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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03863015
Recruitment Status : Completed
First Posted : March 5, 2019
Last Update Posted : August 21, 2020
Sponsor:
Information provided by (Responsible Party):
Christian Hassager, Rigshospitalet, Denmark

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

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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

Resource links provided by the National Library of Medicine

Drug Information available for: Tocilizumab

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




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.



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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03863015


Locations
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Denmark
Rigshospitalet
Copenhagen, Denmark, 2100
Sponsors and Collaborators
Christian Hassager
Investigators
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Principal Investigator: Christian Hassager, MD, DMSc Department of Cardiology, The Heart Center, Rigshospitalet, Copenhagen, Denmark
Publications:
Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation. 2017 Mar 7;135(10):e146-e603. doi: 10.1161/CIR.0000000000000485. Epub 2017 Jan 25. Review. Erratum in: Circulation. 2017 Mar 7;135(10 ):e646. Circulation. 2017 Sep 5;136(10 ):e196.
Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Böttiger BW, Callaway C, Clark RS, Geocadin RG, Jauch EC, Kern KB, Laurent I, Longstreth WT Jr, Merchant RM, Morley P, Morrison LJ, Nadkarni V, Peberdy MA, Rivers EP, Rodriguez-Nunez A, Sellke FW, Spaulding C, Sunde K, Vanden Hoek T. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation. 2008 Dec 2;118(23):2452-83. doi: 10.1161/CIRCULATIONAHA.108.190652. Epub 2008 Oct 23.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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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    Key Record Dates
Last Update Posted: August 21, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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