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Original Research: Genetic and Developmental Disorders |

Effects of Ivacaftor in Patients With Cystic Fibrosis Who Carry the G551D Mutation and Have Severe Lung DiseaseIvacaftor in Severe Cystic Fibrosis FREE TO VIEW

Peter J. Barry, MBBCh; Barry J. Plant, MD; Arjun Nair, MBChB; Stephen Bicknell, MBChB; Nicholas J. Simmonds, MD; Nicholas J. Bell, MBChB; Nadia T. Shafi, MD; Thomas Daniels, MD; Susan Shelmerdine, MBBS; Imogen Felton, MBBS; Cedric Gunaratnam, MBBCh; Andrew M. Jones, MD; Alex R. Horsley, PhD
Author and Funding Information

From the University Hospital of South Manchester NHS Foundation Trust (Drs Barry, Jones, and Horsley), Manchester, England; Royal College of Physicians of Ireland (Dr Barry), Dublin, Ireland; Cork University Hospital (Dr Plant), University College Cork, Cork, Ireland; Royal Brompton Hospital and Imperial College (Drs Nair, Simmonds, Shelmerdine, and Felton), London, England; Gartnavel General Hospital (Dr Bicknell), Glasgow, Scotland; Bristol Adult Cystic Fibrosis Centre (Dr Bell), Bristol, England; Papworth Hospital (Dr Shafi), Cambridge, England; University Hospital Southampton (Dr Daniels), Southampton, England; Beaumont Hospital (Dr Gunaratnam), Dublin, Ireland; and the University of Manchester, Manchester Academic Health Science Centre (Dr Horsley), University Hospital of South Manchester NHS Foundation Trust, Manchester, England.

CORRESPONDENCE TO: Alex R. Horsley, PhD, Manchester Adult Cystic Fibrosis Center, University Hospital of South Manchester, Wythenshawe, Manchester, M23 9LT, England; e-mail: alexander.horsley@manchester.ac.uk


FUNDING/SUPPORT: This study was supported by the Manchester Adult Cystic Fibrosis Centre. Dr Horsley is funded by a National Institute for Health Research Clinician Scientist award [NIHR CS012-013].

Some of the data included in this manuscript have been published in abstract form (Barry P, Plant B, Nair A, et al. J Cyst Fibros. 2013;12[1]:S15 and Barry P, Plant B, Simmonds NJ, et al. J Cyst Fibros. 2013;12[1]:S62) and presented at the European Cystic Fibrosis Conference, June 12-15, 2013, Lisbon, Portugal, and at the North American Cystic Fibrosis Conference, October 17-19, 2013, Salt Lake City, UT.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(1):152-158. doi:10.1378/chest.13-2397
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BACKGROUND:  The development of ivacaftor represents a significant advance in therapeutics for patients with cystic fibrosis (CF) who carry the G551D mutation. Patients with an FEV1 < 40% predicted represent a considerable proportion of eligible patients but were excluded from phase 3 clinical trials, and the effectiveness of the drug in this population is, therefore, unknown.

METHODS:  Data were collected from adult CF centers in the United Kingdom and Ireland with patients enrolled in an ivacaftor compassionate use program (FEV1 < 40% or on lung transplant waiting list). Clinically recorded data were collated from patient records for 1 year prior and for a period of 90 to 270 days following ivacaftor commencement. Each patient was matched to two control subjects who would have met the requirements for the compassionate use program with the exception of genotype.

RESULTS:  Twenty-one patients received ivacaftor for a median of 237 days. Mean FEV1 improved from 26.5% to 30.7% predicted (P = .01), representing a 16.7% relative improvement. Median weight improved from 49.8 to 51.6 kg (P = .006). Median inpatient IV antibiotic days declined from 23 to 0 d/y (P = .001) and median total IV treatment days decreased from 74 to 38 d/y (P = .002) following ivacaftor. Changes in pulmonary function and IV antibiotic requirements were significant compared with control subjects.

CONCLUSIONS:  Ivacaftor was clinically effective in patients with CF who carry the G551D mutation and have severe pulmonary disease. The reductions in treatment requirements were clinically and statistically significant and have not been described in less severe populations.

Figures in this Article

Ivacaftor is an orally bioavailable potentiator of cystic fibrosis transmembrane conductance regulator with particular efficacy in gating (class 3) mutations, where the protein is expressed but does not open and close normally.1,2 The missense mutation G551D is the most prevalent of these, affecting approximately 4% of the cystic fibrosis (CF) population in the United States,3 with higher rates in the United Kingdom (5%-6%)4 and Republic of Ireland (11%).5

In two large phase 3 studies of ivacaftor therapy over 48 weeks, sweat chloride level was halved, and FEV1 % predicted increased by > 10%.6,7 There were additional significant improvements in weight, quality of life, and a 55% reduction in the risk of a pulmonary exacerbation. An important caveat exists: In common with most CF research, the clinical trials were restricted to patients with an FEV1 > 40% predicted.6,7 Only a single patient with an FEV1 < 40% predicted was enrolled, and these data were not reported separately. These patients make up a significant proportion of all adults with CF and represent a disproportionate share of the overall workload.8,9 The response to new treatments cannot simply be assumed to mirror that in milder subjects. Much of the disease in these severely affected lungs may represent irreversible damage. Conversely, these patients may also have the most to gain from the nutritional or spirometric improvements witnessed in other subjects with CF, and the reduction in pulmonary exacerbations may preferentially benefit those with severe pulmonary disease.6,7

In the Republic of Ireland and the United Kingdom, a named-patient compassionate use program was established at the start of 2012 by Vertex Pharmaceuticals Inc to enable selected patients to receive the medication free of charge while awaiting funding approval in the individual countries. This program was limited to those patients with severe respiratory impairment (FEV1 < 40% predicted) or those on an active lung transplant waiting list, for whom delays in obtaining funding may have resulted in adverse clinical outcomes.

We sought to explore the effects of ivacaftor in this group by analyzing clinically collected data from patients before and after receiving ivacaftor on the compassionate use program. In addition, we sought to compare these subjects to matched patients who do not carry the G551D CF mutation and who had not received the therapy. Some of the results of this study have been previously reported in the form of abstracts.10,11

We conducted a retrospective case-control study of patients receiving ivacaftor on the compassionate use program in the United Kingdom and Ireland. All centers with adult patients enrolled into this program were contacted to participate in the study.

Study Population

Inclusion criteria for compassionate use included the presence of at least one G551D allele, highest FEV1 < 40% predicted in the preceding 6 months, and/or lung transplant listing. Cases were required to have a minimum of 3 months treatment with ivacaftor by the time of data collection.

Each case was matched with up to two control subjects from the same center, where available. Matching was performed for sex and age (± 5 years). Control subjects were also required to match inclusion criteria for the named-patient program with the exception of genotype. The main outcome measures consisted of a range of clinically relevant measures of interest following ivacaftor treatment: (1) change in FEV1 % predicted, (2) change in weight, (3) change in number of days in hospital (expressed as days per year), (4) change in number of days receiving IV antibiotics (expressed as days per year), and (5) transplant-free survival.

Data Collection

Clinical data were collected for the 12 months prior to treatment start date and for 3 to 9 months following this. Data were collected on treatment episodes, microbiology, medication changes, and treatment-related adverse events. If performed within 2 years before treatment start date, anonymized chest CT scans were also provided for the ivacaftor group, which were scored by two specialist radiologists using a previously described semiquantitative scoring system12 and as described in the e-Appendix 1 and e-Table 1.

Since anonymized data were collected retrospectively, this study was configured as an audit of treatment outcomes. These data were collected in accordance with the amended Declaration of Helsinki, and informed consent was obtained from all participants. The study was approved by individual hospital research and audit boards. In addition, the Medicines and Healthcare Products Regulatory Agency in the United Kingdom and the Greater Manchester South Research Ethics Committee both reviewed the protocol and confirmed the validity of this approach.

Data Analysis

Outcome measures were defined by comparing the best spirometry and weight in the 3 months prior to ivacaftor introduction, with the best values obtained in the follow-up period. Treatment episodes were normalized to days per year by calculating the proportion of a year patients were followed up and multiplying the antibiotic days observed by its reciprocal.

Data were analyzed using Prism (GraphPad Software Inc) and SPSS, version 20 (IBM). Results are given as mean (SD) or median (interquartile range). A paired t test or Wilcoxon signed rank test was used to assess significance of change in variables following treatment. An unpaired t test or Mann-Whitney U test was used to compare cases and control subjects. The χ2 test was used to compare proportions at baseline. Correlations were assessed using the Pearson correlation coefficient (normally distributed data) or Spearman rank correlation (skewed data). A P value < .05 was considered statistically significant.

Data were collected on 21 patients with severe CF lung disease who received ivacaftor (composing 84% of the eligible adult patients in the United Kingdom and Ireland receiving ivacaftor under the compassionate use program) and 35 matched control subjects who did not carry the G551D mutation. Follow-up data were available for a median of 237 days (range, 125-270 days) after ivacaftor commencement.

Baseline demographics of the study population are contained in Table 1 and e-Table 2. Absolute values for mean (SD) FEV1 were significantly lower in the ivacaftor group vs the non-G551D control subjects (0.91 [0.30] L vs 1.08 [0.29] L, P = .05), though this difference was not maintained when corrected to percent predicted. There were no other significant differences in baseline variables or comorbidities between ivacaftor cases and control subjects.

Table Graphic Jump Location
TABLE 1  ] Baseline Demographics in Cases and Control Subjects

Data are presented as mean (SD) or median (interquartile range) as appropriate, unless otherwise indicated. CF = cystic fibrosis; HBA1C = glycosylated hemoglobin A1C.

Changes in Subjects Treated With Ivacaftor

Following ivacaftor, there was a significant improvement in best FEV1 from a mean (SD) of 0.91 (0.30) L to 1.062 (0.42) L (P = .0095), representing a 16.7% relative increase (e-Table 3). FEV1 % predicted increased from a mean of 26.5 (7.2) % predicted to 30.7 (9.9) % predicted (P = .0068) (Fig 1). There was also a significant improvement in FVC from 2.03 (0.87) L to 2.28 (1.02) L (a mean 13.6% increase, P = .0091). Median time to best spirometry was 100 (56-160) days. Further results regarding the time frame of improvement are reported in e-Appendix 1. There was no significant change in either the slope of FEV1 or the slope of FVC.

Figure Jump LinkFigure 1  Change in best FEV1 from baseline to post-ivacaftor treatment in patients with cystic fibrosis who carry the G551D mutation and have severe pulmonary disease. Each line represents a single subject. Gray lines represent mean FEV1.Grahic Jump Location
Weight and Nutrition

Median weight improved from 49.8 (44.4-60.7) kg to 51.6 (48.6-66.8) kg (P = .0058). Median change in weight was an increase of 4.5% (−1.0 to 9.5) over baseline, or 2.3 (−0.4 to 4.2) kg (e-Table 3, Fig 2). This represented an increase in BMI from 19.1 to 20.2 kg/m2 (P = .010). There was no difference in glycosylated hemoglobin value over the study period.

Figure Jump LinkFigure 2  Change in nutritional parameters from best recorded measure at baseline to post-ivacaftor treatment in patients with cystic fibrosis who carry the G551D mutation and have severe pulmonary disease. Gray lines represent median for weight and mean for BMI.Grahic Jump Location
Treatment

In the 12 months pre-ivacaftor, cases received a median of 23 (14-83) d/y of inpatient IV antibiotics and 20 (0-61) d/y of home IV antibiotic therapy (Table 1). Following ivacaftor, the median time receiving inpatient IV antibiotics fell to 0 (0-48) d/y (P = .0014) (Fig 3). Total time on IV antibiotics fell from 74 (39-121) days in the year pre-ivacaftor to 38 (10-92) d/y following treatment (P = .0016) (e-Fig 1).

Figure Jump LinkFigure 3  Change in IV antibiotic requirements expressed as days per year for the year prior to ivacaftor treatment and the follow-up period while receiving ivacaftor. Gray lines represent medians.Grahic Jump Location

Two patients treated with ivacaftor were able to reduce their oxygen therapy, with one using supplemental oxygen only at night and the other discontinuing altogether. One patient treated with ivacaftor stopped nasogastric feeding.

Subjects Treated With Ivacaftor vs Control Subjects

Patients receiving ivacaftor had a greater increase in FEV1 % predicted compared with control subjects: A median, within-subject, absolute change of 3.8 (0.2-7.7) % predicted occurred in the ivacaftor-treated group compared with 0.6 (−2.1 to 2.8) in control subjects, P = .009) (e-Table 4, Fig 4). There was no significant difference in change in weight: The median increase was 2.3 (−0.4 to 4.2) kg in cases vs 0.6 (−0.5 to 3.2) kg in control subjects (P = .25). Additionally, there was no significant difference in median change in BMI between cases or control subjects (0.84 kg/m2 vs 0.2 kg/m2, respectively; P = .234) (e-Fig 2). Median change in IV antibiotic requirements were significantly greater in cases than control subjects for both in-hospital days per year (−14 vs +1, P = .0006), and total IV antibiotic days per year (−36 vs +10, P = .0003) (Fig 5).

Figure Jump LinkFigure 4  Change in absolute FEV1 % predicted from baseline to follow-up in patients treated with ivacaftor vs control subjects without the G551D mutation. Gray lines represent medians.Grahic Jump Location
Figure Jump LinkFigure 5  Change in IV antibiotic requirements expressed as days per year in patients treated with ivacaftor vs control subjects without the G551D mutation. A, Inpatient IV antibiotic days per year. B, Total IV antibiotic days per year. Gray lines represent medians. abx = antibiotics.Grahic Jump Location
Other Outcome Measures

There were no deaths during the period of data collection for either group. Two previously listed control subjects underwent lung transplantation. There were no changes noted in the predominant lung microbiology in any of the patients treated with ivacaftor. There were no adverse events identified by the clinical teams as being secondary to ivacaftor.

Associations With Response

There was no correlation between change in FEV1 following ivacaftor and the following parameters: (1) baseline FEV1; (2) weight or BMI; and (3) change in IV antibiotic days before and after ivacaftor treatment (e-Fig 3). Chest CT scans within the preceding 2 years were available for 13 patients (62%) treated with ivacaftor (e-Fig 4). Bronchial wall thickness correlated with relative change in FEV1 (r = 0.60, P = .03) and relative change in FVC (r = 0.76, P = .003) (e-Fig 5).

In patients with CF who carry the G551D mutation and have severe pulmonary disease, provision of ivacaftor led to significant improvements in FEV1 and FVC and improvements in weight and BMI. In addition, we have also shown a significant and clinically important reduction in the number of IV treatment days.

The clinical efficacy of ivacaftor in patients with CF who carry the G551D mutation and have mild to moderate pulmonary disease has been established in two large, phase 3 clinical trials.6,7 Both trials excluded patients with more severe pulmonary impairment. These patients are an important group, however, with a high burden of therapy and placing high demands on health-care providers.8 In the present study, patients spent a median of 74 d/y on IV antibiotics in the year prior to starting ivacaftor, in contrast to the 12 d/y on IV antibiotics experienced by the placebo arm in the previous adult clinical trial.7 These patients also represent a significant proportion of the CF population eligible for ivacaftor, representing 18% of eligible adults in the United Kingdom.4 We should be cautious about extending trial findings in one patient group to another, since the effects on the underlying pulmonary disease and interaction with other complications cannot be assumed to be the same. Furthermore, the range of medications used in real clinical practice is broader than those allowed in clinical trials. In this context, it is essential that good-quality clinical outcome data are collected to assess how such patients respond to new therapies. This is particularly important when treatments are potentially toxic or, as in this case, carry a high financial cost.13 This is also relevant for the cystic fibrosis transmembrane conductance regulator correctors currently in development and undergoing assessment in clinical trials.14

For ivacaftor, the improvements in spirometry relative to baseline were very similar to those seen in milder subjects,6,7 indicating that even in those with the most severely affected lungs, there remains, in some cases, a very substantial reversible component. The pattern of improvement, however, appeared to be distinct from the early improvement witnessed in the published trials to date, with the median time to best spirometry recorded as 100 days, and recognition that spirometric differences vs control subjects became significant only after a period of > 90 days (e-Appendix 1, e-Fig 6). Additionally, an intriguing result was that this spirometric improvement showed significant correlation with scores for bronchial wall thickness on CT scans. The CT scans were not contemporaneous, but this observation supports the hypothesis that ivacaftor is leading to improvements in airway inflammation and mucus clearance.15

The nutritional benefits seen in previous phase 3 clinical trials were not as marked in patients in the current study.7 The improvements in weight were, however, significant in a group of patients for whom even maintaining weight presents a daily clinical challenge. These changes, however, were not significantly greater than those seen in control subjects, which may reflect the more unstable study population who exhibited a wide response range in both the case and control groups.

Perhaps the most clinically significant result in this study was the reduction in the requirement for IV antibiotics. In this retrospective study, we were unable to define exacerbations according to specific criteria, and cannot exclude the influence of a placebo effect on both clinicians and patients in the ivacaftor group. Nonetheless, in this intensively treated group, the extent of the treatment reduction is highly significant. Days in hospital and days on IV antibiotics are important measures of disease severity and are recognized to impact significantly on quality of life of patients with CF.16 What is not clear from these observations is whether this reflects an improvement in the ability of the lungs to reduce inflammation and clear infection, or a reduction in the baseline symptom burden such that patients feel less need for rescue therapies. It is notable that reduction in IV antibiotic days did not correlate with improvements in lung function. Therefore, those patients who do not exhibit improvements in lung function may still gain a clinically relevant treatment effect with ivacaftor.

The data reported here were collected retrospectively, and we acknowledge the limitations associated with this approach. Importantly though, this patient cohort represents 84% of all those adult patients with severe CF who had commenced ivacaftor within the study period, and the data are, therefore, highly representative of this patient group. Furthermore, to minimize the chance that baseline data would be affected by an intercurrent clinical event, we used only the best recorded values within the preceding 3 months as our baseline measure. Finally, to ensure that the effects we observed were real, we also collected data on matched subjects who did not carry the G551D mutation. A strength of this study is that we have also reported on IV antibiotic use and inpatient stays, both pragmatic and highly clinically relevant outcomes.

In summary, we have shown clinically and statistically significant improvements in lung function and IV treatment days for patients with the G551D mutation and with severe CF who received ivacaftor. With these data, ivacaftor has now been shown to be effective across the full spectrum of CF. Furthermore, it is one of the few therapies shown to offer major treatment benefits to this population with severe CF.

Author contributions: A. R. H. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. P. J. B. served as principal author. P. J. B., B. J. P., S. B., N. J. S., N. J. B., N. T. S., T. D., A. M. J., and A. R. H. contributed to the study design; P. J. B., B. J. P., A. N., S. B., N. J. S., N. J. B., N. T. S., T. D., S. S., I. F., C. G., and A. R. H. contributed to data acquisition; P. J. B. and A. R. H. contributed to data analysis; P. J. B. and A. R. H. contributed to drafting of the manuscript; and B. J. P., A. N., S. B., N. J. S., N. J. B., N. T. S., T. D., S. S., I. F., C. G., and A. M. J. contributed to the writing of the final draft of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Plant was a principal investigator on the Strive study and has received fees as a consultant and also honoraria speaker fees from Vertex Pharmaceuticals Inc. Dr Jones received personal fees for advisory boards to Vertex Pharmaceuticals Inc, unrelated to the submitted work. Dr Horsley was the local principal investigator in the phase 2 VX-661 trial, sponsored by Vertex Pharmaceuticals Inc. Drs Barry, Nair, Bicknell, Simmonds, Bell, Shafi, Daniels, Shelmerdine, Felton, and Gunaratnam have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: This report presents independent research partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR or the Department of Health. No financial support, involvement, or editorial input of any sort was sought or received from Vertex Pharmaceuticals Inc. The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: The authors warmly acknowledge the assistance provided by Valia Kehagia (University Hospital Southampton, England), Judy Ryan, RN (Papworth Hospital, Cambridge, England), and Michael Harrison, MBBCh (Cork University Hospital, Cork, Ireland) for their help in data collection and to David Hansell, MD (Royal Brompton Hospital, London, England) for assistance in chest CT scan analysis. We are also very grateful to all the patients with cystic fibrosis who agreed to their data being collated and analyzed.

Additional information: The e-Appendix, e-Tables, and e-Figures can be found in the Supplemental Materials section of the online article.

Van Goor F, Hadida S, Grootenhuis PD, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009;106(44):18825-18830. [CrossRef] [PubMed]
 
Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010;363(21):1991-2003. [CrossRef] [PubMed]
 
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry. Bethsesda, MA: Cystic Fibrosis Foundation; 2011.
 
UK Cystic Fibrosis Trust. UK Cystic Fibrosis Registry Annual Report. London, England: UK Cystic Fibrosis Trust; 2010.
 
Cystic Fibrosis Registry of Ireland. Cystic Fibrosis Registry of Ireland Annual Report. Dublin, Ireland: Cystic Fibrosis Registry of Ireland; 2011.
 
Davies JC, Wainwright CE, Canny GJ, et al; VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187(11):1219-1225. [CrossRef] [PubMed]
 
Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. [CrossRef] [PubMed]
 
George PM, Banya W, Pareek N, et al. Improved survival at low lung function in cystic fibrosis: cohort study from 1990 to 2007. BMJ. 2011;342:d1008.
 
Goss CH, Burns JL. Exacerbations in cystic fibrosis. 1: epidemiology and pathogenesis. Thorax. 2007;62(4):360-367. [CrossRef] [PubMed]
 
Barry P, Plant B, Nair A, et al. UK and Ireland review of ivacaftor in severe CF: impact on lung function and weight. J Cyst Fibros. 2013;12(suppl):S15. [CrossRef]
 
Barry P, Plant B, Simmonds NJ, et al. UK and Ireland review of Ivacaftor in severe CF: impact on hospitalisations and antibiotic use. J Cyst Fibros. 2013;12(suppl):S62. [CrossRef]
 
Horsley AR, Davies JC, Gray RD, et al. Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation. Thorax. 2013;68(6):532-539. [CrossRef] [PubMed]
 
Bush A, Simmonds NJ. Hot off the breath: ‘I’ve a cost for’—the 64 million dollar question. Thorax. 2012;67(5):382-384. [CrossRef] [PubMed]
 
Clancy JP, Jain M. Personalized medicine in cystic fibrosis: dawning of a new era. Am J Respir Crit Care Med. 2012;186(7):593-597. [CrossRef] [PubMed]
 
Altes T, Johnson M, Mugler J, et al. The effect of ivacaftor, an investigational CFTR potentiator, on hyperpolarized noble gas magnetic resonance imaging in subjects with cystic fibrosis who have the G551D-CFTR mutation. Am J Respir Crit Care Med. 2012;185(meeting abstracts):A2814.
 
Britto MT, Kotagal UR, Hornung RW, Atherton HD, Tsevat J, Wilmott RW. Impact of recent pulmonary exacerbations on quality of life in patients with cystic fibrosis. Chest. 2002;121(1):64-72. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1  Change in best FEV1 from baseline to post-ivacaftor treatment in patients with cystic fibrosis who carry the G551D mutation and have severe pulmonary disease. Each line represents a single subject. Gray lines represent mean FEV1.Grahic Jump Location
Figure Jump LinkFigure 2  Change in nutritional parameters from best recorded measure at baseline to post-ivacaftor treatment in patients with cystic fibrosis who carry the G551D mutation and have severe pulmonary disease. Gray lines represent median for weight and mean for BMI.Grahic Jump Location
Figure Jump LinkFigure 3  Change in IV antibiotic requirements expressed as days per year for the year prior to ivacaftor treatment and the follow-up period while receiving ivacaftor. Gray lines represent medians.Grahic Jump Location
Figure Jump LinkFigure 4  Change in absolute FEV1 % predicted from baseline to follow-up in patients treated with ivacaftor vs control subjects without the G551D mutation. Gray lines represent medians.Grahic Jump Location
Figure Jump LinkFigure 5  Change in IV antibiotic requirements expressed as days per year in patients treated with ivacaftor vs control subjects without the G551D mutation. A, Inpatient IV antibiotic days per year. B, Total IV antibiotic days per year. Gray lines represent medians. abx = antibiotics.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Baseline Demographics in Cases and Control Subjects

Data are presented as mean (SD) or median (interquartile range) as appropriate, unless otherwise indicated. CF = cystic fibrosis; HBA1C = glycosylated hemoglobin A1C.

References

Van Goor F, Hadida S, Grootenhuis PD, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009;106(44):18825-18830. [CrossRef] [PubMed]
 
Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010;363(21):1991-2003. [CrossRef] [PubMed]
 
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry. Bethsesda, MA: Cystic Fibrosis Foundation; 2011.
 
UK Cystic Fibrosis Trust. UK Cystic Fibrosis Registry Annual Report. London, England: UK Cystic Fibrosis Trust; 2010.
 
Cystic Fibrosis Registry of Ireland. Cystic Fibrosis Registry of Ireland Annual Report. Dublin, Ireland: Cystic Fibrosis Registry of Ireland; 2011.
 
Davies JC, Wainwright CE, Canny GJ, et al; VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187(11):1219-1225. [CrossRef] [PubMed]
 
Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. [CrossRef] [PubMed]
 
George PM, Banya W, Pareek N, et al. Improved survival at low lung function in cystic fibrosis: cohort study from 1990 to 2007. BMJ. 2011;342:d1008.
 
Goss CH, Burns JL. Exacerbations in cystic fibrosis. 1: epidemiology and pathogenesis. Thorax. 2007;62(4):360-367. [CrossRef] [PubMed]
 
Barry P, Plant B, Nair A, et al. UK and Ireland review of ivacaftor in severe CF: impact on lung function and weight. J Cyst Fibros. 2013;12(suppl):S15. [CrossRef]
 
Barry P, Plant B, Simmonds NJ, et al. UK and Ireland review of Ivacaftor in severe CF: impact on hospitalisations and antibiotic use. J Cyst Fibros. 2013;12(suppl):S62. [CrossRef]
 
Horsley AR, Davies JC, Gray RD, et al. Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation. Thorax. 2013;68(6):532-539. [CrossRef] [PubMed]
 
Bush A, Simmonds NJ. Hot off the breath: ‘I’ve a cost for’—the 64 million dollar question. Thorax. 2012;67(5):382-384. [CrossRef] [PubMed]
 
Clancy JP, Jain M. Personalized medicine in cystic fibrosis: dawning of a new era. Am J Respir Crit Care Med. 2012;186(7):593-597. [CrossRef] [PubMed]
 
Altes T, Johnson M, Mugler J, et al. The effect of ivacaftor, an investigational CFTR potentiator, on hyperpolarized noble gas magnetic resonance imaging in subjects with cystic fibrosis who have the G551D-CFTR mutation. Am J Respir Crit Care Med. 2012;185(meeting abstracts):A2814.
 
Britto MT, Kotagal UR, Hornung RW, Atherton HD, Tsevat J, Wilmott RW. Impact of recent pulmonary exacerbations on quality of life in patients with cystic fibrosis. Chest. 2002;121(1):64-72. [CrossRef] [PubMed]
 
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