Consortium "Adolescents with Extreme Obesity" (Competence Network Obesity, CNO)

Speaker: Prof. Dr. Martin Wabitsch Funding: Federal Ministry for Education and Research (BMBF) Duration: 2012 - 2018 Partners: University Children’s Hospitals at Essen, Witten-Herdecke, Berlin and Leipzig; Institute for Epidemiology and Medical Biometry of Ulm University, Helmholtz Center Munich Registry IDs: DRKS00004172, DRKS00004198, DRKS00004195, DRKS00009437, DRKS00004196, DRKS00004197 (Deutsches Register Klin. Studien)

Extremely obese adolescents are at a strongly elevated risk of early death, somatic comorbidities, psychiatric disorders, and social isolation, including unemployment, due to both functional impairment and stigmatization. Despite the dire implications of extreme obesity in adolescents and the frequently overt (e.g. orthopaedic disorders) and non-overt (e.g. hypertension) comorbidity, these adolescents are difficult to reach and treat in medical terms. Thus, only a small percentage actively seeks treatment.

The underlying reasons are poorly understood and may presumably be attributed to the young age, a predominantly low educational and socioeconomic status, as well as to functional impairment due to inactivity and psychiatric comorbidity. Unsuccessful attempts to lose weight on their own and/or within the medical system may have led to frustration with respect to their behaviour in seeking treatment.

In acknowledgement of this, we have developed the "Medical and psychosocial implications of extreme obesity in adolescents - acceptance and effects of structured care study", which is known by its abbreviated title as: "Youth with Extreme obesity Study (YES)". YES aims at improving the medical care and social support structures for this so far widely ignored patient group. Results of this study will improve the medical care and social support structures for youths with extreme obesity in Germany.

Monogenic obesity

Monogenic forms of early onset obesity are very rare. Severe early-onset obesity is often caused by genetic defects. Most of these genes are involved in the central nervous regulation of hunger and satiety. Herein, the leptin-melanocortin system plays a pivotal role. Patients with congential leptin deficiency can be treated with a hormone replacement therapy with metreleptin, a recombinant analogue of the human leptin. Leptin is a highly important hormone stimulating the MC4 pathway with pleiotropic functions mostly elicited via specific leptin receptors. Apart from regulating satiety, some of the most important aspects of leptin function include its influence on energy homeostasis, on glucose homeostasis, on the sympathetic nervous system and on immune function. Our department is one of a few centers worldwide offering leptin replacement therapy to patients. Furthermore, we have identified and treated the first known patients with severe early onset obesity due to a mutation in the leptin gene that renders the hormone biologically inactive (Wabitsch et al., New Engl J Med 2015). Our laboratory investigates the biological functions of leptin and aims to better understand the clinical picture of congenital leptin deficiency. Recently, the MC4R agonist Setmelanotide has been introduced as a new treatment option for patients with POMC and LPR deficiency (please see below - clinical study with Setmelanotide).

An Open Label, 1-Year Trial, including a Double-Blind Placebo-Controlled Withdrawal Period, of Setmelanotide (RM-493), a Melanocortin 4 Recep­tor (MC4R) Agonist, in Leptin Receptor (LEPR) Deficiency Obesity due to Bi-Allelic Loss-of-Function LEPR Genetic Mutation

Investigator: Prof. Dr. Martin Wabitsch Sponsor: Rhythm Pharmaceuticals, Boston, USA Duration: 2017 - 2020 Partners: Dr. Erica van den Akker (Obesity Center CGG, Rotterdam), Prof. Dr. Sadaf Farooqi (University of Cambridge), Prof. Dr. Karine Clément (Sorbonne Université, Paris) Trial ID: RM-493-015

Patients with mutations in the leptin receptor (LEPR) gene suffer from severe hyperphagia and obesity caused by the lack of activation of the MC4 pathway, which prevents control of appetite and weight. LEPR deficiency represents a very rare genetic disorder of obesity.

Unfortunately, these patients cannot benefit from treatment with metreleptin. The investi­gational medicinal product setmelanotide is undergoing clinical trials in patients with loss-of-function mutations in the LEPR gene. Representing a new-generation melanocortin-4 receptor (MC4R) agonist, setmelanotide is thought to activate the melanocortin 4 receptor (MC4R), part of a key biological pathway in humans that regulates appetite, caloric intake and energy expenditure. Setmelanotide is expected to become a potential replacement therapy that may restore lost activity in the MC4 pathway, resulting in substantial reductions in hyperphagia and body weight, re-establishing weight and appetite control. Our Division of Paediatric Endo­crinology and Diabetes is one of four study centres in Europe enrolling patients in a Phase 3 clinical trial evaluating long-term (one year) safety and efficacy of setmelanotide in LEPR defi­ciency obesity.

A randomised, multinational, active-controlled, open-labelled, dose finding, double-blinded, parallel group trial investigating efficacy and safety of once-weekly NNC0195-0092 treatment compared to daily growth hormone treatment (Norditropin® FlexPro®) in growth hormone treatment naïve pre-pubertal children with growth hormone deficiency REAL3 Study (Novo Nordisk)

Investigator: Prof. Dr. Martin Wabitsch Sponsor: Novo Nordisk A/S Duration: 2016 - 2020 Partners: multiple partners (multinational study) Trial ID: NN8640-4172

Growth hormone is crucial for physical development. Growth hormone is needed for normal growth in children. In adults, growth hormone is needed to maintain the proper amounts of body fat, muscle, and bone. Growth hormone deficiency (GHD) is caused by an inadequate secretion of growth hormone from the pituitary gland and leads to diverse physically and psychologically impairments. GHD negatively affects growth and body composition in childhood and adulthood.

Somapacitan or "NNC0195-0092" is a novel long-acting derivative of human growth hormone for treatment of children and adults with GHD. The children need to be pre-pubertal to avoid interference with the growth spurt during puberty with the treatment effect. The aim of the trial is to investigate efficacy and safety of Somapacitan treatment compared to the treatment with Norditropin® FlexPro® which is administered daily. Daily injections for years or lifetime can be inconvenient and distressing for patients. Somapacitan is designed to be administered only once weekly to improve convenience and compliance. The clinical trial is conducted multinationally in different sites around the world, one of which is our Division of Paediatric Endocrinology and Diabetes at Ulm University Hospital.

European Consortium of Lipodystrophies (ECLip) Registry

Speaker: Prof. Dr. Martin Wabitsch Duration: since 2012 Partners: European Consortium of Lipodystrophies (ECLip)

Lipodystrophy syndromes are rare diseases characterised by selective deficiency of adipose tissue. They are categorised in different types based on aetiology (genetic or acquired) and distribution of lost adipose tissue affecting the entire body (generalised) or only regions (partial). Lipodystrophy is frequently associated high morbidity and mortality. Patients suffer from hormonal and metabolic disorders resulting in severe comorbidities. Lipodystrophy syndromes occur very rarely and the different types vary widely in their associated comorbidities, complications and courses. Even very experienced experts in this field do not see more than 50-100 patients in their lives. Due to the rarity of lipodystrophy syndromes and the lack of knowledge about these, physicians are unfamiliar with their diagnosis and management. Sensible clinical and basic research into rare diseases such as lipodystrophy syndromes is only possible in multi-location networks with sufficient case numbers. The European Consortium of Lipodystrophies (ECLip) is a network of European clinical and basic-science research groups working in the field of lipodystrophy syndromes. The network aims to increase the basic understanding of this rare disease and to develop ways to better diagnose, prevent and take in charge patients suffering from lipodystrophy syndromes. ECLip has launched a registry intended to improve the research conditions by consolidating information about lipodystrophy syndromes and collecting patient data on an international level. Upon informed consent, data obtained from patients during their clinical visits in participating centres (registry members) are being entered in a web-based registry platform. In our Centre for Rare Diseases (ZSE Ulm) at Ulm University Medical Center, we are treating patients with lipodystrophy syndromes. Our Division of Paediatric Endocrinology and Diabetes is the leading clinical centre coordinating the ECLip Registry. Ulm University is the governing body, the legal institution, where all data entered in the registry is stored. The ECLip Registry will enable the exchange of patient data for scientific evaluations and will help to recruit suitable subjects for clinical studies.

Ulm Birth Cohort Study (UBCS) ("Ulmer Kinderstudie")

Investigators: Prof. Dr. Hermann Brenner (German Cancer Research Center, Heidelberg), Prof. Dr. Dietrich Rothenbacher (Ulm University), Prof. Dr. Martin Wabitsch Funding: Federal Ministry for Education and Research (BMBF), German Research Foundation (DFG) Duration: since 2000

The Ulm Birth Cohort Study (UBCS) was initiated in 2001/2002 at the Department of Gynecology and Obstetrics of Ulm University Medical Center in order to investigate the impact of perinatal and neonatal factors on growth and metabolic diseases in adulthood (for example cardiovascular diseases, allergies, asthma and oncologic diseases). In total, over 1,000 mothers (including mothers with 22 pairs of twins) have agreed to participate in the study. At the time of the birth of the child, basic data have been collected using a questionnaire and biological samples have been obtained. Since then, the children and their parents have been followed up in regular, defined intervals for over 18 years.

One example of the meaningful results recently obtained from our studies: Circulating insulin concentrations reflect the metabolic cardiovascular risk and may trigger weight gain. The UBCS study showed that fasting plasma insulin concentrations of children are significantly correlated with the BMI values that mothers exhibit before pregnancy, and fasting plasma insulin concentrations of children are significantly correlated with maternal, but not with paternal fasting plasma insulin concentrations. Furthermore, the development of the BMI of a child with high fasting plasma insulin concentrations is altered compared to a child with low concentrations. These findings are in line with the concept of perinatal programming of insulin concentrations and BMI development by maternal factors.

Non-interventional, post-marketing surveillance "Saizen®-online"

Investigator: Prof. Dr. Martin Wabitsch Sponsor: Merck Serono Duration: since 2015 (15 years follow-up period) Partners: global partners (international phase IV study) Trial ID: EMR200104_544

Saizen®, a recombinant human growth hormone (somatropin), is indicated for the treatment of growth hormone deficiency in children and adults, Turner Syndrome, chronic renal failure and children born short for gestational age (SGA). An observational, longitudinal, non-interventional, post-marketing surveillance programme has been initiated to assess the level of adherence under every day conditions and long-term safety and efficacy of therapy with Saizen® in a large number of patients. Our Division Division of Paediatric Endocrinology and Diabetes is one of the study centres involved in the global study.

Post-marketing surveillance to monitor the long-term safety and efficacy of Omnitrope® in infants, children and adolescents (PATRO Children)

Investigator: Prof. Dr. Martin Wabitsch Sponsor: Sandoz Pharmaceuticals / Hexal AG Duration: since 2016 Partners: global partners (international phase IV study) Trial ID: EP00-501

Omnitrope®, a recombinant human growth hormone (somatropin) is used to treat children with growth disorders or genetic disorders like Turner syndrome and Prader-Willi syndrome. It is also used to treat adults with pronounced growth hormone deficiency. Omnitrope® has been used for over a decade since it has been marketed in Europe in 2006. However, some concerns remain about the long-term safety of Omnitrope®, which is administered to the patients on a daily basis. PATRO Children, an observational, longitudinal, non-interventional, post-marketing surveillance programme, investigates the long-term safety and effectiveness assessing the diabetogenic potential of Omnitrope and the risk of malignancies. Our Division of Paediatric Endocrinology and Diabetes is one of the study centres involved in the global study.

Diabetes and Social Jet Lag

Speaker: Dr. Julia von Schnurbein Funding: German Paediatric Diabetes Association (AGPD), Dr.-Herbert-Schiffers-Stiftung Duration: 2013 - 2019 Partners: Dr. Claudia Boettcher (Justus Liebig University Giessen), Prof. Dr. Beate Karges (Bethlehem Gesundheitszentrum Stolberg gGmbH, RWTH Aachen University), Dr. Desiree Dunstheimer (Klinikum Augsburg), Dr. Angela Galler (Charité - Universitätsmedizin Berlin), Prof. Till Roenneberg (Ludwig-Maximilians-University Munich), Dr. Celine Vetter (Brigham and Women’s Hospital and Harvard Medical School Boston)

It is well known that lack of sleep increases the risk for development and deterioration of type 2 diabetes. The multicentre prospective study "Diabetes and Social Jet Lag" investigated the impact of lack of sleep, poor sleep quality and of a sleep timing unsuited to the patients natural sleep timing on blood sugar levels in patients with type 1 diabetes. The study showed that reduced sleep quality has a negative impact on HbA1c levels in patients with type 1 diabetes indicating that advice for a better sleep hygiene should maybe be integrated into the counselling of patients with diabetes.