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

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ClinicalTrials.gov Identifier: NCT04420741
Recruitment Status : Recruiting
First Posted : June 9, 2020
Last Update Posted : June 23, 2020
Sponsor:
Information provided by (Responsible Party):
Pär Johansson, Rigshospitalet, Denmark

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
COVID-19 Respiratory Failure Drug: Iloprost Drug: Isotonic saline Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomization active/placebo (1:1) parallel arms
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The preparation will be done by an unblinded study nurse at the respective ICU´s, who will be responsible for preparing the investigational drug so that it can be administered in blinded fashion. Iloprost is a colorless fluid that is to be diluted in 0.9% saline. The infusion pump containing diluted active drug and placebo will be identical on how the fluid looks and behaves.
Primary Purpose: Treatment
Official Title: Efficacy and Safety of 72-hour Infusion of Prostacyclin (1 Nanogram(ng)/ Kilo(kg)/Minute(Min)) in Patients With COVID-19 Induced Pulmonary Endotheliopathy
Actual Study Start Date : June 15, 2020
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : May 31, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Iloprost

Arm Intervention/treatment
Experimental: Iloprost
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
Continuously infusion for 72 hours at 3 ml/hours. Treatment dose 1 ng/kg/min
Other Name: Ilomedin

Placebo Comparator: Isotonic saline
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
Continuously infusion for 72 hours at 3 ml/hours




Primary Outcome Measures :
  1. Mechanical ventilation free days [ Time Frame: Until ICU discharge, maximun 28 days after randomization ]
    Days alive without mechanical ventilation in the ICU within 28 days


Secondary Outcome Measures :
  1. 28 and 90-day mortality [ Time Frame: Day 28 and 90 after randomization ]
    Vital status of the patient at day 28 and day 90

  2. Modified Sequential Organ Failure Assessment (SOFA) [ Time Frame: Until ICU discharge, maximun 90 days after randomization ]
    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).

  3. Vasopressor free days [ Time Frame: Until ICU discharge, maximun 90 days after randomization ]
    Days alive without vasopressor in the ICU within 28-and 90 days

  4. Renal replacement free days [ Time Frame: Until ICU discharge, maximun 90 days after randomization ]
    Days without renal replacement in the ICU within 28 -and 90 days

  5. Mechanical ventilation free days [ Time Frame: Until ICU discharge, maximun 90 days after randomization ]
    Days alive without mechanical ventilation in the ICU within 90 days

  6. Serious adverse reactions (SARs) [ Time Frame: Until day 7 after randomization ]
    Numbers of serious adverse reactions within the first 7 days

  7. Serious adverse events (SAEs) [ Time Frame: Until day 7 after randomization ]
    Numbers of serious adverse events within the first 7 days



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04420741


Contacts
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Contact: Pär I Johansson, MD, DMSc + 45 3545 2030 Per.johansson@regionh.dk
Contact: Anders Perner, MD, PhD. +45 3545 8333 Anders.Perner@regionh.dk

Locations
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Denmark
Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital Recruiting
Copenhagen, Denmark
Contact: Niels E. Clausen, MD         
Principal Investigator: Niels E. Clausen, MD         
Dept. of Intensive Care, Copenhagen University Hospital, Rigshospitalet Recruiting
Copenhagen, Denmark
Contact: Anders Perner, MD, PhD.         
Principal Investigator: Anders Perner, MD, PhD         
Dept. of Intensive Care, Copenhagen University Hospital Herlev Not yet recruiting
Herlev, Denmark
Contact: Peter Søe-Jensen, MD         
Principal Investigator: Peter Søe-Jensen, MD         
Dept. of Anaesthesia and Intensive Care, Nordsjaelands Hospital Not yet recruiting
Hillerød, Denmark
Contact: Morten Bestle, MD, PhD.         
Principal Investigator: Morten Bestle, MD, Phd         
Dept. of Anaesthesia and Intensive Care, Hvidovre Hospital Not yet recruiting
Hvidovre, Denmark
Contact: Klaus T. Kristiansen, MD         
Principal Investigator: Klaus T Kristiansen, MD         
Sponsors and Collaborators
Pär Johansson
Investigators
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Principal Investigator: Anders Perner, MD, PhD Copenhagen University Hospital, Intensive care Unit 4131
Study Director: Pär I Johansson, MD, DMSc Copenhagen University Hospital, Capital Blood Bank 2034
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Responsible Party: Pär Johansson, Sponsor, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT04420741    
Other Study ID Numbers: COMBAT-COVID-19
2020-001296-33 ( EudraCT Number )
First Posted: June 9, 2020    Key Record Dates
Last Update Posted: June 23, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pär Johansson, Rigshospitalet, Denmark:
COVID-19
SHINE
Endotheliopathy
Additional relevant MeSH terms:
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Respiratory Insufficiency
Respiration Disorders
Respiratory Tract Diseases
Iloprost
Platelet Aggregation Inhibitors
Vasodilator Agents