Ghrelin Signaling Via GOAT Inhibition in Alcohol Use Disorder
Ghrelin Signaling Via GOAT Inhibition in Alcohol Use Disorder
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 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 who are seeking treatment for AUD

 Design:

 Participants will be screened under protocol 14-AA-00181.

 Participants will be admitted to the NIH Clinical Center for up to 32 days. They may leave
 the hospital some of the time. 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 tests each day.

 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.

 ...
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 (Szulc, Mikolajczak et al. 2013, Cepko et
 al. 2014) and decreases in acyl-ghrelin and GHS-R1a function suppresses alcohol consumption
 (Kaur and Ryabinin 2010, Landgren et al. 2012, Bahi et al. 2013, Suchankova et al. 2013,
 Gomez and Ryabinin 2014, Suchankova, Engel et al. 2016 Furthermore, previous human studies
 indicate a positive correlation between endogenous ghrelin levels and alcohol craving and
 drinking (Addolorato, Capristo et al.2006). 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
 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.
-  INCLUSION CRITERIA:

 -  Mild - Moderate Alcohol Use Disorder (2-5 of the I2 symptoms on MINI)

 -  Male or female individuals 18-70 years old (inclusive)

 -  Able to speak, read, write and understand English

 -  Most recent urine drug test for benzodiazepines, barbiturates, cocaine metabolites,
 morphine, oxycodone, methadone, amphetamine, & buprenorphine is negative

 -  Most recent Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar)
 score is less than or equal to 8

 -  Penn Alcohol Craving Score (PACs) is >=15

 Males only:

 -Males agrees agree to sexual abstinence or to use a reliable method of birth control
 during the study and 3 months following the last dose of the study drug. Acceptable methods
 of birth control may include: 1) condom with spermicide; 2) diaphragm with spermicide; or
 3) female condom with spermicide.

 Females only:

 -Women of child-bearing potential may participate in the study:

 -  if they test negative for pregnancy (based on a urine pregnancy test) prior to
 initiation of treatment

 -  they must also agree to use either 1 highly effective method of contraception or a
 combination of 2 effective methods of contraception during the study.

 -  Highly effective method may include hormonal contraceptives (e.g., combined oral
 contraceptives, patch, vaginal ring, injectables, and implants); intrauterine
 device or/ intrauterine system; vasectomy and tubal ligation.

 -  Effective methods may include barrier methods of contraception (e.g., male
 condom, female condom, cervical cap, diaphragm, contraceptive sponge)

 Women may choose to use a double-barrier method of contraception. Barrier methods without
 concomitant use of a spermicide are not reliable or an acceptable method. Thus, each
 barrier method must include use of a spermicide. It should be noted that the use of male
 and female condoms as a double-barrier method is not considered acceptable due to the high
 failure rate when these methods are combined.

 OR

 -Women not of child-bearing potential may participate in the study and include those who
 have

 -  spontaneous amenorrhea for at least 12 months, not induced by a medical condition such
 as anorexia nervosa and not taking medications that induced amenorrhea e.g., oral
 contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, selective
 estrogen receptor modulators, or chemotherapy; or

 -  spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone (FSH)
 level greater than 40 mIU/mL; or

 -  women with a history of hysterectomy or bilateral oophorectomy must be at least 40
 years of age and FSH >40 mIU/mL.

 EXCLUSION CRITERIA:

 -  Lifetime clinical diagnosis of schizophrenia or bipolar disorder

 -  BMI < 18.5 kg/m(2)

 -  BMI >= 40 kg/m(2)

 -  weight less than 60 kg

 -  History of epilepsy and/or seizures

 NOTE: individuals who have a history of alcohol withdrawal seizures may be in the study as
 long as they have been abstinent from alcohol for at least 2 weeks prior to consent and
 during that period of abstinence, there were no seizure episodes (otherwise, participant
 remains not eligible).

 -  Creatinine greater than or equal to 2 mg/dL, AST or ALT > 3 times the upper normal
 limit, hemoglobin <10.5 g/dl

 -  Diagnosis of liver cirrhosis

 -  Clinically significant history or current eating, thyroid, pituitary or adrenal gland
 disorders or disorder of gastric motility as judged by a study clinician as determined
 from medical history and/or current clinical screening information

 -  Clinically significant abnormal ECG

 -  QTcF > 450 msec for men and > 470 msec for women

 -  Family history of Long QT Syndrome.

 -  Patients on weight loss medications within 30 days of dosing

 -  Patients with a history of bariatric surgery

 -  Diagnosis of diabetes and currently on medication

 -  Unable to refrain from or anticipates the use of:

 -  Any drugs known to be significant inhibitors of cytochrome P450 (CYP)3A enzymes
 and/or P-glycoprotein (P-gp) including regular consumption of grapefruit or
 grapefruit juice for 14 days prior to the first dose of study medication.

 [medications like acetaminophen (up to 2 g per 24-hour period) and ibuprofen may be
 permitted during the study]

 -  Any drugs known to be significant inducers of CYP3A enzymes and/or P-gp, including St.
 John s Wort, for 28 days prior to the first dose of study medication.

 -  Any medications that prolong the QTcF, unless the patient has been stable on the
 medication for at least 3 months and has a QTcF equal to or < 450 msec

 -  Benzodiazepines. If a participant received a benzodiazepine as part of their treatment
 during the alcohol detoxification, then s/he can still be enrolled. However, 5
 half-lives (for that benzodiazepine) will be required to elapse before the anticipated
 date of first study drug administration

 -  Currently taking simvastatin >10 mg per day, atorvastatin >20 mg per day, or
 lovastatin >20 mg per day.

 The doses of these statins in combination products should not exceed these defined dose
 levels.

 -  Patients with a history of statin-induced myopathy/rhabdomyolysis.

 -  Vision is unable to be corrected to (Snellen) 20/100

 -  Clinically-significant history of motion or car sickness, or history of vestibular
 disorders

 -  Any other reason or clinical condition for which the PI or the MAI or other study
 clinician will consider unsafe for a possible participant to participate in this study