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

Systemic Inflammatory Response Syndrome Clinical Trial

— EASI  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03145220
• Other study ID #: EASI-Study
• Secondary ID: 2015-005600-28
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 2016
• Est. completion date: October 2018

Study information

• Verified date: June 2018
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 180
• Est. completion date: October 2018
• Est. primary completion date: October 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Coronary Artery Bypass Grafting
• Systemic Inflammatory Response Syndrome

Intervention

Drug:
• EA-230
Active intervention

Other:
• Placebo (NaCl)
Placebo intervention

Locations

Country	Name	City	State
Netherlands	Intensive care, research unit, Radboud University Medical Centre	Nijmegen	Gelderland

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University	Exponential Biotherapies Inc.

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Heart rate	Rate in beats per minute	First 24 post-operative hours, mean values per 30 minutes.
Other	Blood pressure	Pressure in mmHg	First 24 post-operative hours, mean values per 30 minutes.
Other	body temperature	Changes in body temperature in °C over time.	First 24 post-operative hours, measured with an interval of 2 hours.
Other	SOFA score (Sepsis-related Organ Failure Assessment score)	Change in SOFA score	First 24 post-operative hours, twice.
Other	Insulin sensitivity	According to insulin dosing and plasma glucose concentration	First 24 post-operative hours.
Other	length of stay on ICU (LOS ICU)	LOS ICU defined by total amount of days and hours patient is admitted to the intensive care	Up to 90 days.
Other	length of hospital stay (LOS)	LOS defined by total amount of days and hours patient is hospitalized.	Up to 90 days
Other	mortality	28 and 90-days mortality	at day 28 and day 90
Other	Major clinical adverse events	Incidence of major clinical adverse events within 90-days (stroke, MI, rethoracotomy, readmission, pleural and/or pericardial punction	up to 90 days
Other	APACHE IV	APACHE IV score at ICU admission	1 day
Other	Other GFR methods (ECC)	Calculated endogenous clearance of creatine (ECC)	ECC: Urine collection from start of surgery until the morning of the first post-operative day.
Other	Other GFR methods (MDRD)	Estimated GFR with plasma creatinine: MDRD.	Before surgery (baseline) and all other days creatine is measured during during hospital stay (max 7 days)
Other	Plasma kidney function markers	Plasma creatinine and proenkephalin	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
Other	Urine output	Modulation by EA-230 of changes in urine output in mL	1 day
Other	Urinary laboratory parameters	Changes in urea, sodium, creatinine and albumin in urine over time	baseline pre-operative and post-operative until day +1
Other	Renal replacement therapy (RRT)	Need for and length of RRT	up to 90 days
Other	AKI stages	incidence of different stages of AKI according to the RIFLE criteria.	up to 90 days
Other	Vasopressor use	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)	up to 7 days. Every 2 hours in the first 24-hours. Then once a day.
Other	Fluid Therapy	Fluid therapy within the first 24 hours post-op. Expressed in total fluids administered, urine production and drain production.	First 24 post-operative hours, registered every 6 hours.
Other	Fluid balance	net fluid balance measured once a day (morning)	7 days
Other	Cardiac injury markers	Change in plasma CK (Creatine kinase) and Troponin-t.	First 24 post-operative hours, twice.
Other	Chest drain production	Chest drain production measured in mL	During ICU admission, until removal of drains
Other	Cardioplegia fluid	Cardioplegia fluid used during surgery: blood or crystalloid	up to 4 hours
Other	Time until detubation	Time until post-operative detubation, measured in hours	up to 90 days
Other	A-a O2 gradient	Change in A-a O2 gradient.	First 24 post-operative hours, twice.
Other	Pharmacokinetics (PK) of EA-230 (Cmax, t1/2, Clearance, volume of distribution)	Complete PK-profile (Cmax, t1/2, Clearance, volume of distribution) of EA-230, only for a limited amount of patients (n=15)	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.
Other	Peak plasma levels of EA-230 (Cmax)	Plasma peak levels of EA-230	up to 4 hours. At start of CPB and at stop of CPB.
Primary	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
Primary	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	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
Secondary	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.
Secondary	Other cytokines/chemokines (TNFa, IL-8, IL-10, IL-1RA, MCP-1, MIP1a, MIP1ß, 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.
Secondary	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.