A randomised trial of lung sealant versus medical therapy for advanced emphysema

Abstract

Uncontrolled pilot studies demonstrated promising results of endoscopic lung volume reduction using emphysematous lung sealant (ELS) in patients with advanced, upper lobe predominant emphysema. We aimed to evaluate the safety and efficacy of ELS in a randomised controlled setting.Patients were randomised to ELS plus medical treatment or medical treatment alone. Despite early termination for business reasons and inability to assess the primary 12-month end-point, 95 out of 300 patients were successfully randomised, providing sufficient data for 3- and 6-month analysis.57 patients (34 treatment and 23 control) had efficacy results at 3 months; 34 (21 treatment and 13 control) at 6 months. In the treatment group, 3-month lung function, dyspnoea, and quality of life improved significantly from baseline when compared to control. Improvements persisted at 6 months with >50% of treated patients experiencing clinically important improvements, including some whose lung function improved by >100%. 44% of treated patients experienced adverse events requiring hospitalisation (2.5-fold more than control, p=0.01), with two deaths in the treated cohort. Treatment responders tended to be those experiencing respiratory adverse events.Despite early termination, results show that minimally invasive ELS may be efficacious, yet significant risks (probably inflammatory) limit its current utility.

Trial registration: ClinicalTrials.gov NCT01449292.

FIGURE 1

AeriSeal System for Hyperinflation Reduction in Emphysema study schema. DMC: data monitoring committee. ^#: telephone follow-up at 1, 2 and 3 weeks and 1, 2, 4, 5, 7, 8, 10 and 11 months.

FIGURE 2

Consort diagram summarising enrolment, allocation, and follow-up. CT: computed tomography; PFTs: pulmonary function tests; BMI: body mass index; mMRC: modified Medical Research Council dyspnoea scale; 6MWD: 6-min walking distance; ELS: emphysematous lung sealant system. ^#: 47 patients were undergoing screening at the time of study termination.

FIGURE 3

Percentage change in forced expiratory volume in 1 s (FEV₁) from baseline to 6-month follow-up for a) treated patients and b) control patients. Each bar represents an individual patient. The regions outside the shaded zone indicate clinically significant changes in FEV₁. Adverse events requiring hospitalisation for the corresponding individual c) treated patients and d) control patients.

FIGURE 4

Coronal images at equivalent anatomic locations from chest computed tomographic (CT) scans of the same patient at various time points, with corresponding forced expiratory volume in 1 s (FEV₁). The patient had a complicated post-treatment course with repeated admissions for fevers and pneumonia versus pneumonitis. ~6 months after treatment (after termination of the study) the patient was found to have a pulmonary embolus in the left upper lobar artery extending into segmental and subsegmental arteries. Given the location of the clot within collapsed/treated areas, there was suspicion of in situ thrombosis. The patient was treated with anticoagulant therapy. a) Baseline chest CT; b) clinically-acquired chest CT taken almost 6 months post-treatment demonstrates a treatment site in the right upper lobe. Compared with the baseline CT, the diaphragms and fissures (arrows) are now elevated, consistent with deflation. The patient’s FEV₁ improved 84% from baseline (follow-up spirometry obtained outside the study).

FIGURE 5

Axial images from chest computed tomography (CT) scans (performed for clinical indications) of patients treated with the emphysematous lung sealant system, displaying the appearance of the lungs and potential complications post-treatment. a, b) CT obtained 66 days after treatment when patient 1 presented with dyspnoea and abdominal pain. The patient was treated with broad-spectrum antibiotics for pneumonia. A thorough abdominal work-up was negative. Steroids were added to reduce potential systemic inflammation as a result of her treatment (C-reactive protein 66.3 mg·L⁻¹); her symptoms improved rapidly. a) Bilateral apical opacities consistent with treatment sites (arrows), as well as dense consolidation in the posterior left upper lobe (beyond expected treatment site). b) Ground glass opacification in the untreated left lower lobe and a small pleural effusion. c) CT scan obtained 70 days after treatment when patient 2 presented with persistent shortness of breath and fevers despite treatment with broad-spectrum antibiotics. CT shows bilateral upper lobe consolidation and a right-sided pleural effusion (arrow; transudative). The patient’s condition improved upon treatment with steroids. d) CT obtained 23 days after treatment when patient 3 presented with fever, lethargy, and rust-colored sputum. CT demonstrates consolidation and complex air-fluid collections bilaterally, which may indicate lung abscesses rather than post-treatment changes (arrows). The patient improved upon treatment with broad-spectrum antibiotics.