IL-6 Inhibition for Modulating Inflammation After Cardiac Arrest (IMICA)

August 20, 2020 updated by: Christian Hassager

Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest - a Randomized Clinical Trial

Resuscitated cardiac arrest is associated with a systemic inflammatory response that is directly associated with poor prognosis. Inhibition of the IL-6 mediated immune response may potentially inhibit the systemic inflammatory response, potentially improving the prognosis of these severely ill patients.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

INTRODUCTION AND BACKGROUND:

The incidence of out-of-hospital cardiac arrest (OHCA) in Denmark is approximately 4,000 per year, and the mortality remains approximately 90%. Furthermore, in the approximately 30% of patients who are resuscitated and admitted to the intensive care unit (ICU), the mortality within the first month remains between 50% to 70%. Accordingly, an increasing emphasis on post-resuscitation care has been addressed by contemporary guidelines.

The high mortality after resuscitated OHCA has been attributed to a post-cardiac arrest syndrome (PCAS), which includes four mutually interacting components: a systemic inflammatory response (SIRS)-like syndrome, cerebral injury, myocardial dysfunction, and the persistent precipitating cause of the arrest. Despite repeated emphasis on post-resuscitation care, no specific therapies targeting PCAS have been implemented, with the exception of targeted temperature management (TTM), which has been recommended since 2003. Accordingly, research addressing mitigation of the PCAS seems intuitively beneficial.

During and after OHCA, exposure to whole-body ischemia and reperfusion injury triggers activation of inflammatory cascades leading to a sepsis-like syndrome. A multitude of inflammatory markers have been associated with unfavorable outcome after OHCA, including procalcitonin (PCT), c-reactive protein (CRP), interleukin (IL) 6, and IL-10.

Furthermore, the inflammatory markers interleukin 1β (IL-1β), IL-6, IL-10, and tumor necrosis factor α (TNF-α) have all been associated with the severity of PCAS, assessed by sequential organ failure assessment (SOFA) score. Importantly, levels of IL-6 have been shown to be independently associated with unfavorable outcome after adjustment for known risk markers. Further, the level of IL-6 was more strongly associated with PCAS severity compared to classical inflammatory markers such as CRP and PCT.

Interleukin-6 is a pro-inflammatory cytokine secreted by T cells and macrophages. IL-6 readily crosses the blood-brain-barrier and is a mediator of fever. Further, IL-6 is a mediator of the acute phase response and plays a role in activation of the coagulation system, increasing vascular permeability, and weakening papillary muscle contractions leading to myocardial dysfunction. As such, IL-6 is involved in pathological processes including tissue hypoxia, disseminated intravascular coagulation (DIC), and multiorgan failure, all of which represent parts of the SIRS response. IL-6 has been suggested to play a role in ischemia-reperfusion injury in myocardial infarction (MI), and higher levels of IL-6 have been associated both with the magnitude of myocardial injury, mortality and adverse events in this group.

Due to the role of IL-6 in many inflammatory diseases, IL-6 receptor antibodies (IL-6RA) have been developed. The first IL-6RA, tocilizumab, was approved for treatment of rheumatoid arthritis in 2009, and has later been approved for giant cell arthritis and chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome. In addition to the approved indications, tocilizumab has been suggested to have other beneficial immune modulating and organ protective effects.

In patients presenting with non-ST-elevation myocardial infarction (NSTEMI), a one-hour infusion of 280mg tocilizumab decreased the inflammatory response assessed by CRP levels, and further decreased myocardial injury assessed by TnT levels. Importantly, no increased risk of adverse events was observed in patients receiving tocilizumab. Animal data suggest that tocilizumab is safe and effective for treatment of severe acute pancreatitis and associated acute lung injury. Further, tocilizumab had neuroprotective effects in a model of Alzheimer disease. In humans, tocilizumab has been suggested to be effective against the autoimmune neurological disorders neuromyelitis optica and autoimmune encephalitis.

In summary, resuscitated OHCA is associated with a severe SIRS-like response, the magnitude of which has been associated with increased mortality and poor neurological outcome. Inhibiting the IL-6 mediated immune response may inhibit the SIRS-like response and may further inhibit ischemia-reperfusion injury leading to improved outcome.

HYPOTHESIS:

A one-hour infusion of the IL-6RA tocilizumab initiated as soon as possible after ROSC will reduce the SIRS-like response assessed by hsCRP levels after OHCA.

SAMPLE SIZE:

A total of 80 patients will be included, i.e. 40 being allocated to IL-6RA and placebo, respectively. Patients who die or become hemodynamically unstable immediately after randomization before the study drug has been prepared will be excluded from the modified intention to treat population and replaced by randomizing additional patients. Likewise, patients for whom the relatives refuse study participation when informed of the study and asked for consent (before the patients can be asked) will be excluded from the modified intention to treat population and replaced.

Study Type

Interventional

Enrollment (Actual)

80

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Copenhagen, Denmark, 2100
        • Rigshospitalet

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Each of the following criteria must be fulfilled for a subject to be eligible:

  1. Age ≥ 18 years
  2. OHCA of a presumed cardiac cause
  3. Unconsciousness upon admission, i.e. a GCS < 9
  4. Sustained ROSC for more than 20 minutes

Exclusion Criteria:

None of the following criteria must be fulfilled for a subject to be eligible:

  1. Consciousness upon admission, i.e. a GCS ≥ 9
  2. Presumed non-cardiac cause of arrest
  3. Unwitnessed asystole
  4. Suspected or confirmed intracranial bleeding or stroke
  5. Pregnancy, or females in fertile age, unless a negative serum HCG can rule out pregnancy within the inclusion window.
  6. Temperature on admission < 30 °C
  7. Persistent cardiogenic shock* that is not reversed within the inclusion window
  8. Known disease making 180 day survival unlikely
  9. Known limitations in therapy
  10. Known pre-arrest Cerebral Performance Category of 3 to 4
  11. > 240 minutes from ROSC to randomization

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Tocilizumab
A one hour infusion of a single 8mg/kg dose (max. 800mg) of tocilizumab to attenuate systemic inflammation after out-of-hospital cardiac arrest, given as early as possible after hospital admission.
Drug: Tocilizumab 20 Mg/mL Intravenous Solution
Tocilizumab is suspended in isotonic saline to a total volume of 100mL prior to infusion
Other Names:
  • RoActemra
PLACEBO_COMPARATOR: Isotonic saline
A one hour infusion of isotonic saline
Drug: isotonic saline
A one hour infusion of 100mL isotonic saline
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Concentration of hsCRP
Time Frame: Daily measurements from admission to 72 hours after admission.
high sensitivity C-reactive protein
Daily measurements from admission to 72 hours after admission.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Biomarkers of organ damage
Time Frame: Plasma/serum samples and routine biochemistry are collected at admission, 24h, 48h and 72h (NSE only at 48 and 72h)

Markers of cerebral injury: Neuron-specific enolase (NSE) levels (routine biochemistry), and other markers of cerebral injury (analysis of samples in biobank).

Markers of cardiac injury: Troponin T (TnT) and CKMB levels. Markers of kidney injury: Creatinine levels. Markers of hepatic injury: ALAT, ASAT, bilirubin, INR. Markers of endothelial injury: soluble thrombomodulin levels.
Plasma/serum samples and routine biochemistry are collected at admission, 24h, 48h and 72h (NSE only at 48 and 72h)
Markers of inflammation, interleukin levels
Time Frame: At admission, 24h, 48h & 72h
Interleukin levels: INF-g, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8 IL-10, IL-12, IL-13, IL-17A, G-CSF, GM-CSF, MCP-1 og MIP-1beta and TNF-α (analysis of samples in biobank).
At admission, 24h, 48h & 72h
Markers of inflammation, leukocytes
Time Frame: At admission, 24h, 48h & 72h
Leukocyte differential count.
At admission, 24h, 48h & 72h
Markers of inflammation, SOFA score
Time Frame: The first 3 days from admission
Daily Sequential Organ Failure Assessment (SOFA) scores.
The first 3 days from admission
Markers of the coagulation system, fibrinogen
Time Frame: At admission, 48h and 72h
The possible downstream effect of dampened inflammation on the coagulation system is evaluated by the concentration of plasma-fibrinogen.
At admission, 48h and 72h
Markers of the coagulation system, thrombelastography
Time Frame: At admission and 48h
The possible downstream effect of dampened inflammation on the coagulation system is evaluated by whole blood thrombelastography.
At admission and 48h
Markers of hemodynamic function, Swan-Ganz Catheter
Time Frame: At admission, 24h, 48h & 72h
Swan-Ganz based measurements of cardiac output, central venous pressure, pulmonary capillary wedge pressure, and systemic vascular resistance.
At admission, 24h, 48h & 72h
Markers of hemodynamic function, Arterial blood gasses
Time Frame: At admission, 2h, 4h, 6h, 8h, 10h, 12h, 18h, 24h, 30h, 36h, 48h, 72h, 96h and 120h (sampling ceases if the arterial line is discontinued).
Arterial blood gasses including lactate and base excess at frequent intervals.
At admission, 2h, 4h, 6h, 8h, 10h, 12h, 18h, 24h, 30h, 36h, 48h, 72h, 96h and 120h (sampling ceases if the arterial line is discontinued).
Markers of hemodynamic function, Echocardiography
Time Frame: Day 1 and on either day 3, 4 or 5.
Transthoracic echocardiography including assesment of left ventricular ejection fraction (LVEF) and tricuspid annular plane systolic excursion (TAPSE).
Day 1 and on either day 3, 4 or 5.
Clinical endpoints, Survival
Time Frame: At 30 days, 90 days, 180 days, and at end of trial.
Survival.
At 30 days, 90 days, 180 days, and at end of trial.
Clinical endpoints, MOCA score
Time Frame: At 90 days.
Montreal Cognitive Assessment (MOCA) score at 90 days.
At 90 days.
Clinical endpoints, CPC
Time Frame: At 30 days, 90 days and 180 days.
Cerebral Performance Category (CPC) at 30 days, 90 days and 180 days, assessed by telephone interview and/or review of medical file after completion of the 180 days.
At 30 days, 90 days and 180 days.
Safety: incidence of adverse events
Time Frame: From admission till 7 days.
Cumulated incidence of adverse events the first 7 days.
From admission till 7 days.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Predefined sub-study: MRI of heart and brain
Time Frame: The day following admission.
A subset of the trial participants will be enrolled in a sub-study focusing on cardio protection and neuroprotection as a pilot investigation. This sub-study will include an echocardiography, a cerebral MR scan and a cardiac MR scan; all three modalities being performed the day following admission.
The day following admission.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Christian Hassager

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 4, 2019

Primary Completion (ACTUAL)

December 23, 2019

Study Completion (ACTUAL)

June 30, 2020

Study Registration Dates

First Submitted

February 22, 2019

First Submitted That Met QC Criteria

March 4, 2019

First Posted (ACTUAL)

March 5, 2019

Study Record Updates

Last Update Posted (ACTUAL)

August 21, 2020

Last Update Submitted That Met QC Criteria

August 20, 2020

Last Verified

August 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EudraCT:2018-002686-19

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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