CRF1 Antagonist GSK561679 in Alcoholism

NCT01187511 | Completed Phase 2 Results

• 2 other identifiers: 10004610-AA-0046
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

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.

Conditions

Alcohol Dependence

Keywords

Addiction; Alcohol Dependence; Anxiety; CRH Antagonist; Stress Induced Craving

Outcome Measures

Primary Outcomes (16)

• Alcohol Craving in Response to the Alcohol Cue Script

  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).

  15 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Alcohol Cue Script

  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).

  15 minutes prior to the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Alcohol Cue Script

  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).

  30 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Alcohol Cue Script

  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).

  45 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Alcohol Cue Script

  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).

  5 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Alcohol Cue Script

  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).

  60 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Alcohol Cue Script

  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).

  75 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Alcohol Cue Script

  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).

  90 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Stress Script

  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).

  15 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Stress Script

  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).

  15 minutes prior to the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Stress Script

  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).

  30 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Stress Script

  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).

  45 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Stress Script

  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).

  5 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Stress Script

  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).

  60 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Stress Script

  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).

  75 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

• Alcohol Craving in Response to the Stress Script

  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).

  90 minutes after the beginning of script presentation, which occurred on Day 25, 26, or 27 of the treatment period

Secondary Outcomes (35)

• Alcohol Craving in Response to the Trier/Cue-reactivity Procedure

  100 minutes after the beginning of the Trier/cue-reactivity procedure, which occurred on Day 21 of the treatment period

• Alcohol Craving in Response to the Trier/Cue-reactivity Procedure

  15 minutes prior to the beginning of the Trier/cue-reactivity procedure, which occurred on Day 21 of the treatment period

• Alcohol Craving in Response to the Trier/Cue-reactivity Procedure

  20 minutes after the beginning of the Trier/cue-reactivity procedure, which occurred on Day 21 of the treatment period

• Alcohol Craving in Response to the Trier/Cue-reactivity Procedure

  40 minutes after the beginning of the Trier/cue-reactivity procedure, which occurred on Day 21 of the treatment period

• 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

Study Arms (2)

GSK561679

ACTIVE COMPARATOR

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.

Drug: GSK561679

Placebo

PLACEBO COMPARATOR

Placebo was given orally, once a day in the evening, for 21 days, in the form of four tablets that matched those of GSK561679

Drug: Placebo

Interventions

GSK561679 DRUG

Verucerfont is a corticotropin releasing hormone receptor 1 (CRF1) antagonist.

Also known as: Verucerfont

GSK561679

Placebo DRUG

Placebo is an inactive tablet design to look exactly like GSK561679

Placebo

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• DSM-IV diagnosis of alcohol dependence on SCID interview (23), alcohol problems as primary complaint among substance use disorders, and alcohol use within the last month.
• Female sex
• Spielberger trait anxiety inventory (24) score \>39.
• Age 21 65 years.
• Able to comprehend the consent form, and provide informed consent.
• Either:
• of non-childbearing potential defined as pre-menopausal (for definition, see appendix females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \< 40 pg/ml (\<140 pmol/L) is confirmatory\]; or,
• of child-bearing potential, has a negative serum pregnancy test both on screening and during placebo lead-in, and agrees to one of the following methods of contraception:
• i. Practices complete abstinence from intercourse two weeks prior to administration of study drug, throughout participating in the clinical trial and for two weeks following discontinuation of the study medication or,
• iii. Has a sexual partner(s) who is/are exclusively female or,
• iv. Uses oral contraceptives (either combined or progestogen only) with single-barrier method of contraception consisting of spermicide and condom or diaphragm. Women of child-bearing potential using an oral contraceptive in combination with a single-barrier method of contraception are required to continue to use this form of contraception for 6 weeks following discontinuation of study medication.
• v. Uses double-barrier contraception, specifically, a condom plus spermicide and a female diaphragm or cervical cap. The subject must be using this method for at least 2 weeks prior to the administration of the study drug, throughout the study, and 6 weeks following discontinuation of study medication or,
• vi. Uses any intrauterine device (IUD) with published data showing that the highest expected failure rate is less than 1% per year. The subject must have the device inserted at least 2 weeks prior to the first Screen Visit, throughout the study, and 6 weeks following discontinuation of study medication.

You may not qualify if:

• Investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.
• Employees of GlaxoSmithKline (GSK) or immediate family of GSK employees.
• Current participation in another clinical study in which the subject is or will be exposed to an investigational or non-investigational drug or device; participation in a clinical study for an illness unrelated to alcohol use within the preceding month; participation in a clinical study related to alcohol use within the preceding six months; or any previous participation in a trial involving GSK561679 or closely related compounds.
• Inability or unwillingness to participate in an MR scan, including presence of ferromagnetic objects in the body that constitute a contraindication for MRI of the head, or pronounced claustrophobia
• Any medical or psychiatric condition or laboratory finding other than those explicitly listed below that, in the judgment of the investigator could adversely affect subject safety or study integrity.
• Schizophrenia, bipolar disease, or any past or present psychotic disorder other than one determined to be substance induced; past or present dementia, or any other disorder which has led to a cognitive impairment that in the opinion of the investigator interferes with the subject s ability to provide informed consent, or comply with study procedures. Any other psychiatric condition which at the present time requires, or in the past month has required pharmacological intervention other than standard withdrawal treatment as described in the NIAAA Assessment and Treatment Protocol.
• A personality disorder which, in the investigator s judgment could lead to non-compliance with study procedures.
• Subjects, who in the investigator's judgment, pose a significant suicide risk. Evidence of serious suicide risk may include any history of suicidal behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) (25) in the last 2 months.
• Unlikely or unable to complete the treatment program because of impending or likely incarceration while on the protocol.
• Required to receive treatment by a court of law or involuntarily committed to treatment.
• Positive urine test for illegal drug use.
• Human Immunodeficiency Virus (HIV) infection.
• Peptic ulcer disease within the last 10 years, a history of an upper gastro-intestinal (GI) bleeding, or a current stool positive for occult blood (if such stool was obtained without the subject abstaining from red meat for three or more days prior, testing may be repeated once following such abstinence. If that stool is negative for occult blood by the Randomization Day the subject is considered eligible).
• Any clinically significant liver disease; specifically, cirrhosis as determined by ultrasound; positive test for Hepatitis B surface antigen; positive test for Hepatitis C antibody (hepatitis C antibody positivity confirmed by testing the same sample using a highly specific immunoblot assay, or with hepatitis C RNA test on a separate frozen sample); any of the following liver function test abnormalities:
• On screening: gamma glutamyl transpeptidase (GGT) \> 5 times the upper limit of normal (ULN), aspartate aminotransferase (AST) \> 3 times ULN, alanine transaminase (ALT) \> 3 times the ULN or Alkaline Phosphatase \> 1.5 ULN; total bilirubin \>1.5 times the ULN or direct bilirubin \> 35%; Albumin below 3 g/dL; INR \> 1.5;

Sponsors & Collaborators

• National Institute on Alcohol Abuse and Alcoholism (NIAAA): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Heilig M, Egli M. Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther. 2006 Sep;111(3):855-76. doi: 10.1016/j.pharmthera.2006.02.001. Epub 2006 Mar 20.

  PMID: 16545872 BACKGROUND

• Heilig M, Koob GF. A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci. 2007 Aug;30(8):399-406. doi: 10.1016/j.tins.2007.06.006. Epub 2007 Jul 16.

  PMID: 17629579 BACKGROUND

• Epstein DH, Preston KL, Stewart J, Shaham Y. Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology (Berl). 2006 Nov;189(1):1-16. doi: 10.1007/s00213-006-0529-6. Epub 2006 Sep 22.

  PMID: 17019567 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Alcoholism; Behavior, Addictive; Anxiety Disorders

Interventions

NBI 77860

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Compulsive Behavior; Impulsive Behavior; Behavior

Results Point of Contact

• Title: Leggio, Lorenzo
• Organization: National Institute on Alcohol Abuse and Alcoholism

lorenzo.leggio@nih.gov

+1 301 435 9398

Study Officials

• Lorenzo Leggio, M.D.

  National Institute on Alcohol Abuse and Alcoholism (NIAAA)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 21, 2010
• First Posted: August 24, 2010
• Study Start: January 1, 2010
• Primary Completion: September 1, 2015
• Study Completion: September 1, 2015
• Last Updated: November 7, 2016
• Results First Posted: November 7, 2016

Record last verified: 2016-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)