Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Holly R Keir, Merete B Long, Hani Abo-leyah, Yan Hui Giam, Thenmalar Vadiveloo, Thomas Pembridge, Rebecca C Hull, Lilia Delgado, Margaret Band, Fiona McLaren-Neil, Simon Adamson, Eva Lahnsteiner, Amy Gilmour, Chloe Hughes, Benjamin JM New, David Connell, Rebecca Dowey, Helena Turton, Hollian Richardson, Diane CassidyJamie Cooper, Jay Suntharalingam, Lavanya Diwakar, Peter Russell, Jonathan Underwood, Alexander Hicks, Davinder PS Dosanjh, Beth Sage, Devesh Dhasmana, Mark Spears, A A Roger Thompson, Christopher Brightling, Andrew Smith, Manish Patel, Jacob George, Alison M Condliffe, Amelia Shoemark, Graeme MacLennan, James D. Chalmers (Lead / Corresponding author), STOP-COVID19 Investigators

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Abstract

Background: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19.

Methods: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012.

Findings: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57–0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug.

Interpretation: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19.
Original languageEnglish
Number of pages10
JournalThe Lancet Respiratory Medicine
Early online date5 Sep 2022
DOIs
Publication statusE-pub ahead of print - 5 Sep 2022

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