The Safety, Tolerability, and Effects on the Systemic Inflammatory Response and Renal Function of the Human Chorionic Gonadotropin Hormone-Derivative EA-230 Following On-Pump Cardiac Surgery (The EASI Study): Protocol for a Randomized, Double-Blind, Placebo-Controlled Phase 2 Study

Roger van Groenendael, Remi Beunders, Jan Hofland, Wim J Morshuis, Matthijs Kox, Lucas T van Eijk, Peter Pickkers, Roger van Groenendael, Remi Beunders, Jan Hofland, Wim J Morshuis, Matthijs Kox, Lucas T van Eijk, Peter Pickkers

Abstract

Background: The cardiac surgery-induced systemic inflammatory response may induce postoperative hemodynamic instability and impairment of renal function. EA-230, a linear tetrapeptide (A-Q-G-V), is derived from the beta chain of the human chorionic gonadotropin pregnancy hormone. It has shown immunomodulatory and renoprotective effects in several animal models of systemic inflammation. In phase 1 and phase 2a studies, these immunomodulatory effects were confirmed during human experimental endotoxemia, and EA-230 was found to have an excellent safety profile.

Objective: The objective of this first in-patient study is to test the safety and tolerability as well as the immunomodulatory and renoprotective effects of EA-230 in a proof-of-principle design in patients with systemic inflammation following on-pump cardiac surgery.

Methods: We describe a prospective, randomized, double-blind, placebo-controlled study in which 180 elective patients undergoing on-pump coronary artery bypass grafting, with or without concomitant valve surgery, are enrolled. Patients will be randomized in a 1:1 ratio and will receive either EA-230 (90 mg/kg/hour) or a placebo. These will be infused at the start of the surgical procedure until the end of the use of the cardiopulmonary bypass. The primary focus of this first-in-patient study will be on safety and tolerability of EA-230. The primary efficacy end point is the modulation of the inflammatory response by EA-230 quantified as the change in interleukin-6 plasma concentrations after surgery. The key secondary end point is the effect of EA-230 on renal function. The study will be conducted in 2 parts to enable an interim safety analysis by an independent data monitoring committee at a sample size of 60. An adaptive design is used to reassess statistical power halfway through the study.

Results: This study has been approved by the independent competent authority and ethics committee and will be conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, and European Directive 2001/20/CE regarding the conduct of clinical trials. Results of this study will be submitted for publication in a peer-reviewed scientific journal. Enrollment of this study commenced in July 2016, and results are expected at the end of 2018.

Conclusions: This adaptive phase 2 clinical study is designed to test the safety and tolerability of EA-230 in patients undergoing cardiac surgery. In addition, efficacy end points focused on the effect of the systemic inflammatory response and renal function are investigated.

Trial registration: ClinicalTrials.gov NCT03145220; https://ichgcp.net/clinical-trials-registry/NCT03145220 (Archived by WebCite at http://www.webcitation.org/74JPh8GNN).

International registered report identifier (irrid): DERR1-10.2196/11441.

Keywords: EA-230; cardiac surgery; clinical trials, phase II as topic; immunomodulation; inflammation; kidney/therapy; pregnancy; safety.

Conflict of interest statement

Conflicts of Interest: PP received travel reimbursements and consultancy fees from Exponential Biotherapies Inc. All other authors have no conflicts of interest to declare.

©Roger van Groenendael, Remi Beunders, Jan Hofland, Wim J Morshuis, Matthijs Kox, Lucas T van Eijk, Peter Pickkers. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 06.02.2019.

Figures

Figure 1
Figure 1
Study flowchart. Overview of patient recruitment, randomization, and population analysis procedures from screening to follow-up. CABG: coronary artery bypass grafting.
Figure 2
Figure 2
Timeline of study procedures. CPB: cardiopulmonary bypass; ICU: intensive care unit; iGFR: glomerular filtration rate measured by plasma clearance of iohexol; OR: Operating Room.

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