Clinical Trial Results:
Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response after Out-of-Hospital Cardiac Arrest
Summary
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EudraCT number |
2018-002686-19 |
Trial protocol |
DK |
Global end of trial date |
31 Aug 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Sep 2021
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First version publication date |
15 Sep 2021
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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 |
2018-HJEPharma-001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03863015 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
The IMICA Trial: Acronym | ||
Sponsors
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Sponsor organisation name |
Prof. Hassager, Dept. Cardiology, Rigshospitalet
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Sponsor organisation address |
Blegdamsvej 9, Copenhagen, Denmark, 2100
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Public contact |
Department of Cardiology, Copenhagen University Hospital Rigshospitalet, christian.hassager@regionh.dk
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Scientific contact |
Department of Cardiology, Copenhagen University Hospital Rigshospitalet, christian.hassager@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 |
03 Aug 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
23 Dec 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Aug 2020
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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 |
Out-of-hospital cardiac arrest (OHCA) patients remaining comatose after resuscitation are at high risk of morbidity and mortality due to the post cardiac arrest syndrome (PCAS). Systemic inflammation is a major component of PCAS, and interleukin-6 (IL-6) levels are associated with severity of PCAS. Therefore, tocilizumab, which is an IL-6 receptor antagonist, could potentially dampen inflammation after OHCA.
The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after OHCA of presumed cardiac cause and thereby potentially mitigate organ injury.
The primary endpoint of the study was difference in CRP response between the tocilizumab and placebo group during initial 72 hours.
Secondary endpoints included markers of inflammation, organ injury, neurologic outcome, safety and survival.
For a comprehensive presentation and discussion of trial results please see: https://doi.org/10.1161/CIRCULATIONAHA.120.053318
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Protection of trial subjects |
Participation in the trial did not limit the access to any additional treatments and patients were treated according to standard of care as well (described below). Co-participation in other trials was allowed as well.
Patients with know contraindications to treatment with the study drug (tocilizumab) were excluded during screening. Exclusion criteria included previous allergic reactions to tocilizumab, significant liver impairment, and significant infection as there is a potential immunosuppressive effect of tocilizumab.
Further, all patients participating in the trial were treated with prophylactic antibiotics to possibly limit the occurrence of infections during the initial ICU stay.
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Background therapy |
In addition to the trial associated treatment, all patients received "standard of care" including sedation, ventilation and targeted temperature management for at least 24 hours, as well as vasopressors/inotropy as needed. Further all patients received prophylactic antibiotics. | ||
Evidence for comparator |
Isotonic saline was chosen as placebo treatment, and no significant effect of this was expected. | ||
Actual start date of recruitment |
04 Mar 2019
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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: 80
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Worldwide total number of subjects |
80
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EEA total number of subjects |
80
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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) |
41
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From 65 to 84 years |
39
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment was completed in 9 months (ahead of schedule) | |||||||||
Pre-assignment
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Screening details |
Brief inclusion criteria: Adult comatose patients resuscitated from OHCA of presumed cardiac cause. We screened 117 patients and randomized 85 patients - tocilizumab: 42, placebo: 43; 5 patients were excluded prior to analysis (tocilizumab: 3; placebo: 2). Data in this report refer to the resulting modified intention-to-treat population of 80. | |||||||||
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, Carer, Assessor, Subject | |||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Tocilizumab | |||||||||
Arm description |
- | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Tocilizumab
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Investigational medicinal product code |
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Other name |
RoActemra, Actemra
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients allocated to the tocilizumab group received a 1-h infusion of 8 mg tocilizumab per kilogram body weight (maximum dose 800 mg, i.e. 40 mL of concentrate); the study drug was suspended in normal saline to a total volume of 100 mL.
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Arm title
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Placebo | |||||||||
Arm description |
- | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Saline
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Investigational medicinal product code |
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Other name |
Isotonic saline, NaCl
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients allocated to the placebo arm received a 1-h infusion of 100 mL of normal saline.
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Baseline characteristics reporting groups
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Reporting group title |
Tocilizumab
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Tocilizumab
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Reporting group description |
- | ||
Reporting group title |
Placebo
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Reporting group description |
- |
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End point title |
C-reactive protein | ||||||||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Measured at admission, 24, 48, and 72 hours
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Statistical analysis title |
CRP, mixed model analysis | ||||||||||||||||||||||||
Statistical analysis description |
CRP from admission till 72 hours.
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Comparison groups |
Tocilizumab v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||
Confidence interval |
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Notes [1] - Linear mixed model, baseline adjusted. [2] - P value for the treatment-by-time interaction listed above. Time specific comparisons of tocilizumab vs placebo: At 24 hours: p < 0.001 At 48 hours: p < 0.001 At 72 hours: p < 0.001 |
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End point title |
Leukocytes | ||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Measured at admission, 24, 48 and 72 hours
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Statistical analysis title |
Leukocytes, mixed model analysis | ||||||||||||||||||||||||
Statistical analysis description |
Leukocytes from admission till 72 hours
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Comparison groups |
Tocilizumab v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | ||||||||||||||||||||||||
P-value |
= 0.0005 [4] | ||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||
Confidence interval |
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Notes [3] - Linear mixed model, baseline adjusted. [4] - P value for the treatment-by-time interaction listed above. Time specific comparisons of tocilizumab vs placebo: At 24 hours: p < 0.001 At 48 hours: p = 0.004 At 72 hours: p = 0.129 |
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End point title |
Troponin T (TnT) | |||||||||||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Measured at admission, 6, 12, 24, 36, 48 and 72 hours.
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Statistical analysis title |
TnT, mixed model analysis | |||||||||||||||||||||||||||||||||
Statistical analysis description |
TnT from admission till 72 hours.
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Comparison groups |
Tocilizumab v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
other [5] | |||||||||||||||||||||||||||||||||
P-value |
= 0.0932 [6] | |||||||||||||||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||||||||||||||
Confidence interval |
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Notes [5] - Linear mixed model, baseline adjusted. [6] - P value for the treatment-by-time interaction listed above. Time specific comparisons of tocilizumab vs placebo: At 6 hours: p = 0.002 At 12 hours: p = 0.008 At 24 hours: p = 0.065 At 36 hours: NS At 48 hours: NS At 72 hours: NS |
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End point title |
Creatine kinase myocardial band (CKMB) | |||||||||||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Measured at admission, 6, 12, 24, 36, 48 and 72 hours.
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Statistical analysis title |
CKMB, mixed model analysis | |||||||||||||||||||||||||||||||||
Statistical analysis description |
CKMB from admission till 72 hours
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Comparison groups |
Tocilizumab v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
other [7] | |||||||||||||||||||||||||||||||||
P-value |
= 0.0035 [8] | |||||||||||||||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||||||||||||||
Confidence interval |
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Notes [7] - Linear mixed model, baseline adjusted. [8] - P value for the treatment-by-time interaction listed above. Time specific comparisons of tocilizumab vs placebo: At 6 hours: p < 0.001 At: 12 hours: p = 0.001 At 24 hours: p = 0.050 At 36 hours: NS At 48 hours: NS At 72 hour: NS |
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End point title |
N-terminal pro B-type natriuretic peptide (NT-proBNP) | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Measured at admission and 48 hours.
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Statistical analysis title |
NT-proBNP, mixed model analysis | ||||||||||||||||||
Statistical analysis description |
NT-proBNP from admission till 48 hours.
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Comparison groups |
Tocilizumab v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
other [9] | ||||||||||||||||||
P-value |
= 0.0002 [10] | ||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||
Confidence interval |
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Notes [9] - Linear mixed model, baseline adjusted. [10] - P value for the treatment-by-time interaction listed above. Time specific comparisons of tocilizumab vs placebo: At 48 hours: p < 0.001 |
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End point title |
Neuron-specific enolase (NSE) | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Measured at 48 and 72 hours.
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Statistical analysis title |
NSE, mixed model | ||||||||||||||||||
Comparison groups |
Tocilizumab v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
other [11] | ||||||||||||||||||
P-value |
= 0.27 [12] | ||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||
Confidence interval |
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Notes [11] - Linear mixed model. [12] - P value for the treatment-by-time interaction listed above. Time specific comparisons of tocilizumab vs placebo: At 48 hours: p = 0.22 At 72 hours: p = 0.39 |
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End point title |
Cerebral Performance Category (CPC) after 180 days | ||||||||||||
End point description |
A score ≥3 indicate a poor neurologic outcome (incl. death)
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End point type |
Secondary
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End point timeframe |
180 days after Out-of-hospital cardiac arrest
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Statistical analysis title |
CPC after 180 days | ||||||||||||
Statistical analysis description |
Comparing the frequency of a poor neurologic outcome in the two groups
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Comparison groups |
Tocilizumab v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 1 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Confidence interval |
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End point title |
Modified Rankin Scale (mRS) after 180 days | ||||||||||||
End point description |
A score ≥4 indicate a poor neurologic outcome (incl. death)
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End point type |
Secondary
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End point timeframe |
180 days after Out-of-hospital cardiac arrest
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Statistical analysis title |
mRS after 180 days | ||||||||||||
Statistical analysis description |
Comparing the frequency of a poor neurologic outcome in the two groups
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Comparison groups |
Tocilizumab v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.65 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Confidence interval |
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End point title |
Mortality after 180 days | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
180 days after Out-of-hospital cardiac arrest
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Statistical analysis title |
Mortality after 180 days | ||||||||||||
Comparison groups |
Placebo v Tocilizumab
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 1 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
From randomization till 6 months after
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
Study protocol | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
1.91
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Reporting groups
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Reporting group title |
Tocilizumab
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 1% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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. | |||
None reported | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/33081828 http://www.ncbi.nlm.nih.gov/pubmed/33745292 |