[11C]Carfentanil PET Study of GSK1521498

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00976066
First received: September 11, 2009
Last updated: August 23, 2012
Last verified: February 2011
  Purpose

The purpose of this study is to determine whether GSK1521498 attaches to sites in the brain called mu-opioid receptors that are involved in the liking reactions to palatable high fat and high sugar foods. We hope that blocking these receptors may modify certain behaviours that may lead to obesity.


Condition Intervention Phase
Obesity
Drug: Part A Assessing GSK1521498
Drug: Part B Assessing GSK1521498
Drug: Part C Assessing Naltrexone
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: An Open-label, Non-randomized [11C]Carfentanil PET Study in Healthy Male Subjects to Investigate Brain Mu-opioid Receptor Occupancy, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of GSK1521498 and Naltrexone.

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • The degree and time-course of mu-opioid receptor occupancy by GSK1521498 in brain regions of interest as measured by PET [ Time Frame: Assessed at various endpoints to be determined based on emerging results ] [ Designated as safety issue: No ]
  • The relationship between plasma concentration and mu-opioid receptor occupancy by GSK1521498 [ Time Frame: Assessed at various endpoints to be determined based on emerging results ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Adverse events and clinically relevant changes in electrocardiography (ECG); vital signs (blood pressure, heart rate); POMS, Bond and Lader VAS, laboratory safety data and physical examination [ Time Frame: Duration of study ] [ Designated as safety issue: Yes ]
  • Pharmacokinetic endpoints will be: AUC(0-∞), AUC(0-t), maximum observed plasma drug concentration (Cmax), time to maximum observed plasma drug concentration (Tmax), terminal elimination half-life (t½). [ Time Frame: PK samples will be collected throughout the study ] [ Designated as safety issue: Yes ]
  • The degree and time-course of mu-opioid receptor occupancy by naltrexone in brain regions of interest as measured by PET [ Time Frame: Assessed at various endpoints to be determined based on emerging results ] [ Designated as safety issue: No ]
  • The relationship between mu-opioid receptor occupancy by GSK1521498 and naltrexone and fMRI responses during expectation and receipt of a pleasant tasting reward (juice) [ Time Frame: During fMRI scanning sessions ] [ Designated as safety issue: No ]

Enrollment: 26
Study Start Date: June 2009
Study Completion Date: December 2009
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GSK1521498
Subjects will receive a dose of the experimental compound GSK1521498
Drug: Part A Assessing GSK1521498

Each participant will receive up to three [11C]carfentanil PET scans and up to two doses of GSK1521498 in total. The doses used will span the expected receptor occupancy range providing these were well tolerated in the first-time in human study.

Each subject will receive baseline [11C]carfentanil PET and fMRI scans (PET Scan 1 and fMRI Scan 1, respectively), followed by two treatment sessions (Treatment Sessions 1 and 2). Treatment session 1 and 2 are followed by PET scans and an fMRI scan (session 1 only). Sessions will be separated by at least 12 days. PET scans will be timed to coincide with peak brain occupancy. fMRI will begin approximately 30-60 minutes after completion of the PET scan.

Drug: Part B Assessing GSK1521498

The purpose of Part B is to establish the timecourse of receptor occupancy of GSK1521498. Each participant in Part B will receive up to three [11C]carfentanil PET scans and one single oral dose of GSK1521498 expected to provide 50-75% receptor occupancy (selected with reference to data from Part A).

Each Part B subject will receive baseline [11C]carfentanil PET and fMRI scans (PET Scan 1 and fMRI Scan 1, respectively) followed by a single treatment session. The treatment session will consist of a single oral dose of GSK1521498 followed by two subsequent PET scans (PET Scans 2 and 3) and one fMRI scan (fMRI Scan 2).

Active Comparator: Naltrexone
Subjects will receive a dose of the licensed pharmaceutical product, Naltrexone
Drug: Part C Assessing Naltrexone
A range of doses of naltrexone will be tested in up to 12 participants in an adaptive design. Each Part C participant will receive up to three [11C]carfentanil PET scans and a single oral dose of naltrexone. No dose of naltrexone will exceed 50 mg, the dose usually used therapeutically in the treatment of opiate and alcohol dependence. Each Part C subject will receive baseline [11C]carfentanil PET and fMRI scans (PET Scan 1 and fMRI Scan 1, respectively) followed by a single treatment session. The treatment session will consist of a single oral dose of naltrexone followed by two subsequent PET scans (PET Scans 2 and 3) and one fMRI scan (fMRI Scan 2).

Detailed Description:

This imaging study will be an open-label, non-randomised PET receptor occupancy study in healthy male volunteers. The degree and time course of μ-opioid receptor occupancy (RO) following single oral doses of GSK1521498 will be estimated by [11C]carfentanil displacement. Previous pre-clinical and human PET studies indicate that [11C]carfentanil is selective for the μ-opioid receptor and can be used to estimate μ-opioid receptor occupancy in vivo.

The PK/PD relationship between plasma concentrations of GSK1521498 and μ-opioid RO will be described. Potential relationships between μ-opioid RO and functional magnetic resonance imaging (fMRI) endpoints, measured in a food reward paradigm, will be assessed as an exploratory aim. Additionally, the PK/PD relationships between plasma concentrations of naltrexone (a generic μ-opioid receptor antagonist), μ-opioid receptor occupancy, and fMRI measures of reward processing will also be investigated.

  Eligibility

Ages Eligible for Study:   25 Years to 65 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male subjects aged between 25 and 65 years old inclusive.
  • Body weight ≥ 50 kg and BMI within the range 18.5.0 - 30.0 kg/m2 (inclusive).
  • Normal ECG.
  • The subject is able to read, comprehend and record information.
  • A signed and dated written informed consent is obtained from the subject.
  • Compliance with birth control methods as described in the study protocol.

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

  • The subject has a positive pre-study drug/alcohol screen.
  • History of hepatitis B and /or C
  • A positive result for an HIV test.
  • Abnormal thyroid function
  • Positive evaluation for depression.
  • History of heavy alcohol use as described in the study protocol.
  • The subject has participated in a clinical trial and has received an investigational product within: 90 days.
  • Participation in other drug studies within a calendar year.
  • Use of prohibited medications as described in the study protocol.
  • History of sensitivity to any of the study medications.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Past or present use of tobacco products.
  • Consumption of red wine, seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication.
  • Previous radiation dosages in excess of levels acceptable to take part in this study.
  • History of claustrophobia or history of neurological conditions.
  • Presence of a cardiac pacemaker.
  • Works as a welder, metal worker or machinist
  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: NCT00976066

Locations
United Kingdom
GSK Investigational Site
London, United Kingdom, NW10 7EW
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: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00976066     History of Changes
Other Study ID Numbers: 111848
Study First Received: September 11, 2009
Last Updated: August 23, 2012
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by GlaxoSmithKline:
Obesity
Naltrexone
Carfentanil
Receptor Occupancy
mu-opioid Receptor
PET (Positron Emission Tomography)
BOLD-fMRI

Additional relevant MeSH terms:
Obesity
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Naltrexone
Carfentanil
Narcotic Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Analgesics

ClinicalTrials.gov processed this record on September 16, 2014