tetano
Editor, Senior Moderator
Infection
. 2022 Sep 14.
doi: 10.1007/s15010-022-01904-w. Online ahead of print.
DFV890: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function
Ildiko Madurka[SUP] 1 [/SUP], Alexander Vishnevsky[SUP] 2 [/SUP], Joan B Soriano[SUP] 3 [/SUP], Stephanus J Gans[SUP] 4 [/SUP], Danilo Joel Salazar Ore[SUP] 5 [/SUP], Adrian Rendon[SUP] 6 [/SUP], Charlotte S Ulrik[SUP] 7 [/SUP], Sushma Bhatnagar[SUP] 8 [/SUP], Srikanth Krishnamurthy[SUP] 9 [/SUP], Kirsten Mc Harry[SUP] 10 11 [/SUP], Tobias Welte[SUP] 12 [/SUP], Alberto A Fernandez[SUP] 13 [/SUP], Beata Mehes[SUP] 14 [/SUP], Karin Meiser[SUP] 14 [/SUP], Ewa Gatlik[SUP] 14 [/SUP], Ulrike Sommer[SUP] 14 [/SUP], Guido Junge[SUP] 14 [/SUP], Ederlon Rezende[SUP] 15 [/SUP], Study group
Collaborators, Affiliations
Abstract
Background: Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm.
Methods: This randomised, multinational study enrolled hospitalised patients (18-80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety.
Findings: Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC (n = 71) or SoC alone (n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals.
Interpretation: DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS.
Trial registration: ClinicalTrials.gov, NCT04382053.
Keywords: Coronavirus-associated acute respiratory distress syndrome; DFV890; NLRP3 inhibitors; Randomised controlled trial; SARS-CoV-2.
. 2022 Sep 14.
doi: 10.1007/s15010-022-01904-w. Online ahead of print.
DFV890: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function
Ildiko Madurka[SUP] 1 [/SUP], Alexander Vishnevsky[SUP] 2 [/SUP], Joan B Soriano[SUP] 3 [/SUP], Stephanus J Gans[SUP] 4 [/SUP], Danilo Joel Salazar Ore[SUP] 5 [/SUP], Adrian Rendon[SUP] 6 [/SUP], Charlotte S Ulrik[SUP] 7 [/SUP], Sushma Bhatnagar[SUP] 8 [/SUP], Srikanth Krishnamurthy[SUP] 9 [/SUP], Kirsten Mc Harry[SUP] 10 11 [/SUP], Tobias Welte[SUP] 12 [/SUP], Alberto A Fernandez[SUP] 13 [/SUP], Beata Mehes[SUP] 14 [/SUP], Karin Meiser[SUP] 14 [/SUP], Ewa Gatlik[SUP] 14 [/SUP], Ulrike Sommer[SUP] 14 [/SUP], Guido Junge[SUP] 14 [/SUP], Ederlon Rezende[SUP] 15 [/SUP], Study group
Collaborators, Affiliations
- PMID: 36104613
- DOI: 10.1007/s15010-022-01904-w
Abstract
Background: Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm.
Methods: This randomised, multinational study enrolled hospitalised patients (18-80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety.
Findings: Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC (n = 71) or SoC alone (n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals.
Interpretation: DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS.
Trial registration: ClinicalTrials.gov, NCT04382053.
Keywords: Coronavirus-associated acute respiratory distress syndrome; DFV890; NLRP3 inhibitors; Randomised controlled trial; SARS-CoV-2.