Young Adults With Early-onset Obesity Treated With Semaglutide -The RESETTLE Study
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 246
- 试验地点
- 4
- 主要终点
- Change in BMI (weight in kg/height in m^2)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The above-mentioned are masked in terms of semaglutide/placebo. Statistical analysis of primary outcome will be blinded to the assessor.
入排标准
- 年龄范围
- 18 Years 至 28 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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≥
- •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≥
- •Insufficient responders: BMI SDS reduction ≥0.25 BMI SDS during TCOC protocol for more than one year, but still have obesity.
- •Group C: BMI≤
- •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
排除标准
- •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
- •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)
研究组 & 干预措施
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).
干预措施: TCOC treatment (Behavioral)
Non-responders: TCOC+ placebo
Placebo: 2.4 mg/week SC in combination with TCOC treatment (i.e. diet/weight consultations).
干预措施: TCOC treatment (Behavioral)
Excellent Responders and Population-based reference group
No intervention.
Non-responders: TCOC+ placebo
Placebo: 2.4 mg/week SC in combination with TCOC treatment (i.e. diet/weight consultations).
干预措施: Placebo (Semaglutide 3 mg/ml) (Drug)
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).
干预措施: TCOC treatment (Behavioral)
Insufficient responders: TCOC+ placebo
Placebo: 2.4mg/week SC in combination with TCOC treatment (i.e. diet/weight consultations).
干预措施: TCOC treatment (Behavioral)
Insufficient responders: TCOC+ placebo
Placebo: 2.4mg/week SC in combination with TCOC treatment (i.e. diet/weight consultations).
干预措施: Placebo (Semaglutide 3 mg/ml) (Drug)
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).
干预措施: Semaglutide 3 mg/ml (Drug)
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).
干预措施: Semaglutide 3 mg/ml (Drug)
结局指标
主要结局
Change in BMI (weight in kg/height in m^2)
时间窗: Change from baseline to end-of-treatment (68 weeks)
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.
次要结局
- Change in body composition (fat mass)(Change from baseline to end-of-treatment (68 weeks))
- Change in body composition (fat free mass)(Change from baseline to end-of-treatment (68 weeks))
- Change in body composition (fat percentage)(Change from baseline to end-of-treatment (68 weeks))
- Change in metabolic syndrome(Change from baseline to end-of-treatment (68 weeks))
- Change in visceral fat and liver fat(Change from baseline to end-of-treatment (68 weeks))
- Change in 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.(Baseline comparison and change from baseline to end-of-treatment (68 weeks))
- Change in body weight(Change from baseline to end-of-treatment (68 weeks))
研究者
Signe Torekov
Professor
University of Copenhagen