Self-reported chronic therapy use after 24-weeks of follow-up by participants who completed the simplify randomized, controlled trial.

Background: Highly effective CFTR modulator therapy (HEMT) has improved the health of many people with cystic fibrosis (pwCF), offering opportunities to discontinue burdensome therapies. SIMPLIFY included randomized, controlled trials that confirmed non-inferiority of discontinuing versus continuing dornase alfa (DA) or hypertonic saline (HS) for 6 weeks in pwCF on HEMT. In this study of post-trial treatment use by SIMPLIFY participants, we hypothesized that randomization to discontinue DA or HS during the trial would be associated with a higher likelihood of non-use of each medication during follow-up.

Impact of Discontinuing Both Hypertonic Saline and Dornase Alfa after Elexacaftor-Tezacaftor-Ivacaftor in Cystic Fibrosis.

Evaluating approaches to reduce treatment burden is a research priority among people with cystic fibrosis on highly effective modulators, including elexacaftor-tezacaftor-ivacaftor (ETI). We sought to evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. SIMPLIFY participants ≥12 years old on ETI and constituting a subgroup using both HS and DA at study entry were randomized to the HS or DA trial and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks.

The cost of simplifying treatments for cystic fibrosis: Implications of the SIMPLIFY trial.

Background: Dornase alfa and hypertonic saline are mucoactive therapies that can improve respiratory symptoms in people with cystic fibrosis (CF). A recent randomized control trial showed that participants with well-preserved pulmonary function taking elexacaftor + tezacaftor + ivacaftor (ETI) who discontinued dornase alfa or hypertonic saline for 6 weeks had no clinically meaningful decline in lung function. This may prompt discussions with care providers regarding ongoing use of these medications.

Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial.

The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs in at least 85% of people with CF. PROMISE is a postapproval study to understand the broad effects of ETI through 30 months' clinical use in a more diverse U.S.

Long-term azithromycin use is not associated with QT prolongation in children with cystic fibrosis.

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.

Oral Glutathione and Growth in Cystic Fibrosis: A Multicenter, Randomized, Placebo-controlled, Double-blind Trial.

Objectives: The nutritional status of children with cystic fibrosis (CF) is associated with mortality and morbidity. Intestinal inflammation may contribute to impaired digestion, absorption, and nutrient utilization in patients with CF and oral glutathione may reduce inflammation, promoting improved nutritional status in patients with CF.

Methods: The GROW study was a prospective, multicenter, randomized, placebo-controlled, double-blind, phase II clinical trial in pancreatic insufficient patients with CF between the ages of 2 and 10 years.

Pulmonary findings in infants with cystic fibrosis during the first year of life: Results from the Baby Observational and Nutrition Study (BONUS) cohort study.

Importance: Treatment recommendations for infants with CF standardize care, but most surveillance or treatment guidance of pulmonary manifestations are consensus-based due to sparse evidence.

Objective: To report observations about pulmonary correlates of growth and other clinical features in infants with CF.

Methods: We analyzed data from the prospective Baby Observational and Nutrition Study conducted in 28 centers across the US, including clinical features, medications, guardian diaries of respiratory symptoms, oropharyngeal swab cultures and chest radiographs (CXR) collected over the first year of life.

Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial.

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.

Pancreatic Enzyme Replacement Therapy Use in Infants With Cystic Fibrosis Diagnosed by Newborn Screening.

Objectives: The aim of the study is to describe pancreatic enzyme practices during the first year of life in infants with cystic fibrosis (CF) and evaluate associations between dosing and outcomes, including growth and gastrointestinal (GI) symptoms.

Methods: We analyzed data from a subset of infants who were in a prospective cohort study conducted at 28 US CF centers. Anthropometric measurements and medications were recorded at each visit.

Effects of Diagnosis by Newborn Screening for Cystic Fibrosis on Weight and Length in the First Year of Life.

Importance: Since the implementation of universal newborn screening (NBS) for cystic fibrosis (CF), the timing and magnitude of growth deficiency or its association with correlates of disease among infants with CF who underwent NBS has not been well described.

Objective: To examine incremental weight gain, linear growth, and clinical features in the first year of life among infants with CF who underwent NBS.

Design, Setting, And Participants: The Baby Observational and Nutrition Study (BONUS), a multicenter, longitudinal, observational cohort study, was conducted during regular CF clinic visits in the first 12 months of life at 28 US Cystic Fibrosis Foundation-accredited Care Centers from January 7, 2012, through May 31, 2015.

Outcomes and Treatment of Chronic Methicillin-Resistant Staphylococcus aureus Differs by Staphylococcal Cassette Chromosome mec (SCCmec) Type in Children With Cystic Fibrosis.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) infects ∼25% of patients with cystic fibrosis (CF) in the United States. We hypothesized that health-related outcomes differed between healthcare-associated (staphylococcal cassette chromosome mec [SCCmec] II) vs community-associated (SCCmec IV) MRSA strains in patients chronically infected with CF.

Methods: At 7 CF centers, MRSA isolates were prospectively obtained from patients ≤18 years old with 2 or more positive MRSA cultures within 1 year.

Impact of Sustained Eradication of New Pseudomonas aeruginosa Infection on Long-term Outcomes in Cystic Fibrosis.

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.

Multicenter Observational Study on Factors and Outcomes Associated with Various Methicillin-Resistant Staphylococcus aureus Types in Children with Cystic Fibrosis.

Rationale: Methicillin-resistant Staphylococcus aureus (MRSA) prevalence continues to increase in patients with cystic fibrosis (CF) in the United States, reaching 26.5% in 2012. Approximately 30% of strains are SCCmec (staphylococcal cassette chromosome mec) IV type, frequently USA300, which in the general population have different genotypic and phenotypic features than SCCmec II type.

Pulmonary exacerbations in CF patients with early lung disease.

Background: Current definitions of pulmonary exacerbation (PE) in cystic fibrosis are based on studies in participants with significant lung disease and may not reflect the spectrum of findings observed in younger patients with early lung disease.

Methods: We used data from a recent trial assessing the efficacy of azithromycin in children to study signs and symptoms associated with PEs and related changes in lung function and weight.

Results: While increased cough was present in all PEs, acute weight loss and reduction in oxygen saturation were not observed.

Impact of acute antibiotic therapy on the pulmonary exacerbation endpoint in cystic fibrosis clinical trials.

Background: In a chronic disease setting such as cystic fibrosis (CF), antibiotics are often prescribed for emergent symptoms and it is unclear whether this affects endpoints in a clinical trial. Pulmonary exacerbations (PEs) are defined episodes of acute worsening and a key clinical efficacy measure in CF. Our hypothesis was that acute antibiotics given for illnesses not meeting the PE definition may alter estimates of treatment effect that do not account for this antibiotic use.

Association of lung function, chest radiographs and clinical features in infants with cystic fibrosis.

The optimal strategy for monitoring cystic fibrosis lung disease in infancy remains unclear. Our objective was to describe longitudinal associations between infant pulmonary function tests, chest radiograph scores and other characteristics. Cystic fibrosis patients aged ≤24 months were enrolled in a 10-centre study evaluating infant pulmonary function tests four times over a year.

Incidence and clinical significance of elevated liver function tests in cystic fibrosis clinical trials.

Rationale: Emergence of elevated liver function tests (LFTs) during a clinical trial may be due to underlying disease factors of the participants, thus cofounding safety assessments of therapies. Limited data exist addressing the frequency of elevated LFTs in the chronic disease setting of cystic fibrosis (CF). The objectives of this study were to characterize emergence rates of elevated LFTs in CF trials and their association with clinical outcomes.

Open-label, follow-on study of azithromycin in pediatric patients with CF uninfected with Pseudomonas aeruginosa.

Background: We previously performed a randomized placebo-controlled trial to examine the effects of azithromycin in children and adolescents 6-18 years of age with cystic fibrosis uninfected with Pseudomononas aeruginosa and demonstrated that while azithromycin did not acutely improve pulmonary function, azithromycin-reduced pulmonary exacerbations, decreased the initiation of new oral antibiotics, and improved weight gain. We now report the results of the open-label, follow-on study to assess durability of response to azithromycin and continued safety and tolerability.

Methods: Eligible participants were enrolled in a 24-week open-label study of azithromycin to compare efficacy and safety endpoints during the placebo-controlled trial versus open-label study in two groups: participants initially on azithromycin continued azithromycin (azithromycin-azithromycin) and participants initially on placebo who then received azithromycin (placebo-azithromycin).

Lung function from infancy to preschool in a cohort of children with cystic fibrosis.

This study aimed to describe lung function in a cohort of children with cystic fibrosis (CF) who underwent infant pulmonary function tests (IPFTs) and preschool spirometry. Children performed up to four IPFTs (raised volume rapid thoracic compression technique) over 1 yr and five preschool spirometry tests over up to 2 yrs during participation in prospective, multicentre studies of infant and preschool lung function. All lung function data were reviewed centrally for measurement acceptability.

Effect of azithromycin on systemic markers of inflammation in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa.

Background: While the mechanism of action by which azithromycin exerts positive effects inpatients with cystic fibrosis remains unclear, evidence suggests that azithromycin may act as an immunomodulatory agent. We examined changes in systemic inflammatory markers in a doubleblind, randomized, controlled trial of oral azithromycin in patients 6-18 years of age with cystic fibrosis who were uninfected with Pseudomonas aeruginosa.

Methods: WBC counts and differential, serum myeloperoxidase (MPO), high-sensitivity C reactive protein (hsCRP), intracellular adhesion molecule 1, IL-6, calprotectin, serum amyloid A (SAA),and granulocyte colony-stimulating factor (G-CSF) were measured at baseline and after 28 and 168 days of treatment in patients receiving either oral azithromycin or placebo.

Analysis of the associations between lung function and clinical features in preschool children with cystic fibrosis.

Objective: To analyze cross-sectional and longitudinal associations between lung function measures and clinical features in a cohort of preschool children with cystic fibrosis (CF).

Methods: Longitudinal eight-center observational study of children with CF aged 36-60 months at enrollment, who underwent semiannual pulmonary function tests (PFTs) for up to 2 years consisting of spirometry (all 8 sites), forced oscillometry (FO, 5 sites), and measures of thoracoabdominal asynchrony using respiratory inductive plethysmography (IP, 5 sites).

Results: Ninety-three subjects were enrolled; 181 acceptable spirometry measurements from 71 subjects, 128 FO from 47 subjects, and 142 IP from 50 subjects were available for analysis.

Lung function distinguishes preschool children with CF from healthy controls in a multi-center setting.

Rationale: Conducting clinical trials in cystic fibrosis (CF) preschoolers has been limited by lack of sensitive lung function measures performed across sites.

Objectives: (1) Assess feasibility and short-term reproducibility of spirometry, forced oscillometry (FO), and inductance plethysmography (IP) in a multi-center preschool population; (2) compare ability of each technique to differentiate lung function of CF preschoolers and controls; (3) evaluate longitudinal changes in lung function; (4) estimate sample sizes for future trials.

Methods: A longitudinal, multi-center study of CF preschoolers was conducted utilizing standardized equipment, rigorous site training, and centralized lung function data review.

Multicenter evaluation of infant lung function tests as cystic fibrosis clinical trial endpoints.

Rationale: The conducting of clinical trials in infants with cystic fibrosis (CF) has been hindered by lack of sensitive outcome measures.

Objectives: To evaluate safety, feasibility, and ability to detect abnormalities in lung function of serial pulmonary function tests (PFTs) in infants with CF.

Methods: Multicenter observational study using a commercial device, rigorous training, ongoing quality control, and over-reading of data by an independent panel.

Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial.

Context: Azithromycin is recommended as therapy for cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infection, but there has not been sufficient evidence to support the benefit of azithromycin in other patients with CF.

Objective: To determine if azithromycin treatment improves lung function and reduces pulmonary exacerbations in pediatric CF patients uninfected with P. aeruginosa.