tetano
Editor, Senior Moderator
Med (N Y)
. 2022 Mar 11.
doi: 10.1016/j.medj.2022.03.001. Online ahead of print.
A randomized, double-blind, placebo-controlled trial of intravenous alpha-1 antitrypsin for acute respiratory distress syndrome secondary to COVID-19
Oliver J McElvaney[SUP] 1 2 [/SUP], Natalie L McEvoy[SUP] 3 [/SUP], Fiona Boland[SUP] 4 [/SUP], Oisín F McElvaney[SUP] 1 2 [/SUP], Grace Hogan[SUP] 3 [/SUP], Karen Donnelly[SUP] 2 [/SUP], Oisín Friel[SUP] 2 [/SUP], Emmet Browne[SUP] 2 [/SUP], Daniel D Fraughen[SUP] 1 2 [/SUP], Mark P Murphy[SUP] 1 [/SUP], Jennifer Clarke[SUP] 2 3 [/SUP], Orna Ní Choileáin[SUP] 2 [/SUP], Eoin O'Connor[SUP] 2 [/SUP], Rory McGuinness[SUP] 2 [/SUP], Maria Boylan[SUP] 2 [/SUP], Alan Kelly[SUP] 2 [/SUP], John C Hayden[SUP] 5 [/SUP], Ann M Collins[SUP] 6 [/SUP], Ailbhe Cullen[SUP] 6 [/SUP], Deirdre Hyland[SUP] 6 [/SUP], Tomás P Carroll[SUP] 1 [/SUP], Pierce Geoghegan[SUP] 2 [/SUP], John G Laffey[SUP] 7 [/SUP], Martina Hennessey[SUP] 8 [/SUP], Ignacio Martin-Loeches[SUP] 8 [/SUP], Noel G McElvaney[SUP] 1 2 [/SUP], Gerard F Curley[SUP] 2 3 [/SUP]
Affiliations
Abstract
Background: Patients with severe COVID-19 develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous plasma-purified alpha-1 antitrypsin (AAT) for moderate-to-severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15).
Methods: Patients (n=36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at one week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1β, IL-8, IL-10 and soluble TNF receptor 1 and clinical outcomes were assessed as secondary endpoints.
Findings: Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at one week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1β, IL-8 and IL-10. No difference in mortality or ventilator-free days was observed between groups, though a trend towards decreased time-on-ventilator was observed in AAT-treated patients.
Conclusions: In patients with COVID-19 and moderate-to-severe ARDS, treatment with IV AAT was safe, feasible and biochemically efficacious. The data support progression to a phase 3 trial, and prompt further investigation of AAT as an anti-inflammatory therapeutic.
Keywords: Alpha-1 antitrypsin; COVID-19; Clinical trial; Coronavirus; Cytokines; Inflammation; Interleukin-6; Randomized control trial.
. 2022 Mar 11.
doi: 10.1016/j.medj.2022.03.001. Online ahead of print.
A randomized, double-blind, placebo-controlled trial of intravenous alpha-1 antitrypsin for acute respiratory distress syndrome secondary to COVID-19
Oliver J McElvaney[SUP] 1 2 [/SUP], Natalie L McEvoy[SUP] 3 [/SUP], Fiona Boland[SUP] 4 [/SUP], Oisín F McElvaney[SUP] 1 2 [/SUP], Grace Hogan[SUP] 3 [/SUP], Karen Donnelly[SUP] 2 [/SUP], Oisín Friel[SUP] 2 [/SUP], Emmet Browne[SUP] 2 [/SUP], Daniel D Fraughen[SUP] 1 2 [/SUP], Mark P Murphy[SUP] 1 [/SUP], Jennifer Clarke[SUP] 2 3 [/SUP], Orna Ní Choileáin[SUP] 2 [/SUP], Eoin O'Connor[SUP] 2 [/SUP], Rory McGuinness[SUP] 2 [/SUP], Maria Boylan[SUP] 2 [/SUP], Alan Kelly[SUP] 2 [/SUP], John C Hayden[SUP] 5 [/SUP], Ann M Collins[SUP] 6 [/SUP], Ailbhe Cullen[SUP] 6 [/SUP], Deirdre Hyland[SUP] 6 [/SUP], Tomás P Carroll[SUP] 1 [/SUP], Pierce Geoghegan[SUP] 2 [/SUP], John G Laffey[SUP] 7 [/SUP], Martina Hennessey[SUP] 8 [/SUP], Ignacio Martin-Loeches[SUP] 8 [/SUP], Noel G McElvaney[SUP] 1 2 [/SUP], Gerard F Curley[SUP] 2 3 [/SUP]
Affiliations
- PMID: 35291694
- PMCID: PMC8913266
- DOI: 10.1016/j.medj.2022.03.001
Abstract
Background: Patients with severe COVID-19 develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous plasma-purified alpha-1 antitrypsin (AAT) for moderate-to-severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15).
Methods: Patients (n=36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at one week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1β, IL-8, IL-10 and soluble TNF receptor 1 and clinical outcomes were assessed as secondary endpoints.
Findings: Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at one week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1β, IL-8 and IL-10. No difference in mortality or ventilator-free days was observed between groups, though a trend towards decreased time-on-ventilator was observed in AAT-treated patients.
Conclusions: In patients with COVID-19 and moderate-to-severe ARDS, treatment with IV AAT was safe, feasible and biochemically efficacious. The data support progression to a phase 3 trial, and prompt further investigation of AAT as an anti-inflammatory therapeutic.
Keywords: Alpha-1 antitrypsin; COVID-19; Clinical trial; Coronavirus; Cytokines; Inflammation; Interleukin-6; Randomized control trial.