Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory airway disease. The epithelial-derived IL-33 and its receptor ST2 have been implicated in airway inflammation and infection. We aimed to determine whether astegolimab, a selective ST2 IgG2 monoclonal antibody, reduces exacerbations in COPD. METHODS: COPD-ST2OP was a single-centre, randomised, double-blinded, placebo-controlled phase 2a trial in moderate-to-very severe COPD. Participants were randomly assigned (1:1) with a web-based system to received 490 mg subcutaneous astegolimab or subcutaneous placebo, every 4 weeks for 44 weeks. The primary endpoint was exacerbation rate assessed for 48 weeks assessed with a negative binomial count model in the intention-to-treat population, with prespecified subgroup analysis by baseline blood eosinophil count. The model was the number of exacerbations over the 48-week treatment period, with treatment group as a covariate. Safety was assessed in the whole study population until week 60. Secondary endpoints included Saint George's Respiratory Questionnaire for COPD (SGRQ-C), FEV1, and blood and sputum cell counts. The trial was registered with ClinicalTrials.gov, NCT03615040. FINDINGS: The exacerbation rate at 48 weeks in the intention-to-treat analysis was not significantly different between the astegolimab group (2·18 [95% CI 1·59 to 2·78]) and the placebo group (2·81 [2·05 to 3·58]; rate ratio 0·78 [95% CI 0·53 to 1·14]; p=0·19]). In the prespecified analysis stratifying patients by blood eosinophil count, patients with 170 or fewer cells per µL had 0·69 exacerbations (0·39 to 1·21), whereas those with more than 170 cells per µL had 0·83 exacerbations (0·49 to 1·40). For the secondary outcomes, the mean difference between the SGRQ-C in the astegolimab group versus placebo group was -3·3 (95% CI -6·4 to -0·2; p=0·039), and mean difference in FEV1 between the two groups was 40 mL (-10 to 90; p=0·094). The difference in geometric mean ratios between the two groups for blood eosinophil counts was 0·59 (95% CI 0·51 to 0·69; p<0·001) and 0·25 (0·19 to 0·33; p<0·001) for sputum eosinophil counts. Incidence of treatment-emergent adverse events was similar between groups. INTERPRETATION: In patients with moderate-to-very severe COPD, astegolimab did not significantly reduce exacerbation rate, but did improve health status compared with placebo. FUNDING: Funded by Genentech and National Institute for Health Research Biomedical Research Centres.

Role of thoracic ultrasonography in pleurodesis pathways for malignant pleural effusions (SIMPLE): an open-label, randomised controlled trial.

BACKGROUND: Pleurodesis is done as an in-patient procedure to control symptomatic recurrent malignant pleural effusion (MPE) and has a success rate of 75-80%. Thoracic ultrasonography has been shown in a small study to predict pleurodesis success early by demonstrating cessation of lung sliding (a normal sign seen in healthy patients, lung sliding indicates normal movement of the lung inside the thorax). We aimed to investigate whether the use of thoracic ultrasonography in pleurodesis pathways could shorten hospital stay in patients with MPE undergoing pleurodesis. METHODS: The Efficacy of Sonographic and Biological Pleurodesis Indicators of Malignant Pleural Effusion (SIMPLE) trial was an open-label, randomised controlled trial done in ten respiratory centres in the UK and one respiratory centre in the Netherlands. Adult patients (aged ≥18 years) with confirmed MPE who required talc pleurodesis via either a chest tube or as poudrage during medical thorascopy were eligible. Patients were randomly assigned (1:1) to thoracic ultrasonography-guided care or standard care via an online platform using a minimisation algorithm. In the intervention group, daily thoracic ultrasonography examination for lung sliding in nine regions was done to derive an adherence score: present (1 point), questionable (2 points), or absent (3 points), with a lowest possible score of 9 (preserved sliding) and a highest possible score of 27 (complete absence of sliding); the chest tube was removed if the score was more than 20. In the standard care group, tube removal was based on daily output volume (per British Thoracic Society Guidelines). The primary outcome was length of hospital stay, and secondary outcomes were pleurodesis failure at 3 months, time to tube removal, all-cause mortality, symptoms and quality-of-life scores, and cost-effectiveness of thoracic ultrasonography-guided care. All outcomes were assessed in the modified intention-to-treat population (patients with missing data excluded), and a non-inferiority analysis of pleurodesis failure was done in the per-protocol population. This trial was registered with ISRCTN, ISRCTN16441661. FINDINGS: Between Dec 31, 2015, and Dec 17, 2019, 778 patients were assessed for eligibility and 313 participants (165 [53%] male) were recruited and randomly assigned to thoracic ultrasonography-guided care (n=159) or standard care (n=154). In the modified intention-to-treat population, the median length of hospital stay was significantly shorter in the intervention group (2 days [IQR 2-4]) than in the standard care group (3 days [2-5]; difference 1 day [95% CI 1-1]; p<0·0001). In the per-protocol analysis, thoracic ultrasonography-guided care was non-inferior to standard care in terms of pleurodesis failure at 3 months, which occurred in 27 (29·7%) of 91 patients in the intervention group versus 34 (31·2%) of 109 patients in the standard care group (risk difference -1·5% [95% CI -10·2% to 7·2%]; non-inferiority margin 15%). Mean time to chest tube removal in the intervention group was 2·4 days (SD 2·5) versus 3·1 days (2·0) in the standard care group (mean difference -0·72 days [95% CI -1·22 to -0·21]; p=0·0057). There were no significant between-group differences in all-cause mortality, symptom scores, or quality-of-life scores, except on the EQ-5D visual analogue scale, which was significantly lower in the standard care group at 3 months. Although costs were similar between the groups, thoracic ultrasonography-guided care was cost-effective compared with standard care. INTERPRETATION: Thoracic ultrasonography-guided care for pleurodesis in patients with MPE results in shorter hospital stay (compared with the British Thoracic Society recommendation for pleurodesis) without reducing the success rate of the procedure at 3 months. The data support consideration of standard use of thoracic ultrasonography in patients undergoing MPE-related pleurodesis. FUNDING: Marie Curie Cancer Care Committee.

The different phenotypes of COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity and mortality. To improve the health status and reduce symptom burden, it is important to identify a group of patients with similar characteristics and prognosis, called clinical phenotypes. Herein we shall review the different phenotypes of COPD. SOURCES OF DATA: Keywords (COPD, phenotype, acute exacerbation) search was conducted in PubMed, Google Scholar. AREAS OF AGREEMENT: Those with raised blood eosinophil counts respond better to steroid therapy at stable state and exacerbation. AREAS OF CONTROVERSY: There is no universally accepted blood eosinophil cut-off value that will indicate favourable response to corticosteroids and potentially for future biologic therapy. GROWING POINTS: There is an urgent need for further therapeutic options for COPD patients with non-eosinophilic inflammation. AREAS TIMELY FOR DEVELOPING RESEARCH: Well-designed COPD trials with identification of phenotypes for more personalization of the treatment of COPD.

T2 Biologics for Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide. In contrast to other chronic diseases, COPD is increasing in prevalence and is projected to be the third leading cause of death and disability worldwide by 2030. Recent advances in understanding the underlying pathophysiology of COPD has led to the development of novel targeted therapies (biologics and small molecules) that address the underlying pathophysiology of the disease. In severe asthma, biologics targeting type 2 (T2)- mediated immunity have been successful and have changed the treatment paradigm. In contrast, no biologics are currently licensed for the treatment of COPD. Those targeting non-T2 pathways have not demonstrated efficacy and in some cases raised concerns related to safety. With the increasing recognition of the eosinophil and perhaps T2-immunity possibly playing a role in a subgroup of patients with COPD, T2 biologics, specifically anti-IL-5(R), have been tested and demonstrated modest reductions in exacerbation frequency. Potential benefit was related to the baseline blood eosinophil count. These benefits were small compared with asthma. Thus, whether a subgroup of COPD sufferers might respond to anti-IL-5 or other T2-directed biologics remains to be fully addressed and requires further investigation.

Assessment of breath volatile organic compounds in acute cardiorespiratory breathlessness: a protocol describing a prospective real-world observational study.

INTRODUCTION: Patients presenting with acute undifferentiated breathlessness are commonly encountered in admissions units across the UK. Existing blood biomarkers have clinical utility in distinguishing patients with single organ pathologies but have poor discriminatory power in multifactorial presentations. Evaluation of volatile organic compounds (VOCs) in exhaled breath offers the potential to develop biomarkers of disease states that underpin acute cardiorespiratory breathlessness, owing to their proximity to the cardiorespiratory system. To date, there has been no systematic evaluation of VOC in acute cardiorespiratory breathlessness. The proposed study will seek to use both offline and online VOC technologies to evaluate the predictive value of VOC in identifying common conditions that present with acute cardiorespiratory breathlessness. METHODS AND ANALYSIS: A prospective real-world observational study carried out across three acute admissions units within Leicestershire. Participants with self-reported acute breathlessness, with a confirmed primary diagnosis of either acute heart failure, community-acquired pneumonia and acute exacerbation of asthma or chronic obstructive pulmonary disease will be recruited within 24 hours of admission. Additionally, school-age children admitted with severe asthma will be evaluated. All participants will undergo breath sampling on admission and on recovery following discharge. A range of online technologies including: proton transfer reaction mass spectrometry, gas chromatography ion mobility spectrometry, atmospheric pressure chemical ionisation-mass spectrometry and offline technologies including gas chromatography mass spectroscopy and comprehensive two-dimensional gas chromatography-mass spectrometry will be used for VOC discovery and replication. For offline technologies, a standardised CE-marked breath sampling device (ReCIVA) will be used. All recruited participants will be characterised using existing blood biomarkers including C reactive protein, brain-derived natriuretic peptide, troponin-I and blood eosinophil levels and further evaluated using a range of standardised questionnaires, lung function testing, sputum cell counts and other diagnostic tests pertinent to acute disease. ETHICS AND DISSEMINATION: The National Research Ethics Service Committee East Midlands has approved the study protocol (REC number: 16/LO/1747). Integrated Research Approval System (IRAS) 198921. Findings will be presented at academic conferences and published in peer-reviewed scientific journals. Dissemination will be facilitated via a partnership with the East Midlands Academic Health Sciences Network and via interaction with all UK-funded Medical Research Council and Engineering and Physical Sciences Research Council molecular pathology nodes. TRIAL REGISTRATION NUMBER: NCT03672994.

Thoracic Ultrasound as an Early Predictor of Pleurodesis Success in Malignant Pleural Effusion.

BACKGROUND: Malignant pleural effusion (MPE) is common and imposes a significant burden on patients and health-care providers. Most patients require definitive treatment, usually drainage and chemical pleurodesis, to relieve symptoms and prevent fluid recurrence. Thoracic ultrasound (TUS) can identify the presence of pleural adhesions in other clinical scenarios, and could therefore have a role in predicting long-term pleurodesis success or failure in MPE. METHODS: Patients undergoing chest tube drainage and talc slurry pleurodesis for symptomatic MPE were recruited to a prospective observational cohort pilot study assessing whether TUS findings pre-talc and post-talc instillation predicted treatment outcome. Participants underwent TUS examination immediately before, and 24 h after talc slurry administration to derive pleural adherence scores for the affected hemithorax. The recorded TUS scans were additionally scored by two independent assessors blinded to the patient's clinical status. The primary outcome was pleurodesis success at 1-month and 3-month follow-up. RESULTS: Eighteen participants were recruited to the pilot study. Participants who suffered pleurodesis failure had a lower pleural adherence score at 24 h post-talc instillation than those who were successful (difference of 6.27; 95% CI, 3.94-8.59). TUS examination was acceptable to patients, while TUS scoring was highly consistent across all assessors (intraclass correlation coefficient, 0.762; 95% CI, 0.605-0.872). CONCLUSION: A TUS-derived pleural adherence score may facilitate early prediction of long-term outcomes following chemical pleurodesis, with implications for personalized care and decision making in MPE. Further research is needed to evaluate this novel finding. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT02625675; URL: www.clinicaltrials.gov.

Biologic Drugs: A New Target Therapy in COPD?

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease associated with significant morbidity and mortality. Current diagnostic criteria based on the presence of fixed airflow obstruction and symptoms do not integrate the complex pathological changes occurring within the lung and they do not define different airway inflammatory patterns. The current management of COPD is based on 'one size fits all' approach and does not take the importance of heterogeneity in COPD population into account. The available treatments aim to alleviate symptoms and reduce exacerbation frequency but do not alter the course of the disease. Recent advances in molecular biology have furthered our understanding of inflammatory pathways in pathogenesis of COPD and have led to development of targeted therapies (biologics and small molecules) based on predefined biomarkers. Herein we shall review the trials of biologics in COPD and potential future drug developments in the field.

A Pilot Feasibility Study in Establishing the Role of Ultrasound-Guided Pleural Biopsies in Pleural Infection (The AUDIO Study).

BACKGROUND: Pleural infection is a common complication of pneumonia associated with high mortality and poor clinical outcome. Treatment of pleural infection relies on the use of broad-spectrum antibiotics because reliable pathogen identification occurs infrequently. We performed a feasibility interventional clinical study assessing the safety and significance of ultrasound (US)-guided pleural biopsy culture to increase microbiological yield. In an exploratory investigation, the 16S ribosomal RNA technique was applied to assess its utility on increasing speed and accuracy vs standard microbiological diagnosis. METHODS: Twenty patients with clinically established pleural infection were recruited. Participants underwent a detailed US scan and US-guided pleural biopsies before chest drain insertion, alongside standard clinical management. Pleural biopsies and routine clinical samples (pleural fluid and blood) were submitted for microbiological analysis. RESULTS: US-guided pleural biopsies were safe with no adverse events. US-guided pleural biopsies increased microbiological yield by 25% in addition to pleural fluid and blood samples. The technique provided a substantially higher microbiological yield compared with pleural fluid and blood culture samples (45% compared with 20% and 10%, respectively). The 16S ribosomal RNA technique was successfully applied to pleural biopsy samples, demonstrating high sensitivity (93%) and specificity (89.5%). CONCLUSIONS: Our findings demonstrate the safety of US-guided pleural biopsies in patients with pleural infection and a substantial increase in microbiological diagnosis, suggesting potential niche of infection in this disease. Quantitative polymerase chain reaction primer assessment of pleural fluid and biopsy appears to have excellent sensitivity and specificity.

Efficacy of sonographic and biological pleurodesis indicators of malignant pleural effusion (SIMPLE): protocol of a randomised controlled trial.

INTRODUCTION: Malignant pleural effusion (MPE) is common and currently in UK there are an estimated 50 000 new cases of MPE per year. Talc pleurodesis remains one of the most popular methods for fluid control. The value of thoracic ultrasound (TUS) imaging, before and after pleurodesis, in improving the quality and efficacy of care for patients with MPE remains unknown. Additionally, biomarkers of successful pleurodesis including measurement of pleural fluid proteins have not been validated in prospective studies.The SIMPLE trial is an appropriately powered, multicentre, randomised controlled trial designed to assess 'by the patient bedside' use of TUS imaging and pleural fluid analysis in improving management of MPE. METHODS AND ANALYSIS: 262 participants with a confirmed MPE requiring intervention will be recruited from hospitals in UK and The Netherlands. Participants will be randomised (1:1) to undergo either chest drain insertion followed by instillation of sterile talc, or medical thoracoscopy and simultaneous poudrage. The allocated procedure will be done while the patient is hospitalised, and within 3 days of randomisation. Following hospital discharge, participants will be followed up at 1, 3 and 12 months. The primary outcome measure is the length of hospital stay during initial hospitalisation. ETHICS AND DISSEMINATION: The trial has received ethical approval from the South Central-Oxford C Research Ethics Committee (Reference number 15/SC/0600). The Trial Steering Committee includes an independent chair and members, and a patient representative. The trial results will be published in a peer-reviewed journal and presented at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN: 16441661.

Assessment of patient-reported outcome measures in pleural interventions.

INTRODUCTION: There is a lack of data evaluating the clinical effect on symptoms of pleural intervention procedures. This has led to the development of patient-reported outcome measures (PROMs) to define what constitutes patient benefit. The primary aim of this paper was to prospectively assess the effect of pleural procedures on PROMs and investigate the relationship between symptom change and clinical factors. METHODS: We prospectively collected data as part of routine clinical care from 158 patients with pleural effusion requiring interventions. Specific questionnaires included two patient-reported scores (a seven-point Likert scale and a 100 mm visual analogue scale (VAS) to assess symptoms). RESULTS: Excluding diagnostic aspiration, the majority of patients (108/126, 85.7%) experienced symptomatic benefit from fluid drainage (mean VAS improvement 42.6 mm, SD 24.7, 95% CI 37.9 to 47.3). There was a correlation between symptomatic benefit and volume of fluid removed post aspiration. A negative association was identified between the number of septations seen on ultrasound and improvement in dyspnoea VAS score in patients treated with intercostal chest drain. CONCLUSION: The results of our study highlight the effect of pleural interventions from a patient's perspective. The outcomes defined have the potential to form the basis of a clinical useful tool to appraise the effect, compare the efficiency and identify the importance of pleural interventions to the patients.

Bioequivalence of two oral formulations of nizatidine capsules in healthy male volunteers.

PURPOSE: The purpose of this randomized, crossover study was to compare the bioavailability of a generic and an innovator formulation of nizatidine 300 mg capsules under fasting conditions. METHODS: Twenty blood samples per period were collected from 20 healthy, Arab male volunteers over 16 h, plasma nizatidine concentrations were determined by HPLC assay, and pharmacokinetic parameters were determined by the non-compartmental method. RESULTS: Mean+/-SD C(max), T(max), AUC(0-->t), AUC(0-->infinity), and t1/2 were 2.96+/-0.54 and 3.28+/-0.68 microg/ml, 1.31+/-0.70 and 0.93+/-0.38 h, 9.04+/-1.66 and 9.03+/-1.94 microg x h/ml, 9.17+/-1.64 and 9.12+/-1.94 microg x h/ml, and 1.64+/-0.21 and 1.58+/-0.22 h for the generic and innovator formulation, respectively. The parametric 90% confidence intervals on the mean of the difference between log-transformed values were 98.06% to 103.21%, 98.74% to 103.71%, and 83.37% to 101.34%, for AUC(0-->t), AUC(0-->infinity), and C(max), respectively. CONCLUSION: The results indicate that these two formulations are equivalent in the rate and extent of absorption.