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An Open Label Positron Emission Tomography Study in Healthy Male Subjects to Investigate Brain DAT and SERT Occupancy,Pharmacokinetics and Safety of Single Oral Doses of GSK1360707, Using 11C- PE2I and 11C-DASB as PET Ligands

This study has been completed.
Sponsor:
Information provided by:
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01153802
First received: June 29, 2010
Last updated: June 23, 2011
Last verified: June 2011
  Purpose

GSK1360707 is a potent re-uptake inhibitor of the neurotransmitters dopamine, norepinephrine and serotonin. This is a single dose PET study in healthy subjects.A final analyses of safety data following exposure to single oral doses, from the first time in human study, with GSK1360707 has demonstrated that the compound is well tolerated up to a dose of 150mg. This imaging study will be an open label, non-randomised PET occupancy study using healthy male volunteers. The degree and time course of DAT and SERT occupancy by GSK1360707 will be determined. The PK/PD relationship between plasma concentrations of GSK1360707 and DAT and SERT occupancy will be described.This protocol amendment includes the flexibility to split the total dose into two doses e.g. 120mg per day could be split into two doses of 60mg. Splitting the total dose is most likely required to maintain therapeutic occupancy on the transporters over the course of the day; in addition it is expected that splitting the dose may reduce effects on vital signs. Therefore collecting data following split dosing will enable best predictions of therapeutic doses to be progressed in subsequent clinical studies.


Condition Intervention Phase
Depressive Disorder and Anxiety Disorders
Depressive Disorder
Drug: GSK1360707 is a potent re-uptake inhibitor of the neurotransmitters dopamine, norepinephrine and serotonin
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open Label Positron Emission Tomography Study in Healthy Male Subjects to Investigate Brain DAT and SERT Occupancy, Pharmacokinetics and Safety of Single Oral Doses ofGSK1360707, Using 11C- PE2I and 11C-DASB as PET Ligands

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • To estimate the degree of DAT occupancy in brain regions of interest (ROIs)following oral doses of GSK1360707 in healthy male subjects-To estimate the degree of SERT occupancy in brain ROIs following total oral doses of GSK1360707 in healthy male subject [ Time Frame: 6-7 weeks. ] [ Designated as safety issue: No ]
  • To evaluate the relationship between the plasma concentration and the resultant DAT occupancy by GSK1360707.To evaluate the relationship between the plasma concentration and the resultant SERT occupancy by GSK1360707. [ Time Frame: 6 - 7 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To further assess the safety and tolerability of total oral doses of GSK1360707 including the maximal tolerated dose in the FTIH study (150 mg PO)-To further assess the pharmacokinetics of GSK1360707 in healthy male subjects [ Time Frame: 6-7 weeks. ] [ Designated as safety issue: No ]

Enrollment: 12
Study Start Date: April 2009
Study Completion Date: October 2009
Primary Completion Date: October 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Healthy Male Volunteers
All the 12 subjects enrolled in the study were exposed to at least one dose of GSK1360707 15 mg, 30 mg, 60 mg, 90 mg, 120 mg and 150 mg. All the subjects completed the study. The initial dose, given in the study as a single-dose was 15 mg GSK1360707. The remaining subjects were dosed either as a single or split dose, as determined by the PET and tolerability data collected in the preceding subjects. The total dose did not exceed 150 mg per day, the maximum total dose given in the FTIH study.
Drug: GSK1360707 is a potent re-uptake inhibitor of the neurotransmitters dopamine, norepinephrine and serotonin

This is an open label, adaptive design, daily dosing, non-randomized PET occupancy study in healthy adult males.A range of doses may be evaluated. The initial dose, given in the study as a single dose was 150mg GSK1360707. The remaining subjects will be dosed either as a single or split dose, as determined by the PET and tolerability data collected in the preceding subjects. The total dose will not exceed 150mg per day, the maximum total dose given in the FTIH study.If dosing is conducted as a single dose, the dose will be administered after the baseline scan, If a dosing is performed in a split dose manner, dosing will occur after the baseline scan, and up to 12 hours later. The time period between doses will be determined by emerging PET occupancy data.

Subsequent doses, if any, will be chosen based on the observed scan results. No single dose, or total dose split over 2 dosing sessions, will exceed the maximum dose in the FTIH study.


  Show Detailed Description

  Eligibility

Ages Eligible for Study:   35 Years to 55 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 1. Healthy as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the
  • Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

    2.Systolic blood pressure <140 mmHg, diastolic blood pressure <90 mmHg and heart rate <90 beats/min.

    3. Male subjects between 35-55 years of age. 4.Male subjects must agree to use one of the contraception methods as listed in Section 8.1.

    5.Body Mass Index (BMI) within the range 19 - 30 kg/m2 (inclusive) at screening visit.

    6. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form 7.QTcB or QTcF < 450 msec (if the first QTcB reading exceeds the limits above, perform two more ECGs separated at least 5 min apart. Then take the average of the three QTcB to determine if the average satisfies the above criteria).

Exclusion Criteria:

  • 1.Evidence or history of clinically significant hematological, renal, urinary / prostatic, endocrine, pulmonary, gastrointestinal, cardiovascular or other heart disease, glaucoma, diabetes, hepatic, neurologic (e.g. including but not limited to seizures, stroke, cerebrovascular disease or other brain conditions), or allergic disease (except for untreated, asymptomatic, seasonal allergies at time of dosing).

    2. Psychiatric illness currently or within the past year, or any lifetime history of bipolar disorder, major depressive disorder, anxiety disorder, schizophrenia or other psychotic disorder, or substance abuse or dependence (except past history of nicotine abuse/dependence if >6 months prior to screening.

    3. Subjects who, in the investigator's judgment, pose a suicidal or homicidal risk, or any subject with a history of suicidal or homicidal attempts or behaviour.

    4. The subject has a positive pre-study drug/alcohol screen. 5. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.

    6. A positive test for HIV antibody. 7. History of regular excessive alcohol consumption within 6 months of the study defined as: an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units. One unit is equivalent to a half-pint (220mL) of beer or 1 (25mL) measure of spirits or 1 glass (125mL) of wine. 8. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 90 days , 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

    9. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

    10. 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, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.

    11. 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 investigator or GSK Medical Monitor contraindicates their participation. 12. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.

    13. Unwillingness or inability to follow the procedures outlined in the protocol.

    14. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.

    15. Consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication. 16. Controlled or uncontrolled hypertension, or systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥ 90 mmHg at screening or prior to the first dose of study medication.

    17. 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).

    18. History of, or suffers from, claustrophobia or feels that he will be unable to lie still on his back in the PET or MRI scanner for a period of 1-2 hours.

    19. Presence of a cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies as assessed by a standard pre-MRI questionnaire.

    20. Subjects who are smokers will be excluded from this study.

  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: NCT01153802

Locations
United Kingdom
GSK Investigational Site
Harrow, Middlesex, United Kingdom, HA1 3UJ
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Cheri Hudson; Clinical Disclosure Advisor, GSK Clinical Disclosure
ClinicalTrials.gov Identifier: NCT01153802     History of Changes
Other Study ID Numbers: 112773
Study First Received: June 29, 2010
Last Updated: June 23, 2011
Health Authority: United Kingdom: Ethics Committee
United Kingdom: GSK Observational Study

Keywords provided by GlaxoSmithKline:
Positron Emission Tomography
serotonin
inhibitor of the neurotransmitters
safety of single oral doses
norepinephrine
dopamine

Additional relevant MeSH terms:
Anxiety Disorders
Depression
Depressive Disorder
Disease
Behavioral Symptoms
Mental Disorders
Mood Disorders
Pathologic Processes
Dopamine
Dopamine Agents
Norepinephrine
Serotonin
Adrenergic Agents
Adrenergic Agonists
Adrenergic alpha-Agonists
Autonomic Agents
Cardiotonic Agents
Cardiovascular Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Serotonin Agents
Serotonin Receptor Agonists
Sympathomimetics
Therapeutic Uses
Vasoconstrictor Agents

ClinicalTrials.gov processed this record on November 20, 2014