A Phase 2 interventional study of Tocilizumab 20 Mg/mL Intravenous Solution and isotonic saline in Heart Arrest, Out-Of-Hospital Cardiac Arrest and Systemic Inflammatory Response Syndrome, sponsored by Christian Hassager. Completed at 1 site in Denmark. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-08-21.
Sponsored by Christian Hassager · Phase 2, Interventional, and Treatment
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.
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.
966 studies on the registry are indexed under Heart Arrest; 227 are open to participants now.
This study's enrollment of 80 is below the median of 100 across 557 interventional studies indexed under Heart Arrest.
Browse Heart Arrest studies →Christian Hassager is the lead sponsor of 5 studies on the registry; 2 are open to participants now.
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Each of the following criteria must be fulfilled for a subject to be eligible:
Exclusion Criteria:
None of the following criteria must be fulfilled for a subject to be eligible:
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
A one hour infusion of isotonic saline
Drug: isotonic saline
Tocilizumab is suspended in isotonic saline to a total volume of 100mL prior to infusion
Also known as: RoActemra
A one hour infusion of 100mL isotonic saline
Also known as: Placebo
Concentration of hsCRP
high sensitivity C-reactive protein
Time frame: Daily measurements from admission to 72 hours after admission.
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.
Time frame: 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
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).
Time frame: At admission, 24h, 48h & 72h
Markers of inflammation, leukocytes
Leukocyte differential count.
Time frame: At admission, 24h, 48h & 72h
Markers of inflammation, SOFA score
Daily Sequential Organ Failure Assessment (SOFA) scores.
Time frame: The first 3 days from admission
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.
Time frame: At admission, 48h and 72h
Markers of the coagulation system, thrombelastography
The possible downstream effect of dampened inflammation on the coagulation system is evaluated by whole blood thrombelastography.
Time frame: At admission and 48h
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.
Time frame: At admission, 24h, 48h & 72h
Markers of hemodynamic function, Arterial blood gasses
Arterial blood gasses including lactate and base excess at frequent intervals.
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).
Markers of hemodynamic function, Echocardiography
Transthoracic echocardiography including assesment of left ventricular ejection fraction (LVEF) and tricuspid annular plane systolic excursion (TAPSE).
Time frame: Day 1 and on either day 3, 4 or 5.
Clinical endpoints, Survival
Survival.
Time frame: At 30 days, 90 days, 180 days, and at end of trial.
Clinical endpoints, MOCA score
Montreal Cognitive Assessment (MOCA) score at 90 days.
Time frame: At 90 days.
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.
Time frame: At 30 days, 90 days and 180 days.
Safety: incidence of adverse events
Cumulated incidence of adverse events the first 7 days.
Time frame: From admission till 7 days.
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.
Time frame: The day following admission.
Plan to share: Undecided
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Christian Hassager