A total of at least 48 healthy subjects with a history of social drinking will be recruited into this single-centre, randomized, double-blind, cross-over study. Subjects will be genetically stratified to result in equal numbers of A118G 'AA' homozygotes (n=24) and A118G 'G' carriers (n=24). Subjects will participate in all three treatment periods and will be randomized to receive each of the following for 5 days: Treatment A: Placebo, Treatment B: Naltrexone (NTX) 50 mg once daily (25 mg once daily for the first two days) and Treatment C: GSK1521498 10 mg once daily. A washout period will be of at least 14 days between treatments. Subjects will return for a follow-up visit 7-10 days after the final treatment session washout period has been completed. Subjects will attend the clinical research unit on days 1, 2, 3, 4 and 5 to monitor safety and tolerability for both drugs. Subjects will attend the clinical unit on days 4 and 5 for a two day assessment, using a series of pharmacodynamic measurements known to be sensitive to the effects of GSK1521498 and/or NTX: Functional brain response to alcohol and food cues; plasma cortisol; hedonic and consummatory eating behaviors; subjective response to an ethanol challenge; experimental pain threshold; and cognitive tests of attention bias towards alcohol and food cues.
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Brain activation within the reward circuitry in response to consumption of food and alcohol cues, as measured by functional magnetic resonance imaging (fMRI)
Timeframe: Day 5 in each treatment period
Adverse events as a measure of safety and tolerability
Timeframe: Throughout the study, from Day 1 to Day 67
Blood pressure (BP) as a measure of safety and tolerability
Timeframe: Screening (Up to 30 days prior to Day 1), Day 1, Day 2, Day 5 in each treatment period and Follow-up visit.
12-lead ECG and heart rate as a measure of safety and tolerability
Timeframe: Screening (Up to 30 days prior to Day 1), Day 1, Day 2, Day 5 in each treatment period and Follow-up visit.
Clinical chemistry including liver enzymes and hematology as a measure of safety and tolerability
Timeframe: Screening (Up to 30 days prior to Day 1), Day 5 of each of the 3 treatment periods and Follow-up visit
Psychiatric symptom questionnaires-Becks Depression & Anxiety Inventory (BDI-II & BAI)
Timeframe: Screening (Up to 30 days prior to Day 1), Day 1 (pre-dose and approximately 4 hours post dose), Day 2 (prior to discharge), Day 3 (prior to discharge), Day 5 (prior to discharge), in each treatment period and Follow-up visit
Psychiatric symptom questionnaires- Columbia Suicide Severity Rating Scale (C-SSRS)
Timeframe: Screening (Up to 30 days prior to Day 1), Day 1 (pre-dose and approximately 4 hours post dose), Day 2 (prior to discharge), Day 5 (prior to discharge), in each treatment period and Follow-up visit
Psychiatric symptom questionnaires- Bond and Lader Visual Analogue Scales (VAS).
Timeframe: Screening (Up to 30 days prior to Day 1), Day 1 (pre-dose and approximately 4 hours post dose), Day 2 (prior to discharge), Day 3 (prior to discharge), Day 4 (prior to discharge), Day 5 (prior to discharge), in each treatment period and Follow-up visit
Computerized tests of reaction time (CANTAB)
Timeframe: Approximately 1 hour pre-dose on Day 1 and approximately 4 hours post dose on Day 1, Day 2 and Day 5 in each treatment period