JOULE - Metabolic Adaptation to Weight Loss in Response to a Behavioural Lifestyle Program With or Without Semaglutide in Adolescents With Obesity

Phase 4

Not yet recruiting

• Conditions: Obesity (Disorder)
• Interventions: Drug: Semaglutide Pen Injector; Behavioral: Behavioural Lifestyle Program (BLP)

• Registration Number: NCT06852391
• Lead Sponsor: McMaster University

Brief Summary

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.

Detailed Description

The Joule MARS (Metabolic Adaptation to weight loss in Response to a behavioural lifestyle program with or without Semaglutide in adolescents with obesity) study is a single-center, randomized controlled trial designed to investigate the effects of a behaviour lifestyle program and the medication semaglutide (brand name Wegovy®) on resting energy expenditure (REE), work efficiency during standard exercise on a cycle ergometer and related metabolic outcomes in adolescents with obesity. The study will involve two intervention groups:

Group A will participate in a behavioral lifestyle program (BLP) alone for 6 months followed by a combination of semaglutide treatment and a BLP for an additional 6 months.

Group B will receive semaglutide and a BLP for the first 6 months and then terminate the study.

The study objectives are to determine if, in youth aged 12-17 years with obesity and enrolled in a weight management program:

1. the implementation of a BLP and semaglutide, compared to the implementation of a BLP alone leads to less adaptive thermogenesis (AT) at 6 months;

2. the implementation of a BLP and semaglutide, compared to the implementation of a BLP alone for 6-month, leads to:

Less increase in energy work efficiency during standardized exercise

Differences in BAT activity

Differences in health-related quality of life (HRQoL)

Differences in symptoms of depression or anxiety

3. BLP and semaglutide, compared to BLP alone, lead to improvements in metabolic health measures (including lipids, glycemia, liver enzymes, hepatic fat and hepatic stiffness) after 6 months.

4. A longer time enrolled in BLP prior to addition of 6 months of semaglutide alters health outcome response to semaglutide.

A comprehensive assessment will be conducted throughout the study. Using whole-room indirect calorimetry, REE and muscle work efficiency, evaluated during standardized physical activity on a cycle ergometer, will be measured. Body composition (Dual energy x-ray absorptiometry and bioelectric impedance analysis), anthropometry (height, weight, waist circumference, BMI, BMI z score (WHO)), metabolic health, health related quality of life, hepatic fat and cold induced brown adipose tissue activity (MRI) will be assessed. Randomization will be managed via the REDCap EDC system.

Study Timeline

• Study First Submitted: 2025-01-06
• Study First Submitted QC: 2025-02-21
• Study First Posted: 2025-02-28
• Status Verified: 2025-03
• Study Start: 2025-03
• Last Update Submitted: 2025-03-20
• Last Update Posted: 2025-03-24
• Primary Completion: 2027-12-31
• Study Completion: 2027-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 74

Inclusion Criteria

• Youth aged 12-17 years
• Diagnosed with obesity (BMI ≥2 standard deviations above WHO Reference median)
• Enrolled in first six months of GHWM pediatric clinic (ie. have at least one year of the program remaining).

Exclusion Criteria

• Any contraindications for MRI (i.e. claustrophobia, implanted metal, metallic injuries recent tattoo or weight >300lb.
• 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.)
• Current mental health diagnosis including anxiety or depression or high depressive symptoms (score on CES-DC >15 at screening).
• Elevated alanine aminotransferase (ALT) > 5 x upper range of normal at screening.
• Use of glucose lowering or any anti-obesity medication in the previous 3 months.
• Known monogenic, syndromic or hypothalamic causes of obesity.
• Diagnosis of type 1 or 2 diabetes mellitus.
• Prior bariatric surgery or liver transplantation.
• Alcohol intake exceeding 3 drinks per week or reported cannabis use.
• Recent history of cigarette smoking (previous 3 months).
• History or family history of multiple endocrine neoplasia 2 or medullary thyroid cancer.
• History of pancreatitis.
• Presence of untreated endocrine disorder.
• History of an eating disorder.
• History of a cardiac condition that precludes exercise testing or unable to have exercise testing done in the GHWM pediatric clinic, inability to use a cycle ergometer.

Participant who does not have a peak power value obtained in the GHWM pediatric clinic

• Female who is pregnant, breast-feeding or intends to become pregnant.
• Female who refuses to use a means of contraception if sexually active.
• Participation in any interventional clinical study within 90 days before screening.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BLP, then BLP+semaglutide	Semaglutide Pen Injector	Group A will engage in a BLP alone for the first six months of the study, then receive BLP and semaglutide (Wegovy®) for the last six months of the study, beginning with 0.25 mg subcutaneously weekly and being titrated every four weeks up to a maximum of 2.4 mg in approved doses 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2.4 mg.
BLP, then BLP+semaglutide	Behavioural Lifestyle Program (BLP)	Group A will engage in a BLP alone for the first six months of the study, then receive BLP and semaglutide (Wegovy®) for the last six months of the study, beginning with 0.25 mg subcutaneously weekly and being titrated every four weeks up to a maximum of 2.4 mg in approved doses 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2.4 mg.
BLP and semaglutide	Semaglutide Pen Injector	In addition to BLP, Group B will receive semaglutide (Wegovy®) titrated to maximal dose tolerated, in approved doses of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2.4 mg subcutaneously weekly for 6 months .
BLP and semaglutide	Behavioural Lifestyle Program (BLP)	In addition to BLP, Group B will receive semaglutide (Wegovy®) titrated to maximal dose tolerated, in approved doses of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2.4 mg subcutaneously weekly for 6 months .

Primary Outcome Measures

Name	Time	Method
Measurement of Adaptive thermogenesis	6, 12 months	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.

Secondary Outcome Measures

Name	Time	Method
Changes in energy work efficiency from baseline during standardized exercise	Baseline, 6, 12 months	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	From enrollment to 6 months and to 12 months	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)	Baseline to 6 months and to 12 months	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)
Depressive symptoms	Baseline to 6 months and 12 months	Depressive symptoms will be measured using the Center for Epidemiological studies Depression Scale for Children (CES-DC) questionnaire. Score ranges from 0 to 60, with a cutoff score of 15 as being suggestive of depressive symptoms and scores over 15 being indicative of significant levels of depressive symptoms.
Anxiety symptoms	Baseline to 6 months and to 12 months	Anxiety symptoms will be measured using the revised Children's Anxiety and Depression Scale (RCADS-25) questionnaire. This 25-item youth self-report questionnaire also has 5 anxiety subscales (separation anxiety disorder, social phobia, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, which combine for a total anxiety scale. Higher values are consistent with increased anxiety.
Total body mass, fat mass and lean mass	Baseline, 6, 12 months	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.
Hepatic fat content	Baseline, 6, 12 months	Hepatic fat content will be measured via MRI conducted by a technician at St. Joseph's hospital at baseline, 6 months and 12 months using standardized techniques for precision, accuracy and determination of proton density fat fraction (PDFF) quantification of the whole liver
Hepatic stiffness	Baseline, 6 and 12 months	Hepatic stiffness, an indicator of hepatic fibrosis, will be measured via Magnetic resonance elastography (MRE) using standardized techniques for precision and accuracy.
Fasting lipid profile	Baseline, 6, 12 months	Differences in fasting lipids will be collected via fasting bloodwork. The types of lipids that will be collected will be triglycerides, cholesterol, High-density lipoprotein (HDL) and Low-density lipoprotein (LDL) (mmol/L).
Fasting insulin	Baseline, 6, 12 months	Fasting insulin will be measured with bloodwork collected. HOMA-IR will be calculated to determine insulin resistance
Hemoglobin A1C	Baseline, 6 and 12 months	Hemoglobin A1C to be measured in laboratory at Hamilton Health Sciences
Alanine aminotransferase	Baseline, 3, 6, 9 and 12 months	ALT will be measured in the laboratory at Hamilton Health Sciences

Trial Locations

Locations (1)

McMaster University; 🇨🇦 Hamilton, Ontario, Canada