Daily Respiratory Research Analysis
Three practice-informing trials stand out today: a double-blind phase 3b trial shows that as-needed albuterol–budesonide halves severe exacerbations in mild asthma; two phase 3 trials of the PDE4B inhibitor nerandomilast slow FVC decline in idiopathic pulmonary fibrosis over 52 weeks; and a multicenter randomized trial finds navigational bronchoscopy noninferior to transthoracic needle biopsy with far fewer pneumothoraces for peripheral lung nodules.
Summary
Three practice-informing trials stand out today: a double-blind phase 3b trial shows that as-needed albuterol–budesonide halves severe exacerbations in mild asthma; two phase 3 trials of the PDE4B inhibitor nerandomilast slow FVC decline in idiopathic pulmonary fibrosis over 52 weeks; and a multicenter randomized trial finds navigational bronchoscopy noninferior to transthoracic needle biopsy with far fewer pneumothoraces for peripheral lung nodules.
Research Themes
- Anti-inflammatory reliever therapy in mild asthma
- Antifibrotic innovation in idiopathic pulmonary fibrosis
- Diagnostic pathway optimization for peripheral pulmonary nodules
Selected Articles
1. As-Needed Albuterol-Budesonide in Mild Asthma.
In this double-blind, event-driven phase 3b trial (n=2,516), as-needed albuterol–budesonide reduced severe exacerbations by about half versus albuterol alone in mild asthma, with similar adverse events and lower systemic steroid exposure. The trial stopped early for efficacy at interim analysis.
Impact: This provides high-level evidence that an anti-inflammatory reliever strategy benefits patients with mild asthma, a large population with frequent SABA-only use.
Clinical Implications: Clinicians can consider as-needed albuterol–budesonide instead of SABA-only for mild asthma to reduce severe exacerbations and systemic steroid exposure.
Key Findings
- Severe exacerbations: 5.1% with albuterol–budesonide vs 9.1% with albuterol alone (on-treatment; HR 0.53; 95% CI 0.39–0.73; P<0.001).
- Intention-to-treat analysis: 5.3% vs 9.4% (HR 0.54; 95% CI 0.40–0.73; P<0.001).
- Annualized severe exacerbation rate reduced (0.15 vs 0.32; rate ratio 0.47; 95% CI 0.34–0.64).
- Lower mean annual systemic glucocorticoid dose (23.2 vs 61.9 mg/year).
- Adverse events were similar between groups.
Methodological Strengths
- Multicenter, double-blind, randomized, event-driven phase 3b design.
- Efficacy signal robust across on-treatment and ITT analyses with prespecified interim stopping.
Limitations
- Fully virtual, decentralized design may affect generalizability and adherence assessment.
- Trial stopped early for efficacy, which can overestimate effect sizes.
Future Directions: Head-to-head comparisons with maintenance low-dose ICS, real-world effectiveness across diverse health systems, and long-term safety are warranted.
BACKGROUND: As-needed use of albuterol-budesonide has been shown to result in a significantly lower risk of severe asthma exacerbation than as-needed use of albuterol alone among patients with moderate-to-severe asthma. Data on albuterol-budesonide in mild asthma are needed. METHODS: We conducted a fully virtual, decentralized, phase 3b, multicenter, double-blind, event-driven trial involving persons 12 years of age or older with disease that was uncontrolled despite treatment for mild asthma with a short-acting β RESULTS: A total of 2516 participants underwent randomization; 1797 (71.4%) completed the trial. Of 2421 participants in the full analysis population (1209 assigned to the albuterol-budesonide group and 1212 to the albuterol group), 97.2% were 18 years of age or older; 74.4% used a SABA alone at baseline. The trial was stopped for efficacy at a prespecified interim analysis. A severe exacerbation occurred in 5.1% of the participants in the albuterol-budesonide group and in 9.1% of those in the albuterol group in the on-treatment efficacy population (hazard ratio, 0.53; 95% confidence interval [CI], 0.39 to 0.73) and in 5.3% and 9.4%, respectively, in the intention-to-treat population (hazard ratio, 0.54; 95% CI, 0.40 to 0.73) (P<0.001 for both comparisons). The annualized rate of severe asthma exacerbations was lower with albuterol-budesonide than with albuterol (0.15 vs. 0.32; rate ratio, 0.47; 95% CI, 0.34 to 0.64), as was the mean annualized total dose of systemic glucocorticoids (23.2 vs. 61.9 mg per year). Adverse events were similar in the two treatment groups. CONCLUSIONS: As-needed use of albuterol-budesonide resulted in a lower risk of a severe asthma exacerbation than as-needed use of albuterol alone among participants with disease that was uncontrolled despite treatment for mild asthma. (Funded by Bond Avillion 2 Development and AstraZeneca; BATURA ClinicalTrials.gov number, NCT05505734.)See also in
2. Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis.
In a 52-week, double-blind phase 3 trial (n=1,177), nerandomilast attenuated FVC decline in IPF versus placebo, including in patients already receiving nintedanib or pirfenidone. Diarrhea was the most frequent adverse event; serious adverse events were balanced.
Impact: This is a large, well-controlled phase 3 trial of a novel PDE4B inhibitor showing clinically meaningful preservation of lung function in IPF, a disease with high unmet need.
Clinical Implications: Nerandomilast could be considered as an add-on or alternative antifibrotic option to slow lung function decline in IPF; monitoring for gastrointestinal adverse effects is required.
Key Findings
- Adjusted mean FVC change at week 52: −114.7 mL (18 mg), −138.6 mL (9 mg), −183.5 mL (placebo).
- Adjusted differences vs placebo: +68.8 mL (18 mg; 95% CI 30.3–107.4; P<0.001) and +44.9 mL (9 mg; 95% CI 6.4–83.3; P=0.02).
- 77.7% were on nintedanib or pirfenidone at enrollment; benefit observed across background therapy strata.
- Diarrhea occurred in 41.3% (18 mg), 31.1% (9 mg), 16.0% (placebo); serious adverse events were similar across groups.
Methodological Strengths
- Large, multicenter, double-blind randomized design with 52-week follow-up.
- Stratification by background antifibrotic therapy and clinically meaningful primary endpoint (FVC).
Limitations
- Primary endpoint was FVC change; effects on mortality or acute exacerbations were not established.
- Gastrointestinal side effects (notably diarrhea) were more frequent with nerandomilast.
Future Directions: Evaluate long-term outcomes (mortality, exacerbations), head-to-head comparisons with existing antifibrotics, and biomarker-driven responder analyses.
BACKGROUND: Nerandomilast (BI 1015550) is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory effects. In a phase 2 trial involving patients with idiopathic pulmonary fibrosis, treatment with nerandomilast stabilized lung function over a period of 12 weeks. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with idiopathic pulmonary fibrosis in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg twice daily, nerandomilast at a dose of 9 mg twice daily, or placebo, with stratification according to background antifibrotic therapy (nintedanib or pirfenidone vs. none). The primary end point was the absolute change from baseline in forced vital capacity (FVC), measured in milliliters, at week 52. RESULTS: A total of 1177 patients underwent randomization, of whom 77.7% were taking nintedanib or pirfenidone at enrollment. Adjusted mean changes in FVC at week 52 were -114.7 ml (95% confidence interval [CI], -141.8 to -87.5) in the nerandomilast 18-mg group, -138.6 ml (95% CI, -165.6 to -111.6) in the nerandomilast 9-mg group, and -183.5 ml (95% CI, -210.9 to -156.1) in the placebo group. The adjusted difference between the nerandomilast 18-mg group and the placebo group was 68.8 ml (95% CI, 30.3 to 107.4; P<0.001), and the adjusted difference between the nerandomilast 9-mg group and the placebo group was 44.9 ml (95% CI, 6.4 to 83.3; P = 0.02). The most frequent adverse event in the nerandomilast groups was diarrhea, reported in 41.3% of the 18-mg group and 31.1% of the 9-mg group, as compared with 16.0% in the placebo group. Serious adverse events were balanced across trial groups. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, treatment with nerandomilast resulted in a smaller decline in the FVC than placebo over a period of 52 weeks. (Funded by Boehringer Ingelheim; FIBRONEER-IPF ClinicalTrials.gov number, NCT05321069.).
3. Navigational Bronchoscopy or Transthoracic Needle Biopsy for Lung Nodules.
In a multicenter randomized noninferiority trial (n=234 analyzed), navigational bronchoscopy achieved noninferior 12-month diagnostic accuracy compared with transthoracic needle biopsy for 10–30 mm peripheral nodules, while markedly reducing pneumothorax (3.3% vs 28.3%) and need for chest tube or admission.
Impact: The trial supports a safer first-line diagnostic strategy for peripheral pulmonary nodules without sacrificing accuracy, with substantial reductions in pneumothorax risk.
Clinical Implications: For intermediate/high-risk 10–30 mm peripheral nodules, navigational bronchoscopy may be preferred to minimize pneumothorax and downstream resource use while maintaining diagnostic accuracy.
Key Findings
- Diagnostic accuracy at 12 months: 79.0% (navigational bronchoscopy) vs 73.6% (transthoracic biopsy); absolute difference 5.4 percentage points (95% CI −6.5 to 17.2); noninferiority P=0.003.
- Pneumothorax: 3.3% with navigational bronchoscopy vs 28.3% with transthoracic biopsy; chest tube/admission required in 0.8% vs 11.5%, respectively.
- Randomized, multicenter comparison in 10–30 mm peripheral nodules and intermediate/high malignancy risk.
Methodological Strengths
- Randomized, multicenter, parallel-group noninferiority design with 12-month confirmation of diagnosis.
- Clinically meaningful safety endpoints captured (pneumothorax, chest tube, admission).
Limitations
- Operator and center expertise may influence outcomes and limit generalizability.
- Sample size, while adequate for noninferiority, may limit subgroup analyses.
Future Directions: Cost-effectiveness, patient-reported outcomes, and integration with robotic or advanced guidance systems merit evaluation; validation across diverse practice settings is needed.
BACKGROUND: Each year, millions of pulmonary nodules are identified incidentally or through lung cancer screening, and many involve biopsy to distinguish cancer from benign processes. Both navigational bronchoscopy and computed tomography-guided transthoracic needle biopsy are commonly used in patients undergoing biopsies of peripheral pulmonary nodules, but the relative diagnostic accuracy of these two approaches is unclear. METHODS: In this multicenter, randomized, parallel-group, noninferiority trial, we assigned patients with an intermediate-risk or high-risk peripheral pulmonary nodule measuring 10 to 30 mm in diameter to undergo navigational bronchoscopy or transthoracic needle biopsy at seven centers across the United States. The primary outcome was diagnostic accuracy, which was defined as the percentage of patients with biopsies that showed a specific diagnosis (cancer or a specific benign condition) that was confirmed to be accurate through 12 months of clinical follow-up (nonferiority margin, 10 percentage points). Secondary outcomes included procedural complications such as the occurrence of pneumothorax. RESULTS: Among the 234 patients included in the primary-outcome analysis (5 of whom were lost to follow-up), biopsy resulted in a specific diagnosis that was confirmed to be accurate through month 12 in 94 of 119 patients (79.0%) in the navigational bronchoscopy group and in 81 of 110 patients (73.6%) in the transthoracic needle biopsy group (absolute difference, 5.4 percentage points; 95% confidence interval, -6.5 to 17.2; P = 0.003 for noninferiority; P = 0.17 for superiority). Pneumothorax occurred in 4 of 121 patients (3.3%) in the navigational bronchoscopy group and in 32 of 113 patients (28.3%) in the transthoracic needle biopsy group and led to the placement of a chest tube, hospital admission, or both in 1 patient (0.8%) and 13 patients (11.5%), respectively. CONCLUSIONS: The diagnostic accuracy of navigational bronchoscopy was noninferior to that of transthoracic needle biopsy among patients with peripheral pulmonary nodules measuring 10 to 30 mm. (Funded by Medtronic and others; VERITAS ClinicalTrials.gov number, NCT04250194.).