Anti-inflammatory Effects of GTS-21 After LPS

NCT00783068 | Completed DMC

• 1 other identifier: NL 20388.091.07
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Endotoxemia; Sepsis; Vagal Activity

Keywords

Endotoxin; GTS-21; Vagal activity; Autonomic balance

Outcome Measures

Primary Outcomes (1)

• 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.

  24 hours after LPS

Secondary Outcomes (11)

• To measure the effect of LPS administration in the absence and presence of GTS-21 in human volunteers on vagal nerve activity.

  24 hours afte LPS

• Concentration of pro- and anti-inflammatory cytokines.

  24 hours after LPS

• AChR and TLR expression on circulating monocytes

  24 ours after LPS

• Concentration of HMGB-1

  24 hours after LPS

• Leucocyte number, C-reactive protein concentrations

  24 hours after LPS

Study Arms (2)

GTS-21

ACTIVE COMPARATOR

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]; Drug: Lipopolysaccharide E. Coli 113:H 10:K negative

Placebo

PLACEBO COMPARATOR

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; Drug: Lipopolysaccharide E. Coli 113:H 10:K negative

Interventions

GTS-21, [3-(2,4-dimethoxybenzylidene)-anabaseine dihydrochloride] DRUG

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)

Also known as: GTS-21

GTS-21

Placebo DRUG

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).

Also known as: Test

Placebo

Lipopolysaccharide E. Coli 113:H 10:K negative DRUG

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.

Also known as: Endotoxin

GTS-21; Placebo

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Radboud University Medical Center: lead
• CoMentis: collaborator

Study Sites (1)

Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, 6525 GA, Netherlands

Location

MeSH Terms

Conditions

Endotoxemia; Sepsis

Interventions

3-(2,4-dimethoxybenzylidene)anabaseine; Endotoxins

Condition Hierarchy (Ancestors)

Bacteremia; Infections; Toxemia; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Bacterial Toxins; Toxins, Biological; Biological Factors

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: October 30, 2008
• First Posted: October 31, 2008
• Study Start: August 1, 2008
• Primary Completion: December 1, 2009
• Study Completion: August 1, 2010
• Last Updated: November 5, 2010

Record last verified: 2008-10

Locations

NL (1)