Metabolic and Behavioural Effects of CONTRAVE as Potential Mechanisms of Weight Loss in Adults With Obesity

NCT06809166 | Recruiting Phase 4

• 1 other identifier: 2023004
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 3

Brief Summary

Obesity is a common chronic disease linked with increased risk for other illnesses and earlier death. Our team and others have shown that many bodily and psychological changes occur when individuals are on calorie-restricted diets. These changes might undermine dietary adherence and help to explain the relatively poor long-term efficacy of diets. These include increased appetite, increased food 'value' and 'wanting' that leads to overconsumption. Other factors include more sensitive sensory cues (e.g., smelling), higher food liking and craving, and a drop in resting energy expenditure (REE). REE has been shown to predict weight regain. The standard care for obesity may include the use of the weight-loss drug CONTRAVE®. The Federal Drug Agency (FDA) and Health Canada have approved this drug for weight management and obesity treatment. Although CONTRAVE® was designed to reduce appetite, food-related impulsivity and cravings, its mechanisms of action are unclear. In other words, the effects of CONTRAVE® on REE, executive function, and brain changes remain unknown in humans. A better understanding of how this drug works on the brain and body could lead to improvements in obesity management in the future. As such, the goal of this research is to study the effects of 4 weeks of CONTRAVE® (+ diet program) vs. control (placebo pill + diet program) on mood, body composition changes, biological/metabolic measures, and brain measures. Adults aged 18-64 with obesity will be randomized to one of two groups: diet + CONTRAVE® (CONTRAVE®, 20 participants) or diet + Placebo (Placebo, 20 participants). Both groups will be assigned the same study procedures for the entire study duration. The only difference is that Group 1 will receive CONTRAVE® while Group 2 will receive a placebo (non-medical) pill. The study design and intervention is as follows: Participants who meet all the telephone screening criteria will be invited to the Clinical EEG \& Neuroimaging Laboratory at The Royal's IMHR for an in-person screening and test-dose session. Participants who are cleared by the study physician, Dr. Pierre Blier, during the in-person screening will be enrolled in the 4-weeks trial. After the in-person screening visit, participants will attend two baseline testing visits (before starting the medication + diet program). The first will occur at the Behavioural and Metabolic Research Unit at the University of Ottawa. During this in-person visit, measures of body composition, resting energy expenditure, appetite, food craving, impulsivity, eating behaviours, taste and odour sensitivity, energy intake, and food preference will be collected. The second baseline visit (within a week of the first one) will occur at The Royal/IMHR. During this visit, participants will be asked to complete questionnaires. They will undergo an EEG recording while resting and performing computer tasks. They will also get a brain imaging scan, during which they are asked to rest and complete a computer task. Both testing sessions (University of Ottawa and Royal Ottawa testing sessions) will be repeated after four weeks of treatment. The section below provides further description and timing of these visits. As part of the treatment, you will receive an individualized dietary intervention with appropriate energy restriction from a registered dietitian at Dr. Judy Shiau's LEAF weight management clinic (called the 4-week BUDS program). The program involves weekly touch points with a registered dietitian and meal planning/coaching. The diet intervention will commence the same week as the start of the placebo/CONTRAVE®. During the 4-week intervention, participants will be asked to complete online questionnaires at various times.

Conditions

Obesity; Weight Loss; Weight Management; Dietary Intervention; Obesity/Therapy

Keywords

contrave; EEG; MRI; weight loss; appetitive behaviour; executive functioning; mood and weight loss; mood; body composition; symptoms of anxiety; symptoms of depression; energy expenditure; appetite; energy intake; food reward; reward processing; motivation; effort expenditure; delay discounting; brain activation; event related potentials; brain electrical activity

Outcome Measures

Primary Outcomes (5)

• MRI Modalities

  Four MRI modalities will be collected during two identical 45-minute MRI session: one at baseline and another 4-weeks post placebo or Contrave. The first modality is an 8-minute resting-state functional MRI to assess brain activity at rest. Second is a 7-minute structural scan, which will allow us to explore potential changes in brain volume. Third, is a 12-minute task-based functional MRI scan where participants are presented with images of food/non-food visual cues, allowing us to assess brain activity in response to different cues. Last is a 9-minute neuromelanin scan, which allows us to visualize neuromelanin in the brain. Neuromelanin is present in brain regions implicated in the brain's reward system and is a marker of dopamine, which is highly involved in motivation and reward. This exploratory scan will help elude neuromelanin levels and locus coeruleus contrast in individuals with obesity and whether there are correlations with other neuroimaging/clinical measures.

  4 weeks

• Changes in body weight/composition

  Dual Energy X-ray Absorptiometry (DEXA) will be used to measure lean mass, fat mass and percent body fat (Lunar Prodigy, GE Medical Systems)

  4 weeks

• Brain Activity EEG at Rest

  Electroencephalography (EEG) at baseline and 4-weeks post placebo or Contrave. EEG will involve a 16-channel EEG system. Data collection includes resting EEG spectral power extracted from resting EEG and may include the following frequency bands: * Delta (1-4 Hz) * Theta (4-8 Hz) * Alpha (8-13 Hz) * Beta (13-30 Hz) * Gamma (\>30 Hz) Analysis: Power is typically analyzed for each frequency band.

  4 weeks (pre and post contrave or placebo)

• Brain Activity During Food Impulsivity Task

  EEG-derived event-related potentials (ERPs) will be assessed during a food impulsivity task (Go/No-Go task). Specifically, N2 and P3 ERP amplitudes (µV) and latencies (ms) will be measured in response to neutral objects trial, high calorie foods and low calorie foods trials. Behavioural measures, including correct and incorrect responses (%) and reaction times (%) will be measured as secondary outcome measures.

  4-weeks (pre and post contrave or placebo)

• Brain Activity During EEFRT Task

  Using the Effort Expenditure for Rewards Task (EEfRT) specific ERPs associated with reward and error processing will be obtained. Specifically, ERP amplitudes (µV) and latencies (ms) for the Stimulus Preceding Negativity (SPN), and the P3 for the easy and hard trials will be analyzed separately. The number of times participants chose the easy vs. hard trials (difficulty) is analyzed as a measure of motivation.

  4-week (pre and post contrave or placebo)

Secondary Outcomes (7)

• Hedonic Mechanisms

  4 weeks

• Mood

  4 weeks

• Metabolic Effects

  4 weeks

• Executive Functioning

  4 weeks

• Behavioural and EEG During a Delay Discounting Task

  4 weeks (pre and post contrave or placebo)

Study Arms (2)

CONTRAVE

EXPERIMENTAL

A diet program + CONTRAVE®

Drug: Contrave; Behavioral: Diet Program

Placebo

PLACEBO COMPARATOR

Diet Program + Placebo

Drug: Placebo; Behavioral: Diet Program

Interventions

Contrave DRUG

CONTRAVE® will be titrated up to a therapeutic dose (Naltrexone 32mg/Bupropion 360mg) over a 4-week period as per clinical guidelines, and what is typical in the LEAF clinic. Dose recommendation for CONTRAVE® is tablet based, with each tablet containing 8mg of naltrexone and 90mg of bupropion. The maximum recommended daily dose is two tablets, administered orally, twice daily (32mg/360mg), taken once in the morning and once in the evening. Tablets and dispensing schedule will be done under the oversight of The Royal pharmacy (i.e., they will instruct the participants on the dosing schedule). Medication adherence and side effects will be reported daily using our online data capture system (REDCap) (approximately 1min) starting on the evening of the first dose of administration. If adverse events are significantly concerning, there is a mechanism in place for dealing with such events.

Also known as: Naltrexone/Bupropion-NB

CONTRAVE

Placebo DRUG

Placebo intervention will follow the exact same protocol in terms of tablet numbers as the CONTRAVE intervention. Generic Placebo pills will be packaged by The Royal Pharmacy into blister packs identical to Contrave.

Also known as: Vitamin Pill

Placebo

Diet Program BEHAVIORAL

All participants will receive an individualized dietary intervention with appropriate energy restriction from registered dietitians at Dr. Shiau's LEAF weight management clinic (called the 4-week BUDS program, which is offered to clients with obesity at the LEAF clinic). The program involves weekly touch points with a registered dietitian, and meal planning/coaching and integrates a partial meal replacement with a commercial shake.

CONTRAVE; Placebo

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Participants who are able to provide written informed consent prior to the initiation of any protocol-required procedures

You may not qualify if:

• Adults: aged 18-64 years of age (gender and sex will be noted; recruitment is all-gender inclusive).
• Have a BMI\>30.
• Have normal or corrected vision as some of the study aspects will involve viewing/responding to visual stimuli.
• Understand and speak English (as instructions for study criteria will be provided in English).
• Able to participate in the study protocol as described, e.g. have a means of getting to the laboratories and no major mobility issues to the extent that protocols cannot be followed (details below).
• Access to a secure internet connection (for virtual appointments with members of the LEAF clinic).
• Reporting severe depression or reporting significant suicidal ideation, or history of bipolar disorder or psychosis (i.e., major psychiatric condition; this will be ascertained during the screening carried out by research personnel, in keeping with our standard protocols in Dr. Jaworska's laboratory).\*\*\*
• Current use of antidepressants, thyroid medication, or any medication that could affect appetite, or seizure threshold (e.g.., bupropion, tamoxifen, thioridazine).
• Uncontrolled hypertension.
• History of cardiac defects or symptoms suggestive of any cardiac condition (not including coronary artery disease).
• Presence of diabetes.
• Current or past history of addictions or substance use disorder, including undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs.
• History of eating disorder (including Binge Eating Disorder, Bulimia Nervosa or Anorexia Nervosa).
• History of glaucoma.
• Personal or family history of seizure disorders.

Sponsors & Collaborators

• The Royal's Institute of Mental Health Research: lead
• University of Ottawa: collaborator
• The Royal Ottawa Mental Health Centre: collaborator
• Bausch Health, Canada Inc.: collaborator
• Cheo Research Institute: collaborator
• LEAF Weight Management Clinic: collaborator

Study Sites (3)

LEAF Weight Managment Clinic

Ottawa, Ontario, K1J 9L3, Canada

RECRUITING

Behavioural and Metabolic Research Unit

Ottawa, Ontario, K1N 6N5, Canada

RECRUITING

University of Ottawa Institute of Mental Health Research

Ottawa, Ontario, K1Z 7K4, Canada

RECRUITING

MeSH Terms

Conditions

Obesity; Weight Loss; Depression

Interventions

bupropion hydrochloride, naltrexone hydrochoride drug combination; Naltrexone; Vitamins

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Body Weight Changes; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Naloxone; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Micronutrients; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Nutrients; Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages

Study Officials

• Pierre Blier, M.D., Ph.D

  University of Ottawa

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Natalia Jaworska, Ph.D

CONTACT

613-722-6521; natalia.jaworska@theroyal.ca

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director

Study Record Dates

• First Submitted: January 22, 2025
• First Posted: February 5, 2025
• Study Start: July 4, 2024
• Primary Completion: January 1, 2026
• Study Completion (Estimated): July 31, 2026
• Last Updated: July 24, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

CA (3)