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

Study Overview
=================
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.

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).

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

Conditions
-----------------
Systemic Inflammatory Response Syndrome, Coronary Artery Bypass Grafting

Intervention / Treatment
-----------------
* Drug: EA-230
* Other: Placebo (NaCl)


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: EA-230<br>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<br>* Active intervention<br>* Other names: AQGV;|
| Placebo Comparator: Placebo<br>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)<br>* Placebo intervention<br>* Other names: NaCl;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability (treatment related (serious) adverse events) | Safety and tolerability expressed in treatment related (serious) adverse events | Total (serious) adverse events related to treatment at day 90 after treatment | 
| Interleukin-6 (IL-6) | Blood plasma levels 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glomerular filtration rate (GFR) | GFR assessed by plasma clearance of Iohexol. | Up to 3 days. At the day before surgery (baseline) and at the morning of the first post-operative day | 
| Urine kidney injury markers (KIM-1, NGAL, L-FABP, TIMP-2*IGFBP-7, urinary IL-18, NAG, creatine, urea, albumin) | laboratory values | 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. | 
| Other cytokines/chemokines (TNFα, IL-8, IL-10, IL-1RA, MCP-1, MIP1α, MIP1β, VCAM, ICAM, IL-17A) | Laboratory values. | 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. | 
| Leukocyte counts (differentiated) | Plasma leukocyte response, quantified by change of total cell counts, differentiated in lymphocytes, neutrophils, monocytes, basophils and eosinophils. | 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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
EA-230, Systemic Inflammatory Response Syndrome, Acute Kidney Injury, Interleukin-6, Safety, Tolerability, Phase II, Randomized clinical trial