Energy Balance & Weight Loss in Craniopharyngioma-related or Other Hypothalamic Tumors in Hypothalamic Obesity (ECHO)
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|ClinicalTrials.gov Identifier: NCT02664441|
Recruitment Status : Active, not recruiting
First Posted : January 27, 2016
Last Update Posted : April 4, 2019
|Condition or disease||Intervention/treatment||Phase|
|Hypothalamic Obesity||Drug: Exenatide Drug: placebo||Phase 3|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||48 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Glucagon-Like Peptide-1 Agonist Effects on Energy Balance in Hypothalamic Obesity|
|Study Start Date :||March 2016|
|Estimated Primary Completion Date :||December 2019|
|Estimated Study Completion Date :||March 2020|
Active Comparator: Exenatide once weekly extended-release
Injections of glucagon-like peptide (GLP)-1 agonist exenatide once weekly extended-release (Bydureon®) for 36 weeks in randomized intervention followed by 18 weeks open label exenatide once weekly extended-release.
Weekly injections of active drug.
Other Name: Bydureon®
Placebo Comparator: Matching placebo
Weekly injections of placebo for 36 weeks followed by 18 weeks open label exenatide once weekly extended-release.
Weekly placebo injections
- 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 ]
- 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 ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02664441
|United States, Minnesota|
|Children's Hospitals adn Clinics of Minnesota|
|Minneapolis, Minnesota, United States, 55404|
|United States, Tennessee|
|Vanderbilt University School of Medicine|
|Nashville, Tennessee, United States, 37235|
|United States, Washington|
|Seattle, Washington, United States, 98105|
|Principal Investigator:||Christian Roth, MD||Seattle Childrens|