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van CCT (UK)

van CCT (UK)

Het effect van antibiotica en de darmflora op afweerreacties

- candidate number17615
- NTR NumberNTR4549
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR30-apr-2014
- Secondary IDsNL45198.018.13 CCMO
- Public TitleHet effect van antibiotica en de darmflora op afweerreacties
- Scientific TitleThe role of the gut microbiota in the systemic immune response during human endotoxemia
- hypothesisBroad-spectrum antibiotics, which many patients with infectious diseases receive, deplete the gut microbiota. Several studies suggest that the gut microbiota may have a "priming" effect on the innate immune system. Broad- spectrum antibiotics would thus lead to a decreased innate immune response in disease states such as sepsis or endotoxemia.
- Healt Condition(s) or Problem(s) studiedAntibiotics, Gut microbiota, Immune system
- Inclusion criteria1. Healthy, as determined by a responsible physician, based on a medical evaluation including medical history, physical examination and laboratory tests
2. Male between 18 and 35 years of age
3. Capable of giving written informed consent
4. Chemistry panel, including renal and liver function tests, without any clinically relevant abnormality as judged by the investigator
5. Normal defecation pattern
- Exclusion criteria1. Subject has had a major illness in the past 3 months or any significant chronic medical illness
2. Subjects with a history of any type of malignancy
3. Subject has a past or current gastrointestinal disease
4. The subject has a known positive test for hepatitis C antibody, hepatitis B surface antigen or human immunodeficiency virus (HIV) antibody 1 or 2
5. Current or chronic history of liver disease
6. Subject uses tobacco products
7. Subject has a history, within 3 years, of drug abuse
8. History of alcoholism
9. Any clinically relevant abnormality noted on the 12-lead ECG as judged by the investigator or an average QTc > 450 msec
10. The subject has received an investigational product within three months
11. Use of prescription or non-prescription drugs and herbal and dietary supplements
12. Recent (< 12 months) use of antibiotics
13. Known allergy to antibiotics (any kind)
14. Subject has difficultly in donating blood or accessibility of a vein in left or right arm.
15. Subject has donated more than 350 mL of blood in last 3 months
16. Difficulty swallowing pills
17. Body mass index >28 kg/m2
- mec approval receivedyes
- multicenter trialno
- randomisedyes
- masking/blindingNone
- controlNot applicable
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-jun-2014
- planned closingdate1-jun-2016
- Target number of participants16
- InterventionsThe control group receives no antibiotics The antibiotics group receives ciprofloxacin 500mg 2dd1, vancomycin 250mg 3dd2 and metronidazole 500mg 3dd1; all during 7 days

Both groups receive (on day 9) LPS (endotoxin) 2 ng/kg intravenously
- Primary outcomeCytokine production in blood
- Secondary outcomeActivation of coagulation
Composition of gut microbiota
- TimepointsDay 0
Day 9: t = 0 and at 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hours after LPS injection
- Trial web site
- statusplanned
- Sponsor/Initiator Academic Medical Center (AMC), Amsterdam
- Funding
(Source(s) of Monetary or Material Support)
ZON-MW, The Netherlands Organization for Health Research and Development
- Publications
- Brief summaryRationale: Sepsis ranks among the top ten leading causes of death worldwide. Most nonsurvivors die in a state of immunosuppression. The gut microbiota exerts numerous beneficial functions in the host response against infections. Gut flora components express microorganism-associated molecular patterns (MAMPs) such as lipopolysaccharide (LPS), which are recognized by pattern recognition receptors (PRRs) expressed by neutrophils and macrophages. MAMPs from the intestinal microbiota constitutively translocate to the circulation and prime bone marrow derived neutrophils via PRRs. Antibiotic treatment, which is standard of care for all patients with sepsis, depletes the gut microbiota and leads to a diminished release of MAMPs and other bacteria derived products. This causes diminished priming of systemic immunity, which may attribute to sepsis associated immunosuppression and an increased susceptibility to invading bacteria.

Objective: To investigate the role of the gut microbiota in the systemic priming of immune effector cells during human endotoxemia

Study design: Randomized, between- and within-subject-controlled intervention study in human volunteers

Study population: Sixteen healthy male subjects, 18-35 years of age

Intervention: All subjects will receive lipopolysaccharide (endotoxin; 2 ng/kg bodyweight) intravenously to induce experimental endotoxemia. Eight subjects will be pretreated with broad spectrum antibiotics (ciprofloxacin, vancomycin, metronidazole) for seven days (washout period of 36 hours before endotoxemia), in order to deplete the gut microbiota. Blood and faeces will be sampled before, during and after endotoxemia.

Main study parameters/endpoints: Laboratory parameters for inflammatory responses, functional assays and gut microbiota composition.
- Main changes (audit trail)
- RECORD30-apr-2014 - 26-mei-2014

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