pretreatment baseline values compared with a continuous and pronounced decline of ≥8 percentage points among the comparators. In UK patients, in the fourth year of the study, the lung function was above pretreatment baseline values by almost 5 percentage points compared with a decline of approximately 4 percentage points among the comparators.
      Patients with CF are at risk of chronic infections due to decreased mucociliary clearance and an inability to effectively clear bacteria from the lungs [
      • Chmiel J.F.
      • Davis P.B.
      State of the art: why do the lungs of patients with cystic fibrosis become infected and why can't they clear the infection?.
      ]. Our analyses showed a lower prevalence of P. aeruginosa over a 5-year period among ivacaftor-treated patients than among untreated comparators, which may be due to ivacaftor-mediated increases in mucociliary clearance, immunologic involvement, or other mechanisms.
      Acute episodes of worsening pulmonary function referred to as PEx strongly contribute to morbidity and mortality in patients with CF. The results of our study showed a significant reduction in PEx as well as hospitalizations in ivacaftor-treated patients relative to pretreatment baseline values and to untreated comparators in both registries.
      In addition to pulmonary impairment, patients with CF present with many complications contributing to disease progression. One such complication is CFRD, which has been associated with increased mortality and the emergence of microvascular complications [
      • Schwarzenberg S.J.
      • Thomas W.
      • Olsen T.W.
      • Grover T.
      • Walk D.
      • Milla C.
      • et al.
      Microvascular complications in cystic fibrosis-related diabetes.
      ]. The results of this 5-year study suggested favorable trends in CFRD prevalence among ivacaftor-treated patients relative to comparators, consistent with earlier publications suggesting that intervention with ivacaftor may improve glycemic control [
      • Bellin M.D.
      • Laguna T.
      • Leschyshyn J.
      • Regelmann W.
      • Dunitz J.
      • Billings J.
      • et al.
      Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study.
      ,
      • Banerjee A.
      • Brennan A.L.
      • Horsley A.R.
      • Barry P.J.
      Prospective examination of the effects of ivacaftor on glycaemic health.
      ]. Finally, this study showed improvements in nutritional status in ivacaftor-treated patients, supporting earlier reports [
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • McKone E.F.
      • Borowitz D.
      • Drevinek P.
      • Griese M.
      • Konstan M.W.
      • Wainwright C.
      • et al.
      Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST).
      ,
      • Hubert D.
      • Dehillotte C.
      • Munck A.
      • David V.
      • Baek J.
      • Mely L.
      • et al.
      Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2 years of treatment with ivacaftor in a real-world setting.
      ].
      The key strength of our analyses is that the results rely on evaluation of data from two of the largest CF patient registries that maintain a high degree of data completeness. Collectively, the US and UK registries follow almost 40,000 patients with CF, representing approximately half of the population of patients with CF worldwide. Regular audits of select US CF centers have confirmed an 82.6% to 99.9% accuracy rate between patient medical records and the registry-captured data [
      • Knapp E.A.
      • Fink A.K.
      • Goss C.H.
      • Sewall A.
      • Ostrenga J.
      • Dowd C.
      • et al.
      The Cystic Fibrosis Foundation patient registry. Design and methods of a national observational disease registry.
      ]. The UK CFR database is similarly complete, with 95% of patients having annual reviews documented [
      • Cystic Fibrosis Trust
      UK Cystic fibrosis registry 2016 annual data report.
      ]. The size and the coverage of the registries included in this study, as well as their data completeness make them powerful sources for studying the effects of ivacaftor treatment in a real-world setting.
      Although the use of national CF registries in this study allowed for longitudinal analyses in representative populations of patients treated with ivacaftor, our study also had a number of limitations inherent to observational research using previously collected data. CF registries capture only prescription data; thus, the possibility could not be eliminated that some patients with a prescribed drug were not taking it. However, a record of continued long-term ivacaftor use (5 years in the US and 4 years in the UK) was required for patients to be included in analyses, minimizing this concern. It is also possible that some patients may have participated in ivacaftor clinical trials prior to its approval, although the registry data do not allow differentiating these patients; we do not think their inclusion would affect the results significantly because they would be a small cohort.
      Given the differences in the distribution of mutations between the cohorts in this study (predominantly class I-II mutations among the comparators vs predominantly class III mutations in the ivacaftor cohorts), residual confounding by unmeasured factors of disease severity cannot be ruled out. However, previous studies have shown comparable disease phenotypes among patients with class III (eg, G551D) and class II (e.g., F508del) mutations [
      • McKone E.F.
      • Emerson S.S.
      • Edwards K.L.
      • Aitken M.L.
      Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study.
      ,
      • Sawicki G.S.
      • McKone E.F.
      • Millar S.J.
      • Pasta D.J.
      • Konstan M.W.
      • Lubarsky B.
      • et al.
      Patients with cystic fibrosis and a G551D or homozygous F508del mutation: similar lung function decline.
      ]. In this study, as a result of successful matching, both cohorts within each registry were similar in terms of key characteristics at baseline. Although the differential attrition of cohorts over time in the US analyses was noted, it likely resulted in underestimation of treatment benefit with ivacaftor relative to untreated comparators. Notably, this is consistent with the findings of a study examining the predictors of lumacaftor/ivacaftor prescription (among eligible patients) in the 18 months following approval in the US, which found that patients with such prescriptions were more likely to be aged 18 to 30 years and to have ppFEV1 < 90%, more pulmonary exacerbations, and more use of chronic medications [
      • Sawicki G.S.
      • Fink A.K.
      • Schechter M.S.
      • Loeffler D.R.
      • Mayer-Hamblett N.
      Rate and predictors of prescription of lumacaftor - ivacaftor in the 18 months following approval in the United States.
      ]. Furthermore, the findings from the UK registry data analyses that were not impacted by this issue (lumacaftor and ivacaftor combination therapy was not commercially available in the UK during this study period) were consistent with the US findings.
      We recognize the existence of other options for a comparator group, such as within-cohort evaluation of outcomes in patients before and after initiation of therapy, or evaluation of historical data prior to ivacaftor availability. However, these approaches also have limitations. Thus, while we acknowledge the potential pitfalls of using a comparator group with a different genotype, we also recognize that there is no ideal option for a comparator group in this rare disease area, and we are reassured that our findings are consistent with those from studies using different approaches [
      • Kirwan L.
      • Fletcher G.
      • Harrington M.
      • Jeleniewska P.
      • Zhou S.
      • Casserly B.
      • et al.
      Longitudinal trends in real-world outcomes following initiation of ivacaftor: a cohort study from the Cystic Fibrosis Registry of Ireland.
      ,
      • Hubert D.
      • Dehillotte C.
      • Munck A.
      • David V.
      • Baek J.
      • Mely L.
      • et al.
      Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2 years of treatment with ivacaftor in a real-world setting.
      ,
      • Hubert D.
      • Fajac I.
      • Munck A.
      • Marguet C.
      • Benichou J.
      • Payen-Champenois C.
      • et al.
      Clinical effectiveness from the first interim analysis of the BRIO study: an observational study of cystic fibrosis patients treated with ivacaftor in France.
      ].
      The analyses presented in this paper were performed as part of a long-term safety study, and as such, the disease progression analyses were primarily descriptive in nature. No model-based analyses of the rate of lung function decline over the 5-year periods before and after treatment initiation were performed and may be of interest for future research efforts. In particular, for the continuous outcomes of lung function and BMI, in-depth analyses of longitudinal data as repeated measures (eg, using mixed-effects regression) would be valuable areas for future research, as would analyses of the impact of baseline factors on mortality. More detailed analyses to confirm the favorable trends in the prevalence of CFRD and P. aeruginosa may also be of interest. Additionally, considering the potential impact of attrition in the US comparator cohort in our study, future studies using alternative designs and alternative methods for evaluating longitudinal outcomes, such as censoring ivacaftor-treated patients and their specific controls after treatment discontinuation, would help further elucidate the long-term effectiveness of ivacaftor.

      5. Conclusions

      This observational study represents the largest longitudinal analysis of patients treated with ivacaftor in a real-world setting. The study showed better preserved lung function, improved nutritional measures, decreased risk of PEx and hospitalizations, and favorable trends in the prevalence of CFRD and P. aeruginosa in patients treated with ivacaftor for up to 5 years relative to untreated comparator patients. These results support the conclusions of previous studies and strengthen the evidence that the CFTR potentiator ivacaftor modifies the course of disease in patients with CF. It remains important to continue to closely care for patients with CF and seek to optimize therapy for this challenging and progressive disease.

      Acknowledgements

      The authors would like to thank the Cystic Fibrosis Foundation and the Cystic Fibrosis Trust for the use of patient registry data to conduct this study. Additionally, the authors thank the patients, care providers, and clinic coordinators at CF centers throughout the US and the UK for their contributions to the patient registries. Tejendra Patel, PharmD, of Vertex Pharmaceuticals Incorporated, provided editorial support and coordination. Medical writing and editorial support were provided by Kristina Rehm, PhD, of Vertex Pharmaceuticals Incorporated, and by Jennifer Gooch, PhD, Allison Lytle, PhD, and Karen Kaluza Smith, PhD, of ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated.

      Funding

      This work was supported by Vertex Pharmaceuticals Incorporated. Vertex Pharmaceuticals Incorporated developed the protocol (with approval from the EMA) and statistical analysis plan and prepared the study report based on analyses performed by the registry partners.

      Conflict of interest statement

      All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals. Additional disclosures are as follows: NV, KM, JE, DC, ST, CS, and MH: employee of Vertex Pharmaceuticals and may own stock or stock options in Vertex Pharmaceuticals. MWK: grants, personal fees, and nonfinancial support from Vertex Pharmaceuticals, during the course of the study; grants and nonfinancial support from the Cystic Fibrosis Foundation (CFF); grants, personal fees, and nonfinancial support from Corbus, Laurent, PTC, and Savara; personal fees and nonfinancial support from Chiesi, Celtaxsys, Genentech, and Merck; personal fees from Albumedix, Anthera, Ionis, Paranta, Protalix, and Santhera outside the submitted work. GSS: grants and personal fees from Vertex Pharmaceuticals outside the submitted work. AE and BCM: other support from several pharmaceutical companies during the conduct of the study (The CFF has entered into therapeutic development award agreements and licensing agreements to assist with the development of CFTR modulators that may result in intellectual property rights, royalties and other fees provided to CFF by various pharmaceutical companies). SCC: service agreement between Vertex Pharmaceuticals and Cystic Fibrosis Services Limited for statistical analysis. DB: member of the Steering Committee of the UK CF Registry, which provided data for this study.

      Appendix A. Supplementary data

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