A randomized double-blind, placebo-controlled clinical phase IIa trial on safety, immunomodulatory effects and pharmacokinetics of EA-230 during experimental human endotoxaemia

Roger van Groenendael, Matthijs Kox, Guus Leijte, Bouke Koeneman, Jelle Gerretsen, Lucas van Eijk, Peter Pickkers, Roger van Groenendael, Matthijs Kox, Guus Leijte, Bouke Koeneman, Jelle Gerretsen, Lucas van Eijk, Peter Pickkers

Abstract

Aims: EA-230 is a human chorionic gonadotropin hormone-derived linear tetrapeptide, developed for the treatment of systemic inflammation-related disorders. EA-230 has shown promising immunomodulatory and tissue-protective effects in animals and an excellent safety profile in human phase I studies that we performed. The present phase IIa study follows-up on these results by investigating the safety, efficacy and pharmacokinetics of EA-230 under systemic inflammatory conditions induced by experimental human endotoxaemia.

Methods: In this randomized, double blind, placebo-controlled phase IIa study, systemic inflammation was induced by intravenous administration of Escherichia coli-derived lipopolysaccharide (LPS). At t = 0 hours, 36 healthy male volunteers received 2 ng/kg LPS, followed by a 2-hour continuous infusion of EA-230 (15, 45 and 90 mg/kg/h, n = 8 per group) or placebo (n = 12).

Results: EA-230 was well tolerated and showed a favourable safety profile. Treatment with the highest dose of EA-230 resulted in a significant attenuation of the LPS-induced increase in plasma levels of inflammatory mediators interleukin (IL)-6, IL-8, IL-1 receptor antagonist, monocyte chemoattractant protein-1, macrophage inflammatory proteins-1α and -1β, and vascular cell adhesion protein-1 (% reduction of 48, 28, 33, 28, 14, 16 and 19 respectively, p < .01), and reduced fever (peak decrease from 1.8 ± 0.1°C to 1.3 ± 0.2°C, P < .05) and symptom scores (peak decrease from 7.4 ± 1.0 to 4.0 ± 1.2 points, P < .05). EA-230 exhibited a very short elimination half-life and a large volume of distribution in the highest dosage group (geometric mean and 95% confidence interval: 0.17 [0.12-0.24] hours and 2.2 [1.3-3.8] L/kg, respectively).

Conclusion: Administration of EA-230 is safe and results in attenuation of the systemic inflammatory response in humans.

Trial registration: ClinicalTrials.gov NCT02629874.

Keywords: cytokines; drug safety; immunotherapy; inflammation; pharmacokinetics.

Conflict of interest statement

P.P. received consulting fees and travel reimbursements from EBI. All other authors have no competing interests to declare.

All protocols, including amendments, were approved by the local ethics committee (CMO Arnhem‐Nijmegen, NL56102.091.15; 2015–2231). The study was conducted in accordance with the principles of the Declaration of Helsinki, and in compliance with the International Conference on Harmonisation E6 Guideline for Good Clinical Practice (CPMP/ICH/135/95). All healthy volunteers who participated in the study provided written informed consent before the start of any study‐related procedures.

© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1
Figure 1
Schematic overview of study procedures. Time points on the horizontal axes are in hours relative to LPS administration unless specified otherwise. ICU: intensive care unit; LPS: lipopolysaccharide; (S)AEs: (serious) adverse events; h: hours; d: days
Figure 2
Figure 2
Plasma levels of cytokines during endotoxaemia. A, Interleukin (IL)‐6, B, IL‐1 receptor antagonist (RA), C, tumour necrosis factor (TNF)‐α, D, IL‐10. Data are represented as means with standard error of the mean of n = 7 in the EA‐230 90 mg/kg/h group and n = 12 in the placebo group. Grey box indicates the period in which the active group received EA‐230. P‐values between groups were calculated using repeated measures 2‐way analysis of variance (ANOVA, interaction term)
Figure 3
Figure 3
Plasma levels of chemokines during endotoxaemia. A, Interleukin (IL)‐8, B, monocyte chemoattractant protein (MCP)‐1, C, macrophage inflammatory protein (MIP)‐1α D, MIP‐1β. Data are represented as means with standard error of the mean of n = 7 in the EA‐230 90 mg/kg/h group and n = 12 in the placebo group. Grey box indicates the period in which the active group received EA‐230. P‐values between groups were calculated using repeated measures 2‐way analysis of variance (ANOVA, interaction term)
Figure 4
Figure 4
Plasma levels of endothelial cell adhesion molecules during endotoxaemia. A, Vascular cell adhesion molecule (vCAM)‐1; B, intercellular adhesion molecule (iCAM)‐1. Data are represented as means with standard error of the mean of n = 7 in the EA‐230 90 mg/kg/h group and n = 12 in the placebo group. Grey box indicates the period in which the active group received EA‐230. P‐values between groups were calculated using repeated measures 2‐way analysis of variance (ANOVA, interaction term)
Figure 5
Figure 5
Circulating leucocyte numbers during endotoxaemia. A, Leucocytes, B, neutrophils, C, lymphocytes, D, monocytes. Data are represented as means with standard error of the mean of n = 7 in the EA‐230 90 mg/kg/h group and n = 12 in the placebo group. Grey box indicates the period in which the active group received EA‐230. P‐values between groups were calculated using repeated measures 2‐way analysis of variance (ANOVA, interaction term)
Figure 6
Figure 6
Clinical variables during endotoxaemia. A, Increase in body temperature B, symptom scores, C, mean arterial pressure, D, heart rate. Data are represented as means with standard error of the mean of n = 7 in the EA‐230 90 mg/kg/h group and n = 12 in the placebo group. Grey box indicates the period in which the active group received EA‐230. P‐values between groups were calculated using repeated measures 2‐way analysis of variance (ANOVA, interaction term). AU: arbitrary unit; Bpm: beats/min
Figure 7
Figure 7
Pharmacokinetics of EA‐230. A, Plasma concentration‐time profiles of EA‐230. The grey area indicates the study drug administration period. B, C, Dose proportionality of dose‐normalized, log‐transformed exposure parameters Cmax (B), and AUC0‐last (C). Linear regression lines are shown, dotted lines indicate the 95% confidence interval, a P‐value of <.05 would have indicated nonproportionality. Data are expressed as geometric means and 95% confidence interval

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