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Gut Hormones in Obesity, Nicotine and Alcohol Dependence (GHADD)

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ClinicalTrials.gov Identifier: NCT02690987
Recruitment Status : Active, not recruiting
First Posted : February 24, 2016
Last Update Posted : February 13, 2020
Sponsor:
Information provided by (Responsible Party):
Imperial College London

Brief Summary:

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

  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. 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. 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?

Condition or disease Intervention/treatment Phase
Obesity Smoking Cessation Alcoholism Drug: Exenatide Biological: Desacyl ghrelin Biological: Saline Early Phase 1

Detailed Description:

Obesity, smoking and alcohol dependence are major health burdens to society. Relapse after alcohol and smoking abstinence is common despite the use of combined behavioural support and current limited available medications. In obesity, nonsurgical interventions have also been disappointing in achieving longterm weight loss. Therefore, there is a pressing need to develop novel drug treatments for addiction derived from knowledge of brain mechanisms related to relapse and reward responses to food and drugs.

There is evidence in animals that some gut hormones, produced in the stomach and intestine, influence the consumption of food and desire for food, but also alcohol, nicotine and other drugs of abuse. Examples of such gut hormones are glucagon-like peptide1 (GLP1) and ghrelin.

The influence of these hormones is exerted through brain systems involved in the core behavioural components of addiction: reward sensitivity, stress, impulsivity and compulsivity. These components are often also seen in obesity and food-related disorders such as binge eating disorder. It is unknown whether these gut hormones directly influence the core behavioural components of addiction in humans, particularly during abstinence.

The investigators will examine the acute effects of Exenatide (mimics GLP1) and desacyl ghrelin (counteracts active acyl ghrelin), which are infused through a vein, on brain reward systems, craving for food, cigarettes and alcohol, and addictive and eating behaviours.

The investigators will recruit adults with nicotine or alcohol dependence who have recently stopped smoking or drinking, and overweight/obese adults. The investigators will use functional magnetic resonance imaging (MRI) brain scans and computer-based test over 3 separate study days to study different aspects of eating and addictive behaviours.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 95 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: Do Appetitive Gut Hormones Reduce Addictive and Eating Behaviours in Obesity, and Nicotine and Alcohol Dependence?
Actual Study Start Date : August 2015
Actual Primary Completion Date : August 21, 2019
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Exenatide

Arm Intervention/treatment
Experimental: Overweight/obese subjects
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

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.

Other Name: Byetta

Biological: Desacyl ghrelin

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.

Other Name: Unacylated ghrelin

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

Experimental: Ex-smokers

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

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.

Other Name: Byetta

Biological: Desacyl ghrelin

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.

Other Name: Unacylated ghrelin

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

Experimental: Ex-alcohol dependent subjects

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

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.

Other Name: Byetta

Biological: Desacyl ghrelin

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.

Other Name: Unacylated ghrelin

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




Primary Outcome Measures :
  1. Functional MRI measure of brain activation during cigarette, alcohol and food picture evaluation task [ Time Frame: 4 years ]
    Blood oxygen level dependent (BOLD) signal in brain reward systems to cigarette, alcohol and food pictures vs. object pictures


Secondary Outcome Measures :
  1. Functional MRI measure of brain activation during anticipation of winning monetary reward (monetary incentive delay task) [ Time Frame: 4 years ]
    Blood oxygen level dependent (BOLD) signal in striatum to anticipation of winning vs. not winning money

  2. Functional MRI measure of brain activation during negative emotional reactivity task [ Time Frame: 4 years ]
    Blood oxygen level dependent (BOLD) signal in amygdala during viewing of evocative vs. neutral pictures

  3. Functional MRI measure of brain activity in salience resting state network [ Time Frame: 4 years ]
    Network integrity of blood oxygen level dependent (BOLD) signal in salience resting state network

  4. Functional MRI measure of brain activity in limbic resting state network [ Time Frame: 4 years ]
    Network integrity of blood oxygen level dependent (BOLD) signal in limbic resting state network

  5. Functional MRI measure of brain activity in default mode resting state network [ Time Frame: 4 years ]
    Network integrity of blood oxygen level dependent (BOLD) signal in default mode resting state network


Other Outcome Measures:
  1. Hunger visual analogue scale rating [ Time Frame: 4 years ]
    Appetite measure

  2. Alcohol Urge Questionnaire [ Time Frame: 4 years ]
    Alcohol craving measure

  3. Questionnaire of Smoking Urges [ Time Frame: 4 years ]
    Cigarette craving measure

  4. Food craving visual analogue scale rating [ Time Frame: 4 years ]
  5. Progressive ratio task breakpoint [ Time Frame: 4 years ]
    Measure of motivation to obtain sweet palatable food

  6. Percentage of unsuccessful stop trials [ Time Frame: 4 years ]
    Motor response inhibition measure

  7. Energy intake at test meal in kilocalories [ Time Frame: 4 years ]
  8. Energy intake of sugar at test meal as percentage of total [ Time Frame: 4 years ]
  9. Energy intake of fat at test meal as percentage of total [ Time Frame: 4 years ]
  10. Ratio of speed of approach to avoidance for food vs. object pictures [ Time Frame: 4 years ]
  11. Ratio of speed of approach to avoidance for alcohol vs. object pictures [ Time Frame: 4 years ]
  12. Ratio of speed of approach to avoidance for cigarette vs. object pictures [ Time Frame: 4 years ]
  13. Food picture appeal rating [ Time Frame: 4 years ]
  14. Alcohol picture appeal rating [ Time Frame: 4 years ]
  15. Cigarette picture appeal rating [ Time Frame: 4 years ]
  16. Plasma glucose concentration [ Time Frame: 4 years ]
  17. Serum insulin concentration [ Time Frame: 4 years ]
  18. Serum cortisol concentration [ Time Frame: 4 years ]
  19. Serum growth hormone concentration [ Time Frame: 4 years ]
  20. Plasma GLP1 concentration [ Time Frame: 4 years ]
  21. Plasma peptide YY concentration [ Time Frame: 4 years ]
  22. Plasma exenatide concentration [ Time Frame: 4 years ]
  23. Plasma desacyl ghrelin concentration [ Time Frame: 4 years ]
  24. Plasma acyl ghrelin concentration [ Time Frame: 4 years ]
  25. Nausea visual analogue scale rating [ Time Frame: 4 years ]
  26. Fullness visual analogue scale rating [ Time Frame: 4 years ]
  27. Sweet taste intensity visual analogue scale rating [ Time Frame: 4 years ]
  28. Fat taste intensity visual analogue scale rating [ Time Frame: 4 years ]
  29. Fat taste just right visual analogue scale rating [ Time Frame: 4 years ]
  30. Sweet taste just right visual analogue scale rating [ Time Frame: 4 years ]
  31. Sweet taste liking visual analogue scale rating [ Time Frame: 4 years ]
  32. Fat taste liking visual analogue scale rating [ Time Frame: 4 years ]
  33. Fat taste pleasant visual analogue scale rating [ Time Frame: 4 years ]
  34. Sweet taste pleasant visual analogue scale rating [ Time Frame: 4 years ]
  35. Paired associates learning task number of trials required to locate patterns correctly [ Time Frame: 4 years ]
    Episodic memory measure

  36. Paired associates learning task memory score [ Time Frame: 4 years ]
    Episodic memory measure

  37. Paired associates learning task number of stages completed [ Time Frame: 4 years ]
    Episodic memory measure

  38. Cambridge gambling task risk taking measure [ Time Frame: 4 years ]
    Neuropsychological test

  39. Cambridge gambling task quality of decision taking measure [ Time Frame: 4 years ]
    Neuropsychological test

  40. Smoking relapse rate at 6 months after completion of the study in ex-smokers [ Time Frame: 4 years ]
  41. Smoking relapse rate at 12 months after completion of the study in ex-smokers [ Time Frame: 4 years ]
  42. Alcohol relapse rate at 6 months after completion of the study in ex-drinkers [ Time Frame: 4 years ]
  43. Alcohol relapse rate at 12 months after completion of the study in ex-drinkers [ Time Frame: 4 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Male or female volunteers between the ages of 18 and 60 years.
  2. 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.
  3. The subject is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  4. The subject is able to read, comprehend and record information written in English.
  5. For non-dependent groups:

    i) Overweight/obese volunteers with BMI 28.0-50.0 kg/m2.

  6. 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.

Exclusion Criteria:

Potential volunteers will NOT be eligible for inclusion in this study if any of the following criteria apply:

  1. 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.
  2. 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.

  3. 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:

  4. 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.
  5. 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).
  6. 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.
  7. Carbon monoxide levels of =/>10ppm in the overweight/obese and abstinent smoker groups at screening visit.
  8. 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.
  9. 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.
  10. Claustrophobia or feels that they will be unable to lay still on their back in the MRI scanner for a period of ~80 minutes.
  11. Presence of a cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies as assessed by a standard pre-MRI questionnaire and radiographer.
  12. History or presence of a neurological diagnosis (not limited to but including, for example, stroke, epilepsy, space occupying lesions, multiple sclerosis, Parkinson's disease, vascular dementia, transient ischemic attack, that may influence the outcome or analysis of the scan results). A history of alcohol-related or alcohol-withdrawal seizures will be allowed for volunteers in the abstinent alcoholic group.
  13. Significant current or past medical or psychiatric history that, in the opinion of the investigators, contraindicates their participation.
  14. Clinically significant head injury (e.g. requiring hospitalisation or surgical intervention) that in the opinion of the investigators may affect subject safety or outcome measures.
  15. Unwillingness or inability to follow the procedures outlined in the protocol.
  16. Any of the following liver function tests (LFT) abnormalities at screening: Alkaline Phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or gammaGT > 4 x upper limit of normal (ULN), International Normalised ratio (INR) > 1.5, Albumin <25 g/L, raised bilirubin (other than just isolated i.e. without other liver function tests abnormalities).
  17. History of decompensated alcoholic liver disease - i.e. history of variceal bleeding, ascites, jaundice, encephalopathy.
  18. History of pancreatitis from any cause.
  19. History of type 1 or type 2 diabetes mellitus.
  20. ECG abnormality, which in the opinion of the study physician, is clinically significant and represents a safety risk.
  21. The volunteer has participated in a clinical trial and has received an investigational product within the following time period prior to the first experimental visit in the current study: 90 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  22. Exposure to more than 3 new investigational medicinal products within 12 months prior to the scan.
  23. History of sensitivity to any of the peptides, or components thereof, or a history of drug or other allergy that, in the opinion of the investigators, contraindicates their participation.
  24. Diagnosis of endocrine disorder, including uncontrolled hypothyroidism (stable treated hypothyroidism with currently normal thyroid function tests is allowed), history of hyperthyroidism or Cushing's syndrome, which, in the opinion of the investigators, may affect subject safety or outcome measures.
  25. History of ischaemic heart disease, heart failure, cardiac arrhythmia or peripheral vascular or cerebrovascular disease.
  26. History or presence of significant respiratory, gastrointestinal, hepatic, oncological or renal disease or other condition that in the opinion of the Investigators may affect subject safety or outcome measures.
  27. Previous bariatric surgery for obesity including Roux-en-Y gastric bypass, gastric banding, sleeve gastrectomy.
  28. Current pregnancy or breast-feeding in female volunteers.
  29. Vegetarian, vegan, gluten or lactose-intolerant.
  30. Volunteers who have donated, or intend to donate, blood within three months before the screening visit or following study visit completion.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02690987


Locations
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United Kingdom
Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, Hammersmith Hospital
London, United Kingdom, W12 0NN
Sponsors and Collaborators
Imperial College London
Investigators
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Principal Investigator: Tony Goldstone, MD, PhD Imperial College London
Principal Investigator: David Nutt, MD, PhD Imperial College London
Additional Information:
Publications:

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Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT02690987    
Other Study ID Numbers: 15/LO/1041
MR/M007022/1 ( Other Grant/Funding Number: UK Medical Research Council )
First Posted: February 24, 2016    Key Record Dates
Last Update Posted: February 13, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Imperial College London:
tobacco
GLP1
ghrelin
alcohol
appetite
reward
addiction
hormone
cigarette
functional MRI
Additional relevant MeSH terms:
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Obesity
Alcoholism
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Exenatide
Hypoglycemic Agents
Physiological Effects of Drugs
Anti-Obesity Agents
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists