A Study to Investigate the Effects of GW876008 on Brain Activation During Emotional Processing in Healthy Subjects.

A Randomized, Placebo-controlled, Double-dummy, Four-way Crossover Design Study to Investigate the Changes of fMRI BOLD Activation Induced by Emotional Activation Paradigms Following Single Doses of GW876008 and Lorazepam (Comparator) in Healthy Subjects.

Data suggests that imaging activity of the brain can measure the effects of anti-anxiety drugs. This study will investigate the effect of GW876008 on areas of the brain involved with thinking and emotion

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: placebo; Drug: lorazepam; Drug: GW876008

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy males or females aged 18-50 years, inclusive.
• STAI-trait score = or > 40.
• STAI-state score <50th percentile of the normal population distribution.
• Female subjects of non-childbearing.
• Female subjects of childbearing potential must agree to use appropriate contraception.
• Healthy subjects, as determined by a responsible physician
• Body weight ≥ 50 kg (110 lbs), and BMI within the range 19-29.9 kg/m2 inclusive.
• Demonstrates no significant evidence of active disease, physical or mental impairment when assessed by qualified personnel
• Non-smoker (abstinence from smoking for at least 6 months before the start of the study).
• Normal electrocardiogram.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Read, comprehend, and write English at a sufficient level to complete study-related materials.
• Provide a signed and dated written informed consent prior to study participation

Exclusion Criteria:

• As a result of any of the medical interview, physical examination, evaluation of mental state and psychiatric history or screening investigations the physician responsible considers the subject unfit for the study.
• Any history of suicidal attempts or behaviour.
• Any history or current diagnosis of a psychiatric illness.
• Any history of an endocrine disorder including, but not limited to, diabetes or disorders of the hypothalamus, pituitary, adrenal, or thyroid glands, or gonadal disorder or dysfunction of the reproductive organs.
• Abnormal pepsinogen I level at screening.
• Liver Function Tests (LFTs) elevated above the reference range at pre-study screening that remain elevated with a repeat LFT
• Any other clinically significant laboratory abnormality.
• Positive faecal occult blood test.
• Positive pre-study urine drug/alcohol breath screen.
• Positive pre-study HIV 1/2, Hepatitis B surface antigen and positive Hepatitis C antibody result within 3 months of the start of the study.
• Pre-existing or current Helicobactor pylori infection.
• History of alcohol/drug abuse or dependence within 12 months of the study
• Consumption of grapefruit juice or grapefruit within 14 days prior to the first dose of study medication.
• History of peptic ulcer disease.
• Abnormal screening ECG
• History of long QT syndrome (personal or family) or other cardiac conduction disorder, or other clinically significant cardiac disease.
• Systolic blood pressure < 90mmHg or >140mmHg; diastolic blood pressure < 60mmHg or > 90mmHg; pulse rate < 40bpm or > 90bpm.
• Participation in a clinical trial with a drug or new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication.
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
• Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication.
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation.
• History or current diagnosis of acute narrow angle glaucoma.
• Where participation in study would result in donation of blood in excess of 500 mL within a 56 day period.
• Current or recent (within one year) gastrointestinal disease; a history of malabsorption, esophageal reflux, irritable bowel syndrome; frequent (more than once a week) occurrence of heartburn; or any surgical intervention (e.g., cholecystectomy) which would be expected to influence the absorption of drugs.
• Average daily caffeine intake equivalent to > 4 cups of coffee or > 6 cups of tea.
• Subjects who are left handed.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Differences in brain activation elicited by Matching Emotional Face Expression paradigm following single oral doses of GW876008 and lorazepam on day 1, sessions 1-4

Secondary Outcome Measures

Outcome Measure	Time Frame
Clinical laboratory tests
GW876008 blood levels	pre-dose & post-dose, sessions 1-4
clinical rating scales change after dosing: questionnaires collected	pre-dose & up to 6-8 hours post-dose.
Safety: 12-lead ECG, vital signs, adverse events, clinical labs
fMRI BOLD neuroanatomical structure of the emotional brain neurocircuitry and connectivity
fMRI BOLD Signal characteristics and connectivity
fMRI BOLD Response in the emotional brain neurocircuitry and occipital cortex.
ETCo2 in mm Hg, to be recorded for the duration of the scan session and be synchronized with the single fMRI procedure timing
Visual Analog Scale (VAS) measurements of sleepiness, alertness, calm, tension, and anxiety performed before dosing (baseline), pre-fMRI session, post-fMRI session and just before leaving the facility.
Association between the anxiety trait (STAI-trait, test battery for neuroticism or liability for Anxiety Disorders) collected at screening and the various pharmacodynamic parameters measured in the various testing conditions.
GW876008 concentration to determine pharmacokinetic parameters to be collected twice per session,
Pharmacogenetic (PGx) assessments
Safety and tolerability of GW876008 to include Vital signs semi-supine; respiratory rate, pulse oximetry and ECG.
fMRI BOLD ALS signal.
Heart rate (HR; beats per minute), to be recorded for the whole duration of the scan session and to be synchronized with the single fMRI procedure timing.
Respiratory rate (RR: inspiration per minute), to be recorded for the duration of scan session and be synchronized with the single fMRI procedure timing. .

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Investigators: Study Director: GSK Clinical Trials, MBChB, MFPM, GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): December 1, 2007
• Study Completion (Actual): December 1, 2007

Study Registration Dates

• First Submitted: January 17, 2007
• First Submitted That Met QC Criteria: January 18, 2007
• First Posted (Estimate): January 19, 2007

Study Record Updates

• Last Update Posted (Estimate): October 15, 2010
• Last Update Submitted That Met QC Criteria: October 13, 2010
• Last Verified: October 1, 2010

More Information

Terms related to this study

• Keywords: healthy subjects; tolerability,; pharmacodynamics,; fMRI,; Brain imaging,; stimulation,
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticonvulsants; Lorazepam
• Other Study ID Numbers: CRH104150