RAS and Coagulopathy in COVID19

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.