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Valsartan for Prevention of Acute Respiratory Distress Syndrome in Hospitalized Patients With SARS-COV-2 (COVID-19) Infection Disease

Primary Purpose

Acute Respiratory Distress Syndrome, SARS-CoV-2, COVID

Status
Terminated
Phase
Phase 4
Locations
Netherlands
Study Type
Interventional
Intervention
Valsartan (Diovan)
Placebo oral tablet
Sponsored by
Radboud University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Respiratory Distress Syndrome focused on measuring Acute Respiratory Distress Syndrome, SARS-CoV-2, Therapeutics, Valsartan, Angiotensin Receptor Blockade, Angiotensin Receptor Blockers, ARBs, COVID-19

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

  • Adult (age ≥ 18 years)
  • Admitted to the hospital of any participating center
  • Confirmed SARS-CoV-2 infection with either: positive laboratory test for SARS-CoV-2* ; or positive CT thorax diagnostic for SARS-CoV-2 infection according to the prevailing criteria

  • Randomization:

    • Within 24 hours of confirmed in-hospital SARS-CoV-2 infection diagnosis OR

    • within 24 hours of hospital admission in case of pre-hospital confirmed SARS-CoV-2 infection.

      • In case there is a lack of laboratory tests for SARS-CoV-2 in the participating center of the potentially eligible patient, a positive laboratory test for SARS-CoV-2 will be no longer required. In that case, the potentially eligible patient needs to meet the prevailing criteria for the diagnosis of SARS-CoV-2 infection of that participating center, such as typical abnormalities on pulmonary CT in the setting of high clinical suspicion of SARS-CoV-2 infection.

Exclusion Criteria:

  • Admitted to ICU prior to randomization
  • Currently taking an ARB or angiotensin-receptor-neprilysin-inhibitor (ARNI)
  • Use of other investigational drugs at the time of enrollment
  • Prior reaction or intolerance to an ARB or ARNI; or severe intolerance to an ACEi, defined as angio-oedema requiring medical intervention
  • Systolic blood pressure < 105mmHg or diastolic blood pressure <65mmHg
  • Potassium greater than 5.5 mEq/L within 4 weeks of study enrollment.
  • Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 m2 within 4 weeks of study initiation
  • A known history of renal artery stenosis
  • AST and/or ALT > 3 times the upper limit of normal within 4 weeks of study enrollment. In case of mild to moderate liver dysfunction valsartan dosage will be limited to a maximum of 80mg
  • Severe liver dysfunction, biliary cirrhosis or cholestasis
  • Severe volume depletion or severe acute kidney injury that, in the opinion of the investigator, would preclude administration of valsartan
  • Concurrent treatment with Aliskiren
  • Inability to obtain informed consent
  • Pregnancy or breastfeeding
  • In females of childbearing age, unwillingness to use birth control or to be sexually abstinent for the duration of the study

Sites / Locations

  • Jeroen Bosch Ziekenhuis
  • Rijnstate
  • Radboudumc
  • Laurentius Ziekenhuis
  • Erasmus MC
  • Franciscus Gasthuis
  • Ikazia Ziekenhuis

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Active treatment arm

Placebo arm

Arm Description

Valsartan at a dosage and frequency titrated to blood pressure with 80mg or 160mg tablets up to a maximum dose of 160mg b.i.d.

Matching 80mg or 160mg placebo tablets at a dosage and frequency titrated to systolic blood pressure

Outcomes

Primary Outcome Measures

first occurrence of intensive care unit admission, mechanical ventilation or death
Death is defined as all-cause mortality

Secondary Outcome Measures

Death
All-cause mortality; and time to all-cause mortality
Mechanical ventilation
Occurrence of mechanical ventilation and time to ventilation
Intensive care unit admission
Occurrence of ICU admission and time to admission
Occurrence of acute kidney injury
Defined as a 50% decline in estimated glomerular filtration rate relative to baseline, or decrease of >30 ml/min/1.73m2 and to a value below 60 ml/min/1.73m2

Full Information

First Posted
April 2, 2020
Last Updated
September 19, 2021
Sponsor
Radboud University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT04335786
Brief Title
Valsartan for Prevention of Acute Respiratory Distress Syndrome in Hospitalized Patients With SARS-COV-2 (COVID-19) Infection Disease
Official Title
PRAETORIAN-COVID: A Double-blind, Placebo-controlled Randomized Clinical Trial With Valsartan for PRevention of Acute rEspiraTORy dIstress Syndrome in hospitAlized patieNts With SARS-COV-2 (COVID-19) Infection Disease
Study Type
Interventional

2. Study Status

Record Verification Date
April 2020
Overall Recruitment Status
Terminated
Why Stopped
Enrollment was stopped to facilitate successful enrollment for the ACE2RAS-domain of the REMAP-CAP trial.
Study Start Date
April 17, 2020 (Actual)
Primary Completion Date
May 25, 2021 (Actual)
Study Completion Date
May 25, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Rationale: The current SARS-CoV-2 pandemic has a high burden of morbidity and mortality due to development of the so-called acute respiratory distress syndrome (ARDS). The renin-angiotensin-system (RAS) plays an important role in the development of ARDS. ACE2 is one of the enzymes involved in the RAS cascade. Virus spike protein binds to ACE2 to form a complex suitable for cellular internalization. The downregulation of ACE2 results in the excessive accumulation of angiotensin II, and it has been demonstrated that the stimulation of the angiotensin II type 1a receptor (AT1R) increases pulmonary vascular permeability, explaining the increased lung pathology when activity of ACE2 is decreased. Currently available AT1R blockers (ARBs) such as valsartan, have the potential to block this pathological process mediated by angiotensin II. There are presently two complementary mechanisms suggested: 1) ARBs block the excessive angiotensin-mediated AT1R activation, and 2) they upregulate ACE2, which reduces angiotensin II concentrations and increases the production of the protective vasodilator angiotensin 1-7. In light of the above, ARBs may prevent the development of ARDS and avert morbidity (admission to intensive care unit (ICU) and mechanical ventilation) and mortality. Objective: To investigate the effect of the ARB valsartan in comparison to placebo on the occurrence of one of the following items, within 14 days of randomization:1) ICU admission; 2) Mechanical ventilation; 3) Death. Study design: A double-blind, placebo-controlled 1:1 randomized clinical trial Study population: Adult hospitalized SARS-CoV-2-infected patients (n=651). Intervention: The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160mg b.i.d. and the placebo arm will receive a matching placebo also titrated to blood pressure. Treatment duration will be 14 days or up to hospital discharge < 14 days or occurrence of the primary endpoint if < 14 days. Main study endpoint: The primary study endpoint is the occurrence within 14 days of randomization of either: 1) ICU admission; 2) Mechanical ventilation; 3) Death.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Respiratory Distress Syndrome, SARS-CoV-2, COVID, COVID-19, Severe Acute Respiratory Syndrome
Keywords
Acute Respiratory Distress Syndrome, SARS-CoV-2, Therapeutics, Valsartan, Angiotensin Receptor Blockade, Angiotensin Receptor Blockers, ARBs, COVID-19

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Active treatment arm
Arm Type
Experimental
Arm Description
Valsartan at a dosage and frequency titrated to blood pressure with 80mg or 160mg tablets up to a maximum dose of 160mg b.i.d.
Arm Title
Placebo arm
Arm Type
Placebo Comparator
Arm Description
Matching 80mg or 160mg placebo tablets at a dosage and frequency titrated to systolic blood pressure
Intervention Type
Drug
Intervention Name(s)
Valsartan (Diovan)
Intervention Description
At the time of randomization each participant will start with study treatment and continue up to 14 days, or up to reaching the primary endpoint, or up to hospital discharge, or up to any of the pre-defined stopping criteria. Study drug dosages will be titrated to blood pressure with a maximum of 160mg b.i.d.
Intervention Type
Drug
Intervention Name(s)
Placebo oral tablet
Intervention Description
At the time of randomization each participant will start with study treatment and continue up to 14 days, or up to reaching the primary endpoint, or up to hospital discharge, or up to any of the pre-defined stopping criteria.
Primary Outcome Measure Information:
Title
first occurrence of intensive care unit admission, mechanical ventilation or death
Description
Death is defined as all-cause mortality
Time Frame
within 14 days
Secondary Outcome Measure Information:
Title
Death
Description
All-cause mortality; and time to all-cause mortality
Time Frame
Within 14 days, 30 days, 90 days and at 1 year
Title
Mechanical ventilation
Description
Occurrence of mechanical ventilation and time to ventilation
Time Frame
within 14 days
Title
Intensive care unit admission
Description
Occurrence of ICU admission and time to admission
Time Frame
within 14 days
Title
Occurrence of acute kidney injury
Description
Defined as a 50% decline in estimated glomerular filtration rate relative to baseline, or decrease of >30 ml/min/1.73m2 and to a value below 60 ml/min/1.73m2
Time Frame
Within 14 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Adult (age ≥ 18 years) Admitted to the hospital of any participating center Confirmed SARS-CoV-2 infection with either: positive laboratory test for SARS-CoV-2* ; or positive CT thorax diagnostic for SARS-CoV-2 infection according to the prevailing criteria Randomization: Within 24 hours of confirmed in-hospital SARS-CoV-2 infection diagnosis OR within 24 hours of hospital admission in case of pre-hospital confirmed SARS-CoV-2 infection. In case there is a lack of laboratory tests for SARS-CoV-2 in the participating center of the potentially eligible patient, a positive laboratory test for SARS-CoV-2 will be no longer required. In that case, the potentially eligible patient needs to meet the prevailing criteria for the diagnosis of SARS-CoV-2 infection of that participating center, such as typical abnormalities on pulmonary CT in the setting of high clinical suspicion of SARS-CoV-2 infection. Exclusion Criteria: Admitted to ICU prior to randomization Currently taking an ARB or angiotensin-receptor-neprilysin-inhibitor (ARNI) Use of other investigational drugs at the time of enrollment Prior reaction or intolerance to an ARB or ARNI; or severe intolerance to an ACEi, defined as angio-oedema requiring medical intervention Systolic blood pressure < 105mmHg or diastolic blood pressure <65mmHg Potassium greater than 5.5 mEq/L within 4 weeks of study enrollment. Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 m2 within 4 weeks of study initiation A known history of renal artery stenosis AST and/or ALT > 3 times the upper limit of normal within 4 weeks of study enrollment. In case of mild to moderate liver dysfunction valsartan dosage will be limited to a maximum of 80mg Severe liver dysfunction, biliary cirrhosis or cholestasis Severe volume depletion or severe acute kidney injury that, in the opinion of the investigator, would preclude administration of valsartan Concurrent treatment with Aliskiren Inability to obtain informed consent Pregnancy or breastfeeding In females of childbearing age, unwillingness to use birth control or to be sexually abstinent for the duration of the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Niels van Royen, MD PhD
Organizational Affiliation
Radboud University Medical Center
Official's Role
Study Chair
Facility Information:
Facility Name
Jeroen Bosch Ziekenhuis
City
's-Hertogenbosch
Country
Netherlands
Facility Name
Rijnstate
City
Arnhem
ZIP/Postal Code
6815AD
Country
Netherlands
Facility Name
Radboudumc
City
Nijmegen
Country
Netherlands
Facility Name
Laurentius Ziekenhuis
City
Roermond
Country
Netherlands
Facility Name
Erasmus MC
City
Rotterdam
Country
Netherlands
Facility Name
Franciscus Gasthuis
City
Rotterdam
Country
Netherlands
Facility Name
Ikazia Ziekenhuis
City
Rotterdam
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
32512291
Citation
Gommans DHF, Nas J, Pinto-Sietsma SJ, Koop Y, Konst RE, Mensink F, Aarts GWA, Konijnenberg LSF, Cortenbach K, Verhaert DVM, Thannhauser J, Mol JQ, Rooijakkers MJP, Vos JL, van Rumund A, Vart P, Hassing RJ, Cornel JH, de Jager CPC, van den Heuvel MM, van der Hoeven HG, Verbon A, Pinto YM, van Royen N, van Kimmenade RRJ; Event committee; de Leeuw PW, van Agtmael MA, Bresser P; Data Safety Monitoring Board; van Gilst WH, Vonk-Noordergraaf A, Tijssen JGP; Steering committee; van Royen N, de Jager CPC, van den Heuvel MM, van der Hoeven HG, Verbon A, Pinto YM, van Kimmenade RRJ. Rationale and design of the PRAETORIAN-COVID trial: A double-blind, placebo-controlled randomized clinical trial with valsartan for PRevention of Acute rEspiraTORy dIstress syndrome in hospitAlized patieNts with SARS-COV-2 Infection Disease. Am Heart J. 2020 Aug;226:60-68. doi: 10.1016/j.ahj.2020.05.010. Epub 2020 May 21.
Results Reference
derived

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Valsartan for Prevention of Acute Respiratory Distress Syndrome in Hospitalized Patients With SARS-COV-2 (COVID-19) Infection Disease

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