Young Adults With Early-onset Obesity Treated With Semaglutide

Obesity, Adolescent Clinical Trial

— RESETTLE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05574439
• Other study ID #: U1111-1215-8606
• Secondary ID: 2019-002274-31
• Status: Recruiting
• Phase: Phase 4
• Start date: June 1, 2022
• Est. completion date: June 1, 2026

Study information

• Verified date: October 2022
• Source: University of Copenhagen
• Contact: Signe S Torekov, Prof, PhD
• Phone: +4535327509
• Email: torekov[@]sund.ku.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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. 130-170 young adults (age 18-28) will be recruited from The Children's Obesity Clinic (TCOC), Department of Pediatrics, Holbæk Hospital. Based on their previous response to the TCOC protocol the participants will be divided in three groups:

Group A: Non-responders: 55-75 young adults (BMI>30 kg/m2) who have not succeeded in losing weight during the structured lifestyle intervention (BMI SDS reduction <0.1)

Group B: Insufficient responders: 55-75 young adults (BMI>30 kg/m2) who have succeeded in losing weight during the structured lifestyle intervention (BMI SDS reduction >0.25), but still have obesity.

Group C: Excellent responders: 20 young adults, who have succeeded in losing weight during the structured lifestyle intervention (BMI SDS reduction >0.5) and no longer have obesity (BMI<30 kg/m2).

Group A and B are randomized 2:1 to either semaglutide or placebo for 68 weeks. Group C 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.

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 Children's 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 RA's 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.

Endpoints:

Primary endpoint:

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

Secondary endpoints:

1. Change in body composition and body weight from before to after semaglutide treatment in non-responders to TCOC protocol compared to placebo

2. Change in BMI (weight in kg/height in m^2), body composition and body weight from before to after semaglutide treatment in insufficient responders to TCOC protocol compared to placebo

3. Compare BMI (weight in kg/height in m^2), body composition and body weight between excellent responders, non-responders and insufficient responders.

Other prespecified endpoints:

To determine the effect of GLP-1 RA treatment, and compare baseline data between the two intervention groups to excellent responders for the 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 Furthermore, the investigator will use eye tracking as well as galvanic skin response to record the participants' emotional response to the standardized food items using iMotion Software. 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 "American College Medical Genetics and Genomics" 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 170
• Est. completion date: June 1, 2026
• Est. primary completion date: October 30, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 28 Years

Eligibility

Inclusion Criteria:

• Age 18-28 years

• The period from the initial treatment with TCOC protocol until inclusion in the study must be within 10 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 (BMI>30).

• 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 (BMI>30).

• Only baseline examination: 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 (BMI<30).

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

• 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.

Related Conditions & MeSH terms

• Obesity
• Obesity, Adolescent
• Pediatric Obesity

Intervention

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
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.

Locations

Country	Name	City	State
Denmark	University of Copenhagen, Department of Biomedical Sciences	Copenhagen
Denmark	Holbæk University Hospital	Holbæk	Region Zeeland

Sponsors (5)

Lead Sponsor	Collaborator
Signe Torekov	Holbaek Sygehus, Karolinska Institutet, Rigshospitalet, Denmark, University of Leeds

Country where clinical trial is conducted

Denmark, 

References & Publications (23)

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Christensen BJ, Iepsen EW, Lundgren J, Holm L, Madsbad S, Holst JJ, Torekov SS. Instrumentalization of Eating Improves Weight Loss Maintenance in Obesity. Obes Facts. 2017;10(6):633-647. doi: 10.1159/000481138. Epub 2017 Dec 6. — View Citation

Færch K, Torekov SS, Vistisen D, Johansen NB, Witte DR, Jonsson A, Pedersen O, Hansen T, Lauritzen T, Sandbæk A, Holst JJ, Jørgensen ME. GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study. Diabetes. 2015 Jul;64(7):2513-25. doi: 10.2337/db14-1751. Epub 2015 Feb 12. — View Citation

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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. — View Citation

GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C, Ahmed MB, Al-Aly Z, Alkerwi A, Al-Raddadi R, Amare AT, Amberbir A, Amegah AK, Amini E, Amrock SM, Anjana RM, Ärnlöv J, Asayesh H, Banerjee A, Barac A, Baye E, Bennett DA, Beyene AS, Biadgilign S, Biryukov S, Bjertness E, Boneya DJ, Campos-Nonato I, Carrero JJ, Cecilio P, Cercy K, Ciobanu LG, Cornaby L, Damtew SA, Dandona L, Dandona R, Dharmaratne SD, Duncan BB, Eshrati B, Esteghamati A, Feigin VL, Fernandes JC, Fürst T, Gebrehiwot TT, Gold A, Gona PN, Goto A, Habtewold TD, Hadush KT, Hafezi-Nejad N, Hay SI, Horino M, Islami F, Kamal R, Kasaeian A, Katikireddi SV, Kengne AP, Kesavachandran CN, Khader YS, Khang YH, Khubchandani J, Kim D, Kim YJ, Kinfu Y, Kosen S, Ku T, Defo BK, Kumar GA, Larson HJ, Leinsalu M, Liang X, Lim SS, Liu P, Lopez AD, Lozano R, Majeed A, Malekzadeh R, Malta DC, Mazidi M, McAlinden C, McGarvey ST, Mengistu DT, Mensah GA, Mensink GBM, Mezgebe HB, Mirrakhimov EM, Mueller UO, Noubiap JJ, Obermeyer CM, Ogbo FA, Owolabi MO, Patton GC, Pourmalek F, Qorbani M, Rafay A, Rai RK, Ranabhat CL, Reinig N, Safiri S, Salomon JA, Sanabria JR, Santos IS, Sartorius B, Sawhney M, Schmidhuber J, Schutte AE, Schmidt MI, Sepanlou SG, Shamsizadeh M, Sheikhbahaei S, Shin MJ, Shiri R, Shiue I, Roba HS, Silva DAS, Silverberg JI, Singh JA, Stranges S, Swaminathan S, Tabarés-Seisdedos R, Tadese F, Tedla BA, Tegegne BS, Terkawi AS, Thakur JS, Tonelli M, Topor-Madry R, Tyrovolas S, Ukwaja KN, Uthman OA, Vaezghasemi M, Vasankari T, Vlassov VV, Vollset SE, Weiderpass E, Werdecker A, Wesana J, Westerman R, Yano Y, Yonemoto N, Yonga G, Zaidi Z, Zenebe ZM, Zipkin B, Murray CJL. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017 Jul 6;377(1):13-27. doi: 10.1056/NEJMoa1614362. Epub 2017 Jun 12. — View Citation

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. — View Citation

Hebebrand J, Holm JC, Woodward E, Baker JL, Blaak E, Durrer Schutz D, Farpour-Lambert NJ, Frühbeck 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. — View Citation

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. — View Citation

Iepsen EW, Lundgren J, Dirksen C, Jensen JE, Pedersen O, Hansen T, Madsbad S, Holst JJ, Torekov SS. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss. Int J Obes (Lond). 2015 May;39(5):834-41. doi: 10.1038/ijo.2014.177. Epub 2014 Oct 7. — View Citation

Iepsen EW, Lundgren J, Holst JJ, Madsbad S, Torekov SS. Successful weight loss maintenance includes long-term increased meal responses of GLP-1 and PYY3-36. Eur J Endocrinol. 2016 Jun;174(6):775-84. doi: 10.1530/EJE-15-1116. Epub 2016 Mar 14. — View Citation

Iepsen EW, Zhang J, Thomsen HS, Hansen EL, Hollensted M, Madsbad S, Hansen T, Holst JJ, Holm JC, Torekov SS. Patients with Obesity Caused by Melanocortin-4 Receptor Mutations Can Be Treated with a Glucagon-like Peptide-1 Receptor Agonist. Cell Metab. 2018 Jul 3;28(1):23-32.e3. doi: 10.1016/j.cmet.2018.05.008. Epub 2018 May 31. — View Citation

Jensen SBK, Janus C, Lundgren JR, Juhl CR, Sandsdal RM, Olsen LM, Andresen A, Borg SA, Jacobsen IC, Finlayson G, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Exploratory analysis of eating- and physical activity-related outcomes from a randomized controlled trial for weight loss maintenance with exercise and liraglutide single or combination treatment. Nat Commun. 2022 Aug 15;13(1):4770. doi: 10.1038/s41467-022-32307-y. — View Citation

Lundgren JR, Janus C, Jensen SBK, Juhl CR, Olsen LM, Christensen RM, Svane MS, Bandholm T, Bojsen-Møller KN, Blond MB, Jensen JB, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med. 2021 May 6;384(18):1719-1730. doi: 10.1056/NEJMoa2028198. — View Citation

Mollerup PM, Gamborg M, Trier C, Bøjsøe 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. — View Citation

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. — View Citation

Rubino DM, Greenway FL, Khalid U, O'Neil PM, Rosenstock J, Sørrig R, Wadden TA, Wizert A, Garvey WT; STEP 8 Investigators. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA. 2022 Jan 11;327(2):138-150. doi: 10.1001/jama.2021.23619. — View Citation

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. — View Citation

Torekov SS, Holst JJ, Ehlers MR. Dose response of continuous subcutaneous infusion of recombinant glucagon-like peptide-1 in combination with metformin and sulphonylurea over 12 weeks in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014 May;16(5):451-6. doi: 10.1111/dom.12240. Epub 2013 Dec 10. — View Citation

Torekov SS, Kipnes MS, Harley RE, Holst JJ, Ehlers MR. Dose response of subcutaneous GLP-1 infusion in patients with type 2 diabetes. Diabetes Obes Metab. 2011 Jul;13(7):639-43. doi: 10.1111/j.1463-1326.2011.01388.x. — View Citation

Torekov SS, Madsbad S, Holst JJ. Obesity - an indication for GLP-1 treatment? Obesity pathophysiology and GLP-1 treatment potential. Obes Rev. 2011 Aug;12(8):593-601. doi: 10.1111/j.1467-789X.2011.00860.x. Epub 2011 Mar 15. Review. — View Citation

Trier C, Hollensted M, Schnurr TM, Lund MAV, Nielsen TRH, Rui G, Andersson EA, Svendstrup M, Bille DS, Gjesing AP, Fonvig CE, Frithioff-Bøjsøe C, Balslev-Harder M, Quan S, Gamborg M, Pedersen O, Ängquist L, Holm JC, Hansen T. Obesity treatment effect in Danish children and adolescents carrying Melanocortin-4 Receptor mutations. Int J Obes (Lond). 2021 Jan;45(1):66-76. doi: 10.1038/s41366-020-00673-6. Epub 2020 Sep 13. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	HOMA-IR	Fasting insulin (µU/mL) * fasting glucose (mmol/L) / 22.5	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Matsuda Index	10000/sqrt(fasting glucose * fasting insulin * mean glucose * mean insulin)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Plasma Glucose	mmol/L	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Plasma Insulin	pmol/L	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	HbA1c	mmol/mol	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Lipids	Cholesterol (Total, HDL, LDL, VLDL) and triglycerides (TG)) (mmol/L)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Free Fatty Acids	umol/L	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	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)
Other	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)
Other	Heart rate	Heart rate (bpm)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	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)
Other	Neural activation in the resting state and in response to food-cues	Structural and Functional Magnetic resonance imaging (MRI)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Bone mineral density	Dual energy x-ray absorptiometry (DEXA) (g/cm^2)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Bone markers	CTX (ng/l) and P1NP (µg/L)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Hormonal appetite regulation during meal tests and in fasting	GLP-1, Peptide YY, Glucagon, Leptin, Ghrelin, LEAP2, Adiponectin	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Systemic biomarkers of inflammation	sCD163, hsCRP, IL-1, IL-1Rap IL-6, TNF-a, SAA1, SAA2, ORM1, ORM2	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Systemic biomarkers of oxidation	Malonyldialdehyde and F2-Isoprostanes	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	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)
Other	RNA sequencing on subcutaneous adipose tissue	Illumina sequencing	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Food preferences	Leeds Food Preference Questionnaire (LFPQ)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Biometric responses to food items	Eye tracking and galvanic skin response (iMotion Software)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Subjective appetite sensation	Electronic visual analogue scales (VAS)	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	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)
Other	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)
Other	Metabolomics in urine	Urine samples	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Metabolomics in plasma	Metabolomics technique	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Other	Proteomics in plasma	Proteomics technique	Baseline comparison and change from baseline to end-of-treatment (68 weeks)
Primary	Change in BMI (weight in kg/height in m^2) in non-responders	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	Change in body composition (fat mass and fat free mass) and body weight from before to after semaglutide treatment in non-responders to TCOC protocol compared to placebo	Body composition: 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)
Secondary	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 in insufficient responders to TCOC protocol compared to placebo.	Dual-energy X-ray absorptiometry scans will be performed in fasting state to measure fat mass and lean mass (kg)	Change from baseline to end-of-treatment (68 weeks)
Secondary	Compare BMI (weight in kg/height in m^2), body composition (fat mass and fat free mass) and body weight between 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