Anti-inflammatory Effects of GTS-21 After LPS

This study has been completed.
Sponsor:
Collaborator:
CoMentis, 280 Utah Avenue, Suite 275, South San Francisco, CA 94080
Information provided by:
Radboud University
ClinicalTrials.gov Identifier:
NCT00783068
First received: October 30, 2008
Last updated: November 4, 2010
Last verified: October 2008
  Purpose

Rationale: The vagus nerve exerts an anti-inflammatory effect in in vitro and animal experiments. This 'vagal anti-inflammatory pathway' is mediated by the nicotinergic α7nACh receptor that can be selectively stimulated by GTS-21. Activation of the cholinergic anti-inflammatory pathway via vagus nerve stimulation or α7nAChR agonists improves outcome in animal models of endotoxemia, sepsis and experimental arthritis. Up to now, the anti-inflammatory effects of oral administration of GTS-21 in humans in vivo has not been investigated.

Objective: Primary aim: to investigate the anti-inflammatory effects of oral administration of GTS-21 on the inflammatory response in the human endotoxemia model and the subsequent inflammation-induced subclinical organ dysfunction. Secondary aim: to measure the effect of LPS administration in the absence or presence of GTS-21 in human volunteers on vagal nerve activity measured by heart rate variability analysis.

Study design: Double-blind placebo-controlled randomized cross-over intervention study in healthy human volunteers during experimental endotoxemia.

Study population: Non-smoking healthy male volunteers, age 18-35 yrs Intervention: Subjects will be tested in a cross-over design in 2 separate sequential sessions, 2-4 weeks apart. A total of 12 subjects will be randomly assigned to one of two dosing groups in a 1:1 ratio: GTS-21 followed by Placebo n=6, Placebo followed by GTS-21 n=6. Subjects will receive 150mg GTS-21 or placebo orally tid 3 days before LPS injection and an oral dose of 150 mg GTS-21 or placebo the morning of the day of LPS administration (07:00 AM). Subjects will then receive an oral dose of 150 mg GTS-21 or placebo at 08:00 AM and another oral dose of 150 mg GTS-21 or placebo at 1 hour before LPS administration (t=0). Before LPS injection, prehydration will be performed by infusion of 1.5 L 2.5% glucose/0.45% saline solution in 1 hour. One hour after the last dose of GTS-21 or placebo, LPS derived from E coli O:113 will be injected (2 ng/kg iv in 1 minute). There will be a 14 day washout period for patients in all groups. The last group of subjects will be subjected to an identical dose of LPS and placebo at two different moments 2-4 weeks apart to obtain time controls.

Main study parameters/endpoints: Main study endpoint is the concentration of circulating cytokines after LPS in the absence and presence of GTS-21.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: A medical interview and physical examination is part of this study. Approximately 350 ml blood will be withdrawn and urine will be collected. There will be mild discomfort associated with participation in this study, as LPS induces flu-like symptoms for approximately 4 hrs. GTS-21 was found to be well tolerated at a dose of 150 mg three times daily (450 mg/day).


Condition Intervention
Endotoxemia
Sepsis
Vagal Activity
Drug: GTS-21, [3-(2,4-dimethoxybenzylidene)-anabaseine dihydrochloride]
Drug: Placebo
Drug: Lipopolysaccharide E. Coli 113:H 10:K negative

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: The Effect of the Alpha-7 Nicotinic AChR Agonist GTS-21 on Inflammation and End-organ Dysfunction During Human Endotoxemia

Resource links provided by NLM:


Further study details as provided by Radboud University:

Primary Outcome Measures:
  • To investigate the putative anti-inflammatory effects of oral administration of GTS-21 on the inflammatory response and subsequent subclinical organ dysfunction in the human endotoxemia model. [ Time Frame: 24 hours after LPS ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To measure the effect of LPS administration in the absence and presence of GTS-21 in human volunteers on vagal nerve activity. [ Time Frame: 24 hours afte LPS ] [ Designated as safety issue: No ]
  • Concentration of pro- and anti-inflammatory cytokines. [ Time Frame: 24 hours after LPS ] [ Designated as safety issue: No ]
  • AChR and TLR expression on circulating monocytes [ Time Frame: 24 ours after LPS ] [ Designated as safety issue: No ]
  • Concentration of HMGB-1 [ Time Frame: 24 hours after LPS ] [ Designated as safety issue: No ]
  • Leucocyte number, C-reactive protein concentrations [ Time Frame: 24 hours after LPS ] [ Designated as safety issue: No ]
  • Hemodynamic parameters, Severity of clinical symptoms [ Time Frame: 24 hours after LPS ] [ Designated as safety issue: No ]
  • Markers of endothelial damage (adhesion molecules) [ Time Frame: 24 hours after LPS ] [ Designated as safety issue: No ]
  • Urine excretion of markers of proximal (GSTA1-1) and distal (GSTP1-1) renal tubular damage [ Time Frame: 24 hours after LPS ] [ Designated as safety issue: No ]
  • Vagal activity as measured by heart rate variability analysis [ Time Frame: 24 hours after LPS ] [ Designated as safety issue: No ]
  • Body temperature [ Time Frame: 24 hours after LPS ] [ Designated as safety issue: No ]
  • Additional blood samples will be drawn for measurement of: TLR-expression, Genetics; micro array analyses and determination of intercellular signalling pathways. [ Time Frame: 24 hours after LPS ] [ Designated as safety issue: No ]

Enrollment: 12
Study Start Date: August 2008
Study Completion Date: August 2010
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: GTS-21
Subjects will be randomized to oral pre-treatment with GTS-21 (150 mg tid 3 days before LPS injection and an oral dose of 150 mg GTS-21 on the morning of the day of the experiment (07:00 AM). Subjects will then receive an oral dose of 150 mg GTS-21 or placebo at 08:00 AM and another oral dose of 150 mg GTS-21 or placebo at 1 hour before LPS administration (t=0).
Drug: GTS-21, [3-(2,4-dimethoxybenzylidene)-anabaseine dihydrochloride]
Subjects will receive GTS-21 or placebo 3 day before injection of LPS (150 mg tid) and a single oral dose of 150 mg of GTS-21 or placebo the morning of LPS injection (07:00 AM). Subjects will then receive an oral dose of 150 mg GTS-21 or placebo at 08:00 AM and another oral dose of 150 mg GTS-21 or placebo at 1 hour before LPS administration (t=0)
Other Name: GTS-21
Drug: Lipopolysaccharide E. Coli 113:H 10:K negative
Subjects will be randomized to oral pre-treatment with GTS-21 (150 mg tid 3 days before LPS injection and an oral dose of 150 mg GTS-21 on the morning of the day of the experiment (07:00 AM). Subjects will then receive an oral dose of 150 mg GTS-21 or placebo at 08:00 AM and another oral dose of 150 mg GTS-21 or placebo at 1 hour before LPS administration (t=0). One hour after ingestion of the last dosage of the study drug, purified LPS prepared from E coli O:113 (2 ng/kg iv) will be injected intravenously.
Other Name: Endotoxin
Placebo Comparator: Placebo
Subjects will receive placebo 3 day before injection of LPS (150 mg tid) and a single oral dose of 150 mg of placebo the morning of LPS injection (07:00 AM). Subjects will then receive an oral dose of 150 mg placebo at 08:00 AM and another oral dose of 150 mg placebo at 1 hour before LPS administration (t=0).
Drug: Placebo
Subjects will receive placebo 3 day before injection of LPS (150 mg tid) and a single oral dose of 150 mg of placebo the morning of LPS injection (07:00 AM). Subjects will then receive an oral dose of 150 mg placebo at 08:00 AM and another oral dose of 150 mg placebo at 1 hour before LPS administration (t=0).
Other Name: Test
Drug: Lipopolysaccharide E. Coli 113:H 10:K negative
Subjects will be randomized to oral pre-treatment with GTS-21 (150 mg tid 3 days before LPS injection and an oral dose of 150 mg GTS-21 on the morning of the day of the experiment (07:00 AM). Subjects will then receive an oral dose of 150 mg GTS-21 or placebo at 08:00 AM and another oral dose of 150 mg GTS-21 or placebo at 1 hour before LPS administration (t=0). One hour after ingestion of the last dosage of the study drug, purified LPS prepared from E coli O:113 (2 ng/kg iv) will be injected intravenously.
Other Name: Endotoxin

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age ≥ 18 and ≤ 35 yrs
  • Male
  • Healthy

Exclusion Criteria:

  • Use of any medication
  • Smoking
  • History, signs or symptoms of cardiovascular disease
  • (Family) history of cerebrovascular disease
  • Previous vagal collapse
  • Hypertension (defined as RR systolic > 160 or RR diastolic > 90)
  • Hypotension (defined as RR systolic < 100 or RR diastolic < 50)
  • Renal impairment (defined as plasma creatinin >120 μmol/l)
  • Liver enzyme abnormalities or positive hepatitis serology
  • Positive HIV test
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00783068

Locations
Netherlands
Radboud University Nijmegen Medical Centre
Nijmegen, GLD, Netherlands, 6525 GA
Sponsors and Collaborators
Radboud University
CoMentis, 280 Utah Avenue, Suite 275, South San Francisco, CA 94080
  More Information

No publications provided

Responsible Party: Prof. Dr. J.G. van der Hoeven, Radboud University Nijmegen Medial Centre
ClinicalTrials.gov Identifier: NCT00783068     History of Changes
Other Study ID Numbers: NL 20388.091.07
Study First Received: October 30, 2008
Last Updated: November 4, 2010
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Radboud University:
Endotoxin
GTS-21
Vagal activity
Autonomic balance

Additional relevant MeSH terms:
Sepsis
Endotoxemia
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Bacteremia
Toxemia
3-(2,4-dimethoxybenzylidene)anabaseine
Nicotinic Agonists
Cholinergic Agonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 29, 2014