Primary objective: To determine if a single administration of SRT2379, at multiple dose levels, attenuates the inflammatory response in normal healthy male subjects after exposure to low-dose endotoxin (LPS)Secondary objectives: (1) To determine…
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Source
Brief title
Condition
- Other condition
- Ancillary infectious topics
Synonym
Health condition
Door endotoxine veroorzaakte inflammatie reactie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine if a single administration of SRT2379, at multiple dose levels,
attenuates the inflammatory response in normal healthy male subjects after
exposure to low-dose endotoxin (LPS)
Secondary outcome
(1) To determine pharmacokinetics (PK) of SRT2379 at multiple dose levels in
normal healthy male subjects exposed to low-dose endotoxin (LPS); (2) To
determine the safety profile of SRT2379 at multiple dose levels in healthy male
subjects exposed to low-dose endotoxin (LPS)
Background summary
Activation of SIRT1 (silent information regulator transcript) results in
inhibition of inflammation. SRT2379 is a potent small molecule activator of
SIRT1 that has been found to inhibit systemic inflammation induced by
intravenous injection of lipopolysaccharide (LPS) in mice. SRT2379 may be a
novel compound in the treatment of inflammatory disorders in man.
Study objective
Primary objective: To determine if a single administration of SRT2379, at
multiple dose levels, attenuates the inflammatory response in normal healthy
male subjects after exposure to low-dose endotoxin (LPS)
Secondary objectives: (1) To determine pharmacokinetics (PK) of SRT2379 at
multiple dose levels in normal healthy male subjects exposed to low-dose
endotoxin (LPS); (2) To determine the safety profile of SRT2379 at multiple
dose levels in healthy male subjects exposed to low-dose endotoxin (LPS)
Exploratory objectives: (1) To determine the slope of the exposure-response
relationship by assessing the effect of SRT2379 at multiple dose levels on the
inflammatory response following low-dose endotoxin (LPS) exposure in humans.
(2) To determine the effect of SRT2379 on other parameters following low-dose
endotoxin (LPS) exposure in humans (by measuring the following biomarkers
including, but not limited to, serum amyloid A, fibrinogen, and C-reactive
protein. (3) To determine the effect of low dose endotoxin (LPS) on white blood
cell sub-populations.
Study design
Single-blind, placebo-controlled intervention study
Intervention
This study consists of four treatment arms (N = 8 per arm). Subjects will be
randomized 1:1:1:1. Subjects in Arm 1 will receive a single dose of SRT2379 (50
mg), subjects in Arm 2 will receive a single dose of SRT2379 (250 mg), subjects
in Arm 3 will receive a single dose of SRT2379 (1000 mg), and subjects in Arm 4
will receive Placebo. Study Drug (SRT2379 or Placebo) administration will
occur only on Day 1. Subjects will take Study Drug approximately 15 minutes
following consumption of a standardized meal on Day 1. Subjects must wait at
least 1 hour after Study Drug administration before consuming additional
calories. On Day 1, all subjects will be given an intravenous dose of LPS
(standardized LPS preparation provided by the National Institutes of Health
(NIH), Bethesda, USA; (4 ng/kg body weight). LPS will be given 4 hours after
Study Drug administration.
Study burden and risks
The burden of this study involves a screening visit, two 2-nights admission to
the clinical research unit, the ingestion of SRT2379 and the intravenous
injection of LPS. Intravenous LPS induces a transient
influenza-like/inflammatory syndrome in humans consisting of chills, fever,
nausea, headache and muscle ache. SRT2379 has been well-tolerated at all dose
levels investigated. In the current study the potential anti-inflammatory
effects of SRT2379 will be tested in the human endotoxemia model. The risks are
low, whereas the study will generate information regarding the
anti-inflammatory activity of SRT2379. This knowledge may be of future benefit
to patients with inflammatory diseases.
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Age
Inclusion criteria
A subject will be eligible for inclusion in this study only if all of the following criteria apply: 1. Healthy, as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination and laboratory tests carried out within 21 days prior to day 1. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. 2. Male between 18 and 35 years of age inclusive, at the time of signing the informed consent 3. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form 4. Chemistry panel including renal and liver function tests without any clinically relevant abnormality as judged by the Investigator. 5. Subjects must agree to use double-barrier birth control or abstinence while participating in the study and for 7 days following the last dose of study drug
Exclusion criteria
1. Subject has had a major illness in the past three months or any significant chronic medial illness that the investigator would deem unfavourable for enrolment including inflammatory diseases 2. Subjects with a history of any type of malignancy with the exception of successfully treated basal cell cancer of the skin 3. Subject has a past or current gastro-intestinal disease which may influence drug absorption 4. The subject has a known positive test for hepatitis C antibody or hepatitis B surface antigen or human immunodeficiency virus (HIV) antibody 1 or 2. 5. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) 6. Subject has a history, within three years, of drug abuse (including benzodiazepines, opioids, amphetamine, cocaine, THC) or a positive drug results at the Screening visit 7. History of alcoholism and/or is drinking more than 3 drinks per day. Alcoholism is defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits 8. The subject has participated in a clinical trial and has received an investigational product within three months of the first dosing day in the current study 9. Use of prescription or non-prescription drugs, and herbal and dietary supplements within 7 days unless in the opinion of the Investigator and Medical Monitor the medication will not interfere with the study procedures or compromise subject safety 10. Subject has difficultly in donating blood or accessibility of a vein in left or right arm 11. Subject has donated more than 350 mL of blood in last 3 months 12. Subject uses tobacco products 13. Any clinically relevant abnormality noted on the 12-lead ECG as judged by the Investigator or an average QTcB or QTcF < 450 msec 14. Any other issue that, in the opinion of the Principal Investigator, would could be harmful to the subject or compromise interpretation of the data 15. Prior participation in a trial where the subject received intravenous endotoxin (LPS) infusion
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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In other registers
Register | ID |
---|---|
EudraCT | EUCTR2011-002266-20-NL |
CCMO | NL37063.018.11 |