Effect of GET73 on MRS Measures of Central Glutamate and GABA in Individuals With Alcohol Use Disorder

NCT03418623 | Completed Phase 2 FDA Drug

• 1 other identifier: GET73 ¹H-MRS
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This study is aimed at examining whether GET73 modulates the indices of central glutamate and γ-aminobutyric acid (GABA) levels in recently abstinent subjects that meet Alcohol Use Disorder (AUD) criteria, as measured by proton nuclear magnetic resonance spectroscopy (¹H-MRS), in order to provide a human translation of the findings demonstrated in different preclinical models, both in vitro and in vivo. In addition, the study will examine the effects of GET73 on alcohol cue induced brain activation by using a well-established blood-oxygen-level-dependent (BOLD) functional magnetic resonance (fMRI) paradigm in the same individuals. In summary, the study should provide important information on (i) the potential mechanism of action of GET73, (ii) on the brain mechanisms that would support its potential use for reduction in craving and drinking in AUD patients, and (iii) expand data on its safe use as a medication in heavy drinking individuals.

Conditions

Alcohol Use Disorder

Keywords

Glutamate; Alcohol use; GABA; GET73; Non-treatment seeking

Outcome Measures

Primary Outcomes (1)

• Concentrations of glutamate in dorsal anterior cingulate measured via Proton Magnetic Resonance Spectroscopy

  The presence of water and glutamate will be quantified through ¹H-MRS and the change in glutamate/water concentration between baseline and end of treatment will be assessed

  After 5 doses of medication administered over 2 days, repeated after a wash-out period of 7 to 21 days (crossover design)

Secondary Outcomes (2)

• Concentrations of GABA in dorsal anterior cingulate measured via Proton Magnetic Resonance Spectroscopy

  After 5 doses of medication administered over 2 days, repeated after a wash-out period of 7 to 21 days (crossover design)

• Change in the blood oxygenation level dependent (BOLD) signal to alcohol cues

  After 5 doses of medication administered over 2 days, repeated after a wash-out period of 7 to 21 days (crossover design)

Study Arms (2)

GET73

EXPERIMENTAL

GET73 is administered at the dose of 300 mg t.i.d. per day, with a minimum gap of 4 hours between administrations and a maximum gap of 9 hours. Each subject ingests a total of 5 capsules of GET73: 3 capsules of GET73 on the first day of the related phase, according to randomization, and 2 capsules on the second day of each phase.

Drug: GET73

Placebo

PLACEBO COMPARATOR

Placebo is administered t.i.d. per day, with a minimum gap of 4 hours between administrations and a maximum gap of 9 hours. Each subject ingests a total of 5 capsules of Placebo: 3 capsules of Placebo on the first day of the related phase, according to randomization, and 2 capsules on the second day.

Other: Placebo

Interventions

GET73 DRUG

GET73 300 mg oral capsules, administered three times a day on Visit 2 and 4, and twice a day on Visit 3 and 5.

GET73

Placebo OTHER

Placebo oral capsules, administered three times a day on Visit 2 and 4, and twice a day on Visit 3 and 5.

Placebo

Eligibility Criteria

• Age: 21 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male participants, or females who are post-menopausal or surgically sterile.
• Age between 21 and 40 years old (inclusive).
• Meets Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria for current Alcohol Use Disorder, moderate severity (4 or more criteria met) as indicated by the Structured Clinical Interview for DSM-5 (SCID-5-RV).
• Reports drinking, on average, \> 20 standard drinks per week in the 90 days prior to screening evaluation, and in the last week prior to screening.
• Must report drinking within the 48 hours prior to the first dose of medication in each study medication period.
• Positive for Ethyl Glucuronide (EtG) in urine (\> 100 ng/ml) at screening and prior to the first dose of medication in each study medication period.
• Currently not engaged in, and does not want treatment for, alcohol related problems.
• Able to read and understand questionnaires and informed consent.

You may not qualify if:

• Current DSM-5 diagnosis of any other substance use disorder except Nicotine Use Disorder.
• Any psychoactive substance use (except marijuana and nicotine) within the last 30 days before the screening visit, as indicated by self-report and/or urine drug screen.
• No marijuana use within the last seven days before the screening visit, by verbal report and negative urine drug test (\< 50 ng/mL); if positive at screening, must be negative or decreasing urine Delta9-Tetrahydrocannabinol (THC) levels (corrected for urine creatinine level) at the second test (Day1 A-1).
• Current DSM-5 Axis I diagnosis, including major depression, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, bipolar affective disorder, schizophrenia, dissociative disorders, eating disorders, or any other psychotic or organic mental disorder.
• Current suicidal or homicidal ideation.
• Need for maintenance or acute treatment with any psychoactive medication, including antiepileptic medications.
• Current use, or use in the past 30 days, of any medication known to affect alcohol intake (e.g., disulfiram, naltrexone, acamprosate, topiramate).
• History of severe alcohol withdrawal (e.g., seizure, delirium tremens), as evidenced by self-report or a Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) score \> 10.
• Clinically significant medical problems (e.g., unstable hypertension, neurological, cardiovascular, renal, gastrointestinal, or endocrine problems) that would impair participation or limit medication ingestion.
• Current or past hepatocellular disease, as indicated by verbal report or elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 300% the upper limit of the normal range, or bilirubin \> 150% the upper limit of the normal range.
• Lack of a stable living situation.
• Presence of ferrous metal in the body, as evidenced by metal screening and self-report.
• Severe claustrophobia or weight \> 300 pounds that preclude placement in the MRI scanner.
• History of head injury with \> 2 minutes of unconsciousness.
• Participation in any behavioral and/or pharmacological study within the past 30 days;

Sponsors & Collaborators

• Laboratorio Farmaceutico Ct S.r.l.: lead
• Latis S.r.l.: collaborator

Study Sites (1)

Department of Psychiatry and Behavioral Sciences - Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Related Publications (1)

• Schacht JP, Anton RF, Voronin KE, Randall PK, Li X, Henderson S, Myrick H. Interacting effects of naltrexone and OPRM1 and DAT1 variation on the neural response to alcohol cues. Neuropsychopharmacology. 2013 Feb;38(3):414-22. doi: 10.1038/npp.2012.195. Epub 2012 Oct 3.

  PMID: 23032071 BACKGROUND

MeSH Terms

Conditions

Alcoholism; Alcohol Drinking

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Drinking Behavior; Behavior

Study Officials

• Raymond F Anton, MD

  Department of Psychiatry and Behavioral Sciences - Medical University of South Carolina

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The study will be double-blinded. At initiation visit the Investigator will be instructed on the method for blind breaking. The Contract Research Organization (CRO) will provide the Investigator with a set of sealed envelopes, each containing the unblinding information for a patient kit; the envelopes will be kept in the Pharmacy until the end of the study. A second set of sealed envelopes will be kept by the Sponsor pharmacovigilance officer. Unblinding codes should only be used in emergency situations for reasons of patient safety. The Investigator should contact the Sponsor before breaking the blind or the Sponsor should be informed immediately afterwards. The reason for breaking the blind must be fully documented and entered on the case report form. The unblinding envelopes will be checked for integrity by the Clinical Research Associate (CRA) and returned to the Sponsor at the end of the study. The subjects for whom the blind will be broken will be withdrawn from the study.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: After the eligibility of a subject has been determined in an initial screening period, the study will be conducted in 2 consecutive phases: in the first phase (phase A) the participant will be administered GET73 or placebo in a randomized order, in the other phase (phase B), the participant will be administered the treatment not received during phase A.

Study Record Dates

• First Submitted: January 8, 2018
• First Posted: February 1, 2018
• Study Start: March 8, 2018
• Primary Completion: March 13, 2020
• Study Completion: March 13, 2020
• Last Updated: October 8, 2020

Record last verified: 2020-10

Locations

US (1)