A randomised, placebo-controlled pilot study of a nebulised antitumour necrosis factor receptor-1 domain antibody in patients at risk of postoperative lung injury.

Ryan, James, Bayliffe, Andrew I, McAuley, Daniel F, Yeung, Joyce, Thickett, David R, Howells, Phillip A, O'Donnell, Ciara, Vassallo, Arlette M, Wright, Tracey J, McKie, Elizabeth, Hardes, Kelly, Summers, Charlotte, Shields, Martin O, Powley, William, Wilson, Robert, Lazaar, Aili L, Fowler, Andrew and Perkins, Gavin D (2020) A randomised, placebo-controlled pilot study of a nebulised antitumour necrosis factor receptor-1 domain antibody in patients at risk of postoperative lung injury. European journal of anaesthesiology. ISSN 1365-2346.

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Official URL: https://journals.lww.com/ejanaesthesiology/

Abstract

BACKGROUND

Tumour necrosis factor receptor 1 (TNFR1) signalling mediates the cell death and inflammatory effects of TNF-α.

OBJECTIVE

The current clinical trial investigated the effects of a nebulised TNFR1 antagonist (GSK2862277) on signs of lung injury in patients undergoing oesophagectomy.

DESIGN

Randomised double-blind (sponsor unblind), placebo-controlled, parallel group study.

SETTING

Eight secondary care centres, the United Kingdom between April 2015 and June 2017.

PATIENTS

Thirty-three patients undergoing elective transthoracic oesophagectomy.

INTERVENTIONS

Patients randomly received a single nebulised dose (26 mg) of GSK2862277 (n = 17) or placebo (n = 16), given 1 to 5 h before surgery; 14 and 16, respectively competed the study.

MAIN OUTCOME MEASUREMENTS

Physiological and biochemical markers of lung injury, pharmacokinetic and safety endpoints were measured. The primary endpoint was the change from baseline in pulmonary vascular permeability index (PVPI) at completion of surgery, measured using single-indicator transpulmonary thermodilution. Adjusted point estimates and 95% credible intervals (analogous to conventional confidence intervals) were constructed for each treatment using Bayesian statistical models.

RESULTS

The mean change (with 95% credible intervals) from baseline in PVPI on completion of surgery was 0.00 (-0.23, 0.39) in the placebo and 0.00 (-0.24, 0.37) in the GSK2862277 treatment groups. There were no significant treatment-related differences in PaO2/FiO2 or Sequential Organ Failure Assessment score. Levels of free soluble TNFR1, Macrophage Inflammatory Protein-1 alpha and total protein were significantly reduced in the bronchoalveolar lavage fluid of patients treated with GSK2862277 (posterior probability of decrease with GSK2862277 vs. placebo:≥0.977; equivalent to P < 0.05). The frequency of adverse events and serious adverse events were distributed evenly across the two treatment arms.

CONCLUSION

Pre-operative treatment with a single 26 mg inhaled dose of GSK2862277 did not result in significantly lower postoperative alveolar capillary leak or extra vascular lung water. Unexpectedly small increases in transpulmonary thermodilution-measured PVPI and extra vascular lung water index at completion of surgery suggest less postoperative lung injury than historically reported, which may have also compromised a clear assessment of efficacy in this trial. GSK2862277 was well tolerated, resulted in expected lung exposure and reduced biomarkers of lung permeability and inflammation.

TRIAL REGISTRATION

clinicaltrials.gov: NCT02221037.

Item Type: Article
Subjects: QZ Pathology. Oncology
WI Digestive system. Gastroenterology
WO Surgery
WO Surgery > WO500 Anaesthesia
Divisions: Clinical Support > Anaesthetics
Related URLs:
Depositing User: Jamie Edgar
Date Deposited: 11 Jun 2020 10:36
Last Modified: 11 Jun 2020 10:36
URI: http://www.repository.uhblibrary.co.uk/id/eprint/3164

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