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Immunomodulation of EA-230 Following On-pump Coronary Artery Bypass Grafting (CABG) (EASI)

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ClinicalTrials.gov Identifier: NCT03145220
Recruitment Status : Active, not recruiting
First Posted : May 9, 2017
Last Update Posted : June 26, 2018
Sponsor:
Collaborator:
Exponential Biotherapies Inc.
Information provided by (Responsible Party):
Peter Pickkers, Radboud University

Brief Summary:
EA-230 is a newly developed synthetic compound with anti-inflammatory properties, it is a linear tetrapeptide derived from the human chorionic gonadotropin hormone (hCG). Recently, its immunomodulatory effects in humans were confirmed in a phase I trial and an optimal dose was established. To establish this anti-inflammatory effect in a selected patient population and assess clinical outcome, a combined phase IIa/IIb trial will be conducted with patients undergoing cardiac surgery.

Condition or disease Intervention/treatment Phase
Systemic Inflammatory Response Syndrome Coronary Artery Bypass Grafting Drug: EA-230 Other: Placebo (NaCl) Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Double Blind Placebo-controlled Phase II Study on the Effects of EA-230 on the Systemic Inflammatory Response Following On-pump Cardiac Surgery
Study Start Date : June 2016
Estimated Primary Completion Date : October 2018
Estimated Study Completion Date : October 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: EA-230
Intravenous infusion of EA-230, 90 mg/kg/hour. Administered from start of surgical incision until stoppage of the cardio-pulmonary bypass pump, for a maximum of 4 hours.
Drug: EA-230
Active intervention
Other Name: AQGV

Placebo Comparator: Placebo
Intravenous infusion of NaCl (equivalent osmolarity with active intervention EA-230). Administered from start of surgical incision until stoppage of the cardio-pulmonary bypass pump, for a maximum of 4 hours.
Other: Placebo (NaCl)
Placebo intervention
Other Name: NaCl




Primary Outcome Measures :
  1. Safety and tolerability (treatment related (serious) adverse events) [ Time Frame: Total (serious) adverse events related to treatment at day 90 after treatment ]
    Safety and tolerability expressed in treatment related (serious) adverse events

  2. Interleukin-6 (IL-6) [ Time Frame: 1 day: at baseline, start of the cardiopulmonary bypass (CPB), stop of CPB, 2h after stop of CPB, 4h after stop of CPB, 6h after stop of CPB and first post-operative day. ]
    Blood plasma levels IL-6


Secondary Outcome Measures :
  1. Glomerular filtration rate (GFR) [ Time Frame: Up to 3 days. At the day before surgery (baseline) and at the morning of the first post-operative day ]
    GFR assessed by plasma clearance of Iohexol.

  2. Urine kidney injury markers (KIM-1, NGAL, L-FABP, TIMP-2*IGFBP-7, urinary IL-18, NAG, creatine, urea, albumin) [ Time Frame: Up to1 day: at baseline (before surgery), 2h after stop of CPB, 4h after stop of CPB, 6h after stop of CPB and first post-operative day. ]
    laboratory values

  3. Other cytokines/chemokines (TNFα, IL-8, IL-10, IL-1RA, MCP-1, MIP1α, MIP1β, VCAM, ICAM, IL-17A) [ Time Frame: Up to 1 day: at baseline, start of the cardiopulmonary bypass (CPB), stop of CPB, 2h after stop of CPB, 4h after stop of CPB, 6h after stop of CPB and first post-operative day. ]
    Laboratory values.

  4. Leukocyte counts (differentiated) [ Time Frame: Up to 1 day: at baseline, start of the cardiopulmonary bypass (CPB), stop of CPB, 2h after stop of CPB, 4h after stop of CPB, 6h after stop of CPB and first post-operative day. ]
    Plasma leukocyte response, quantified by change of total cell counts, differentiated in lymphocytes, neutrophils, monocytes, basophils and eosinophils.


Other Outcome Measures:
  1. Heart rate [ Time Frame: First 24 post-operative hours, mean values per 30 minutes. ]
    Rate in beats per minute

  2. Blood pressure [ Time Frame: First 24 post-operative hours, mean values per 30 minutes. ]
    Pressure in mmHg

  3. body temperature [ Time Frame: First 24 post-operative hours, measured with an interval of 2 hours. ]
    Changes in body temperature in °C over time.

  4. SOFA score (Sepsis-related Organ Failure Assessment score) [ Time Frame: First 24 post-operative hours, twice. ]
    Change in SOFA score

  5. Insulin sensitivity [ Time Frame: First 24 post-operative hours. ]
    According to insulin dosing and plasma glucose concentration

  6. length of stay on ICU (LOS ICU) [ Time Frame: Up to 90 days. ]
    LOS ICU defined by total amount of days and hours patient is admitted to the intensive care

  7. length of hospital stay (LOS) [ Time Frame: Up to 90 days ]
    LOS defined by total amount of days and hours patient is hospitalized.

  8. mortality [ Time Frame: at day 28 and day 90 ]
    28 and 90-days mortality

  9. Major clinical adverse events [ Time Frame: up to 90 days ]
    Incidence of major clinical adverse events within 90-days (stroke, MI, rethoracotomy, readmission, pleural and/or pericardial punction

  10. APACHE IV [ Time Frame: 1 day ]
    APACHE IV score at ICU admission

  11. Other GFR methods (ECC) [ Time Frame: ECC: Urine collection from start of surgery until the morning of the first post-operative day. ]
    Calculated endogenous clearance of creatine (ECC)

  12. Other GFR methods (MDRD) [ Time Frame: Before surgery (baseline) and all other days creatine is measured during during hospital stay (max 7 days) ]
    Estimated GFR with plasma creatinine: MDRD.

  13. Plasma kidney function markers [ Time Frame: Up to 7 days: At baseline (before surgery), at stop of CPB, 2h after stop of CPB, 4h after stop of CPB, 6h after stop of CPB, 12h after stop of CPB, first post-operative day and at all other days creatine is measured during during hospital stay ]
    Plasma creatinine and proenkephalin

  14. Urine output [ Time Frame: 1 day ]
    Modulation by EA-230 of changes in urine output in mL

  15. Urinary laboratory parameters [ Time Frame: baseline pre-operative and post-operative until day +1 ]
    Changes in urea, sodium, creatinine and albumin in urine over time

  16. Renal replacement therapy (RRT) [ Time Frame: up to 90 days ]
    Need for and length of RRT

  17. AKI stages [ Time Frame: up to 90 days ]
    incidence of different stages of AKI according to the RIFLE criteria.

  18. Vasopressor use [ Time Frame: up to 7 days. Every 2 hours in the first 24-hours. Then once a day. ]
    Vasopressor use expressed as inotropic score ((dopamine dose × 1 µg/kg/min) + (dobutamine dose × 1 µg/kg/min) + (adrenaline dose × 100 µg/kg/min) + (noradrenaline dose × 100 µg/kg/min) + (phenylephrine dose × 100 µg/kg/min)) and ratio of inotropic score to the mean arterial pressure (MAP)

  19. Fluid Therapy [ Time Frame: First 24 post-operative hours, registered every 6 hours. ]
    Fluid therapy within the first 24 hours post-op. Expressed in total fluids administered, urine production and drain production.

  20. Fluid balance [ Time Frame: 7 days ]
    net fluid balance measured once a day (morning)

  21. Cardiac injury markers [ Time Frame: First 24 post-operative hours, twice. ]
    Change in plasma CK (Creatine kinase) and Troponin-t.

  22. Chest drain production [ Time Frame: During ICU admission, until removal of drains ]
    Chest drain production measured in mL

  23. Cardioplegia fluid [ Time Frame: up to 4 hours ]
    Cardioplegia fluid used during surgery: blood or crystalloid

  24. Time until detubation [ Time Frame: up to 90 days ]
    Time until post-operative detubation, measured in hours

  25. A-a O2 gradient [ Time Frame: First 24 post-operative hours, twice. ]
    Change in A-a O2 gradient.

  26. Pharmacokinetics (PK) of EA-230 (Cmax, t1/2, Clearance, volume of distribution) [ Time Frame: up to 6 hours: Sampling times in minutes after stop of CPB: t=0 (stop CPB), 1, 2, 5, 10, 20, 30, 60, 120, 240, 360. ]
    Complete PK-profile (Cmax, t1/2, Clearance, volume of distribution) of EA-230, only for a limited amount of patients (n=15)

  27. Peak plasma levels of EA-230 (Cmax) [ Time Frame: up to 4 hours. At start of CPB and at stop of CPB. ]
    Plasma peak levels of EA-230



Information from the National Library of Medicine

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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:

  1. Patients scheduled for elective on-pump CABG surgery.

    • Part 1: 60 patients undergoing CABG surgery, of which circa 40 low risk patients without valve replacement (range: 35-45)
    • Part 2: CABG surgery with or without valve replacement
  2. Written informed consent to participate in this trial prior to any study-mandated procedure.
  3. Patients aged >18, both male and female.
  4. Patients have to agree to use a reliable way of contraception with their partners from study entry until 3 months after study drug administration.

Exclusion Criteria:

  1. Immunocompromised

    • Solid organ transplantation
    • Known HIV
    • Pregnancy
    • Systemic use of immunosuppressive drugs
  2. Non-elective/Emergency surgery
  3. Hematological disorders

    • Known disorders from myeloid and/or lymphoid origin
    • Leucopenia (leucocyte count < 4x109/L)
  4. Known hypersensitivity to any excipients of the drug formulations used
  5. Treatment with investigational drugs or participation in any other intervention clinical trial within 30 days prior to study drug administration
  6. Inability to personally provide written informed consent (e.g. for linguistic or mental reasons)
  7. Known or suspected of not being able to comply with the trial protocol.

    In addition, for part 1 only (to select low-risk patients):

  8. Euroscore II <4
  9. Kidney function impairment: serum creatinine >200 µmol/L
  10. Liver function impairment: Alanine transaminase/Aspartate transaminase (ALAT/ASAT) >3 times above upper level of reference range
  11. Left ventricular dysfunction: Ejection fraction<35%
  12. CABG procedure with valve replacement

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): NCT03145220


Locations
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Netherlands
Intensive care, research unit, Radboud University Medical Centre
Nijmegen, Gelderland, Netherlands, 6525 GA
Sponsors and Collaborators
Radboud University
Exponential Biotherapies Inc.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Peter Pickkers, prof. dr., Radboud University
ClinicalTrials.gov Identifier: NCT03145220     History of Changes
Other Study ID Numbers: EASI-Study
2015-005600-28 ( EudraCT Number )
First Posted: May 9, 2017    Key Record Dates
Last Update Posted: June 26, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Peter Pickkers, Radboud University:
EA-230
Systemic Inflammatory Response Syndrome
Acute Kidney Injury
Interleukin-6
Safety
Tolerability
Phase II
Randomized clinical trial

Additional relevant MeSH terms:
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Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Shock