A Multicenter Pharmacoepidemiological Cohort on Real Life Use of Semaglutide in Adolescents or Adults With Monogenic Obesity (ObGeSema)

Rare genetic forms of obesity, so called monogenic obesity are linked to alteration in energy balance involving hypothalamic pathways.

More than 60 genes encoding for proteins located in the hypothalamic leptin/melanocortin pathway have been described in the French National Protocol for Diagnostic and Care (PNDS).

While pathogenic and likely pathogenic variants in these genes are well-established causes of monogenic obesity, current evidence supports a broader genetic architecture of obesity, better understood as a continuum ranging from rare high-impact variants to polygenic susceptibility.

Variants of uncertain significance (VUS) as well as variants currently classified as benign or likely benign are frequently identified in clinical practice, and their classification may evolve over time as genomic databases expand and functional data accumulate In addition, polygenic background may interact with rare variants and contribute to the severity of the phenotype, disease progression, and therapeutic response.

The natural history of monogenic obesity is characterized by an early onset in childhood, with a major increase in weight in adolescence and young adulthood. The worsening of obesity exposes these patients to severe complications.

Severe obesity and eating disorders have a major impact on the quality of life of the person but also of the family and caregivers. Clinical management is complex and requires comprehensive, specialized and multidisciplinary management. The usual lifestyle approaches have so far shown disappointing results, similarly to bariatric surgery which leads to a more frequent weight regain in the situation of monogenic obesity, justifying new approaches.

In this context, evaluating the response to treatment in the particular condition of monogenic obesity is crucial to propose therapeutic options as early as possible to limit weight evolution and its complications.

GLP-1 (glucagon-like peptide 1) based innovative therapies have recently emerged as a promising option for treatment of obesity and its complications. This is the case for Semaglutide marketed as OZEMPIC® and WEGOVY®, developed by Novo Nordisk. However, there is a lack of data to confirm that semaglutide could be also effective in monogenic obesity.

The aim of the ObGeSema project is to set up a cohort composed of patients (1) having already initiated a treatment and (2) newly treated by Semaglutide in 21 pediatric and adult Specialized Obesity Centres (CSOs) and describe their evolution over a 4 years follow-up.

Study Overview

• Status: Recruiting
• Conditions: Monogenic Obesity

Detailed Description

Rare genetic forms of obesity, so called monogenic obesity are linked to alteration in energy balance involving hypothalamic pathways. More than 60 genes encoding for proteins located in the hypothalamic leptin/melanocortin pathway have been described in the French National Protocol for Diagnostic and Care (PNDS) https://www.has-sante.fr/jcms/p_3280217/fr/generique-obesites-de-causes-rares).

While pathogenic and likely pathogenic variants in these genes are well-established causes of monogenic obesity, current evidence supports a broader genetic architecture of obesity, better understood as a continuum ranging from rare high-impact variants to polygenic susceptibility.

Variants of uncertain significance (VUS) as well as variants currently classified as benign or likely benign are frequently identified in clinical practice, and their classification may evolve over time as genomic databases expand and functional data accumulate In addition, polygenic background may interact with rare variants and contribute to the severity of the phenotype, disease progression, and therapeutic response.

The natural history of monogenic obesity is characterized by an early onset in childhood, with a major increase in weight in adolescence and young adulthood. The worsening of obesity exposes these patients to severe complications. Severe obesity and eating disorders have a major impact on the quality of life of the person but also of the family and caregivers. Clinical management is complex and requires comprehensive, specialized and multidisciplinary management. The usual lifestyle approaches have so far shown disappointing results, similarly to bariatric surgery which leads to a more frequent weight regain in the situation of monogenic obesity, justifying new approaches.

In this context, evaluating the response to treatment in the particular condition of monogenic obesity is crucial to propose therapeutic options as early as possible to limit weight evolution and its complications.

GLP-1 based innovative therapies have recently emerged as a promising option for treatment of obesity and its complications. This is the case for Semaglutide marketed as OZEMPIC® and WEGOVY®, developed by Novo Nordisk. However, there is a lack of data to confirm that semaglutide could be also effective in monogenic obesity, particularly across the full spectrum of genetic variants involved in the leptin-melanocortin pathway.

In France, semaglutide is currently accessible through several regulatory frameworks:

OZEMPIC® (up to 2 mg/week) is reimbursed by the French Social Security for the treatment of type 2 diabetes in adult patients.

WEGOVY® (up to 2.4 mg/week) was available through an Early Access Programme from May 2022 to September 2024 for adults with BMI >40 kg/m² and at least one comorbidity. Treatment initiated in this framework can be continued until December 2025.

Since November 2024, WEGOVY® (up to 2.4 mg/week) has had marketing authorization for the treatment of adolescents and adults ≥12 years with BMI ≥30 kg/m². However, the drug is not yet reimbursed, except in rare cases through individual exceptional reimbursement for rare and complex diseases.

Given this evolving regulatory landscape, it is essential to assess the real-life efficacy and safety of semaglutide in individuals with including both adolescents and adults carrying variants across the continuum of genetic susceptibility.

The aim of the ObGeSema project is to set up a cohort composed of patients (1) having already initiated a treatment and (2) newly treated by Semaglutide in 21 pediatric and adult Specialized Obesity Centres (CSOs) and describe their evolution over a 4 years follow-up.

• Study Type: Observational
• Enrollment (Estimated): 175

Contacts and Locations

• Study Contact: Name: Christine POITOU-BERNERT, MD,PhD; Phone Number: +33(0)142175771; Email: christine.poitou-bernert@aphp.fr
• Study Contact Backup: Name: Sarra POCHON; Phone Number: +33(0)142167574; Email: sarra.pochon@aphp.fr

Study Locations

• France
  • Paris, France, 75013
    • Not yet recruiting
    • Centre de référence Syndrome de Prader-Willi et autres obésités avec troubles du comportement alimentaire (PRADORT). Service de Nutrition, GH Pitié-Salpêtrière, APHP
    • Contact: Emilie GUILLON; Email: emilie.guillon-ext@aphp.fr
    • Contact: Sarra POCHON; Phone Number: +33(1)42167574; Email: sarra.pochon@aphp.fr
  • Paris, France, 75013
    • Recruiting
    • CHU Pitié Salpêtrière - APHP
    • Contact: Christine POITOU-BERNERT, MD, PhD; Phone Number: +33(0)142175771
    • Principal Investigator: Christine POITOU-BERNERT, MD,PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients (≥12 years) with monogenic obesity due to any variant regardless of pathogenicity classification and already treated or with the physician's decision to initiate treatment with Semaglutide in the standard care. Patients under legal protection and State Medical Assistance (AME) will be included.

Description

Inclusion Criteria:

• Patients (≥12 years) having already initiated a treatment with SEMAGLUTIDE (regardless of the context: early access, routine care, self-financing, or exceptional reimbursement) or with a physician's decision to initiate treatment in the standard care. All patients having initiated treatment will be proposed to participate, including those having already stopped the treatment at the time of study initiation.
• Confirmation of monogenic obesity, as practiced in clinical routine, regardless of current classification (i.e., pathogenic, likely pathogenic, variant of uncertain significance [VUS], or benign) in a gene with leptin-melanocortin pathway described in PNDS (https://www.has-sante.fr/jcms/p_3280217/fr/generique-obesites-de-causes-rares). ) For patients with VUS or benign variants, inclusion is conditional on the availability of a polygenic risk score (PRS)
• Patients duly informed and not objecting to participate in the study. For patients ≥12 years <18 years Parents duly informed and not objecting that their child taking part in the study
• Patients affiliated to a social security scheme or State Medical Assistance (AME).

Exclusion Criteria:

• Pregnant and breastfeeding women

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in weight and Body Mass Index (BMI)	Percentage of subjects with a change in weight and Body Mass Index (BMI).Weight will be measured at initiation and at 12 months of the Semaglutide treatment	From baseline (T0) to T12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction of body weight equal to or above 5%	Percentage of subjects achieving a reduction of body weight equal to or above 5%(number of subjects with a % of body weight changes > -5%)X100/ number of the total subject	From baseline (T0) to 6 and/or 12 and/or 24 and/or 36 and/or 48 and/or 60 months
Change in Hunger score	Number and percentage of subjects with change in Hunger score	From baseline (T0) to 12 and/or 24 and/or 36 and/or 48 and/or 60 months
Change in eating behaviour measured by Food Craving questionnaire	Number and percentage of subjects with change in Food Craving scale	From baseline (T0) to 12 months
Change in eating behaviour measured by the Binge Eating Scale (BES)	Number and percentage of subjects with change in Binge Eating Scale (BES)	From baseline (T0) to 12 months
Change in eating behaviour measured by the Dutch Eating Behaviour Questionnaire (DEBQ)	Number and percentage of subjects with change in Dutch Eating Behaviour Questionnaire (DEBQ)	From baseline (T0) to 12 months
Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)	Number of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)	From baseline (T0) to 6 and/or 12 and/or 24 and/or 36 and/or 48 and/or 60 months
Change in weight and Body Mass Index (BMI)	Percentage of subjects with a change in weight and Body Mass Index (BMI). Weight will be measured at initiation of the Semaglutide treatment and at each visit	From baseline (T0) to 6 and/or 24 and/or 36 and/or 48 and/or 60 months
Change in eating behaviour measured by the Dykens questionnaire for ≥18 years patients	Number and percentage of subjects with change in Hyperphagia score with the Dykens questionnaire for intellectual disability	From baseline (T0) to 12 months
Change in eating behaviour measured by the Child Eating Behaviour Questionnaire (CEBQ)	Number and percentage of subjects with change in the Child Eating Behaviour Questionnaire (CEBQ) for intellectual disability for ≥18 years patients	From baseline (T0) to 12 months
Change in the International physical activity questionnaire (IPAQ - short form) for ≥18 years patients	Number and percentage of subjects with change of the International physical activity	From baseline (T0) to 12 months
Change in Digestive disorders (GIQLI ) for ≥18 years patients	Number and percentage of subjects with change in Digestive disorders (GIQLI ). Digestive disorders are measured by the Gastrointestinal Quality of Life Index (GIQLI)	From baseline (T0) to 12 and/or 24 and/or 36 and/or 48 and/or 60 months
Change in score of quality of life scores (patient and parents) for ≥18 years patients	Number and percentage of subjects with change in score of quality of life scores .Quality of life is measured with the Impact of Weight on Quality of Life-Lite scale (IWQOL-Lite)	From baseline (T0) to 12 months
Change in sleep disorder (MCTQ score) for ≥18 years patients	Number and percentage of subjects with Change in sleep disorder. Sleep disorder is measured with the Micro Munich Chronotype Questionnaire (MCTQ)	From baseline (T0) to 12 months
Change in anxiety and depression score for ≥18 years patients	Number and percent of subjects with change in anxiety and depression score. Anxiety and depression is measured with the Hospital Anxiety and Depression scale (HAD)	From baseline (T0) to 12 and/or 24 and/or 36 and/or 48 and/or 60 months
● Change in Body Mass Index : BMI Z-score for 12 to <18 years	Weight will be measured at initiation of the Semaglutide treatment and at each visit	From baseline (T0) to 6 and/or 12 and/or 24 and/or 36 and/or 48 and/or 60 months
Change in eating behaviour scores CEBQ ( Child Eating Behaviour Questionnaire) or Hyperphagia score with the Dykens questionnaire and for intellectual disability. For 12 to <18 years patients	Number and percentage of subjects with change	From baseline (T0) to 12 months
Change in score of IWQOL Impact of Weight on Quality of Life (patient and parents). For 12 to <18 years patients	Number and percentage of subjects with change in score Impact of Weight on Quality of Life	From baseline (T0) to 12 months
Change in Digestive disorders GIQLI score (Gastrointestinal Quality of Life Index). For 12 to <18 years patients	Number and percentage of subjects with change	From baseline (T0) to 12 and/or 24 and/or 36 and/or 48 and/or 60 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Christine POITOU-BERNERT, MD,PhD, Assistance Publique - Hôpitaux de Paris; Study Director: Béatrice DUBERN, MD,PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2024
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): November 30, 2027

Study Registration Dates

• First Submitted: April 11, 2024
• First Submitted That Met QC Criteria: April 22, 2024
• First Posted (Actual): April 23, 2024

Study Record Updates

• Last Update Posted (Actual): June 24, 2026
• Last Update Submitted That Met QC Criteria: June 19, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Semaglutide; Monogenic obesity; WEGOVY
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Obesity
• Other Study ID Numbers: APHP230441; IDRCB : 2023-A02003-42 (Other Identifier: ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Data are available upon reasonable request. The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.

Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.

• IPD Sharing Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
• IPD Sharing Access Criteria: Researchers who provide a methodological sound proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

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