Streamlined Treatment of Pulmonary Exacerbations in Pediatrics

Compare the difference in pulmonary function between arms by evaluating change in spirometry-measured percent predicted forced expiratory volume (ppFEV1). A spirometry test measures the amount of air a person can forcibly exhale after a deep breath (forced vital capacity, or FVC) and the amount of air they can exhale in one second (forced expiratory volume in one second, or FEV1). A lower measured value compared to the reference value indicates lung disease.

Compare the difference in pulmonary function between arms by evaluating change in Lung Clearance Index (LCI). LCI increases when there is lung disease, which causes ventilation inhomogeneity. LCI is calculated as the number of lung volume turnovers (cumulative expired volume divided by the functional residual capacity [FRC]) required to reduce end-tidal nitrogen concentration to 1/40th of the original level.

Compare recovery to baseline between arms over the 28-day period after the first pulmonary exacerbation (PEx), by spirometry-measured percent predicted forced expiratory volume (ppFEV1), and after all pulmonary exacerbations, measured by CRISS symptom scores. The Chronic Respiratory Infection Symptom Score (CRISS) ranges from 0 to 100, with higher scores indicating more symptoms.

Compare recovery to baseline between arms over the 28-day period after the first pulmonary exacerbation (PEx) in LCI, and after all exacerbations for symptom scores. The Chronic Respiratory Infection Symptom Score (CRISS) ranges from 0 to 100, with higher scores indicating more symptoms.

Compare cumulative oral antibiotic exposure in each treatment arm.

Compare the number of respiratory illnesses reported over the study period in each treatment arm.

Compare the proportion of respiratory illnesses treated with antibiotics during the 28-day pulmonary exacerbation (PEx) treatment period in each treatment arm.

Compare the number of pulmonary exacerbations (PEx) treated with IV antibiotics over the study period in each treatment arm.

Compare the proportion of pulmonary exacerbations (PEx) failing to recover to baseline symptoms at Day 28 in each treatment arm.

Compare the proportion of pulmonary exacerbations (PEx) with spirometry-measured percent predicted forced expiratory volume (ppFEV1) below baseline at Day 28 in each treatment arm.

Compare the time from initial randomized pulmonary exacerbation (PEx) to next respiratory illness in each treatment arm.

Compare the targeted adverse events (patient report of antibiotic side effects during pulmonary exacerbation period) in each treatment arm.

Compare treatment-emergent CF microorganisms on clinical respiratory cultures in each treatment arm.

To understand benefits and challenges associated with assigned treatment through targeted qualitative interviews of caregivers we will describe caregivers' experience managing study treatment and report themes that emerge regarding caregivers' experiences.

To understand benefits and challenges associated with assigned treatment through targeted qualitative interviews of caregivers we will evaluate study treatment impact on child and family daily life and report themes that emerge regarding caregivers' experiences.

Compare total estimated cost of antibiotics used over the course of the study between treatment arms.

Compare health care utilization over the course of the study between treatment arms, including number of primary care visits and number of emergency room visits.

To compare parent Work Productivity and Activity Impairment (WPAI) measures between study arms. The WPAI includes four scores assessing absenteeism, presenteeism, work productivity loss (overall work impairment/absenteeism plus presenteeism), and activity impairment in the last seven days. Scores range from 0 to 100, with higher scores indicating greater impairment.

Estimate the proportion of preschool and non-HEMT (Highly Effective Modulator Therapy) participants randomized to the tailored therapy arm that has no antibiotic exposure in the 28 days following a pulmonary exacerbation (PEx).

Compare percent predicted forced expiratory volume (ppFEV1) and Lung Clearance Index (LCI) recovery using Day 28 values compared to nearest pre-PEx baseline measure in both treatment arms.

Compare time to symptom recovery (number of days to recover to baseline CRISS score) between treatment arms. The Chronic Respiratory Infection Symptom Score (CRISS) ranges from 0 to 100, with higher scores indicating more symptoms.

Compare targeted adverse events (participant report of antibiotic side effects during PEx period) between treatment arms.

Compare treatment-emergent CF microorganisms on clinical respiratory cultures between treatment arms.

Compare treatment with additional non-protocol assigned antibiotics within the 28 days post-randomization between treatment arms.

Compare time to IV antibiotics following a randomized PEx (using CF Foundation Patient Registry data, if available) between treatment arms.

Measure the proportion of approached patients that enrolls.

Measure the proportion of respiratory symptoms meeting randomization criteria.

Measure the proportion of respiratory symptoms meeting randomization criteria resulting in treatment initiation within assigned arm.

Through targeted qualitative interviews of caregivers we will describe caregivers' experience managing study treatment and report themes that emerge regarding caregivers' experiences in order to understand motivations, benefits and challenges associated with assigned treatment arm.

Use quantitative polymerase chain reaction (qPCR) and metagenomic sequencing to quantitatively define throat swab microbiology at baseline, at exacerbation diagnosis, and after treatment. Metagenomic sequencing analyzes the genomes of all microorganisms in a sample, providing a broad overview of the ecosystem's composition. It can be used to study the diversity of bacteria, detect the abundance of microbes, and study unculturable microorganisms.

Correlate throat microbiota measures (both pre-treatment microbial taxonomic or functional gene abundances, and changes in those abundances) with clinical outcome measures within antibiotic treatments.

Assess the feasibility of home collection of nasal swabs for viral testing at the time of pulmonary exacerbation (PEx) and determine the frequency of viral illness at the time of PEx diagnosis.

Assess the feasibility of home collection of throat swabs for bacterial testing at the time of pulmonary exacerbation (PEx).

Evaluate the association between the presence of viral illness and symptom recovery (number of days to recover to baseline CRISS score) between treatment arms. The Chronic Respiratory Infection Symptom Score (CRISS) ranges from 0 to 100, with higher scores indicating more symptoms.

Evaluate the association between the presence of viral illness and spirometry-measured forced expiratory volume (FEV1) at Day 28.

Evaluate the association between the presence of viral illness and the percent of subjects in the tailored therapy arm requiring antibiotic treatment.

Determine the concordance of bacteria identified on CF pathogen testing at the time of pulmonary exacerbation (PEx) compared to the most recent routine clinic visit. In addition, assess how frequently new bacterial pathogens are identified at the time of PEx and how this impacts treatment changes, including the need to change or add antibiotic therapy.

Describe the feasibility and user acceptability of home spirometry during pulmonary exacerbations (PEx) in children with CF via survey of participants at the end of the study.

Describe the feasibility and user acceptability of BioButton use during pulmonary exacerbations in children with CF via survey of participants at the end of the study.

Describe the change from nearest baseline-state FEV1 to Day 0 exacerbation state measurement and the trajectory of change during the exacerbation state (through Day 28).

Compare measurements and their change measured by home spirometry vs. clinic spirometry during the exacerbation state.

Describe changes in resting heart rate from Day 0 to 14 of the exacerbation state.

Describe changes in Resting respiratory rate from Day 0 to 14 of the exacerbation state.

Describe changes activity level, measured using actigraphy, and summarized as the mean (SD) number of active minutes in a day, from Day 0 to 14 of the exacerbation state.

Describe changes in sleep time from Day 0 to 14 of the exacerbation state.

Compare changes in resting HR to averages from a 7-day period during baseline state.

Compare changes in BioButton-measured Resting respiratory rate to averages from a 7-day period during baseline state.

Compare BioButton-measured change in activity level during pulmonary exacerbation (PEx) to averages from a 7-day period during baseline state.

Compare BioButton change in sleep during PEx to averages from a 7-day period during baseline state.

Determine correlations between changes from Day 0 to 14 in forced expiratory volume (FEV1) and CRISS score to Resting Heart Rate (HR). The Chronic Respiratory Infection Symptom Score (CRISS) ranges from 0 to 100, with higher scores indicating more symptoms.

Determine correlations between changes from Day 0 to 14 in forced expiratory volume (FEV1) and CRISS score to Resting Respiratory rate. The Chronic Respiratory Infection Symptom Score (CRISS) ranges from 0 to 100, with higher scores indicating more symptoms.

Determine correlations between changes from Day 0 to 14 in forced expiratory volume (FEV1) and CRISS score to Activity level, measured with actigraphy. The Chronic Respiratory Infection Symptom Score (CRISS) ranges from 0 to 100, with higher scores indicating more symptoms.

Determine correlations between changes from Day 0 to 14 in forced expiratory volume (FEV1) and CRISS score to sleep duration. The Chronic Respiratory Infection Symptom Score (CRISS) ranges from 0 to 100, with higher scores indicating more symptoms.