Heterogeneity of CFTR modulator-induced sweat chloride concentrations in people with cystic fibrosis.

BACKGROUND: Sweat chloride (SC) concentrations in people with cystic fibrosis (PwCF) reflect relative CF transmembrane conductance regulator (CFTR) protein function, the primary CF defect. Populations with greater SC concentrations tend to have lesser CFTR function and more severe disease courses. CFTR modulator treatment can improve CFTR function within specific CF genotypes and is commonly associated with reduced SC concentration. However, SC concentrations do not necessarily fall to concentrations seen in the unaffected population, suggesting potential for better CFTR treatment outcomes. We characterized post-modulator SC concentration variability among CHEC-SC study participants by genotype and modulator. METHODS: PwCF receiving commercially approved modulators for ≥90 days were enrolled for a single SC measurement. Clinical data were obtained from chart review and the CF Foundation Patient Registry (CFFPR). Variability of post-modulator SC concentrations was assessed by cumulative SC concentration frequencies. RESULTS: Post-modulator SC concentrations (n = 3787) were collected from 3131 PwCF; most (n = 1769, 47 %) were collected after elexacaftor/tezacaftor/ivacaftor (ETI) treatment. Modulator use was associated with lower SC distributions, with post-ETI concentrations the lowest on average. Most post-ETI SC concentrations were <60 mmol/L (79 %); 26 % were <30 mmol/L. Post-ETI distributions varied by genotype. All genotypes containing at least one F508del allele had individuals with post-ETI SC ≥60 mmol/L, with the largest proportion being F508del/minimal function (31 %). CONCLUSIONS: Post-modulator SC concentration heterogeneity was observed among all genotypes and modulators, including ETI. The presence of PwCF with post-modulator SC concentrations within the CF diagnostic range suggests room for additional treatment-associated CFTR restoration in this population.

Willingness of people with cystic fibrosis receiving elexacaftor/tezacaftor/ivacaftor (ETI) to participate in randomized modulator and inhaled antimicrobial clinical trials.

OBJECTIVE: To assess the feasibility of enrolling people with CF (pwCF) taking the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI) in clinical trials of a new modulator. METHODS: PwCF receiving ETI at CHEC-SC study (NCT03350828) enrollment were surveyed for interest in 2-week to 6-month placebo- (PC) and active-comparator (AC) modulator studies. Those taking inhaled antimicrobials (inhABX) were surveyed for interest in PC inhABX studies. RESULTS: Of 1791 respondents, 75% [95% CI 73, 77] would enroll in a 2-week PC modulator study versus 51% [49, 54] for a 6-month study; 82% [81, 84] and 63% [61, 65] would enroll in 2-week and 6 month AC studies; 77% [74, 80] of 551 taking inhABX would enroll in a 2-week PC inhABX study versus 59% [55, 63] for a 6-month study. Previous clinical trial experience increased willingness. CONCLUSIONS: Study designs will affect feasibility of future clinical trials of new modulators and inhABX in people receiving ETI.

Characterizing CFTR modulated sweat chloride response across the cf population: Initial results from the CHEC-SC study.

BACKGROUND: CHEC-SC is an ongoing epidemiologic study characterizing modulator-induced sweat chloride (SC) responses across the CF population, with interim results available prior to the availability of triple combination modulator therapy. METHODS: Eligible participants had been prescribed a modulator for ≥90 days with re-enrollment allowed upon establishment of a new modulator. Pre-modulator SC values were obtained from chart review; post-modulator sweat was collected and analyzed locally. SC changes were descriptively summarized with biologic sex effects adjusted for age, weight, and CFTR genotype. Heterogeneity in ivacaftor SC response was characterized in relation to published CFTR functional responses. RESULTS: 1848 participants provided 2004 SC measurements, 26.2% on ivacaftor, 39.1% on lumacaftor/ivacaftor, and 34.7% on tezacaftor/ivacaftor. Average SC changes for all modulators were consistent with those reported in previous clinical studies, with greater variation in SC response observed among rarer mutations and notable shifts in the proportion with SC <60mmol/L independent of the magnitude of SC change. Ivacaftor induced in vitro CFTR functional change was significantly correlated with ivacaftor-modulated SC response (Pearson correlation= ‒0.52, 95% CI: ‒0.773, ‒0.129). Average SC change from ivacaftor to tezacaftor/ivacaftor was ‒4.9 mmol/L (n=17,95% CI:‒9.3, ‒0.5) and differed from those switching from lumacaftor/ivacaftor (10.0 mmol/L, n=139, 95% CI:7.8,12.3). Sex at birth was not associated with SC response. CONCLUSIONS: CHEC-SC is the largest study characterizing modulator-induced SC changes across the CF population. There was a strong association between ivacaftor induced in vitro CFTR function and SC response across a genotypically heterogenous cohort. Biological sex was not associated with SC response.

Accelerated Approval or Risk Reduction? How Response Biomarkers Advance Therapeutics through Clinical Trials in Cystic Fibrosis.

Progress in the development of new therapies for cystic fibrosis (CF) has benefited from therapeutically responsive biomarkers to streamline drug development. Paradoxically, these response biomarkers have been proven to be essential even in the presence of data demonstrating a lack of correlation with clinical outcomes across individuals with CF. This finding is unsurprising, particularly in the setting of a rare disease given complex disease processes and an often-limited pool of clinically effective therapies by which to link biomarkers and clinical responsiveness. While many response biomarkers will be unable to progress from their status as markers of biological efficacy to either established correlates of clinical efficacy or surrogate endpoints, they remain critical to the overall success of therapeutic development.

Building global development strategies for cf therapeutics during a transitional cftr modulator era.

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.

KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa.

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 ppFEV1 from placebo favoring KB001-A was observed at week 16 (95% CI: 1.12, 5.30, p=0.003). Mean changes from baseline in log10 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 FEV1 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.

Risk of hemoptysis in cystic fibrosis clinical trials: A retrospective cohort study.

BACKGROUND: Cystic fibrosis (CF) is characterized by airway infection and inflammation resulting in respiratory complications including hemoptysis. The objectives of this study were to characterize the risk of hemoptysis attributable to underlying disease and in the presence of standard of care therapy. METHODS: This retrospective cohort study estimated hemoptysis rates overall and by relevant risk factors utilizing adverse event data from longitudinal prospective CF clinical trials. RESULTS: Of the 1008 participants, 73% were ≤18 years old; of 929 with available spirometry, 27% had an FEV1<70% predicted. During the average 8.2 months of follow-up, 8% experienced ≥1 hemoptysis events (95% CI: 6%, 10%). Of the 125 events, 76% were mild in severity and only 9% were serious. Hemoptysis rates were greater among adults than children, those with FEV1<70% predicted, and participants infected with P. aeruginosa but not with S. aureus. CONCLUSIONS: Hemoptysis is a common adverse event among CF clinical trial participants, and particularly in adults with more severe lung disease. These results can be used to predict event occurrence in future clinical trials.

Rationale and design of a randomized trial of home electronic symptom and lung function monitoring to detect cystic fibrosis pulmonary exacerbations: the early intervention in cystic fibrosis exacerbation (eICE) trial.

BACKGROUND: Acute pulmonary exacerbations are central events in the lives of individuals with cystic fibrosis (CF). Pulmonary exacerbations lead to impaired lung function, worse quality of life, and shorter survival. We hypothesized that aggressive early treatment of acute pulmonary exacerbation may improve clinical outcomes. PURPOSE: Describe the rationale of an ongoing trial designed to determine the efficacy of home monitoring of both lung function measurements and symptoms for early detection and subsequent early treatment of acute CF pulmonary exacerbations. STUDY DESIGN: A randomized, non-blinded, multi-center trial in 320 individuals with CF aged 14 years and older. The study compares usual care to a twice a week assessment of home spirometry and CF respiratory symptoms using an electronic device with data transmission to the research personnel to identify and trigger early treatment of CF pulmonary exacerbation. Participants will be enrolled in the study for 12 months. The primary endpoint is change in FEV1 (L) from baseline to 12 months determined by a linear mixed effects model incorporating all quarterly FEV1 measurements. Secondary endpoints include time to first acute protocol-defined pulmonary exacerbation, number of acute pulmonary exacerbations, number of hospitalization days for acute pulmonary exacerbation, time from the end of acute pulmonary exacerbation to onset of subsequent pulmonary exacerbation, change in health related quality of life, change in treatment burden, change in CF respiratory symptoms, and adherence to the study protocol. CONCLUSIONS: This study is a first step in establishing alternative approaches to the care of CF pulmonary exacerbations. We hypothesize that early treatment of pulmonary exacerbations has the potential to slow lung function decline, reduce respiratory symptoms and improve the quality of life for individuals with CF.

Association between Stenotrophomonas maltophilia and lung function in cystic fibrosis.

BACKGROUND: Stenotrophomonas maltophilia (SM) is a Gram-negative non-fermenting bacteria cultured from the sputum of patients with cystic fibrosis (CF). To date, no information is available regarding the effect of this organism on lung function in CF. METHODS: A cohort study was conducted to assess the effect of SM on lung function among CF patients aged > or =6 years in the CF Foundation National Patient Registry from 1994 to 1999. Repeated measures regression was used to assess the association between SM and lung function. RESULTS: The cohort consisted of 20 755 patients with median age at entry of 13.8 years and median follow up time of 3.8 years; 2739 patients (13%) were positive at least once for SM and 18 016 (87%) were never positive. After adjusting for sex, height and age, patients with SM had a mean forced expiratory volume in 1 second which was 0.09 l less (95% CI 0.05 to 0.14) than those without SM. The mean rate of decline associated with SM positivity was 0.025 l/year (95% CI 0.012 to 0.037) but, after adjusting for confounders (sex, height, weight, intravenous antibiotic courses, hospital admissions, pancreatic insufficiency, and Pseudomonas aeruginosa and Burkholderia cepacia status), the mean rate of decline decreased to 0.008 l/year (-0.008, 95% CI -0.019 to 0.003). CONCLUSIONS: Although CF patients with SM have worse lung function at the time of positivity, no association was found between SM and increased rate of decline after controlling for confounders.

The cystic fibrosis therapeutics development network (CF TDN): a paradigm of a clinical trials network for genetic and orphan diseases.

Clinical trials have become critical to the advancement of medical science and to the evolution of patient care in medicine. The science of clinical research has advanced from early studies in which treatment was assessed without controls to sophisticated multinational collaborative randomized, double-blind, placebo controlled trials of therapeutic interventions. To facilitate the advancement of clinical research, clinical trials networks have been developed to conduct multicenter studies. This review describes the history of clinical trials, clinical trials networks, and the goals of such networks in the United States. The Cystic Fibrosis Therapeutics Development Network, a network that represents the paradigm for genetic and orphan diseases, is described in detail. This network has been extremely successful in its first 3.5 years of existence conducting 18 different clinical trials in patients with Cystic Fibrosis. Unique aspects of the network include the use of internet applications for study conduct and communication, the development of statistical methodology to enhance the efficiency of clinical trial design, the development of outcome measures specific to Cystic Fibrosis, and the development of infrastructure necessary for expediting protocol development. In the current environment, clinical research faces significant challenges related to ensuring the safe and ethical conduct of clinical research while promoting fast and efficient clinical trials. To succeed and move forward to provide treatments and find cures for diseases, clinical trials networks must continue to evolve. The Cystic Fibrosis Therapeutics Development Network represents a network that has met this challenge and will continue to provide a venue for the safe and efficient conduct of clinical trials in Cystic Fibrosis.

A regression modeling approach for describing patterns of HIV genetic variation.

We introduce a novel approach for describing patterns of HIV genetic variation using regression modeling techniques. Parameters are defined for describing genetic variation within and between viral populations by generalizing Simpson's index of diversity. Regression models are specified for these variation parameters and the generalized estimating equation framework is used for estimating both the regression parameters and their corresponding variances. Conditions are described under which the usual asymptotic approximations to the distribution of the estimators are met. This approach provides a formal statistical framework for testing hypotheses regarding the changing patterns of HIV genetic variation over time within an infected patient. The application of these methods for testing biologically relevant hypotheses concerning HIV genetic variation is demonstrated in an example using sequence data from a subset of patients from the Multicenter AIDS Cohort Study.