What will happen during the study?

Participants will be enrolled at their well baseline state of health (“well state”). At the enrollment visit, spirometry and multiple breath washout (MBW) will be performed and the age-appropriate symptom report (Chronic Respiratory Infection Symptom Score (CRISS) [18]) completed. All patient-facing materials will be available in both English and Spanish. The primary CF provider will be provided with a list of standard oral antibiotics used to treat CF respiratory organisms. The provider will be asked to select a PEx antibiotic for that participant, which can be updated during the study based on results of clinical respiratory cultures or other new clinical information. This selection may be completed in consultation with the participant based on previous experience with antibiotics or preference. The primary CF provider will also be asked to specify inhaled therapies (dornase or hypertonic saline) that the participant should continue, increase, or re-start during an exacerbation. There will be study visits at 3, 6, 9 and 12 months (± 1 month). The 12-month visit may occur as late as 14 months to allow for at least 14 days since completion of most recent course of antibiotics or a Day 28 visit. Study visits will be completed at the time of clinic visits when possible. and spirometry and MBW will be performed. 

During the well state, participants will continue routine clinical care. Caregivers will be instructed to contact the research team within 3 to 7 days of the onset of new respiratory symptoms. Weekly text messages will be sent via REDCap asking if participants are experiencing new or increased cough and if so, they will be contacted by the research team. 

At the time of detection of a new PEx, either remotely (i.e., the participant or their caregiver notifies the study team or responds to a weekly text message) or at a clinic visit, participants will be assessed for eligibility for treatment of the event according to assigned arm based on symptom severity and duration (i.e., that they are not too sick to be treated according to study protocol). An in-person visit is not required. Participants will be randomized to immediate antibiotics or tailored therapy at their first PEx that meets acceptability criteria and treated according to their assigned arm. All subsequent eligible PEx for a participant will be treated in the same arm through the end of the study year. Any PEx that does not meet acceptability criteria will be treated clinically. Participants/caregivers will complete the age appropriate CRISS, CFQ-R, and WPAI.

For each eligible PEx, participants randomized to immediate antibiotics will be instructed to begin oral antibiotics for 14 days with the antibiotic previously selected by the primary CF provider. Those randomized to tailored therapy will not begin antibiotics immediately. 

Participants in both arms will be instructed to use their usual airway clearance at least 3 times daily according to CF Foundation guidelines [26] for 7 days or until symptoms return to near baseline, whichever comes first. They will also be instructed to use inhaled therapies (e.g., hypertonic saline, dornase alfa) as directed by their primary CF clinician at the enrollment visit.

Participants in both arms will be contacted by the study team on days 5, 8, 15, and 22 (± 1 day and at least 2 days apart) after initiation of study treatment. They will be instructed to contact the study team if symptoms worsen. If symptoms meet pre-specified criteria, participants in the tailored therapy arm will be started on oral antibiotics with the antibiotic previously selected by the primary CF provider and participants in the immediate antibiotics arm will return to clinical care. Participants in either arm who meet pre-specified criteria for worsening despite oral antibiotics will return to clinical care for consideration of additional interventions.

During the PEx period, participants or their caregivers (as detailed below) will complete an electronic treatment and targeted adverse event diary and the age appropriate CRISS daily for 7 days, then every other day through day 15. The caregiver will also complete the WPAI weekly. Any clinical questions unrelated to antibiotic management (e.g., nutrition issues, school or work issues) will be managed by the clinical team.

A Day 28 (±3 days) visit will occur for all PEx during the study period for which treatment according to the assigned arm was initiated. The Day 28 visit is only in-person for the first PEx; any subsequent Day 28 visits are remote. At the in-person Day 28 visit, participants will perform spirometry and MBW. At all Day 28 visits, participants/caregivers will complete the age appropriate CRISS, CFQ-R, and WPAI. Concomitant medications, antibiotic use, and AEs during the PEx period will be reviewed. On Day 28, if symptoms have not returned to baseline or ppFEV1 is more than 10% predicted below most recent well-state baseline, the participant will be referred to the clinical team for additional evaluation and management if necessary. 

A final in-person study visit will occur 12 months after enrollment, at which point participants will perform spirometry and MBW and then exit from the study. This visit can occur up to month 14 to ensure that it is scheduled a minimum of 14 days after completion of a course of oral or IV antibiotics and a minimum of 14 days after a Day 28 visit (in-person or remote) as there may be PEx that occur very late in the study period.