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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
Sponsor:
Information provided by (Responsible Party):
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)

Condition or disease Intervention/treatment Phase
COVID Biological: TRV027 Other: sodium chloride 0.9% Early Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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).
Biological: TRV027
peptide for infusion

Placebo Comparator: Patients with confirmed/suspected C19 given no intervention
Saline infusion.
Other: sodium chloride 0.9%
placebo comparator for infusion




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Markers of dysregulation of coagulation system [ Time Frame: Day 1, 3, 5 and Day 8 ]
    Absolute D-Dimer - (Fibrin Equivalent units)

  2. Markers of dysregulation of coagulation system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]
    platelet count (E9 /L)

  3. Markers of dysregulation of coagulation system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]
    aPTT (Activated Partial Thromboplastin time) - seconds

  4. Markers of dysregulation of coagulation system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]
    INR - (calculated as a ratio from aPTT)

  5. Markers of dysregulation of coagulation system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]
    fibrinogen (g/L)

  6. Markers of dysregulation of coagulation system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]
    Ferritin Ug/mL

  7. Markers of dysregulation of RAS [ Time Frame: Day 1 ]
    Plasma Renin Mass and activity (nmol/L/h)

  8. Markers of Haemolysis/inflammation [ Time Frame: Day 1, 3, Day 5 and Day 8 ]
    Total bilirubin (umol/L)

  9. Markers of Haemolysis/Inflammation [ Time Frame: Day 3, Day 5 and Day 8 ]
    LDH u/L

  10. Markers of Haemolysis/inflammation [ Time Frame: Day 1, 3, Day 5 and Day 8 ]
    Haptoglobin g/L

  11. Markers of Inflammation (bacterial sepsis) [ Time Frame: day 1, 3, 5 and 8 ]
    Pro-calcitonin ug/L

  12. Markers of organ dysregulation - kidney [ Time Frame: Day 1, 3, Day 5 and Day 8 ]
    Creatinine (umol/L)

  13. Markers of dysregulation of cardiovascular system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]
    BNP (B-type natriuetic Peptide) ng/L

  14. Markers of dysregulation of cardiovascular system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]
    Troponin ng/L

  15. marker of dysregulation of endocrine system [ Time Frame: Day 1, 3, Day 5 and Day 8 ]
    glucose mmol/L



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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:

  1. Hospitalised with confirmed COVID-19 infection.
  2. Screened within 96hrs of SARS-COV-2 positive PCR.
  3. Age 18 or over
  4. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  5. 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:

  1. 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.
  2. Concomitant medication which inhibit the action of TRV027 (ARB's).
  3. Any clinically significant medical conditions that in the opinion of the investigator would compromise subjects' safety or compliance with study procedures.
  4. Any clinical condition which in the opinion of the principal investigator would compromise the scientific integrity of the study
  5. Unwillingness or inability to follow the procedures outlined in the protocol.
  6. Subject is pregnant or breastfeeding

Information from the National Library of Medicine

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


Locations
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United Kingdom
Imperial College NHS Trust
London, United Kingdom, W12 0HS
Sponsors and Collaborators
Imperial College London
Investigators
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Principal Investigator: DAVID OWEN National Health Service, United Kingdom
Principal Investigator: Katrina Pollock National Health Service, United Kingdom
  Study Documents (Full-Text)

Documents provided by Imperial College London:
Study Protocol  [PDF] March 12, 2021

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Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT04419610    
Other Study ID Numbers: 283093
First Posted: June 5, 2020    Key Record Dates
Last Update Posted: May 27, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hemostatic Disorders
Blood Coagulation Disorders
Hematologic Diseases
Vascular Diseases
Cardiovascular Diseases
Hemorrhagic Disorders