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Reducing treatment burden is a priority for people with cystic fibrosis, whose health has benefited from using new modulators that substantially increase CFTR protein function. The SIMPLIFY study aimed to assess the effects of discontinuing nebulised hypertonic saline or dornase alfa in individuals using the CFTR modulator elexacaftor plus tezacaftor plus ivacaftor (ETI).The SIMPLIFY study included two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials at 80 participating clinics across the USA in the Cystic Fibrosis Therapeutics Development Network. We included individuals with cystic fibrosis aged 12-17 years with percent predicted FEVFrom Aug 25, 2020, to May 25, 2022, a total of 672 unique participants were screened for eligibility for one or both trials, resulting in 847 total random assignments across both trials with 594 unique participants. 370 participants were randomly assigned in the hypertonic saline trial and 477 in the dornase alfa trial. Participants across both trials had an average ppFEVIn individuals with cystic fibrosis on ETI with relatively well preserved pulmonary function, discontinuing daily hypertonic saline or dornase alfa for 6 weeks did not result in clinically meaningful differences in pulmonary function when compared with continuing treatment.

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Approximately 5% of people with CF have residual function (RF) CFTR mutations that result in partially retained CFTR activity. Published literature on disease trajectory among those with RF mutations is limited. In this retrospective study, we characterized lung function decline across different age groups in CFTR modulator-untreated people with CF heterozygous for F508del and an RF mutation (F/RF).Rate of decline in percent predicted forced expiratory volume in 1 s (ppFEVThe estimated annualized rate of ppFEVProgressive lung function decline was observed in people with F/RF genotypes across all assessed age groups, reinforcing the importance of early intervention and clinical monitoring to preserve lung function in all people with CF.In people with cystic fibrosis, lung function typically decreases over time and is linked to the severity of the disease. How fast lung function decreases (referred to as the rate of lung function decline) in cystic fibrosis depends on the specific mutations (changes) in the CFTR gene (which causes the disease). Lung function decline has been well studied in some mutation groups, but not many previous studies have looked at lung function decline in people with one copy of the F508del-CFTR mutation (which is the most common CFTR mutation and results in little to no functional CFTR protein) and another CFTR mutation called a residual function mutation (referred to as people with F/RF genotypes). We used data from the US Cystic Fibrosis Foundation Patient Registry (which collects information on the health of people in the USA who have cystic fibrosis), to look at the rate of lung function decline in people with F/RF genotypes. We found that people with cystic fibrosis who have F/RF genotypes experience lung function loss over time. We also found that this lung function loss occurred in people of all ages with F/RF genotypes. This finding supports the importance of early treatment to help prevent lung function loss in all people with cystic fibrosis, including people with F/RF genotypes.

Chronic azithromycin improves outcomes in cystic fibrosis (CF), but its mechanism of action is unclear. The OPTIMIZE trial demonstrated improvement in time to first pulmonary exacerbation in children with new Pseudomonas treated with azithromycin. Azithromycin effect on systemic markers of inflammation over 18 months was assessed by change from baseline for high-sensitivity C-reactive protein, myeloperoxidase, calprotectin and absolute neutrophil count in the OPTIMIZE population. Subjects treated with chronic azithromycin or placebo had samples collected at baseline, 39 and 78 weeks of treatment. In 129 subjects, a significant decrease in high-sensitivity C-reactive protein was present at 39 weeks in the azithromycin group compared to placebo, but no significant difference between the groups at 78 weeks. No differences in change from baseline in myeloperoxidase, calprotectin or absolute neutrophil count were present at either time point. This supports the concept of a transient immunomodulatory effect for chronic azithromycin therapy in children with CF.

RATIONALE: Studies estimating rate of lung function decline in cystic fibrosis (CF) have been inconsistent regarding methods used. How the methodology used impacts validity of the results and comparability between studies is unknown.OBJECTIVES: The Cystic Fibrosis Foundation established a workgroup whose tasks were to examine the impact of differing approaches to estimating rate of decline in lung function and to provide analysis guidelines.METHODS: We utilized a natural history cohort of 35,252 individuals with CF aged > 6 years of the Cystic Fibrosis Foundation Patient Registry (CFFPR), 2003-2016. Modeling strategies using linear and nonlinear forms of marginal and mixed-effects models, which have previously quantified rate of forced expiratory volume in 1 second (FEV1) decline (% predicted/year), were evaluated under clinically relevant scenarios of available lung function data. Scenarios varied by sample size (overall CFFPR, medium-sized cohort of 3,000 subjects, and small-sized cohort of 150), data collection/reporting frequency (encounter, quarterly, and annual), inclusion of FEV1 during pulmonary exacerbation, and follow-up length (RESULTS: Rate-of-FEV1-decline estimates (% predicted/year) differed between linear marginal and mixed-effects models; overall cohort estimates (95% confidence interval) were 1.26 (1.24-1.29) and 1.40 (1.38-1.42), respectively. Marginal models consistently estimated less rapid lung function decline than mixed-effects models across scenarios except for short-term follow-up (both were ~1.4). Rate-of-decline estimates from nonlinear models diverged by age 30. Among mixed-effects models, nonlinear and stochastic terms fit best except for short-term follow-up (< 2 years). Overall CFFPR analysis from a joint longitudinal-survival model implied that an increase in rate of decline of 1% predicted/year in FEV1 associated with a 1.52-fold (52%) increase in the hazard of death/lung transplantation, but results exhibited immortal cohort bias.CONCLUSIONS: Differences were as high as 0.5% predicted/year between rate-of-decline estimates, but we found estimates were robust to lung function data availability scenarios except short-term follow-up and older age ranges. Inconsistencies among previous study results may be attributable to inherent differences in study design, inclusion criteria, or covariate adjustment. Results-based decision points reported herein will support researchers in selecting a strategy to model lung function decline most reflective of nuanced, study-specific goals.

In 2017, Nkam et al. published a prognostic score to predict death or lung transplant within 3 years among adult cystic fibrosis (CF) patients. Their model was developed using French CF registry data and was subsequently validated in the Canadian CF registry. We evaluated this prognostic score using data from adult patients with CF in the United States (US) CF Foundation Patient registry, combined with lung transplant records from the United Network for Organ Sharing (UNOS) Registry (2013 to 2016) (n=11,542). We found that the prognostic score had a very good discriminative index predicting death or lung transplant in the US CF population (AUC 0.88, 95% CI 0.88-0.89) with an odds ratio (OR) of 2.83 (95% CI 2.69 – 2.97) for each unit increase in the score. However, it did not provide significant additional utility over an FEV1 ≤30% of predicted as a predictor of death or lung transplant.

BACKGROUND: Given future challenges in conducting large randomized, placebo controlled trials for future CF therapeutics development, we evaluated the potential for using external historical controls to either enrich or replace traditional concurrent placebo groups in CF trials METHODS: The study included data from sequentially completed, randomized, controlled clinical trials, EPIC and OPTIMIZE respectively, evaluating optimal antibiotic therapy to reduce the risk of pulmonary exacerbation in children with early Pseudomonas aeruginosa infection. The primary treatment effect in OPTIMIZE, the risk of pulmonary exacerbation associated with azithromycin, was re-estimated in alternative designs incorporating varying numbers of participants from the earlier trial (EPIC) as historical controls. Bias and precision of these estimates were characterized. Propensity scores were derived to adjust for baseline differences across study populations, and both Poisson and Cox regression used to estimate treatment efficacy. RESULTS: Replacing 86 OPTIMIZE placebo participants with 304 controls from EPIC to mimic a fully historically controlled trial resulted an 8% reduction in risk of pulmonary exacerbations (Hazard ratio (HR):0.92 95% CI 0.61, 1.34) when not adjusting for key baseline differences between study populations. After adjustment, a 37% decrease in risk of exacerbation (HR:0.63, 95% CI 0.50,0.80) was estimated, comparable to the estimate from the original trial comparing the 86 placebo participants to 77 azithromycin participants on azithromycin (45%, HR:0.55, 95% CI: 0.34,0.86). Other adjusted approaches provided similar estimates for the efficacy of azithromycin in reducing exacerbation risk: pooling all controls from both studies provided a HR of 0.60 (95%CI 0.46, 0.77) and augmenting half the OPTIMIZE placebo participants with EPIC controls gave a HR 0.63 (95% CI 0.48, 0.82). CONCLUSIONS: The potential exists for future CF trials to utilize historical control data. Careful consideration of both the comparability of controls and of optimal methods can reduce the potential for biased estimation of treatment effects.

RationaleInhaled tobramycin and oral azithromycin are common chronic therapies in people with cystic fibrosis and Pseudomonas aeruginosa airway infection. Some studies have shown that azithromycin can reduce the ability of tobramycin to kill P. aeruginosa. This trial was done to test the effects of combining azithromycin with inhaled tobramycin on clinical and microbiological outcomes in people already using inhaled tobramycin. We theorised that those randomised to placebo (no azithromycin) would have greater improvement in forced expiratory volume in one second (FEV1) and greater reduction in P. aeruginosa sputum in response to tobramycin.MethodsA 6-week prospective, randomised, placebo-controlled, double-blind trial testing oral azithromycin versus placebo combined with clinically prescribed inhaled tobramycin in individuals with cystic fibrosis and P. aeruginosa airway infection.ResultsOver a 6-week period, including 4 weeks of inhaled tobramycin, the relative change in FEV1 did not statistically significantly differ between groups (azithromycin (n=56) minus placebo (n=52) difference: 3.44%; 95% CI: −0.48 to 7.35; p=0.085). Differences in secondary clinical outcomes, including patient-reported symptom scores, weight and need for additional antibiotics, did not significantly differ. Among the 29 azithromycin and 35 placebo participants providing paired sputum samples, the 6-week change in P. aeruginosa density differed in favour of the placebo group (difference: 0.75 log10 CFU/mL; 95% CI: 0.03 to 1.47; p=0.043).ConclusionsDespite having greater reduction in P. aeruginosa density in participants able to provide sputum samples, participants randomised to placebo with inhaled tobramycin did not experience significantly greater improvements in lung function or other clinical outcomes compared with those randomised to azithromycin with tobramycin.

Highlights • Pulmonary exacerbation difference is an important clinical trial efficacy endpoint. • Regulators have stressed use of Fuchs criteria-based exacerbation definitions. • We compared criteria-based definitions to investigator assessments of 751 events. • Criteria-based definitions were insensitive, nonspecific, and prone to bias. • An alternative exacerbation definition is needed for future CF drug development., Background Cystic fibrosis (CF) pulmonary exacerbations can be serious respiratory events and reduction in exacerbation rate or risk are important efficacy endpoints for CF therapeutic trials. Variability in exacerbation diagnoses and treatment have led drug developers to employ “objective” exacerbation definitions combining antimicrobial treatment (AT) and the presence of ≥4 of 12 respiratory criteria (first published by Fuchs et al. [NEJM 1994;331(10):637–42]). Assumptions underlying this approach have yet to be formally evaluated. Methods Respiratory events (RE) observed during a 48-week trial of ataluren (NCT02139306), a read-through agent for premature nonsense codons, were compared across six exacerbation definitions: any AT, intravenous AT (IVAT), ≥4 Fuchs criteria present, AT plus ≥4 Fuchs criteria, IVAT plus ≥4 Fuchs criteria, and investigator assessment. Fuchs definitions were evaluated by assessing missingness of individual criteria and associations between criteria presence and clinician exacerbation assessment. Results Among 751 RE, more than one third had ≥4 Fuchs criteria present but were not assessed as exacerbations by investigators. Data for ≥1 and for 4 Fuchs criteria, respectively, were missing for ~ 90% and >30% of RE. Only 6/12 Fuchs criteria were present more often when investigators assessed RE as exacerbations than when they did not. Conclusions “Objective” definitions have shortcomings inconsistent with their purpose of optimizing exacerbation capture in clinical trials : 1) they capture events clinicians do not consider exacerbations, 2) are prone to data missingness which can bias the likelihood of meeting the definition, and 3) employ criteria that are not associated with investigator assessment of exacerbation.

IntroductionTherapeutic advances have markedly increased life expectancy for those with cystic fibrosis (CF), resulting in a median predicted survival over 50 years. Consequently, people with CF (pwCF) are living through their reproductive years and the rate of pregnancy is rapidly rising. Despite the increased relevance of this topic, multicentre studies investigating the association between maternal health and choices made during pregnancy on maternal and fetal outcomes do not exist. Furthermore, there are very limited data on the outcomes following CF transmembrane conductance regulator (CFTR) modulator use during pregnancy and lactation.Methods and analysisMaternal andFetal Outcomes in theEra of Modulators(MAYFLOWERS) is a prospective, multicentre observational clinical trial which will enrol approximately 285 pregnant pwCF including those who are modulator ineligible and those who choose to continue or discontinue CFTR modulator therapy during pregnancy and lactation. The primary aim of this 35-month study is to assess whether lung function changes during pregnancy differ based on the continued use of modulators or other factors such as pre-existing comorbid conditions. Secondary objectives include evaluation of pregnancy related and obstetrical complications and changes in mental health.Ethics and disseminationThe design of this study required special consideration of study burden on pregnant and lactating people with chronic illness in the setting of a substantial number of unanswered questions under these conditions. MAYFLOWERS is the first prospective clinical trial examining pregnancy in CF; the outcomes will guide providers on pregnancy management in pwCF and others with chronic respiratory disease.

Rationale The prevalence of adults living with cystic fibrosis (CF) who have early-stage lung disease is increasing. Objectives Describe the prevalence and evaluate spirometric risk factors associated with the subgroup of patients with early-stage lung disease and FEV1 decline of ≥5% predicted/year. Methods Retrospective cohort study of patients ≥18 years with FEV1% predicted ≥80% included in the US CF Foundation Patient Registry from 2010–2013. Regression models were developed to estimate FEV1 rate of decline. Multivariable logistic analysis was used to assess if spirometric risk factors were associated with FEV1 decline. Measurements and main results 3,029 subjects were in the study cohort. Approximately 15% of the cohort had a substantial decline in lung function ≥5% predicted/year. In multivariable models adjusted for confounders, FEV1/FVC ratio Conclusions Even among adults with early-stage lung disease, approximately 15% are shown to progress and experience a large decline in lung function. This reinforces the concept that lung function in early-stage CF is not normal or mild. Rather, lung function decline may be delayed, but not avoided, in these individuals. Variability in FEV1% predicted and airway obstruction as measured by FEV1/FVC ratio may identify individuals at increased risk of decline. Adults with early-stage lung disease should be followed in clinic to monitor for onset of decline.

Chronic Azithromycin (AZM) is a common treatment for lung infection. Among adults at risk of cardiac events, AZM use has been associated with cardiovascular harm. We assessed cardiovascular safety of AZM among children with CF, as a secondary analysis of a placebo-controlled, clinical trial, in which study drug was taken thrice-weekly for a planned 18 months. Safety assessments using electrocardiogram (ECG) occurred at study enrollment, and then after 3 weeks and 18 months of participation. Among 221 study participants with a median of 18 months follow-up, increased corrected QT interval (QTc) of ≥30 msec was rare, at 3.4 occurrences per 100 person-years; and incidence of QTc prolongation was no higher in the AZM arm than the placebo arm (1.8 versus 5.4 per 100 person-years). No persons experienced QTc intervals above 500 msec. Long-term chronic AZM use was not associated with increased QT prolongation.

Improved methods are needed to risk-stratify patients with cystic fibrosis (CF) and reduced FEVWhat are the predictors of death or lung transplantation (LTx) within 2 years among patients with CF whose FEVPatients with CF, age ≥ 6 years with FEVFEVAmong individuals with CF and FEV

Inhaled tobramycin and oral azithromycin are common chronic therapies in people with cystic fibrosis andA 6-week prospective, randomised, placebo-controlled, double-blind trial testing oral azithromycin versus placebo combined with clinically prescribed inhaled tobramycin in individuals with cystic fibrosis andOver a 6-week period, including 4 weeks of inhaled tobramycin, the relative change in FEVDespite having greater reduction in

OBJECTIVECSF shunt infection treatment requires both surgical and antibiotic decisions. Using the Hydrocephalus Clinical Research Network (HCRN) Registry and 2004 Infectious Diseases Society of America (IDSA) guidelines that were not proactively distributed to HCRN providers, the authors previously found high adherence to surgical recommendations but poor adherence to intravenous (IV) antibiotic duration recommendations. In general, IV antibiotic duration was longer than recommended. In March 2017, new IDSA guidelines expanded upon the 2004 guidelines by including recommendations for selection of specific antibiotics. The objective of this study was to describe adherence to both 2004 and 2017 IDSA guideline recommendations for CSF shunt infection treatment, and to report reinfection rates associated with adherence to guideline recommendations.METHODSThe authors investigated a prospective cohort of children younger than 18 years of age who underwent treatment for first CSF shunt infection at one of 7 hospitals from April 2008 to December 2012. CSF shunt infection was diagnosed by recovery of bacteria from CSF culture (CSF-positive infection). Adherence to 2004 and 2017 guideline recommendations was determined. Adherence to antibiotics was further classified as longer or shorter duration than guideline recommendations. Reinfection rates with 95% confidence intervals (CIs) were generated.RESULTSThere were 133 children with CSF-positive infections addressed by 2004 IDSA guideline recommendations, with 124 at risk for reinfection. Zero reinfections were observed among those whose treatment was fully adherent (0/14, 0% [95% CI 0%–20%]), and 15 reinfections were observed among those whose infection treatment was nonadherent (15/110, 14% [95% CI 8%–21%]). Among the 110 first infections whose infection treatment was nonadherent, 74 first infections were treated for a longer duration than guidelines recommended and 9 developed reinfection (9/74, 12% [95% CI 6%–22%]). There were 145 children with CSF-positive infections addressed by 2017 IDSA guideline recommendations, with 135 at risk for reinfection. No reinfections were observed among children whose treatment was fully adherent (0/3, 0% [95% CI 0%–64%]), and 18 reinfections were observed among those whose infection treatment was nonadherent (18/132, 14% [95% CI 8%–21%]).CONCLUSIONSThere is no clear evidence that either adherence to IDSA guidelines or duration of treatment longer than recommended is associated with reduction in reinfection rates. Because IDSA guidelines recommend shorter IV antibiotic durations than are typically used, improvement efforts to reduce IV antibiotic use in CSF shunt infection treatment can and should utilize IDSA guidelines.

Highlights • The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) global pandemic has significantly impacted CF clinical research. • An electronic survey was sent to Therapeutic Development Network (TDN) sites to monitor the impact. • SARS-CoV-2 had an early impact on participant enrollment, research team stability, and procedures such as spirometry and sputum induction. • Trends steadily improved over the months as research activities began to recover across the TDN. • SARS-CoV-2 highlights new opportunities to expand CF research focusing on data collection outside of research centers and increased access for remote participation., The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) global pandemic significantly impacted CF clinical research within the Cystic Fibrosis Foundation Therapeutics Development Network (CFF TDN). A Research Electronic Data Capture (REDCap) survey was developed and sent to network sites to monitor and understand the impact on research teams, ongoing and anticipated clinical research, and specific clinical and research procedures. Key findings indicated an early impact on participant enrollment, research team stability, and procedures such as spirometry and sputum induction. These trends steadily improved over the months as research activities began to recover across the TDN. While SARS-CoV-2 created a significant challenge it also highlights new opportunities to expand CF research with greater focus on data collection outside of research centers and increased access for remote participation.

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Rationale: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence. Objectives: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence. Methods: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS. Measurements and Main Results: The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37–0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01–2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints. Conclusions: Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Cystic fibrosis (CF) remains the most common life-shortening hereditary disease in white populations, with high morbidity and mortality related to chronic airway mucus obstruction, inflammation, infection, and progressive lung damage. In 1989, the discovery that CF is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene that encodes a cAMP-dependent anion channel vital for proper Cl(−) and HCO(3)(−) transport across epithelial surfaces provided a solid foundation for unraveling underlying disease mechanisms and the development of therapeutics targeting the basic defect in people with CF. In this review, we focus on recent advances in our understanding of the molecular defects caused by different classes of CFTR mutations, implications for pharmacological rescue of mutant CFTR, and insights into how CFTR dysfunction impairs key host defense mechanisms, such as mucociliary clearance and bacterial killing in CF airways. Furthermore, we review the path that led to the recent breakthrough in the development of highly effective CFTR-directed therapeutics, now applicable for up to 90% of people with CF who carry responsive CFTR mutations, including those with just a single copy of the most common F508del mutation. Finally, we discuss the remaining challenges and strategies to develop highly effective targeted therapies for all patients and the unprecedented potential of these novel therapies to transform CF from a fatal to a treatable chronic condition.

Background Chronic Pseudomonas aeruginosa ( Pa ) airways infection, exuberant local inflammation, and progressive lung function loss are hallmarks of cystic fibrosis (CF). KB001-A is an anti-PcrV PEGylated monoclonal antibody fragment to the Type III secretion system of Pa . This 16-week study evaluated KB001-A associated effect on time-to-need for antibiotics for worsening respiratory signs and symptoms, as well as safety, and treatment-associated changes in symptom scores, inflammatory markers, and spirometry. Methods This was a randomized, double-blind, placebo-controlled, repeat-dose study in CF subjects with Pa. Intravenous 10mg/kg KB001-A or placebo infusions were administered at baseline and weeks 2, 4, 8, and 16, with a 4-week follow-up. Sputum inflammatory markers were assessed in a sub-study. Time-to-need for antibiotics was compared between groups by Kaplan Meier analysis and Cox proportional hazards modeling adjusting for randomization strata. Results Of 182 subjects, 169 received at least one infusion of KB001-A ( n =83) or placebo ( n =86). KB001-A was generally safe and well-tolerated as compared to placebo, with no significant emergent adverse effects other than one serious adverse event of elevated hepatic enzymes of unclear etiology. Time to need for antibiotics did not differ between groups (HR: 1.00; 95% CI: 0.69, 1.45, p =0.995). A 3.2 increase in ppFEV 1 from placebo favoring KB001-A was observed at week 16 (95% CI: 1.12, 5.30, p =0.003). Mean changes from baseline in log 10 sputum neutrophil elastase (NE) had a non-significant decrease (−0.27, 95% CI: −0.58,0.04, p =0.084) while IL-8 concentrations at week 16 were significantly lower (−0.27, 95% CI: −0.55,0.00, p =0.048) among KB001-A subjects ( n =16) relative to placebo ( n =13). Conclusions KB001-A was safe and well-tolerated and associated with a modest FEV 1 benefit and reduction in select sputum inflammatory markers (IL-8). KB001-A was not associated with an increased time to need for antibiotics. The lack of efficacy seen with KB001-A may be due, in part, to the low levels of the type III secretion proteins previously reported in sputum of CF patients chronically infected with Pa.

BACKGROUND: Patients with cystic fibrosis (CF) experience variable lung disease phenotypes. The R117H mutation is often associated with preserved lung function. Our objective was to compare the rate of lung function decline in patients with the R117H mutation and patients homozygous for the F508del mutation. METHODS: Rate of decline in percentage-of-predicted FEV(1) (ppFEV(1)) was analyzed using the 2006-2010 US CF Foundation Patient Registry. RESULTS: 4-year rate of decline was slower in 156 R117H patients compared with 6251 F508del patients (−0.61 vs −2.03 ppFEV(1)/year, P

Background Previous studies of cerebrospinal fluid (CSF) shunt infection treatment have been limited in size and unable to compare patient and treatment characteristics by infecting organism. Our objective was to describe variation in patient and treatment characteristics for children with first CSF shunt infection, stratified by infecting organism subgroups outlined in the 2017 Infectious Disease Society of America’s (IDSA) guidelines. Methods We studied a prospective cohort of children Results There were 145 children whose infections were diagnosed by CSF culture and addressed by IDSA guidelines, including 47 with Staphylococcus aureus, 52 with coagulase-negative Staphylococcus, 37 with Gram-negative bacilli, and 9 with Propionibacterium acnes. No differences in many patient and treatment characteristics were seen between infecting organism subgroups, including age at initial shunt, gender, race, insurance, indication for shunt, gastrostomy, tracheostomy, ultrasound, and/or endoscope use at all surgeries before infection, or numbers of revisions before infection. A larger proportion of infections were caused by Gram-negative bacilli when antibiotic-impregnated catheters were used at initial shunt placement (12 of 23, 52%) and/or subsequent revisions (11 of 23, 48%) compared with all other infections (9 of 68 [13%] and 13 of 68 [19%], respectively). No differences in reinfection were observed between infecting organism subgroups. Conclusions The organism profile encountered at infection differs when antibiotic-impregnated catheters are used, with a higher proportion of Gram-negative bacilli. This warrants further investigation given increasing adoption of antibiotic-impregnated catheters.

OBJECTIVECSF shunt infection requires both surgical and antibiotic treatment. Surgical treatment includes either total shunt removal with external ventricular drain (EVD) placement followed by new shunt insertion, or distal shunt externalization followed by new shunt insertion once the CSF is sterile. Antibiotic treatment includes the administration of intravenous antibiotics. The Hydrocephalus Clinical Research Network (HCRN) registry provides a unique opportunity to understand reinfection following treatment for CSF shunt infection. This study examines the association of surgical and antibiotic decisions in the treatment of first CSF shunt infection with reinfection.METHODSA prospective cohort study of children undergoing treatment for first CSF infection at 7 HCRN hospitals from April 2008 to December 2012 was performed. The HCRN consensus definition was used to define CSF shunt infection and reinfection. The key surgical predictor variable was surgical approach to treatment for CSF shunt infection, and the key antibiotic treatment predictor variable was intravenous antibiotic selection and duration. Cox proportional hazards models were constructed to address the time-varying nature of the characteristics associated with shunt surgeries.RESULTSOf 233 children in the HCRN registry with an initial CSF shunt infection during the study period, 38 patients (16%) developed reinfection over a median time of 44 days (interquartile range [IQR] 19–437). The majority of initial CSF shunt infections were treated with total shunt removal and EVD placement (175 patients; 75%). The median time between infection surgeries was 15 days (IQR 10–22). For the subset of 172 infections diagnosed by CSF culture, the mean ± SD duration of antibiotic treatment was 18.7 ± 12.8 days. In all Cox proportional hazards models, neither surgical approach to infection treatment nor overall intravenous antibiotic duration was independently associated with reinfection. The only treatment decision independently associated with decreased infection risk was the use of rifampin. While this finding did not achieve statistical significance, in all 5 Cox proportional hazards models both surgical approach (other than total shunt removal at initial CSF shunt infection) and nonventriculoperitoneal shunt location were consistently associated with a higher hazard of reinfection, while the use of ultrasound was consistently associated with a lower hazard of reinfection.CONCLUSIONSNeither surgical approach to treatment nor antibiotic duration was associated with reinfection risk. While these findings did not achieve statistical significance, surgical approach other than total removal at initial CSF shunt infection was consistently associated with a higher hazard of reinfection in this study and suggests the feasibility of controlling and standardizing the surgical approach (shunt removal with EVD placement). Considerably more variation and equipoise exists in the duration and selection of intravenous antibiotic treatment. Further consideration should be given to the use of rifampin in the treatment of CSF shunt infection. High-quality studies of the optimal duration of antibiotic treatment are critical to the creation of evidence-based guidelines for CSF shunt infection treatment.

BACKGROUND: Chronic Pseudomonas aeruginosa lung infection is associated with significant morbidity and mortality in cystic fibrosis (CF). It is not known whether recent advances in care have affected the rates of chronic infection. We aimed to determine if the rates of developing new chronic P. aeruginosa infection among adolescents and adults with CF significantly changed over time. METHODS: The cohort consisted of individuals with CF followed in the Cystic Fibrosis Foundation Patient Registry aged ≥13 years without chronic P. aeruginosa at baseline. Multivariable regression models accounting for within-patient correlation were used to assess the change in rate of developing chronic P. aeruginosa infection between 2003 and 2012. RESULTS: A total of 15504 individuals were followed for a median of 5 (interquartile range, 2–9) years. The annual rates of developing new chronic P. aeruginosa decreased from 14.3% in 2003 to 6.4% in 2012. After adjusting for potential confounders, relative risk (RR) of developing chronic P. aeruginosa infection decreased significantly over time compared to 2003 (P value test of trend < .001). Compared with 2003, the RR of developing chronic P. aeruginosa infection in 2012 was 0.33 (95% confidence interval, 0.30–0.37). No significant increases in risk of chronic infections with other major CF bacterial pathogens relative to 2003 were identified. CONCLUSIONS: Among individuals with CF, a significant decrease in the risk and rates of developing chronic P. aeruginosa infection between 2003 and 2012 was observed. Whether this decline results in changes in clinical outcomes warrants further exploration.

Background Lung transplantation (LTx) is frequently considered for patients with cystic fibrosis (CF) when the FEV 1 reaches 1 Methods We conducted a retrospective cohort study using the CF Foundation Patient Registry from January 1, 2003 to December 31, 2013. Adult patients (≥ 18 years) with FEV 1 Results There were 3,340 patients with an FEV 1 1 Conclusions Median survival was > 6.5 years for patients with CF and an FEV 1 1

Background We recognize an unprecedented opportunity to study the effects of withdrawing one or more chronic treatments in people with CF (PwCF) who benefit greatly from CFTR modulator therapy, but feasibility and acceptance of such a study within the community is unknown. Methods We surveyed PwCF, their families, and their acquaintances between November 16, 2018, and December 2, 2018, and CF clinicians between December 19, 2018, and January 2, 2019, about treatment withdrawal research. We sought feedback from these groups about their level of interest in this research, the consistency with which they were taking modulator and non-modulator treatments, the ways in which they conceptualized health changes, and what chronic non-modulator treatments they were most interested in stopping. We also asked for stakeholder perspectives on the design of a treatment withdrawal trial, but we intend to report these perspectives elsewhere. Results Eighty percent (541/675) of CF community respondents and 95% (206/218) of CF clinicians said that a trial of treatment simplification should be performed in the context of highly effective modulator therapy. Most current CFTR modulator users (292/359, 81%) have not stopped another chronic treatment. Worsening lung function by spirometry or increased daily symptoms were important health indicators. PwCF, their families, and/or their acquaintances ranked airway clearance techniques and inhaled antibiotics as the most burdensome treatments. Conclusions There is considerable support among the CF community and CF clinicians in the U.S. for controlled trials to assess the safety and impact of treatment simplification in patients taking highly effective modulator therapy.

The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis (CF), which was once a fatal disease of infants and young children. However, although life expectancy for people with CF has increased substantially, the disease continues to limit survival and quality of life, and results in a significant burden of care for people with CF and their families. Moreover, recent epidemiological studies in the past two decades have shown that CF occurs and is more frequent than was previously thought in non-European populations and in regions of the world where it had not previously been described. The Lancet Respiratory Medicine Commission was formed to assess the global health and economic costs of CF care over the next three decades and to identify opportunities for progress in the care of people with CF. challenges that need to be addressed, and to serve as a blueprint for the future of CF care. This Commission was established at a time of immense change in CF clinical care including enhanced survival, widespread genetic testing supporting the diagnosis of CF in regions of the world where it was previously thought to be or non-existent and the advent of a growing number of CFTR-directed therapies which are likely to further alter the natural trajectory of the disease. This document is intended to bring to the attention of patients, health-care professionals, researchers, funders, service providers, policy makers the variety of challenges associated with this changing landscape and to serve as a blueprint for the future of CF care. what was previously a universally fatal disease of children. In considering the future of CF care, the Commission focused on five key areas, which are discussed in this report: the changing epidemiology of CF (section 1); future challenges of clinical care and its delivery (section 2); the building of CF care globally (section 3); novel therapeutics (section 4); and patient engagement (section 5) (summarized in panel 1). Since the discovery of the cystic fibrosis transmembrane regulator (CFTR) gene in the late 1980’s, triggered a surge of basic research which has enhanced understanding of the pathophysiology and the genotype/phenotype relationships of this clinically variable disease. Until recently, available treatments could be used to control symptoms and limit the complications of CF, but advances in CFTR modulator therapies to address the basic defect of CF have been phenomenal and the field is evolving rapidly. Advances in clinical care have been multifaceted and include earlier diagnosis through the implementation of newborn screening programmes, formalised airway clearance therapy, and reduced malnutrition through the use of effective pancreatic enzyme replacement and a high-energy, high protein diet. Centre-based care has become the norm in high-income countries, allowing patients to benefit from the skills of expert members of multi-disciplinary teams. Pharmacological interventions to address pulmonary manifestations now include agents that target airway mucus and airway surface liquid hydration, as well as antimicrobial therapy, including antibiotic eradication treatment in early infection and protocols for maintenance therapy in chronic infection. The challenges faced by all stakeholders in building and developing CF care globally are substantial, but many opportunities exist for improved care and better health outcomes for patients. Here, we discuss changes in diagnostic approaches including advances in genetic testing, advances in newborn screening and how it is changing landscape of the CF population, The occurrence and impact of CF in non-European populations and on different continents is explored as is. We highlight the current and future opportunities as well are the challenges for clinical care in both countries with established CF care programs and what care might look like for low- and middle-income countries where care programs more fragmented and less well funded. to the availability of integrated multi-disciplinary care and new disease-modifying treatments. The recent advances in CFTR modulator therapies to address the basic defect of CF have been phenomenal and current knowledge and future directions are appraised. The cost of new therapies is currently high and there are concerns about the affordability of those medications currently available and those under development especially when considered from a global perspective. As median age of CF has increased, there has been an associated rapid rise in the adult population, we evaluate opportunities for the use of new technologies to support engagement between patients and healthcare providers in novel ways to positively impact on the burden of care and support patient choice and yet to optimise healthcare outcomes. Challenges and opportunities in these key areas are being discussed to provide a conceptional framework for future CF care throughout the world. PANEL 1 KEY MESSAGES OF THE LANCET COMMISSION FOR CYSTIC FIBROSIS: SECTION 1 THE CHANGING EPIDEMIOLOGY OF CYSTIC FIBROSIS: 1. Newborn screening testing has been implemented in many parts of the world supporting an early diagnosis of CF. 2. Improved molecular genetic diagnostics have allowed the identification of CF in non-European populations and in individuals with nonclassical presentations of CF and related disorders. 3. CFTR related disease represents a spectrum ranging from single organ manifestations to a multi-system disease. Defining the threshold of CFTR function associated with disease manifestations is a priority to guide monitoring and treatment decisions. SECTION 2 CLINICAL CARE AND ITS DELIVERY: 1. Children with CF are healthier and the vast majority are living well into adulthood. 2. Diagnostics to allow earlier diagnosis of disease manifestations, deterioration of organ function and new airway infections are key priorities. 3. Models of care need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation and yet limit the burden of care. SECTION 3 CYSTIC FIBROSIS CARE IN DEVELOPING NATIONS: 1. Information about genetic and clinical features CF in non-European populations have improved understanding of the disease in low- and middle-income countries. 2. Access to CF therapies which is sustained and affordable for people with CF living in LMIC is needed which requires partnerships between lay organisations, governments and the pharmaceutical industry. 3. Clinical registries in countries where CF is now recognised are developing and there is a need to harmonise data elements including established CF registries to support understanding of health care outcomes especially in LMIC. SECTION 4 NOVEL THERAPEUTICS: 1. CFTR modulator therapy targeting the basic molecular defect have been developed for specific CFTR mutations and is associated with improved health outcomes including better pulmonary function and nutritional status and enhanced quality of life. 2. New CFTR modulator drugs are showing promise in CFTR mutation where earlier modulators were ineffective. Early commencement of CFTR-directed therapies may prevent the establishment of irreversible airways complications and slow progression disease in older patients. 3. Drug development requires substantial investment and contributes to the current high-cost of approved CFTR modulators. This has in turn contributed to delays in funding for such therapies in many countries and current drug prices make them unaffordable for many LMICs. SECTION 5 PATIENT EXPERIENCE, ENGAGEMENT AND INVOLVEMENT: 1. Complexity of care has increased for people with CF in parallel with increased life expectancy leading to significant burden of care and disease monitoring. Novel technologies have the potential to support self-monitoring and shared decision making between patient and health care team. 2. Mental health complications are more common in people with CF (including parents of children with CF) than the general community, impacting on quality of life. Adherence to complex therapeutic regimens is often sub-optimal and impacts of clinical outcomes. 3. Patients are highly engaged in the approaches to delivery of clinical care and their perspective of the important research priorities. CF patient organisations provide important roles in patient advocacy to delivery of clinical care, treatment access, and support and education for patients with CF and their families.

Purpose To provide a review of the status of biomarkers in cystic fibrosis drug development, including regulatory definitions and considerations, a summary of biomarkers in current use with supportive data, current gaps, and future needs. Methods Biomarkers are considered across several areas of CF drug development, including cystic fibrosis transmembrane conductance regulator modulation, infection, and inflammation. Results Sweat chloride, nasal potential difference, and intestinal current measurements have been standardized and examined in the context of multicenter trials to quantify CFTR function. Detection and quantification of pathogenic bacteria in CF respiratory cultures (e.g.: Pseudomonas aeruginosa ) are commonly used in early phase antimicrobial clinical trials, and to monitor safety of therapeutic interventions. Sputum (e.g.: neutrophil elastase, myeloperoxidase, calprotectin) and blood biomarkers (e.g.: C reactive protein, calprotectin, serum amyloid A) have had variable success in detecting response to inflammatory treatments. Conclusions Biomarkers are used throughout the drug development process in CF, and many have been used in early phase clinical trials to provide proof of concept, detect drug bioactivity, and inform dosing for later-phase studies. Advances in the precision of current biomarkers, and the identification of new biomarkers with ‘omics-based technologies, are needed to accelerate CF drug development.

Background Lung transplantation is an intervention that improves survival for adult patients with cystic fibrosis (CF). Some patients with CF are never referred for lung transplant evaluation despite meeting physiologic criteria for referral. Methods We performed a retrospective analysis of adult patients (≥18years of age) in the Cystic Fibrosis Foundation Patient Registry (CFFPR), eligible for their first evaluation for lung transplantation during the years 2001–2008 based on FEV1 Results Within the CFFPR, 1240 patients met eligibility criteria. Eight hundred and nine (65.2%) were referred for lung transplant evaluation, and 431 (34.8%) were not referred. In a multivariable model, Medicaid insurance (OR 1.79, 95% CI 1.29–2.47), older age (per 5year increase; OR 1.25, 95% CI 1.13–1.39), lack of high school graduate education (OR 2.27, 95% CI 1.42–3.64), and Burkholderia cepacia complex sputum culture positivity (OR 2.48, 95% CI 1.50–4.12) were associated with non-referral, while number of pulmonary exacerbations (OR 0.93, 95% CI 0.87–0.99) and supplemental oxygen use (OR 0.59, 95% CI 0.43–0.81) were associated with increased referral. Conclusions Despite meeting lung function criteria for lung transplant evaluation, 35% of patients with CF had not yet been referred to a lung transplant center. Predictors of non-referral included markers of low socioeconomic status, older age and B. cepacia complex sputum culture. Further work is needed to understand the outcomes for non-referred patients in order to refine referral recommendations in this population.

Cystic fibrosis (CF) is a life-shortening genetic disease affecting approximately 70 000 individuals worldwide. Until recently, drug development efforts have emphasised therapies treating downstream signs and symptoms resulting from the underlying CF biological defect: reduced function of the CF transmembrane conductance regulator (CFTR) protein. The current CF drug development landscape has expanded to include therapies that enhance CFTR function by either restoring wild-type CFTR protein expression or increasing (modulating) the function of mutant CFTR proteins in cells. To date, two systemic small-molecule CFTR modulators have been evaluated in pivotal clinical trials in individuals with CF and specific mutant CFTR genotypes that have led to regulatory review and/or approval. Advances in the discovery of CFTR modulators as a promising new class of therapies have been impressive, yet work remains to develop highly effective, disease-modifying modulators for individuals of all CF genotypes. The objectives of this review are to outline the challenges and opportunities in drug development created by systemic genotype-specific CFTR modulators, highlight the advantages of sweat chloride as an established biomarker of CFTR activity to streamline early-phase development and summarise options for later phase clinical trial designs that respond to the adoption of approved genotype-specific modulators into standard of care. An optimal development framework will be needed to move the most promising therapies efficiently through the drug development pipeline and ultimately deliver efficacious and safe therapies to all individuals with CF.

Rationale Lumacaftor-ivacaftor (LUM-IVA) was approved in the US in 2015 for patients with CF aged >12 homozygous for the delF508 mutation, and patients aged 6 to 12 in 2016. Objectives To examine the rate of initial LUM-IVA prescriptions following approval. Methods We compared patients eligible for LUM-IVA in the CF Foundation Patient Registry with and without prescriptions in 2015–2016. Results 5534 (53%) eligible patients had reported prescriptions. Prescription rate in children ages 6–11 was 19% and 61% among patients ≥12 years old. Individuals ≥12 with prescriptions more likely observed among those with private insurance, clinical trial participation, ages 18–30, FEV1 Conclusions LUM-IVA uptake was less rapid than what was previously observed for ivacaftor, a CFTR modulator approved for a different population. Age, insurance status, disease severity and use of other therapies differed in those prescribed LUM-IVA in the initial post-approval period.

Background. Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the airways in individuals with cystic fibrosis. A key question is whether children with newly acquired Pa infection who are able to achieve sustained eradication after early antipseudomonal therapy demonstrate improved long-term health outcomes compared with those who are unable to achieve a sustained microbiologic response. Methods. This cohort study utilized observational follow-up data on children participating in the Early Pseudomonas Infection Control trial who received standardized therapy for newly acquired Pa. Sustained eradicators were defined as those who maintained Pa-negative cultures for 12 months after initial antipseudomonal therapy. Associations between eradication status and outcomes were assessed. Results. Of the 249 trial participants included in the study, 172 (69%) achieved sustained eradication of Pa during the trial (sustained eradicators). Over the median 5-year follow-up, sustained eradicators had a 74% reduced risk of developing chronic Pa (hazard ratio [HR], 0.26; 95% confidence interval [CI], .17–.40) and a 57% reduced risk of mucoidy (HR, 0.43; 95% CI, .25–.73) compared with nonsustained eradicators. Sustained eradicators had significantly less anti-Pa antibiotic usage during follow-up compared with nonsustained eradicators. There was no association between eradication status and clinical outcomes including rate of exacerbation and lung function decline. Conclusions. This is the first study to quantify the long-term durability of microbiological response associated with early antipseudomonal therapy, demonstrating the critical importance of optimizing antipseudomonal therapies during early Pa infection. The clinical impact of failure to achieve sustained Pa eradication remains unclear, however, and may be confounded by anti-Pa antibiotic usage. Clinical Trials Registration. NCT00097773.

BackgroundCF infants often do not grow as expected which adversely affects later clinical outcomes, thus sensitive early measures of growth deficiency are important. This study compared attained growth for age with velocity standards to determine which better predicts growth deficits at 24months of age.MethodsGrowth deficiency in infancy based on weight and length velocity, and attained growth was calculated for 1992 infants in the US CF Foundation National Registry using the World Health Organization (WHO) and US growth standards. One, two and three month increments were used for calculating velocity and pooled for each age interval. Sensitivity and specificity of early indicators to predict growth deficiency at 24months were calculated.ResultsObserved prevalence of weight deficiency (

Objective Patients with cystic fibrosis (CF) and mutations associated with residual CFTR chloride transport have improved survival rates compared with those homozygous for the F508del-CFTR mutation. Since little is known about rate of lung function decline in patients with CF and residual function (RF) mutations, we evaluated differences in rates of percent predicted FEV1 (ppFEV1) decline between patients with an RF mutation who were heterozygous for F508del and those who were homozygous for F508del, and whether rates of ppFEV1 decline differed across age groups. Methods Patients in the US CF Foundation Patient Registry from 2006 to 2014 with an RF mutation heterozygous for F508del were compared with F508del-homozygous patients. Mutations were identified based on clinical or in vitro evidence of residual ion transport. Annual rates of ppFEV1 decline were estimated for patients 6 to 45 years of age with ≥3 ppFEV1 values spanning ≥0.5 years in a randomly chosen 2 year period that began at the first ppFEV1 measurement in the calendar year. Results A total of 1242 RF and 11,916 F508del-homozygous patients were included. At the first visit, the RF cohort was older (mean [SD], 23.0 [12.1] vs 18.0 [9.6] years) and had better nutritional status (mean [SD] BMI z score, 0.36 [1.09] vs −0.29 [1.08]). Mean (SD) ppFEV1 differed at the first visit between cohorts (80.4 [24.8] vs 73.4 [26.5]; p Conclusion Patients with CF and an RF mutation have lower rates of lung function decline compared with F508del-homozygous patients. However, patients with an RF mutation still demonstrate progressive lung disease, particularly during young adulthood. Please refer to page A259 for declarations of interest in relation to abstract P255.

Individuals with cystic fibrosis (CF) experience frequent acute pulmonary exacerbations, which lead to decreased lung function and reduced quality of life.The goal of this study was to determine if an intervention directed toward early detection of pulmonary exacerbations using home spirometry and symptom monitoring would result in slower decline in lung function than in control subjects.We conducted a multicenter, randomized trial at 14 CF centers with subjects at least 14 years old. The early intervention arm subjects measured home spirometry and symptoms electronically twice per week. Sites were notified if a participant met criteria for an exacerbation and contacted participants to determine if treatment for acute exacerbation was required. Participants in the usual care arm were seen every 3 months and were asked to contact the site if they were concerned about worsening pulmonary symptoms.The primary outcome was the 52-week change in FEVAn intervention of home monitoring among patients with CF was able to detect more exacerbations than usual care, but this did not result in slower decline in lung function. Clinical trial registered with www.clinicaltrials.gov (NCT01104402).

Purpose of review Evolving cystic fibrosis 'standards of care' have influenced recent cystic fibrosis clinical trial designs for new therapies; care additions/improvements will require innovative trial designs to maximize feasibility and efficacy detection. Recent findings Three cystic fibrosis therapeutic areas (pulmonary exacerbations, Pseudomonas aeruginosa airway infections, and reduced cystic fibrosis transmembrane conductance regulator [CFTR] protein function) differ with respect to the duration for which recognized 'standards of care' have been available. However, developers of new therapies in all the three areas are affected by similar challenges: standards of care have become so strongly entrenched that traditional placebo-controlled studies in cystic fibrosis populations likely to benefit from newer therapies have become less and less feasible. Today, patients/clinicians are more likely to entertain participation in active-comparator trial designs, that have substantial challenges of their own. Foremost among these are the selection of 'valid' active comparator(s), estimation of a comparator's current clinical efficacy (required for testing noninferiority hypotheses), and effective blinding of commercially available comparators. Summary Recent and future cystic fibrosis clinical trial designs will have to creatively address this collateral result of successful past development of effective cystic fibrosis therapies: patients and clinicians are much less likely to accept simple, placebo-controlled studies to evaluate future therapies.