Exenatide-test for Diagnosing Endogenous Hyperinsulinemic Hypoglycemia

Study Overview
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Brief Summary
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This study is to evaluate the concept of the exenatide test for diagnosis of EHH (earlier induction of symptomatic hypoglycemia compared to placebo within 4 hours after injection).

Detailed Description
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Endogenous hyperinsulinemic hypoglycemia (EHH) is defined as inappropriate endogenous insulin secretion leading to hypoglycemia and associated symptoms. The most frequent diagnosis is an insulin-secreting pancreatic neuroendocrine tumor, but other diagnoses such as nesidioblastosis of the pancreatic islets are also possible. Biochemically, EHH is characterized by low glucose concentrations in the presence of inappropriately increased C-peptide (endogenous insulin secretion) and insulin levels. The conventional fasting test is at present the gold standard to document EHH. Radiolabeled Exenatide for localizing insulinomas in patients with biochemically proven EHH has been evaluated and an exenatide-test in an outpatient setting may be able to replace the fasting test, by an early symptomatic hypoglycemia compared to a prolonged inpatient monitoring. This study is to investigate the concept of the exenatide test to diagnose EHH.

Official Title
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Exenatide-test for Diagnosing Endogenous Hyperinsulinemic Hypoglycemia

Conditions
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Endogenous Hyperinsulinism

Intervention / Treatment
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* Drug: Exenatide
* Drug: 0.9% saline solution


Participation Criteria
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Eligibility Criteria
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Patients with suspicion for an insulinoma fulfilling all of the following inclusion criteria are eligible for the study: Inclusion Criteria: Informed Consent as documented by signature Biochemically proven endogenous hyperinsulinemic hypoglycemia: neuroglycopenic symptoms in the fasting state with low plasma glucose, inappropriately high serum insulin and C-peptide concentrations (standardized 72h fasting test).). Participants as control subjects fulfilling all of the following inclusion criteria are eligible for the study: Inclusion Criteria: Informed Consent as documented by signature (Appendix Informed Consent Form) Possession of the adequate match criteria (age, BMI and gender) to patients with suspicion for an insulinoma Exclusion Criteria: Known hypersensitivity or allergy to Exenatide Pregnant or breastfeeding female patients. A pregnancy test will be performed in all women of child bearing potential. Calculated creatinine clearance below 40 ml/min No signed informed consent Intake of any glucagon-like peptide (GLP)-1 analogue (such as Byetta® or Bydureon®[= Exenatide]) prediabetes or diabetes (HbA1c > 5.7 %) Previous abdominal surgery in the gastrointestinal tract Any concomitant glucose-lowering drug (i. e. insulin, sulfonyl urea) Any known intolerance to standardized meal (Maizena) Any uncontrolled significant medical, psychiatric or surgical condition (active infection, unstable angina pectoris, cardiac arrhythmia, poorly controlled hypertension, uncontrolled congestive heart disease, etc.) or laboratory findings that might jeopardize the patient's safety or that would limit compliance with the objectives and assessments of the study. Any mental conditions which prevent the patient from understanding the type, extent and possible consequences of the study and/or an uncooperative attitude from the patient

Ages Eligible for Study
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Minimum Age: 18 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Prospective, single-center, cross-over, placebo controlled pilot, proof of principle clinical study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (EHH Patients)<br>Group A will receive a placebo injection (0.9% saline solution) on Day 1 and 10μg Exenatide injection on Day 2. | Drug: Exenatide<br>* Day1: After a standardized night meal (Maizena 40g plus dessert) at 22 p.m. on the day before, patients receive Exenatide study medication according to the randomization list (injection done slowly over 2 min.). Regular clinical examination of vegetative and neurological state will be done as well as continuous blood sugar measurements and blood withdrawals will be performed. Day2: The procedure is equal to study day 1. Instead of Exenatide, a 10ml 0.9% saline solution will be administered intravenously.<br>* Other names: Day 1 Exenatide; Day 2 : 0.9% saline solution;Drug: 0.9% saline solution<br>* Day1: After a standardized night meal (Maizena 40g plus dessert) at 22 p.m. on the day before, patients receive 0.9% saline solution according to the randomization list (injection done slowly over 2 min.). Regular clinical examination of vegetative and neurological state will be done as well as continuous blood sugar measurements and blood withdrawals will be performed. Day2: The procedure is equal to study day 1. Instead of 0.9% saline solution, Exenatide will be administered intravenously.<br>* Other names: Day 1 : 0.9% saline solution, Day 2 Exenatide;|
| Experimental: Group B (EHH Patients)<br>Group B will receive a 10μg Exenatide injection on Day 1 and placebo injection (0.9% saline solution) on Day 2. | Drug: Exenatide<br>* Day1: After a standardized night meal (Maizena 40g plus dessert) at 22 p.m. on the day before, patients receive Exenatide study medication according to the randomization list (injection done slowly over 2 min.). Regular clinical examination of vegetative and neurological state will be done as well as continuous blood sugar measurements and blood withdrawals will be performed. Day2: The procedure is equal to study day 1. Instead of Exenatide, a 10ml 0.9% saline solution will be administered intravenously.<br>* Other names: Day 1 Exenatide; Day 2 : 0.9% saline solution;Drug: 0.9% saline solution<br>* Day1: After a standardized night meal (Maizena 40g plus dessert) at 22 p.m. on the day before, patients receive 0.9% saline solution according to the randomization list (injection done slowly over 2 min.). Regular clinical examination of vegetative and neurological state will be done as well as continuous blood sugar measurements and blood withdrawals will be performed. Day2: The procedure is equal to study day 1. Instead of 0.9% saline solution, Exenatide will be administered intravenously.<br>* Other names: Day 1 : 0.9% saline solution, Day 2 Exenatide;|
| Experimental: Group C (control subjects)<br>Control subjects without evidence for EHH defined by no glucose levels below 3.0 mmol/l during a 7-day CGFS (Freestyle libre) and matched to EHH patients for age, gender and BMI will receive only on one study day a single intravenous injection of 10μg Exenatide and compared to group A patients on Day 2. They will not receive a Placebo injection. | Drug: Exenatide<br>* Day1: After a standardized night meal (Maizena 40g plus dessert) at 22 p.m. on the day before, patients receive Exenatide study medication according to the randomization list (injection done slowly over 2 min.). Regular clinical examination of vegetative and neurological state will be done as well as continuous blood sugar measurements and blood withdrawals will be performed. Day2: The procedure is equal to study day 1. Instead of Exenatide, a 10ml 0.9% saline solution will be administered intravenously.<br>* Other names: Day 1 Exenatide; Day 2 : 0.9% saline solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time to symptomatic hypoglycemia after exenatide test compared to placebo | time to symptomatic hypoglycemia after exenatide test compared to placebo | within 4 hours after injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time dependent decrease (time Δ from injection in min) of blood glucose (% or mmol/l)) | time dependent decrease (time Δ from injection in min) of blood glucose (% or mmol/l)) that can best discriminate from placebo injection | within 4 hours after injection | 
| time to symptoms | time to symptoms of the exenatide test in comparison to the placebo injection of 10ml 0.9% saline solution | within 4 hours after injection | 
| time to hypoglycemia (time to reach blood sugar level ≤ 2.5 mmol/l) in the exenatide test in comparison to the placebo | time to hypoglycemia (time to reach blood sugar level ≤ 2.5 mmol/l) in the exenatide test in comparison to the placebo | within 4 hours after injection | 
| time to hypoglycemia (time to reach blood sugar level ≤ 2.5 mmol/l) in the exenatide test in comparison to the fasting test | time to hypoglycemia (time to reach blood sugar level ≤ 2.5 mmol/l) in the exenatide test in comparison to the fasting test | within 4 hours after injection | 
| time to symptoms in the exenatide test in comparison to the fasting test | time to symptoms in the exenatide test in comparison to the fasting test | within 4 hours after injection | 
| change in levels of plasma glucose compared to placebo compared to placebo | change in levels of plasma glucose compared to placebo | within 4 hours after injection | 
| change in levels of insulin compared to placebo | change in levels of insulin compared to placebo | within 4 hours after injection | 
| change in levels of C-peptide compared to placebo | change in levels of C-peptide compared to placebo compared to placebo | within 4 hours after injection | 
| change in levels of proinsulin compared to placebo | change in levels of proinsulin compared to placebo | within 4 hours after injection | 
| change in levels of ß-hydroxybutyrate compared to placebo | change in levels of ß-hydroxybutyrate compared to placebo | within 4 hours after injection | 
| costs of exenatide test setting (CHF) | Comparison of costs of exenatide test setting with fasting test setting | within 4 hours after injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fasting test, Blood glucose, insulin, proinsulin, C-peptide, betahydroxybutyrate, hypoglycemia