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.
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.
Drug: Iloprost
Continuously infusion for 72 hours at 3 ml/hours. Treatment dose 1 ng/kg/min
Other Name: Ilomedin
Drug: Isotonic saline
Continuously infusion for 72 hours at 3 ml/hours
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
Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital
Copenhagen, Denmark
Dept. of Intensive Care, Copenhagen University Hospital, Rigshospitalet
Copenhagen, Denmark
Dept. of Intensive Care, Copenhagen University Hospital Herlev
Herlev, Denmark
Dept. of Anaesthesia and Intensive Care, Nordsjaelands Hospital
Hillerød, Denmark
Dept. of Anaesthesia and Intensive Care, Hvidovre Hospital
Hvidovre, Denmark