Infusion of Prostacyclin (Iloprost) vs Placebo for 72-hours in COVID-19 Patients With Respiratory Failure

Study Overview
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Brief Summary
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The purpose of this trial is to investigate the efficacy and safety of continuous intravenous administration of low dose iloprost versus placebo for 72-hours, in 80 patients with COVID-19 suffering from respiratory failure. The study hypothesis is that iloprost may be beneficial as an endothelial rescue treatment as it is anticipated to deactivate the endothelium and restore vascular integrity in COVID-19 patients suffering from respiratory failure caused by endothelial breakdown, ultimately improving survival. Given that the pulmonary system, apart from the brain, is the most highly vascularized vital organ in the body, extensive endothelial damage is a central feature of acute respiratory distress syndrome (ARDS) with respiratory failure being the rationale for the current study COMBAT-COVID-19.

Detailed Description
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Patients with the most severe type of sepsis, those with septic shock have a mortality rate between 30% to 45% due to multiple organ failure. The poor outcome of shocked patients, and especially those with sepsis, may by related to microvascular endothelial dysfunction. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by coronavirus 2 (SARS-CoV-2) and, thus, being a novel cause of sepsis. The disease was first identified in 2019 in Wuhan, the capital of Hubei, China, and has since spread globally, resulting in the 2019-20 coronavirus pandemic. Common symptoms include fever, cough and shortness of breath, muscle pain and sputum production. While many cases result in mild symptoms, some progress to pneumonia and multi-organ failure. In particular COVID-19 is associated with ARDS with respiratory failure and high mortality. Evidence support that iloprost infusion significantly improved endothelial function and integrity, The main objective in this trial is to investigate whether continuous infusion of lov dose iloprost at a dose of 1 ng/kg/min for 72-hours is safe and significantly reduce the need of respiratory support in the intensive care unit (ICU) compared to infusion of placebo in patients with COVID-19 induced pulmonary endotheliopathy (SHINE). Patients that are eligible for this trial will be temporarily incompetent due to acute severe illness relating to respiratory failure, therefore informed consent will be obtained from a scientific guardian. Next-of kin and subsequently the patient will co-sign as soon as possible hereafter. During the trial, patient will be given continuous infusion of low dose iloprost or placebo for 72 hours and additional blood samples will be obtained at baseline and at 24 hours. Follow up on respiratory failure and mortality will be performed on dag 28 and 90. This trial is conducted in accordance with the Helsinki 2 Declaration and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Guideline for Good Clinical Practice (ICH-GCP) and in compliance with the protocol. As part of the quality assurance on-site monitoring visit will be performed by the an independent GCP-unit including source data verification. Standard Operation Procedure (SOP) to address protocol specific procedures such as data collection and adverse event reporting are developed. The number of patients participating is based on a power calculation using the data on days alive and free from mechanical ventilation in the ICU within 28 days from a randomized, double blind, placebo controlled clinical trial in patients with acute respiratory distress syndrome ARDS (NTC 02622724). The number of patients may be increased if required for regulatory approval for this indication.

Official Title
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Efficacy and Safety of 72-hour Infusion of Prostacyclin (1 Nanogram(ng)/ Kilo(kg)/Minute(Min)) in Patients With COVID-19 Induced Pulmonary Endotheliopathy

Conditions
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COVID-19, Respiratory Failure

Intervention / Treatment
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* Drug: Iloprost
* Drug: Isotonic saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult intensive care patients (aged 18 years or above) Confirmed COVID-19 infection Need for mechanical ventilation (< 72 hours at time of screening) Soluble thrombomodulin (sTM) ≥ 4 ng/mL Exclusion Criteria: Withdrawal from active therapy Pregnancy (non-pregnancy confirmed by patient being postmenopausal (age 60 or above) or having a negative urine- or plasma-hCG) Known hypersensitivity to iloprost or to any of the other ingredients. Previously included in this trial or a prostacyclin trial within 30 days Consent cannot be obtained Life-threatening bleeding defined by the treating physician Known severe heart failure (NYHA class IV) Suspected acute coronary syndrome

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomization active/placebo (1:1) parallel arms
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Iloprost<br>Patients randomized to active treatment (n=40 patients) will receive continuous infusion of iloprost for 72 hours after inclusion or until discharge to ward or death, whichever comes first. | Drug: Iloprost<br>* Continuously infusion for 72 hours at 3 ml/hours. Treatment dose 1 ng/kg/min<br>* Other names: Ilomedin;|
| Placebo Comparator: Isotonic saline<br>Patients randomized to placebo treatment (n=40 patients) will receive continuous infusion of placebo for 72 hours after inclusion or until discharge to ward or death, whichever comes first. | Drug: Isotonic saline<br>* Continuously infusion for 72 hours at 3 ml/hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mechanical ventilation free days | Days alive without mechanical ventilation in the ICU within 28 days | Until ICU discharge, maximun 28 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28 and 90-day mortality | Vital status of the patient at day 28 and day 90 | Day 28 and 90 after randomization | 
| Modified Sequential Organ Failure Assessment (SOFA) | Mean daily modified SOFA score in the intensive care unit (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; range score 0-20). | Until ICU discharge, maximun 90 days after randomization | 
| Vasopressor free days | Days alive without vasopressor in the ICU within 28-and 90 days | Until ICU discharge, maximun 90 days after randomization | 
| Renal replacement free days | Days without renal replacement in the ICU within 28 -and 90 days | Until ICU discharge, maximun 90 days after randomization | 
| Mechanical ventilation free days | Days alive without mechanical ventilation in the ICU within 90 days | Until ICU discharge, maximun 90 days after randomization | 
| Serious adverse reactions (SARs) | Numbers of serious adverse reactions within the first 7 days | Until day 7 after randomization | 
| Serious adverse events (SAEs) | Numbers of serious adverse events within the first 7 days | Until day 7 after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, SHINE, Endotheliopathy