Clinical Trial Results:
“Efficacy and safety of 72-hour infusion of Prostacyclin (1 ng/kg/min) in patients with septic shock induced endotheliopathy – a multicentre randomized, placebo-controlled, blinded, investigator-initiated trial”
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Summary
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EudraCT number |
2019-001131-31 |
Trial protocol |
DK |
Global end of trial date |
28 Jun 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Nov 2024
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First version publication date |
23 Nov 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
COMBAT-SHINE
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04123444 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Rigshospitalet
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Sponsor organisation address |
Blegdamsvej 9, Copenhagen, Denmark, DK-2100
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Public contact |
Jakob Stensballe, Section for transfusion Medicines, Capital Region Blood Bank, Copenhagen University Hospital, +45 354538587, jakob.stensballe@regionh.dk
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Scientific contact |
Jakob Stensballe, Section for transfusion Medicines, Capital Region Blood Bank, Copenhagen University Hospital, +45 35458587, jakob.stensballe@regionh.dk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
07 Feb 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 Jun 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Jun 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective in this trial is to investigate whether continuous infusion of iloprost at a dose of 1 ng/kg/min for 72-hours is safe and significantly reduce organ failure score in the ICU compared to infusion of placebo in patients with septic shock and SHINE.
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Protection of trial subjects |
Patients included in this trial is admitted to the ICU with septisk shock, therefore these patients will receive the best possible care and monitored closely during their hospital stay. All included patients and/or next-of-kin will sign informed consent to participate.
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Background therapy |
Standard of care for treatment for septisk shock | ||
Evidence for comparator |
Crystalloids are the recommended volume therapy for patients with septic. We have therefore chosen that the placebo should be saline 0.9 % (NaCl) to maintain blinding in the trial as iloprost is diluted in saline. Patients receiving placebo will receive an equal volume of fluid administered in the same way as the iloprost infusion. | ||
Actual start date of recruitment |
30 Oct 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Denmark: 279
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Worldwide total number of subjects |
279
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EEA total number of subjects |
279
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
107
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From 65 to 84 years |
163
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85 years and over |
9
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Recruitment
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Recruitment details |
Patients are recruited in the periode from October 30, 2019 to April 6, 2022 in one of the 5 ICUs in the Capital Region of Denmark and at the ICU in Region Zealand University Hospital. | |||||||||
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Pre-assignment
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Screening details |
Patients are subject for screening if they are 18 years old or above and admitted the ICU with confirmed septisk shock. Septic shock, defined as (i) suspected or documented infection, (ii) persisting hypotension requiring vasopressors to maintain MAP ≥65 mm Hg AND (iii) lactate level >2 mmol/L despite fluid therapy. | |||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||
Blinding implementation details |
The trial is double-blinded with saline 0.9 % (NaCl) as placebo to maintain blinding. iloprost is diluted in saline and therefore both solutions are colorless fluids. Patients receiving placebo will receive an equal
volume of fluid administered in the same way as the iloprost infusion. The preparation of trial medication will be done by an unblinded nurse, outside the ICU´s, who will be responsible for preparing the investigational drug so that it can be administered in blinded facion.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Intervention arm | |||||||||
Arm description |
Iloprost (Ilomedin®) is a marketed product which will be administered in this trial as the IMP. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Ilomedin
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Investigational medicinal product code |
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Other name |
Prostacyclin
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Pharmaceutical forms |
Solution for solution for infusion
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Routes of administration |
Infusion
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Dosage and administration details |
All patients will receive 72-hour continuous infusion of either active investigational drug or placebo. Patients on active treatment will receive continuous infusion of 1 ng/kg/min iloprost. The infusion
volume of the active investigational drug and placebo will be 72 ml per 24h.
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Arm title
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Placebo arm | |||||||||
Arm description |
Saline 0.9% is used as comparator | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Saline 0.9%
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Investigational medicinal product code |
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Other name |
sodium chloride
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Pharmaceutical forms |
Solution for solution for infusion
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Routes of administration |
Infusion
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Dosage and administration details |
All patients will receive 72-hour continuous infusion of either active investigational drug or placebo. Patients on placebo will receive continuous infusion equivalent to iloprost. The infusion volume of the
active investigational drug and placebo will be 72 ml per 24h.
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Baseline characteristics reporting groups
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Reporting group title |
Intervention arm
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Reporting group description |
Iloprost (Ilomedin®) is a marketed product which will be administered in this trial as the IMP. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo arm
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Reporting group description |
Saline 0.9% is used as comparator | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Intervention arm
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Reporting group description |
Iloprost (Ilomedin®) is a marketed product which will be administered in this trial as the IMP. | ||
Reporting group title |
Placebo arm
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Reporting group description |
Saline 0.9% is used as comparator | ||
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End point title |
Mean daily modified Sequential Organ Failure Assessment (SOFA) score | ||||||||||||
End point description |
Mean daily SOFA score during ICU admission up to day 90 for the intention to treat population
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End point type |
Primary
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End point timeframe |
From Baseline up to day 90
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Statistical analysis title |
Primary endpoint | ||||||||||||
Statistical analysis description |
For the ITT analysis
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Comparison groups |
Intervention arm v Placebo arm
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Number of subjects included in analysis |
278
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.7 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
IQR | ||||||||||||
Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
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upper limit |
- | ||||||||||||
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End point title |
Mortality day 28 | |||||||||
End point description |
Number of death from baseline until day 28
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End point type |
Secondary
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End point timeframe |
From baseline until day 90
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| No statistical analyses for this end point | ||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
SAE and SAR are collected from baseline to day 7
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Adverse event reporting additional description |
Only selected serious adverse events and serious adverse reaction are collected as these patients are severily ill. Therefore, recording of all AE and SAEs in the CRF will not add valuable information to the patient’s safety in this trial and will make it difficult be distinguish the real safety signal and those sight of the significant reactions.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
none | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
0
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Reporting groups
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Reporting group title |
Overall
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Reporting group description |
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| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Only certain SAE is reported in this trial due to the severity ilness of the incluted patients |
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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17 Dec 2019 |
Description of change: Modification of doses volume as not enough volume to prime the infusion set. |
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12 Nov 2020 |
Description of changes: Addition blood sample for sub study of 20 patients and a corresponding healthy cohort |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
