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A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro.
We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study).
At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was −3.5 mV (range, −8.3 to 0.5; P = 0.02 for the within-subject comparison, P = 0.13 vs. placebo), and the median change in the level of sweat chloride was −59.5 mmol per liter (range, −66.0 to −19.0; P = 0.008 within-subject, P = 0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P = 0.008 for the within-subject comparison, P = 0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770.
This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis.
Cystic fibrosis is a progressive lung disease1 caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial ion channel involved in salt and fluid transport in multiple organs, including the lung.2,3 Current treatments for cystic fibrosis target the secondary effects of CFTR dysfunction. Although the median predicted survival among patients with cystic fibrosis has improved,4 the life expectancy of these patients remains well below normal, and the treatment burden to maintain health is high,5 indicating a need for better therapies. A strategy with potential advantages over current regimens involves improving defective CFTR function systemically; this strategy aims to slow lung damage and reduce the manifestations of extrapulmonary disease and the treatment burden.6
Some mutations permit CFTR protein to reach the epithelial-cell surface, but the protein is defective in chloride transport.7 The most prevalent mutation of this type in patients with cystic fibrosis causes a substitution of glycine for aspartic acid at amino acid 551 (G551D-CFTR); this mutation occurs in approximately 4 to 5% of persons with cystic fibrosis.4 Agents that increase the ion-channel function of activated cell-surface CFTR are referred to as “potentiators.” VX-770 is an investigational, orally bioavailable CFTR potentiator that has been shown to increase the activity of wild-type and defective cell-surface CFTR protein in vitro.8 The greatest effect of VX-770 was on cells with G551D-CFTR.
The primary end points of this randomized, placebo-controlled trial involving subjects with the G551D-CFTR mutation were the safety and adverse-event profile of VX-770. Evidence of improvement in CFTR-mediated ion transport and pulmonary status were evaluated as secondary end points.
Part 1 of this two-part, double-blind, placebo-controlled, multicenter, phase 2 trial had a modified crossover design, and part 2 had a parallel design (Fig. 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The protocol (available at NEJM.org) was reviewed and approved by the institutional review board in each participating center, and each subject provided written informed consent. Subjects had to be 18 years of age or older and have cystic fibrosis,9 a G551D mutation on at least one CFTR allele, and a forced expiratory volume in 1 second (FEV1) of 40% or more of the predicted value for age, sex, and height.10
The first author wrote the first draft of the manuscript and made the decision to submit the article for publication after consultation with the other authors. All authors vouch for the accuracy and completeness of the reported data. The authors also certify that the study as reported conforms with the protocol.
Part 1 of the study involved subjects who were randomly assigned to receive VX-770 every 12 hours at doses of 25, 75, or 150 mg or placebo. The study drug was administered during two 14-day periods separated by a washout period. Part 2 of the study involved new subjects who were randomly assigned to receive VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 consecutive days.
The primary objective was to evaluate the safety and adverse-event profile of VX-770. Secondary end points included assessment of biomarkers of CFTR ion-channel function, pulmonary function, and health-related quality of life. The CFTR chloride transport function was evaluated in the airway epithelium on the basis of the nasal potential difference11 and outside the respiratory tract on the basis of the sweat chloride concentration. Clinical efficacy was evaluated on the basis of the change in the FEV1 from baseline and a disease-specific health-related quality-of-life instrument, the Cystic Fibrosis Questionnaire–revised (CFQ-R) (in part 2 of the study only).12 Each CFQ-R domain is scored on a 100-point scale, with higher scores indicating a lower effect of symptoms on the patient’s quality of life. A minimal clinically important difference of 4 points has been determined for the respiratory symptoms domain.13
Further details of the study design, measurement of biomarkers and lung function, and the health-related quality-of-life instrument are provided in the Supplementary Appendix.
Twenty subjects received a study drug in part 1 of the study, and 19 subjects received a study drug in part 2. The baseline characteristics of the subjects are shown in Table 1. The sex distribution was well balanced, and the body-mass index and other relevant baseline clinical and demographic characteristics were similar between the groups in each part of the study. The median rate of adherence to treatment was high among subjects in both parts of the study (96.4% [range, 60.7 to 100] in part 1 and 100% [range, 92.6 to 100] in part 2).
All subjects who began to receive a study drug completed the assigned study drugs (randomization and study-drug assignments are shown in Fig. 2 in the Supplementary Appendix). The frequency of adverse events was similar between the groups and between the parts of the study. Most adverse events were reported in one or two subjects in any group, with more frequent events being fever (in four subjects in the group of subjects who received 75 mg of VX-770); cough (in three subjects in the placebo group in part 1 of the study and in three subjects who received 250 mg of VX-770 in part 2 of the study); and nausea, pain, and rhinorrhea (in three subjects each in the group of subjects who received 75 mg of VX-770). All adverse events are listed in Table 1 in the Supplementary Appendix.
Adverse events that were considered moderate (grade 2) or severe (grade 3) are shown in Table 2. Six adverse events were severe; all occurred during part 1 of the study. These events consisted of diffuse macular rash in one subject who was receiving VX-770 at a dose of 150 mg and an elevated blood glucose level on three occasions (two occurred within the same treatment period and were counted once in Table 2) and urine that was positive for glucose on two occasions in one subject over both treatment periods (VX-770 at doses of 75 mg and 150 mg). The subject in whom the macular rash developed had received intravenous antibiotics during hospitalization to treat a mild pulmonary exacerbation. The pulmonary exacerbation and macular rash in this subject were the only adverse events in the study that met the definition of serious adverse events. The subject in whom elevated blood and urine glucose levels developed had a history of insulin-dependent diabetes. All serious or severe adverse events resolved without discontinuation of the study drug.
We evaluated the effects of VX-770 on measurements of the potential difference across the nasal mucosa and on the chloride concentration of sweat, both markers of CFTR function. Figure 1 shows the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution), a measure of CFTR-mediated chloride transport. In part 1 of the study, significant within-subject changes from baseline to day 14 were observed in the VX-770 75-mg group (mean, −4.7 mV; 95% confidence interval [CI], −7.5 to −1.9; P=0.003) and in the 150-mg group (mean, −5.4 mV; 95% CI, −9.3 to −1.6; P = 0.01). No significant change from baseline was detected in the placebo group (−1.7 mV; 95% CI, −6.1 to 2.6; P = 0.41) or the VX-770 25-mg group (−1.6 mV; 95% CI, −5.6 to 2.5; P = 0.43). None of the changes from baseline were significant as compared with the placebo group (P = 0.95, P = 0.24, and P = 0.21 for the VX-770 25-mg, 75-mg, and 150-mg groups, respectively). In part 2 of the study, the median within-subject change from baseline to day 28 was significant in the VX-770 150-mg group (−3.5 mV; range, −8.3 to 0.5; P = 0.02) and the 250-mg group (−5.5 mV; range, −28.5 to 2.0; P = 0.05), but not in the placebo group (−0.4 mV; range, −2.3 to 4.0; P = 0.88). In the VX-770 treatment groups, the changes from baseline were not significantly different from placebo (P = 0.13 and P = 0.16 in the VX-770 150-mg and 250-mg groups, respectively). Responses in the VX-770 treatment groups were similar to baseline values after the washout period in part 1 of the study (Fig. 3 in the Supplementary Appendix).
After 14 days of treatment with VX-770, some subjects for whom data were available in parts 1 and 2 of the study were considered to have had a response according to the predefined response criterion of a decrease from baseline of 5 mV or more in the nasal potential difference after the administration of a chloride-free isoproterenol solution. These subjects were the following: 1 of 7 in the 25-mg group (14%), 5 of 15 in the 75-mg group (33%), 10 of 16 in the 150-mg group (62%), and 3 of 7 in the 250-mg group (43%). None of the subjects had a response in the placebo group. We observed significant improvements in sodium transport, as measured by the basal and amiloride responses in the nasal potential difference, in part 1 but not in part 2 of the study (Table 2 in the Supplementary Appendix).
The change in the sweat chloride concentration from baseline is shown in Figure 2 (the actual sweat chloride concentrations at days 14 and 28 are shown in Fig. 4 in the Supplementary Appendix). In part 1 of the study, the mean change in the sweat chloride concentration from baseline to day 14 was −32.9 mmol per liter (95% CI, −42.4 to −23.3) in the group that received 25 mg of VX-770, −40.4 mmol per liter (95% CI, −48.7 to −32.2) in the group that received 75 mg of VX-770, and −42.3 mmol per liter (95% CI, −52.8 to −31.8) in the group that received 150 mg of VX-770. The changes were significant (P<0.001) in both within-subject comparisons and versus placebo in all VX-770 groups. The mean change from baseline in the placebo group was 4.4 mmol per liter (95% CI, −10.4 to 19.1; P = 0.53). In part 2, the median change from baseline to day 28 was −59.5 mmol per liter (range, −66.0 to −19.0) in the VX-770 150-mg group and −38.0 mmol per liter (range, −47.0 to −10.5) in the VX-770 250-mg group. Results in both VX-770 groups were significant for within-subject comparisons (P = 0.008 for VX-770 at a dose of 150 mg and P = 0.02 for VX-770 at a dose of 250 mg) and versus placebo (P = 0.02 for the VX-770 150-mg group and P = 0.03 for the VX-770 250-mg group). Over the same time frame, the median change from baseline in the placebo group was 5.0 mmol per liter (range, −2.0 to 11.0; P = 0.38). Sweat chloride concentrations in the VX-770 treatment groups returned toward baseline concentrations after the washout period in part 1 of the study (Fig. 3 in the Supplementary Appendix). Considering parts 1 and 2 of the study together, after 14 days, the number of subjects with available data who achieved the prespecified response criterion of a decrease from baseline of 20 mmol per liter or more was 6 of 8 subjects in the VX-770 25-mg group (75%), 11 of 13 subjects in the VX-770 75-mg group (85%), 13 of 14 subjects in the VX-770 150-mg group (93%), and 4 of 7 subjects in the VX-770 250-mg group (57%). No subjects had a response in the placebo group.
Results of the absolute FEV1 in liters and the relative percentage change in the predicted FEV1 are shown in Figure 3. Results of other spirometric measurements are provided in Figures 5, 6, and 7 in the Supplementary Appendix. In part 1 of the study, at day 14, the mean within-subject change in FEV1 from baseline was 0.09 liters (95% CI, −0.06 to 0.24) in the VX-770 25-mg group, 0.19 liters (95% CI, 0.08 to 0.29) in the VX-770 75-mg group, and 0.22 liters (95% CI, 0.08 to 0.36) in the VX-770 150-mg group. In the placebo group, the mean change was −0.03 liters (95% CI, −0.20 to 0.15). Improvements in the VX-770 75-mg and 150-mg groups were significant for within-subject change (P = 0.003 and P = 0.006, respectively) and as compared with placebo (P=0.05 and P=0.04, respectively); changes were not significant in the VX-770 25-mg group (P = 0.19 for the within-subject change, P=0.28 vs. placebo) and placebo group (P=0.76 for the within-subject change). Among the subjects who received VX-770, the mean relative change from baseline in the percentage of predicted FEV1 was 4.9% (95% CI, −2.6 to 12.5) in the 25-mg group, 10.0% (95% CI, 4.5 to 15.6) in the 75-mg group, and 10.5% (95% CI, 3.3 to 17.7) in the 150-mg group. The mean change in the placebo group was 0.7% (95% CI, −8.8 to 10.2). Within-subject improvements in the percentage of predicted FEV1 were significant in the VX-770 75-mg and 150-mg groups (P = 0.002 and P = 0.008, respectively), but not in the VX-770 25-mg or placebo groups (P = 0.18 and P = 0.88, respectively). Differences in comparisons with the placebo group did not reach significance (P = 0.45, P = 0.09, and P=0.10, respectively, for the VX-770 25-mg, 75-mg, and 150-mg groups).
In part 2 of the study, at day 28, the median within-subject change from baseline in FEV1 was 0.25 liters (range, 0.05 to 0.75) in the VX-770 150-mg group, 0.17 liters (range, 0 to 0.37) in the VX-770 250-mg group, and 0.20 liters (range, 0.12 to 0.33) in the placebo group. The within-subject change was significant in both VX-770 treatment groups (P = 0.008 and P = 0.03 for 150 mg and 250 mg, respectively), but not in the placebo group (P = 0.38). Comparisons between the treatment and placebo groups were not significant (P = 1.0 and P = 0.65 for 150 mg and 250 mg of VX-770, respectively). The median relative change from baseline in the percentage of predicted FEV1 was 8.7% (range, 2.3 to 31.3; within-subject comparison, P = 0.008) in the VX-770 150-mg group and 4.4% (range, 0 to 18.3; within-subject comparison, P=0.03) in the 250-mg group. In the placebo group, although there was an improvement from baseline of 7.3% (range, 5.2 to 8.2), this difference did not achieve statistical significance (within-subject comparison, P=0.13). Comparisons between the treatment and placebo groups were not significant (P = 0.56 and P = 0.78 for 150 mg and 250 mg of VX-770, respectively).
The combined part 1 and part 2 data for the change from baseline to day 14 of study treatment for spirometric analysis and CFTR biomarkers (nasal potential difference and sweat chloride concentration) are shown in Figure 8 in the Supplementary Appendix.
The CFQ-R was administered in part 2 of the study only (Table 3 in the Supplementary Appendix). No change from baseline in any CFQ-R domain was significant. After 14 days of treatment, subjects reported median improvements from baseline in the respiratory domain of 5.6 points (range, 0 to 16.7; P = 0.06 within-subject) in the VX-770 150-mg group, 5.6 points (range, −11.1 to 11.1; P = 0.16) in the VX-770 250-mg group, and 2.8 points (range, −5.6 to 11.1; P = 0.75) in the placebo group. Comparisons between the treatment and placebo groups were not significant (P = 0.61 and P = 0.71 for the VX-770 150-mg and 250-mg groups, respectively). At day 28, the median improvements from baseline were 8.3 points (range, 0 to 16.7; P=0.06 within-subject) in the VX-770 150-mg group and 11.1 points (range, −5.6 to 33.3; P = 0.08) in the 250-mg group, whereas scores in the placebo group were identical to those at day 14. Comparisons between the treatment and placebo groups were not significant (P = 0.45 and P = 0.47 for the VX-770 150-mg and 250-mg groups, respectively).
This randomized, double-blind, placebo-controlled, multicenter trial of oral VX-770 involved subjects with cystic fibrosis and the G551D mutation on at least one allele. The primary end points of the study were safety and the adverse-event profile associated with treatment. No subject withdrew from the study, and the frequency of adverse events was similar between the study groups. The safety profile of VX-770 in this study provides support for further clinical evaluation. In addition, VX-770 was associated with within-subject improvements in CFTR ion-channel function in the nasal epithelium and sweat glands and within-subject improvements in lung function, suggesting a potential clinical benefit. The findings in the nasal potential difference and sweat chloride biomarkers associated with VX-770 are consistent with improved CFTR ion-channel function. Previous studies of agents aimed at improving CFTR function, including oral and topical drug candidates as well as topically applied gene-therapy vectors, showed improvement in measures of chloride transport in the nasal potential difference,14–17 but they did not measure sweat chloride concentrations. Single-center studies of oral lithium and of intravenous gentamicin have shown decreases in sweat chloride concentrations.18,19 The study of gentamicin also showed an improvement in the nasal potential difference.19 The current placebo-controlled, multicenter trial showed within-subject improvement in both the nasal potential difference and sweat chloride concentrations. Administration of VX-770 resulted in a much greater reduction in sweat chloride levels than has been observed with other compounds; sweat chloride levels in some subjects were outside the diagnostic range for cystic fibrosis after VX-770 treatment.
VX-770 was associated with a modest but significant within-subject improvement in lung function after 14- and 28-day treatment regimens. Improvement at day 28 in the groups of subjects who received VX-770 was similar to that at day 14, and the improvements were statistically significant within the treatment group. The change in FEV1 was not significant among subjects who received placebo in part 1 and part 2 of the study; however, the lack of significance should be interpreted with caution considering the small sample size within these groups. The reason for numerical improvement in some subjects who received placebo in part 2 is unclear and could be related to improved adherence to concomitant therapies within the clinical-trial setting. In addition to lung function, an improvement in the respiratory symptoms domain of the CFQ-R was observed in the groups of subjects who received VX-770; this improvement exceeded the minimal clinically important difference for this domain,13 although the improvements did not reach statistical significance. It is not known to what extent lung function can be improved in persons with cystic fibrosis in the long term and how changes in spirometric measures over the short term may reflect long-term disease progression.
The marked magnitude of the effect of VX-770 on sweat chloride concentration, as compared with the nasal potential difference and pulmonary function, may be explained by physiological differences between the sweat gland, where CFTR is involved in chloride absorption, and the airway, where CFTR is involved in chloride secretion. The variability in the end-point measures and the statistical limitations within this small study also probably contributed to the differences between outcome measures. It is not known whether there are important interindividual differences in responses to VX-770, and the biomarker and clinical responses in large groups of subjects have not been confirmed.
We did not investigate the mechanism by which VX-770 affects the airway surface and respiratory symptoms. VX-770 is known to improve CFTR-mediated ion transport and to reduce surface liquid absorption in cultured human bronchial epithelial cells,8 so it may have similar effects in vivo. Improvement in mucus clearance through better hydration of the airway surface could ameliorate airway obstruction by decreasing mucus plugging.
In summary, VX-770, an oral potentiator of CFTR in vitro, was associated with few severe side effects in this clinical evaluation. Some secondary end points showed no statistically significant differences versus placebo, although we observed significant within-subject improvements in respiratory (nasal potential difference) and nonrespiratory (sweat chloride concentration) biomarkers of CFTR function and improvements in lung function (spirometric assessment). The effects of VX-770 on CFTR-mediated ion transport and lung function suggest that the improvement of CFTR function may be a viable therapeutic approach in cystic fibrosis.
Supported by Vertex Pharmaceuticals, Cystic Fibrosis Foundation Therapeutics, and grants from the Food and Drug Administration Office of Orphan Products Development (FD-R-003432-01), the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) (K23 DK075788, to Dr. Rowe), Cystic Fibrosis Foundation Therapeutics (CLANCY05Y2, to Dr. Clancy and the University of Alabama at Birmingham for coordinating the nasal potential difference qualification process; Clinical Facilitation Award DURIE06A0, to Dr. Durie; and RAMSEY03Y0, for the Therapeutics Development Network Coordinating Center, to Dr. Ramsey), the National Center for Research Resources of the NIH (GCRC UL1 RR025005, to Johns Hopkins; GCRC M01 RR00070 and CTSA 1UL1 RR025744, to Stanford University; UL1 RR024989, to Case Western Reserve University; GCRC M01 RR02172, to Children’s Hospital Boston; CTSA UL1 RR025014, to the Institute of Translational Health Sciences and the University of Washington; K23 RR018611-05, to Dr. Sagel; CTSA UL1 RR025780, to the University of Colorado Denver; CTSA UL 1RR025747, to the University of North Carolina at Chapel Hill; CTSA UL1 RR024153, to Children’s Hospital of Pittsburgh; and CTSA UL1 RR024134, to Children’s Hospital of Philadelphia), and the National Heart, Lung, and Blood Institute of the NIH (U01 HL081335, to the University of Colorado Denver).
Dr. Accurso reports receiving consulting fees from Inspire and PTC Therapeutics, grant support from Digestive Care, PTC Therapeutics, Gilead, Vertex, Altus, KaloBios, Axcan Pharma, Yasoo Health, INO Therapeutics, Mpex, and Genentech, and travel support from Vertex Pharmaceuticals, PTC Therapeutics, Inspire Pharmaceuticals, and Gilead Sciences; Dr. Rowe, receiving grant support from Vertex, Novartis, and PTC Therapeutics and consulting fees from PTC Therapeutics and Vertex; Dr. Clancy, receiving consulting fees from Transave and grant support from Vertex, MedImmune, Inspire, Gilead, Transave, and PTC Therapeutics; Dr. Boyle, receiving consulting fees from Novartis, Genentech, Gilead, and Bayer and grant support from Vertex; Dr. Dunitz, receiving grant support from Inspire, Vertex, Altus, Gilead, and Roche (through a clinical trial subcontract with Duke) and travel support from Vertex; Dr. Durie, receiving grant support from Vertex and consulting fees and travel support from Vertex; Dr. Sagel, receiving grant support from Vertex, Yasoo Health, and INO Therapeutics; Dr. Donaldson, receiving consulting fees from Liquidia Technologies, grant support from Inspire, Vertex, and Gilead, and travel support from Gilead and Vertex; Dr. Hornick, receiving consulting fees from Pfizer and Genentech, speaking fees from Pfizer and Boehringer Ingelheim, and travel support from Pfizer, Boehringer Ingelheim, and Genentech; Dr. Konstan, receiving grant support from Vertex, Novartis, Boehringer Ingelheim, Ovation, Axcan Pharma, Genentech, and Altus, consulting fees and travel support from Vertex, Axcan Pharma, Boehringer Ingelheim, CSL Bering, Digestive Care, Genentech, GlaxoSmithKline, Gilead, NanoBio, Nektar, Novartis, PTC Therapeutics, Solvay, and Transave, and speaking fees from Roche and Genentech, and serving on the scientific advisory board for Aradigm; Dr. Moss, receiving consulting fees from Vertex, Novartis, Inspire, Genentech, Mpex, PTC Therapeutics, Aridis, AOP/Lantibio, Johnson & Johnson, and 23andMe, grant support from Vertex, Gilead, PTC Therapeutics, Inspire, and GlaxoSmithKline, speaking fees from Novartis, Genentech, and AstraZeneca and travel support from AstraZeneca, Novartis, Vertex, and Genentech, and owning stock in Gilead and Genentech; Dr. Pilewski, receiving grant support from Novartis and Vertex; Dr. Rubenstein, receiving consulting fees from Transave; Dr. Uluer, receiving grant support from Vertex, Boehringer Ingelheim, Education Development Center, and Bayer, speaking fees from Vertex, and travel support from Vertex and Bayer; Dr. Aitken, receiving grant support from Pharmaxis, Transave, Vertex, and PTC Therapeutics and travel support from Pharmaxis and Vertex; Dr. Freedman, receiving grant support from Vertex, Pfizer, Hood Foundation, Gerber Foundation, and Merck; Drs. Dong, Zha, Olson, Ordoñez, and Ms. Stone, being employees of Vertex and holding stock in and receiving travel support from Vertex; and Dr. Ramsey, receiving grants from AlgiPharma, Aradigm, Bayer, CSL Behring, Eurand, GlaxoSmithKline, Inspire, Johnson & Johnson, KaloBios, Mpex, N30 Pharmaceuticals, Novartis, Pharmaxis, PTC Therapeutics, Seed-One Ventures, Transave, and Vertex.
We thank all the subjects involved in the study and the study coordinators, nurses, and technicians performing the nasal potential difference procedure at investigative sites for their contributions, including Churee Pardee and Lisa Monchil (University of Colorado Denver); Heather Young, Ginger Reeves, and Gina Sabbatini (University of Alabama at Birmingham); Lois Brass and Dr. Kelvin MacDonald (Johns Hopkins Medical Institutions); Brooke Noren, Cynthia Williams, and Dale Carlquist (University of Minnesota); Julie Avolio (Hospital for Sick Children, Toronto); Myra Slutsky (St. Michael’s Hospital, Toronto); Cheri Lux, Janice Launspach, and Dr. Mary Teresi (University of Iowa Carver School of Medicine); Roberta Ksenich and Timothy R. Myers (Case Western Reserve University); Carol Barlow, Nadia Bendahmane, and Caroline O’Connor (University of North Carolina at Chapel Hill); Colleen Dunn and Zoe Davies (Stanford University); Elizabeth Hartigan, Sandra Hurban, and Adrienne Horn (University of Pittsburgh); Christina Kubrak (Children’s Hospital of Philadelphia); Erin M. Leone (Children’s Hospital Boston); Alan Genatossio and Sharon McNamara (Seattle Children’s Hospital); and Louis J. Boitano (University of Washington, Seattle). We also thank Dr. Robert J. Beall (Cystic Fibrosis Foundation) and Niki Hoagland (Seattle Children’s Hospital) for contributions and support; Morty Cohen (Seattle Children’s Hospital) for providing solutions for testing the nasal potential difference; John Beamer (Seattle Children’s Hospital) for standard operating procedures related to testing of the nasal potential difference; and Dr. Barry Lubarsky (Vertex Pharmaceuticals) for coordinating the editing and submission of an earlier version of the manuscript. We also thank the following cystic fibrosis treatment centers for referring subjects for this study: University of Utah (Dr. Ted Liou), Yale University (Dr. John McArdle), Children’s Hospital of Michigan (Dr. Debbie Toder), Children’s Hospital Medical Center of Akron (Dr. Nathan Kraynack), and Vanderbilt University (Dr. Bonnie Slovis).
No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.