Manipulating Ghrelin Signaling Via GOAT Inhibition in Alcohol Use Disorder

Phase 1

Completed

Conditions: Alcohol Use Disorder

Interventions: Other: Placebo
Drug: GLWL-01

Registration Number: NCT03896516

Lead Sponsor: National Institute on Drug Abuse (NIDA)

Brief Summary: Background:

People with alcohol use disorder (AUD) have trouble controlling their drinking. Medications can help some people with AUD but are not effective for many others. Researchers want to test new drugs to better treat the disease.

Objective:

To see if the investigational drug GLWL-01 is safe to use in people with alcohol problems. Also, to find out if the drug reduces the urge to drink alcohol.

Eligibility:

People ages 18-70 with Alcohol Use Disorder (AUD)

Design:

Participants will be screened under protocol 06-DA-N415.

Participants will be admitted to the inpatient facility, Clinical Research Unit (CRU) on the Johns Hopkins Bayview Medical Center for up to 21 days. They may leave the CRU on specified days pending approval. All their meals will be provided. They cannot drink alcohol.

Participants will take either the study drug or a placebo by mouth twice daily. They will not know which they are receiving.

Participants will complete many questionnaires.

Participants may have urine tests.

Participants will complete tasks on a computer.

Participants will have blood samples obtained on some study days.

Participants will taste and indicate their preference for sweet liquids.

Participants' blood pressure, pulse, respiratory rate, body temperature and weight, heart rate and rhythm will be measured.

Participants will have breath testing to obtain information about smoking.

Participants will be exposed to alcohol cues, water, and food cues in a bar-like room. Cues are things that might make them feel the urge to eat or drink alcohol.

Participants will take part in a virtual buffet experiment - They will wear a virtual reality headset, walk around a virtual room, and select virtual food and drink.

Detailed Description: Background and Objective: Acyl-ghrelin is a 28-amino acid peptide that stimulates appetite and food intake. It is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1a). Preclinical studies suggest that acyl-ghrelin increases alcohol intake and decreases in acyl-ghrelin and GHS-R1a function suppresses alcohol consumption. Furthermore, previous human studies indicate a positive correlation between endogenous ghrelin levels and alcohol craving and drinking. In clinical studies conducted by our group with individuals with AUD, intravenous (IV) acyl-ghrelin administration, versus placebo 1) increased alcohol craving during alcohol cue-exposure and 2) increased IV alcohol self-administration as well as decreased latency to first infusion of alcohol and 3) increased brain activation in the amygdala in anticipation of alcohol reward.

Together, this preclinical and human data suggest that manipulating the ghrelin signal may be a novel and potentially effective pharmacological approach to treat individuals with alcohol use disorder.

After the discoveries of GHS-R1a and acyl-ghrelin, a next step was identifying ghrelin O-acyltransferase (GOAT) the enzyme that catalyzes the conversion of des-acyl-ghrelin (DAG) to acyl-ghrelin via octanoylation. GOAT is thus the master switch for the ghrelin system , as acyl-ghrelin, not DAG, is biologically active at the GHSR-1a. GOAT s structure is highly conserved, is produced by endocrine cells in the stomach and is co-expressed with ghrelin. Therefore, GOAT is a promising target for manipulating the ghrelin system by altering the peripheral acyl-to-total ghrelin ratio (where total ghrelin = acyl-ghrelin + DAG). Recently, the ghrelin system has been investigated as a potential treatment target for AUDs.

As such, an oral bioavailable GOAT inhibitor offers encouraging potential as a treatment for alcohol use disorder. GLWL-01 is an existing GOAT inhibitor for which GLWL Research Inc. has recently and successfully completed a first-in-human safety clinical trial. The goal of this protocol is to conduct a proof-of-concept human laboratory study to assess a potential early signal of efficacy of GLWL-01 in relation to alcohol-related outcomes.

Study population: Males and females (N = 43) with alcohol use disorder.

Study Design: A within-subject, counterbalanced, double-blind, placebo-controlled study. Participants will take GLWL-01 450 mg b.i.d. or matched placebo for a minimum of 4 days (Stage I). After a minimum 2 day wash-out window, Stage II will take place during which the counterbalanced study drug will be administered for a minimum of 4 days.

Primary outcome measure: The co-primary aims will be to determine whether: 1) the number of adverse events (AEs) experienced differ in the GLWL-01 condition, compared to placebo; and 2) GLWL-01, compared to placebo, reduces alcohol cue-elicited craving using a validated alcohol cue-reactivity procedure.

Secondary outcome measures: The main secondary aim will be the effects of GLWL-01 on food choices using a virtual buffet experimental procedure. We will also monitor a wide range of behavioral measures including e.g., pain, anxiety, depression, alcohol craving and withdrawal, and smoking.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
GLWL-01, then Placebo	Placebo	Participants receive GLWL-01 450 mg orally twice daily for a minimum of four days (Stage I) followed by a minimum of two day wash-out period then placebo orally twice daily for a minimum of four days (stage II).
Placebo, then GLWL-01	Placebo	Participants receive placebo orally twice daily for a minimum of four days (Stage I) followed by a minimum of two day wash-out period then GLWL-01 450 mg orally twice daily for a minimum of four days (stage II).
GLWL-01, then Placebo	GLWL-01	Participants receive GLWL-01 450 mg orally twice daily for a minimum of four days (Stage I) followed by a minimum of two day wash-out period then placebo orally twice daily for a minimum of four days (stage II).
Placebo, then GLWL-01	GLWL-01	Participants receive placebo orally twice daily for a minimum of four days (Stage I) followed by a minimum of two day wash-out period then GLWL-01 450 mg orally twice daily for a minimum of four days (stage II).

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs)	Up to one month	Number of participants with adverse events related to intervention. Adverse events were collected from participants self reporting.
Alcohol Cue-elicited Craving Assessed in a "Bar-like" Laboratory	AUQ scores were collected 5-6 days per intervention [initial dosing days (2-3 days), the virtual reality buffet day (1 day), the cue-reactivity day (1 day), and the final study day (1 day)]	Alcohol cue elicited 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). Higher score indicated higher alcohol craving. AUQ was collected on each initial dosing days (2-3 days), the virtual reality buffet day (1 day), the cue-reactivity day (1 day), and the final study day (1 day), for a total of 5-6 days per intervention. The least squares average for each intervention was calculated using a linear mixed effects model including a random intercept for each participant.

Secondary Outcome Measures