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.
Participants who are able to provide written informed consent prior to the initiation of any protocol-required procedures
Have been referred to the LEAF clinic by their physician or have self-referred to the LEAF clinic for weight loss, and have been deemed appropriate for weight loss treatment offered by the LEAF clinic (i.e., these criteria are at the discretion of the clinical team at the LEAF clinic, outlined below in the
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).
Parallel
Contrave
DrugCONTRAVE® 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.
Placebo
DrugPlacebo 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.
Diet Program
BehavioralAll 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.
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.
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)
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.
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.
Hedonic Mechanisms
Food palatability and appetite ratings (hunger, fullness, desire to eat, and prospective food consumption) will be measured using a 100-mm Visual analog scale (VAS) at fasting, at 0, 30, 60, 90, 120, 180 min after a standardized breakfast administered in the laboratory. Changes in both state and trait-related food craving will be assessed by the self-reported Food Craving Questionnaire. The relative reinforcing value of snack foods in relation to healthy food alternatives will also be assessed. Lunch will be served at approximately 12h30. Participants will be asked to self-select foods from a food menu. They will be instructed to eat as much as they desire of these foods. Energy intake and food preferences will then be assessed from the weight of the different foods consumed.
Mood
Self-reports of depression and anxiety symptoms will be assessed using the Beck Depression Inventory (BDI) and the Generalized Anxiety Disorder (GAD-7). These will be collected on an iPad or pen-and-paper (as per participant's preference). Data collected on an iPad will be collected using REDCap (a data collection platform used/available at The Royal, which is known to comply with privacy standards; all imputed data will be only liked with the participant code). The active drug condition (contrave) may influence mood; thus, we will track mood changes before vs. after 4-weeks of intervention. Mood scores (i.e., anxiety and depression) will be used as covariates in the analyses of behavioural and brain activity (MRI, EEG, ERP) measures listed in the primary and secondary outcomes.
Metabolic Effects
Resting and Post-Prandial Energy Expenditure: Energy expenditure (EE) will be measured fasting and after a standardized breakfast with indirect calorimetry (Vmax Encore 29N metabolic cart by SensorMedics, Yorba Linda, CA, USA). (approximately 45 min for resting and then 30 min every hour for 2 hours after a standardized breakfast, which will be provided in the laboratory).
Executive Functioning
Measured with NIH cognition toolbox.
Click on the lead sponsor to view all of their trials.
The Royal's Institute of Mental Health Research
Lead sponsor
University of Ottawa
Collaborator
The Royal Ottawa Mental Health Centre
Collaborator
Bausch Health Americas, Inc.
Collaborator
Cheo Research Institute
Collaborator
LEAF Weight Management Clinic
Collaborator
