Streamlined Treatment of Pulmonary Exacerbations in Pediatrics

Streamlined Treatment of Pulmonary Exacerbations in Pediatrics Randomized Controlled Trial (STOP PEDS RCT)

The STOP PEDS RCT is a multicenter, parallel, open label randomized controlled trial evaluating the long-term (one year) and short-term safety and efficacy of two antibiotic treatment strategies for the management of outpatient pulmonary exacerbations (PEx) in the pediatric CF population.

The STOP PEDS pilot study demonstrated that a randomized trial of treatment strategies for mild pulmonary exacerbations (PEx) in children with CF was feasible and that assignment to a tailored therapy arm (defined below) may reduce antibiotic exposure.

Based on the research priorities identified by CF families and clinicians and the results of the pilot study, the STOP PEDS RCT is a multicenter, parallel, open label randomized controlled trial evaluating the long-term (one year) and short-term safety and efficacy of two antibiotic treatment strategies for the management of outpatient PEx in the pediatric CF population. The two treatment arms are immediate antibiotics and tailored therapy. In both arms, participants will be instructed to increase airway clearance at the onset of an eligible PEx. In the immediate antibiotics arm, they will also begin 14 days of oral antibiotics preselected by their primary CF providers, while in the tailored therapy they will only begin antibiotics if prespecified criteria for worsening symptoms or failure to improve are met.

The STOP PEDS study will enroll three cohorts. In the main cohort, children ages 6-18 on highly effective modulator therapy (HEMT) will be enrolled when well and followed for 12 months. Participants will be randomly assigned to a treatment arm and maintain that treatment assignment for all subsequent eligible PEx during their 12-month enrollment period. Two additional pilot cohorts, the preschool cohort (children ages 3 to 5 on HEMT) and the non-HEMT cohort (children ages 6-18 not eligible for HEMT), will be enrolled in parallel pilot studies. Participants will enroll when well and be followed through one randomized PEx.

Participants in the STOP PEDS RCT at selected sites will have the opportunity to enroll in optional substudies if eligible. These substudies include:

• Clinic throat swab substudy
• Home throat and nasal swab substudy
• Remote monitoring substudy (Home monitoring of lung function, vital signs, activity and sleep)

Inclusion Criteria:

1. Age

   1. For main cohort and non-HEMT cohort: age 6 to <19 years
   2. For preschool cohort: age 3 to <6 years

2. Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria:

   1. sweat chloride ≥ 60 mEq/liter
   2. two disease-causing variants in the cystic fibrosis transmembrane conductive regulator (CFTR) gene

3. Written informed consent (and assent when applicable) obtained from participant or participant's legal representative and ability of participant to comply with the requirements of the study

4. Highly Effective Modulator Therapy

   1. For main cohort and preschool cohort: Taking HEMT for at least 3 months at enrollment
   2. For non-HEMT cohort: not eligible for HEMT based on CFTR genotype or eligible but not taking for at least 3 months and no plans to start HEMT in the next year, and also not taking tezacaftor-ivacaftor or lumacaftor-ivacaftor for at least 3 months

5. For main cohort and non-HEMT cohort: able to perform acceptable and reproducible spirometry

6. For main cohort and non-HEMT cohort: ppFEV1 ≥ 50% predicted at enrollment based on the Global lung Initiative (GLI) reference equations

7. Ability to receive text messages and access the internet

Exclusion Criteria:

1. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the individual or the quality of the data
2. Receiving an acute course of oral or IV antibiotics at the time of enrollment or within the 14 days prior to enrollment. Individuals may be re-screened ≥21 days after completion of antibiotics if they are at their baseline state of health, per self-report
3. Treatment with systemic corticosteroids at enrollment or within the 14 days prior to enrollment. Individuals may be re- screened ≥21 days after completion of systemic corticosteroids if they are at their clinical baseline, per self-report
4. History of solid organ transplant
5. History of positive culture for Mycobacterium abscessus in the 12 months prior to enrollment
6. Treatment with antibiotics for any non-tuberculous mycobacteria (NTM) at enrollment
7. Three or more IV antibiotic-treated PEx in the 12 months prior to enrollment
8. Treatment with chronic oral antibiotics other than azithromycin at enrollment
9. Treatment with systemic corticosteroids for allergic bronchopulmonary aspergillosis (ABPA) in the 12 months prior to enrollment