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

• ClinicalTrials.gov Identifier: NCT03863015
• Recruitment Status: Completed
• First Posted: March 5, 2019
• Last Update Posted: August 21, 2020
• Sponsor: Christian Hassager
• Information provided by (Responsible Party): Christian Hassager, Rigshospitalet, Denmark

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Heart Arrest; Out-Of-Hospital Cardiac Arrest; Systemic Inflammatory Response Syndrome	Drug: Tocilizumab 20 Mg/mL Intravenous Solution; Drug: isotonic saline	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subjects will be randomized in a 1:1 fashion to receive IL-6RA or placebo. Patients being allocated to IL-6RA will receive a one-hour infusion of 8 mg tocilizumab per kg body weight (maximum dose 800 mg, 40 mL), equivalent to 0.4 mL per kg bodyweight (study drug concentration 20 mg/mL). Patients being allocated to placebo will receive a one-hour infusion of 0.4 mL /kg body weight of normal saline (maximum dose 40 mL)
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest - a Randomized Clinical Trial
• Actual Study Start Date: March 4, 2019
• Actual Primary Completion Date: December 23, 2019
• Actual Study Completion Date: June 30, 2020

Arms and Interventions

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 Name: RoActemra
Placebo Comparator: Isotonic saline; A one hour infusion of isotonic saline	Drug: isotonic saline; A one hour infusion of 100mL isotonic saline; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Concentration of hsCRP [ Time Frame: Daily measurements from admission to 72 hours after admission. ]
   high sensitivity C-reactive protein

Secondary Outcome Measures :

1. 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.

2. 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).
3. Markers of inflammation, leukocytes [ Time Frame: At admission, 24h, 48h & 72h ]
   Leukocyte differential count.
4. Markers of inflammation, SOFA score [ Time Frame: The first 3 days from admission ]
   Daily Sequential Organ Failure Assessment (SOFA) scores.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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).
10. Clinical endpoints, Survival [ Time Frame: At 30 days, 90 days, 180 days, and at end of trial. ]
    Survival.
11. Clinical endpoints, MOCA score [ Time Frame: At 90 days. ]
    Montreal Cognitive Assessment (MOCA) score at 90 days.
12. 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.
13. Safety: incidence of adverse events [ Time Frame: From admission till 7 days. ]
    Cumulated incidence of adverse events the first 7 days.

Other Outcome Measures:

1. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Denmark

Rigshospitalet

Copenhagen, Denmark, 2100

Sponsors and Collaborators

Christian Hassager

Investigators

• Principal Investigator: Christian Hassager, MD, DMSc; Department of Cardiology, The Heart Center, Rigshospitalet, Copenhagen, Denmark

More Information

Publications:

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Meyer MAS, Wiberg S, Grand J, Kjaergaard J, Hassager C. Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response after Out-of-Hospital Cardiac Arrest (IMICA): study protocol for a double-blinded, placebo-controlled, single-center, randomized clinical trial. Trials. 2020 Oct 20;21(1):868. doi: 10.1186/s13063-020-04783-4.

• Responsible Party: Christian Hassager, Professor, MD, DMSc, FESC, Rigshospitalet, Denmark
• ClinicalTrials.gov Identifier: NCT03863015
• Other Study ID Numbers: EudraCT:2018-002686-19
• First Posted: March 5, 2019
• Last Update Posted: August 21, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Christian Hassager, Rigshospitalet, Denmark:

OHCA; PCAS; SIRS; Inflammation; RoActemra; Tociluzumab

Additional relevant MeSH terms:

Heart Arrest; Out-of-Hospital Cardiac Arrest; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Shock