A Randomized Clinical Trial of Antimicrobial Duration for Cystic Fibrosis Pulmonary Exacerbation Treatment

Abstract

Rationale: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. Objectives: To test differing durations of intravenous antimicrobials for CF exacerbations. Methods: STOP2 (Standardized Treatment of Pulmonary Exacerbations 2) was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7-10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days' total antimicrobial duration; all others were randomized to 14 or 21 days' duration. Measurements and Main Results: The primary outcome was percent predicted FEV1 (ppFEV1) change from treatment initiation to 2 weeks after cessation. Among early responders, noninferiority of 10 days to 14 days was tested; superiority of 21 days compared with 14 days was compared for the others. Symptoms, weight, and adverse events were secondary. Among 982 randomized people, 277 met improvement criteria and were randomized to 10 or 14 days of treatment; the remaining 705 received 21 or 14 days of treatment. Mean ppFEV1 change was 12.8 and 13.4 for 10 and 14 days, respectively, a ‒0.65 difference (95% CI [‒3.3 to 2.0]), excluding the predefined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV1 changes, a difference of ‒0.10 (‒1.3 to 1.1). Secondary endpoints and sensitivity analyses were supportive. Conclusions: Among adults with CF with early treatment improvement during exacerbation, ppFEV1 after 10 days of intravenous antimicrobials is not inferior to 14 days. For those with less improvement after one week, 21 days is not superior to 14 days. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

Keywords: respiratory infection; clinical trial; intravenous antibiotic therapy.

Figures

Figure 1.

Consolidated Standards of Reporting Trials (CONSORT) diagram. Note: A participant can be excluded from the PP population for more than one reason. Exclusions due to protocol violations: *i.v. antibiotic treatment ending outside the allowed window for a deviation from assigned treatment duration: ± 1 day for 10- and 14-day assignments, ± 3 days for 21-day assignments; †restarting i.v. antibiotic treatment 1 or 2 days after the actual completion of i.v treatment; ‡any acute oral or inhaled antibiotic started before the scheduled completion of i.v treatment and continued after the scheduled completion of i.v. treatment; §any acute oral or inhaled antibiotic started after the scheduled completion of the i.v. treatment and before Visit 3, except continuation of ongoing chronic treatment of initiation of new chronic antibiotic therapy; and ∥spirometry measures done 4 or more days outside of the allowed window for Visit 3 (± 2 days). abx = antibiotics; ERR = early robust responder; NERR = non–early robust responder.

Figure 2.

Outcomes by visit, allocation, and antimicrobial treatment duration: (A) Primary outcome ppFEV1. (B) Chronic respiratory infection symptom score (CRISS). (C) Weight. V1 = visit 1 at start of intravenous antimicrobials; V2 = visit 2 when randomization occurs; and V3 = visit 3 was targeted for 14 days after scheduled end of intravenous antimicrobial treatment. Table E1 in the online supplement provides realized timing of each visit by allocation and duration assignment. CI = confidence interval; ERR = early robust responder; NERR = non–early robust responder; ppFEV1 = percent of predicted FEV1.

Figure 3.

Point estimates and 95% confidence intervals for treatment differences in sensitivity analysis populations: (A) Primary endpoint ppFEV1 change from visit 1 to visit 3; (B) CRISS change from visit 1 to visit 3; (C) weight change from visit 1 to visit 3. Adjusted = ANOVA adjusted for randomization strata: ppFEV1 < 50%, location of intravenous treatment, corticosteroid use, and history of PEx in the year before. Interim adjusted = bias adjustment for interim analyses (according to prespecified boundary parameters). CI = confidence interval; CRISS = Chronic Respiratory Infection Symptom Score; ERR = early robust responder; LOCF = last observation carried forward; NERR = non–early robust responder; PEx = pulmonary exacerbations; ppFEV1 = percent of predicted FEV1.

Figure 4.

Kaplan-Meier survival curves of time to next PEx requiring intravenous antimicrobials ascertained from the U.S. Cystic Fibrosis Foundation patient registry: (A) Early robust responders per protocol (10 d, n = 104; 14 d, n = 105). (B) Non–early robust responders, intent to treat (14 d, n = 346; 21 d, n = 343). ERR = early robust responder; ITT = intent to treat; PEx = pulmonary exacerbations; PP = per protocol; NERR = non–early robust responder.