IL-6 Inhibition for Modulating Inflammation After Cardiac Arrest

Out-Of-Hospital Cardiac Arrest Clinical Trial

— IMICA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03863015
• Other study ID #: EudraCT:2018-002686-19
• Status: Completed
• Phase: Phase 2
• Start date: March 4, 2019
• Est. completion date: June 30, 2020

Study information

• Verified date: August 2020
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: June 30, 2020
• Est. primary completion date: December 23, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Arrest
• Out-of-Hospital Cardiac Arrest
• Systemic Inflammatory Response Syndrome

Intervention

Drug:
• Tocilizumab 20 Mg/mL Intravenous Solution
Tocilizumab is suspended in isotonic saline to a total volume of 100mL prior to infusion
• isotonic saline
A one hour infusion of 100mL isotonic saline

Locations

Country	Name	City	State
Denmark	Rigshospitalet	Copenhagen

Sponsors (1)

Lead Sponsor	Collaborator
Christian Hassager

Country where clinical trial is conducted

Denmark, 

References & Publications (25)

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* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Predefined sub-study: MRI of heart and brain	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.
Primary	Concentration of hsCRP	high sensitivity C-reactive protein	Daily measurements from admission to 72 hours after admission.
Secondary	Biomarkers of organ damage	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)
Secondary	Markers of inflammation, interleukin levels	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-a (analysis of samples in biobank).	At admission, 24h, 48h & 72h
Secondary	Markers of inflammation, leukocytes	Leukocyte differential count.	At admission, 24h, 48h & 72h
Secondary	Markers of inflammation, SOFA score	Daily Sequential Organ Failure Assessment (SOFA) scores.	The first 3 days from admission
Secondary	Markers of the coagulation system, fibrinogen	The possible downstream effect of dampened inflammation on the coagulation system is evaluated by the concentration of plasma-fibrinogen.	At admission, 48h and 72h
Secondary	Markers of the coagulation system, thrombelastography	The possible downstream effect of dampened inflammation on the coagulation system is evaluated by whole blood thrombelastography.	At admission and 48h
Secondary	Markers of hemodynamic function, Swan-Ganz Catheter	Swan-Ganz based measurements of cardiac output, central venous pressure, pulmonary capillary wedge pressure, and systemic vascular resistance.	At admission, 24h, 48h & 72h
Secondary	Markers of hemodynamic function, Arterial blood gasses	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).
Secondary	Markers of hemodynamic function, Echocardiography	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.
Secondary	Clinical endpoints, Survival	Survival.	At 30 days, 90 days, 180 days, and at end of trial.
Secondary	Clinical endpoints, MOCA score	Montreal Cognitive Assessment (MOCA) score at 90 days.	At 90 days.
Secondary	Clinical endpoints, CPC	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.
Secondary	Safety: incidence of adverse events	Cumulated incidence of adverse events the first 7 days.	From admission till 7 days.