Gut Hormones in Obesity, Nicotine and Alcohol Dependence

NCT02690987 | Unknown Early Phase 1 DMC

• 2 other identifiers: 15/LO/1041MR/M007022/1
• Study Type: interventional
• Target: 95
• Locations: 1 country
• Sites: 1

Brief Summary

The "Gut Hormones in Addiction" study is a proof-of-concept experimental medicine human study to answer the following questions:

1. 1.Does the administration of the hormone desacyl ghrelin reduce core behavioural components of addiction in dependent individuals who have recently stopped smoking tobacco or drinking alcohol, or overweight/obese subjects?
2. 2.Does the administration of the drug Exenatide reduce core behavioural components of addiction in dependent individuals who have recently stopped smoking tobacco or drinking alcohol, or overweight/obese subjects?
3. 3.Does the administration of desacyl ghrelin or Exenatide reduce reward responses to high-calorie foods and appetite in dependent individuals who have recently stopped smoking tobacco or drinking alcohol, or overweight/obese subjects?

Conditions

Obesity; Smoking Cessation; Alcoholism

Keywords

tobacco; GLP1; ghrelin; alcohol; appetite; reward; addiction; hormone; cigarette; functional MRI

Outcome Measures

Primary Outcomes (1)

• Functional MRI measure of brain activation during cigarette, alcohol and food picture evaluation task

  Blood oxygen level dependent (BOLD) signal in brain reward systems to cigarette, alcohol and food pictures vs. object pictures

  4 years

Secondary Outcomes (5)

• Functional MRI measure of brain activation during anticipation of winning monetary reward (monetary incentive delay task)

  4 years

• Functional MRI measure of brain activation during negative emotional reactivity task

  4 years

• Functional MRI measure of brain activity in salience resting state network

  4 years

• Functional MRI measure of brain activity in limbic resting state network

  4 years

• Functional MRI measure of brain activity in default mode resting state network

  4 years

Other Outcomes (43)

• Hunger visual analogue scale rating

  4 years

• Alcohol Urge Questionnaire

  4 years

• Questionnaire of Smoking Urges

  4 years

Study Arms (3)

Overweight/obese subjects

EXPERIMENTAL

Overweight/obese volunteers with BMI 28.0-50.0 kg/m2, otherwise healthy. This group will receive interventions with saline as placebo, Exenatide and desacyl ghrelin infusions at separate visits in a within subject randomised crossover design.

Drug: Exenatide; Biological: Desacyl ghrelin; Biological: Saline

Ex-smokers

EXPERIMENTAL

Abstinent tobacco dependent individuals who score at least moderately on tobacco dependence as measured retrospectively using the Fagerström Test for Nicotine Dependence (FTND), and who have been in stable tobacco abstinence for at least 6 weeks. This group will receive interventions with saline as placebo, Exenatide and desacyl ghrelin infusions at separate visits in a within subject randomised crossover design.

Drug: Exenatide; Biological: Desacyl ghrelin; Biological: Saline

Ex-alcohol dependent subjects

EXPERIMENTAL

Abstinent alcohol dependent individuals who score at least moderately alcohol dependent as measured retrospectively using the Severity of Alcohol Dependence Questionnaire (SADQ), and who have been abstinent for at least 6 weeks. This group will receive interventions with saline as placebo, Exenatide and desacyl ghrelin infusions at separate visits in a within subject randomised crossover design.

Drug: Exenatide; Biological: Desacyl ghrelin; Biological: Saline

Interventions

Exenatide DRUG

Exenatide is a commercially available GLP-1 receptor agonist. It is a synthetic form of exendin-4, a protein extracted from the saliva of a Gila monster lizard, which exhibits 53% sequence identity to human GLP-1. The planned intravenous Exenatide infusion dose is expected to be 0.06 pmol/kg/min aiming for maintenance plasma concentrations of \~130-190 pg/mL.

Also known as: Byetta

Ex-alcohol dependent subjects; Ex-smokers; Overweight/obese subjects

Desacyl ghrelin BIOLOGICAL

Ghrelin is a 28 amino acid stomach-derived peptide hormone, with the desacyl ghrelin (DAG) form inactive at the GHSR1a receptor. Good Manufacturing Practice (GMP)-grade DAG is obtained from Clinalfa (Bachem AG, Bubendorf, Switzerland). The planned intravenous DAG infusion dose is expected to be 4.0 mcg/kg/hour aiming for maintenance plasma concentrations of \~13-19 ng/mL.

Also known as: Unacylated ghrelin

Ex-alcohol dependent subjects; Ex-smokers; Overweight/obese subjects

Saline BIOLOGICAL

The placebo visit will involve an intravenous infusion of normal saline.

Ex-alcohol dependent subjects; Ex-smokers; Overweight/obese subjects

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female volunteers between the ages of 18 and 60 years.
• Healthy as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, laboratory tests, cardiac monitoring and a psychiatric evaluation. Any volunteer with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included, only if the investigators concur that the finding is unlikely to jeopardize either volunteer safety or study integrity.
• The subject is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• The subject is able to read, comprehend and record information written in English.
• For non-dependent groups:
• i) Overweight/obese volunteers with BMI 28.0-50.0 kg/m2.
• For addiction groups:
• Subjects meeting Diagnostic and Statistical Manual (DSM)-V criteria for previous nicotine or alcohol dependence, but who are in early stable abstinence (\>6 weeks). Minor lapses within this time period will be allowed but not relapses into dependence.
• ii) Abstinent alcohol dependent individuals who score at least moderately alcohol dependent as measured retrospectively using the Severity of Alcohol Dependence Questionnaire (SADQ), and who have been abstinent for \>6 weeks.
• iii) Abstinent tobacco dependent individuals who score at least moderately on tobacco dependence as measured retrospectively using the Fagerström Test for Nicotine Dependence (FTND), and who have been in stable tobacco abstinence for \>6 weeks.

You may not qualify if:

• Previous history of recreational use or abuse of other substances of addiction will be permissible, but there should be no use of any illegal drugs (except cannabis) in the month prior to the Screening Visit or during the course of the study, except where specified for individual groups below.
• For individual groups:
• i) Overweight/obese group: history of or current alcohol abuse or dependence; nicotine use other than "never smoked", i.e. \>100 cigarettes lifetime use; history of dependence, abuse or heavy recreational use of cocaine, cannabis, opiates or other substance of abuse; history of problem gambling. Any previous or current psychiatric diagnosis listed in Diagnostic and Statistical Manual (DSM)-V Axis I, which in the opinion of the clinical team will compromise conduct and interpretability of the study.
• ii) Abstinent tobacco dependent group: history of or current alcohol abuse or dependence; current dependence for cocaine, cannabis, opiates or other substance of abuse, or problem gambling (previous history will be allowed); taking varenicline, bupropion or other prescription medications for smoking cessation. Any previous or current psychiatric diagnosis listed in Diagnostic and Statistical Manual (DSM)-V Axis I, which in the opinion of the clinical team will compromise conduct and interpretability of the study.
• iii) Abstinent alcohol dependent group: current dependence for cocaine, cannabis, opiates or other substance of abuse, or problem gambling (previous history will be allowed); taking prescription medication for alcohol or smoking cessation or withdrawal; smoking is allowed past or present including dependence; current nicotine replacement therapy is allowed.
• Currently suffering from Diagnostic and Statistical Manual (DSM)-V depressive disorder or on anti-depressant medication, though a history of depression or anxiety will be allowed. A current or past history of enduring severe mental illness (e.g., schizophrenia, bipolar affective disorder) will not be allowed.
• For all groups:
• Cannabis use up to five times in the month prior to the Screening Visit will be allowed, but no use within one week of experimental assessments; no use of any other illegal drugs in the month prior to the Screening Visit or during the course of the study.
• Intoxication at any of the visits, as manifested by difficulty in walking, slurring of speech, difficulty concentrating or drowsiness (or by the subject volunteering this information directly to the research team).
• Positive drug/alcohol screens on testing at the screening visit, other than that explicable by other causes (e.g. recent use of opiate containing analgesic etc), at the discretion of the research team.
• Carbon monoxide levels of =/\>10ppm in the overweight/obese and abstinent smoker groups at screening visit.
• Use of current regular prescriptions (including smoking or alcohol cessation medicines such as Disulfiram, Acamprosate, Naltrexone, Bupropion; weight loss medication including Orlistat, Metformin, GLP-1 agonists, Bupropion, Naltrexone), or over-the-counter medications that in the opinion of the Investigators may affect subject safety or outcome measures.
• Pulse rate \<40 or \>100 beats per minute OR systolic blood pressure \>160 and \<100 and a diastolic blood pressure \>95 and \<50 in the semi-supine position.
• Claustrophobia or feels that they will be unable to lay still on their back in the MRI scanner for a period of \~80 minutes.
• Presence of a cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies as assessed by a standard pre-MRI questionnaire and radiographer.

Sponsors & Collaborators

• Imperial College London: lead

Study Sites (1)

Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, Hammersmith Hospital

London, W12 0NN, United Kingdom

Location

Related Publications (9)

• Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E. The role of the central ghrelin system in reward from food and chemical drugs. Mol Cell Endocrinol. 2011 Jun 20;340(1):80-7. doi: 10.1016/j.mce.2011.02.017. Epub 2011 Feb 24.

  PMID: 21354264 BACKGROUND

• Egecioglu E, Engel JA, Jerlhag E. The glucagon-like peptide 1 analogue Exendin-4 attenuates the nicotine-induced locomotor stimulation, accumbal dopamine release, conditioned place preference as well as the expression of locomotor sensitization in mice. PLoS One. 2013 Oct 18;8(10):e77284. doi: 10.1371/journal.pone.0077284. eCollection 2013.

  PMID: 24204788 BACKGROUND

• Goldstone AP, Prechtl CG, Scholtz S, Miras AD, Chhina N, Durighel G, Deliran SS, Beckmann C, Ghatei MA, Ashby DR, Waldman AD, Gaylinn BD, Thorner MO, Frost GS, Bloom SR, Bell JD. Ghrelin mimics fasting to enhance human hedonic, orbitofrontal cortex, and hippocampal responses to food. Am J Clin Nutr. 2014 Jun;99(6):1319-30. doi: 10.3945/ajcn.113.075291. Epub 2014 Apr 23.

  PMID: 24760977 BACKGROUND

• Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO. The Fagerstrom Test for Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict. 1991 Sep;86(9):1119-27. doi: 10.1111/j.1360-0443.1991.tb01879.x.

  PMID: 1932883 BACKGROUND

• Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption--II. Addiction. 1993 Jun;88(6):791-804. doi: 10.1111/j.1360-0443.1993.tb02093.x.

  PMID: 8329970 BACKGROUND

• Shirazi RH, Dickson SL, Skibicka KP. Gut peptide GLP-1 and its analogue, Exendin-4, decrease alcohol intake and reward. PLoS One. 2013 Apr 16;8(4):e61965. doi: 10.1371/journal.pone.0061965. Print 2013.

  PMID: 23613987 BACKGROUND

• Tong J, Davis HW, Summer S, Benoit SC, Haque A, Bidlingmaier M, Tschop MH, D'Alessio D. Acute administration of unacylated ghrelin has no effect on Basal or stimulated insulin secretion in healthy humans. Diabetes. 2014 Jul;63(7):2309-19. doi: 10.2337/db13-1598. Epub 2014 Feb 18.

  PMID: 24550190 BACKGROUND

• van Bloemendaal L, IJzerman RG, Ten Kulve JS, Barkhof F, Konrad RJ, Drent ML, Veltman DJ, Diamant M. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes. 2014 Dec;63(12):4186-96. doi: 10.2337/db14-0849. Epub 2014 Jul 28.

  PMID: 25071023 BACKGROUND

• Scholtz S, Miras AD, Chhina N, Prechtl CG, Sleeth ML, Daud NM, Ismail NA, Durighel G, Ahmed AR, Olbers T, Vincent RP, Alaghband-Zadeh J, Ghatei MA, Waldman AD, Frost GS, Bell JD, le Roux CW, Goldstone AP. Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding. Gut. 2014 Jun;63(6):891-902. doi: 10.1136/gutjnl-2013-305008. Epub 2013 Aug 20.

  PMID: 23964100 BACKGROUND

MeSH Terms

Conditions

Obesity; Smoking Cessation; Alcoholism; Behavior, Addictive

Interventions

Exenatide; ghrelin, des-n-octanoyl; Sodium Chloride

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Health Behavior; Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Compulsive Behavior; Impulsive Behavior

Intervention Hierarchy (Ancestors)

Peptides; Amino Acids, Peptides, and Proteins; Venoms; Complex Mixtures; Toxins, Biological; Biological Factors; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Tony Goldstone, MD, PhD

  Imperial College London

  PRINCIPAL INVESTIGATOR

• David Nutt, MD, PhD

  Imperial College London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 11, 2015
• First Posted: February 24, 2016
• Study Start: August 1, 2015
• Primary Completion: August 21, 2019
• Study Completion: August 1, 2020
• Last Updated: February 13, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)