The Joule MARS study is a single center, randomized, open label clinical trial aiming to explore the metabolic adaptations that occur in response to weight management in adolescents with obesity. Behavioural lifestyle intervention with and without a pharmacological intervention - semaglutide- will be studied. Study participants will be randomized to one of two groups. Group A will follow a behavioral lifestyle program (BLP) alone for 6 months, followed by BLP and treatment with semaglutide for six months. Group B will be enrolled in BLP and semaglutide from baseline to 6 months. The primary research question will assess, in youth aged 12-17 years diagnosed with obesity and enrolled in a weight management program, if the implementation of a BLP together with semaglutide, compared to the implementation of BLP alone for 6 months leads to less adaptive thermogenesis.
Youth aged 12-17 years
Diagnosed with obesity (BMI ≥2 standard deviations above WHO Reference median)
Enrolled in Growing Health Weight Management or Next Step pediatric clinics (ie. have at least one year of the program remaining).
Any contraindications for MRI (i.e. claustrophobia, implanted metal, metallic injuries recent tattoo or weight >300lb. Ineligible for imaging visit only.
Use of atypical anti-psychotics.
Use of the following medication classes: (i.e. Beta-blocker medications, Steatogenic medications, Anti-hyperglycemic medications, HIV drugs, Antidepressants, anxiolytic drugs, anti-psychotic drugs, Thyroid drugs, Antiemetic or amphetamine, dextromethorphan and metoclopramide.)
Elevated alanine aminotransferase (ALT) > 5 x upper range of normal at screening.
Parallel
Semaglutide Pen Injector
DrugSemaglutide will be delivered by a subcutaneous injection using an injectable pen once weekly. Semaglutide is formulated with 5 approved doses (0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2.4 mg). Treatment will commence with the lowest dose and will be increased every 4 weeks to the maximum tolerable dose where they will remain for the remainder of the treatment. Participants who are taking the drug will have monthly visits to assess any adverse events, dose titration and drug adherence.
Behavioural Lifestyle Program (BLP)
BehavioralThe BLP will be delivered by the Growing Healthy Weight Management (GHWM) pediatric program at McMaster Children's Hospital. GHWM is a family-based program addressing health behaviours (nutritional pattern and eating behaviours, physical activity, sedentary time and sleep) and physical and mental health issues. In Year 1, the program typically includes 2 group sessions and monthly individualized sessions with the participant and their family. The interdisciplinary weight management team is comprised of a registered dietician, exercise physiologist, kinesiologist, social worker and/or psychologist, general pediatrician and pediatric endocrinologists.
Measurement of Adaptive thermogenesis
Adaptive thermogenesis will be calculated as the difference between measured and predicted REE after the intervention. Measured REE will be assessed with the participant awake, but at rest, in a whole room indirect calorimeter. Predicted REE will be calculated based on an equation derived using baseline data from this study population as is currently recommended. Variables that will be considered in deriving the equation include fat-free mass, fat mass, age and sex. We will compare adaptive thermogenesis (primary outcome) and work efficiency between the two treatments utilizing linear regression analysis. Separate analyses for males and females will ensure relevance of study findings to both sexes.
Changes in energy work efficiency from baseline during standardized exercise
Energy work efficiency will be measured by measuring the physical activity energy expenditure (PAEE) from cycle ergometry using whole room calorimetry. This will be calculated as follows: Net mechanical efficiency (mechanical efficiency above resting): Ratio of power generated (kcal/min) / (PA EE - REE). One kcal/hour = 1.163 W Thus, \[Power (W) x 0.01433 (kcal/min) / (PA EE (kcal/min) - resEE (kcal/min))\] x100 = Work efficiency (%)
Brown Adipose Tissue (BAT) activity
Relative decline in supraclavicular fat proton density fat fraction after cold exposure as previously published (Ahmed et al., 2021)
Health-related quality of life (HRQoL)
This will be measured using the Impact of Weight on Quality of Life kids (IWQOL-kids) questionnaire. Score ranges from 0 to 100, with 100 representing the best quality of life. In addition to a total score, there are scores on four domains: Physical Comfort (6 items) Body Esteem (9 items) Social life (6 items) Family Relations (6 items)
Total body mass, fat mass and lean mass
Body composition will be preferentially measured using Dual-energy X-ray absorptiometry (DXA) scans (Lunar PRODIGY Advance 8743; GE, Healthcare, Waukesha, WI). If the participant has a weight exceeding the limits for the machine, Bioelectrical Impedance Analysis (BIA) (InBody 570) will be utilized.
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McMaster University
Lead sponsor
Canadian Institutes of Health Research (CIHR)
Collaborator
Diabetes Canada
Collaborator
