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Trial record 1 of 1 for:    NCT04335786
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Valsartan for Prevention of Acute Respiratory Distress Syndrome in Hospitalized Patients With SARS-COV-2 (COVID-19) Infection Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04335786
Recruitment Status : Recruiting
First Posted : April 6, 2020
Last Update Posted : June 9, 2020
Sponsor:
Information provided by (Responsible Party):
Radboud University

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.


Condition or disease Intervention/treatment Phase
Acute Respiratory Distress Syndrome SARS-CoV-2 COVID COVID-19 Severe Acute Respiratory Syndrome Drug: Valsartan (Diovan) Drug: Placebo oral tablet Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 651 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : April 17, 2020
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
Experimental: Active treatment arm
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.
Drug: Valsartan (Diovan)

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.


Placebo Comparator: Placebo arm
Matching 80mg or 160mg placebo tablets at a dosage and frequency titrated to systolic blood pressure
Drug: Placebo oral tablet
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 Measures :
  1. first occurrence of intensive care unit admission, mechanical ventilation or death [ Time Frame: within 14 days ]
    Death is defined as all-cause mortality


Secondary Outcome Measures :
  1. Death [ Time Frame: Within 14 days, 30 days, 90 days and at 1 year ]
    All-cause mortality; and time to all-cause mortality

  2. Mechanical ventilation [ Time Frame: within 14 days ]
    Occurrence of mechanical ventilation and time to ventilation

  3. Intensive care unit admission [ Time Frame: within 14 days ]
    Occurrence of ICU admission and time to admission

  4. Occurrence of acute kidney injury [ Time Frame: Within 14 days ]
    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



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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

  • 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

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): NCT04335786


Contacts
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Contact: Roland RJ van Kimmenade, MD PhD +31243616785 Roland.vanKimmenade@radboudumc.nl
Contact: Frank Gommans, MD PhD frank.gommans@radboudumc.nl

Locations
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Netherlands
Jeroen Bosch Ziekenhuis Recruiting
's-Hertogenbosch, Netherlands
Contact: Peter de Jager, MD PhD         
Rijnstate Recruiting
Arnhem, Netherlands, 6815AD
Contact: Robert-Jan Hassing, MD PhD         
Radboudumc Recruiting
Nijmegen, Netherlands
Contact: Roland van Kimmenade, MD PhD         
Laurentius Ziekenhuis Recruiting
Roermond, Netherlands
Contact: Ragnar Lunde         
Erasmus MC Recruiting
Rotterdam, Netherlands
Contact: Corstiaan A Den Uil, MD PhD         
Franciscus Gasthuis Recruiting
Rotterdam, Netherlands
Contact: P.R. Nierop, MD         
Ikazia Ziekenhuis Recruiting
Rotterdam, Netherlands
Contact: Regina A Carels, MD         
Sponsors and Collaborators
Radboud University
Investigators
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Study Chair: Niels van Royen, MD PhD Radboud University
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT04335786    
Other Study ID Numbers: NL73547.091.20
2020-001320-34 ( EudraCT Number )
First Posted: April 6, 2020    Key Record Dates
Last Update Posted: June 9, 2020
Last Verified: April 2020

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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
Keywords provided by Radboud University:
Acute Respiratory Distress Syndrome
SARS-CoV-2
Therapeutics
Valsartan
Angiotensin Receptor Blockade
Angiotensin Receptor Blockers
ARBs
COVID-19
Additional relevant MeSH terms:
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Severe Acute Respiratory Syndrome
Coronavirus Infections
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Syndrome
Disease
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Lung Injury
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Valsartan
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action