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

Phase 2

Completed

• Conditions: Alcohol Use Disorder
• Interventions: Other: Placebo; Drug: GET73

• Registration Number: NCT03418623
• Lead Sponsor: Laboratorio Farmaceutico Ct S.r.l.

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.

Detailed Description

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.

The enrolment period will last approximately 18 to 21 months. For each subject the study will last 25 to 45 days.

The primary objective of the study is to evaluate whether GET73 modulates central glutamate levels in recently abstinent individuals with AUD, using proton nuclear magnetic resonance spectroscopy (¹H-MRS).

The secondary objectives of the study are:

1. To evaluate whether GET73 modulates central GABA levels in recently abstinent individuals with AUD, using proton nuclear magnetic resonance spectroscopy (¹H-MRS)

2. To evaluate whether GET73 affects alcohol cue induced brain activity in reward areas of brain.

3. To explore whether the effects of GET73 on glutamate and GABA levels are related to its effects on alcohol cue induced brain activity.

Safety Objective To evaluate the safety profile of GET73 in individuals with AUD, comparing Adverse Events (AEs) occurrence during GET73 treatment period vs placebo treatment period.

This is a within-subject cross-over, randomized, double-blind, placebo-controlled study.

Being a double blinded study, GET73 and placebo will be packaged identically. Both the Investigator and the study participant will be unaware of the treatment administered.

The investigational product will be supplied to the Center packaged in "patient kits". Each "patient kit" will be made of 2 bottles (bottle A and bottle B) each containing 20 capsules of either GET73 or placebo.

Being a cross-over design, all participants will receive both placebo and active treatment. The sequential order in which they will be administered to each participant will be defined by the randomization list. The participant will always receive bottle A in the phase A of the study and bottle B in phase B, but the content of the two bottles varies according to the randomization list. Research personnel will be blind to the content of the bottles, i.e. what study medication the subject is taking.

Study Timeline

• Study First Submitted: 2018-01-08
• Study First Submitted QC: 2018-01-25
• Study First Posted: 2018-02-01
• Study Start: 2018-03-08
• Primary Completion: 2020-03-13
• Study Completion: 2020-03-13
• Status Verified: 2020-10
• Last Update Submitted: 2020-10-05
• Last Update Posted: 2020-10-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

1. Male participants, or females who are post-menopausal or surgically sterile.
2. Age between 21 and 40 years old (inclusive).
3. 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).
4. 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.
5. Must report drinking within the 48 hours prior to the first dose of medication in each study medication period.
6. 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.
7. Currently not engaged in, and does not want treatment for, alcohol related problems.
8. Able to read and understand questionnaires and informed consent.

Exclusion Criteria

1. Current DSM-5 diagnosis of any other substance use disorder except Nicotine Use Disorder.
2. 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.
3. 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).
4. 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.
5. Current suicidal or homicidal ideation.
6. Need for maintenance or acute treatment with any psychoactive medication, including antiepileptic medications.
7. Current use, or use in the past 30 days, of any medication known to affect alcohol intake (e.g., disulfiram, naltrexone, acamprosate, topiramate).
8. 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.
9. Clinically significant medical problems (e.g., unstable hypertension, neurological, cardiovascular, renal, gastrointestinal, or endocrine problems) that would impair participation or limit medication ingestion.
10. 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.
11. Lack of a stable living situation.
12. Presence of ferrous metal in the body, as evidenced by metal screening and self-report.
13. Severe claustrophobia or weight > 300 pounds that preclude placement in the MRI scanner.
14. History of head injury with > 2 minutes of unconsciousness.
15. Participation in any behavioral and/or pharmacological study within the past 30 days;
16. Concomitant use of CYP2C19 substrates; use of CYP2C19 and CYP3A4 inhibitors or inducers in the 14 days before dosing.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	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.
GET73	GET73	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.

Primary Outcome Measures

Name	Time	Method
Concentrations of glutamate 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)	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

Secondary Outcome Measures

Name	Time	Method
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)	The presence of water and GABA will be quantified through ¹H-MRS and the change in GABA/water concentration between baseline and end of treatment will be assessed
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)	Magnitude of change in the blood oxygenation level dependent (BOLD) signal to alcohol cues, relative to neutral beverage cues, in the ventral striatum and dorsal anterior cingulate cortex (alcohol cue reactivity task described in Schacht et al., 2013)

Trial Locations

Locations (1)

Department of Psychiatry and Behavioral Sciences - Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States