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

Sponsor

Radboud University Medical Center (Other)

Overall Status

Unknown status

CT.gov ID

NCT03145220

Collaborator

Exponential Biotherapies Inc. (Industry)

180

Enrollment

Location

Arms

Duration (Months)

6.4

Patients Per Site Per Month

Study Details

Study Description

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

Detailed Description

Systemic inflammation is a condition in which the innate immune system is activated due to a variety of causes such as sepsis, trauma, and major surgical interventions. The clinical condition in which the body responds to such stimuli by the release of circulating inflammatory mediators is well known as the systemic inflammatory response syndrome (SIRS) and is defined by tachypnoea, tachycardia, leucocytosis or leucopenia and hyper- or hypothermia.

Although this activation of the immune system is essential for survival, the often subsequent overwhelming pro-inflammatory response may be detrimental. Of the many downstream consequences of this exaggerated inflammatory response, organ injury and failure is the most serious, most often involving the kidneys. Multiple organ failure (MOF) is associated with high morbidity and mortality, whereas failure of kidneys is an independent prognostic factor for mortality in critically ill patients.

This exaggerated systemic pro-inflammation also occurs during major surgical procedures, especially in cardiac surgery procedures. Multiple stimuli during these procedures, such as sternotomy, extra-corporal cardio-pulmonary bypass (ECC) and aortal cross-clamping, account for substantial systemic inflammatory activation. The extent of inflammation following this procedures is directly associated with patient outcome, as high post-operative levels of IL-6 have been proven to correlate with adverse outcome and mortality. Also at organ level, the incidence of inflammation associated development of acute kidney injury (AKI) following cardiac surgery is high and correlates with adverse outcome and mortality.

To date, no immunomodulatory treatments, aimed at dampening the (acute) systemic inflammatory reaction following cardiac surgery with cardio-pulmonary bypass, have shown to improve essential outcome. Current strategies consist of prevention and supportive treatment; new strategies aiming at attenuating this exaggerated pro-inflammatory response are therefore warranted.

EA-230 is a novel pharmacological compound, developed for the treatment of systemic inflammation and associated organ dysfunction. It is a linear tetrapeptide derived from the human chorionic gonadotropin hormone (hCG). It has shown anti-inflammatory properties and protects against organ failure and associated mortality in several pre-clinical models of sepsis or systemic inflammation. As EA-230 attenuates the pro-inflammatory response in neutrophils and monocytes ex vivo, and neutrophil influx in tissues during systemic inflammation in vivo is abrogated, it is thought that EA-230 acts by protecting the host against the detrimental effects of neutrophils during acute systemic inflammatory diseases, thereby preventing organ damage.

A recently performed phase I study into the safety and tolerability of EA-230 in 24 subjects showed that continuous administration of EA-230 up to 90 mg/kg/hour infused intravenously is well tolerated and has an excellent safety profile. This profile was confirmed in a consequent executed phase IIa study in which 36 healthy subjects received the same dosages of EA-230 during human experimental endotoxemia. In this human model of controlled systemic inflammation elicited by the administration of a low dose of endotoxin, the anti-inflammatory effects of EA-230 shown in pre-clinical studies were confirmed and the optimal dose was established. Subjects treated with the highest dose (90 mg/kg/hour) showed less flu-like symptoms, development of fever was suppressed, and reduced levels of pro-inflammatory mediators (among others Interleukin-6 and Interleukin-8) were observed compared to placebo-treated subjects.

This current study is a combined phase IIa/IIb, randomized, placebo-controlled, double-blind, clinical trial. In the first part, phase IIa, the study aims to confirm safety and tolerability in a patient population (n=60, 30 active and 30 placebo) with systemic inflammation elicited by on-pump cardiac surgery. In the second part, phase IIb, the immunomodulatory effect of EA-230 is studied in a same patient population (n=180, 90 active and 90 placebo, including patients from part 1).

After inclusion of 90 patients, halfway the study, an additional adaptive power analysis will be performed to re-evaluate group size and power. Efficacy and sample size re-determination will be performed by the statistician of the Data Safety Management Board (DSMB).

Study Design

Study Type:

Interventional

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 :

Jun 1, 2016

Anticipated Primary Completion Date :

Oct 1, 2018

Anticipated Study Completion Date :

Oct 1, 2018

Arms and Interventions

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 Names: 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 Names: NaCl

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 Names:

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 Names:

NaCl

Outcome Measures

Primary Outcome Measures

Safety and tolerability (treatment related (serious) adverse events) [Total (serious) adverse events related to treatment at day 90 after treatment]
Safety and tolerability expressed in treatment related (serious) adverse events
Interleukin-6 (IL-6) [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

Glomerular filtration rate (GFR) [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.
Urine kidney injury markers (KIM-1, NGAL, L-FABP, TIMP-2*IGFBP-7, urinary IL-18, NAG, creatine, urea, albumin) [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
Other cytokines/chemokines (TNFα, IL-8, IL-10, IL-1RA, MCP-1, MIP1α, MIP1β, VCAM, ICAM, IL-17A) [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.
Leukocyte counts (differentiated) [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

Heart rate [First 24 post-operative hours, mean values per 30 minutes.]
Rate in beats per minute
Blood pressure [First 24 post-operative hours, mean values per 30 minutes.]
Pressure in mmHg
body temperature [First 24 post-operative hours, measured with an interval of 2 hours.]
Changes in body temperature in °C over time.
SOFA score (Sepsis-related Organ Failure Assessment score) [First 24 post-operative hours, twice.]
Change in SOFA score
Insulin sensitivity [First 24 post-operative hours.]
According to insulin dosing and plasma glucose concentration
length of stay on ICU (LOS ICU) [Up to 90 days.]
LOS ICU defined by total amount of days and hours patient is admitted to the intensive care
length of hospital stay (LOS) [Up to 90 days]
LOS defined by total amount of days and hours patient is hospitalized.
mortality [at day 28 and day 90]
28 and 90-days mortality
Major clinical adverse events [up to 90 days]
Incidence of major clinical adverse events within 90-days (stroke, MI, rethoracotomy, readmission, pleural and/or pericardial punction
APACHE IV [1 day]
APACHE IV score at ICU admission
Other GFR methods (ECC) [ECC: Urine collection from start of surgery until the morning of the first post-operative day.]
Calculated endogenous clearance of creatine (ECC)
Other GFR methods (MDRD) [Before surgery (baseline) and all other days creatine is measured during during hospital stay (max 7 days)]
Estimated GFR with plasma creatinine: MDRD.
Plasma kidney function markers [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
Urine output [1 day]
Modulation by EA-230 of changes in urine output in mL
Urinary laboratory parameters [baseline pre-operative and post-operative until day +1]
Changes in urea, sodium, creatinine and albumin in urine over time
Renal replacement therapy (RRT) [up to 90 days]
Need for and length of RRT
AKI stages [up to 90 days]
incidence of different stages of AKI according to the RIFLE criteria.
Vasopressor use [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)
Fluid Therapy [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.
Fluid balance [7 days]
net fluid balance measured once a day (morning)
Cardiac injury markers [First 24 post-operative hours, twice.]
Change in plasma CK (Creatine kinase) and Troponin-t.
Chest drain production [During ICU admission, until removal of drains]
Chest drain production measured in mL
Cardioplegia fluid [up to 4 hours]
Cardioplegia fluid used during surgery: blood or crystalloid
Time until detubation [up to 90 days]
Time until post-operative detubation, measured in hours
A-a O2 gradient [First 24 post-operative hours, twice.]
Change in A-a O2 gradient.
Pharmacokinetics (PK) of EA-230 (Cmax, t1/2, Clearance, volume of distribution) [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)
Peak plasma levels of EA-230 (Cmax) [up to 4 hours. At start of CPB and at stop of CPB.]
Plasma peak levels of EA-230

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Written informed consent to participate in this trial prior to any study-mandated procedure.
Patients aged >18, both male and female.
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:

Immunocompromised

Solid organ transplantation
Known HIV
Pregnancy
Systemic use of immunosuppressive drugs

Non-elective/Emergency surgery
Hematological disorders

Known disorders from myeloid and/or lymphoid origin
Leucopenia (leucocyte count < 4x109/L)

Known hypersensitivity to any excipients of the drug formulations used
Treatment with investigational drugs or participation in any other intervention clinical trial within 30 days prior to study drug administration
Inability to personally provide written informed consent (e.g. for linguistic or mental reasons)
Known or suspected of not being able to comply with the trial protocol.

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

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