Primary Objective•To assess the pharmacodynamic response after single dose administration of NOX H94 in healthy subjects during experimental endotoxemia.Secondary Objective• To determine the pharmacodynamic effects of NOX H94 after single dose…
ID
Source
Brief title
Condition
- Anaemias nonhaemolytic and marrow depression
- Autoimmune disorders
- Ancillary infectious topics
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint
• Change in serum iron concentration at 9 hours after LPS administration versus
baseline; comparison of subjects treated with NOX H94 versus placebo.
Secondary outcome
Secondary endpoints
• Change in serum iron concentrations at 6 and 12 hours after LPS
administration versus baseline
• Concentrations of serum iron and of markers of iron homeostasis up to 48 h
after LPS injection: serum iron, transferrin saturation (TSAT), ferritin,
reticulocyte hemoglobin content (CHR), hemoglobin (Hb), mean cell volume (MCV),
mean cell hemoglobin (MCH): AUC of serum iron concentrations, ANOVA of repeat
measures of all data points
• Concentration of hepcidin up to 1 week after LPS injection
• Concentrations of pro-inflammatory and anti-inflammatory cytokines up to 48 h
after LPS injection: TNF α, IL 6, IL 1RA, IL 10 to document the inflammatory
reaction
• Pharmacokinetic profile of NOX H94
• Safety and tolerability
Background summary
The purpose of this study is to assess the effect of the hepcidin specific
antagonist NOX-H94 on the innate immune response and the subsequent changes in
hepcidin and iron hemostasis during systemic inflammation induced by
experimental human endotoxemia.
In the human endotoxemia model, intravenously administered lipopolysaccharide
(LPS) elicits an inflammatory response with release of pro-inflammatory
cytokines, such as IL06 and TNF-alfa, with subsequent induction of hepcidin.
As a consequence of hepcidin induction, serum iron concentrations decrease.
Thus, LPS induced human endotoxemia represents a model for a pathophysiological
process underlying anemia of inflammation which is characterized by high
circulating hepcidin concentrations leading to iron restriction and ineffective
erythropoiesis.
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 with a
background of malignancy, inflammation, or chronic kidney disease.
Study objective
Primary Objective
•To assess the pharmacodynamic response after single dose administration of NOX
H94 in healthy subjects during experimental endotoxemia.
Secondary Objective
• To determine the pharmacodynamic effects of NOX H94 after single dose
administration in healthy subjects during experimental endotoxemia in relation
to its pharmacokinetics.
• To assess the effect of a single dose administration of NOX H94 on the innate
immune response during experimental endotoxemia.
• To determine the safety of NOX H94 after single dose administration in
healthy subjects during experimental endotoxemia.
Study design
Randomized double blind placebo controlled intervention study in healthy human
volunteers during experimental endotoxemia.
Intervention
The volunteers will be randomized to 2 intervention groups.
Group 1. NOX-H94 (N=12):
T= 0: 2ng/kg LPS i.v.
T=0.5 hrs: NOX-H94 1.2 mg/kg i.v.
Group 2. Placebo (N=12):
T= 0: 2ng/kg LPS i.v.
T= 0.5 hrs: Placebo i.v.
Before any intervention pre-hydration will be performed by infusion of 1.5 L
2.5% glucose/0.45% saline solution in approximately 45 minutes, to ensure
optimal hydration status. Thereafter LPS derived from E coli O:113 will be
injected (2 ng/kg iv., infusion rate: 1 minute). At 30 minutes after LPS
infusion NOX-H94 is administered intravenously.
Study burden and risks
• Endotoxin infusion is accompanied by flu-like symptoms such as temperature
increase (possibly chills), headache, muscleache, backache, loss of appetite
and sometimes nausea. Endotoxin can increase also the heart rate and slightly
lower the blood pressure. These symptoms normalise within hours.
• NOX-H94 was accompanied by mild side effects in a previous trial, like
headache and tiredness. When higher dosages (i.e. 2 and 4 times higher than
used in the present study) of the Study drug were administered a temporary mild
elevation of liver enzymes was seen. This was only a very mild rise that was
completely reversible.
• A catheter is inserted in the artery of the wrist for blood sampling and
monitoring. This induces a small chance of a hematoma.
• The amount of blood taken during the study is up to 450 ml per experiment.
• There are no data available yet about the effect of NOX H94 on sperm or its
production in the body or about effects on the development of the foetus.
Therefore the subjects have to agree to use an effective contraceptive measure
for 2 months after study drug administration.
The subjects will not benefit directly from participation in the study. A
subject fee is to be provided.
Max-Dohrn-Strasse 8-10
10589 Berlijn
DE
Max-Dohrn-Strasse 8-10
10589 Berlijn
DE
Listed location countries
Age
Inclusion criteria
1. Written informed consent to participate in this trial
2. Male subjects aged 18 to 35 years inclusive
3. Subjects and their female partners have to agree to use a reliable way of contraception from screening until 2 months after study drug administration.
4. BMI between 18 and 30 kg/m², with a lower limit of body weight of 50 kg
5. Healthy as determined by medical history, physical examination, vital signs, 12 lead electrocardiogram, and clinical laboratory parameters
6. Serum iron and red blood parameters Hb, MCV, ferritin, serum iron, and total iron binding capacity within reference range
Exclusion criteria
1. Use of any medication, recreational drugs or anti-oxidant vitamin supplements within 7 days prior to profiling day
2. Use of caffeine, nicotine, or alcohol or within 1 day prior to profiling day
3. Previous participation in a trial where LPS was administered
4. Surgery or trauma with significant blood loss or blood donation within 3 months prior to profiling day
5. History, signs or symptoms of cardiovascular disease, in particular
• History of frequent vaso-vagal collapse or of orthostatic hypotension
• Resting pulse rate <=45 or >=100 beats / min
• Hypertension (RR systolic >160 or RR diastolic >90)
• Hypotension (RR systolic <100 or RR diastolic <50)
• conduction abnormalities on the ECG consisting of a 1st degree atrioventricular block or a complex bundle branch block
6. Renal impairment: plasma creatinine >120 µmol/L
7. Liver function tests (alkaline phosphatase, AST, ALT and γ-GT) outside of the reference range or total bilirubin >20 µmol/L
8. Hemoglobin or iron parameters (iron, transferrin saturation, ferritin) outside of the reference ranges
9. History of asthma
10. Immuno-deficiency
11. Positive test of HIV type 1/2 antibodies, HBs antigen, HBc antibodies and HCV antibodies unless antibody titer is induced by vaccination
12. CRP > reference range or clinically significant acute illness, including infections, within 2 weeks before profiling day of study drug.
13. Treatment with investigational drugs or participation in any other clinical trial within 30 days prior to study drug administration
14. Known or suspected of not being able to comply with the trial protocol.
15. Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-005022-22-NL |
| ClinicalTrials.gov | NCTnummervolgt |
| CCMO | NL38191.091.11 |