NEJM original articles

Background. Mucoactive agents are widely used in patients with acute respiratory failure despite limited evidence of their effectiveness or safety.

Methods. We conducted a multicenter, open-label, randomized trial with a 2-by-2 factorial design that involved critically ill, mechanically ventilated participants 16 years of age or older with acute respiratory failure and difficult-to-clear secretions. All participants received usual care along with carbocisteine (750 mg three times daily enterally), 6% or 7% nebulized hypertonic saline (HTS) (4 ml four times daily), both interventions, or usual care alone for up to 28 days. The primary outcome was duration of mechanical ventilation (from randomization to first successful unassisted breathing). The primary comparisons were between any carbocisteine and no carbocisteine and between any HTS and no HTS, with each comparison comprising two treatment groups.

Results. A total of 1956 participants underwent randomization: 486 were assigned to carbocisteine, 485 to HTS, 492 to both treatments, and 493 to usual care alone (472, 474, 479, and 478, respectively, were included in the primary analysis). No evidence of treatment interaction was found (hazard ratio, 1.01, 95% confidence interval [CI], 0.83 to 1.22; P = 0.91). The median duration of mechanical ventilation was 186.1 hours (95% CI, 168.3 to 196.6) with carbocisteine and 172.7 hours (95% CI, 165.2 to 190.4) with no carbocisteine (adjusted hazard ratio, 0.96; 95% CI, 0.87 to 1.05; P = 0.34) and 184.5 hours (95% CI, 165.6 to 194.1) with HTS and 174.3 hours (95% CI, 166.9 to 192.7) with no HTS (adjusted hazard ratio, 1.00; 95% CI, 0.91 to 1.10; P = 0.98). Clinically important upper gastrointestinal bleeding occurred significantly more often with carbocisteine than with no carbocisteine (13 of 965 [1.4%] vs. 2 of 966 [0.2%]; risk ratio, 6.51; 95% CI, 1.47 to 28.76; P = 0.01). Bronchoconstriction leading to bronchodilator use occurred significantly more often with HTS than with no HTS (23 of 967 [2.4%] vs. 4 of 964 [0.4%]; risk ratio, 5.73; 95% CI, 1.99 to 16.52; P = 0.001), as did hypoxemia during nebulization (40 of 967 [4.1%] vs. 3 of 964 [0.3%]; risk ratio, 13.29; 95% CI, 4.12 to 42.83; P<0.001). One serious adverse reaction was reported in the combination group.

Conclusions. Among critically ill patients with acute respiratory failure, neither carbocisteine nor HTS significantly reduced the duration of mechanical ventilation, and each was associated with harm. (Funded by the NIHR Health Technology Assessment Programme and the Belfast Health and Social Care Trust Charitable Trust Fund; MARCH ISRCTN Registry number, ISRCTN17683568.).

Background. Wheezing illnesses are a leading cause of hospitalization for preschool-age children and are frequently treated with antibiotics. Observational studies have shown more frequent isolation of three pathogenic bacteria (Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae) from nasopharyngeal samples from children with recurrent episodes of wheezing than from those without such illnesses.

Methods. In this multicenter trial, we randomly assigned patients 18 to 59 months of age who presented to an emergency department with a moderate-to-severe episode of wheezing to receive azithromycin once daily at a dose of 12 mg per kilogram of body weight or matching placebo for 5 days. The primary outcome was the sum of scores on the Asthma Flare-up Diary for Young Children (ADYC) over 5 days. Primary-outcome scores could range from 5 to 35, with higher scores indicating more severe wheezing-related symptoms. Efficacy was assessed separately in patients who tested positive for pathogenic bacteria (the positive cohort) and in those who tested negative (the negative cohort). Secondary outcomes were length of stay in the emergency department, length of hospital stay, and return emergency department visits or hospitalizations within 72 hours. Bacterial clearance and antimicrobial resistance were measured at follow-up visits 1 to 3 weeks after randomization.

Results. Among 840 patients who underwent randomization, 521 tested positive for pathogenic bacteria. The trial was stopped for futility by the data and safety monitoring board after a planned interim analysis. ADYC scores did not differ significantly between the azithromycin and placebo groups in either the positive cohort (median, 9.59 [interquartile range, 7.29 to 12.60] vs. 9.72 [interquartile range, 7.66 to 12.17]; P = 0.70) or the negative cohort (median, 9.30 [interquartile range, 6.97 to 11.62] vs. 9.10 [interquartile range, 7.19 to 11.45]; P = 0.69). In the positive cohort, bacterial clearance was 58.7% in the azithromycin group and 11.4% in the placebo group. Secondary outcomes appeared to be similar in the two groups for both cohorts, as did the development of bacterial resistance and the incidence of adverse events.

Conclusions. Azithromycin did not lead to a greater reduction in the severity of wheezing-related symptoms than placebo in preschool-age children who presented to the emergency department with moderate-to-severe acute wheezing. (Funded by the National Heart, Lung, and Blood Institute and others; AZ-SWED ClinicalTrials.gov number, NCT04669288.).

Background. Sunvozertinib received accelerated approval for use in later lines of therapy for patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations. Data are needed on the efficacy and safety of sunvozertinib as a first-line treatment for NSCLC.

Methods. In this phase 3, international trial, we randomly assigned, in a 1:1 ratio, patients with advanced nonsquamous NSCLC with EGFR exon 20 insertions to receive sunvozertinib or chemotherapy (carboplatin-pemetrexed). The primary end point was progression-free survival as assessed by blinded independent central review. Crossover to the sunvozertinib group was allowed after disease progression was confirmed. Secondary end points included overall survival, investigator-assessed progression-free survival, objective response (complete or partial response), change in tumor size, and duration of response.

Results. A total of 324 patients were randomly assigned to receive sunvozertinib (163 patients) or chemotherapy (161 patients). Treatment with sunvozertinib led to significantly longer median progression-free survival than chemotherapy (10.3 vs. 7.5 months; hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.50 to 0.85; P<0.001). At 12 months, progression-free survival was reported in 46.1% of the patients in the sunvozertinib group and in 26.7% of those in the chemotherapy group; the data for overall survival were immature (38.9% maturity). The percentage of patients with an objective response was 58.9% in the sunvozertinib group and 31.1% in the chemotherapy group; the median best percentage change in tumor size was -42.1% and -24.7% respectively, and the median duration of response was 11.2 and 7.1 months. Grade 3 or higher adverse events were reported in 75.5% of the patients in the sunvozertinib group and in 56.7% of those in the chemotherapy group. In the sunvozertinib group, the most common adverse events of grade 3 or higher included increased serum creatine kinase levels, diarrhea, and anemia. No deaths were attributed to adverse events considered by the investigators to be related to sunvozertinib.

Conclusions. The efficacy of sunvozertinib was superior to that of chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions. (Funded by Dizal Pharmaceuticals; WU-KONG28 ClinicalTrials.gov number, NCT05668988.).

Background. Although medications with glucagon-like peptide-1 (GLP-1) receptor agonist activity have transformed the management of obesity and shown substantial cardiometabolic benefits, unmet needs remain. Survodutide, an investigational glucagon receptor-GLP-1 receptor dual agonist, led to substantial weight reduction in a phase 2 trial involving adults with obesity without diabetes.

Methods. In this phase 3, double-blind trial, we randomly assigned adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher, or 27 or higher with at least one obesity-related complication (excluding diabetes), in a 1:1:1 ratio to receive once-weekly survodutide administered subcutaneously at a dose adjusted up to 3.6 mg or 6.0 mg or placebo, in addition to counseling for lifestyle modification. The two primary end points were the percent change in body weight and a reduction in body weight of at least 5% from baseline to week 76. The primary efficacy analysis was conducted according to the treatment-regimen estimand, which incorporates the effects of any early discontinuation of survodutide or placebo, the use of protocol-prohibited obesity medications, and a prolonged dose-escalation period.

Results. Among 725 participants (241 in the 3.6-mg survodutide group, 242 in the 6.0-mg survodutide group, and 242 in the placebo group), the mean age was 47.1 years; 294 participants (40.6%) were men. At baseline, the mean BMI was 37.9, and the mean body weight was 108.8 kg. At week 76, the mean change in body weight from baseline according to the treatment-regimen estimand was -12.2% (95% confidence interval [CI], -13.6 to -10.8) in the 3.6-mg group, -13.0% (95% CI, -14.4 to -11.6) in the 6.0-mg group, and -5.4% (95% CI, -6.9 to -4.0) in the placebo group; 72.6%, 71.9% and 46.3% of the participants, respectively, had weight reduction of at least 5% (P<0.001 for all comparisons with placebo). The most common adverse events were gastrointestinal symptoms (typically mild to moderate), which occurred in 80.9% of the participants in the 3.6-mg group, in 89.7% of those in the 6.0-mg group, and in 47.9% of those in the placebo group. No deaths were reported.

Conclusions. Survodutide led to significantly greater reductions in body weight than placebo in adults with obesity without diabetes. (Funded by Boehringer Ingelheim; SYNCHRONIZE-1 ClinicalTrials.gov number, NCT06066515.).