Nutritional and Metabolic Diseases

Symptoms and General Pathology

All Conditions

Neoplasms

Musculoskeletal Diseases

Nervous System Diseases

Rare Diseases

Obesity

Weight Loss

Body Weight

Craniopharyngioma

Adamantinoma

Hypothalamic Neoplasms

Overweight

Overnutrition

Nutrition Disorders

Hypothalamic Obesity

Gastrointestinal Agents

All Drugs and Chemicals

Hypoglycemic Agents

Anti-Obesity Agents

Glucagon

Glucagon-Like Peptide 1

Exenatide

Glucagon-Like Peptide-1 Receptor Agonists

Incretins

Hormones

Hormone Antagonists

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 placebo for 36 weeks followed by 18 weeks open label exenatide once weekly extended-release.

placebo

Christian Roth, MD

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).

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.

Energy Balance & Weight Loss in Craniopharyngioma-related or Other Hypothalamic Tumors in Hypothalamic Obesity

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

Percent change of body mass index (BMI), as calculated by the formula: body weight in kg divided by height in meters², between baseline and the end of the 36-week randomized drug treatment phase.

Body composition change between baseline and the end of the 36-week randomized drug treatment phase assessed by dual energy x-ray absorptiometry (DEXA) and expressed as the change in adipose tissue mass.

Changes in fat and total calorie intake during free buffet meals assessed at baseline and after 36-weeks of study drug treatment.

The buffet meal is an objective measure of satiety as it assesses food intake and choice after a caloric preload. A standardized test meal preload provided 20% of estimated daily caloric requirements,based on the Schofield-HW equation. The purpose of the test meal is to ensure that study participants are in an equally fed state. Ninety minutes later, an ad libitum buffet meal was served consisting of a wide variety of food items and more than the child's estimated daily calorie requirements will be offered (5,000 kcal). Children had access to the buffet for 30 min, after which calorie intake and composition of consumed foods was measured by weighing back uneaten food.

Change in fasting blood glucose between baseline and the end of the 36-week randomized drug treatment phase.

Change in fasting HDL cholesterol and triglycerides between baseline and the end of the 36-week randomized drug treatment phase.

Change in C-reactive protein (CRP) between baseline and the end of the 36-week randomized drug treatment phase.

Changes of insulin resistance estimated by the homeostasis model assessment of insulin resistance (HOMA-IR) using the formula HOMA-IR = insulin \[mU/l\] x glucose \[mmol/l\]) / 22.5 where both insulin and glucose values are obtained from a fasting blood sample.

Change in circulating leptin between baseline and the end of the 36-week randomized drug treatment phase.

Total energy expenditure in the free-living environment was measured using doubly labeled water which estimates carbon dioxide production by measuring the elimination of the tracers deuterium (²H) and oxygen-18 (¹⁸O) from the body. These measures are used to determine the average daily rate of carbon dioxide production which is then used to calculate total energy expenditure using an equation from Weir and an assumed food quotient (0.85).

Self-reported daily energy intake was assessed by Automated Self-Administered 24-Hour Dietary Recall (ASA24-Kids, http://appliedresearch.cancer.gov/tools/instruments/asa24/), a web-based diet assessment tool that allows 24-hour diet recall using branded food items.

Change in blood glucose measures 120 minutes post-glucose bolus during an oral glucose tolerance test between baseline and the end of the 36-week randomized drug treatment phase.

Children's Hospitals and Clinics of Minnesota

Vanderbilt University

Seattle Children's Hospital

Professor

Injections of glucagon-like peptide (GLP)-1 agonist exenatide once weekly extended-release (Bydureon®) for 36 weeks in randomized intervention

Exenatide: Weekly injections of active drug.

Double-Blind Exenatide Once Weekly Extended-release

Weekly injections of placebo for 36 weeks in randomized intervention

placebo: Weekly placebo injections

Double-Blind Placebo

18 weeks open label exenatide once weekly extended-release (Bydureon®) arm.

Exenatide: Weekly injections of active drug.

Open Label 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.

Exenatide: Weekly injections of active drug.

Exenatide Once Weekly Extended-release

Weekly injections of placebo for 36 weeks followed by 18 weeks open label exenatide once weekly extended-release.

placebo: Weekly placebo injections

Matching Placebo

Total

One participant withdrawn in placebo group

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Calculated by the formula: body weight in kg divided by height in meters².

Body Mass Index

Christian L. Roth, MD

Analyses include all participants randomized to a study drug and received at least one drug treatment administration. Missing data was imputed using a last observation carry-forward approach.

Percent Change of Body Mass Index (BMI) as Calculated by the Formula: Body Weight in kg Divided by Height in Meters².

Of the 41 enrolled participants, 20 out of 23 participants randomized to exenatide once weekly extended-release and 15 out of 18 participants randomized to placebo completed both pre- and post-treatment assessments and are included in this analysis.

Changes in Body Composition as Assessed by Body Fat Mass Using Dual Energy X-ray Absorptiometry (DEXA)

Fat Intake

Total Calorie Intake

Of the 41 enrolled participants, 18 out of 23 participants randomized to exenatide once weekly extended-release and 15 out of 18 participants randomized to placebo completed both pre- and post-treatment assessments and are included in this analysis.

Changes in Fat and Total Calorie Intake Assessed by Free Buffet Meal Analysis.

Changes in Fasting Glucose

HDL Cholesterol

Triglycerides

Changes in HDL Cholesterol and Triglycerides Assessed by Fasting Lipids

Changes in Inflammation Assessed by C-reactive Protein (CRP)

Changes of Insulin Resistance Assessed by Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)

Changes of Circulating Leptin Levels

Of the 41 enrolled participants, 19 out of 23 participants randomized to exenatide once weekly extended-release and 14 out of 18 participants randomized to placebo completed both pre- and post-treatment assessments and are included in this analysis.

Changes of Energy Expenditure Assessed by Doubly Labeled Water Analysis

Of the 41 enrolled participants, 14 out of 23 participants randomized to exenatide once weekly extended-release and 9 out of 18 participants randomized to placebo completed both pre- and post-treatment assessments and are included in this analysis.

Spots Global Cancer Trial Database for change of weight status