Clinical trial NCT05574439: Young Adults with Early-onset Obesity Treated with Semaglutide
Official title: Young Adults with Early-onset Obesity Treated with Semaglutide -The RESETTLE Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Obesity, Adolescent
Keywords: GLP-1 RA
Semaglutide
Weight loss
Treatment resistant
Lead sponsor: University of Copenhagen
Sponsor class: OTHER
Collaborators: name: University of Leeds
name: Karolinska Institutet
name: Holbaek Sygehus
name: Rigshospitalet, Denmark
First posted: 2022-10-10
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Maximum age (years): 28
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Four groups will be identified based on their previous response to structured lifestyle interventions. Non-responders (group A) and insufficient responders (group B) are randomized 2:1 to either Semaglutide 2.4 mg/ week sc or placebo for 68 weeks. Group C (excellent responders) and Group D (population-based reference group with normal weight development) will attend baseline examinations only and not undergo intervention.
Primary purpose: TREATMENT

Brief summary: 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 (BMI≥30 kg/m2) who have not succeeded in losing weight during the structured lifestyle intervention (BMI SDS reduction \&lt;0.1)

Group B: Insufficient responders: 55-85 young adults (BMI≥30 kg/m2) who have succeeded in losing weight during the structured lifestyle intervention (BMI SDS reduction \&gt;0.25), but still have obesity.

Group C: Excellent responders: 35-50 young adults, who have succeeded in losing weight during the structured lifestyle intervention (BMI SDS reduction \&gt;0.5) and no longer have obesity (BMI\&lt;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.

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 \&gt;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 with insufficient weight loss to the structured lifestyle intervention (TCOC protocol) and remain obese, 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:

1. Change in body composition and body weight from before to after semaglutide treatment compared to placebo
2. Proportion of reduction in body weight of at least 5 %, 10 %, 15 %, and 20 % with semaglutide treatment relative to placebo will be described.

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. Circulating biomarkers of metabolic regulation to evaluate metabolic health (e.g.

   glucose and insulin for HOMA-IR and Matsuda index, HbA1c, lipids i.e. cholesterol, HDL, LDL, triglycerides, FFA and determination of glucose-tolerance status) will be measured. Furthermore, the investigator will measure blood pressure, pulse, and hip and waist circumference.
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.
3. 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) using our standard methodologies. In plasma samples various biomarkers of inflammation will be measured (eg sCD163, hsCRP, IL-1, IL- 1Rap IL-6, TNF-α, SAA1, SAA2, ORM1, ORM2) and oxidation (eg malonyldialdehyde, F2-Isoprostanes, etc.), IPS and metabolomics using plasma metabolomics and proteomics technique.
4. 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).
5. 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.
6. To explore the effect on brain activation using magnetic resonance (MR) imaging:

   MR imaging of the brain will be conducted in a subset of participants by trained personnel at a registered clinical facility. An MRI scanner is composed of a long tube surrounded by a coil that forms a powerful magnetic field. Participants will be placed on an examination table in the centre of the tube in a supine position. By changing gradients in the magnetic field and transmitting radio waves, resonance of the atomic nuclei of the brain can be induced. During the scan the investigator will acquire both structural and functional information about the brain. The structural MRI sequences will provide a high-resolution anatomical image of the brain. A functional MRI (fMRI) scan provides the opportunity to track changes in e.g., blood oxygenation, which serve as an index for neural activation in different parts of the brain while the participants are at rest. This protocol includes morphological neuroimaging and resting-state fMRI. The MRI scanning session will last approximately one hour.
7. 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 \&amp;amp;#34;American College Medical Genetics and Genomics\&amp;amp;#34; List.
8. 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.
9. 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.
10. 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.

Eligibility criteria: 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 (\&lt;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 \&gt;0.25 BMI SDS during TCOC protocol for more than one year, but still have obesity.
* Group C: BMI\&lt;30. Excellent responders: BMI SDS reduction \&gt;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 \&gt; 7 mmol/l)
* Angina pectoris, coronary heart disease, congestive heart failure (NYHA III-IV)
* Severe renal impairment (creatinine clearance (GFR) \&lt;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)

Primary outcomes:
measure: Change in BMI (weight in kg/height in m^2)
timeFrame: Change from baseline to end-of-treatment (68 weeks)
Secondary outcomes:
measure: Change in body composition (fat mass and fat free mass) and body weight from before to after semaglutide treatment compared to placebo
timeFrame: Change from baseline to end-of-treatment (68 weeks)
measure: Change in BMI (weight in kg/height in m^2), body composition (fat mass and fat free mass) and body weight from before to after semaglutide treatment compared to placebo separately in non-responders and insufficient responders to TCOC protocol.
timeFrame: Change from baseline to end-of-treatment (68 weeks)
measure: Compare BMI (weight in kg/height in m^2), body composition (fat mass and fat free mass) and body weight between population-based reference group, excellent responders, non-responders and insufficient responders.
timeFrame: Baseline comparison
Other outcomes:
measure: HOMA-IR
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Matsuda Index
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Plasma Glucose
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Plasma Insulin
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: HbA1c
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Lipids
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Free Fatty Acids
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Waist and hip circumference
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Blood pressure
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Heart rate
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Ectopic fat accumulation in liver, viscera and muscle
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Neural activation in the resting state and in response to food-cues
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Bone mineral density
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Bone markers
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Hormonal appetite regulation during meal tests and in fasting
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Systemic biomarkers of inflammation
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Systemic biomarkers of oxidation
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Immunometabolic profile of subcutaneous adipose tissue
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: RNA sequencing on subcutaneous adipose tissue
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Food preferences
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Subjective appetite sensation
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Genetic risk score correlated to treatment response
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Gut microbiota composition
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Metabolomics in urine
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Metabolomics in plasma
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
measure: Proteomics in plasma
timeFrame: Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Locations:
city: Holbæk
country: Denmark
facility: Holbæk University Hospital
state: Region Zeeland
city: Copenhagen
country: Denmark
facility: University of Copenhagen, Department of Biomedical Sciences
Study officials:
affiliation: University of Copenhagen
name: Signe S Torekov, Prof, PhD
role: STUDY_DIRECTOR
affiliation: Holbæk University Hospital
name: Jens-Christian Holm, Ass. Prof, PhD
role: STUDY_CHAIR
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