A Phase 1 interventional study of Part A Assessing GSK1521498 and Part B Assessing GSK1521498 in Obesity, sponsored by GlaxoSmithKline. Completed at 1 site in United Kingdom. Open to male participants aged 25 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2017-06-20.
Sponsored by GlaxoSmithKline · Phase 1, Interventional, and Basic science
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.
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.
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Exclusion Criteria:
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
Subjects will receive a dose of the experimental compound GSK1521498
Drug: Part A Assessing GSK1521498 · Drug: Part B Assessing GSK1521498
Subjects will receive a dose of the licensed pharmaceutical product, Naltrexone
Drug: Part C Assessing Naltrexone
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.
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).
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).
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
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
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
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
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
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
Plan to share: Yes — Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
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