Novel outcome measures for clinical trials in cystic fibrosis.

Cystic fibrosis (CF) is a common inherited condition caused by mutations in the gene encoding the CF transmembrane regulator protein. With increased understanding of the molecular mechanisms underlying CF and the development of new therapies there comes the need to develop new outcome measures to assess the disease, its progression and response to treatment. As there are limitations to the current endpoints accepted for regulatory purposes, a workshop to discuss novel endpoints for clinical trials in CF was held in Anaheim, California in November 2011. The pros and cons of novel outcome measures with potential utility for evaluation of novel treatments in CF were critically evaluated. The highlights of the 2011 workshop and subsequent advances in technologies and techniques that could be used to inform the development of clinical trial endpoints are summarized in this review. Pediatr Pulmonol. © 2014 The Authors. Pediatric Pulmonology published by Wiley Periodicals, Inc.

Reduced sodium transport with nasal administration of the prostasin inhibitor camostat in subjects with cystic fibrosis.

BACKGROUND: Prostasin, a trypsin-like serine protease, is a channel-activating protease and major regulator of epithelial sodium channel-mediated sodium absorption. Its direct inhibition by camostat represents a potential approach to inhibiting sodium transport in cystic fibrosis (CF). METHODS: To determine whether a topical formulation of camostat represents an efficacious and tolerable approach to reducing Na+ transport in the CF airway, we conducted a two-part randomized, double-blind, placebo-controlled, crossover, ascending single-dose study to evaluate the pharmacodynamics, safety, and pharmacokinetics of camostat administered through a nasal spray pump in subjects with CF. Nasal potential difference (PD) was measured before and after treatment, and safety and pharmacokinetics were assessed by a standardized approach. RESULTS: In part 1, nine subjects were enrolled, and six completed crossover dosing at the maximally tolerated dose. The change in maximal (most polarizing) basal PD 2 h following administration of camostat was +13.1 mV (1.6-mg dose group) compared with -8.6 mV following placebo (P<.005). Intrasubject change in Ringer and amiloride-sensitive PDs exhibited similar and consistent responses. Bayesian analysis in an additional six subjects in part 2 estimated a dose of 18 µg/mL to provide 50% of the maximum effect. There was no significant change in chloride transport or total nasal symptom score, nasal examination rating, and laboratory parameters. CONCLUSIONS: This study establishes the proof of concept that a reduction in sodium transport in the human CF airway can be achieved through inhibition of prostasin activity, identifying a potential therapeutic target in the disease. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT00506792; URL: www.clinicaltrials.gov.

Inhaled amiloride and tobramycin solutions fail to eradicate Burkholderia dolosa in patients with cystic fibrosis.

BACKGROUND: Burkholderia dolosa can result in chronic airway infection and rapid decline in lung function in patients with cystic fibrosis (CF). Amiloride has antibacterial properties that may be synergistic with aminoglycosides against other species belonging to the Burkholderia cepacia complex (Bcc). We attempted to eradicate B. dolosa using a combination of nebulized tobramycin and nebulized amiloride in infected CF patients. METHODS: A 6-month, open-label trial of continuous inhaled amiloride, delivered via nebulization four times daily, and continuous inhaled tobramycin (TIS or TOBI®) nebulized twice daily, was offered to all CF patients at our institution who are chronically infected with B. dolosa. RESULTS: Twenty two of 27 patients with B. dolosa were eligible and twelve elected to participate. Eradication of B. dolosa was not noted in any study subject. While patients tolerated treatment with no adverse effects, there was also no apparent impact on other secondary outcome measures. CONCLUSIONS: Concurrent, continuous inhalation of amiloride and tobramycin for 6 months was not effective for the eradication of chronic B. dolosa airway infection in CF patients.

Role of bacteriocins in mediating interactions of bacterial isolates taken from cystic fibrosis patients.

Pseudomonas aeruginosa (Pa) and Burkholderia cepacia complex (Bcc) lung infections are responsible for much of the mortality in cystic fibrosis (CF). However, little is known about the ecological interactions between these two, often co-infecting, species. This study provides what is believed to be the first report of the intra- and interspecies bacteriocin-like inhibition potential of Pa and Bcc strains recovered from CF patients. A total of 66 strains were screened, and shown to possess bacteriocin-like inhibitory activity (97 % of Pa strains and 68 % of Bcc strains showed inhibitory activity), much of which acted across species boundaries. Further phenotypic and molecular-based assays revealed that the source of this inhibition differs for the two species. In Pa, much of the inhibitory activity is due to the well-known S and RF pyocins. In contrast, Bcc inhibition is due to unknown mechanisms, although RF-like toxins were implicated in some strains. These data suggest that bacteriocin-based inhibition may play a role in governing Pa and Bcc interactions in the CF lung and may, therefore, offer a novel approach to mediating these often fatal infections.

The impact of incident methicillin resistant Staphylococcus aureus detection on pulmonary function in cystic fibrosis.

The incidence of methicillin resistant Staphylococcus aureus (MRSA) infection is increasing in cystic fibrosis (CF), but the impact of MRSA detection on clinical outcomes is unclear. Our objective was to determine whether incident detection of MRSA is associated with a change in pulmonary function over time in CF patients. We analyzed data from the Epidemiologic Study of Cystic Fibrosis (ESCF), a prospective observational study of CF patients in North America. Multivariable piecewise linear regression was used to model the impact of incident detection of MRSA on pulmonary function over time, measured by percent predicted forced expiratory volume in one second (FEV(1)% predicted), adjusting for potential confounders. There were 5,090 patients >or=6 years old who were MRSA negative for at least 2 calendar years. Five hundred ninety-three (12%) of these patients acquired MRSA during the years 2001-2003, with detection rates of MRSA during those years rising from 4.4% to 6.9%. MRSA positive patients had a lower FEV(1)% predicted and received more antibiotic and other therapies than patients who remained MRSA negative. After adjusting for antibiotic therapy and other potential confounders, MRSA positive patients also had a higher rate of decline in FEV(1)% predicted both before and after the incident culture, although the rate of FEV(1)% predicted decline did not change significantly after MRSA detection. In conclusion, although MRSA in CF was a marker for more aggressive therapy and may reflect increased disease severity, incident MRSA detection was not associated with a changing rate of FEV(1)% predicted decline.

MDCT evaluation of the prevalence of tracheomalacia in children with mediastinal aortic vascular anomalies.

OBJECTIVE: The purpose of this study is to determine the prevalence of tracheomalacia (TM) associated with different types of mediastinal aortic vascular anomalies in symptomatic children using paired inspiratory-expiratory multidetector computed tomography (MDCT). MATERIALS AND METHODS: The study group consisted of 15 consecutive symptomatic pediatric patients (12 males/3 females; mean age of 4.4 y; age range of 2 wk to 16 y) with mediastinal aortic vascular anomalies, who were referred for paired inspiratory-expiratory MDCT during a 35-month time period. Computed tomography (CT) angiography was also concurrently performed during the end-inspiration phase of the study. Two radiologists in consensus reviewed all CT images in a randomized and blinded fashion. End-inspiration and end-expiration CT images were reviewed for the presence and severity of tracheal narrowing and the type of mediastinal aortic vascular anomaly involved. TM was defined as > or =50% reduction in tracheal cross-sectional luminal area between end-inspiration and end-expiration. The presence of TM was correlated with the type of mediastinal aortic vascular anomaly and compared with the bronchoscopy results when available (n=9). RESULTS: Mediastinal aortic vascular anomalies included innominate artery compression (IAC) (n=6), a right aortic arch with an aberrant left subclavian artery (n=5), double aortic arch (n=3), and a left aortic arch with an aberrant right subclavian artery (n=1). Eight of 15 (53.3%) patients demonstrated TM. TM was seen in all 6 patients (100%) with IAC, 1 of 3 (33.3%) patients with double aortic arch, and 1 of 5 (20%) patients with a right aortic arch with an aberrant left subclavian artery. CT results were concordant with the results of bronchoscopy in all patients who underwent this procedure (n=9). CONCLUSIONS: Symptomatic pediatric patients with mediastinal aortic vascular anomalies have a relatively high prevalence of TM, especially those with IAC. Paired inspiratory-expiratory MDCT should be considered part of the routine preoperative evaluation of TM in symptomatic children with IAC and also has the potential to play a role in evaluating patients with other mediastinal aortic vascular anomalies.

MDCT assessment of tracheomalacia in symptomatic infants with mediastinal aortic vascular anomalies: preliminary technical experience.

BACKGROUND: Mediastinal aortic vascular anomalies are relatively common causes of extrinsic central airway narrowing in infants with respiratory symptoms. Surgical correction of mediastinal aortic vascular anomalies alone might not adequately treat airway symptoms if extrinsic narrowing is accompanied by intrinsic tracheomalacia (TM), a condition that escapes detection on routine end-inspiratory imaging. Paired inspiratory-expiratory multidetector CT (MDCT) has the potential to facilitate early diagnosis and timely management of TM in symptomatic infants with mediastinal aortic vascular anomalies. OBJECTIVE: To assess the technical feasibility of paired inspiratory-expiratory MDCT for evaluating TM among symptomatic infants with mediastinal aortic vascular anomalies. MATERIALS AND METHODS: The study group consisted of five consecutive symptomatic infants (four male, one female; mean age 4.1 months, age range 2 weeks to 6 months) with mediastinal aortic vascular anomalies who were referred for paired inspiratory-expiratory MDCT during a 22-month period. CT angiography was concurrently performed during the end-inspiration phase of the study. Two pediatric radiologists in consensus reviewed all CT images in a randomized and blinded fashion. The end-inspiration and end-expiration CT images were reviewed for the presence and severity of tracheal narrowing. TM was defined as > or =50% reduction in tracheal cross-sectional luminal area between end-inspiration and end-expiration. The presence of TM was compared to the bronchoscopy results when available (n = 4). RESULTS: Paired inspiratory-expiratory MDCT was technically successful in all five patients. Mediastinal aortic vascular anomalies included a right aortic arch with an aberrant left subclavian artery (n = 2), innominate artery compression (n = 2), and a left aortic arch with an aberrant right subclavian artery (n = 1). Three (60%) of the five patients demonstrated focal TM at the level of mediastinal aortic vascular anomalies. The CT results were concordant with the results of bronchoscopy in all patients who underwent bronchoscopy (n = 4). CONCLUSION: Paired inspiratory-expiratory MDCT is technically feasible for evaluating TM in symptomatic infants with mediastinal aortic vascular anomalies and has the potential to facilitate prompt diagnosis and treatment.

Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial.

Previous studies have demonstrated that delivery of a recombinant adeno-associated virus (AAV) vector encoding the complete human cystic fibrosis transmembrane regulator (CFTR) cDNA (tgAAVCF) to the nose, sinus, and lungs of subjects with cystic fibrosis (CF) was safe and well tolerated. In a small randomized, double-blind study of three doses of aerosolized tgAAVCF or placebo at 30-day intervals, encouraging but non-significant trends in pulmonary function and induced sputum interleukin 8 (IL-8) levels were seen at early time points. This larger study was conducted to verify these trends. One hundred and two subjects aged 12 years and older with mild-to-moderate cystic fibrosis (forced expiratory flow in 1 sec [FEV1]:60% predicted) were randomized to two aerosolized doses of 1x10(13)DNase-resistant particles of tgAAVCF (n=51) or matching placebo (n=51) administered 30 days apart. Although tgAAVCF was well tolerated, the study did not meet its primary efficacy end point of statistically significant improvement in FEV1 30 days after initial administration of tgAAVCF compared with placebo. There were no significant differences in spirometric lung function over time, induced sputum biologic markers, or days of antibiotic use in either treatment group. Thus repeated doses of aerosolized tgAAVCF were safe and well tolerated, but did not result in significant improvement in lung function over time. Because gene transfer is the simplest, most basic way to correct the underlying genetic defect that leads to disease in CF, further research is warranted to develop an effective gene transfer agent for the treatment of CF.

Oral corticosteroid therapy in cystic fibrosis patients hospitalized for pulmonary exacerbation: a pilot study.

BACKGROUND: We hypothesized that adding 5 days of prednisone to standard therapy for acute pulmonary exacerbations in patients with cystic fibrosis (CF) would result in a more rapid and greater increase in lung function. METHODS: CF patients with an acute pulmonary exacerbation were randomized to receive oral placebo or prednisone, 2 mg/kg/d up to 60 mg, on days 1 to 5 in addition to standard therapy. Study evaluations on days 1 to 6, 14, and 42 included spirometry, glucose measurements, sputum analysis, and symptom scores. RESULTS: Twelve subjects were randomized to each arm. The slope of FEV(1) between day 1 and day 6 did not differ between evaluable subjects in the prednisone vs placebo groups (52 mL/d vs 51 mL/d, respectively). Mean increase in FEV(1) percentage of predicted did not differ significantly between prednisone vs placebo groups (day 6 [mean +/- SD], 12.2 +/- 5.2% vs 8.1 +/- 10.5%; day 14, 14.7 +/- 8.8% vs 10.2 +/- 11.2%, respectively). Sputum inflammatory markers and symptom scores decreased between day 1 and day 14, but mean values did not differ between groups. Glucosuria occurred in six prednisone subjects, two of whom had hyperglycemia develop. CONCLUSIONS: In this pilot study, addition of oral corticosteroids to standard CF pulmonary exacerbation therapy did not result in a statistically significant effect on lung function or sputum markers of inflammation. Based on a trend toward improvement in pulmonary function with prednisone therapy, we obtained information for power calculations for a definitive study: 250 randomized subjects are required to detect a four-percentage-point treatment effect in FEV(1) percentage of predicted at day 14 to discriminate between null and alternative hypotheses.

Duration of treatment effect after tobramycin solution for inhalation in young children with cystic fibrosis.

RATIONALE: Among young children with cystic fibrosis (CF), Pseudomonas aeruginosa (Pa) airway infection is associated with increased morbidity and mortality. Early intervention strategies include tobramycin solution for inhalation (TSI), which can eradicate lower airway Pa from cultures obtained at the end of 28 days of treatment in young children. METHODS: We conducted an open label, sequential cohort study of TSI in young children with CF to investigate duration of antimicrobial treatment effect. The primary outcome was lower airway Pa eradication per bronchoalveolar lavage (BAL) fluid culture. Sequential treatment cohorts varied by duration of treatment (28 or 56 days) and timing of follow-up BAL (at Days 56, 84, or 112). Subjects (N = 36) were treated with TSI, 300 mg twice daily, for 28 days or 56 days per cohort assignment. RESULTS: Among 31 evaluable subjects, culture based, lower airway Pa eradication was observed in the majority of subjects for up to 1-3 months following TSI treatment: 75% in Cohort 28/56 (days of treatment/day of follow-up BAL), 63% in Cohort 28/84, 82% in Cohort 56/112, and 75% in Cohort 28/112. Non-mucoid Pa at baseline and/or exotoxin A seronegativity were associated with higher rates of eradication. There was a less pronounced effect of TSI treatment on Pa eradication from oropharyngeal cultures in all cohorts. TSI treatment was associated with reduced neutrophilic airway inflammation and was not related to any serious adverse events. CONCLUSION: TSI monotherapy is safe and can eradicate lower airway Pa for up to 3 months after treatment in young children with CF.

Membranous obliterative bronchitis: a proposed unifying model.

Three adults with cystic fibrosis (one after lung transplantation) presented with fever, chest pain, and acute radiographic changes. The changes included a cavitary lesion of the lung, acute dense infiltrates, and lobar collapse. After failing conventional antibiotic therapy, the patients underwent flexible bronchoscopy. All had bronchial obstruction by a membrane that had completely occluded the bronchial orifice at the bifurcation of the bronchi. Therapeutic interventions ranged from continuing intravenous antibiotics, bronchoscopy-assisted perforation of the membrane by sharp instrumentation, and transthoracic needle-guided perforation of the membrane with subsequent stenting of the orifice. The patients recovered, but the posttransplant patient had recurrent membranous obstructions with multiple interventions. The cause and triggers of the process are unknown. Based on repeated observations of the evolution of the membranes, and histologic material from bronchoscopies, we propose a putative paradigm of the natural history of the process. We suggest that local stimuli generate a richly vascularized granulation polyp, which progresses in a "shutter-like" motion to form partial or completely obstructive membranes. The subsequent course depends on the vascular supply to the membrane. We also propose that similar processes may be the underlying pathologic events in some cases of lung abscess and necrotizing pneumonia.

Impact of Burkholderia dolosa on lung function and survival in cystic fibrosis.

RATIONALE: Chronic infection with Burkholderia cepacia complex bacteria in cystic fibrosis is associated with accelerated decline in pulmonary function and increased mortality. Clinical implications of the recently characterized genomovar VI, B. dolosa, are unknown. OBJECTIVES: Characterization of impact of B. dolosa on pulmonary function and mortality in cystic fibrosis. METHODS: We compared patients chronically infected with B. dolosa (n = 31) with unmatched patients with B. multivorans (n = 24) and with age- and sex-matched control subjects without Burkholderia species (n = 58). We analyzed rates of pulmonary function decline (% predicted FEV(1)) using a random effects model assuming segmented linear trends. All available FEV(1) measurements from 5 yr (median, 4.8) before until 2.5 yr (median, 1.5) after the first positive culture for Burkholderia (reference date) were analyzed. Survival was compared using the Kaplan-Meier method and proportional hazards model. MEASUREMENTS AND MAIN RESULTS: Baseline FEV(1) and rate of decline were similar in the cohorts. Decline in FEV(1) after the reference date accelerated in patients with B. dolosa (-2.3 percentage points/yr pre vs. -7.1 post, p = 0.002), but was unchanged in the B. multivorans and control patients (-2.3 vs. -0.8 post, p = 0.38, and -2.1 pre vs. -0.5 post, p = 0.20, respectively). The probability of dying within 18 mo of the reference date was 13, 7, and 3% for B. dolosa, B. multivorans, and control patients, respectively (B. dolosa vs. control hazard ratio, 10.8; 95% confidence interval, 1.3-92.8; p = 0.03). CONCLUSIONS: B. dolosa chronic infection in cystic fibrosis is associated with accelerated loss of lung function and decreased survival.

Cutaneovisceral angiomatosis with thrombocytopenia.

We describe 10 children with multiple vascular lesions of the skin and gastrointestinal tract associated with sustained, minor thrombocytopenia. In some children, there was involvement of the lung (n = 5), bone (n = 2), liver (n = 1), spleen (n = 1), and muscle (n = 1). The cutaneous lesions were congenital, multifocal, discrete, red-brown and variably blue macules and papules; in 3 children, a large dominant plaque was also present. All children developed hematemesis and/or melena and endoscopic evaluation revealed several to numerous small mucosal lesions that involved all levels of the gastrointestinal tract. Three of 5 children with pulmonary nodules had cough and 1 also had hemoptysis. Biopsies of cutaneous, gastrointestinal, and pulmonary lesions showed thin-walled, blood-filled vascular channels and variable endothelial hyperplasia. The endothelial nuclei were elongated, round, crescentic, or hobnailed. Cytoplasmic and extracellular periodic acid-Schiff positive deposits were often present in the zones of endothelial hyperplasia. The platelets were small in some children, suggesting a primary defect, possibly accounting for the thrombocytopenia. Gastrointestinal hemorrhage and hemoptysis required antiangiogenic therapy. The constellation of findings defines a congenital proliferative disorder of blood vessels with a distinctive microscopic appearance. We have termed this relatively indolent or slowly progressive disorder cutaneovisceral angiomatosis with thrombocytopenia because this designation incorporates its major clinical and histopathologic features.

Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review.

Tracheomalacia and tracheobronchomalacia are disorders that are encountered in both pediatric and adult medicine. Despite increasing recognition of these disease processes, there remains some uncertainty regarding their identification, causes, and treatment. This article is intended to be a comprehensive review of both the adult and pediatric forms of the diseases, and includes sections on the historical aspects of the disorders, and their classification, associated conditions, histopathology, and natural history. We also review the various modalities that are used for diagnosis as well as the state of the art of treatment, including airway stent placement and surgical intervention.