NCT04335786

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

Terminated Phase 4 Last updated 24 September 2021

What this trial tests

Phase 4 trial testing Valsartan (Diovan) in Acute Respiratory Distress Syndrome in 23 participants. Terminated before completion.

Timeline

17 April 2020

Primary endpoint
25 May 2021

25 May 2021

Quick facts

Lead sponsor	Radboud University Medical Center
Phase	Phase 4
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	23
Start date	17 April 2020
Primary completion	25 May 2021
Estimated completion	25 May 2021
Sites	7 locations across Netherlands

Drugs / interventions tested

• Valsartan (Diovan) — full drug profile →
• Placebo oral tablet — full drug profile →

Conditions studied

• Acute Respiratory Distress Syndrome — all drugs for Acute Respiratory Distress Syndrome →
• SARS-CoV-2 — all drugs for SARS-CoV-2 →
• COVID — all drugs for COVID →
• COVID-19 — all drugs for COVID-19 →

Sponsor

Radboud University Medical Center

Who can join

18 and older, any sex, with Acute Respiratory Distress Syndrome or SARS-CoV-2. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: Lessons from SARS and MERS, and potential therapeutic interventions.
   Jafarzadeh A, Chauhan P, Saha B, Jafarzadeh S, et al · · 2020 · cited 246× · PMID 32687918 · DOI 10.1016/j.lfs.2020.118102
2. Cytokine Storm in COVID-19: Immunopathogenesis and Therapy.
   Zanza C, Romenskaya T, Manetti AC, Franceschi F, et al · · 2022 · cited 211× · PMID 35208467 · DOI 10.3390/medicina58020144
3. SARS-CoV-2 pandemic and research gaps: Understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy.
   Datta PK, Liu F, Fischer T, Rappaport J, et al · · 2020 · cited 191× · PMID 32642005 · DOI 10.7150/thno.48076
4. COVID-19 and Cancer: a Comprehensive Review.
   Gosain R, Abdou Y, Singh A, Rana N, et al · · 2020 · cited 187× · PMID 32385672 · DOI 10.1007/s11912-020-00934-7
5. An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment.
   Drożdżal S, Rosik J, Lechowicz K, Machaj F, et al · · 2021 · cited 186× · PMID 34991982 · DOI 10.1016/j.drup.2021.100794
6. Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.
   Cohen JB, Hanff TC, William P, Sweitzer N, et al · · 2021 · cited 183× · PMID 33422263 · DOI 10.1016/s2213-2600(20)30558-0
7. COVID-19 and heart failure: from infection to inflammation and angiotensin II stimulation. Searching for evidence from a new disease.
   Tomasoni D, Italia L, Adamo M, Inciardi RM, et al · · 2020 · cited 181× · PMID 32412156 · DOI 10.1002/ejhf.1871
8. ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities - Role of gut microbiota dysbiosis.
   Viana SD, Nunes S, Reis F. · · 2020 · cited 122× · PMID 32683039 · DOI 10.1016/j.arr.2020.101123