Study design considerations for the Standardized Treatment of Pulmonary Exacerbations 2 (STOP2): A trial to compare intravenous antibiotic treatment durations in CF

Abstract

Background: Pulmonary exacerbations (PEx) in cystic fibrosis (CF) are common and contribute to morbidity and mortality. Duration of IV antibiotic therapy to treat PEx varies widely in the US, and there are few data to guide treatment decisions.

Methods: We combined a survey of CF stakeholders with retrospective analyses of a recent observational study of CF PEx to design a multicenter, randomized, prospective study comparing the efficacy and safety of different durations of IV antibiotics for PEx to meet the needs of people with CF and their caregivers.

Results: IV antibiotic duration was cited as the most important PEx research question by responding CF physicians and top concern among surveyed CF patients/caregivers. During PEx, forced expiratory volume in 1s (FEV₁% predicted) and symptom responses at 7-10days of IV antibiotics identified two distinct groups: early robust responders (ERR) who subsequently experienced greater FEV₁ improvements compared to non-ERR (NERR). In addition to greater FEV₁ and symptom responses, only 14% of ERR patients were treated with IV antibiotics for >15days, compared with 45% of NERR patients.

Conclusions: A divergent trial design that evaluates subjects' interim improvement in FEV₁ and symptoms to tailor randomization to IV treatment duration (10 vs. 14days for ERR, 14 vs. 21days for NERR) may alleviate physician and patient concerns about excess or inadequate treatment. Such a study has the potential to provide evidence necessary to standardize IV antibiotic duration in CF PEx care -a first step to conducting PEx research of other treatment features.

Keywords: Cystic fibrosis; FEV1; Pulmonary exacerbation; Symptoms.

Figure 1. Mean FEV₁ change from admission through Day 7–10 and Follow-Up (Day 28) by ERR/NERR threshold

Panel A, Patients meeting the FEV₁ improvement threshold and having a CRISS improvement of ≥11 points at Day 7–10 (ERR). Panel B, patients not meeting both the ERR FEV₁ threshold and CRISS criteria at Day 7–10 (NERR). The X-axis shows the Day 7–10 FEV₁ change exceeded by ERR patients. Mean FEV₁ changes at Day 7–10 are shown in white, mean FEV₁ changes at Follow-Up are shown in gray. Sample sizes are shown in parentheses; bars are 95% confidence intervals for means. Day 7–10 total n=104 with both FEV₁ and CRISS; Day 28 Follow-Up total n=89 with FEV₁.

Figure 2. Categorical antibiotic treatment durations for ERR and NERR patients across different ERR FEV₁ thresholds

Panel A, STOP ERR adults; Panel B, STOP NERR adults. Open circles, patients treated less than 12 days. Gray circles, patients treated between 12 and 15 days. Black circles, patients treated >15 days. Total n=89 with FEV1 and CRISS at Day7–10 and treatment duration recorded.

Figure 3. Mean absolute change in FEV₁ % predicted in STOP adults

from start of IV antibiotic treatment to Day 7–10, end of IV treatment, and Day 28, by ERR (FEV₁ ≥ 8% and CRISS improvement ≥11) and NERR (FEV₁ < 8% or CRISS improvement <11). Vertical lines span from 25^th to 75^th percentiles; n at each time point shown on figure.

Figure 4. STOP2 Study Schema

Patients enrolled in the study begin receiving IV antibiotics at Visit 1. Their change in FEV₁ and CRISS from Visit 1 is evaluated at Visit 2, between 7 and 10 days after Visit 1. Patients with an FEV₁ improvement of ≥8% predicted and CRISS improvement of ≥11 points are allocated to the ERR (Early Robust Rersponse) study branch, where they will be randomized 1:1 to receive either 10 (±1) or 14 (±) total days of antibiotic treatment. All other patients are allocated to the non-ERR (NERR) study branch, where they will be randomized 1:1 to receive either 14 (±1) or 21 (±3) total days of antibiotic treatment. Dark gray bars, IV antibiotic treatment; white bars, post-treatment follow-up; V, Study Visit; D, Study Day.