RAS and Coagulopathy in COVID19

Early Phase 1

Completed

Conditions: COVID

Interventions: Biological: TRV027
Other: sodium chloride 0.9%

Registration Number: NCT04419610

Lead Sponsor: Imperial College London

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

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 28

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Patients with confirmed/suspected C19 given intervention	TRV027	Intravenous infusion of either placebo or TRV027 at 12mg/hr. Treatment will continue until discharge or for 7 days (whichever is sooner).
Patients with confirmed/suspected C19 given no intervention	sodium chloride 0.9%	Saline infusion.

Primary Outcome Measures

Name	Time	Method
Coagulopathy Associated With COVID-19	Day 1 (baseline) and Day 3).	Change from Day 1 (Baseline) in D-dimer Levels at Day 3

Secondary Outcome Measures

Name	Time	Method
Markers of Dysregulation of Coagulation System	Baseline (day 1) to Day 3	Ferritin Ug/mL -Change from Baseline (day 1) to Day 3
Markers of Dysregulation of Coagulation System Change From Baseline	Baseline (Day 1) to Day 3	Activated Partial Thromboplastin Time (aPTT) - Change from Baseline (day 1) to Day 3
Marker of Dysregulation of Endocrine System	Baseline (day 1) to Day 3	glucose mmol/L - Change from Baseline (day 1) to Day 3
Markers of Dysregulation of RAS	Baseline (day 1) to Day 3	Plasma Renin activity (nmol/L/h) -Change from Baseline (day 1) to Day 3
Markers of Haemolysis/Inflammation	Baseline (day 1) to Day 3	Haptoglobin g/L - Change from Baseline (day 1) to Day 3
Markers of Inflammation (Bacterial Sepsis)	Baseline (day 1) to Day 3	Pro-calcitonin ug/L - Change from Baseline (day 1) to Day 3
Markers of Organ Dysregulation - Kidney	Baseline (day 1) to Day 3	Creatinine (umol/L) - Change from Baseline (day 1) to Day 3
Markers of Dysregulation of Cardiovascular System	Baseline (day 1) to Day 3	Troponin ng/L - Change from Baseline (day 1) to Day 3