Effects of Ghrelin on Alcohol Cue Reactivity and Craving

• Sponsor: Brown University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01190085
• Collaborator: (none)
• Enrollment: 45
• Location: 1
• Arms: 3

Study Details

Study Description

Brief Summary

Only a few medications are approved for the treatment of alcohol dependence and there exists a substantial need for discovering ways to provide more effective treatments. Accordingly, identifying new potential neuropharmacological targets in the treatment of alcohol dependence represents a high priority in public health. Ghrelin is a 28-amino acid peptide acting as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Ghrelin was first isolated from the stomach, but a central hypothalamic production of ghrelin has also been demonstrated. Ghrelin plays a key role in the regulation of appetite. Consistent with the common neurobiological substrates for control of food and alcohol consumption, preclinical investigations suggest that ghrelin plays a role in the neurobiology of alcohol dependence, thus representing a new potential neuropharmacology target. In keeping with the preclinical studies, human investigations showed that alcohol consumption affects blood ghrelin levels and that blood ghrelin levels significantly and positively correlate with craving measurements in alcohol-dependent individuals. The effects of exogenous ghrelin injected intravenous (i.v.) in alcohol-dependent individuals, however, have never been investigated. The current project proposes a randomized double-blind placebo-controlled 3-group between-subject laboratory study aimed at investigating the effects of exogenous ghrelin i.v. on non-treatment seeking alcohol-dependent subjects in terms of urges to drink, attention to cues and related psychophysiological measures. This project has the goals to: i) conduct an alcohol laboratory study testing the role of ghrelin i.v., therefore demonstrating the feasibility of such a study and the safety of ghrelin i.v. when administered to alcohol-dependent individuals; and ii) explore the effects of ghrelin i.v. on alcohol craving assessed under controlled conditions, such as a cue-reactivity (CR) experiment.

This study will address whether alcohol craving is affected when ghrelin levels are modified acutely via a ghrelin i.v. injection. Given the crucial need to expand our understanding of the underlying neurobiology of alcoholism, this study potentially will lead to identify new targets for the development of pharmacological treatments that may improve interventions for alcohol dependent individuals.

Condition or Disease	Intervention/Treatment	Phase
Alcoholism	Drug: Ghrelin; Drug: Ghrelin; Drug: Saline solution	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Official Title: Effects of Ghrelin on Alcohol Cue Reactivity and Craving
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ghrelin (1 microg/kg) A 1 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	Drug: Ghrelin; A 1 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.; Other Names: human acetylated ghrelin
Active Comparator: Ghrelin (3 microg/kg) A 3 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	Drug: Ghrelin; A 3 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.; Other Names: human acetylated ghrelin
Placebo Comparator: Saline Solution Intravenous saline solution (matched placebo) was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	Drug: Saline solution; Intravenous saline solution (matched placebo) was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.; Other Names: matched placebo

Outcome Measures

Primary Outcome Measures

1. Alcohol Visual Analogue Scale (A-VAS) [approximately 30 minutes after drug administration]

   Whether ghrelin intravenous (i.v.), as compared to saline i.v., dose-dependently results in increased cue-reactivity (CR) responses to alcohol cues in terms of urge to drink [as measured by the Alcohol Visual Analogue Scale (A-VAS)]. The A-VAS was rated on 11-point anchored Likert-type scales, where 0 is the minimum score (no craving) and 11 is the maximum score (highest craving intensity). The change in the A-VAS score (deltaA-VAS) was used to indicate decrease (-d) or increase (+d) in craving intensity.

2. Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability. [participants will be followed after the cue-reactivity experiment, an expected average of 7 days]

   Whether ghrelin intravenous (i.v.), as compared to saline i.v., does not significantly increase Adverse Events (AEs).

3. Salivation [approximately 30 minutes after drug administration]

   Whether ghrelin intravenous (i.v.), as compared to saline i.v., dose-dependently results in increased cue-reactivity (CR) responses to alcohol cues in terms of psychophysiological responses, namely salivation changes.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Understanding that this is not a treatment study.

• Breath alcohol concentration (BAC) equal to 0.00 when the participants sign the informed consent document.

• Age between 18 and 70 years old (inclusive).

• Female participants must be postmenopausal for at least one year, surgically sterile, or practicing an effective method of birth control before entry and throughout the study; have a negative urine pregnancy test at screening and cue-reactivity (CR) visits.

• Diagnosis of Alcohol dependence using Module E of the structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders - Text Revised (DSM-IV-TR).

• Participants must meet criteria for heavy drinking, defined as averaging ≥4 drinks/day for women and ≥5 drinks/day for men during a consecutive 30-day period within the 90 days prior to baseline evaluation

• Good health as confirmed by medical history, physical examination, electrocardiogram (ECG), laboratory tests and vital signs.

• Participant must be willing to receive an I.V. line.

Exclusion Criteria:

• Individuals expressing interest in treatment for alcoholism.

• Females who are of child bearing potential and not practicing effective birth control.

• Current (last 12 months) diagnosis of dependence on any psychoactive substance other than alcohol and nicotine (according to the DSM-IV-TR)

• DSM-IV-TR Axis I criteria for a lifetime diagnosis of schizophrenia, bipolar disorder, or other psychoses; an active illness within the past 6 months that meet the DSM-IV-TR criteria for a diagnosis of Major Depressive Disorder or Anxiety Disorder; in the investigators' opinion, moderate to severe risk of suicide (e.g. active plan, or attempt in last 6 months).

• History of hospitalization for alcohol intoxication delirium, alcohol withdrawal delirium or seizure.

• Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-Ar) ≥ 10, at any assessment.

• Positive urine drug screen at baseline for any illegal substance other than marijuana (a urine drug screen may be repeated once during the screening period).

• Subjects who have received any behavioral and/or pharmacological treatment for alcoholism within the past 30 days.

• Current use of psychotropic medications that cannot be discontinued.

• Clinically significant medical abnormalities [e.g., alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >300% the upper limit of normal].

• Significant medical conditions, such as cancer, liver cirrhosis, heart chronic failure, chronic kidney failure, chronic intestinal diseases (e.g., Crohn's disease), chronic neurological disorders (e.g., tardive dyskinesia, epilepsy, Parkinson's disease), diabetes, obesity [Body Mass Index(BMI) ≥ 30 kg/m2].

• Participants with a history of hypotension clinically significant (e.g.: history of fainting and/or syncopal attacks).

• No history of adverse reactions or hypersensitivity to ghrelin i.v. nor history of adverse reactions to needle puncture.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brown University Center for Alcohol and Addiction Studies	Providence	Rhode Island	United States	02903

Sponsors and Collaborators

• Brown University

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Addolorato G, Capristo E, Leggio L, Ferrulli A, Abenavoli L, Malandrino N, Farnetti S, Domenicali M, D'Angelo C, Vonghia L, Mirijello A, Cardone S, Gasbarrini G. Relationship between ghrelin levels, alcohol craving, and nutritional status in current alcoholic patients. Alcohol Clin Exp Res. 2006 Nov;30(11):1933-7.
• Jerlhag E, Egecioglu E, Landgren S, Salomé N, Heilig M, Moechars D, Datta R, Perrissoud D, Dickson SL, Engel JA. Requirement of central ghrelin signaling for alcohol reward. Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11318-23. doi: 10.1073/pnas.0812809106. Epub 2009 Jun 29.
• Leggio L, Addolorato G, Cippitelli A, Jerlhag E, Kampov-Polevoy AB, Swift RM. Role of feeding-related pathways in alcohol dependence: A focus on sweet preference, NPY, and ghrelin. Alcohol Clin Exp Res. 2011 Feb;35(2):194-202. doi: 10.1111/j.1530-0277.2010.01334.x. Epub 2010 Nov 8. Review.
• Leggio L, Ferrulli A, Cardone S, Nesci A, Miceli A, Malandrino N, Capristo E, Canestrelli B, Monteleone P, Kenna GA, Swift RM, Addolorato G. Ghrelin system in alcohol-dependent subjects: role of plasma ghrelin levels in alcohol drinking and craving. Addict Biol. 2012 Mar;17(2):452-64. doi: 10.1111/j.1369-1600.2010.00308.x. Epub 2011 Mar 11.
• Leggio L. Role of the ghrelin system in alcoholism: Acting on the growth hormone secretagogue receptor to treat alcohol-related diseases. Drug News Perspect. 2010 Apr;23(3):157-66. doi: 10.1358/dnp.2010.23.3.1429490.

• Responsible Party: Lorenzo Leggio, Principal Investigator, Brown University
• ClinicalTrials.gov Identifier: NCT01190085
• Other Study ID Numbers: 1005000183
• First Posted: Aug 27, 2010
• Last Update Posted: May 15, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by Lorenzo Leggio, Principal Investigator, Brown University: alcoholism; ghrelin; craving
• Additional relevant MeSH terms: Alcoholism

Study Results

Participant Flow

Recruitment Details	Individuals were recruited via advertisements in local public transportation and mass-media

Arm/Group Title	Ghrelin (1 Microg/kg)	Ghrelin (3 Microg/kg)	Saline Solution
Arm/Group Description	A 1 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	A 3 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	Intravenous saline solution (matched placebo) was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.
Period Title: Overall Study
STARTED	13	14	18
COMPLETED	13	14	18
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Ghrelin (1 Microg/kg)	Ghrelin (3 Microg/kg)	Saline Solution	Total
Arm/Group Description	A 1 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	A 3 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	Intravenous saline solution (matched placebo) was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	Total of all reporting groups
Overall Participants	13	14	18	45
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	13 100%	14 100%	18 100%	45 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.8 (9.8)	43.9 (8.6)	46.6 (9.0)	44.7 (9.1)
Sex: Female, Male (Count of Participants)
Female	4 30.8%	5 35.7%	7 38.9%	16 35.6%
Male	9 69.2%	9 64.3%	11 61.1%	29 64.4%
Region of Enrollment (participants) [Number]
United States	13 100%	14 100%	18 100%	45 100%

Outcome Measures

1. Primary Outcome

Title	Alcohol Visual Analogue Scale (A-VAS)
Description	Whether ghrelin intravenous (i.v.), as compared to saline i.v., dose-dependently results in increased cue-reactivity (CR) responses to alcohol cues in terms of urge to drink [as measured by the Alcohol Visual Analogue Scale (A-VAS)]. The A-VAS was rated on 11-point anchored Likert-type scales, where 0 is the minimum score (no craving) and 11 is the maximum score (highest craving intensity). The change in the A-VAS score (deltaA-VAS) was used to indicate decrease (-d) or increase (+d) in craving intensity.
Time Frame	approximately 30 minutes after drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ghrelin (1 Microg/kg)	Ghrelin (3 Microg/kg)	Saline Solution
Arm/Group Description	A 1 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	A 3 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	Intravenous saline solution (matched placebo) was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.
Measure Participants	13	14	18
Mean (Standard Deviation) [units on a scale]	1.95 (2.19)	2.66 (2.19)	4.29 (2.17)

2. Primary Outcome

Title	Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability.
Description	Whether ghrelin intravenous (i.v.), as compared to saline i.v., does not significantly increase Adverse Events (AEs).
Time Frame	participants will be followed after the cue-reactivity experiment, an expected average of 7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ghrelin (1 Microg/kg)	Ghrelin (3 Microg/kg)	Saline Solution
Arm/Group Description	A 1 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	A 3 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	Intravenous saline solution (matched placebo) was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.
Measure Participants	13	14	18
Number [participants]	11 84.6%	12 85.7%	15 83.3%

3. Primary Outcome

Title	Salivation
Description	Whether ghrelin intravenous (i.v.), as compared to saline i.v., dose-dependently results in increased cue-reactivity (CR) responses to alcohol cues in terms of psychophysiological responses, namely salivation changes.
Time Frame	approximately 30 minutes after drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ghrelin (1 Microg/kg)	Ghrelin (3 Microg/kg)	Saline Solution
Arm/Group Description	A 1 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	A 3 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.	Intravenous saline solution (matched placebo) was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.
Measure Participants	13	14	18
Mean (Standard Deviation) [gram]	1.8 (1.4)	1.9 (1.4)	3.2 (1.4)

Adverse Events

Time Frame	Adverse events were collected +17 minutes and +29 minutes after the ghrelin/placebo administration was ended.
Adverse Event Reporting Description	The Systematic Assessment for Treatment Emergent Events (SAFTEE) was used for adverse events. For references, see: Levine J, Schooler NR (1986). Psychopharmacology bulletin. 22:343-381; and Johnson BA, Ait-Daoud N, Roache JD (2005). Journal of Studies on Alcohol Supplement.157-167; discussion 140.
Arm/Group Title	Ghrelin (1 Microg/kg)		Ghrelin (3 Microg/kg)		Saline Solution
Arm/Group Description	A 1 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.		A 3 microg/kg dose of intravenous human acetylated ghrelin was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.		Intravenous saline solution (matched placebo) was administered once approximately 10 minutes before the start of the alcohol cue-reactivity experiment.
All Cause Mortality
	Ghrelin (1 Microg/kg)		Ghrelin (3 Microg/kg)		Saline Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ghrelin (1 Microg/kg)		Ghrelin (3 Microg/kg)		Saline Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/14 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Ghrelin (1 Microg/kg)		Ghrelin (3 Microg/kg)		Saline Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/13 (84.6%)		12/14 (85.7%)		15/18 (83.3%)
Cardiac disorders
fast heart beat	0/13 (0%)		0/14 (0%)		1/18 (5.6%)
Eye disorders
Changes in Vision	0/13 (0%)		2/14 (14.3%)		2/18 (11.1%)
eye pain	0/13 (0%)		0/14 (0%)		2/18 (11.1%)
Gastrointestinal disorders
Constipation	0/13 (0%)		1/14 (7.1%)		1/18 (5.6%)
Diarrhea	0/13 (0%)		0/14 (0%)		1/18 (5.6%)
Nausea	0/13 (0%)		0/14 (0%)		1/18 (5.6%)
General disorders
Decreased sweating	0/13 (0%)		0/14 (0%)		1/18 (5.6%)
Musculoskeletal and connective tissue disorders
Muscle aches	0/13 (0%)		0/14 (0%)		4/18 (22.2%)
Nervous system disorders
Increase in appetite	8/13 (61.5%)		11/14 (78.6%)		8/18 (44.4%)
Decrease in appetite	0/13 (0%)		4/14 (28.6%)		7/18 (38.9%)
Dizziness	0/13 (0%)		4/14 (28.6%)		3/18 (16.7%)
Sleepness	2/13 (15.4%)		2/14 (14.3%)		4/18 (22.2%)
Fatigue	2/13 (15.4%)		0/14 (0%)		2/18 (11.1%)
Difficulty with coordination	1/13 (7.7%)		4/14 (28.6%)		3/18 (16.7%)
Difficulty with Concentration	0/13 (0%)		0/14 (0%)		1/18 (5.6%)
Tingling in Fingers or Toes	1/13 (7.7%)		0/14 (0%)		2/18 (11.1%)
Word finding Difficulties	0/13 (0%)		0/14 (0%)		2/18 (11.1%)
Memory Difficulties	0/13 (0%)		0/14 (0%)		3/18 (16.7%)
Change in Taste	1/13 (7.7%)		1/14 (7.1%)		2/18 (11.1%)
Tremor	1/13 (7.7%)		3/14 (21.4%)		4/18 (22.2%)
Headache	0/13 (0%)		0/14 (0%)		2/18 (11.1%)
Restlessness	2/13 (15.4%)		1/14 (7.1%)		7/18 (38.9%)
Irritability	1/13 (7.7%)		1/14 (7.1%)		2/18 (11.1%)
Confusion	0/13 (0%)		1/14 (7.1%)		2/18 (11.1%)
Psychiatric disorders
Anxiety	7/13 (53.8%)		2/14 (14.3%)		4/18 (22.2%)
Mood Disturbance	0/13 (0%)		3/14 (21.4%)		5/18 (27.8%)
Renal and urinary disorders
Difficulty passing urine	0/13 (0%)		0/14 (0%)		1/18 (5.6%)
Reproductive system and breast disorders
Changes in Libido	0/13 (0%)		0/14 (0%)		3/18 (16.7%)
Respiratory, thoracic and mediastinal disorders
Slowed Breathing	0/13 (0%)		1/14 (7.1%)		2/18 (11.1%)
Difficulty breathing	1/13 (7.7%)		0/14 (0%)		1/18 (5.6%)
Swelling of throat or tongue	0/13 (0%)		1/14 (7.1%)		1/18 (5.6%)
Skin and subcutaneous tissue disorders
itching	0/13 (0%)		0/14 (0%)		2/18 (11.1%)

Limitations/Caveats

Small proof-of-concept study

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.