Pharmacokinetics/Pharmacodynamics of NOX-H94 in the Human Endotoxemia Model

Randomized Double Blind Placebo Controlled PK/PD Study on the Effects of a Single Intravenous Dose of NOX-H94 on Serum Iron During Experimental Human Endotoxemia

The purpose of this study is to assess the effect of the anti-hepcidin Spiegelmer NOX-H94 on iron homeostasis during systemic inflammation induced by endotoxin.

In the human endotoxemia model, intravenously administered lipopolysaccharide elicits an inflammatory response with release of pro-inflammatory cytokines, such as IL-6 and TNF-alfa, with subsequent induction of hepcidin. As a consequence of hepcidin induction, serum iron concentrations decrease.

This study in healthy subjects investigates the capacity of NOX-H94 to inactivate hepcidin and to prevent serum iron decrease in a pathophysiological model prior to studying the efficacy of NOX-H94 in patients with anemia of chronic disease.

Study Overview

• Status: Completed
• Conditions: Anemia of Chronic Disease
• Intervention / Treatment: Drug: NOX-H94; Drug: Placebo solution

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6500 HB
    • Radboud University Nijmegen Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 31 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Main Inclusion Criteria:

• BMI between 18 and 30 kg/m², with a lower limit of body weight of 50 kg
• Healthy as determined by medical history, physical examination, vital signs, 12 lead electrocardiogram, and clinical laboratory parameters
• Serum iron and red blood parameters Hb, MCV, ferritin, serum iron, and total iron binding capacity within reference range

Main Exclusion Criteria:

• Use of any medication, recreational drugs or anti-oxidant vitamin supplements within 7 days
• Use of caffeine, nicotine, or alcohol within 1 day
• Previous participation in a trial where LPS was administered
• Surgery or trauma with significant blood loss or blood donation within 3 months
• History, signs or symptoms of cardiovascular disease (vaso-vagal collapse or of orthostatic hypotension, Resting pulse rate ≤45 or ≥100/min, Hypertension, Hypotension, ECG conduction abnormalities)
• Renal impairment: plasma creatinine >120 µmol/L
• Liver function tests (alkaline phosphatase, AST, ALT and γ-GT) outside of the reference range or total bilirubin >20 µmol/L
• Hemoglobin or iron parameters (iron, transferring saturation, ferritin) outside of the reference ranges
• History of asthma
• Immuno-deficiency
• Positive test of HIV type 1/2 antibodies, HBs antigen, HBc antibodies and HCV antibodies unless antibody titer is induced by vaccination
• CRP > reference range or clinically significant acute illness, including infections, within 2 weeks
• Treatment with investigational drugs or participation in any other clinical trial within 30 days prior to study drug administration
• Known or suspected of not being able to comply with the trial protocol
• Inability to personally provide written informed consent and/or take part in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NOX-H94; Single dose of NOX-H94	Drug: NOX-H94; single i.v. infusion; Other Names: lexaptepid pegol
Placebo Comparator: Placebo; Single dose of placebo control	Drug: Placebo solution; single i.v. infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
serum iron	Change versus baseline; comparison of subjects treated with NOX-H94 versus placebo	9 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamics: Effects of NOX-H94 on Iron homeostasis	Change from baseline and group comparison (NOX-H94 vs. placebo) of: serum iron, transferrin saturation, ferritin	up to 2 Weeks
Pharmacokinetic profile of NOX-H94	plasma concentration-time profile T0 to 2 weeks	12 time points over 2 Weeks
Safety and tolerability	Safety and tolerability parameters will be evaluated along the entire study duration consisting of spontaneously reported adverse events, physical examination and vital signs, hematology and clinical chemistry laboratory examinations.	up to 2 Weeks
Effects of NOX-H94 on innate immune response	To assess the effect of a single dose administration of NOX H94 on the innate immune response during experimental endotoxemia: TNF-α, IL-6, IL-1RA, IL-10	up to 2 weeks
Pharmacokinetics: Cmax of NOX-H94		Day 1
Pharmacokinetics: AUC of NOX-H94		0-2 weeks
Pharmacokinetics: Clearance of NOX-H94		0-2 weeks
Pharmacodynamics: effect of NOX-H94 on Red blood cell parameters	Change versus baseline and group comparison: reticulocyte hemoglobin content, hemoglobin, mean cell volume, mean cell hemoglobin	0- 2 weeks

Collaborators and Investigators

• Sponsor: TME Pharma AG
• Investigators: Principal Investigator: Peter Pickkers, MD, PhD, Radboud University Medical Center

Publications and helpful links

General Publications

• van Eijk LT, John AS, Schwoebel F, Summo L, Vauleon S, Zollner S, Laarakkers CM, Kox M, van der Hoeven JG, Swinkels DW, Riecke K, Pickkers P. Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans. Blood. 2014 Oct 23;124(17):2643-6. doi: 10.1182/blood-2014-03-559484. Epub 2014 Aug 27.

Helpful Links

• Result summary: Abstract 3452, ASH 2012
• Publication of clinical trial (open access)

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): April 1, 2012

Study Registration Dates

• First Submitted: January 18, 2012
• First Submitted That Met QC Criteria: January 27, 2012
• First Posted (Estimate): February 1, 2012

Study Record Updates

• Last Update Posted (Estimate): November 10, 2014
• Last Update Submitted That Met QC Criteria: November 7, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Sepsis; Bacteremia; Toxemia; Chronic Disease; Endotoxemia
• Other Study ID Numbers: SNOXH94C101; 2011-005022-22 (EudraCT Number)