Clinical trial NCT04604626: Rare Obesity Cohorts With Food Behavioral Disorders : Better Diagnosis for Better Treatment
Official title: Rare Obesity Cohorts With Food Behavioral Disorders : Better Diagnosis for Better Treatment
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Obesity
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-10-27
Enrollment: 10000
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Population 1: Adults and children with severe obesity ie (BMI\> 35 kg / m² for adults and Z BMI score\> 3DS for age and sex for children) and / or eating disorders with genetic diagnosis as part of care This population will be divided into 5 groups according to the genetic diagnosis made

* Prader willi syndrome (SPW)
* syndromic obesity except prader willi (OS)
* obesity by homozygous mutation of the melanocortin pathway (HomMel)
* obesity by heterozygous mutation of the melanocortin pathway (HetMel)
* controls without genetic abnormality found in view of the final results of the genetic diagnosis(CON) Population 2: Adults and children with obesity and / or eating disorders hypothalamic lesion (craniopharyngioma example)

Brief summary: Hypothalamic obesity (HO) is defined as obesity secondary to functional or anatomical alterations of the hypothalamus, the central organ of energy homeostasis. The causes of HO are related either to hypothalamic lesions (eg craniopharyngioma) either to genetic diseases (syndromic obesity such as Prader-Willi syndrome or monogenic non syndromic obesity such as variants on leptin/melanocortin pathway). HO, which accounts for about 5 to 10% of obesity, groups complex disorders characterized by severe obesity associated with eating disorders, cognitive and behavioral disorders, endocrine and metabolic alterations and sometimes a visual deficit, with a major impact on quality of life, morbidity and mortality. There is currently no specific treatment of HO.

Clinical management is essentially behavioral, based on daily support of eating behavior and physical activities. HO is characterized by an intense and almost permanent hunger; a satiety disorder and an obsessive interest in food.

The education regarding food intake behavior of the caregivers and relateds is critical with advices concerning the control of the access to food and the setting up of a precise food frame on the quantities, with low energetic density, and schedules. HO are complex medical situations, often refractory to current lifestyle therapies. However innovative therapies with molecules targeting the hypothalamus are emerging. The investigator's main hypothesis is that HO have alterations in eating behavior that can be improved by innovative treatments such as, for example, molecule targeting the melanocortin pathway. The response to therapy could depend on hypothalamic origin and especially on the genotype. ObeRar cohort aims to i) improve early diagnosis of HO and ii) characterize the natural history of obesity and eating disorders, the associated phenotypes and "lifestyle" profiles (physical activity, sleep, nutrition) and cardio-metabolic and neuropsychological parameters. Defining profiles will help personalize individual care management and target patients who can participate in clinical trials with innovative therapeutics. ObeRar-cohort will thus improve the early diagnosis, prognosis, medical management and innovative therapies of these particularly severe forms of rare obesities.

Detailed description: Hypothalamic obesity (HO) is defined as a rare obesity secondary to impaired functioning of the hypothalamus nuclei, the central organ of energy and weight homeostasis. Among the causes of HO, there are those related to a hypothalamic lesion (lesional) such as craniopharyngioma (CP) or inflammatory (sarcoidosis, tuberculosis etc ..) and those called genetic, with variations in gene involved in the central regulation of energy homeostasis. The genetic causes of obesity can be either "monogenic" by mutation of genes involved in the leptin / melanocortin pathway, or "syndromic", defined by the association of obesity and other clinical signs (syndrome), especially neuropsychological traits, such as Prader-Willi syndrome (PWS) or Bardet-Biedl syndrome. PWS, which has a frequency of 1/15000 births, is one of the most well-known obesity-related syndromes. PWS is characterized by muscle hypotonia at birth, severe hyperphagia and food impulsivity, dysmorphic features, and intellectual disability with cognitive-behavioral abnormalities. Monogenic obesity involves rare clinical situations with variants in one of the genes in the MC4R pathway, which plays a pivotal role in the hypothalamic control of food intake and energy expenditure. To date, at least 10 genes directly involved in or regulating the leptin/melanocortin pathway are known: leptin (LEP), leptin receptor (LEPR), pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), melanocortin receptor type 4 (MC4R) and its regulator Melanocortin Receptor Accessory Protein 2 (MRAP2), single -minded homolog 1 (SIM1), brain-derived neurotrophic factor (BDNF), neurotrophic tyrosine kinase receptor type 2 (NTRK2) and more recently, adenylate cyclase 3 (ADCY3). It is of interest to mention that some genes involved in syndromic obesity, such as PWS and BBS, are also involved in the MC4R pathway.

Although HO has various pathophysiological origins, there are common linked phenotypes with the presence of severe obesity and abnormal food intake behovior, having a heavy impact on the morbidity and mortality. Obesity is multifactorial, associated with an increase in energy intake, a decrease in energy expenditure and an alteration of peripheral metabolism with abnormal organ cross-talks. People with HO have often cognitive deficits, learning difficulties and social skills disorders. These factors alter patients' quality of life. At present, there is no specific treatment of HO. Drug treatments have been proposed such as melatonin, somatostatin analogue or sympathomimetics but with limited effects on weight and feeding behavior, resulting in no prescribing recommendations given the lack of randomized studies with sufficient patient samples. Sibutramine tested in patients with lesional or genetic HO was withdrawed from the market in France since 2010 for potentially deleterious effects on the cardiovascular system. GLP 1 analogues are an interesting therapeutic approach in patients with craniopharyngioma with some efficacy on weight, but are currently dedicated for diabetic patients in France. Regarding bariatric surgery in rare and secondary obesities, the French Haute Autorité de Santé recommends that "the indication must be exceptional and discussed on a case by case basis".

So current management is essentially behavioral, based on daily support of eating behavior and physical activity. Food management requires from a very young age and during the whole life, a permanent food control, to fight against primary impulsivity of central origin, can be a cause of frustration and behavioral disorders. Indeed, the hypothalamic impairment is characterized by intense and permanent hunger, a lack of satiety and an obsession for food. The affected patients are completely overwhelmed by this addictive behavior. It is extremely difficult or impossible for the child as for the adult with this syndrome to control his dietary intake. The caregivers and relateds must therefore control access to food at home and abroad. This requires constant supervision. An early education of food in the family is essential because today it there is no possible and sustainable autonomy regarding diet for these patients.

So, if the global, specialized and multidisciplinary care is to be implemented as early as possible, from early childhood, the development of new therapeutic strategies is essential due to the severe and early obesity. In recent years, research in therapeutic innovation has developed in an interesting way in genetic obesity, in particular by targeting the melanocortin pathway. HO have various origins but have a common phenotype, that is the presence of eating disorders with hyperphagia and food impulsivity. This is responsible for weight gain which can lead to obesity, having a significant impact on the morbidity and mortality. However, no precise data are available currently on the specific phenotype of each origin, the genotype/phenotype correlation, and national medical history of OH throughout life, from birth to adulthood, as well as the associated phenotypes, are still to be precisely described.

Eligibility criteria: Inclusion Criteria:

* Population 1:

  1. Adults ≥ 18 years old with BMI\> 35 kg / m² or children \<18 years old with BMI Zscore\> + 3DS for age and sex and / or eating behavior disorders consulting in one of the participating centers
  2. Patient benefiting from a genetic diagnosis as part of his usual care according to criteria justifying a genetic analysis such as:

     obesity with early onset (\<12 years) or very severe BMI\> 50 kg / m² and / or presence of eating disorders, endocrine abnormalities or other symptoms suggestive of a genetic anomaly (such as: intellectual disability, retinopathy of pigmentation or other)
  3. Adult patient or holders of parental authority (for children) having received the information and having signed a free, informed and written consent (or for adult patients under legal protection measure or unable to consent, information and obtaining the consent of the legal representative, the support person, or the relative / close relative).
* Population 2

  1. Adult or child with obesity and / or eating disorder due to hypothalamic lesion (craniopharyngioma for example)
  2. Adult patient or holders of parental authority (for children) having received the information and having signed a free, informed and written consent (or for adult patients under legal protection measure or unable to consent, information and obtaining the consent of the legal representative, the support person, the relative / relative).

Exclusion Criteria:

1. Refusing to participate in the study
2. Not mastering the french language
3. Safety measure

Primary outcomes:
measure: This criterion is the age of obesity beginning
timeFrame: For adults, at inclusion. For children at inclusion and every three years (from date of inclusion until the date of first documented BMI>IOTF 30 kg/m²) (e.g from date of inclusion until the end of follow up, so 20 years)
Secondary outcomes:
measure: Maximum weight in kg
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Maximum height in m
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: number of calories/24h with distribution of macronutrients
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: binge eating behavior
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: hyperphagia
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: hunger and satiety before and after meals
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: Quantification of physical activity in minutes / day
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: waist circumference
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: percentage of fat mass
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: quantification of visceral fat in cm²
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: Quality of life
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: depression and anxiety
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: Resting energy expenditure
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: Metabolic assessment
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: ejection fraction
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: Total Intelligence quotient
timeFrame: at the inclusion
measure: Adult: Assessment of interoceptive capacities: counting of heartbeats
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Adult: Family history of obesity (parents, siblings)
timeFrame: at inclusion and during follow-up evaluation visit every 5 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: Age of adiposity rebound (years) determined
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: Severity of obesity
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: number of calories and distribution of macronutrients
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: hunger and satiety before and after meals
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: Quantification of physical activity in min / day
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: waist circumference
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: percentage of fat mass
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: Resting energy expenditure
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: lipids, HOMA-IR, liver enzymes
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: IGF1, FT4, TSH, testosterone, vitamin D, PTH, others according to the clinical picture
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: ejection fraction
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: Total Intelligence quotient
timeFrame: at the inclusion
measure: Children: Quality of life
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: Hyperphagia
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children: Food behaviour
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children : over 15 years old : binge eating behavior
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children : over 15 years old : depression and anxiety
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
measure: Children : over 15 years old : addiction
timeFrame: at inclusion and during follow-up evaluation visit every 3 years (e.g from date of inclusion until the end of follow up, so 20 years)
Other outcomes:
Locations:
city: Paris La Defense
country: France
facility: Pitié-Salpêtrière Hospital, AP-HP -Nutrition department
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: CHRISTINE POITOU-BERNERT, Professor
role: PRINCIPAL_INVESTIGATOR
References: