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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
23
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.
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.
Jeroen Bosch Ziekenhuis
's-Hertogenbosch, Netherlands
Rijnstate
Arnhem, Netherlands
Radboudumc
Nijmegen, Netherlands
Laurentius Ziekenhuis
Roermond, Netherlands
Erasmus MC
Rotterdam, Netherlands
Franciscus Gasthuis
Rotterdam, Netherlands
Ikazia Ziekenhuis
Rotterdam, Netherlands
first occurrence of intensive care unit admission, mechanical ventilation or death
Death is defined as all-cause mortality
Time frame: within 14 days
Death
All-cause mortality; and time to all-cause mortality
Time frame: Within 14 days, 30 days, 90 days and at 1 year
Mechanical ventilation
Occurrence of mechanical ventilation and time to ventilation
Time frame: within 14 days
Intensive care unit admission
Occurrence of ICU admission and time to admission
Time frame: within 14 days
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
Time frame: Within 14 days
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