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

Keir, Holly R and Long, Merete B and Abo-Leyah, Hani and Giam, Yan Hui and Vadiveloo, Thenmalar and Pembridge, Thomas and Hull, Rebecca C and Delgado, Lilia and Band, Margaret and McLaren-Neil, Fiona and Adamson, Simon and Lahnsteiner, Eva and Gilmour, Amy and Hughes, Chloe and New, Benjamin JM and Connell, David and Dowey, Rebecca and Turton, Helena and Richardson, Hollian and Cassidy, Diane and Cooper, Jamie and Suntharalingam, Jay and Diwakar, Lavanya and Russell, Peter and Underwood, Jonathan and Hicks, Alexander and Dosanjh, Davinder PS and Sage, Beth and Dhasmana, Devesh and Spears, Mark and Thompson, AA Roger and Brightling, Christopher and Smith, Andrew and Patel, Manish and George, Jacob and Condliffe, Alison M and Shoemark, Amelia and MacLennan, Graeme and Chalmers, James D and Chalmers, James and Almaden-Boyle, Christine and Taylor, Jennifer and Strachan, Jodie and Loftus, Heather and Young, Lesley and Strachan, Angela and Pilvinyte, Kristina and Miller, David and Cook, Gemma and Wilson, Jayne, STOP-COVID19 Investigators (2022) Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19 : a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial. The Lancet Respiratory Medicine, 10 (12). pp. 1119-1128. ISSN 2213-2619 (https://doi.org/10.1016/S2213-2600(22)00261-2)

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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. Funding: Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial.


Keir, Holly R, Long, Merete B, Abo-Leyah, Hani, Giam, Yan Hui, Vadiveloo, Thenmalar, Pembridge, Thomas, Hull, Rebecca C, Delgado, Lilia, Band, Margaret, McLaren-Neil, Fiona, Adamson, Simon, Lahnsteiner, Eva, Gilmour, Amy, Hughes, Chloe, New, Benjamin JM, Connell, David, Dowey, Rebecca, Turton, Helena, Richardson, Hollian, Cassidy, Diane, Cooper, Jamie, Suntharalingam, Jay, Diwakar, Lavanya, Russell, Peter, Underwood, Jonathan, Hicks, Alexander, Dosanjh, Davinder PS, Sage, Beth, Dhasmana, Devesh, Spears, Mark, Thompson, AA Roger, Brightling, Christopher, Smith, Andrew, Patel, Manish ORCID logoORCID: https://orcid.org/0000-0003-3012-7507, George, Jacob, Condliffe, Alison M, Shoemark, Amelia, MacLennan, Graeme, Chalmers, James D, Chalmers, James, Almaden-Boyle, Christine, Taylor, Jennifer, Strachan, Jodie, Loftus, Heather, Young, Lesley, Strachan, Angela, Pilvinyte, Kristina, Miller, David, Cook, Gemma and Wilson, Jayne;