MESOS main manuscript accepted but prepublication version.pdf (405.13 kB)
Download file

Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial

Download (405.13 kB)
journal contribution
posted on 04.06.2018, 15:26 by Richard J. Russell, Latifa Chachi, J. Mark FitzGerald, Vibeke Backer, Ronald Olivenstein, Ingrid L. Titlestad, Charlotte Suppli Ulrik, Timothy Harrison, Dave Singh, Rekha Chaudhuri, Brian Leaker, Lorcan McGarvey, Salman Siddiqui, Millie Wang, Martin Braddock, Lars H. Nordenmark, David Cohen, Himanshu Parikh, Gene Colice, Christopher E Brightling
Background: The role of interleukin 13 in airway inflammation and remodelling in asthma is unclear. Tralokinumab is a human monoclonal antibody that neutralises interleukin 13. We aimed to evaluate whether tralokinumab would have an effect on airway eosinophilic infiltration, blood and sputum eosinophil concentrations, eosinophil activation, and airway remodelling. Methods: We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 15 centres across the UK, Denmark, and Canada. We enrolled participants of either sex aged 18–75 years with inadequately controlled moderate-to-severe asthma for 12 months or more, requiring treatment with inhaled corticosteroids at a stable dose. We randomly assigned participants (1:1) to receive tralokinumab (300 mg) or placebo by an interactive web-based system or voice response system. Participants and study personnel were masked to treatment allocation. Both tralokinumab and placebo were administered subcutaneously every 2 weeks. The primary outcome measure was change from baseline to week 12 in bronchial biopsy eosinophil coun t. Secondary outcome measures included change in blood and sputum eosinophil counts. Exploratory outcomes included fractional exhaled nitric oxide (FENO) and blood IgE concentrations. Safety analyses were carried out in all participants who received study drug. This trial is registered with ClinicalTrials.gov, number NCT02449473, and with the European Clinical Trials Database, EudraCT 2015-000857-19. Findings: Between Sept 25, 2015, and June 21, 2017, 224 participants were enrolled and screened. Of these participants, 79 were randomly assigned to receive tralokinumab (n=39) or placebo (n=40). Tralokinumab did not significantly affect bronchial eosinophil count compared with placebo at week 12 (treatment effect ratio 1·43, 95% CI 0·63–3·27; p=0·39). Compared with placebo, tralokinumab did not significantly affect blood eosinophil count (treatment effect ratio 1·21, 95% CI 1·00–1·48; p=0·055) or sputum eosinophil count (0·57, 0·06–6·00; p=0·63), but FENO concentration (0·78, 0·63–0·96; p=0·023) and total blood IgE concentration (0·86, 0·77–0·97; p=0·014) were significantly reduced. 33 (85%) of 39 patients receiving tralokinumab and 32 (80%) of 40 receiving placebo reported at least one adverse event during the treatment period. No deaths in either treatment group were observed. Treatment-related adverse events occurred more frequently in the tralokinumab group than in the placebo group (11 [28%] of 39 vs seven [18%] of 40). Interpretation: Tralokinumab did not significantly affect eosinophilic inflammation in bronchial submucosa, blood, or sputum compared with placebo, but did reduce FENO and IgE concentrations. These results suggest interleukin 13 is not crucial for eosinophilic airway inflammation control in moderate-to-severe asthma. Funding: AstraZeneca.

Funding

This trial was funded by AstraZeneca and supported by the National Institute for Health Research (NIHR) Respiratory Translational Research Collaboration and NIHR Biomedical Research Centres. AstraZeneca contributed to study design, data interpretation, and writing of the report, and coordinated data collection and data analysis. The authors had full access to the study data and vouch for the accuracy of the findings. The corresponding author had final responsibility for the decision to submit for publication.

History

Citation

The Lancet Respiratory Medicine, 2018

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Infection, Immunity and Inflammation

Version

AM (Accepted Manuscript)

Published in

The Lancet Respiratory Medicine

Publisher

Elsevier

issn

2213-2600

eissn

2213-2619

Copyright date

2018

Available date

21/11/2018

Publisher version

https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S2213260018302017?returnurl=https://linkinghub.elsevier.com/retrieve/pii/S2213260018302017?showall=true&referrer=

Notes

The file associated with this record is under embargo until 6 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.

Language

en

Usage metrics

Categories

Keywords

Exports