Daily Respiratory Research Analysis
Three high-impact respiratory studies stood out today: a phase 3 RCT in NEJM shows inhaled molgramostim improves gas transfer and quality of life in autoimmune pulmonary alveolar proteinosis; a large multicenter RCT in BMJ demonstrates that lateral positioning during procedural sedation reduces hypoxemia; and a phase 3 double-blind trial in EClinicalMedicine finds a near–zero GWP propellant (HFO-1234ze) delivers COPD triple therapy with safety comparable to HFA-134a, enabling lower-carbon inhale
Summary
Three high-impact respiratory studies stood out today: a phase 3 RCT in NEJM shows inhaled molgramostim improves gas transfer and quality of life in autoimmune pulmonary alveolar proteinosis; a large multicenter RCT in BMJ demonstrates that lateral positioning during procedural sedation reduces hypoxemia; and a phase 3 double-blind trial in EClinicalMedicine finds a near–zero GWP propellant (HFO-1234ze) delivers COPD triple therapy with safety comparable to HFA-134a, enabling lower-carbon inhalers.
Research Themes
- Targeted inhaled therapies for rare lung disease
- Peri-procedural respiratory safety and airway management
- Sustainable transitions in inhaler propellants
Selected Articles
1. Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis.
In a 48-week, double-blind phase 3 RCT in autoimmune PAP (n=164), inhaled molgramostim significantly improved DLCO versus placebo at 24 weeks (difference 6.0 percentage points; P<0.001) and 48 weeks, and improved SGRQ total score at 24 weeks. Adverse events and serious adverse events were similar between groups.
Impact: This is the largest rigorous RCT to date demonstrating clinically meaningful improvement with targeted inhaled GM‑CSF in aPAP, a rare disease with limited options.
Clinical Implications: Inhaled molgramostim may become a disease-directed therapy for aPAP, potentially reducing reliance on whole lung lavage and improving gas transfer and quality of life.
Key Findings
- Primary endpoint: LS mean DLCO change at week 24 was 9.8% with molgramostim vs 3.8% with placebo (difference 6.0 pp; 95% CI 2.5–9.4; P<0.001).
- Week 48 DLCO improvement persisted: 11.6% with molgramostim vs 4.7% with placebo (P<0.001).
- SGRQ total score improved at week 24 (−11.5 vs −4.9; P=0.007); safety and serious adverse events were similar between groups.
Methodological Strengths
- Phase 3, multicenter, double-blind, placebo-controlled randomized trial
- Pre-specified primary endpoint with multiplicity-adjusted key secondary outcomes
Limitations
- Primary outcome is a physiological surrogate (DLCO) rather than hard clinical endpoints such as need for whole lung lavage or survival
- No significant difference in SGRQ activity at 24 weeks; subsequent secondary endpoints not inferentially tested after hierarchal gate
Future Directions: Evaluate long-term clinical outcomes (e.g., frequency of whole lung lavage, oxygen requirement, exacerbations) and biomarkers to guide patient selection and dosing; assess comparative effectiveness versus lavage.
BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia caused by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), which alveolar macrophages require to clear surfactant. Molgramostim is a formulation of inhaled recombinant human GM-CSF, but its efficacy and safety in patients with aPAP have not been studied sufficiently. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with aPAP to receive molgramostim at a dose of 300 μg or placebo once daily for 48 weeks. The primary end point was the change from baseline to week 24 in the diffusing capacity of the lungs for carbon monoxide (DLCO), which was adjusted for hemoglobin concentration and expressed as a percentage of the predicted value. Secondary end points adjusted for multiplicity were the change from baseline in DLCO at 48 weeks and the change from baseline in the St. George's Respiratory Questionnaire total (SGRQ-T) and activity (SGRQ-A) scores (scores range from 0 to 100, with lower scores indicating better quality of life) and in exercise capacity at 24 and 48 weeks. RESULTS: A total of 164 patients underwent randomization: 81 were assigned to receive molgramostim and 83 to receive placebo. The least-squares mean change in DLCO from baseline to week 24 was 9.8 percentage points (95% confidence interval [CI], 7.3 to 12.3) with molgramostim and 3.8 percentage points (95% CI, 1.4 to 6.3) with placebo (estimated treatment difference, 6.0 percentage points; 95% CI, 2.5 to 9.4; P<0.001). The least-squares mean change in DLCO from baseline to week 48 was 11.6 percentage points (95% CI, 8.7 to 14.5) with molgramostim and 4.7 percentage points (95% CI, 1.8 to 7.6) with placebo (P<0.001), and the least-squares mean change in the SGRQ-T score at week 24 was -11.5 points (95% CI, -15.0 to -8.0) and -4.9 points (95% CI, -8.3 to -1.5), respectively (P = 0.007). No significant between-group difference in the change in SGRQ-A score was observed at 24 weeks, so no statistical inference was drawn with respect to subsequent secondary end points. The percentage of patients with at least one adverse event and the percentage with at least one serious adverse event were similar in the two groups. CONCLUSIONS: Once-daily inhaled molgramostim led to a greater increase in pulmonary gas transfer than placebo in patients with aPAP. (Funded by Savara; IMPALA-2 ClinicalTrials.gov number, NCT04544293; European Union Clinical Trials Information System number, 2024-511052-41-00.).
2. Effect of lateral versus supine positioning on hypoxaemia in sedated adults: multicentre randomised controlled trial.
In a multicenter RCT of 2,143 sedated adults, lateral positioning significantly reduced hypoxemia compared with supine (5.4% in the lateral group), lowered severity, and reduced airway rescue interventions without compromising safety.
Impact: A simple, scalable, non-pharmacologic intervention reduces hypoxemia during sedation, applicable across diverse procedural settings and resource levels.
Clinical Implications: Adopt lateral positioning during procedural sedation to reduce hypoxemia and airway rescue needs, especially in resource-limited settings where monitoring and rescue capacity may be constrained.
Key Findings
- Primary outcome: hypoxemia incidence was significantly lower with lateral positioning; 5.4% (58/1073) in the lateral group versus higher in supine (significant difference).
- Lateral positioning reduced the severity of desaturation and the need for airway rescue interventions.
- No safety compromise was observed; the strategy is low-cost and easily implementable.
Methodological Strengths
- Prospective multicenter randomized controlled design with large sample size
- Pragmatic intervention applicable across 14 tertiary hospitals
Limitations
- Blinding to body position is not feasible and may introduce performance bias
- Generalizability to very elderly or high-BMI populations needs confirmation as noted by authors
Future Directions: Assess effectiveness in high-risk populations (advanced age, obesity, OSA) and evaluate integration with oxygen delivery strategies and capnography in diverse settings.
OBJECTIVES: To evaluate the effect of lateral versus supine positioning on incidence of hypoxaemia in sedated patients and to provide evidence based recommendations for respiratory strategies. DESIGN: Prospective, multicentre, randomised controlled trial. SETTING: 14 tertiary hospitals in China, July to November 2024. PARTICIPANTS: 2159 adults (≥18 years) who underwent sedation. INTERVENTIONS: Sedated patients were randomly assigned (1:1) to receive either lateral positioning or conventional supine positioning, stratified by study centres. MAIN OUTCOME MEASURES: The primary outcome was incidence of hypoxaemia (peripheral oxygen saturation (SpO RESULTS: Of 2159 patients randomised, 2143 were included in the primary analysis. The mean age of the patients was 53.1 years, mean body mass index was 23.9, and 53.7% (1150/2143) were women. The incidence of hypoxaemia was significantly lower in the lateral group compared with supine group (5.4% (58/1073) CONCLUSIONS: Placing sedated adults in the lateral position significantly reduces the incidence and severity of hypoxaemia and decreases the need for airway rescue interventions without compromising safety. Given its simplicity and low cost, lateral positioning could offer advantages in remote or resource constrained clinical settings. Further replication studies targeting patients with advanced age and high body mass index are needed to improve the generalisability of the findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT06459167.
3. Safety of budesonide/glycopyrronium/formoterol fumarate dihydrate delivered by HFO-1234ze versus HFA-134a in chronic obstructive pulmonary disease: a phase 3, multi-site, randomised, double-blind, parallel-group, active-comparator study.
In 558 COPD patients randomized to BGF delivered by near‑zero GWP HFO‑1234ze versus HFA‑134a, adverse event incidence was balanced at 12 weeks (44.3% vs 41.0%) and in a 52‑week extension (66.7% vs 78.3%), with no new safety signals. Findings support transitioning pMDIs to HFO‑1234ze.
Impact: Clinically validates a climate‑friendly propellant for triple therapy delivery in COPD without compromising safety, enabling decarbonization of widely used pMDIs.
Clinical Implications: Health systems can consider formulary transition to HFO‑1234ze‑based BGF pMDIs to reduce carbon footprint while maintaining patient safety; real‑world effectiveness and switching strategies should be planned.
Key Findings
- Adverse event incidence at 12 weeks was balanced: HFO‑1234ze 44.3% (124/280) vs HFA‑134a 41.0% (114/278).
- In the 52‑week extension (first 120 per arm), AE incidence remained comparable: HFO‑1234ze 66.7% vs HFA‑134a 78.3%.
- No new safety signals across vitals, labs, or ECGs; supports HFO‑1234ze as a viable low‑GWP propellant for BGF delivery.
Methodological Strengths
- Phase 3 randomized, double‑blind, active‑comparator design across 9 countries
- Prespecified safety endpoints with 12‑ and 52‑week assessments
Limitations
- Primarily a safety study; not powered for comparative efficacy or environmental outcomes
- Generalizability limited to BGF formulation; only a subset continued to 52 weeks
Future Directions: Conduct real‑world effectiveness and switch studies, quantify lifecycle carbon reductions, and expand HFO‑1234ze adoption across other pMDIs and indications.
BACKGROUND: Pressurised metered dose inhalers (pMDIs) contain a hydrofluorocarbon propellant, such as hydrofluoroalkane-134a (HFA-134a), which is known to have global warming potential (GWP). Transitioning pMDIs to propellants with lower GWP will reduce the environmental impact of pMDIs. This study assessed the safety of a near-zero GWP propellant, hydrofluoroolefin-1234ze (HFO-1234ze), compared with HFA-134a when used in the delivery of budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) in participants with chronic obstructive pulmonary disease (COPD). The results of this study advance our understanding of the safety of HFO-1234ze compared with HFA-134a. METHODS: This phase 3, double-blind, parallel-group study (ClinicalTrials.govNCT05573464) across 9 countries (Argentina, Bulgaria, Canada, Germany, Mexico, Poland, Turkey, the United Kingdom, the United States) included participants (aged 40-80 years) with physician-diagnosed COPD using dual or triple inhaled maintenance therapies, COPD Assessment Test score ≥10, ≥10 pack-years smoking history, and no comorbid diagnosis of asthma or other clinically significant diseases impacting study outcomes. Participants were randomised (1:1) to receive either BGF HFO-1234ze or BGF HFA-134a (two inhalations of 160/7·2/5·0 μg twice daily) for 12 weeks in the main safety analysis set (or 52 weeks [first 120 participants per treatment]). Safety endpoints included the incidence of adverse events (AEs), measures of vital signs, clinical laboratory tests, and electrocardiograms. FINDINGS: Participants were recruited between 27 September 2022 and 19 May 2023. A total of 874 participants were screened. Of 558 treated participants (mean [standard deviation] age, 67·0 [7·4] years; male, 315 [56·5%]) in the 12-week safety analysis set, 280 received BGF HFO-1234ze, and 278 received BGF HFA-134a. The AE incidence was balanced between formulations in the 12-week (HFO-1234ze, 124 [44·3%]; HFA-134a, 114 [41·0%]) and 52-week (HFO-1234ze, 80 [66·7%]; HFA-134a, 94 [78·3%]) safety analysis sets. INTERPRETATION: These findings support the potential for HFO-1234ze to replace HFA-134a in pMDIs containing BGF, which could be evaluated further in a real-world setting. FUNDING: The study was supported by AstraZeneca.