CRF1 Antagonist GSK561679 in Alcoholism

Phase 2

Completed

Conditions: Alcohol Dependence

Interventions: Drug: GSK561679
Drug: Placebo

Registration Number: NCT01187511

Lead Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Brief Summary: Objective:

To evaluate GSK561679, an orally available, brain penetrant selective CRH1 antagonist for its ability to reduce alcohol craving in recently detoxified alcohol dependent women in response to stress or alcohol-associated stimuli.

Study population:

Up to 60 anxious, alcohol dependent women, aged 21-65 years will be enrolled to complete the study in 50 patients.

Background:

* Anxiety, irritability, anger, and depression can all cause stress that may lead to continued drinking in heavy drinkers. One way the brain responds to stress is through a protein on brain cells called a CRH receptor. Previous research has shown that the CRH receptor is involved in negative emotional states and that chronic alcohol consumption increases the activity of CRH receptors in the brain. Medications that block CRH receptors can decrease stress-triggered alcohol consumption.

* GSK561679, an experimental drug that blocks the CRH receptors, can reduce negative emotions such as anxiety and a person s desire for alcohol. By looking at the brain s response to stress and the study drug using functional magnetic resonance imaging (fMRI) scans, researchers hope to learn whether GSK561679 can be an effective treatment for stress-related alcohol abuse.

Objectives:

- To evaluate the usefulness of GSK561679 in reducing stress-related alcohol craving in alcohol-dependent women.

Design:

* Participants in the study will be enrolled in the standard NIH treatment program for alcohol dependence, and will be required to stay at the NIH inpatient treatment unit for an additional 31 days.

* Participants will receive either the study medication or a placebo to be taken once a day in the evening for 4 weeks.

* Participants will have the following procedures while on the study medication:

* Questionnaires about alcohol craving, depression, and anxiety.

* Recordings and responses to personal emotional reactions to stressful, nonstressful, and alcohol-related situations, with blood samples taken during the responses.

* Regular blood tests to measure stress hormones in the blood.

* Speech preparation and presentation (Trier test), along with blood samples, to measure stress hormones in the blood.

* Sessions to measure responses to alcohol-related cues.

* Functional magnetic resonance imaging (fMRI) scans.

* Participants will return for follow-up visits 1 week and 1 month after stopping the study drug and being discharged from the study.

Detailed Description: Objective:

To evaluate GSK561679, an orally available, brain penetrant selective CRH1 antagonist for its ability to reduce alcohol craving in recently detoxified alcohol dependent women in response to stress or alcohol-associated stimuli.

Study population:

Up to 60 anxious, alcohol dependent women, aged 21-65 years will be enrolled to complete the study in 50 patients.

Design:

Subjects will be inpatients and enter the present protocol once withdrawal treatment, if needed, is completed. One week of single blind placebo will be followed by randomized double blind treatment with active medication or placebo for approximately 3 weeks. Spontaneous craving for alcohol and ratings of psychopathology will be obtained twice weekly throughout the study. During the placebo lead-in week, a diurnal cortisol curve will be obtained, and a baseline dexamethasone-CRH test may be carried out. These measures will be repeated after 10-14 days of randomized treatment. Around this time, craving responses will also be assessed in a challenge session that combines a social stressor and exposure to physical alcohol cues. During the final week, three sessions of guided imagery will be carried out, on separate days and in a counter-balanced order, exposing the subject to personalized stress-, alcohol- or neutral condition associated stimuli. An fMRI session will be carried out last. Subjects will remain hospitalized throughout the study, and will remain on the unit for a 3 day post-medication monitoring period.

Outcome measures:

The primary outcome will be craving for alcohol on guided imagery challenge sessions. Secondary outcomes will include craving as measured in the combined social stress alcohol cue challenge session, spontaneous craving and psychopathology ratings repeatedly measured on the inpatient unit over time. Exploratory blood biomarkers and brain responses to positive and negative affective stimuli on the fMRI session will also be obtained.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 44

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GSK561679	GSK561679	GSK561679 was given orally, once a day in the evening, for 21 days, at a dose of 350mg, administered as four tablets consisting of 3 x 100mg tablets plus 1 x 50mg tablet.
Placebo	Placebo	Placebo was given orally, once a day in the evening, for 21 days, in the form of four tablets that matched those of GSK561679

Primary Outcome Measures

Name	Time	Method
Alcohol Craving in Response to the Alcohol Cue Script	90 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Alcohol Craving in Response to the Stress Script	90 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).

Secondary Outcome Measures

Name	Time	Method
Alcohol Craving in Response to the Trier/Cue-reactivity Procedure	70 minutes after the beginning of the Trier/cue-reactivity procedure, which occurred on Day 21 of the treatment period	Alcohol craving was measured using the Alcohol Urges Questionnaire (AUQ). The AUQ is an 8-item self-administered instrument that assesses craving for alcohol among alcohol users in the current context (i.e., right now). The score ranges from 8 (lowest craving value) to 56 (highest craving value).
Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period	Day 7 of the treatment period	Anxiety symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Depression Symptom Ratings Measured Bi-weekly During the Treatment Period	Day 7 of the treatment period	Depression symptoms were measured using the Comprehensive Psychopathological Rating Scale (CPRS). The CPRS is an 18-item interview-based instrument for assessing depression and anxiety. There are two 10-item subscales, the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Each subscale ranges from 0 (lowest symptom severity) to 60 (highest symptom severity).
Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period	Day 7 of the treatment period	Alcohol craving was measured using the Penn Alcohol Craving Scale (PACS). The PACS is a five-item self-administered instrument for assessing alcohol craving over the course of the past week. The score ranges from 0 (lowest craving value) to 30 (highest craving value).