Septic ShockPhase 2/3COMBAT-SHINENCT04123444
Infusion of Prostacyclin (Iloprost) vs Placebo for 72-hours in Patients With Septic Shock Suffering From Organ Failure
A Phase 2/3 study testing Iloprost and Isotonic saline in people with Septic Shock, run by Jakob Stensballe, MD, PhD at 6 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 up to a total of 380 patients with septic shock suffering from organ failure. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Septic Shock
- 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
- 279 participants
- Where
- 6 sitesDenmark
- Study dates
- 30 Oct 2019to 28 Jun 2022
- Phase
- Phase 2/3
- 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
- All the following criteria must be fulfilled:
- Adult intensive care patients (age ≥ 18 years)
- Septic shock defined according to the Sepsis-3 criteria:
- suspected or documented infection
- persisting hypotension requiring vasopressors to maintain a mean arterial blood pressure of 65 mmHg or above
- Lactate level of 2 mmol/L or above despite fluid therapy within the last 3 hours at screening
- Soluble thrombomodulin (sTM) above 10 ng/mL
Who cannot join
- Patients who fulfil any of the following criteria will be excluded:
- Withdrawal from active therapy
- Pregnancy
- Known hypersensitivity to iloprost.
- Life-threatening bleeding as defined by the treating physician
- Known severe heart failure (New York Heart Association (NYHA) class IV)
Show all 11Show fewer
- Suspected acute coronary syndrome
- Previously included in this trial
- Septic shock for more than 12 hours at the time of screening
- Informed consent cannot be obtained
- Included in other clinical trials with prostacyclin within 90 days
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
Denmark6 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
Region Sealand University Hospital
Køge
About this study
Official title: Efficacy and Safety of 72-hour Infusion of Prostacyclin (1 Nanogram(ng)/Kilo(kg)/Minute(Min)) in Patients With Septic Shock Induced Endotheliopathy - a Multicentre Randomized, Placebo-controlled, Blinded, Investigator-initiated Trial"
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 up to a total of 380 patients with septic shock suffering from organ 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 septic shock patients suffering from organ failure caused by endothelial breakdown, ultimately improving survival.
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. 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 organ failure score in the intensive care unit (ICU) compared to infusion of placebo in patients with septic shock induced endotheliopathy (SHINE).
Patients that are eligible for this trial will be temporarily incompetent due to acute severe illness relating to septic shock, 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 give continuous infusion of low dose iloprost or placebo for 72 hours as well as additional blood samples will be obtained daily for the first 72 hours. Follow up on organ failure, mortality and quality of life 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 mean daily SOFA score from a recent randomized, double blind, placebo controlled clinical trial in patients with septic shock: Levosimendan for the prevention of acute organ dysfunction in sepsis (LeoPARD). If the true effect of the intervention is a reduction in mean daily SOFA score of 20% (relative) and providing the trial with 90% power to detect this difference at a significance level of 0.05 will require a sample size of 380 patients.
A pre-planned, blinded interim analysis will be performed after 200 patients have been included in the trial and followed for 90 days.
- Conditions
- Septic Shock
- Being tested
- Iloprost, Isotonic saline
- Medical subject headings
- Shock, Septic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IloprostDrug
Also called Iloprost infusion
Continuously infusion for 72 hours. treatment dose 1 ng/kg/min
Isotonic salineDrug
Also called Isotonic saline infusion
Continuously infusion for 72 hours.
| Study group | Role | What they receive |
|---|---|---|
| Iloprost | Experimental | Patients randomized to active treatment (n=190 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 |
| Placebo | Placebo comparator | Patients randomized to placebo treatment (n=190 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.
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: Up to 90 days after randomization
Secondary outcomes (6)
28 and 90-day mortality
Vital status of the patient at day 28 and day 90
Measured: Day 28 and 90 after randomization
Vasopressor free days
Days alive and without vasopressor at day 90.
Measured: Until ICU discharge, maximun 90 days after randomization
Mechanical ventilation free days
Days alive and without invasive mechanical ventilation at day 90
Measured: Until ICU discharge, maximun 90 days after randomization
Renal replacement free days
Days alive and without renal replacement therapy at day 90
Measured: Until ICU discharge, maximun 90 days after randomization
Serious adverse reactions (SARs)
Numbers of patients with one or more serious adverse reactions (SARs) and total number of SARs
Measured: Until day 7 after randomization
Serious adverse events (SAEs)
Numbers of patients with one or more and total number of serious adverse events and total number of SAEs; SAEs defined as ischaemic events and bleeding events (requiring more than 2 red blood cells (RBCs) within 24 hours or ongoing bleeding.
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 posted11 Oct 2019
- Study start30 Oct 2019
- Primary completion28 Jun 2022
- Study completion28 Jun 2022
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 Septic ShockStudies 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 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomization in 2 parallel arms Adaptive phase 2b/3 trial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 279 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jakob Stensballe, MD, PhD
- Sponsor type
- University, hospital or other
- Collaborators
- Innovation Fund Denmark, Independent Research Fund Denmark
- Responsible party
- Sponsor-investigator, Jakob Stensballe, MD, PhD, Copenhagen University Hospital, Rigshospitalet
- Investigators
- Morten Bestle, MD, PhD, Principal investigator, Nordsjaelands Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04123444
- Sponsor's protocol ID
- COMBAT-SHINE
- Other IDs
- 2019-001131-31, 2019
- Acronym
- COMBAT-SHINE
- Status last verified
- May 2024
- First submitted
- 9 Oct 2019
- Last updated
- 7 May 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Bestle MH, Stensballe J, Lange T, Clausen NE, Soe-Jensen P, Pedersen KH, Gybel-Brask M, Kjaer MN, Steensen CO, Jensen DB, Gartner R, Schonemann-Lund M, Kristiansen KT, Lindhardt A, Johansson PI, Perner A. Iloprost and Organ Dysfunction in Adults With Septic Shock and Endotheliopathy: A Randomized Clinical Trial. JAMA Netw Open. 2024 Sep 3;7(9):e2432444. doi: 10.1001/jamanetworkopen.2024.32444.
PubMed 39259541Bestle MH, Clausen NE, Soe-Jensen P, Kristiansen KT, Lange T, Johansson PI, Stensballe J, Perner A. Efficacy and safety of iloprost in patients with septic shock-induced endotheliopathy-Protocol for the multicenter randomized, placebo-controlled, blinded, investigator-initiated trial. Acta Anaesthesiol Scand. 2020 May;64(5):705-711. doi: 10.1111/aas.13546. Epub 2020 Feb 3.
PubMed 31950481
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 Septic Shock Induced Endotheliopathy - a Multicentre Randomized, Placebo-controlled, Blinded, Investigator-initiated Trial"
- ClinicalTrials.gov ID
- NCT04123444
- Acronym / sponsor ID
- COMBAT-SHINE / COMBAT-SHINE
- Conditions
- Septic Shock
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 279 participants (actual)
- Lead sponsor
- Jakob Stensballe, MD, PhDUniversity, hospital or other
- Collaborators
- Innovation Fund Denmark, Independent Research Fund Denmark
- Study start
- 30 Oct 2019 (actual)
- Primary completion
- 28 Jun 2022 (actual)
- Study completion
- 28 Jun 2022 (actual)
- First posted
- 11 Oct 2019 (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 up to a total of 380 patients with septic shock suffering from organ 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 septic shock patients suffering from organ failure caused by endothelial breakdown, ultimately improving survival.
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. 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 organ failure score in the intensive care unit (ICU) compared to infusion of placebo in patients with septic shock induced endotheliopathy (SHINE).
Patients that are eligible for this trial will be temporarily incompetent due to acute severe illness relating to septic shock, 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 give continuous infusion of low dose iloprost or placebo for 72 hours as well as additional blood samples will be obtained daily for the first 72 hours. Follow up on organ failure, mortality and quality of life 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 mean daily SOFA score from a recent randomized, double blind, placebo controlled clinical trial in patients with septic shock: Levosimendan for the prevention of acute organ dysfunction in sepsis (LeoPARD). If the true effect of the intervention is a reduction in mean daily SOFA score of 20% (relative) and providing the trial with 90% power to detect this difference at a significance level of 0.05 will require a sample size of 380 patients.
A pre-planned, blinded interim analysis will be performed after 200 patients have been included in the trial and followed for 90 days.
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 in 2 parallel arms Adaptive phase 2b/3 trial
| Arm | Type | Receives |
|---|---|---|
| Iloprost | Experimental | Drug: IloprostPatients randomized to active treatment (n=190 patients) will receive continuous infusion of iloprost for 72 hours after inclusion or until discharge to ward or death, whichever comes first. |
| Placebo | Placebo comparator | Drug: Isotonic salinePatients randomized to placebo treatment (n=190 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 (7 listed)
- Adult intensive care patients (age ≥ 18 years)
- Septic shock defined according to the Sepsis-3 criteria:
- Soluble thrombomodulin (sTM) above 10 ng/mL
Key exclusion criteria (11 listed)
- Withdrawal from active therapy
- Pregnancy
- Known hypersensitivity to iloprost.
- Life-threatening bleeding as defined by the treating physician
- Known severe heart failure (New York Heart Association (NYHA) class IV)
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: Iloprost infusionContinuously infusion for 72 hours. treatment dose 1 ng/kg/min | Drug | Iloprost |
| Isotonic salineAlso: Isotonic saline infusionContinuously infusion for 72 hours. | Drug | Placebo |
Primary outcome
Modified Sequential Organ Failure Assessment (SOFA)
Time frame: Up to 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).
6 secondary outcomes
28 and 90-day mortality
Time frame: Day 28 and 90 after randomization
Vasopressor 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
Renal replacement 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.
- Derived from this study: PubMed 39259541Bestle MH, Stensballe J, Lange T, Clausen NE, Soe-Jensen P, Pedersen KH, Gybel-Brask M, Kjaer MN, Steensen CO, Jensen DB, Gartner R, Schonemann-Lund M, Kristiansen KT, Lindhardt A, Johansson PI, Perner A. Iloprost and Organ Dysfunction in Adults With Septic Shock and Endotheliopathy: A Randomized Clinical Trial. JAMA Netw Open. 2024 Sep 3;7(9):e2432444. doi: 10.1001/jamanetworkopen.2024.32444.
- Derived from this study: PubMed 31950481Bestle MH, Clausen NE, Soe-Jensen P, Kristiansen KT, Lange T, Johansson PI, Stensballe J, Perner A. Efficacy and safety of iloprost in patients with septic shock-induced endotheliopathy-Protocol for the multicenter randomized, placebo-controlled, blinded, investigator-initiated trial. Acta Anaesthesiol Scand. 2020 May;64(5):705-711. doi: 10.1111/aas.13546. Epub 2020 Feb 3.
- Individual participant dataSharing planned: No
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Sepsis
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.
Morten Bestle, MD, PhD principal investigator
Nordsjaelands Hospital
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Iloprost and Isotonic saline in people with Septic Shock, run by Jakob Stensballe, MD, PhD at 6 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 7 inclusion and 11 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 6 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 combined 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.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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?
Modified Sequential Organ Failure Assessment (SOFA) (time frame: Up to 90 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 NCT04123444, 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.