Clinical Trial: Energy Balance & Weight Loss in Craniopharyngioma-related Hypothalamic Obesity

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Glucagon-Like Peptide-1 Agonist Effects on Energy Balance in Hypothalamic Obesity

Brief 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 Summary:

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
Sponsor: Seattle Children's Hospital

Current Primary Outcome: Percent change of body mass index (BMI) as calculated by the formula: body weight in kg divided by height in meters². [ Time Frame: Baseline and 36 weeks ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Changes in in body composition as assessed by body fat mass using dual energy x-ray absorptiometry (DEXA) [ Time Frame: Baseline and 36 weeks ]
  • Changes in fat and total calorie intake assessed by free buffet meal analysis. [ Time Frame: Baseline and 36 weeks ]
  • Changes in fasting glucose [ Time Frame: Baseline and 36 weeks ]
  • Changes in HDL cholesterol and triglycerides assessed by fasting lipids [ Time Frame: Baseline and 36 weeks ]
  • Changes in inflammation assessed by high sensitive cardio-reactive protein (hsCRP) [ Time Frame: Baseline and 36 weeks ]
  • Changes of insulin resistance assessed by fasting insulin used for homeostasis model assessment of insulin resistance (HOMA-IR) using the formula insulin [mU/l] x glucose [mmol/l]) / 22.5 [ Time Frame: Baseline and 36 weeks ]
  • Changes of circulating leptin levels [ Time Frame: Baseline and 36 weeks ]
  • Changes of energy expenditure assessed by doubly labeled water analysis [ Time Frame: Baseline and 36 weeks ]
  • Changes of energy intake assessed by Automated Self-Administered 24-Hour Dietary Recall (ASA24-Kids) [ Time Frame: Baseline and 36 weeks ]
  • Changes in glucose 120 minutes following an oral glucose tolerance test [ Time Frame: Baseline and 36 weeks ]


Original Secondary Outcome: Same as current

Information By: Seattle Children's Hospital

Dates:
Date Received: January 4, 2016
Date Started: March 2016
Date Completion: July 2019
Last Updated: April 28, 2017
Last Verified: April 2017