Bradykinin inhibition in COVID-19: a randomised, double-blind trial of icatibant versus placebo

<bold>Introduction:</bold> At an early stage of infection, COVID-19 causes cough, dyspnoea, loss of taste/smell and oedema seen as infiltrates on chest imaging. Coagulopathy, thrombosis and hypotension can occur. These features may be due to the contact-kinin system which triggers clotting and produces vasoactive bradykinin. <bold>Hypothesis</bold> There is excess accumulation of bradykinin in symptomatic COVID-19. Bradykinin causes oedema in the lungs, leading to hypoxia. It also causes vasodilation and cytokine release. <bold>Aim:</bold> To inhibit bradykinin in early stage hypoxic COVID-19 patients. <bold>Methods:</bold> Hypoxic PCR positive patients with symptoms ≤7 days were randomised to a single dose of bradykinin antagonist (icatibant 30mg) or placebo subcutaneously. Patients/investigators were blinded to treatment. Arterial blood sampling and cardiovascular (CVS) measurements were completed at baseline and 3 hours post treatment. The primary outcome was change in the Alveolar-arterial oxygen (A-a O2) gradient. The secondary outcome was change in CVS measurements. <bold>Results:</bold> 14 patients received icatibant and 16 placebo. A-a O2 gradient decreased by 0.09kPa (p=0.772) with icatibant (n=14) and increased by 0.07kPa (p=0.773) with placebo. Change between groups was 0.16kPa (p=0.61). MAP increased by 4.21mmHg (p=0.13) for icatibant and 3.44mmHg (p=0.16) for placebo. Change between groups was 0.77mmHg (p=0.91). <bold>Conclusion:</bold> This is the first double-blind placebo controlled trial of icatibant in early COVID-19. Single dose icatibant therapy did not improve oxygenation or MAP in acute COVID-19. <bold>Trial registration</bold> Clinicaltrials.gov <ext-link>NCT05407597</ext-link>