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Continuous alternating inhaled antibiotics for chronic pseudomonal infection in cystic fibrosis

Open AccessPublished:May 24, 2016DOI:https://doi.org/10.1016/j.jcf.2016.05.001

      Abstract

      Background

      Inhaled antibiotics are standard of care for treating chronic pseudomonal respiratory infections in cystic fibrosis patients, initially approved for intermittent administration. However, use of continuous inhaled antibiotic regimens of differing combinations is growing.

      Methods

      This double-blind trial compared continuous alternating therapy (CAT) to an intermittent treatment regimen. Subjects were treated with 3 cycles of 28-days inhaled aztreonam (AZLI) or placebo 3-times daily alternating with 28-days open-label tobramycin inhalation solution (TIS).

      Results

      90 subjects were randomized over 18 months. Study enrollment was limited, in part because of evolving practices by clinicians of adopting a CAT regimen in clinical practice; consequently the study was underpowered. AZLI/TIS treatment reduced exacerbation rates by 25.7% (p = 0.25; primary endpoint) and rates of respiratory hospitalizations by 35.8% compared with placebo/TIS (p = 0.14). AZLI/TIS CAT therapy was well tolerated.

      Conclusions

      This trial illustrates challenges with studying treatment regimens in a constantly evolving CF care environment. Nonetheless, the results of this trial indicate that AZLI/TIS CAT is well tolerated and may provide additional clinical benefit in CF patients compared with intermittent use of TIS alone.
      Clinicaltrials.gov: NCT01641822.

      Abbreviations:

      AZLI (aztreonam for inhalation solution), CAT (continuous alternating therapy), CFQ-R RSS (Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptoms Scale), CFRSD–CRISS (Cystic Fibrosis Respiratory Symptom Diary–Chronic Respiratory Infection Symptom Score), MIC (minimum inhibitory concentration), MMRM (mixed effect model repeated measures), NE (not estimable), PA (Pseudomonas aeruginosa), TIS (tobramycin inhalation solution)

      Keywords

      1. Introduction

      The standard of care for treating chronic Pseudomonas aeruginosa (PA) pulmonary infections in patients with cystic fibrosis (CF) is inhalation of antibiotics as aerosol mists or dry powder [
      • Mogayzel Jr., P.J.
      • Naureckas E.T.
      • Robinson K.A.
      • Mueller G.
      • Hadjiliadis D.
      • Hoag J.B.
      • et al.
      Pulmonary clinical practice guidelines. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health.
      ,
      • Smyth A.R.
      • Bell S.C.
      • Bojcin S.
      • Bryon M.
      • Duff A.
      • Flume P.
      • et al.
      European Cystic Fibrosis Society standards of care: best practice guidelines.
      ]. Inhaled antibiotics offer advantages over systemic therapy (oral or intravenous [IV]) because relatively high drug concentrations can be delivered to the site of lung infection with minimal systemic absorption, thus reducing the risk of side effects associated with exposure.
      The initial registration studies for tobramycin inhalation solution (TIS; TOBI®; Novartis Pharmaceuticals Corp.) established the 28-day chronic, intermittent regimen (also known as the “on/off” regimen), which has become the current treatment paradigm for inhaled antibiotics [
      • Ramsey B.W.
      • Pepe M.S.
      • Quan J.M.
      • Otto K.L.
      • Montgomery A.B.
      • Williams-Warren J.
      • et al.
      Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group.
      ]. However, evidence from clinical trials shows that during the “off” periods, patients lose lung function that was gained during “on” treatment periods and experience a worsened quality of life [
      • Konstan M.W.
      • Flume P.A.
      • Kappler M.
      • Chiron R.
      • Higgins M.
      • Brockhaus F.
      • et al.
      Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: the EAGER trial.
      ,
      • Assael B.M.
      • Pressler T.
      • Bilton D.
      • Fayon M.
      • Fischer R.
      • Chiron R.
      • et al.
      Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: a comparative efficacy trial.
      ,
      • Oermann C.M.
      • Retsch-Bogart G.Z.
      • Quittner A.L.
      • Gibson R.L.
      • McCoy K.S.
      • Montgomery A.B.
      • et al.
      An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis.
      ]. As a result, many CF physicians have moved to using continuous inhaled antibiotic therapy in their patients, either as monotherapy with a single agent used every month or as continuous alternating therapy (CAT) with 2 or more agents [
      • Dasenbrook E.C.
      • Konstan M.W.
      • VanDevanter D.R.
      Association between the introduction of a new cystic fibrosis inhaled antibiotic class and change in prevalence of patients receiving multiple inhaled antibiotic classes.
      ].
      This practice has led to a need for randomized, prospective clinical trial data to determine whether a continuous antibiotic regimen offers further improvement in pulmonary outcomes compared with an intermittent strategy. The primary objective of the Phase 3 clinical trial was to evaluate the safety and efficacy of a CAT regimen with aztreonam for inhalation solution (AZLI; Cayston®; Gilead Sciences, Inc.) and TIS in adult and pediatric subjects with CF and chronic pulmonary PA infections.

      2. Methods

      2.1 Study design

      This 28-week, randomized, double-blind, placebo-controlled trial was conducted at 45 US CF centers (Dec. 2012–Jan. 2015). Enrolled subjects received TIS 300 mg twice daily (BID) during a 28-day run-in phase (Fig. supplement). This was followed by randomization to a 24-week comparative phase. Eligible subjects were stratified by disease severity (forced expiratory volume at 1 s [FEV1] ≤50% or >50% predicted at Day 1) and number of acute respiratory exacerbations (1, 2, or ≥3; determined by the investigator) that required hospitalization or IV antibiotic use during the previous year. Subjects received 3 cycles of 28-days of double-blind AZLI or placebo (1:1 randomization) alternating with 28-days of open-label TIS.
      TIS was delivered using an LC Plus nebulizer (PARI Respiratory Equipment) and Pulmo-Aide compressor (DeVilbiss Healthcare). AZLI was delivered using the eFlow Nebulizer System (PARI). Administration of TIS (300 mg BID) and AZLI (75 mg three times daily [TID]) was consistent with prescribing information for each product [
      • Gilead Sciences Inc
      Cayston® (aztreonam for inhalation solution) prescribing information.
      ,
      • Novartis Pharmaceuticals Corporation
      TOBI® (tobramycin inhalation solution, USP) nebulizer solution. US prescribing information.
      ]. Placebo was lactose monohydrate and sodium chloride, reconstituted with the same diluent used for AZLI (0.17% w/v sodium chloride solution). A short acting bronchodilator was administered before every AZLI/placebo dose; patients continued any routine bronchodilator therapy. Treatment compliance was assessed by counting returned used/unused vials. Spirometry was performed according to American Thoracic Society guidelines. FEV1% predicted calculations used Hankinson [
      • Hankinson J.L.
      • Odencrantz J.R.
      • Fedan K.B.
      Spirometric reference values from a sample of the general U.S. population.
      ] and Wang [
      • Wang X.
      • Dockery D.W.
      • Wypij D.
      • Fay M.E.
      • Ferris Jr., B.G.
      Pulmonary function between 6 and 18 years of age.
      ] equations for adults and children, respectively. Age-appropriate versions of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) were employed for subjects 6–11 years of age (interviewer-administered), 12–13 years of age (self-administered), and ≥14 years of age (self-administered); the CFQ-R was administered before other study procedures [
      • Quittner A.L.
      • Sawicki G.S.
      • McMullen A.
      • Rasouliyan L.
      • Pasta D.J.
      • Yegin A.
      • et al.
      Psychometric evaluation of the Cystic Fibrosis Questionnaire-Revised in a national sample.
      ].
      The study was conducted in accordance with the principles of the Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South Africa), International Conference on Harmonization Guidelines, or US laws and regulations, which ever afforded the greatest protection to the subjects and was conducted according to Good Clinical Practice principles. An Institutional Review Board for each site approved the study. Each subject or his/her parent, guardian, or legally authorized representative provided written informed consent (or assent if applicable) before any study-related procedures were performed.

      2.2 Participants

      Eligible subjects with a CF diagnosis were ≥6 years of age with documented evidence of PA lung infection, FEV1 25–75% predicted, and had received ≥1 course of IV antibiotic treatment for a pulmonary exacerbation within the previous 12 months. Subjects were required to have a stable regimen for any chronic use of azithromycin, bronchodilators, dornase alfa, hypertonic saline, and/or corticosteroid medications, or physiotherapy techniques/regimen for ≥28 days before enrollment. Subjects receiving any antibiotic treatment, including AZLI or TIS, were eligible for screening, including subjects receiving intermittent, continuous, or continuous alternating aerosolized antibiotic treatment, but subjects could not be receiving any antibiotics (except azithromycin) when starting the TIS run-in phase. Subjects who used <50% of expected vials during any course of antibiotics were discontinued from study treatment. Complete inclusion/exclusion criteria are listed in the online supplement.

      2.3 Endpoints

      The primary efficacy endpoint was the rate of protocol-defined pulmonary exacerbations (PDEs) from Day 1 through Week 24. PDEs were defined as a change or worsening from baseline of 1 or more documented signs or symptoms (decreased exercise tolerance or appetite; increased cough, sputum, or chest congestion; or other signs/symptoms) associated with use of IV or non-study inhaled antibiotics and were verified by a blinded independent adjudication committee review of the data. Secondary endpoints included average absolute change from baseline FEV1% predicted after each AZLI/placebo course, percent of subjects treated for a PDE, time to first PDE, rate of hospitalization for a respiratory event, and average change from baseline scores (0–100) on the CFQ-R Respiratory Symptom Scale (RSS) after each AZLI/placebo course. The blinded adjudication committee identified respiratory-related hospitalizations. Average weekly changes from baseline scores (0–100) in Cystic Fibrosis Respiratory Symptom Diary (CFRSD)–Chronic Respiratory Infection Symptom Score (CRISS) was an exploratory endpoint; CFRSD–CRISS was completed daily by subjects ≥12 years of age [
      • University of Washington Departments of Medicine and Health Services
      Cystic fibrosis respiratory symptom diary (CFRSD) — U.S. version 2.0 user manual.
      ]. Microbiology endpoints included change from baseline sputum PA density, presence/absence of respiratory pathogens, and change from baseline minimum inhibitory concentrations (MIC) of aztreonam, tobramycin, and other antibiotics active against PA. Safety was monitored by assessing adverse events, airway reactivity after first study drug doses, vital signs, physical examination and clinical laboratory results.

      2.4 Statistics

      Planned enrollment was 250 subjects; 125 subjects per arm would provide ≥85% power to declare superiority of alternating AZLI/TIS to placebo/TIS in the PDE rate, assuming an approximately 40% difference in exacerbation rate (2-sided, 0.05 level). Sample size calculations were based on previous study results [
      • Assael B.M.
      • Pressler T.
      • Bilton D.
      • Fayon M.
      • Fischer R.
      • Chiron R.
      • et al.
      Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: a comparative efficacy trial.
      ].
      Efficacy analyses included all randomized subjects (intent-to-treat). Safety analyses included treated subjects. A family alpha-spending rule controlled the Type 1 error rate of 0.05, with the primary endpoint analysis serving as the gatekeeper and secondary endpoints tested sequentially (α = 0.05) based on the closed testing procedure [
      • Dmitrienko A.
      • Offen W.W.
      • Westfall P.H.
      Gatekeeping strategies for clinical trials that do not require all primary effects to be significant.
      ].
      The primary endpoint (rate of PDEs) was analyzed by negative binomial regression with an offset parameter accounting for follow-up time (2-sided, 0.05 level). Average changes from baseline FEV1% predicted and CFQ-R RSS scores were analyzed using an MMRM method, with terms for baseline value, previous exacerbations (1, 2, ≥3), treatment, visit, and treatment-by-visit interaction. Other methods for analyzing secondary endpoints are provided in the text.

      3. Results

      3.1 Study progress

      During the enrollment period (Dec 2012–May 2014), 73 sites were activated; only 45 enrolled subjects. The study was ultimately closed to enrollment early because successive site feasibility surveys indicated enrollment goals would not be reached. During the course of the trial, investigators were queried as to the key hurdles hampering enrollment. These included competing CF trials, increasing use during the enrollment period of CAT treatment as standard care for CF patients, a lack of a pulmonary exacerbation in the previous 12 months, approval of a dry powder formulation of inhaled tobramycin after the study started with some potential subjects expressing a preference for this medication rather than the TIS used in the study, and screen failures because of acute exacerbations prior to randomization. These were the primary factors which resulted in patients and clinicians being unwilling or unable to enroll in this randomized, placebo-controlled trial.

      3.2 Subject disposition

      Of 136 subjects screened for the study, 107 were enrolled and 93 completed the TIS run-in treatment (Fig. 1). Ninety subjects (AZLI: 43; placebo: 47) were randomized and 88 (AZLI: 42; placebo: 46) were treated during the comparative-treatment phase, with 72 (AZLI: 36; placebo: 36) completing comparative-phase treatment. Two subjects discontinued comparative-phase treatment due to adverse events (AZLI: 1, pulmonary mycosis; placebo: 1, FEV1 decreased). The majority of comparative-phase subjects took ≥80% of expected vials of AZLI (n = 37/42, 88.1%), placebo (n = 36/46, 78.3%), and TIS (AZLI/TIS: n = 39/40, 97.5%; placebo/TIS: n = 38/45, 84.4%).

      3.3 Subject characteristics

      Subject characteristics in each comparative-phase treatment group were similar (Table 1). One, 2, or ≥3 pulmonary exacerbations treated with IV antibiotics during the previous year were experienced by 22 (52.4%), 9 (21.4%), and 11 (26.2%) of 42 AZLI-treated subjects, respectively, and 27 (58.7%), 6 (13.0%), and 13 (28.3%) of 46 placebo-treated subjects.
      Table 1Characteristics of randomized subjects who were treated during the comparative phase.
      AZLI

      (N = 42)
      Placebo

      (N = 46)
      Total

      (N = 88)
      P-value
      P-values are from a 2-sided Fisher exact test for categorical variables and a Wilcoxon rank-sum test for continuous variables.
      Age at Day 1, years, mean (SD)28.5 (12.1)28.3 (10.8)28.4 (11.4)0.96
      Age group at Day 1, n (%)
       <18 years8 (19.0)6 (13.0)14 (15.9)0.56
       ≥18 years34 (81.0)40 (87.0)74 (84.1)
      Female, n (%)24 (57.1)27 (58.7)51 (58.0)1.00
      BMI, kg/m2 at Day 1, mean (SD)21.5 (4.3)21.2 (3.2)21.3 (3.7)0.92
      FEV1, % predicted at Day 1, mean (SD)49.9 (17.7)50.1 (15.3)50.0 (16.4)0.96
      FEV1, % predicted at Day 1, n (%)
       >50%21 (50.0)20 (43.5)41 (46.6)0.67
       ≤50%21 (50.0)26 (56.5)47 (53.4)
      CFQ-R RSS score at Day 1,
      CFQ-R RSS scores were available for 41, 46, and 87 subjects for the 3 columns. PA status was assessed for 40, 44, and 84 subjects. MIC values were determined for isolates from 38, 41, and 79 subjects; analyses were performed on 60, 68, and 128 isolates.
      mean (SD)
      60.2 (18.3)64.2 (15.2)62.3 (16.8)0.16
      Azithromycin use at Day 1 and/or during comparative phase, yes, n (%)34 (81.0)36 (78.3)70 (79.5)0.80
      PA present at Day 1,
      CFQ-R RSS scores were available for 41, 46, and 87 subjects for the 3 columns. PA status was assessed for 40, 44, and 84 subjects. MIC values were determined for isolates from 38, 41, and 79 subjects; analyses were performed on 60, 68, and 128 isolates.
      yes, n (%)
      38 (95.0)42 (95.5)80 (95.2)1.00
      MIC50 of aztreonam for all PA isolates at Day 1
      CFQ-R RSS scores were available for 41, 46, and 87 subjects for the 3 columns. PA status was assessed for 40, 44, and 84 subjects. MIC values were determined for isolates from 38, 41, and 79 subjects; analyses were performed on 60, 68, and 128 isolates.
      444-
      MIC50 of tobramycin for all PA isolates at Day 1
      CFQ-R RSS scores were available for 41, 46, and 87 subjects for the 3 columns. PA status was assessed for 40, 44, and 84 subjects. MIC values were determined for isolates from 38, 41, and 79 subjects; analyses were performed on 60, 68, and 128 isolates.
      222-
      Number of acute respiratory exacerbations requiring IV antibiotic treatment during the year before screening
       122 (52.4)27 (58.7)49 (55.7)
       29 (21.4)6 (13.0)15 (17.0)
       ≥311 (26.2)13 (28.3)24 (27.3)
      BMI = body mass index; CFQ-R = Cystic Fibrosis Questionnaire-Revised; FEV1 = forced expiratory volume at 1 s; MIC50 = minimum inhibitory concentration for 50% of the isolates; RSS = Respiratory Symptom Scale.
      Note: Day 1 is the beginning of the 24-week comparative-treatment phase.
      a P-values are from a 2-sided Fisher exact test for categorical variables and a Wilcoxon rank-sum test for continuous variables.
      b CFQ-R RSS scores were available for 41, 46, and 87 subjects for the 3 columns. PA status was assessed for 40, 44, and 84 subjects. MIC values were determined for isolates from 38, 41, and 79 subjects; analyses were performed on 60, 68, and 128 isolates.

      3.4 Effect on pulmonary exacerbations

      The rate of PDEs, as determined by investigators and the adjudication committee, was numerically lower in the AZLI group (1.31 PDEs per subject-year) than in the placebo group (1.76 PDEs per subject-year), representing a 25.7% reduction in exacerbation rate for the AZLI group, although the difference between groups was not statistically significant (p = 0.25, risk ratio: 0.74, 95% confidence interval [CI]: 0.45, 1.24). Risk ratios numerically favoring the AZLI group over the placebo group were seen for subgroups based on gender (female), age (<18 years, ≥18 years), FEV1% predicted (≤50%, >50%), history of pulmonary exacerbations in the year prior to enrollment (1, 2, ≥3) and use of azithromycin (yes), although none of these subgroups reached statistical significance (Fig. 2). The risk ratios progressively favored AZLI as the number of prior exacerbations in the previous year increased.
      Fig. 2
      Fig. 2Rate of protocol-defined exacerbations (primary endpoint) for subgroups of all randomized subjects. Risk ratio = risk of PDE for AZLI-treated subjects/risk for placebo-treated subjects.
      For the secondary endpoints, a numerically larger percentage of placebo-treated subjects (n = 26/47, 55.3%) than AZLI-treated subjects (n = 21/43, 48.8%) used non-study IV/inhaled antibiotics for PDEs from Day 1 through Week 24 (p = 0.67; Fisher exact test). Median (95% CI) time to first PDE was longer in the AZLI group (175.0 days [76.0, not estimable (NE)]) than in the placebo group (140.0 days [90.0, NE]) (hazard ratio [95% CI]: 0.89 [0.50, 1.59]; p = 0.71; Kaplan–Meier and log rank test). The rate of hospitalizations for a respiratory event during the comparative-treatment phase was numerically higher in the placebo group (1.62 per subject-year) than in the AZLI group (1.04 per subject-year); representing a 35.8% reduction in the respiratory hospitalization rate for the AZLI group; however, the difference between groups was not statistically significant (p = 0.14, risk ratio; 0.642, 95% CI: 0.36, 1.16; negative binomial regression).

      3.5 Effect on pulmonary function

      Adjusted mean actual FEV1% predicted increased from baseline after each AZLI course (Weeks 4, 12, and 20) and increased from baseline after 2 of 3 placebo courses (Weeks 4 and 20; Fig. 3A ). Values at Weeks 4, 12, and 20 were averaged, and the adjusted mean (SE) change from baseline was larger in the AZLI (1.37 [0.67]) than in the placebo (0.04 [0.66]) group, although the difference (95% CI) between treatment groups (1.33 [−0.55, 3.20]) was not statistically significant (p = 0.16).
      Fig. 3
      Fig. 3Adjusted mean change from baseline for FEV1% Predicted (A) and Log10 P. aeruginosa CFUs/g sputum (B). Adjusted means were based on a mixed effect model repeated measures (MMRM) that included terms for treatment, visit, baseline, previous exacerbations, and treatment-by-visit interaction (for FEV1% predicted) and terms for changes from baseline at all postbaseline visits through Week 24 (for PA density).

      3.6 Effect on respiratory symptoms

      Adjusted mean (SE) CFQ-R RSS scores averaged from Weeks 4, 12, and 20 improved 1.00 (1.74) from baseline for AZLI-treated subjects and worsened −2.06 (1.63) for placebo-treated subjects (p = 0.21). Mean (SD) CFRSD–CRISS weekly average scores prior to baseline were 33.9 (12.8) for AZLI-treated and 28.4 (12.2) for placebo-treated subjects. At each week except Week 20, mean scores numerically improved (decreased) 0.4–4.2 points from baseline for AZLI-treated subjects (except at Week 20) and were more variable for placebo-treated subjects (improvements; ≤1.3 points; worsenings: ≤2.9 points). For subjects with an exacerbation, the mean (SD) CFRSD–CRISS change from baseline for the average score of the 7 days before the first exacerbation was comparable for the AZLI (9.5 [14.4], n = 17) and placebo (9.1 [9.4], n = 24) treatment groups. Changes from baseline were also comparable for the 14 days before the first exacerbation (AZLI: 5.0 [10.1], n = 18; placebo: 6.5 [9.6], n = 24).

      3.7 Effect on microbiology

      Adjusted mean changes from baseline sputum PA density after each course of AZLI/placebo or TIS during the comparative-treatment phase were small (0.36 to −0.55 log10 CFU/g; Fig. 3B). Differences between treatment groups were not statistically significant.
      Most subjects evaluated (n = 81/85, 95.3%) were culture-positive for PA at baseline and most had PA present at ≥1 visit during Weeks 4–24 (AZLI: n = 41/42, 97.6%, placebo: n = 44/45, 97.8%). Incidences of other respiratory pathogens during Weeks 4–24 were also comparable between treatment groups, including Achromobacter spp. (AZLI: n = 6/42, 14.3%; placebo: n = 5/45, 11.1%), Stenotrophomonas maltophilia (AZLI: n = 9/42, 21.4%; placebo: n = 11/45, 24.4%), methicillin-sensitive Staphylococcus aureus (MSSA; AZLI: n = 11/42, 26.2%; placebo: n = 13/34, 28.9%), and Aspergillus spp. (AZLI: n = 11/42, 26.2%; placebo: n = 14/45, 31.1%). More placebo-treated (n = 18/45, 40.0%) than AZLI-treated (n = 11/42, 26.2%) subjects had methicillin-resistant S. aureus (MRSA) present at ≥1 visit. Burkholderia spp. were isolated in 1 subject (AZLI; during Weeks 16–24).
      During the comparative phase, aztreonam and tobramycin MIC50 values for all PA isolates changed ≤2-fold from baseline for both treatment groups. The MIC50 of amikacin, cefepime, ceftazidime, ciprofloxacin, meropenem, piperacillin, piperacillin/tazobactam, and ticarcillin/clavulanate for all PA isolates changed ≤2-fold from baseline through Week 24 except for isolated 4-fold increases in piperacillin/tazobactam (Week 16) and piperacillin (Week 20) MIC50 values for AZLI-treated subjects.

      3.8 Safety

      The most common treatment-emergent adverse events during the comparative phase were cough (AZLI/TIS: n = 32/42, 76.2%; placebo: n = 33/46, 71.7%), sputum increased (AZLI: n = 20/42, 47.6%; placebo/TIS: n = 31/46, 67.4%), and dyspnea (AZLI/TIS: n = 13/42, 31.0%; placebo/TIS: n = 24/46, 52.2%; Online Table 1). Adverse events of Grade 3 or Grade 4 severity were reported for 31.0% of AZLI/TIS-treated (n = 13/42) and 30.4% of placebo/TIS-treated (n = 14/46) subjects, most commonly lung disorder (AZLI/TIS: n = 6/42, 14.3%; placebo/TIS: n = 5/46, 10.9%) and infective pulmonary exacerbation of CF (AZLI/TIS: n = 4/42, 9.5%; placebo/TIS: n = 4/46, 8.7%). Treatment-related adverse events were reported for 3 subjects in each treatment group; all were Grade 1 or Grade 2 in severity. Serious adverse events were reported for 50.0% of AZLI/TIS-treated (n = 21/42) and 52.2% of placebo/TIS-treated (n = 24/46) subjects; none was considered treatment-related.

      4. Discussion

      Inhaled antibiotics have become standard of care for treating patients with CF and chronic airways infection. Approved inhaled antibiotics use a 28-day on/off (intermittent) treatment strategy, which was based upon the observations that there was little added benefit to lung function following 4 weeks of therapy and the assumption that intermittent antibiotic use would reduce the selection of resistant bacteria [
      • Smith A.L.
      • Ramsey B.W.
      • Hedges D.L.
      • Hack B.
      • Williams-Warren J.
      • Weber A.
      • et al.
      Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis.
      ]. It now appears that loss of the lung function treatment benefit occurs when the antibiotic pressure is removed and that a clinical response occurs even when highly resistant bacteria are present in the sputum cultures [
      • Ramsey B.W.
      • Pepe M.S.
      • Quan J.M.
      • Otto K.L.
      • Montgomery A.B.
      • Williams-Warren J.
      • et al.
      Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group.
      ,
      • Moss R.B.
      Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis.
      ]. Further, progressive loss of lung function continues over time and although studies have demonstrated a reduced number of pulmonary exacerbations, they still occur. There are few literature reports regarding prolonged continuous exposure to inhaled tobramycin. An early phase study preceding the development of TIS showed increased lung function over the 90 days of exposure [
      • Smith A.L.
      • Ramsey B.W.
      • Hedges D.L.
      • Hack B.
      • Williams-Warren J.
      • Weber A.
      • et al.
      Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis.
      ]. The initial improvement was followed by a decrease at 8 weeks, although lung function remained above baseline after 12 weeks of treatment. Therefore, it is reasonable to consider continuous use of inhaled antibiotics to suppress airways infection.
      Although one could compare continued and intermittent use of the same inhaled antibiotic, we chose to evaluate a rotation of antibiotics for 2 key reasons. First, this strategy allowed us to perform a double-blinded, placebo-controlled study with fewer potential biases. Second, the observation that a change in inhaled antibiotics is associated with a subsequent increase in lung function [
      • McCoy K.S.
      • Quittner A.L.
      • Oermann C.M.
      • Gibson R.L.
      • Retsch-Bogart G.Z.
      • Montgomery A.B.
      Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis.
      ] suggests that there may be an advantage to rotating antibiotics over time.
      What we had not anticipated was the challenge in enrolling such a trial, primarily because of evolving clinical practices including the availability of a new inhaled antibiotic product and many clinicians had already adopted a CAT treatment regimen for their patients. Some investigators had recommended removal of the exclusion criterion of no prior history of acute pulmonary exacerbation in the previous 12 months, but such patients have a lower risk of future exacerbations [
      • Vandevanter D.R.
      • Yegin A.
      • Morgan W.J.
      • Millar S.J.
      • Pasta D.J.
      • Konstan M.W.
      Design and powering of cystic fibrosis clinical trials using pulmonary exacerbation as an efficacy endpoint.
      ] and making such an amendment would have required a larger sample size. Therefore, the decision was made to cease further enrollment based on expected future recruitment futility, leaving us with an underpowered study. Nonetheless, the results are intriguing with the totality of evidence favoring CAT. Although the differences were not statistically significant, clinical endpoints improved in subjects treated with an AZLI/TIS CAT regimen compared with those treated with a placebo/TIS regimen: exacerbation rates were reduced (by 25%), rates of respiratory hospitalizations were reduced (by 35.8%), fewer subjects were treated with non-study antibiotics for PDEs, and the median time to first PDE was longer (175 vs 140 days),. Improvements in lung function were observed while subjects were treated with AZLI, with the largest improvement observed during the first 28-day treatment cycle (although not significant).
      In subgroup analyses of rate of PDE (primary endpoint), there was a numerical trend supporting a greater treatment effect with CAT for subjects with a greater number of pulmonary exacerbations in the prior year. In a recent study, the number of prior year exacerbations strongly correlated with the time to next exacerbation [
      • VanDevanter D.R.
      • Pasta D.J.
      • Konstan M.W.
      Treatment and demographic factors affecting time to next pulmonary exacerbation in cystic fibrosis.
      ]. Taken together, these data can be viewed as identifying a potential risk factor for patients that may benefit from AZLI/TIS CAT therapy.
      The CAT regimen was well tolerated over 3 treatment courses of AZLI alternating with TIS. The adverse event profile was consistent with previously established clinical trial experience with both AZLI and TIS [
      • Gilead Sciences Inc
      Cayston® (aztreonam for inhalation solution) prescribing information.
      ,
      • Novartis Pharmaceuticals Corporation
      TOBI® (tobramycin inhalation solution, USP) nebulizer solution. US prescribing information.
      ]. There was no apparent clinically-relevant selection of resistant pathogens; that is, there were no changes in the susceptibility of all PA isolates to aztreonam or tobramycin or treatment-emergent isolation of other respiratory pathogens. However, it should be noted that this is a small sample and a relatively short time frame so a difference may not be detected.
      In conclusion, the results of this trial demonstrate the challenges with evaluating new medications or treatment regimens in the CF populations where clinical practices are rapidly evolving. Although this study was underpowered and did not achieve statistical significance, the results suggest that there may be clinical benefit to continuous alternating treatment with inhaled antibiotics, specifically alternating AZLI and TIS, compared with intermittent use of TIS alone. These findings are consistent with the evolving treatment practices in CF of adopting a CAT regimen. In this context, the CF medical community will need to evaluate and determine the clinical value of these study results.
      Fig. supplement

      Acknowledgments

      We would like to thank all of the patients and their families who participated in this study and all of the participating sites and enrolling investigators (Steven Boas, Perry Brown, Anne Marie Cairns, Francisco Calimano, John Clancy, Rubin Cohen, John Colombo, Daniel Dorgan, Stanley Fiel, Patrick Flume, Caralee Forseen, Gavin Graff, Pamela Hofley, Wynton Hoover, Michelle Howenstine, Raksha Jain, Patricia Joseph, Claire Keating, Thomas Keens, Dana Kissner, Jorge Lascano, Laurie LeClair, Theodore Liou, Floyd Livingston, Joel Mermis, Susan Millard, Samya Nasr, David Nichols, Greg Omlor, Byron Quick, Diana Quintero, Peggy Radford, Hengameh Raissy, Santiago Reyes, Mark Rolfe, James Royall, Matthias Salathe, Iman Sami-Zakhari, Gregory Sawicki, David Schaeffer, Pedro Sepulveda, Kevin Shaw, Jonathan Spahr, Pierre Vauthy, and Seth Walker).
      This study was sponsored by Gilead Sciences. The Sponsor was involved in the study design, in the collection, analysis, and interpretation of the data. The Sponsor and all other authors were involved in the writing of this report and in the decision to submit the article for publication. We would also like to acknowledge the statistical programming support performed by Wei Lei and Chen Chi of Gilead Sciences and medical writing assistance from Kate Loughney, under the sponsorship of Gilead Sciences. Members of the independent blinded adjudication committee were Bonnie W. Ramsey, MD, D. Elizabeth Tullis, MD, and George Z. Retsch-Bogart, MD. Members of the Data Monitoring Committee were Lynne M. Quittell, MD, John C. Conlon, PhD, and David Speert, MD.

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