Energy Balance & Weight Loss in Craniopharyngioma-related or Other Hypothalamic Tumors in Hypothalamic Obesity
Condition: Hypothalamic Obesity
MeSH terms: Obesity
Study type: Interventional
Phase: Phase 3

Summary: 
      The proposed multicenter study will test the effect of glucagon-like peptide (GLP)-1 agonist
      exenatide once weekly extended-release (ExQW, Bydureon®) on clinical outcomes and metabolic
      parameters in a double-blind, placebo-controlled 36 week randomized trial with an 18 week
      open label extension. Following baseline testing, 48 patients will be randomly assigned with
      equal allocation to ExQW or matching placebo injection for 36 weeks, followed by an 18 week
      open label extension during which all patients receive ExQW. Changes of weight status, body
      composition, free-living total daily energy expenditure (EE) by doubly labeled water (DLW),
      activity by acetimetry, energy intake (questionnaires and food diary), as well as glucose
      tolerance and hormonal parameters of energy homeostasis and insulin resistance will be
      assessed before treatment and at the end of the placebo-controlled phase (week 36). Activity,
      metabolic outcomes, energy intake will be also assessed at study week 18 (mid treatment of
      randomized study), as well as week 54 (end of open label treatment).
    

Detailed description: 
      Excessive weight gain and its cardiometabolic sequela are frequent complications of
      hypothalamic tumors, a condition known as hypothalamic obesity (HO). Most tumors in this
      region are craniopharyngiomas (CP),1 which constitute 5-9% of childhood brain tumors.
      Patients with CP typically become obese and have more features of the metabolic syndrome
      compared to matched controls. Overall, a 3-19-fold higher cardiovascular mortality had been
      reported, and a recent nationwide population-based study in Sweden demonstrated increased
      rates for cerebral infarction (7-fold), death due to cerebrovascular diseases (5-fold), and
      type 2 diabetes mellitus (6-fold) in CP patients in comparison to the general population.
      Thus, early and effective management of obesity is vital for this population, which is more
      resistant to treatment than uncomplicated obesity. Recognized risk factors for severe obesity
      include large hypothalamic tumors or lesions affecting several medial and posterior
      hypothalamic nuclei that impact satiety signaling pathways. Structural damage in these nuclei
      often lead to uncontrolled appetite, rapid weight gain, central insulin and leptin
      resistance, decreased sympathetic activity, low energy expenditure (EE), and increased energy
      storage in adipose tissue. Recently, the investigators developed a semi-quantitative
      assessment of hypothalamic damage on brain magnetic resonance imaging (MRI) to predict the
      risk for HO development in CP.

      Previous results of treating HO with a glucagon-like-peptide-1 receptor agonist (GLP1RA) in
      rats and humans provide promising proof-of-principle data to support this current randomized
      clinical trial. The primary hypothesis of this study is that drugs causing weight loss via
      intact hindbrain signaling pathways offer a desperately needed option for treatment of HO,
      even in very obese HO subjects with severe hypothalamic damage. Induction of weight loss by
      GLP1RAs is believed to be related to multiple mechanisms involving the gastrointestinal
      tract, vagus nerve, and the brain leading to increased satiety. Peripheral administration of
      GLP-1 or GLP1RA reduces blood glucose and energy intake in humans and rodents, and long-term
      treatment results in loss of body weight. Critically, the investigators do not know whether
      GLP1RA treatment affects EE and activity, or whether the site and size of brain lesions
      affect responses to GLP1RA treatment.

      The investigators' previous clinical studies of the GLP1RA exenatide in obese adolescents and
      adults have generated the critical safety and efficacy data needed to design a clinical
      trial. In a pilot study conducted at Children's Hospitals and Clinics of MN, pretreatment
      hyperphagia was associated with BMI reduction. Using these data, the investigators have
      designed a prospective, multicenter trial that will examine the effects of GLP1RA on BMI,
      cardiovascular disease (CVD) risk factors, energy homeostasis and other factors in subjects
      with HO secondary to CP.
    

Intervention name(s): Exenatide; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Weekly injections of active drug.; Weekly placebo injections
Other intervention name(s): Bydureon®
Intervention MeSH terms: Exenatide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Obesity; Drug intervention; Children; Adolescents; Young adults; Hypothalamic lesion; Change of weight status; Food intake; Energy expenditure; Hormonal changes; Glucagon-like peptide-1 agonist; Bydureon; Weight Loss; Energy balance