Clinical Trial Results:
Endothelial Dysfunction in Resuscitated Cardiac Arrest (ENDR-RCA): Safety and efficacy of low-dose Iloprost administration and blood pressure target in addition to standard therapy, as compared to standard therapy alone, in post-cardiac-arrest-syndrome patients – a randomized, controlled, double-blinded
investigator-initiated trial.
Summary
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EudraCT number |
2014-002998-11 |
Trial protocol |
DK |
Global end of trial date |
27 Feb 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Apr 2020
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First version publication date |
30 Apr 2020
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Other versions |
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 |
ENDO-RCA
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02685618 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Rigshospitalet, Capital Region Bloodbank 2034, Section for Transfusion Medicine
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Sponsor organisation address |
Blegdamsvej 9, Copenhagen, Denmark, DK-2100
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Public contact |
Sponsor (Pär I. Johansson), Rigshospitalet, Capital Region Bloodbank 2034, Section for Transfusion Medicine, 0045 35452030, per.johansson@regionh.dk
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Scientific contact |
Sponsor (Pär I. Johansson), Rigshospitalet, Capital Region Bloodbank 2034, Section for Transfusion Medicine, 0045 35452030, per.johansson@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 |
21 Oct 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
27 Feb 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Feb 2017
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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 |
Assessment of the safety and efficacy of low-dose Iloprost administration on endothelial damage and blood pressure in post-cardiac-arrest-syndrome patients. To evaluate a possible interaction between exogenously administered catecholamines and iloprost efficacy on the endothelium.
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Protection of trial subjects |
All patients receive standard of care treatment including standardized temperature management and guideline supported achievement of mean arterial artery pressure using noradrenalin and dopamin during the intensive unit care stay.
Patients with ROSC (return of spontaneous circulation) above 240 minuts before screening, un-witnessed arrest with systoles as the initial rhythm, suspected or known acute intracranial hemorrhage or stroke were excluded from the trial.
Patients are in a critical acute condition resulting in mental impairment or sedation, therefore scientific guardians will co-sign the informed consent form. Next-of-kin and the patients' general practitioner will co-sign.
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Background therapy |
Standard of care. | ||
Evidence for comparator |
saline is used as placebo in this trial. | ||
Actual start date of recruitment |
25 Feb 2016
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy, Scientific research | ||
Long term follow-up duration |
6 Months | ||
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: 46
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Worldwide total number of subjects |
46
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EEA total number of subjects |
46
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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) |
26
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From 65 to 84 years |
19
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85 years and over |
1
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Recruitment
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Recruitment details |
Recruitment period 01.03.2016 to 31.08.2016. All patients were recruited at: Department Cardiology 2143, Copenhagen University Hospital, Denmark. Inclusion criteria were patients 18 years or older with (out-of-hospital-cardiac-arrest (OHCA) | |||||||||||||||
Pre-assignment
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Screening details |
A total of 77 patients were pre-screened of these 66 patients were assessed for eligibility. Of these 50 patients were randomised but only 46 patients were included in the trial of these 40 completed the 96-hour endpoint. Patients were recruited in 1:2 ration (active:placebo). | |||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
50 [1] | |||||||||||||||
Number of subjects completed |
46 | |||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
other nationality: 1 | |||||||||||||||
Reason: Number of subjects |
Consent withdrawn by subject: 1 | |||||||||||||||
Reason: Number of subjects |
Died prior to intervention: 1 | |||||||||||||||
Reason: Number of subjects |
Protocol deviation: 1 | |||||||||||||||
Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: A total of 4 patients were not included in the trial. |
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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 |
Investigator, Monitor, Data analyst, Subject, Carer, Assessor | |||||||||||||||
Blinding implementation details |
To circumvent selection bias, researchers and healthcare personnel was blinded to the treatment assignment. furthermore, to avoid investigator, healthcare staff and patient performance and detection bias, patients was randomized by computer to receive either iloprost or placebo similar in colour, consistency and volumen. Unblinded study nurse performed preparation of the study drug.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Iloprost | |||||||||||||||
Arm description |
Patients receiving iloprost. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Iloprost
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Investigational medicinal product code |
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Other name |
Ilomedin
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Pharmaceutical forms |
Concentrate and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Administration of 1 ng/kg/min for 48 hours.
Iloprost was diluated in 0.9% saline to a final volumen of 100 ml. Infusion rate was 4 ml / hours.
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Investigational medicinal product name |
Isotonic saline
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Investigational medicinal product code |
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Other name |
natriumchloride 0.9%
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Iloprost is diluted into saline to a final volumen of 100 ml
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Arm title
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Placebo | |||||||||||||||
Arm description |
Saline infusion 0.9% | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
isotonic saline
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Investigational medicinal product code |
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Other name |
natriumchloride 0.9%
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Infusion: 0.9% saline to a final volumen of 100 ml with an infusion rate of 4 ml/hours for 48 hours.
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Baseline characteristics reporting groups
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Reporting group title |
Iloprost
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Reporting group description |
Patients receiving iloprost. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Saline infusion 0.9% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Iloprost
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Reporting group description |
Patients receiving iloprost. | ||
Reporting group title |
Placebo
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Reporting group description |
Saline infusion 0.9% |
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End point title |
Change in endothelial biomarkers | |||||||||||||||||||||||||||
End point description |
Change in biomarkers of endothelial damage at 48 hours post baseline. The 2 arms were compared using baseline corrected Proc Mixed repeated measurement models.
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End point type |
Primary
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End point timeframe |
At 48 hours post baseline
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Attachments |
Untitled (Filename: Endothel biomarkører - ENDO-RCA.pdf) |
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Statistical analysis title |
Thrombomodulin | |||||||||||||||||||||||||||
Statistical analysis description |
Change in the biomarker thrombomodulin from baseline to 48 hours.
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Comparison groups |
Iloprost v Placebo
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Number of subjects included in analysis |
44
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | |||||||||||||||||||||||||||
P-value |
= 0.16 [2] | |||||||||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||||||||
Confidence interval |
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Notes [1] - Exploratory [2] - Group*Time at the 48-hour endpoints |
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Statistical analysis title |
Syndecain | |||||||||||||||||||||||||||
Statistical analysis description |
Change in the biomarker syndecain from baseline to 48 hours.
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Comparison groups |
Iloprost v Placebo
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Number of subjects included in analysis |
44
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | |||||||||||||||||||||||||||
P-value |
= 0.12 [4] | |||||||||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||||||||
Confidence interval |
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Notes [3] - Exploratory [4] - Group*Time at the 48-hour endpoints |
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Statistical analysis title |
VEcad | |||||||||||||||||||||||||||
Statistical analysis description |
Change in the biomarker VE-Cadherine from baseline to 48 hours.
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Comparison groups |
Iloprost v Placebo
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Number of subjects included in analysis |
44
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Analysis specification |
Pre-specified
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Analysis type |
other [5] | |||||||||||||||||||||||||||
P-value |
= 0.81 [6] | |||||||||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||||||||
Confidence interval |
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Notes [5] - Exploratory [6] - Group*Time at the 48-hour endpoints |
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Statistical analysis title |
E-Selectin | |||||||||||||||||||||||||||
Statistical analysis description |
Change in the biomarker E-selectin from baseline to 48 hours.
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Comparison groups |
Iloprost v Placebo
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Number of subjects included in analysis |
44
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Analysis specification |
Pre-specified
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Analysis type |
other [7] | |||||||||||||||||||||||||||
P-value |
= 0.1 [8] | |||||||||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||||||||
Confidence interval |
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Notes [7] - Exploratory [8] - Group*Time at the 48-hour endpoints |
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Statistical analysis title |
VEGF | |||||||||||||||||||||||||||
Statistical analysis description |
Change in the biomarker VEGF from baseline to 48 hours.
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Comparison groups |
Iloprost v Placebo
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Number of subjects included in analysis |
44
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Analysis specification |
Pre-specified
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Analysis type |
other [9] | |||||||||||||||||||||||||||
P-value |
= 0.6 [10] | |||||||||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||||||||
Confidence interval |
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Notes [9] - Exploratory [10] - Group*Time at the 48-hour endpoints |
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End point title |
Chnage in plasma levels of Adrenaline/Noradrenaline | ||||||||||||||||||
End point description |
Change in plasma levels over time from baseline to 48 hours. The 2 arms were compaired using baseline corected proc Mixed models
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End point type |
Primary
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End point timeframe |
At 48 hours post baseline
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Statistical analysis title |
Change in adrenaline level at 48 h | ||||||||||||||||||
Statistical analysis description |
Change in plasma levels over time from baseline to 48 hours
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Comparison groups |
Iloprost v Placebo
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Number of subjects included in analysis |
44
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
P-value |
= 0.88 [11] | ||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||
Confidence interval |
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Notes [11] - Group*Time at the 48-hour endpoints |
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Statistical analysis title |
Change in noradrenaline level at 48 h | ||||||||||||||||||
Statistical analysis description |
Change in plasma levels over time from baseline to 48 hours
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Comparison groups |
Iloprost v Placebo
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Number of subjects included in analysis |
44
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
P-value |
= 0.89 [12] | ||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||
Confidence interval |
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Notes [12] - Group*Time at the 48-hour endpoints |
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End point title |
Change in endothelial biomarker (sTM) at 96 hours | |||||||||||||||
End point description |
Changes in endothelial damage and activation from baseline. The 2 arms were compared using baseline corrected proc Mixed models
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End point type |
Primary
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End point timeframe |
At 96 hours post baseline
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Statistical analysis title |
Endpoint sTM at 96 hours | |||||||||||||||
Comparison groups |
Placebo v Iloprost
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Number of subjects included in analysis |
40
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||
P-value |
< 0.021 [13] | |||||||||||||||
Method |
Mixed models analysis | |||||||||||||||
Parameter type |
Mean difference (final values) | |||||||||||||||
Point estimate |
1.0909
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.7426 | |||||||||||||||
upper limit |
1.4392 | |||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.6966
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Notes [13] - Group*Time at the 96-hour endpoints |
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End point title |
Mortality | ||||||||||||||||||
End point description |
Number of death within 30, 90 and 180 days post baseline
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End point type |
Other pre-specified
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End point timeframe |
30, 90 and 180 days post intervention
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Statistical analysis title |
90-day mortality | ||||||||||||||||||
Comparison groups |
Iloprost v Placebo
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
P-value |
= 0.14 | ||||||||||||||||||
Method |
Fisher exact | ||||||||||||||||||
Confidence interval |
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Statistical analysis title |
180-day mortality | ||||||||||||||||||
Comparison groups |
Iloprost v Placebo
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
P-value |
= 0.02 | ||||||||||||||||||
Method |
Fisher exact | ||||||||||||||||||
Parameter type |
Log hazard ratio | ||||||||||||||||||
Point estimate |
2.84
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
1.1 | ||||||||||||||||||
upper limit |
7.4 | ||||||||||||||||||
Statistical analysis title |
30-day mortality | ||||||||||||||||||
Comparison groups |
Iloprost v Placebo
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
P-value |
= 0.14 | ||||||||||||||||||
Method |
Fisher exact | ||||||||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events are reported until day 30 post intervention start
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
10
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Reporting groups
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Reporting group title |
Intervention
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Reporting group description |
The 13 patients in this intervention group | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
All patients receiving placebo | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 2% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
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. | |||
Electronic randomization allocation patients in a 2:1 manner instead of 1:1. The randomization allocation 1:2 resulted in a small sample size in the iloprost group with increased risk of type I and type II errors. Also limitation due to pilot trial | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/31710844 http://www.ncbi.nlm.nih.gov/pubmed/31945586 |