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Ghrelin Signaling Via GOAT Inhibition in Alcohol Use Disorder

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ClinicalTrials.gov Identifier: NCT03896516
Recruitment Status : Not yet recruiting
First Posted : April 1, 2019
Last Update Posted : October 16, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )

Tracking Information
First Submitted Date  ICMJE March 27, 2019
First Posted Date  ICMJE April 1, 2019
Last Update Posted Date October 16, 2019
Estimated Study Start Date  ICMJE October 21, 2019
Estimated Primary Completion Date November 26, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 29, 2019)
Primary outcome mesure: 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 validated cue-r... [ Time Frame: 1-year ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03896516 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 29, 2019)
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, withdrawal, smoking [ Time Frame: 1-year ]
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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ghrelin Signaling Via GOAT Inhibition in Alcohol Use Disorder
Official Title  ICMJE Manipulating Ghrelin Signaling Via GOAT Inhibition in Alcohol Use Disorder
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 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.

...

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 (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 7 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 7 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Condition  ICMJE Alcohol Use Disorder
Intervention  ICMJE
  • Drug: GLWL-01
    Participants will take GLWL-01 450 mg b.i.d. or matched placebo for up to 16 days (Stage I). After a wash-out window, Stage II will take place during which the counterbalanced study drug will be administered for up to 16 days.
  • Other: Placebo
    Participants will take GLWL-01 450 mg b.i.d. or matched placebo for up to 16 days
Study Arms  ICMJE
  • Experimental: Active Drug
    GOAT Inhibitor
    Intervention: Drug: GLWL-01
  • Placebo Comparator: Placebo
    Placebo
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: March 29, 2019)
43
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 26, 2020
Estimated Primary Completion Date November 26, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:
  • Male or female individuals 18-70 years old (inclusive)
  • Able to speak, read, write and understand English
  • Seeking treatment for alcohol problems
  • Most recent urine drug test for illegal drugs of abuse is negative
  • Most recent Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar) score is less than or equal to 8

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
  • 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.
  • Unable to pass a finger rub hearing test
  • 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 will consider unsafe for a possible participant to participate in this study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lisa A Farinelli, R.N. (301) 496-0836 farinellila@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03896516
Other Study ID Numbers  ICMJE 190075
19-AA-0075
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )
Study Sponsor  ICMJE National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Lorenzo Leggio, M.D. National Institute on Alcohol Abuse and Alcoholism (NIAAA)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date May 20, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP