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

Sponsor

Radboud University Medical Center (Other)

Overall Status

Terminated

CT.gov ID

NCT04335786

Collaborator

(none)

Enrollment

Locations

Arms

13.2

Actual Duration (Months)

3.3

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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.

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

Study Design

Study Type:

Interventional

Actual Enrollment :

23 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 :

Apr 17, 2020

Actual Primary Completion Date :

May 25, 2021

Actual Study Completion Date :

May 25, 2021

Arms and Interventions

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.

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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
Intensive care unit admission [within 14 days]
Occurrence of ICU admission and time to admission
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Jeroen Bosch Ziekenhuis	's-Hertogenbosch	Netherlands
2	Rijnstate	Arnhem	Netherlands	6815AD
3	Radboudumc	Nijmegen	Netherlands
4	Laurentius Ziekenhuis	Roermond	Netherlands
5	Erasmus MC	Rotterdam	Netherlands
6	Franciscus Gasthuis	Rotterdam	Netherlands
7	Ikazia Ziekenhuis	Rotterdam	Netherlands