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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Anemia of Chronic Disease

Intervention / Treatment
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* Drug: NOX-H94
* Drug: Placebo solution


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 |