Clinical trial NCT04489446: Sildenafil in COVID-19
Official title: Sildenafil for Treating Patients With COVID-19 and Perfusion Mismatch: A Pilot Randomised Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Covid19
SARS-COV2 Infection
Keywords: COVID19
SARS-COV2 Infection
Sildenafil
Phosphodiesterase 5 inhibitors
Lead sponsor: Universidad Nacional Andres Bello
Sponsor class: OTHER
Collaborators: name: Hospital Naval Almirante Nef, Viña del Mar, Chile
First posted: 2020-07-28
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eligible participants will be randomised to either sildenafil or placebo for up to seven days.
Primary purpose: TREATMENT

Brief summary: This randomised trial aims to assess the role of sildenafil in improving oxygenation amongst hospitalised patients with COVID19.

Detailed description: Perfusion anomalies, namely hypoperfusion of healthy lung and vasoplegia with hyperperfusion of diseased lung areas, have been recently described amongst patients with COVID19. In this triple-blind pilot randomised trial, adult patients with high clinical suspicion of SARS-CoV2 infection and perfusion defects in a substraction computed tomography angiography will be randomised in a 1:1 ratio to receive sildenafil or placebo. Informed consent will be obtained from every included participant. Patients requiring mechanical ventilation at baseline will be excluded, as will those who present a contraindication to sildenafil, previous users of sildenafil, those requiring therapy with nitrates, patients in which an order to limit therapeutic efforts has been issued, pregnant or breastfeeding women and those who decline to participate in this study. The primary outcome for this trial wil be oxygenation changes in blood gas analyses. Secondary outcomes will include clinical deterioration requiring admission to an intensive care unit, requirement of high-flow nasal cannula or invasive mechanical ventilation and overall survival. Patients will be followed-up until hospital discharge or up to fifteen days after randomisation. Statistical analyses will be undertaken by a statistician unaware of treatment allocation under the intention-to-treat principle.

Eligibility criteria: Inclusion Criteria:

* Adult participant with high clinical suspicion of a SARS-CoV2 infection.
* Hypoperfusion of healthy lung areas in a substraction computed tomography angiography within 24 hours of admission to the hospital.

Exclusion Criteria:

* Requirement of therapy with nitrates of nitrites
* Arterial hypotension at presentation
* Recent diagnosis of coronary artery disease (\<6 months)
* Acute heart failure at presentation
* Recent stroke (\< 6 months)
* Chronic respiratory failure with CO2 retention
* Known hypersensitivity to sildenafil
* Advanced liver disease (Child-Pugh class B or higher)
* Users of cytochrome P450 3A4 inhibitors (Erythromycin, Ketoconazole, Itraconazole, Saquinavir)
* Pulmonary hypertension
* Chronic users of phosphodiesterase 5 inhibitors
* Requirement of invasive mechanical ventilation at baseline
* Decision to limit therapeutic efforts at baseline
* Pregnancy or lactation
* History of retinitis pigmentosa
* Known obstruction to left-ventricular outflow tract
* Unwillingness to participate in the trial

Primary outcomes:
measure: Arterial Oxygenation
timeFrame: One hour after sildenafil administration
measure: Arterial Oxygenation
timeFrame: Daily until the end of follow-up (up to 15 days after randomisation)
measure: Alveolo-arterial gradient
timeFrame: One hour after sildenafil administration
measure: Alveolo-arterial gradient
timeFrame: Daily until the end of follow-up (up to 15 days after randomisation)
Secondary outcomes:
measure: Intensive care unit admission
timeFrame: Up to two weeks after randomisation
measure: Noninvasive Mechanical Ventilation or Requirement of High-Flow Nasal Cannula
timeFrame: Up to two weeks after randomisation
measure: Invasive mechanical ventilation
timeFrame: Up to two weeks after randomisation
measure: Survival
timeFrame: Up to two weeks after randomisation
Other outcomes:
measure: Adverse events
timeFrame: Up to two weeks after randomisation
Locations:
city: Viña Del Mar
country: Chile
facility: Hospital Naval Almirante Nef
state: Valparaiso
Study officials:
affiliation: Hospital Naval Almirante Nef
name: Mario Santamarina, MD
role: STUDY_DIRECTOR
affiliation: Universidad Andres Bello
name: Felipe Martinez, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11.
citation: Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med. 2020 Jun 25;58(7):1131-1134. doi: 10.1515/cclm-2020-0198. No abstract available.
citation: Santamarina MG, Boisier D, Contreras R, Baque M, Volpacchio M, Beddings I. COVID-19: a hypothesis regarding the ventilation-perfusion mismatch. Crit Care. 2020 Jul 6;24(1):395. doi: 10.1186/s13054-020-03125-9. No abstract available.
citation: Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, Raizada MK, Grant MB, Oudit GY. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ Res. 2020 May 8;126(10):1456-1474. doi: 10.1161/CIRCRESAHA.120.317015. Epub 2020 Apr 8.
citation: Wu Z, Hu R, Zhang C, Ren W, Yu A, Zhou X. Elevation of plasma angiotensin II level is a potential pathogenesis for the critically ill COVID-19 patients. Crit Care. 2020 Jun 5;24(1):290. doi: 10.1186/s13054-020-03015-0. No abstract available.
citation: Santamarina MG, Beddings I, Lomakin FM, Boisier Riscal D, Gutierrez Claveria M, Vidal Marambio J, Retamal Baez N, Pavez Novoa C, Reyes Allende C, Ferreira Perey P, Gutierrez Torres M, Villalobos Mazza C, Vergara Sagredo C, Ahumada Bermejo S, Labarca Mellado E, Barthel Munchmeyer E, Marchant Ramos S, Volpacchio M, Vega J. Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial. Crit Care. 2022 Jan 3;26(1):1. doi: 10.1186/s13054-021-03885-y.