Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysis.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) has potential as a prognostic biomarker in asthma, but its prognostic value among other recognised indicators is unclear. We assessed the added prognostic value of baseline FeNO to blood eosinophil count and prior severe asthma exacerbations for subsequent exacerbations. METHODS: In this post-hoc analysis of the 52-week, double-blind, phase 3 LIBERTY ASTHMA QUEST study, we identified 620 patients with moderate-to-severe asthma who were randomly assigned to placebo; had uncontrolled asthma with inhaled glucocorticoids plus up to two controllers; one or more exacerbations in the previous year; FEV1 percent predicted 40-80%; FEV1 reversibility of 12% or higher and 200 mL; Asthma Control Questionnaire (ACQ-5) score of 1·5 or higher; and complete data on baseline type 2 biomarkers (FeNO, eosinophils, and total IgE) with no baseline minimum requirement. Annualised severe exacerbation rate was assessed by baseline FeNO (<25 ppb, ≥25 to <50 ppb, ≥50 ppb; negative binomial model) and cross-classified by baseline blood eosinophils (<150 cells per µL, ≥150 to <300 cells per µL, ≥300 cells per µL) and prior exacerbations (one, two or more), all adjusted for baseline ACQ-5, postbronchodilator FEV1, and other clinical characteristics. Post-hoc analyses were done in the intention-to-treat population. The LIBERTY ASTHMA QUEST STUDY is registered on ClinicalTrials.gov, NCT02414854, and is complete. FINDINGS: Patients with baseline FeNO of 50 ppb or higher (n=144) had a 1·54-times higher exacerbation rate than patients with FeNO of less than 25 ppb (n=291; relative risk 1·54 [95% CI 1·11-2·14]; p=0·0097). Patients with baseline FeNO of 25 to <50 ppb (n=185) had a 1·33-times higher exacerbation rate than patients with FeNO of less than 25 ppb (1·33 [0·99-1·78]; p=0·0572). Patients with baseline FeNO of 25 ppb or higher, a blood eosinophil count of 150 cells per µL or higher, and two or more prior exacerbations (n=157) had an exacerbation rate 3·62-times higher than patients with FeNO of less than 25 ppb, a blood eosinophil count of less than 150 cells per µL, and one prior exacerbation (n=116; 3·62 [1·67-7·81]; p=0·0011). INTERPRETATION: In uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations. FUNDING: Sanofi and Regeneron Pharmaceuticals.

Dupilumab Efficacy in Patients with Uncontrolled, Moderate-to-Severe Allergic Asthma.

BACKGROUND: Dupilumab blocks the shared receptor component for IL-4 and IL-13, key drivers of type 2 inflammation, including IgE-mediated allergic inflammation in asthma. In the LIBERTY ASTHMA QUEST (NCT02414854) study, dupilumab reduced severe asthma exacerbations and improved forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers (blood eosinophils and fractional exhaled nitric oxide) at baseline. OBJECTIVE: We assessed dupilumab's effect on key asthma outcomes in QUEST patients with/without evidence of allergic asthma (total serum IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35 kU/L at baseline). METHODS: Severe exacerbation rates and change from baseline in FEV1, asthma control, and markers of type 2 inflammation during the 52-week treatment period were assessed. RESULTS: In the allergic asthma subgroup (n = 1083), dupilumab 200/300 mg every 2 weeks versus placebo reduced severe asthma exacerbation rates (-36.9%/-45.5%; both P < .01), improved FEV1 at week 12 (0.13 L/0.16 L; both P < .001; improvements were evident by the first evaluation at week 2) with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers at baseline, and improved asthma control. Dupilumab treatment also resulted in rapid and sustained reductions in type 2 inflammatory biomarkers. Comparable results were observed in patients without evidence of allergic asthma (n = 819). CONCLUSION: Dupilumab reduced severe exacerbation rates, improved FEV1 and asthma control, and suppressed type 2 inflammatory biomarkers in patients with uncontrolled, moderate-to-severe asthma with or without evidence of allergic asthma, highlighting the key role of IL-4 and IL-13 in airway inflammation.

Risk factors for disease progression in idiopathic pulmonary fibrosis.

In this retrospective study of a randomised trial of simtuzumab in idiopathic pulmonary fibrosis (IPF), prodromal decline in forced vital capacity (FVC) was significantly associated with increased risk of mortality, respiratory and all-cause hospitalisations, and categorical disease progression. Predictive modelling of progression-free survival event risk was used to assess the effect of population enrichment for patients at risk of rapid progression of IPF; C-index values were 0.64 (death), 0.69 (disease progression), and 0.72 (adjudicated respiratory hospitalisation) and 0.76 (all-cause hospitalisation). Predictive modelling may be a useful tool for improving efficiency of clinical trials with categorical end points.

Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis.

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.

Quantitative high-resolution computed tomography fibrosis score: performance characteristics in idiopathic pulmonary fibrosis.

We evaluated performance characteristics and estimated the minimal clinically important difference (MCID) of data-driven texture analysis (DTA), a high-resolution computed tomography (HRCT)-derived measurement of lung fibrosis, in subjects with idiopathic pulmonary fibrosis (IPF).The study population included 141 subjects with IPF from two interventional clinical trials who had both baseline and nominal 54- or 60-week follow-up HRCT. DTA scores were computed and compared with forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide, distance covered during a 6-min walk test and St George's Respiratory Questionnaire scores to assess the method's reliability, validity and responsiveness. Anchor- and distribution-based methods were used to estimate its MCID.DTA had acceptable reliability in subjects appearing stable according to anchor variables at follow-up. Correlations between the DTA score and other clinical measurements at baseline were moderate to weak and in the hypothesised directions. Acceptable responsiveness was demonstrated by moderate to weak correlations (in the directions hypothesised) between changes in the DTA score and changes in other parameters. Using FVC as an anchor, MCID was estimated to be 3.4%.Quantification of lung fibrosis extent on HRCT using DTA is reliable, valid and responsive, and an increase of ∼3.4% represents a clinically important change.

Using hyperpolarized 129Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis.

BACKGROUND: Assessing functional impairment, therapeutic response and disease progression in patients with idiopathic pulmonary fibrosis (IPF) continues to be challenging. Hyperpolarized 129Xe MRI can address this gap through its unique capability to image gas transfer three-dimensionally from airspaces to interstitial barrier tissues to red blood cells (RBCs). This must be validated by testing the degree to which it correlates with pulmonary function tests (PFTs) and CT scores, and its spatial distribution reflects known physiology and patterns of disease. METHODS: 13 healthy individuals (33.6±15.7 years) and 12 patients with IPF (66.0±6.4 years) underwent 129Xe MRI to generate three-dimensional quantitative maps depicting the 129Xe ventilation distribution, its uptake in interstitial barrier tissues and its transfer to RBCs. For each map, mean values were correlated with PFTs and CT fibrosis scores, and their patterns were tested for the ability to depict functional gravitational gradients in healthy lung and to detect the known basal and peripheral predominance of disease in IPF. RESULTS: 129Xe MRI depicted functional impairment in patients with IPF, whose mean barrier uptake increased by 188% compared with the healthy reference population. 129Xe MRI metrics correlated poorly and insignificantly with CT fibrosis scores but strongly with PFTs. Barrier uptake and RBC transfer both correlated significantly with diffusing capacity of the lungs for carbon monoxide (r=-0.75, p<0.01 and r=0.72, p<0.01), while their ratio (RBC/barrier) correlated most strongly (r=0.94, p<0.01). RBC transfer exhibited significant anterior-posterior gravitational gradients in healthy volunteers, but not in IPF, where it was significantly impaired in the basal (p=0.02) and subpleural (p<0.01) lung. CONCLUSIONS: Hyperpolarized129Xe MRI is a rapid and well-tolerated exam that provides region-specific quantification of interstitial barrier thickness and RBC transfer efficiency. With further development, it could become a robust tool for measuring disease progression and therapeutic response in patients with IPF, sensitively and non-invasively.

Quantitative analysis of hyperpolarized 129 Xe gas transfer MRI.

PURPOSE: Hyperpolarized 129 Xe magnetic resonance imaging (MRI) using Dixon-based decomposition enables single-breath imaging of 129 Xe in the airspaces, interstitial barrier tissues, and red blood cells (RBCs). However, methods to quantitatively visualize information from these images of pulmonary gas transfer are lacking. Here, we introduce a novel method to transform these data into quantitative maps of pulmonary ventilation, and 129 Xe gas transfer to barrier and RBC compartments. METHODS: A total of 13 healthy subjects and 12 idiopathic pulmonary fibrosis (IPF) subjects underwent thoracic 1 H MRI and hyperpolarized 129 Xe MRI with one-point Dixon decomposition to obtain images of 129 Xe in airspaces, barrier and red blood cells (RBCs). 129 Xe images were processed into quantitative binning maps of all three compartments using thresholds based on the mean and standard deviations of distributions derived from the healthy reference cohort. Binning maps were analyzed to derive quantitative measures of ventilation, barrier uptake, and RBC transfer. This method was also used to illustrate different ventilation and gas transfer patterns in a patient with emphysema and one with pulmonary arterial hypertension (PAH). RESULTS: In the healthy reference cohort, the mean normalized signals were 0.51 ± 0.19 for ventilation, 4.9 ± 1.5 x 10-3 for barrier uptake and 2.6 ± 1.0 × 10-3 for RBC (transfer). In IPF patients, ventilation was similarly homogenous to healthy subjects, although shifted toward slightly lower values (0.43 ± 0.19). However, mean barrier uptake in IPF patients was nearly 2× higher than in healthy subjects, with 47% of voxels classified as high, compared to 3% in healthy controls. Moreover, in IPF, RBC transfer was reduced, mainly in the basal lung with 41% of voxels classified as low. In healthy volunteers, only 15% of RBC transfer was classified as low and these voxels were typically in the anterior, gravitationally nondependent lung. CONCLUSIONS: This study demonstrates a straightforward means to generate semiquantitative binning maps depicting 129 Xe ventilation and gas transfer to barrier and RBC compartments. These initial results suggest that the method could be valuable for characterizing both normal physiology and pathophysiology associated with a wide range of pulmonary disorders.

An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology. OBJECTIVES: The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis. METHODS: We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis. MEASUREMENTS AND MAIN RESULTS: We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study-wide significant (P < 4.5 × 10-7) case enrichment of qualifying variants in TERT, RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of-function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 × 10-22). CONCLUSIONS: We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.

Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial.

BACKGROUND: Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the efficacy and safety of simtuzumab, a monoclonal antibody against LOXL2, in patients with IPF. METHODS: In this randomised, double-blind, phase 2 trial, we recruited patients aged 45-85 years with definite IPF diagnosed prior to 3 years of screening from 183 hospitals and respiratory clinics in 14 countries. Eligible patients, stratified by baseline forced vital capacity (FVC), serum LOXL2 (sLOXL2) concentrations, and pirfenidone and nintedanib use, were randomly assigned (1:1) to inject 125 mg/mL simtuzumab or placebo subcutaneously once a week. The primary endpoints were progression-free survival, defined as time to all-cause death or a categorical decrease from baseline in FVC % predicted, in the intention-to-treat population, in patients with sLOXL2 concentrations in the 50th percentile or higher, and in patients with sLOXL2 concentrations in the 75th percentile or higher. Treatment duration was event-driven, and interim analyses were planned and conducted after approximately 120 and 200 progression-free survival events, respectively, occurred. We compared treatment groups with the stratified log-rank test. This study is registered with ClinicalTrials.gov, number NCT01769196. FINDINGS: Patients with IPF were recruited between Jan 31, 2013, and June 1, 2015. The intention-to-treat population included 544 randomly assigned patients (272 patients in both groups), and the safety population included 543 randomly assigned patients who received at least one dose of study medication. The study was terminated when the second interim analysis met the prespecified futility stopping criteria in the intention-to-treat population. We noted no difference in progression-free survival between simtuzumab and placebo in the intention-to-treat population (median progression free survival times of 12·6 months and 15·4 months for simtuzumab and placebo, respectively; stratified HR 1·13, 95% CI 0·88-1·45; p=0·329) and in patients with baseline sLOXL2 in the 50th percentile or higher (median progression-free survival 11·7 months and 14·3 months for simtuzumab and placebo, respectively; stratified HR 1·03, 95% CI 0·74-1·43; p=0·851), or in the 75th percentile or higher (median progression-free survival 11·6 months and 16·9 months for simtuzumab and placebo, respectively; stratified HR 1·20, 95% CI 0·72-2·00; p=0·475). The incidence of adverse events and serious adverse events was similar between treatment groups. The most common adverse events in both the simtuzumab and placebo groups were dyspnoea, cough, upper respiratory tract infection, and worsening of IPF; and the most common grade 3 or 4 adverse events were worsening of IPF, dyspnoea, and pneumonia. INTERPRETATION: Simtuzumab did not improve progression-free survival in a well-defined population of patients with IPF. Our data do not support the use of simtuzumab for patients with IPF. FUNDING: Gilead Sciences Inc.

Rational Drug Development for Mucous Dehydration and Mucous Metaplasia.

Airway diseases that are clinically characterized by mucous hypersecretion are associated with dehydrated secretions and impaired mucociliary clearance. The failure to clear pro-inflammatory proteases can further exacerbate the mucous dehydration, giving rise to a positive feedback loop that produces a mucous metaplasia and lung remodeling. Increased understanding of the complex mechanisms that regulate airway hydration in health and disease is a prerequisite for rational design of novel therapies. Clinical trials of aerosolized osmolytes and of modulators of epithelial ion channels have provided support for the hypothesis that correcting mucus hydration improves clinical benefit, with the caveat that many of these agents have direct mucolytic properties that are likely to be synergistic with enhanced hydration.

Thiazolidinediones are associated with a reduced risk of COPD exacerbations.

BACKGROUND: Thiazolidinediones (TZDs) are oral antihyperglycemic medications that are selective agonists to peroxisome proliferator-activated receptor gamma and have been shown to have potent anti-inflammatory effects in the lung. OBJECTIVE: The purpose of this study was to assess whether exposure to TZDs is associated with a decreased risk of chronic obstructive pulmonary disease (COPD) exacerbation. METHODS: A cohort study was performed by collecting data on all US veterans with diabetes and COPD who were prescribed oral antihyperglycemic medications during from period of October 1, 2005 to September 30, 2007. Patients who had two or more prescriptions for TZDs were compared with patients who had two or more prescriptions for an alternative oral anti-hyperglycemic medication. Multivariable negative binomial regression was performed with adjustment for potential confounding factors. The primary outcome was COPD exacerbations, including both inpatient and outpatient exacerbations. RESULTS: We identified 7,887 veterans who were exposed to TZD and 42,347 veterans who were exposed to non-TZD oral diabetes medications. COPD exacerbations occurred in 1,258 (16%) of the TZD group and 7,789 (18%) of the non-TZD group. In multivariable negative binomial regression, there was a significant reduction in the expected number of COPD exacerbations among patients who were exposed to TZDs with an incidence rate ratio of 0.86 (95% CI 0.81-0.92). CONCLUSION: Exposure to TZDs was associated with a small but significant reduction in risk for COPD exacerbation among diabetic patients with COPD.

Pulmonary hypertension in idiopathic pulmonary fibrosis with mild-to-moderate restriction.

The clinical course of pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) is not known except in advanced disease.488 subjects in a placebo-controlled study of ambrisentan in IPF with mild-moderate restriction in lung volume, underwent right heart catheterisation (RHC) at baseline and 117 subjects (24%) had repeated haemodynamic measurements at 48 weeks. The subjects were categorised into a) World Health Organization (WHO) Group 3 PH (PH associated with pulmonary disease), n=68 (14%); b) WHO Group 2 PH (PH associated with left-sided cardiac disease), n=25 (5%); c) no PH but elevated pulmonary artery wedge pressure (PAWP), n=21 (4%); and d) no PH but without elevation of PAWP, n=374 (77%). The WHO Group 3 PH subjects had a lower diffusion capacity, 6MWD and oxygen saturation compared to the subjects with no PH. There was no significant change in mean pulmonary arterial pressure with ambrisenten or placebo after 12 months. Subjects with IPF associated with WHO Group 3 PH had impaired gas exchange and exercise capacity compared to patients without PH. An additional 9% of the subjects had haemodynamic evidence of subclinical left-ventricular dysfunction. Pulmonary artery pressures remained stable over 1 year in the majority of the cohort.

Development of novel agents for idiopathic pulmonary fibrosis: progress in target selection and clinical trial design.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease. Until recently, the standard therapy for this disease has been essentially supportive, with the exception of a minority of patients who were eligible for lung transplantation. The development pathway for novel medications for IPF has been complicated. There have been several challenges, including an incomplete understanding of the pathogenesis, unpredictable clinical course, lack of validated biomarkers, the low clinical predictive value of animal models of lung injury, and the need to commit to large clinical trials of long duration to obtain initial evidence of clinical efficacy. Despite these challenges, the combination of recent advances in translational medicine and the unprecedented increase in clinical data accumulated from recent large clinical trials has stimulated an increase in the number of clinical development programs for IPF. Clinical programs are increasingly characterized by rational target selection, preclinical optimization of therapeutic molecules, and an emphasis on efficient clinical trial design. A lower rate of functional decline in patients treated with pirfenidone and nintedanib was demonstrated in large clinical trials. In October 2014, these two drugs became the first agents to be approved by the US Food and Drug Administration for the treatment of IPF. (Pirfenidone had already been approved in several countries outside the United States.) In November 2014, the European Medicines Agency approved the use of nintedanib for IPF. The landscape for management of IPF has markedly changed with the advent of approved therapeutic options for IPF. In this article, we review the strategies that are being used to increase the likelihood of success in clinical development programs of novel disease-modifying agents in IPF.

Quality of Life Questionnaire-Bronchiectasis: final psychometric analyses and determination of minimal important difference scores.

BACKGROUND: The Quality of Life-Bronchiectasis (QOL-B), a self-administered, patient-reported outcome measure assessing symptoms, functioning and health-related quality of life for patients with non-cystic fibrosis (CF) bronchiectasis, contains 37 items on 8 scales (Respiratory Symptoms, Physical, Role, Emotional and Social Functioning, Vitality, Health Perceptions and Treatment Burden). METHODS: Psychometric analyses of QOL-B V.3.0 used data from two double-blind, multicentre, randomised, placebo-controlled, phase III trials of aztreonam for inhalation solution (AZLI) in 542 patients with non-CF bronchiectasis and Gram-negative endobronchial infection. RESULTS: Excellent internal consistency (Cronbach's α ≥0.70) and 2-week test-retest reliability (intraclass correlation coefficients ≥0.72) were demonstrated for each scale. Convergent validity with 6 min walk test was observed for Physical and Role Functioning scores. No floor or ceiling effects (baseline scores of 0 or 100) were found for the Respiratory Symptoms scale (primary endpoint of trials). Baseline Respiratory Symptoms scores discriminated between patients based on baseline FEV1% predicted in only one trial. The minimal important difference score for the Respiratory Symptoms scale was 8.0 points. AZLI did not show efficacy in the two phase III trials. QOL-B responsivity to treatment was assessed by examining changes from baseline QOL-B scores at study visits at which protocol-defined pulmonary exacerbations were reported. Mean Respiratory Symptoms scores decreased 14.0 and 14.2 points from baseline for placebo-treated and AZLI-treated patients with exacerbations, indicating that worsening respiratory symptoms were reflected in clinically meaningful changes in QOL-B scores. CONCLUSIONS: Previously established content validity, reliability and responsivity of the QOL-B are confirmed by this final validation study. The QOL-B is available for use in clinical trials and routine clinical practice.

Oral GS-5806 activity in a respiratory syncytial virus challenge study.

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of infant hospitalizations and is increasingly recognized as a cause of considerable morbidity and mortality. No accepted antiviral treatment exists. METHODS: We conducted a double-blind, placebo-controlled study of GS-5806, an oral RSV-entry inhibitor, in healthy adults who received a clinical challenge strain of RSV intranasally. Participants were monitored for 12 days. At the time of a positive test for RSV infection or 5 days after inoculation, whichever occurred first, participants were randomly assigned to receive GS-5806 or placebo in one of seven sequential cohorts. Cohorts 1 to 4 received a first dose of 50 mg of GS-5806 and then 25 mg daily for the next 4 days, cohort 5 received a first dose of 50 mg and then 25 mg daily for the next 2 days, cohort 6 received one 100-mg dose, and cohort 7 received a first dose of 10 mg and then 5 mg daily for the next 4 days. Dose selection for cohorts 5, 6, and 7 occurred after an interim analysis of data for cohorts 1 to 4. The primary end point was the area under the curve (AUC) for the viral load, which was assessed after administration of the first dose through the 12th day after inoculation. Secondary end points were mucus weight and symptom scores. RESULTS: Among the 54 participants in cohorts 1 to 4 who were infected with RSV, active treatment was associated with a lower viral load (adjusted mean, 250.7 vs. 757.7 log10 plaque-forming-unit equivalents [PFUe] × hours per milliliter; P<0.001), lower total mucus weight (mean, 6.9 g vs. 15.1 g; P=0.03), and a lower AUC for the change from baseline in symptom scores (adjusted mean, -20.2 vs. 204.9 × hours; P=0.005). The results were similar in cohorts 5, 6, and 7. Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving GS-5806. CONCLUSIONS: Treatment with GS-5806 reduced the viral load and the severity of clinical disease in a challenge study of healthy adults. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01756482.).

Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials.

BACKGROUND: The clinical benefit of inhaled antibiotics in non-cystic fibrosis bronchiectasis has not been established in randomised controlled trials. We aimed to assess safety and efficacy of aztreonam for inhalation solution (AZLI) in patients with non-cystic fibrosis bronchiectasis and Gram-negative bacterial colonisation. METHODS: AIR-BX1 and AIR-BX2 were two double-blind, multicentre, randomised, placebo-controlled phase 3 trials, which included patients aged 18 years or older who had bronchiectasis and history of positive sputum or bronchoscopic culture for target Gram-negative organisms. Patients were randomly assigned to receive either AZLI or placebo (1:1). Randomisation was done without stratification and the code was generated by a Gilead designee. In both studies, two 4-week courses of AZLI 75 mg or placebo (three-times daily; eFlow nebulizer) were each followed by a 4-week off-treatment period. Primary endpoint was change from baseline Quality of Life-Bronchiectasis Respiratory Symptoms scores (QOL-B-RSS) at 4 weeks. These trials are registered with ClinicalTrials.gov, numbers are NCT01313624 for AIR-BX1 and NCT01314716 for AIR-BX2. FINDINGS: We recruited participants from 47 ambulatory clinics for AIR-BX1 and 65 ambulatory clinics for AIR-BX2; studies were done between April 25, 2011, and July 1, 2013. In AIR-BX1, of the 348 patients screened, 134 were randomly assigned to receive AZLI and 132 to receive placebo. In AIR-BX2, of the 404 patients screened, 136 were randomly assigned to receive AZLI and 138 to receive placebo. The difference between AZLI and placebo for adjusted mean change from baseline QOL-B-RSS was not significant at 4 weeks (0.8 [95% CI -3.1 to 4.7], p=0.68) in AIR-BX1, but was significant (4.6 [1.1 to 8.2], p=0.011) in AIR-BX2. The 4.6 point difference in QOL-B-RSS after 4 weeks in AIR-BX2 was not deemed clinically significant. In both studies, treatment-related adverse events were more common in the AZLI group than in the placebo group, as were discontinuations from adverse events. The most commonly reported treatment-emergent adverse events were dyspnea, cough, and increased sputum. Each was more common for AZLI-treated than for placebo-treated patients, but the incidences were more balanced in AIR-BX2. INTERPRETATION: AZLI treatment did not provide significant clinical benefit in non-cystic fibrosis bronchiectasis, as measured by QOL-B-RSS, suggesting a continued need for placebo-controlled studies to establish the clinical benefit of inhaled antibiotics in patients with this disorder. FUNDING: Gilead Sciences.

Thiazolidinediones and the risk of asthma exacerbation among patients with diabetes: a cohort study.

BACKGROUND: Thiazolidinediones are oral diabetes medications that selectively activate peroxisome proliferator-activated receptor gamma and have potent anti-inflammatory properties. While a few studies have found improvements in pulmonary function with exposure to thiazolidinediones, there are no studies of their impact on asthma exacerbations. Our objective was to assess whether exposure to thiazolidinediones was associated with a decreased risk of asthma exacerbation. METHODS: We performed a cohort study of diabetic Veterans who had a diagnosis of asthma and were taking oral diabetes medications during the period of 10/1/2005 - 9/30/2006. The risk of asthma exacerbations and oral steroid use during 10/1/2006 - 9/30/2007 was compared between patients who were prescribed thiazolidinediones and patients who were on alternative oral diabetes medications. Multivariable logistic regression and negative binomial regression analyses were used to characterize this risk. A sensitivity analysis was performed, restricting our evaluation to patients who were adherent to diabetes therapy. RESULTS: We identified 2,178 patients who were on thiazolidinediones and 10,700 who were not. Exposure to thiazolidinediones was associated with significant reductions in the risk of asthma exacerbation (OR = 0.79, 95% CI, 0.62 - 0.99) and oral steroid prescription (OR = 0.73, 95% CI 0.63 - 0.84). Among patients who were adherent to diabetes medications, there were more substantial reductions in the risks for asthma exacerbation (OR = 0.64, 95% CI 0.47 - 0.85) and oral steroid prescription (OR = 0.68, 95% CI 0.57 - 0.81). CONCLUSIONS: Thiazolidinediones may provide a novel anti-inflammatory approach to asthma management by preventing exacerbations and decreasing the use of oral steroids.