RAS and Coagulopathy in COVID19

Investigating the Relationship Between the Renin Angiotensin System and the Coagulopathy Associated With COVID-19

To determine whether the coagulopathy associated with COVID-19 infection is driven by overactivation of the renin angiotensin system (RAS)

The proposed study will be run as a double-blind, randomized controlled experimental medicine study in male and female hospitalised (n=60) aged 18 or over, with confirmed COVID-19 infection. Patients who are admitted due to confirmed COVID-19 infection will be screened with a routine medical assessment (see Table 1) and enrolled if they meet the eligibility criteria. Subjects will be block randomised based on age to continuous intravenous infusion of placebo or TRV027 for 7 days. Day 1 procedures can occur on the same day of screening and include a venous blood test prior to commencing an intravenous infusion of either placebo or TRV027 at 12mg/hr. The infusions will continue for 7 days. Venous blood tests will be repeated at days 3, 5 and 8, amounting to approximately 120mLs of blood in total over the 8-day period. Once the infusion has finished, the subjects will remain in hospital for a further 24 hours for vital signs and adverse event monitoring. If a subject exits the trial before the 7-day infusion finishes, they will be advised to remain in hospital for a 24 hour period for monitoring. Subjects will be followed up on Day 30 either via telephone or via medical records. . The role of the renin angiotensin system (RAS) in COVID-19 infection has been widely discussed for two reasons. First, SARS-COV-2, the virus causing COVID-19, invades type II pneumocytes in the lung by binding to an enzyme called angiotensin converting enzyme 2 (ACE2). As the virus enters the cell, via one of its receptors, ACE2, it is thought that this is internalised and is hence unable to perform its physiological action of converting Angiotensin II (AngII) to Ang(1-7). Second, it has been noted that severe COVID-19 infection has many features which are strikingly similar to the effects of overactivation of the RAS. Indeed, these features are apparent in preclinical models using AngII infusions and include lung injury, lung inflammation, myocardial microinfarcts, characteristic glomerular thrombosis and coagulopathy. The coagulopathy is particularly noteworthy given an early increase in D-Dimer has very high positive predictor value for death in COVID-19, and D-dimer concentrations are unusually high in COVID-19, over and above what would be expected for an acute phase response or a pneumonia caused by a respiratory virus such as influenza. AngII and Ang(1-7) affect various aspects of the coagulation system including platelets and endothelial cells, and we therefore hypothesise that overaction of RAS is partly responsible for the coagulopathy present in COVID-19 infection. Because the over activation of the RAS in COVID-19 infection is due to both Angiotensin II excess and Ang(1-7) depletion, standard tools to modulate RAS (angiotensin converting enzyme inhibitors and angiotensin receptor blockers) cannot be used to test this hypothesis as they address the Angiotensin II excess, but not the Ang(1-7) depletion. TRV027 is a similar peptide to Ang(1-7) but is a much more potent biased agonist at AT1R than Ang(1-7) and would be expected to oppose the effects of AngII accumulation, and functionally correct the Ang(1-7) deficiency. Hence it is an appropriate tool to examine the link between RAS activation and coagulopathy in the context of COVID-19 infection.

Intravenous infusion of either placebo or TRV027 at 12mg/hr. Treatment will continue until discharge or for 7 days (whichever is sooner).

Mean change from baseline D-dimer at day 1 to day 3 post randomisation following administration of TRV027 or placebo.

INCLUSION CRITERIA A subject will be eligible for inclusion in this study only if all of the following criteria apply at the time of screening: Hospitalised with confirmed COVID-19 infection. Screened within 96hrs of SARS-COV-2 positive PCR. Age 18 or over Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Systolic blood pressure between 100 and 180 EXCLUSION CRITERIA A subject will not be eligible for inclusion in this study if any of the following criteria apply at the time of screening: Any unrelated clinical condition, which, in the opinion of the investigator, may affect D-dimer during the course of the study, independent of COVID-19 infection, e.g. subsets of cancers and coagulopathies. Concomitant medication which inhibit the action of TRV027 (ARB's). Any clinically significant medical conditions that in the opinion of the investigator would compromise subjects' safety or compliance with study procedures. Any clinical condition which in the opinion of the principal investigator would compromise the scientific integrity of the study Unwillingness or inability to follow the procedures outlined in the protocol. Subject is pregnant or breastfeeding