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CompletedNCT04419610Updated May 3, 2024Results posted

RAS and Coagulopathy in COVID19

An Early Phase 1 interventional study of TRV027 and sodium chloride 0.9% in COVID, sponsored by Imperial College London. Completed at 1 site in United Kingdom. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-05-03.

Sponsored by Imperial College London · Early Phase 1, Interventional, and Health services research

Phase
Early Phase 1
Study type
Interventional
Enrollment
28
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

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

Read the 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.

02

Conditions studied

  • COVID
03

In context

Hemostatic Disorders

503 studies on the registry are indexed under Hemostatic Disorders; 71 are open to participants now.

This study's enrollment of 28 is below the median of 51 across 253 interventional studies indexed under Hemostatic Disorders.

Browse Hemostatic Disorders studies →

Lead sponsor

Imperial College London is the lead sponsor of 824 studies on the registry; 178 are open to participants now.

Of its 9 completed or terminated interventional studies of FDA-regulated products, 6 (67%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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
05

Study design

Phase
Early Phase 1
Primary purpose
Health services research
Allocation
Randomized
Intervention model
Single group
Masking
Double (Participant, Investigator)
Enrollment
28 participants (actual)

Study arms

  • 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

  • Placebo comparator
    Patients with confirmed/suspected C19 given no intervention

    Saline infusion.

    Other: sodium chloride 0.9%

Interventions

  • BiologicalTRV027

    peptide for infusion

  • Othersodium chloride 0.9%

    placebo comparator for infusion

06

What researchers measure

Primary outcomes

  1. Coagulopathy Associated With COVID-19

    Change from Day 1 (Baseline) in D-dimer Levels at Day 3

    Time frame: Day 1 (baseline) and Day 3).

Secondary outcomes

  1. Markers of Dysregulation of Coagulation System

    Change from Day 1 (Baseline) in platelet count Levels at Day 3 (10E9 platelets/L)

    Time frame: Day 1 (baseline) and Day 3

  2. Markers of Dysregulation of Coagulation System Change From Baseline

    Activated Partial Thromboplastin Time (aPTT) - Change from Baseline (day 1) to Day 3

    Time frame: Baseline (Day 1) to Day 3

  3. Markers of Dysregulation of Coagulation System

    INR - Change from Baseline (day 1) to Day 3: INR (International Normalised Ratio)

    Time frame: Baseline (day 1) to Day 3

  4. Markers of Dysregulation of Coagulation System

    fibrinogen (g/L) -Change from Baseline (day 1) to Day 3

    Time frame: Baseline (day 1) to Day 3

  5. Markers of Dysregulation of Coagulation System

    Ferritin Ug/mL -Change from Baseline (day 1) to Day 3

    Time frame: Baseline (day 1) to Day 3

  6. Markers of Dysregulation of RAS

    Plasma Renin activity (nmol/L/h) -Change from Baseline (day 1) to Day 3

    Time frame: Baseline (day 1) to Day 3

  7. Markers of Haemolysis/Inflammation

    Total bilirubin (umol/L) -Change from Baseline (day 1) to Day 3

    Time frame: Baseline (day 1) to Day 3

  8. Markers of Haemolysis/Inflammation

    LDH u/L -Change from Baseline (day 1) to Day 3

    Time frame: Baseline (day 1) to Day 3

  9. Markers of Haemolysis/Inflammation

    Haptoglobin g/L - Change from Baseline (day 1) to Day 3

    Time frame: Baseline (day 1) to Day 3

  10. Markers of Inflammation (Bacterial Sepsis)

    Pro-calcitonin ug/L - Change from Baseline (day 1) to Day 3

    Time frame: Baseline (day 1) to Day 3

  11. Markers of Organ Dysregulation - Kidney

    Creatinine (umol/L) - Change from Baseline (day 1) to Day 3

    Time frame: Baseline (day 1) to Day 3

  12. Markers of Dysregulation of Cardiovascular System

    BNP (B-type natriuetic Peptide) ng/L - Change from Baseline (day 1) to Day 3

    Time frame: Baseline (day 1) to Day 3

  13. Markers of Dysregulation of Cardiovascular System

    Troponin ng/L - Change from Baseline (day 1) to Day 3

    Time frame: Baseline (day 1) to Day 3

  14. Marker of Dysregulation of Endocrine System

    glucose mmol/L - Change from Baseline (day 1) to Day 3

    Time frame: Baseline (day 1) to Day 3

07

Results

Posted May 1, 2024

Participant flow

Participant flow — Overall Study
MilestonePatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Started1513
Completed1011
Not completed52
Withdrew: Withdrawal by subject31
Withdrew: Adverse event10
Withdrew: Discharged early11

Outcome measures

PrimaryCoagulopathy Associated With COVID-19

Change from Day 1 (Baseline) in D-dimer Levels at Day 3

Time frame:
Day 1 (baseline) and Day 3).
Reported as:
Median · ng/mL FEU
Coagulopathy Associated With COVID-19
ng/mL FEUPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Coagulopathy Associated With COVID-19-313 (-1253 to 822)-129.5 (-365 to 710)
SecondaryMarkers of Dysregulation of Coagulation System

Change from Day 1 (Baseline) in platelet count Levels at Day 3 (10E9 platelets/L)

Time frame:
Day 1 (baseline) and Day 3
Reported as:
Median · 10E9 platelets/L
Markers of Dysregulation of Coagulation System
10E9 platelets/LPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Dysregulation of Coagulation System25 (-12 to 129)28.5 (-113 to 107)
SecondaryMarkers of Dysregulation of Coagulation System Change From Baseline

Activated Partial Thromboplastin Time (aPTT) - Change from Baseline (day 1) to Day 3

Time frame:
Baseline (Day 1) to Day 3
Reported as:
Median · SECONDS
Markers of Dysregulation of Coagulation System Change From Baseline
SECONDSPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Dysregulation of Coagulation System Change From Baseline-1.3 (-5.2 to 2.3)-0.5 (-4.8 to 2.7)
SecondaryMarkers of Dysregulation of Coagulation System

INR - Change from Baseline (day 1) to Day 3: INR (International Normalised Ratio)

Time frame:
Baseline (day 1) to Day 3
Reported as:
Median · Unitless RATIO
Markers of Dysregulation of Coagulation System
Unitless RATIOPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Dysregulation of Coagulation System1.25 (-1.6 to 3.6)0 (0 to 0.1)
SecondaryMarkers of Dysregulation of Coagulation System

fibrinogen (g/L) -Change from Baseline (day 1) to Day 3

Time frame:
Baseline (day 1) to Day 3
Reported as:
Median · g/L
Markers of Dysregulation of Coagulation System
g/LPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Dysregulation of Coagulation System-0.67 (-2.8 to 1.68)-0.94 (-1.81 to 2.11)
SecondaryMarkers of Dysregulation of Coagulation System

Ferritin Ug/mL -Change from Baseline (day 1) to Day 3

Time frame:
Baseline (day 1) to Day 3
Reported as:
Median · ug/L
Markers of Dysregulation of Coagulation System
ug/LPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Dysregulation of Coagulation System52.5 (-324 to 838)-14 (-572 to 886)
SecondaryMarkers of Dysregulation of RAS

Plasma Renin activity (nmol/L/h) -Change from Baseline (day 1) to Day 3

Time frame:
Baseline (day 1) to Day 3
Reported as:
Median · NMOL/L/h
Markers of Dysregulation of RAS
NMOL/L/hPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Dysregulation of RAS0 (0 to 0)-0.9 (-3.3 to 0.1)
SecondaryMarkers of Haemolysis/Inflammation

Total bilirubin (umol/L) -Change from Baseline (day 1) to Day 3

Time frame:
Baseline (day 1) to Day 3
Reported as:
Median · UMOL/L
Markers of Haemolysis/Inflammation
UMOL/LPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Haemolysis/Inflammation-0.5 (-4 to 2)0 (-4 to 2)
SecondaryMarkers of Haemolysis/Inflammation

LDH u/L -Change from Baseline (day 1) to Day 3

Time frame:
Baseline (day 1) to Day 3
Reported as:
Median · u/L
Markers of Haemolysis/Inflammation
u/LPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Haemolysis/Inflammation-17 (-217 to 270)1 (-151 to 102)
SecondaryMarkers of Haemolysis/Inflammation

Haptoglobin g/L - Change from Baseline (day 1) to Day 3

Time frame:
Baseline (day 1) to Day 3
Reported as:
Median · g/L
Markers of Haemolysis/Inflammation
g/LPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Haemolysis/Inflammation0 (-1.09 to 0.08)0.13 (0 to 0.74)
SecondaryMarkers of Inflammation (Bacterial Sepsis)

Pro-calcitonin ug/L - Change from Baseline (day 1) to Day 3

Time frame:
Baseline (day 1) to Day 3
Reported as:
Median · ug/L
Markers of Inflammation (Bacterial Sepsis)
ug/LPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Inflammation (Bacterial Sepsis)0 (-0.03 to 0.16)0 (-1.12 to 0.03)
SecondaryMarkers of Organ Dysregulation - Kidney

Creatinine (umol/L) - Change from Baseline (day 1) to Day 3

Time frame:
Baseline (day 1) to Day 3
Reported as:
Median · UMOL/L
Markers of Organ Dysregulation - Kidney
UMOL/LPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Organ Dysregulation - Kidney-4 (-16 to 11)-5 (-14 to 10)
SecondaryMarkers of Dysregulation of Cardiovascular System

BNP (B-type natriuetic Peptide) ng/L - Change from Baseline (day 1) to Day 3

Time frame:
Baseline (day 1) to Day 3
Reported as:
Median · ng/L
Markers of Dysregulation of Cardiovascular System
ng/LPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Dysregulation of Cardiovascular System60 (-5 to 762)-19 (-66 to 62)
SecondaryMarkers of Dysregulation of Cardiovascular System

Troponin ng/L - Change from Baseline (day 1) to Day 3

Time frame:
Baseline (day 1) to Day 3
Reported as:
Median · ng/L
Markers of Dysregulation of Cardiovascular System
ng/LPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Markers of Dysregulation of Cardiovascular System-2.5 (-50 to 0)-2.5 (-3 to 0)
SecondaryMarker of Dysregulation of Endocrine System

glucose mmol/L - Change from Baseline (day 1) to Day 3

Time frame:
Baseline (day 1) to Day 3
Reported as:
Median · mmol/L
Marker of Dysregulation of Endocrine System
mmol/LPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
Marker of Dysregulation of Endocrine System-1.1 (-2 to 0.1)-0.00 (-4.7 to 3.8)

Adverse events

Collected over Day 1 to day 7 and day 30 - 7 days of infused drug and follow up call on day 30. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Patients With Confirmed/Suspected C19 Given Intervention2/15 (13.3%)5/15 (33.3%)3/15 (20%)
Patients With Confirmed/Suspected C19 Given no Intervention1/13 (7.7%)3/13 (23.1%)1/13 (7.7%)
Most frequent serious events
Most frequent serious events
EventPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
severe COVID 19 pneumoniaRespiratory, thoracic and mediastinal disorders2/151/13
pulmonary embolismRespiratory, thoracic and mediastinal disorders1/151/13
Bacterial SepsisInfections and infestations0/151/13
confusionNervous system disorders1/150/13
HypotensionVascular disorders1/150/13
Most frequent other events
Most frequent other events
EventPatients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no Intervention
InfectionInfections and infestations2/151/13
injection site reactionSurgical and medical procedures0/151/13
EpistaxisBlood and lymphatic system disorders1/150/13

Baseline characteristics

Age, Continuous
Age, Continuous(years)Patients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no InterventionTotal
Median67 (47 to 89)70 (43 to 79)68.5 (43 to 89)
Sex: Female, Male
Sex: Female, Male(Participants)Patients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no InterventionTotal
Female7916
Male8412
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Patients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no InterventionTotal
white527
Mixed101
Asian033
Black022
Other7512
Not reported213
Region of Enrollment
Region of Enrollment(Participants)Patients With Confirmed/Suspected C19 Given InterventionPatients With Confirmed/Suspected C19 Given no InterventionTotal
United Kingdom151328
08

Study locations

1 site
  • Imperial College NHS Trust
    London, W12 0HS, United Kingdom
09

References and documents

Publications

  • Robbins AJ, Che Bakri NA, Toke-Bjolgerud E, Edwards A, Vikraman A, Michalsky C, Fossler M, Lemm NM, Medhipour S, Budd W, Gravani A, Hurley L, Kapil V, Jackson A, Lonsdale D, Latham V, Laffan M, Chapman N, Cooper N, Szydlo R, Boyle J, Pollock KM, Owen D. The effect of TRV027 on coagulation in COVID-19: A pilot randomized, placebo-controlled trial. Br J Clin Pharmacol. 2023 Apr;89(4):1495-1501. doi: 10.1111/bcp.15618. Epub 2022 Dec 14. PubMed 36437688 ↗

Study documents

  • Study protocol · Mar 12, 2021
  • Statistical analysis plan · Jan 28, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on May 3, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT04419610
Lead sponsor
Imperial College London
Responsible party
Sponsor
First posted
Jun 5, 2020
Start date
Oct 9, 2020
Primary completion
May 12, 2021
Completion
May 12, 2021
Results posted
May 1, 2024
Last update
May 3, 2024

Study contacts

DAVID OWEN
principal investigator · National Health Service, United Kingdom
Katrina Pollock
principal investigator · National Health Service, United Kingdom

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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