Clinical Trial Results:
Efficacy and safety of 72-hour infusion of Prostacyclin (1 ng/kg/min) in patients with COVID-19 induced respiratory failure – a multicentre randomized, placebo-controlled, blinded, investigator-initiated trial
|
Summary
|
|
EudraCT number |
2020-001296-33 |
Trial protocol |
DK |
Global end of trial date |
26 Apr 2021
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
15 Jun 2022
|
First version publication date |
15 Jun 2022
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
COMBAT-COVID-19
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT04420741 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Rigshospitalet
|
||
Sponsor organisation address |
Blegdamsvej 9, Copenhagen, Denmark, DK-2100
|
||
Public contact |
Pär Johansson, Section for Transfusion Medicine, Capital Region Blood Bank, Copenhagen University Hospital, +45 35452030, per.johansson@regionh.dk
|
||
Scientific contact |
Pär Johansson, Section for Transfusion Medicine, Capital Region Blood Bank, Copenhagen University Hospital, 35452030 35452030, per.johansson@regionh.dk
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
28 Apr 2022
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
26 Apr 2021
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
26 Apr 2021
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The primary objective is to investigate whether continuous infusion of iloprost at a dose of 1 ng/kg/min for 72-hours reduces the severity of respiratory failure in the ICU as compared to placebo.
|
||
Protection of trial subjects |
Patients included in this trial is admitted to the ICU with COVÌD19 requiring respiratory support, therefore these patients will receive the best possible care and monitored closely during their hospital stay.
|
||
Background therapy |
Standard of care for treatment of COVID19 | ||
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 |
01 May 2020
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Denmark: 80
|
||
Worldwide total number of subjects |
80
|
||
EEA total number of subjects |
80
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
34
|
||
From 65 to 84 years |
46
|
||
85 years and over |
0
|
||
|
||||||||||
|
Recruitment
|
||||||||||
Recruitment details |
Patients are recruited in the periode fra June 2020 to January 2021 in one of the 5 ICU2 in the Capital Region of Denmark. | |||||||||
|
Pre-assignment
|
||||||||||
Screening details |
Patients are subject for screening if they are 18 years old or above and admitted to an ICU with confirmed COVID19 infection requirering mechanical ventilation. However patients can only be included if souble thrombomodulin is 4 ng/mL or above. | |||||||||
|
Period 1
|
||||||||||
Period 1 title |
Overall trial (overall period)
|
|||||||||
Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
|
|||||||||
Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, 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 fashion.
|
|||||||||
|
Arms
|
||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||
|
Arm title
|
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
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
Prostacyclin
|
|||||||||
Pharmaceutical forms |
Solution for solution for infusion
|
|||||||||
Routes of administration |
Infusion
|
|||||||||
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 1.0 ng/kg/min iloprost. The infusion volume of the active investigational drug and placebo will be 72 ml per 24h.
|
|||||||||
|
Arm title
|
Placebo arm | |||||||||
Arm description |
Saline 0.9% is used as comparator | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Saline 0.9%
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
sodium chloride
|
|||||||||
Pharmaceutical forms |
Solution for infusion
|
|||||||||
Routes of administration |
Infusion
|
|||||||||
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.
|
|||||||||
|
||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Intervention arm
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Iloprost (Ilomedin®) is a marketed product which will be administered in this trial as the IMP. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo arm
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Saline 0.9% is used as comparator | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Intervention arm
|
||
Reporting group description |
Iloprost (Ilomedin®) is a marketed product which will be administered in this trial as the IMP. | ||
Reporting group title |
Placebo arm
|
||
Reporting group description |
Saline 0.9% is used as comparator | ||
|
||||||||||||||||
End point title |
Days alive without mechanical care | |||||||||||||||
End point description |
Number of days alive and without mechanical ventilation in the ICU for the intention to treat population
|
|||||||||||||||
End point type |
Primary
|
|||||||||||||||
End point timeframe |
Number of days from baseline to dag 28
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
Primary endpoint | |||||||||||||||
Statistical analysis description |
for the ITT population
|
|||||||||||||||
Comparison groups |
Intervention arm v Placebo arm
|
|||||||||||||||
Number of subjects included in analysis |
80
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
other | |||||||||||||||
P-value |
≤ 0.05 | |||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | |||||||||||||||
Confidence interval |
||||||||||||||||
|
|||||||||||||
End point title |
Mortality day 28 | ||||||||||||
End point description |
Number of deaths from baseline to day 28
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At day 28
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Mortality day 90 | ||||||||||||
End point description |
Number of deaths from baseline to day 90
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Day 90
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Days alive without vasopressor day 28 | ||||||||||||
End point description |
Number of days alive and without vasopressor in the ICU
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Number of days from baseline to dag 28
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Days alive without vasopressor day 90 | ||||||||||||
End point description |
Number of days alive and without vasopressor in the ICU
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Number of days from baseline to dag 90
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Days alive without renal replacement therapy day 28 | ||||||||||||
End point description |
Number of days alive and without RRT in the ICU
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Number of days from baseline to dag 28
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Days alive without renal replacement therapy day 90 | ||||||||||||
End point description |
Number of days alive and without RRT in the ICU
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Number of days from baseline to dag 90
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Serious adverse events | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Number of events from baseline to dag 7
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Serious adverse reaction | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Number of reactions from baseline to dag 7
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Days alive without mechanical care day 90 | ||||||||||||
End point description |
Number of days alive and without mechanical ventilation in the ICU
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Number of days from baseline to dag 90
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information [1]
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
SAE and SAR are collected from baseline to day 7
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
none | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall trail
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
|||
| http://www.ncbi.nlm.nih.gov/pubmed/34813414 |
|||
