Young Adults With Early-onset Obesity Treated With Semaglutide (RESETTLE)

Young Adults With Early-onset Obesity Treated With Semaglutide -The RESETTLE Study

Introduction:

The increasing prevalence of obesity is particularly pronounced among adolescents. Currently available treatment options consist of structured lifestyle interventions. However, 25 % of adolescents do not respond to lifestyle treatment, why new effective treatment strategies are needed. Therefore, the aim of this study is to investigate the effect of lifestyle interventions combined with the GLP-1 receptor agonist semaglutide to young adults with otherwise treatment resistant obesity.

Methods and analysis:

This is an investigator-initiated, randomized, placebo-controlled trial. 180-270 young adults (age 18-28) will be recruited from The Childrens Obesity Clinic (TCOC), Department of Pediatrics, Holbæk Hospital. Based on their previous response to the TCOC protocol the participants will be divided in four groups:

Group A: Non-responders: 55-85 young adults with obesity (BMI≥30 kg/m2) who have not reduced adiposity, defined as BMI SDS reduction <0.1, during the structured lifestyle counselling as children.

Group B: Insufficient responders: 55-85 young adults who have reduced adiposity, defined as BMI SDS reduction >0.25, during the structured lifestyle counselling as children but still have obesity as young adults (BMI≥30 kg/m2)

Group C: Excellent responders: 35-50 young adults, who have reduced adiposity, defined as BMI SDS reduction >0.5, during the structured lifestyle counselling as children and no longer have obesity as young adults (BMI<30 kg/m2)

Group D: Population-based reference group (normal weight development): 35-50 young adults, who have participated in The Holbaek Study as children.

Group A and B are randomized 2:1 to either semaglutide or placebo for 68 weeks. Group C and D will attend baseline examinations only and not undergo intervention. The primary endpoint is change in BMI from randomization to end-of-treatment.

Ethics and dissemination: The trial has been approved by the Danish Medicines Agency (EudraCT 2019-002274-31) and by the ethical committee of the Capital Region of Denmark (H-20039422). The trial will be conducted in agreement with the Declaration of Helsinki and monitored to follow the guidelines for good clinical practice. Results will be submitted for publication in international peer-reviewed scientific journals.

Study Overview

• Status: Completed
• Conditions: Obesity, Adolescent
• Intervention / Treatment: Behavioral: TCOC treatment; Drug: Semaglutide 3 mg/ml; Drug: Placebo (Semaglutide 3 mg/ml)

Detailed Description

Background:

The prevalence of obesity in adolescents has increased markedly in the past decades, thus entailing increased cumulative incidences of type 2 diabetes, cardiovascular disease, and chronic kidney disease (1). Adolescents with obesity are at a substantially elevated risk of developing morbid obesity and type 2 diabetes in early adulthood (2,3) and a recent large scale meta-analysis revealed that mortality increased approximately log-linearly with BMI over 25.0 kg/m² in all continents; and that this increment was greater in younger than older people (4). Furthermore, obesity increase the risk of stigmatization with respect to social relationships, entry into the job market, reduced self-esteem and other psychological problems (5). Thus, adolescents with obesity require particular medical attention.

Since 2008, The Childrens Obesity Clinic (TCOC), Department of Pediatrics, Copenhagen University Hospital Holbæk has treated more than 4000 children and adolescents with overweight or obesity using the TCOC protocol which includes regular counselling on diet, exercise, lifestyle and general health. The TCOC protocol has proven successful with a reduction in BMI standard deviation score (SDS) after 1.5 years of treatment obtained in 74% of the children and adolescents (6). In addition, significant improvements in lipid profile (7) the degree of hypertension (8), hepatic steatosis (9) and the presence of visceral fat (9) have been reported.

However, approximately one in four of the children following the TCOC protocol do not achieve a reduction in BMI SDS. Furthermore, for the majority of children who reduce BMI SDS, obesity remains and represents a medical and personal issue. Lifestyle intervention is the method of choice for children with obesity, however, new effective treatment strategies for non-responders are urgently required.

Glucagon-like peptide-1 (GLP-1) is secreted from endocrine cells in the intestine upon meal intake and reduces blood glucose and food intake in a dose-dependent manner (10-13). It has previously been shown that 1) people with obesity have impaired GLP-1 secretion already in the overweight state, indicating that low concentrations of GLP-1 may be part of obesity development (14), 2) weight loss induces a marked increase in GLP-1 response and this increase is part of a successfully maintained weight loss of >10 kg (15), 3) treatment with a GLP-1 receptor agonist (GLP-1 RA) facilitates long term weight loss maintenance (13 kg) accompanied by substantial improvement in metabolic health, compared to similar diet-induced weight loss maintenance (15-17),4) appetite sensation and eating behavior are important factors in maintenance of weight loss (18,19). Pathogenic mutations in the appetite-regulating melanocortin-4 receptor represent the most common cause of early-onset monogenic obesity that has been shown to be a type of obesity that is more resistant to lifestyle interventions (20) and even to bariatric surgery (21). Interestingly, this population is responsive to treatment with GLP-1 RA (liraglutide 3.0 mg daily) (22). This indicates that GLP-1 RAs can overrule lifestyle modification-resistant obesity due to the appetite-inhibiting effect. A new GLP1-1 RA (semaglutide) was approved by the European Medical Agency (EMA) for weight management in adults with obesity in January 2022. Placebo subtracted weight loss with semaglutide 2.4 mg was 13.9 % compared to 4.5% with liraglutide 3.0 mg after 68 weeks in adults with overweight or obesity (23). Thus, semaglutide has a potentially larger treatment effect also in young adults with childhood onset obesity. The treatment effect of semaglutide 2.4 mg in young adults with lifestyle-treatment-resistant childhood onset obesity is currently unknown, why the outcomes of this study is of high clinical and socioeconomic relevance.

Study hypothesis:

Treatment with a GLP-1 RA will facilitate weight loss in young adults with and without treatment-resistant childhood-onset obesity.

Objectives:

A) To treat young adults with obesity, who have been resistant to structured lifestyle intervention (TCOC protocol), with the GLP-1 RA, semaglutide 2.4 mg/ week.

B) To treat young adults with obesity, who have responded insufficiently to the structured lifestyle intervention (TCOC protocol) and still have obesity, with semaglutide 2.4 mg/ week.

C) To identify underlying mechanisms of lifestyle-untreatable versus treatable childhood-onset obesity.

D) Assess the efficacy of an exercise-based strategy to discontinue obesity medication while sustaining a healthy body composition in youth with childhood-onset obesity.

Endpoints:

Primary endpoint:

1. Change in BMI (weight in kg/height in m^2) from before to after semaglutide treatment compared to placebo.

Secondary endpoints (changes from before to after semaglutide treatment compared to placebo):

1. Body composition (fat mass, fat percentage, fat-free mass, visceral fat, liver fat)

2. Changes in metabolic health:

   (e.g. glucose and insulin for HOMA-IR and Matsuda index, HbA1c, lipids i.e. cholesterol, HDL, LDL, triglycerides, FFA glucose-tolerance status, blood pressure, pulse, and hip and waist circumference, and calculate metabolic syndrome prevalence and metabolic syndrome z-score, and waist-to-height ratio.

3. Body weight
4. Proportion with a reduction in body weight of at least 5%, 10%, 15%, and 20%

The changes in endpoints from baseline (randomization) to after 68 weeks of treatment will be analyzed for all participants treated with semaglutide compared with all participants receiving placebo, and separately in non-responders and insufficient responders to the TCOC protocol, semaglutide compared with placebo.

Other prespecified endpoints:

To determine the effect of GLP-1 RA treatment, and compare data between the two intervention groups, excellent responders and a population-based reference group with normal weight development for the above-mentioned and following outcomes:

1. Questionnaires will be given to the participants to determine self-rated quality of life (SF-36 and PedsQL), eating habits (three-factor eating questionnaire, BED-Q), physical activity (IPAQ), food preferences, self-efficacy (G-SES), sleep quality (PSQI), and appetite (VAS)
2. Conventional Magnetic resonance imaging (MRI) and spectroscopy is used to assess effects on fat deposits in liver, viscera, and muscle. Site-specific bone-measurements, collection of bone markers (CTX and P1NP), and DEXA scans will be performed to assess bone-health.

2. To explore the effects on appetite regulation and systemic markers of immuno-metabolism: Hormonal appetite regulation will be measured during meal tests and fasting (eg. GLP-1, Peptide YY, Glucagon, Leptin, Ghrelin, Liver-Expressed Antimicrobial Peptide 2 (LEAP2), Adiponectin, GDF-15, N-lactoyl-phenylalanine, neurotensin, neprilysin) using our standard methodologies. In plasma samples various biomarkers of inflammation will be measured (e.g., sCD163, hsCRP, IL1, IL2, IL4, IL8, IL10, IL12p70, IL13, IL-1Rap IL-6, TNF-α, SAA1, SAA2, ORM1, ORM2, ICAM-1, VCAM-1, tPA, vWF) and oxidation (eg malonyldialdehyde, F2-Isoprostanes, etc.), IPS, sphingolipids, and metabolomics using plasma metabolomics and proteomics technique. We will also measure metabolic disruptors (e.g., per- and polyfluorinated substances (PFAS)) and store cells for induction of pluripotent stem cell cultures (iPSC), and perform peripheral blood mononuclear cells (PBMNCs) isolation, including DNA collection.

3. To explore the effects on immuno-metabolic profile in human subcutaneous (sc) adipose tissue and gene expression profile of adipose tissue and in circulating inflammatory cells (PBMNCs),we will perform RNA sequencing (Illumina sequencing 30 million paired-end reads/sample) and determine the changes in pro-inflammatory (e.g. IL-6, IL1b, MCP-1, resistin, leptin, chemerin, etc.) and anti-inflammatory (e.g. adiponectin) adipocytokines, and in adipocyte differentiation markers such as FAB4, CABPA and PPAR-γ as well as markers of macrophages infiltration (CD163, CD68) and M1/M2 phenotype of them such as CD40, CCR7, CD207 etc. (all by qRTPCR).

4. To explore the effect on food preferences and appetite sensation: Food preferences are assessed by a picture display test where standardized pictures of food items are shown. Subjective appetite sensations will be obtained during a fixed standardized meal using electronic visual analogue scales (VAS) to record hunger, satiety, fullness, prospective food consumption, desire to eat something fatty, salty, sweet or savory, and palatability of the meals.

5. To explore the effect on brain structure and activity using magnetic resonance imaging (MRI): Brain MRI will be conducted in a subset of participants by trained personnel at the Neurobiological Research Unit, at Copenhagen University Hospital, Rigshospitalet. Pre- and post-meal scans will be performed. From brain MRI we will examine functional connectivity (whole-brain, seed-to-voxel analysis (with the hypothalamus as the primary seed and additional regions of interest (ROI)), and ROI-to-ROI analysis), resting-state networks, brain age, and structural measures such as gray matter volume. Resting-state networks will be examined using Independent Component Analysis in the CONN toolbox. Structural measures, including gray matter volume, will be obtained with FreeSurfer software, and brain age will be estimated using the Pyment software package. Each brain MRI session will last approximately one hour.

6. To explore the genetic risk scores correlated to treatment response: All participants are chip genotyped to define polygenic risk scores. DNA material will be extracted from blood samples. The Infinium Global Screening Array will be used to analyze the array with Illumina Genome Studio before the bioinformatic removal of SNPs containing genes mentioned in the "American College Medical Genetics and Genomics" List.

7. To explore the effect on the microbiota: The microbiome will be measured in fecal and saliva samples of participants. Furthermore, fecal and saliva samples were collected from the same individuals when they were children with obesity, allowing for comparison of potential differences already evident in childhood that may indicate later treatment response to lifestyle change and GLP-1RA treatment.

8. To explore the effect on metabolomics in urine: Urine samples are collected at the two test days and will be stored frozen for later analyses for potential changes in the metabolomic profile.

9. Psycho-social aspects of obesity development and treatment response We will evaluate the effect of adversity measures across upbringing and current living conditions and explore eating practices and individual weight trajectories in relation to psychological and social factors.

10. A physical activity tracker will be worn on the wrist throughout the study period to assess habitual physical activity and sleep habits.

11. To explore the effect of post medication phase on limiting weight and fat regain: We will investigate whether a post medication program after GLP-1RA discontinuation, comprising data-driven supervised exercise, sleep, and healthy eating behaviour, can limit weight and fat regain and limit deterioration of metabolic health. We will perform DEXA scans 26 weeks after medication termination to investigate changes in body fat percentage, fat mass, and lean mass. We will investigate changes in the outcomes mentioned above and grip strength.

• Study Type: Interventional
• Enrollment (Actual): 246
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2200
    • University of Copenhagen, Department of Biomedical Sciences
  • Region Zeeland
    • Holbæk, Region Zeeland, Denmark, 4300
      • Holbæk University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 28 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age 18-28 years
• The period from the initial treatment with TCOC protocol until inclusion in the study must be within 15 years.
• Group A: BMI≥30. Non-responders: No BMI SDS reduction (≤0.1 BMI SDS) during TCOC protocol for more than one year and still have obesity.
• Group B: BMI≥30. Insufficient responders: BMI SDS reduction ≥0.25 BMI SDS during TCOC protocol for more than one year, but still have obesity.
• Group C: BMI≤30. Excellent responders: BMI SDS reduction ≥0.5 BMI SDS during TCOC protocol for more than one year and no longer have obesity.
• Group D: Young adults who have participated in The Holbaek Study and have had normal weight development during childhood

Exclusion Criteria:

• Participants diagnosed with known serious chronic illness including type 1 or 2 diabetes (or a randomly measured fasting plasma glucose >7 mmol/l)
• Angina pectoris, coronary heart disease, congestive heart failure (NYHA III-IV)
• Severe renal impairment (creatinine clearance (GFR) <30 mL/min)
• Severe hepatic impairment
• Inflammatory bowel disease
• Diabetic gastroparesis
• Cancer
• Chronic obstructive lung disease
• Severe psychiatric disease, a history of major depressive or other severe psychiatric disorders
• Use of medications causing clinically significant weight gain or loss
• Previous bariatric surgery
• A history of idiopathic acute pancreatitis
• A family or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma
• Pregnancy, expecting pregnancy or breastfeeding. If a study participant is in doubt whether she could be pregnant, a urine pregnancy test is performed. Women with reproductive potential who are not using adequate contraceptive methods (combined oral contraceptive pill, progestin-only contraceptive pill, condoms, intrauterine device, injection, implant, or sterilization). Adequate contraception must be used throughout the study period and at least 2 months after discontinuation of trial medication (semaglutide will be present in the circulation for 5-7 weeks after the last dose).
• Allergy to any of the ingredients/excipients of the study medication: Semaglutide, disodium phosphate dihydrate, propylene glycol, phenol, hydrochloric acid, sodium hydroxide.
• Exclusion criteria for MRI: Pacemaker, claustrophobia, metal splinters or any other magnetic devices that cannot be removed prior to the scan (Participants can join the trial without MR scan)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Non-responders: TCOC+ semaglutide; Semaglutide: 2.4 mg/week SC, concentration: 3.0 mg/ml) in combination with TCOC treatment (i.e. diet/weight consultations).	Behavioral: TCOC treatment; The TCOC protocol is a chronic care, family-based and multidisciplinary childhood obesity treatment program involving behavior-changing techniques, based on current guidelines for best-practice and authoritative recommendations involving a multidisciplinary tertiary team of health care professionals.; Drug: Semaglutide 3 mg/ml; Participants will be instructed to initiate at 0.24 mg SC once weekly for 4 weeks, and in 4 week intervals, increase the dose until a dose of 2.4 mg is reached. In case of prolonged side effects the dose may be adjusted to lower than 2.4mg/week.
Placebo Comparator: Non-responders: TCOC+ placebo; Placebo: 2.4 mg/week SC in combination with TCOC treatment (i.e. diet/weight consultations).	Behavioral: TCOC treatment; The TCOC protocol is a chronic care, family-based and multidisciplinary childhood obesity treatment program involving behavior-changing techniques, based on current guidelines for best-practice and authoritative recommendations involving a multidisciplinary tertiary team of health care professionals.; Drug: Placebo (Semaglutide 3 mg/ml); Participants will be instructed to initiate at 0.24 mg SC once weekly for 4 weeks, and in 4 week intervals, increase the dose until a dose of 2.4 mg is reached. In case of prolonged side effects the dose may be adjusted to lower than 2.4mg/week.
Active Comparator: Insufficient responders: TCOC+ semaglutide; Semaglutide: 2.4 mg/week SC, concentration: 3.0 mg/ml) in combination with TCOC treatment (i.e. diet/weight consultations).	Behavioral: TCOC treatment; The TCOC protocol is a chronic care, family-based and multidisciplinary childhood obesity treatment program involving behavior-changing techniques, based on current guidelines for best-practice and authoritative recommendations involving a multidisciplinary tertiary team of health care professionals.; Drug: Semaglutide 3 mg/ml; Participants will be instructed to initiate at 0.24 mg SC once weekly for 4 weeks, and in 4 week intervals, increase the dose until a dose of 2.4 mg is reached. In case of prolonged side effects the dose may be adjusted to lower than 2.4mg/week.
Placebo Comparator: Insufficient responders: TCOC+ placebo; Placebo: 2.4mg/week SC in combination with TCOC treatment (i.e. diet/weight consultations).	Behavioral: TCOC treatment; The TCOC protocol is a chronic care, family-based and multidisciplinary childhood obesity treatment program involving behavior-changing techniques, based on current guidelines for best-practice and authoritative recommendations involving a multidisciplinary tertiary team of health care professionals.; Drug: Placebo (Semaglutide 3 mg/ml); Participants will be instructed to initiate at 0.24 mg SC once weekly for 4 weeks, and in 4 week intervals, increase the dose until a dose of 2.4 mg is reached. In case of prolonged side effects the dose may be adjusted to lower than 2.4mg/week.
No Intervention: Excellent Responders and Population-based reference group; No intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in BMI (weight in kg/height in m^2)	Weight will be measured to the nearest 0.1 kg. The same set of scales should ideally be used throughout the trial. Weight should be measured in a fasting state without shoes and wearing light indoor clothes. Height will be measured to the nearest 0.1 cm.	Change from baseline to end-of-treatment (68 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in body composition (fat mass)	Dual-energy X-ray absorptiometry scans will be performed in fasting state to measure body fat mass (kg).	Change from baseline to end-of-treatment (68 weeks)
Change in body composition (fat percentage)	Dual-energy X-ray absorptiometry scans will be performed in fasting state to measure body fat percentage (%).	Change from baseline to end-of-treatment (68 weeks)
Change in body composition (fat free mass)	Dual-energy X-ray absorptiometry scans will be performed in fasting state to measure fat-free mass (kg).	Change from baseline to end-of-treatment (68 weeks)
Change in visceral fat and liver fat	MRI will be performed in fasting state to measure fat content	Change from baseline to end-of-treatment (68 weeks)
Change in metabolic syndrome	z-score	Change from baseline to end-of-treatment (68 weeks)
Change in waist-to-height ratio	waist-to-height ratio	Change from baseline to end-of-treatment (68 weeks)
Compare BMI (weight in kg/height in m^2), body composition, body weight, and metabolic health between population-based reference group, excellent responders, non-responders and insufficient responders.	Dual-energy X-ray absorptiometry scans will be performed in fasting state to measure fat mass and lean mass (kg)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Change in body weight	Body weight change and proportion with at least 5%, 10%, 15%, and 20%	Change from baseline to end-of-treatment (68 weeks)
Change in metabolic syndrome	Prevalence (%)	Change from baseline to end-of-treatment (68 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HOMA-IR	Fasting insulin (μU/mL) * fasting glucose (mmol/L) / 22.5	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Matsuda Index	10000/sqrt(fasting glucose * fasting insulin * mean glucose * mean insulin)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Plasma Glucose	mmol/L	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Plasma Insulin	pmol/L	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
HbA1c	mmol/mol	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Lipids	Cholesterol (Total, HDL, LDL, VLDL) and triglycerides (TG)) (mmol/L)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Free Fatty Acids	umol/L	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Waist and hip circumference	Waist circumference, the midpoint between lowest rib and iliac crest, and hip circumference, the level of the great trochanters, will be measured in duplicate to the nearest 0.1 cm after gentle expiration.	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Blood pressure	Blood pressure (systolic/diastolic) will be measured in duplicate from the non-dominant arm with a digital blood pressure monitor in sitting position after at least 5 min of rest (mmHg).	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Heart rate	Heart rate (bpm)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Ectopic fat accumulation in liver, viscera and muscle	Magnetic resonance imaging (MRI) and spectroscopy	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Bone mineral density	Dual energy x-ray absorptiometry (DEXA) (g/cm^2)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Bone markers	CTX (ng/l) and P1NP (µg/L)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Systemic biomarkers of oxidation	Malonyldialdehyde and F2-Isoprostanes	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Immunometabolic profile of subcutaneous adipose tissue	Pro-inflammatory (e.g. IL-6, IL1b, MCP-1, resistin, leptin, chemerin, etc.) and anti-inflammatory (e.g. adiponectin) adipocytokines.	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
RNA sequencing on subcutaneous adipose tissue	Illumina sequencing	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Food preferences	Leeds Food Preference Questionnaire (LFPQ)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Genetic risk score correlated to treatment response	From blood samples, DNA material will be extracted and analyzed using the Infinium Global Screening Array and Illumina Genome Studio	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Gut microbiota composition	Collection of saliva and fecal samples and extraction of genomic DNA	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Metabolomics in urine	Urine samples	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Metabolomics in plasma	Metabolomics technique	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Proteomics in plasma	Proteomics technique	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Brain structure and function	Magnetic resonance imaging (MRI) will be performed in the fasting and fed states to assess brain structure and function.	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Hormonal appetite regulation during meal tests and in fasting	GLP-1, Peptide YY, Glucagon, Leptin, Ghrelin, LEAP2, Adiponectin, GDF-15, N-lactoyl-phenylalanine, neurotensin, neprilysin	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Systemic biomarkers of inflammation	e.g. sCD163, hsCRP, IL1, IL2, IL4, IL8, IL10, IL12p70, IL13, IL-1Rap IL-6, TNF-α, SAA1, SAA2, ORM1, ORM2, ICAM-1, VCAM-1, tPA, vWF) and oxidation (e.g., malonyldialdehyde, F2-Isoprostanes, etc.), IPS, sphingolipids, metabolomics using plasma metabolomics, and proteomics	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Subjective appetite sensation	Electronic visual analogue scales (VAS) (0-100 scale)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Health-related quality of life	SF-36 component scores	Change from baseline to end-of-treatment (68 weeks)
Psycho-social aspects of obesity development and treatment response by qualitative content analysis of semi-structured interviews	Open-ended semi-structured interviews will be conducted to measure adversity, resources, eating practices, and individual weight trajectories (score)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Eating behavior	Three-factor eating questionnaire (0-100 scale where higher score means a better outcome)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Systemic levels of metabolic disruptors	Measurement of plasma/serum concentrations of metabolic disruptors (e.g. per- and polyfluorinated substances (PFAS))	Change from baseline to end-of-treatment (68 weeks)
Induction of pluripotent stem cell cultures (iPSC)	One blood sample from each participant is used for induction of pluripotent stem cell culture (iPSC).	Baseline comparison
Muscle Strength	Hand grip strength	Change from 68 weeks to week 94
Physical activity level	Measured by wrist-worn activity tracker (min/week)	Baseline comparison and changes from baseline to end-of-treatment (week 68)
Sleep	Measured by wrist-worn activity tracker (min/night)	Baseline comparison and changes from baseline to end-of-treatment (week 68)
Change in body composition after medication (fat percentage)	Dual-energy X-ray absorptiometry scans will be performed in fasting state to measure body fat percentage (%).	Week 68 to 94
Change in body composition after medication (fat mass)	Dual-energy X-ray absorptiometry scans will be performed in fasting state to measure body fat mass (kg).	Week 68 to 94
Change in body composition after medication (fat-free mass)	Dual-energy X-ray absorptiometry scans will be performed in fasting state to measure fat-free mass (kg).	Week 68 to 94
Change in body weight after medication	Body weight change (kg)	Change from week 68 to 94
Change in waist-to-height ratio after medication	Waist-to-height ratio	Change from week 68 to 94
Change in visceral fat and liver fat after medication	MRI will be performed in fasting state to measure fat content	Change from week 68 to 94
Change in metabolic syndrome after medication	z-score	Change from week 68 to 94
Health-related quality of life after medication	SF-36 component scores (0-100 scale where higher score means a better outcome)	Change from week 68 to 94
Physical activity level	Measured by International Physical Activity Questionnaire (min/week)	Baseline comparison and changes from baseline to end-of-treatment (week 68)
Sleep quality	PSQI score	Baseline comparison and changes from baseline to end-of-treatment (week 68)

Collaborators and Investigators

• Sponsor: Signe Torekov
• Collaborators: Karolinska Institutet; Rigshospitalet, Denmark; University of Leeds; Holbaek Sygehus
• Investigators: Study Director: Signe S Torekov, Prof, PhD, University of Copenhagen; Study Chair: Jens-Christian Holm, Ass. Prof, PhD, Holbæk University Hospital

Publications and helpful links

General Publications

• Bjerregaard LG, Jensen BW, Angquist L, Osler M, Sorensen TIA, Baker JL. Change in Overweight from Childhood to Early Adulthood and Risk of Type 2 Diabetes. N Engl J Med. 2018 Apr 5;378(14):1302-1312. doi: 10.1056/NEJMoa1713231.
• The NS, Suchindran C, North KE, Popkin BM, Gordon-Larsen P. Association of adolescent obesity with risk of severe obesity in adulthood. JAMA. 2010 Nov 10;304(18):2042-7. doi: 10.1001/jama.2010.1635.
• Global BMI Mortality Collaboration, Di Angelantonio E, Bhupathiraju ShN, Wormser D, Gao P, Kaptoge S, Berrington de Gonzalez A, Cairns BJ, Huxley R, Jackson ChL, Joshy G, Lewington S, Manson JE, Murphy N, Patel AV, Samet JM, Woodward M, Zheng W, Zhou M, Bansal N, Barricarte A, Carter B, Cerhan JR, Smith GD, Fang X, Franco OH, Green J, Halsey J, Hildebrand JS, Jung KJ, Korda RJ, McLerran DF, Moore SC, O'Keeffe LM, Paige E, Ramond A, Reeves GK, Rolland B, Sacerdote C, Sattar N, Sofianopoulou E, Stevens J, Thun M, Ueshima H, Yang L, Yun YD, Willeit P, Banks E, Beral V, Chen Zh, Gapstur SM, Gunter MJ, Hartge P, Jee SH, Lam TH, Peto R, Potter JD, Willett WC, Thompson SG, Danesh J, Hu FB. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet. 2016 Aug 20;388(10046):776-86. doi: 10.1016/S0140-6736(16)30175-1. Epub 2016 Jul 13.
• Hebebrand J, Holm JC, Woodward E, Baker JL, Blaak E, Durrer Schutz D, Farpour-Lambert NJ, Fruhbeck G, Halford JGC, Lissner L, Micic D, Mullerova D, Roman G, Schindler K, Toplak H, Visscher TLS, Yumuk V. A Proposal of the European Association for the Study of Obesity to Improve the ICD-11 Diagnostic Criteria for Obesity Based on the Three Dimensions Etiology, Degree of Adiposity and Health Risk. Obes Facts. 2017;10(4):284-307. doi: 10.1159/000479208. Epub 2017 Jul 22.
• Mollerup PM, Gamborg M, Trier C, Bojsoe C, Nielsen TR, Baker JL, Holm JC. A hospital-based child and adolescent overweight and obesity treatment protocol transferred into a community healthcare setting. PLoS One. 2017 Mar 6;12(3):e0173033. doi: 10.1371/journal.pone.0173033. eCollection 2017.
• Nielsen TR, Gamborg M, Fonvig CE, Kloppenborg J, Hvidt KN, Ibsen H, Holm JC. Changes in lipidemia during chronic care treatment of childhood obesity. Child Obes. 2012 Dec;8(6):533-41. doi: 10.1089/chi.2011.0098.
• Hvidt KN, Olsen MH, Ibsen H, Holm JC. Effect of changes in BMI and waist circumference on ambulatory blood pressure in obese children and adolescents. J Hypertens. 2014 Jul;32(7):1470-7; discussion 1477. doi: 10.1097/HJH.0000000000000188.
• Fonvig CE, Chabanova E, Ohrt JD, Nielsen LA, Pedersen O, Hansen T, Thomsen HS, Holm JC. Multidisciplinary care of obese children and adolescents for one year reduces ectopic fat content in liver and skeletal muscle. BMC Pediatr. 2015 Dec 30;15:196. doi: 10.1186/s12887-015-0513-6.
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Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2022
• Primary Completion (Actual): April 1, 2026
• Study Completion (Actual): April 1, 2026

Study Registration Dates

• First Submitted: October 6, 2022
• First Submitted That Met QC Criteria: October 6, 2022
• First Posted (Actual): October 10, 2022

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Semaglutide; Weight loss; GLP-1 RA; Treatment resistant
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Body Weight Changes; Overweight; Obesity; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Weight Loss; Pediatric Obesity; semaglutide
• Other Study ID Numbers: U1111-1215-8606; 2019-002274-31 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No