RAS and Coagulopathy in COVID19
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|ClinicalTrials.gov Identifier: NCT04419610|
Recruitment Status : Completed
First Posted : June 5, 2020
Last Update Posted : May 27, 2021
|Condition or disease||Intervention/treatment||Phase|
|COVID||Biological: TRV027 Other: sodium chloride 0.9%||Early Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||Double (Participant, Investigator)|
|Primary Purpose:||Health Services Research|
|Official Title:||Investigating the Relationship Between the Renin Angiotensin System and the Coagulopathy Associated With COVID-19|
|Actual Study Start Date :||October 9, 2020|
|Actual Primary Completion Date :||May 12, 2021|
|Actual Study Completion Date :||May 12, 2021|
Experimental: Patients with confirmed/suspected C19 given intervention
Intravenous infusion of either placebo or TRV027 at 12mg/hr. Treatment will continue until discharge or for 7 days (whichever is sooner).
peptide for infusion
Placebo Comparator: Patients with confirmed/suspected C19 given no intervention
Other: sodium chloride 0.9%
placebo comparator for infusion
- Coagulopathy associated with COVID-19 [ Time Frame: Day 1 and Day 8 ]Mean change from baseline D-dimer at day 1 to day 3 post randomisation following administration of TRV027 or placebo.
- Markers of dysregulation of coagulation system [ Time Frame: Day 1, 3, 5 and Day 8 ]Absolute D-Dimer - (Fibrin Equivalent units)
- Markers of dysregulation of coagulation system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]platelet count (E9 /L)
- Markers of dysregulation of coagulation system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]aPTT (Activated Partial Thromboplastin time) - seconds
- Markers of dysregulation of coagulation system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]INR - (calculated as a ratio from aPTT)
- Markers of dysregulation of coagulation system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]fibrinogen (g/L)
- Markers of dysregulation of coagulation system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]Ferritin Ug/mL
- Markers of dysregulation of RAS [ Time Frame: Day 1 ]Plasma Renin Mass and activity (nmol/L/h)
- Markers of Haemolysis/inflammation [ Time Frame: Day 1, 3, Day 5 and Day 8 ]Total bilirubin (umol/L)
- Markers of Haemolysis/Inflammation [ Time Frame: Day 3, Day 5 and Day 8 ]LDH u/L
- Markers of Haemolysis/inflammation [ Time Frame: Day 1, 3, Day 5 and Day 8 ]Haptoglobin g/L
- Markers of Inflammation (bacterial sepsis) [ Time Frame: day 1, 3, 5 and 8 ]Pro-calcitonin ug/L
- Markers of organ dysregulation - kidney [ Time Frame: Day 1, 3, Day 5 and Day 8 ]Creatinine (umol/L)
- Markers of dysregulation of cardiovascular system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]BNP (B-type natriuetic Peptide) ng/L
- Markers of dysregulation of cardiovascular system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]Troponin ng/L
- marker of dysregulation of endocrine system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]glucose mmol/L
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04419610
|Imperial College NHS Trust|
|London, United Kingdom, W12 0HS|
|Principal Investigator:||DAVID OWEN||National Health Service, United Kingdom|
|Principal Investigator:||Katrina Pollock||National Health Service, United Kingdom|