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.
Name: GSK1521498
Description: White HPMC capsule containing 10 mg of GSK1521498Type: DrugTreatment C
Name: Naltrexone (NTX)
Description: Swedish orange gelatin capsule containing 25mg of NTX or 50mg of NTXType: DrugTreatment B
Name: Placebo
Description: Matching placebo capsules to GSK1521498 or NTXType: DrugTreatment A
Description: To test that the OPRM1 A118G polymorphism modulates the effects of GSK1521498 10 mg on brain reward function and processing
Measure: Brain activation within the reward circuitry in response to consumption of food and alcohol cues, as measured by functional magnetic resonance imaging (fMRI) Time: Day 5 in each treatment periodDescription: Number of subjects with any adverse events during the treatment periods
Measure: Adverse events as a measure of safety and tolerability Time: Throughout the study, from Day 1 to Day 67Description: Systolic and diastolic BP will be measured
Measure: Blood pressure (BP) as a measure of safety and tolerability Time: Screening (Up to 30 days prior to Day 1), Day 1, Day 2, Day 5 in each treatment period and Follow-up visit.Description: 12-lead electrocardiograph (ECG) will be measured
Measure: 12-lead ECG and heart rate as a measure of safety and tolerability Time: Screening (Up to 30 days prior to Day 1), Day 1, Day 2, Day 5 in each treatment period and Follow-up visit.Description: Hematology/Chemistry assessments to be done at screening (fasted) and day 5 for each treatment session (un-fasted).
Measure: Clinical chemistry including liver enzymes and hematology as a measure of safety and tolerability Time: Screening (Up to 30 days prior to Day 1), Day 5 of each of the 3 treatment periods and Follow-up visitDescription: Mood anxiety will be assessed by The Beck Anxiety Inventory (BAI), The Beck Depression Inventory (BDI-II).
Measure: Psychiatric symptom questionnaires-Becks Depression & Anxiety Inventory (BDI-II & BAI) Time: 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 visitDescription: Suicidality will be assessed by C-SSRS.
Measure: Psychiatric symptom questionnaires- Columbia Suicide Severity Rating Scale (C-SSRS) Time: 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 visitDescription: Mood anxiety and suicidality will be assessed by VAS.
Measure: Psychiatric symptom questionnaires- Bond and Lader Visual Analogue Scales (VAS). Time: 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 visitDescription: CANTAB attention tasks comprising of Simple Reaction Time (SRT), Choice Reaction Time (CRT) and Rapid Visual Information Processing (RVP) will be done to measure the power of attention
Measure: Computerized tests of reaction time (CANTAB) Time: 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 periodDescription: Plasma cortisol concentrations will be measured under fasting conditions to test that the OPRM1 A118G polymorphism modulates the effect of GSK1521498 10mg on plasma cortisol
Measure: Plasma cortisol concentrations Time: Day 1 and Day 5 pre-dose, at approximately the same time, and on Day 5 post dose in each treatment period.Description: Pressure pain threshold and sensitivity will be measured in response to cutaneous pressure. Pressure pain thresholds and tolerance will be assessed at two tender points (left and right trapezius points, as defined by American College of Rheumatology)
Measure: Pressure pain threshold and sensitivity Time: Day 4 in each treatment period.Description: Eating behaviour will be assessed by ad libitum snacking , Menu choices and ad libitum intake of test buffet meals, Appetite Visual Analogue Scales (A-VAS) and Binge Eating Scale (BES)
Measure: Consummatory eating behaviour Time: Day 5 in each treatment period.Description: Response to sweet and high fat samples (tasting sweetened dairy products), will be performed in a fasted state. The Hedonic 9 point preference scale and Sensory Stimuli Scale will be performed after each sample has been tasted.
Measure: Hedonic taste preference Time: Day 5 in each treatment period.Description: It will be measured using self-report questionnaires Biphasic alcohol effects scale (BAES), Subjective High Assessment Scale (SHAS), Profile of Mood States (POMS-B), and Alcohol Rating Scale (ARS)
Measure: Subjective responses to intravenous doses of ethanol Time: Day 4 in each treatment periodDescription: The comparison will be done for the all efficacy endpoints as mentioned earlier which include Plasma cortisol; fMRI and cognitive measures of reward processing; pain threshold; hedonic and consummatory eating behaviour, subjective response to ethanol
Measure: To compare the placebo-controlled effects of GSK1521498 10 mg to the placebo-controlled effects of NTX 50 mg Time: Day 5 in each treatment period.Allocation: Randomized
Crossover Assignment
There is one SNP
A Randomized, Double-blind, Placebo-controlled, Crossover Study to Evaluate the Influence of the A118G Polymorphism in the mu Opioid Receptor Gene (OPRM1) on Effects of GSK1521498 and Naltrexone on Physiological and Behavioural Markers of Brain Function in Healthy Social Drinkers. --- A118G ---
To Evaluate the Influence of the A118G Polymorphism in the mu Opioid Receptor Gene (OPRM1) on Effects of GSK1521498 and Naltrexone on Physiological and Behavioural Markers of Brain Function in Healthy Social Drinkers 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. --- A118G ---
Subjects will be genetically stratified to result in equal numbers of A118G 'AA' homozygotes (n=24) and A118G 'G' carriers (n=24). --- A118G ---
Subjects will be genetically stratified to result in equal numbers of A118G 'AA' homozygotes (n=24) and A118G 'G' carriers (n=24). --- A118G --- --- A118G ---
To test that the OPRM1 A118G polymorphism modulates the effects of GSK1521498 10 mg on brain reward function and processing. --- A118G ---
Plasma cortisol concentrations will be measured under fasting conditions to test that the OPRM1 A118G polymorphism modulates the effect of GSK1521498 10mg on plasma cortisol. --- A118G ---