Efficacy and Safety of Exenatide in the Treatment of Hypothalamic Obesity After Craniopharyngioma Therapy

Study Overview
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Brief Summary
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This hypothalamic obesity is associated with serious metabolic and psychosocial consequences. The purpose of the study is to compare the change of body weight after 6 months treatment with a lifestyle intervention + exenatide compare to the one after the same lifestyle intervention+ placebo in adults patients suffering from a hypothalamic obesity due to treatment of craniopharyngioma.

Detailed Description
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The development of glucagon-like peptide-1 (GLP-1) analogues might be a solution since native GLP-1 suppresses appetite and energy intake in both normal weight and obese individuals as well as in people with type 2 diabetes and delays gastric emptying. The underlying mechanisms that mediate the effects of weight involve not only central regions like the hypothalamus and the solitary tractus nucleus and area postrema but also peripheral regions as the gastrointestinal tract. These extra hypothalamic effects are of particular interest in the cases of obesity due to hypothalamic lesions. Exenatide is a glucagon-like peptide-1 (GLP-1) analogue with a high structural homology to human GLP-1, a gut derived incretin hormone. Since exenatide causes a dose-dependent weight loss, decreasing concentration of glycosylated haemoglobin as well as improving ß-cell function and systolic blood pressure, it could be an attractive treatment for both type 2 diabetes and obesity. In a double-blind placebo-controlled 24-week trial, it has been recently shown that non diabetic obese patients maintained on exenatide 10µg x 2/j lost significantly more weight than did those on placebo (5.1 kg versus 1.6).

Official Title
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Multicentre Double-blind Randomized Clinical Trial Assessing Efficacy and Safety of Exenatide in the Treatment of Hypothalamic Obesity After Craniopharyngioma Therapy

Conditions
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Craniopharyngiomas, Hypothalamic Obesity

Intervention / Treatment
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* Drug: Exenatide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: They are between 18 and 75 yrs. They had been diagnosed with a craniopharyngioma treated by surgery and/or irradiation without sign of recurrence. They have a BMI upper than 30kg/m² with intractable weight gain following therapy for craniopharyngioma. They demonstrate at least one other endocrinopathy, as a marker of hypothalamic damage. All pituitary deficiencies are correctly treated. They gave their written, informed consent before the beginning of the study. Exclusion Criteria: They have type 1 diabetes. They have type 2 diabetes treated with insulin. Acidocetosis. Bariatric surgery Previous personal history of thyroid or pancreatic cancer. Hypercalcitoninemia. They have been previously treated by GLP1 analogs. Hypertriglyceridemia upper than 5g/l They had previously demonstrated voluntary weight loss during the three previous months. They are under the age of 18 years or over the age of 65 yrs. They are maintained on medical treatment against obesity. They are receiving supraphysiologic hydrocortisone therapy (upper than 30 mg/jour). Their GH status change during the course of the study. Exenatide is contraindicated. Psychological and/or medical problems that would create difficulties for the patient to comply with the study protocol are present.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exenatide<br>Treatment with exenatide at the initial dose of 5 µg x 2/day (subcutaneously administered) during 4 weeks, and treatment with 10 µg x 2/day during 5 months. | Drug: Exenatide<br> <br> |
| Placebo Comparator: Placebo<br>Patients will be maintained on placebo (injected subcutaneously, twice a day) with the same dose and frequency than exenatide arm. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare body weight change thanks to weighing machine | The primary outcome will be assessed by a weighing machine that measure until 200 kg. | baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment tolerance thanks to digestive parameters | Tolerance will be assessed by the presence of: - Nauseas, vomiting. | 6 months | 
| Treatment tolerance thanks to dermatologic parameter | Tolerance will be assessed by the presence of: - Injection-site symptoms. | 6 months | 
| Treatment tolerance thanks to pulse rate | Tolerance will be assessed by the presence of : - Increasing of pulse rate. | 6 months | 
| Treatment tolerance thanks to Beck scale | Tolerance will be assessed by the presence of : - Anxiety by Beck scale. | 6 months | 
| Treatment tolerance thanks to HAD scale | Tolerance will be assessed by the presence of : - depression evaluated by HAD scale. | 6 months | 
| Treatment tolerance thanks to enzymatic parameters | Tolerance will be assessed by the presence of : - Increasing of pancreatic enzymes. | 6 months | 
| Treatment tolerance thanks to glycemia parameter | Tolerance will be assessed by the presence of : - Hypoglycaemia | 6 months | 
| Assess cardiovascular risks thanks to glucose profil | Levels of blood glucose and insulin, oral glucose tolerance testing, haemoglobin A1C | 6 months | 
| Assess cardiovascular risks thanks to lipid profil | Levels of HDL cholesterol, triglycerides, LDL cholesterol. | 6 months | 
| Assess cardiovascular risks thanks to metabolic parameters | The metabolic parameters considered: - Body composition (Dual energy-ray absorptiometry) and abdominal obesity (waist circumference). | 6 months | 
| Assess eating behaviour thanks to physiological parameters | The eating behaviour will be evaluated by: - Plasma level of ghrelin measured after an overnight fast. | 6 months | 
| Assess eating behaviour thanks to energy intake |  | 6 months | 
| Assess eating behaviour thanks to Three factor eating | The eating behaviour will be evaluated by: - Scores of restriction, hunger and disinhibition (French version of the Three factor Eating Questionnaire). | 6 months | 
| Assess eating behaviour thanks to visual analogic scales | The eating behaviour will be evaluated by: - Scores of desire to eat, hunger and fullness at visual analogic scales. | 6 months | 
| Assess quality of life thanks to Beck questionnaire | The quality of life will be assessed by: - Scores of depression (short questionnaire of Beck). | 6 months | 
| Assess quality of life thanks to ORWELL questionnaire | The quality of life will be assessed by: - Scores of quality of life (ORWELL questionnaire). | 6 months | 
| Assess energy expenditure thanks to physical activity | The energy expenditure will be estimated thanks to pedometer. - Resting metabolic rate (indirect calorimetry). | 6 months | 
| Assess energy expenditure thanks to indirect calorimetry | The energy expenditure will be estimated thanks to: - Resting metabolic rate | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glucagon-like peptide-1, exenatide, placebo, multicenter trial