Clinical trial NCT00468806: Study of Safety, Blood Levels and Brain Receptor Occupancy of GSK598809 Using PET Imaging in Health Males.
Official title: An Open Label Positron Emission Tomography Study in Healthy Male Subjects to Investigate Brain Dopamine D3 Occupancy Kinetics, Pharmacokinetics and Safety of Single Oral Doses of GSK598809, Using [11C]-(+)-PHNO as PET Ligand.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Keywords: PET scan
Health Males
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-05-03
Enrollment: 25
Sex: MALE
Minimum age (years): 25
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to look at how much of a new drug, GSK598809 binds to specific proteins in the brain and how much stays in the blood over a range of different doses.


Eligibility criteria: Inclusion Criteria:

Healthy male subjects, defined as individuals who are free from clinically significant illness or disease as determined by their medical history (including family), physical examination, laboratory studies, and other tests.

* Aged 25-55 years inclusive, at screening visit.
* Body weight \> 50 kg and body mass index (BMI) between 19.0 - 29.0 kg/m2 inclusive.
* Capable of giving informed consent and can comply with the study requirements and timetable.
* Self-administered Beck Depression Inventory II scale total score no greater than 9, and suicide question score of zero.
* Able to read, comprehend and record information.
* A signed and dated written informed consent is obtained from the subject.

Exclusion Criteria:

* The physician responsible considers the subject unfit for the study based upon medical history, physical examination and psychiatric history and evaluation.
* History of a drug or other allergy which in the opinion of the physician responsible contraindicates their participation in the study.
* Participation in a clinical trial and has received a drug or a 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.
* A screening ECG outside of ranges specified in the protocol
* Pulse rate \<55 or \>100 bpm OR a systolic blood pressure \>140 and \<100 OR a diastolic blood pressure \>90 and \<60.
* History of long QT syndrome (personal or family) or other cardiac conduction disorder, or other clinically significant cardiac disease.
* An electrolyte value outside the normal range at pre-study screening. Subjects who do not fall within the normal reference ranges may be included within the study if in the opinion of the Principal Investigator and Medical Monitor this will not compromise the subject.
* Liver function tests (LFT) elevated above the reference range at pre-study screening that remain elevated with a repeat LFT.
* Any other clinically significant laboratory abnormality.
* Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John'sWort) 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, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety.
* History of regular alcohol consumption averaging \>14 drinks/week for men. One drink is equivalent to(12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits) within 6 months of screening.
* Smokes or has smoked in the last 6 months.
* Donation of more than 450 ml blood within the 56 days before dosing.
* An unwillingness of male subjects to abstain from sexual intercourse with pregnant or lactating women from the time of administration of study medication (GSK598809) until 90 days following administration of study medication or an unwillingness of the male subject to use a condom/spermicide in addition to having their female partner use another form of contraception if the woman could become pregnant from the time of administration of study medication until 90 days following administration of study medication.
* 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., cholecysectomy) which would be expected to influence the absorption of drugs.
* Any previous or current psychiatric diagnosis listed in DSMIV Axis I or II.
* Any history of suicidal attempts, suicidal ideation or behaviour.
* Chronic Hepatitis B and C, as evidenced by positive Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody.
* A positive test for HIV.
* Past history of drug abuse (i.e. meeting DSM IV or ICD 10 criteria for substance dependence) or has tested positive for urine drugs of abuse at pre-study screening and/or prior to dosing.
* Previous inclusion in a research and/or medical protocol involving nuclear medicine, PET or radiological investigations with significant radiation burden (a significant radiation burden being defined as ICRP category IIb or above: No more than 10 mSv in addition to natural background radiation, in the previous 3 years including the dose from this study).
* Family history of cancer (one or more first-degree relative diagnosed before the age of 55).
* History of or suffers from claustrophobia or feels that they will be unable to lie still on their back in the PET camera for a period of 2 hours.
* History or presence of a neurological diagnosis (not limited to but including for example, stroke, traumatic brain injury, epilepsy, space occupying lesions, multiple sclerosis, Parkinson's disease, vascular dementia, transient ischemic attack, schizophrenia, major depression etc) that may influence the outcome or analysis of the scan results.
* Presence of a cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies as assessed by a standard pre-MRI.

Primary outcomes:
measure: %D3 RO at Tmax
timeFrame: approx 1.5 hrs
measure: Percentage occupancy at Tmax
timeFrame: approx 1.5 hrs
measure: Ttrough
timeFrame: approx 24 hrs
measure: time course of GSK598809 plasma concentration following a single oral dose of GSK598809
timeFrame: at predose,1,1.5,2,3,4,8,24 and 48 hrs.
Secondary outcomes:
measure: Prolactin/TSH levels
timeFrame: at predose,1, 2, 4,8 & 24 hrs postdose
measure: Akathisia
timeFrame: at baseline at 1, 4 hrs postdose
measure: EPQ, BIS-BAS:
timeFrame: at screening
measure: POMS, CRT:
timeFrame: at predose & 4 hrs postdose
measure: VAS:
timeFrame: at predose, 1, 4 hrs postdose
measure: LSEQ
timeFrame: at screening, baseline scan & 24 hrs
measure: neuroendocrine and behavioural measures following GSK598809 administration.
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials, MD
role: STUDY_DIRECTOR
References:
citation: Searle G, Beaver JD, Comley RA, Bani M, Tziortzi A, Slifstein M, Mugnaini M, Griffante C, Wilson AA, Merlo-Pich E, Houle S, Gunn R, Rabiner EA, Laruelle M. Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C]PHNO, and a selective D3 receptor antagonist. Biol Psychiatry. 2010 Aug 15;68(4):392-9. doi: 10.1016/j.biopsych.2010.04.038.