Summer 2021

https://scholarlycommons.baptisthealth.net/bg-bh-ebp-council-news/1001/thumbnail.jp

Dyspnoea and restrictive lung disease due to mediastinal and pleural lipomatosis in morbid obesity

Dyspnoea in obese patients can be multifactorial and complex. Mediastinal and pleural lipomatosis can be associated with obesity and is usually considered asymptomatic and benign. We report an obese 39‐year‐old man who presented with progressive dyspnoea, where in addition to obstructive sleep apnoea and obesity hypoventilation syndrome, was found to have massive mediastinal and pleural lipomatosis causing restrictive lung disease. Pleural lipomatosis are generally slow growing so conservative management is recommended. However, complications such as haemorrhage and compression of adjoining organs can occur in pleural lipomas, so surgical excision can be considered in some instances

Recombinant Alpha-1 Antitrypsin–Fc Fusion Protein INBRX-101 in Adults With Alpha-1 Antitrypsin Deficiency: A Phase 1 Study

Background: Alpha-1 antitrypsin deficiency (AATD) is characterized by low alpha-1 antitrypsin (AAT) levels, predisposing individuals to lung disease. The standard of care, plasma-derived AAT (pdAAT), is delivered as weekly infusions to maintain serum AAT concentrations ≥11µM (≈50% of those in healthy individuals). INBRX-101, a recombinant human AAT-Fc fusion protein, was designed to have a longer half-life and achieve higher AAT levels than pdAAT. Methods: In this phase 1 dose-escalation study (N=31), adults with AATD received 1 dose (part 1) or 3 doses (part 2) of 10 (part 1), 40, 80, or 120mg/kg INBRX-101 every 3 weeks (Q3W) via intravenous infusion. The primary endpoint was safety and tolerability. Secondary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of INBRX-101. Results: INBRX-101 was well tolerated. Most treatment-emergent adverse events were grade ≤2. In part 2 (n=18; each dose, n=6), dose-related increases in serum functional AAT (fAAT) were observed; mean fAAT levels remained above the 21µM target for up to 4 weeks after the final dose in the 120-mg/kg cohort. Antidrug antibodies had no meaningful impact on PK or PD. INBRX-101 was detected in pulmonary epithelial lining fluid (PELF) from all patients assessed (n=11), and PELF fAAT increased after dosing. PK/PD modeling projected steady-state serum fAAT ≥21µM at 120 mg/kg Q3W (average concentration ≈43µM; trough concentration ≈28µM) and Q4W (≈34µM; ≈21µM). Conclusion: The favorable safety profile and ability to maintain serum fAAT levels >21µM with extended-interval dosing, support a phase 2 trial evaluating Q3W and Q4W dosing of INBRX-101

Preventing adverse cardiac events (PACE) in chronic obstructive pulmonary disease (COPD): Study protocol for a double-blind, placebo controlled, randomised controlled trial of bisoprolol in COPD

Introduction: Heart disease in chronic obstructive pulmonary disease (COPD) is a common but neglected comorbidity. Patients with COPD are frequently excluded from clinical trials of treatments aimed at reducing cardiac morbidity and mortality, which has led to undertreatment of cardiovascular disease in patients with COPD. A particular concern in COPD is the underuse of beta (β)-blockers. There is observational evidence that cardioselective β-blockers are safe and may even reduce mortality risk in COPD, although some evidence is conflicting. There is an urgent need to answer the research question: Are cardioselective β-blockers safe and of benefit in people with moderately severe COPD? The proposed study will investigate whether cardioselective β-blocker treatment in patients with COPD reduces mortality and cardiac and respiratory morbidity. Methods and analyses: This is a double-blind, randomised controlled trial to be conducted in approximately 26 sites in Australia, New Zealand, India, Sri Lanka and other countries as required. Participants with COPD will be randomised to either bisoprolol once daily (range 1.25–5 mg, dependent on tolerated dose) or matched placebo, in addition to receiving usual care for their COPD over the study duration of 24 months. The study will enrol 1164 participants with moderate to severe COPD, aged 40–85 years. Participants will be symptomatic from their COPD and have a postbronchodilator forced expiratory volume in 1 s (FEV1) ≥30% and ≤70% predicted and a history of at least one exacerbation requiring systemic corticosteroids, antibiotics or both in the prior 24 months. Ethics and dissemination: The study protocol has been approved by the Sydney Local Health District Human Research Ethics Committee at The Concord Repatriation General Hospital. Trial registration numbers: NCT03917914; CTRI/2020/08/027322

Cohort Characteristics.

<p>Differences between patients who died and those who survived were assessed by chi-squared for categorical data and Wilcoxon rank-sum tests for continuous data. IQR = inter quartile range.</p

30-day mortality according to biomarker levels on admission.

<p>Mortality was lower in patients with normal NT-proBNP and Troponin T levels than patients with elevated NT-proBNP alone (9/86, p = 0.0002) and both elevated NT-proBNP and Troponin T (14/62, p<0.0001).</p