COVID-19Phase 2COMBAT-COVIDNCT04420741
Infusion of Prostacyclin (Iloprost) vs Placebo for 72-hours in COVID-19 Patients With Respiratory Failure
A Phase 2 study testing Iloprost and Isotonic saline in people with COVID-19 and Respiratory Failure, run by Pär Johansson at 5 sites in Denmark.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- COVID-19, Respiratory Failure
- What is being tested?
- Iloprost and Isotonic saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 80 participants
- Where
- 5 sitesDenmark
- Study dates
- 15 Jun 2020to 23 Apr 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
Denmark5 sites
Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital
Copenhagen
Dept. of Intensive Care, Copenhagen University Hospital, Rigshospitalet
Copenhagen
Dept. of Intensive Care, Copenhagen University Hospital Herlev
Herlev
Dept. of Anaesthesia and Intensive Care, Nordsjaelands Hospital
Hillerød
Dept. of Anaesthesia and Intensive Care, Hvidovre Hospital
Hvidovre
About this study
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
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.
Read the 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.
- Conditions
- COVID-19, Respiratory Failure
- Being tested
- Iloprost, Isotonic saline
- Keywords
- COVID-19, SHINE, Endotheliopathy
- Medical subject headings
- COVID-19, Respiratory Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IloprostDrug
Also called Ilomedin
Continuously infusion for 72 hours at 3 ml/hours. Treatment dose 1 ng/kg/min
Isotonic salineDrug
Continuously infusion for 72 hours at 3 ml/hours
| Study group | Role | What they receive |
|---|---|---|
| Iloprost | Experimental | 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. Receives: Drug: Iloprost |
| Isotonic saline | Placebo comparator | 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. Receives: Drug: Isotonic saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mechanical ventilation free days
Days alive without mechanical ventilation in the ICU within 28 days
Measured: Until ICU discharge, maximun 28 days after randomization
Secondary outcomes (7)
28 and 90-day mortality
Vital status of the patient at day 28 and day 90
Measured: 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).
Measured: Until ICU discharge, maximun 90 days after randomization
Vasopressor free days
Days alive without vasopressor in the ICU within 28-and 90 days
Measured: Until ICU discharge, maximun 90 days after randomization
Renal replacement free days
Days without renal replacement in the ICU within 28 -and 90 days
Measured: Until ICU discharge, maximun 90 days after randomization
Mechanical ventilation free days
Days alive without mechanical ventilation in the ICU within 90 days
Measured: Until ICU discharge, maximun 90 days after randomization
Serious adverse reactions (SARs)
Numbers of serious adverse reactions within the first 7 days
Measured: Until day 7 after randomization
Serious adverse events (SAEs)
Numbers of serious adverse events within the first 7 days
Measured: Until day 7 after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jun 2020
- Study start15 Jun 2020
- Primary completion23 Feb 2021
- Study completion23 Apr 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for COVID-19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomization active/placebo (1:1) parallel arms
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 80 participants (actual)
Sponsor and investigators
- Lead sponsor
- Pär Johansson
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Pär Johansson, Copenhagen University Hospital, Rigshospitalet
- Investigators
- Anders Perner, MD, PhD, Principal investigator, Copenhagen University Hospital, Intensive care Unit 4131Pär I Johansson, MD, DMSc, Study director, Copenhagen University Hospital, Capital Blood Bank 2034
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04420741
- Sponsor's protocol ID
- COMBAT-COVID-19
- Other IDs
- 2020-001296-33
- Acronym
- COMBAT-COVID
- Status last verified
- May 2024
- First submitted
- 4 Jun 2020
- Last updated
- 7 May 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Johansson PI, Soe-Jensen P, Bestle MH, Clausen NE, Kristiansen KT, Lange T, Stensballe J, Perner A. Prostacyclin in Intubated Patients with COVID-19 and Severe Endotheliopathy: A Multicenter, Randomized Clinical Trial. Am J Respir Crit Care Med. 2022 Feb 1;205(3):324-329. doi: 10.1164/rccm.202108-1855OC.
PubMed 34813414Johansson PI, Bestle M, Soe-Jensen P, Kristiansen KT, Stensballe J, Clausen NE, Perner A. The effect of prostacyclin (Iloprost) infusion at a dose of 1 ng/kg/min for 72 hours compared to placebo in mechanically ventilated patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials. 2020 Aug 26;21(1):746. doi: 10.1186/s13063-020-04696-2.
PubMed 32847626
Study at a glance
From the registry record, last updated by the sponsor on 7 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04420741
- Acronym / sponsor ID
- COMBAT-COVID / COMBAT-COVID-19
- Conditions
- COVID-19, Respiratory Failure
- Keywords
- COVID-19, SHINE, Endotheliopathy
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 80 participants (actual)
- Lead sponsor
- Pär JohanssonUniversity, hospital or other
- Study start
- 15 Jun 2020 (actual)
- Primary completion
- 23 Feb 2021 (actual)
- Study completion
- 23 Apr 2021 (actual)
- First posted
- 9 Jun 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Randomization active/placebo (1:1) parallel arms
| Arm | Type | Receives |
|---|---|---|
| Iloprost | Experimental | Drug: IloprostPatients 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. |
| Isotonic saline | Placebo comparator | Drug: Isotonic salinePatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IloprostAlso: IlomedinContinuously infusion for 72 hours at 3 ml/hours. Treatment dose 1 ng/kg/min | Drug | Iloprost |
| Isotonic salineContinuously infusion for 72 hours at 3 ml/hours | Drug | Isotonic saline |
Primary outcome
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
7 secondary outcomes
28 and 90-day mortality
Time frame: Day 28 and 90 after randomization
Modified Sequential Organ Failure Assessment (SOFA)
Time frame: Until ICU discharge, maximun 90 days after randomization
Vasopressor free days
Time frame: Until ICU discharge, maximun 90 days after randomization
Renal replacement free days
Time frame: Until ICU discharge, maximun 90 days after randomization
Mechanical ventilation free days
Time frame: Until ICU discharge, maximun 90 days after randomization
Serious adverse reactions (SARs)
Time frame: Until day 7 after randomization
Serious adverse events (SAEs)
Time frame: Until day 7 after randomization
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 May 2024.
- Background: PubMed 34813414Johansson PI, Soe-Jensen P, Bestle MH, Clausen NE, Kristiansen KT, Lange T, Stensballe J, Perner A. Prostacyclin in Intubated Patients with COVID-19 and Severe Endotheliopathy: A Multicenter, Randomized Clinical Trial. Am J Respir Crit Care Med. 2022 Feb 1;205(3):324-329. doi: 10.1164/rccm.202108-1855OC.
- Results publication: PubMed 32847626Johansson PI, Bestle M, Soe-Jensen P, Kristiansen KT, Stensballe J, Clausen NE, Perner A. The effect of prostacyclin (Iloprost) infusion at a dose of 1 ng/kg/min for 72 hours compared to placebo in mechanically ventilated patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials. 2020 Aug 26;21(1):746. doi: 10.1186/s13063-020-04696-2.
- Individual participant dataSharing planned: No
Related trials for COVID-19
Not yet recruitingPhase 1
Phase I Open-Label Safety Trial of Pembrolizumab for Neurological Post- Acute Sequelae of SARS-CoV-2 (PD1-PASC I)
Post-Acute COVID-19 Syndrome
Active, not recruitingPhase 1
A Safety and Immunogenicity Trial of OCU500, ChAd36 Vector Encoding SARS-CoV-2 Spike Vaccine Via Intranasal and Inhalational Routes in Previously Vaccinated Adults
COVID-19
Active, not recruiting
Intervention to Address Disparate Mental Health Consequences of COVID-19 Pandemic on Latinx and African Newcomers
Mental Health Issue, Mental Health Disorder
Recruiting
Home-Based Exercise Tele-Rehabilitation After COVID-19
Post SARS-CoV2 (COVID-19)
Not yet recruitingPhase 1
A Safety, Reactogenicity and Immunogenicity Trial of RVX-sCPD9 Booster Intranasal COVID-19 Vaccine
COVID -19
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anders Perner, MD, PhD principal investigator
Copenhagen University Hospital, Intensive care Unit 4131
Pär I Johansson, MD, DMSc study director
Copenhagen University Hospital, Capital Blood Bank 2034
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Iloprost and Isotonic saline in people with COVID-19 and Respiratory Failure, run by Pär Johansson at 5 sites in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mechanical ventilation free days (time frame: Until ICU discharge, maximun 28 days after randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04420741, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 May 2024.