Sildenafil in COVID-19

Study Overview
=================
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.

Official Title
-----------------
Sildenafil for Treating Patients With COVID-19 and Perfusion Mismatch: A Pilot Randomised Trial

Conditions
-----------------
Covid19, SARS-COV2 Infection

Intervention / Treatment
-----------------
* Drug: Sildenafil
* Drug: Placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible participants will be randomised to either sildenafil or placebo for up to seven days.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sildenafil<br>Patients allocated to this arm will receive Sildenafil 25mg every 8 hours orally for up to seven consecutive days. | Drug: Sildenafil<br>* Patients allocated to this arm will receive Sildenafil 25mg every 8 hours orally for up to seven consecutive days.<br>|
| Placebo Comparator: Control<br>Patients allocated to this arm will receive a placebo that will be similar in form to sildenafil pills in the interventional arm. These doses will be scheduled every 8 hours and wil be administered orally por up to seven consecutive days. | Drug: Placebo<br>* Patients allocated to this arm will receive a matching placebo similar to Sildenafil pills used in the intervention arm. Placebos will be delivered orally every 8 hours for up to seven consecutive days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arterial Oxygenation | Mean difference in alveolar oxygen pressure to inspired oxygen fraction (Pa/Fi) ratios. | One hour after sildenafil administration | 
| Arterial Oxygenation | Mean difference in alveolar oxygen pressure to inspired oxygen fraction (Pa/Fi) ratios. | Daily until the end of follow-up (up to 15 days after randomisation) | 
| Alveolo-arterial gradient | Mean difference in the alveolo-arterial gradient between study groups. | One hour after sildenafil administration | 
| Alveolo-arterial gradient | Mean difference in the alveolo-arterial gradient between study groups. | Daily until the end of follow-up (up to 15 days after randomisation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intensive care unit admission | Proportion of patients requiring admission to an intensive care unit in each study group | Up to two weeks after randomisation | 
| Noninvasive Mechanical Ventilation or Requirement of High-Flow Nasal Cannula | Proportion of patients requiring noninvasive mechanical ventilation o high-flow nasal cannula unit in each study group | Up to two weeks after randomisation | 
| Invasive mechanical ventilation | Proportion of patients requiring invasive mechanical ventilation in each study group | Up to two weeks after randomisation | 
| Survival | Proportion of patients that survived COVID19 in each study group | Up to two weeks after randomisation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Phosphodiesterase 5 inhibitors, COVID19, SARS-COV2 Infection, Sildenafil