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

Phase 4

Terminated

• Conditions: Acute Respiratory Distress Syndrome; COVID-19; Severe Acute Respiratory Syndrome; SARS-CoV-2; COVID
• Interventions: Drug: Valsartan (Diovan); Drug: Placebo oral tablet

• Registration Number: NCT04335786
• Lead Sponsor: Radboud University Medical Center

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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Status Verified: 2020-04
• Study First Submitted: 2020-04-02
• Study First Submitted QC: 2020-04-02
• Study First Posted: 2020-04-06
• Study Start: 2020-04-17
• Primary Completion: 2021-05-25
• Study Completion: 2021-05-25
• Last Update Submitted: 2021-09-19
• Last Update Posted: 2021-09-24

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 23

Inclusion Criteria

Not provided

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active treatment arm	Valsartan (Diovan)	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.
Placebo arm	Placebo oral tablet	Matching 80mg or 160mg placebo tablets at a dosage and frequency titrated to systolic blood pressure

Primary Outcome Measures

Name	Time	Method
first occurrence of intensive care unit admission, mechanical ventilation or death	within 14 days	Death is defined as all-cause mortality

Secondary Outcome Measures

Name	Time	Method
Intensive care unit admission	within 14 days	Occurrence of ICU admission and time to admission
Death	Within 14 days, 30 days, 90 days and at 1 year	All-cause mortality; and time to all-cause mortality
Mechanical ventilation	within 14 days	Occurrence of mechanical ventilation and time to ventilation
Occurrence of acute kidney injury	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

Trial Locations

Locations (7)

Ikazia Ziekenhuis; 🇳🇱 Rotterdam, Netherlands

Jeroen Bosch Ziekenhuis; 🇳🇱 's-Hertogenbosch, Netherlands

Rijnstate; 🇳🇱 Arnhem, Netherlands

Laurentius Ziekenhuis; 🇳🇱 Roermond, Netherlands

Erasmus MC; 🇳🇱 Rotterdam, Netherlands

Franciscus Gasthuis; 🇳🇱 Rotterdam, Netherlands

Radboudumc; 🇳🇱 Nijmegen, Netherlands