Copeptin After a Subcutaneous Stimulation With Glucagon in Adults

Study Overview
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Brief Summary
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This study is to evaluate copeptin values after the subcutaneous injection of glucagon in adults (healthy volunteers and patients with diabetes insipidus or primary polydipsia). It is to investigate whether glucagon stimulates the release of copeptin as a surrogate of vasopressin.

Detailed Description
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The differentiation between central diabetes insipidus (cDI) and primary polydipsia (PP) is cumbersome. To date the test with the highest diagnostic accuracy is copeptin measurement after hypertonic saline Infusion. Instead of hypertonic saline Infusion, arginine infusion - known to stimulate growth hormone - is a potent stimulator of the neurohypophysis and provides a new diagnostic tool in the differential diagnosis of cDI. Copeptin measurements upon arginine stimulation discriminated patients with diabetes insipidus vs. patients with primary polydipsia with a high diagnostic accuracy of 94%. Glucagon has been shown to stimulate GH-secretion. In analogy to the known stimulatory effect of arginine Infusion it is hypothesized that glucagon might stimulate the posterior pituitary gland and could therefore be a novel diagnostic test in the polyuria-polydipsia syndrome. This study is to evaluate copeptin values after the subcutaneous injection of glucagon in adults (healthy volunteers and patients with diabetes insipidus or primary polydipsia). This study is planned as a double-blind randomized-controlled cross-over trial consisting of two parts, including healthy adults (study part 1 - proof of concept) and adults with known diagnosis of cDI or PP (study part 2 - pilot study). Study parts 1 and 2 will be conducted consecutively. If the results of study part 1 suggest that glucagon is a potent stimulator of Copeptin in healthy adults, study part 2 will be conducted. Participants will receive glucagon injection and placebo injection in random order.

Official Title
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Copeptin After a Subcutaneous Stimulation With Glucagon in Adults (Healthy Volunteers and Patients With Diabetes Insipidus or Primary Polydipsia) - The Glucacop-Study

Conditions
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Diabetes Insipidus

Intervention / Treatment
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* Diagnostic Test: Glucagon
* Diagnostic Test: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for healthy volunteers: no medication except hormonal contraception Inclusion criteria for patients: Documented primary polydipsia or diabetes insipidus based on a water deprivation test or hypertonic saline Infusion Accordingly patients must have evidence of disordered drinking habits and diuresis defined as polyuria >50ml/kg body weight/24h and polydipsia >3l /24h, or must be on regular daily Desmopressin medication. Exclusion Criteria for healthy volunteers: BMI > 25kg/m2 or < 18.5 kg/m2 participation in a trial with investigational drugs within 30 days vigorous physical exercise within 24 hours before the study participation Alcohol intake within 24 hours before study participation pregnancy and breastfeeding Evidence of disordered drinking habits and diuresis defined as polyuria >50ml/kg Body weight/24h and polydipsia >3l /24h Intention to become pregnant during the study Known allergy towards glucagon Evidence of an acute illness Long QT syndrome Hemoglobin level below 120 g/l Exclusion criteria for patients: BMI > 25kg/m2 or < 18.5 kg/m2 participation in a trial with investigational drugs within 30 days vigorous physical exercise within 24 hours before the study participation Alcohol intake within 24 hours before study participation pregnancy and breastfeeding Evidence of an acute illness Long QT syndrome Hemoglobin level below 120 g/l

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Double-blind randomized-controlled cross-over trial consisting of two parts, including healthy adults (study part 1 - proof of concept) and adults with known diagnosis of cDI or PP (study part 2 - pilot study). Study parts 1 and 2 will be conducted consecutively. If the results of study part 1 suggest that glucagon is a potent stimulator of Copeptin in healthy adults, study part 2 will be conducted. The half of the study group will start with test day A (injection of glucagon), followed by test day B (injection of placebo) and the other half will start with test day B (injection of placebo), followed by test day A (injection of glucagon). The randomization will be performed by an independent third party.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: study part 1: healthy adult volunteers<br>22 Healthy volunteers: The half of the study group will start with test day A (injection of glucagon), followed by test day B (injection of placebo) and the other half will start with test day B (injection of placebo), followed by test day A (injection of glucagon). | Diagnostic Test: Glucagon<br>* Glucagon with the empirical formula of C153H225N43O49S, and a molecular weight of 3483 g/mol, is a single-chain polypeptide containing 29 amino acid residues. Glucagon is provided in a single dose vial as powder. One container contains 1 mg of glucagon which results in a concentration of 1 mg/ml after dissolution in a volume of 1 ml (Glucagen NovoNordisk (Hypokit)). The currently used standard dose regimen is 1 mg of glucagon in adults. The solution for subcutaneous injection will be prepared by the study personnel according to the attached package leaflet.<br>Diagnostic Test: Placebo<br>* As placebo 1 ml sodium chloride (NaCl) 0.9% to inject subcutaneous is used. It has the same optical appearance as glucagon.<br>|
| Experimental: study part 2: adult patients with primary polydipsia or central diabetes insipidus<br>If results of study part 1 suggest that glucagon stimulates copeptin (proof of concept),10 patients with primary polydipsia and 10 patients with central diabetes insipidus will be additionally included (study part 2): The half of the study group will start with test day A (injection of glucagon), followed by test day B (injection of placebo) and the other half will start with test day B (injection of placebo), followed by test day A (injection of glucagon). | Diagnostic Test: Glucagon<br>* Glucagon with the empirical formula of C153H225N43O49S, and a molecular weight of 3483 g/mol, is a single-chain polypeptide containing 29 amino acid residues. Glucagon is provided in a single dose vial as powder. One container contains 1 mg of glucagon which results in a concentration of 1 mg/ml after dissolution in a volume of 1 ml (Glucagen NovoNordisk (Hypokit)). The currently used standard dose regimen is 1 mg of glucagon in adults. The solution for subcutaneous injection will be prepared by the study personnel according to the attached package leaflet.<br>Diagnostic Test: Placebo<br>* As placebo 1 ml sodium chloride (NaCl) 0.9% to inject subcutaneous is used. It has the same optical appearance as glucagon.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal increase in copeptin level | Maximal increase in copeptin level within three hours after the injection of a single subcutaneous dose of 1mg glucagon or 0.9% NaCl. That is the difference between the maximal copeptin value measured between 30 and 180 minutes after the injection and the baseline value. measured before the injection. | Within three hours after the injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in copeptin values | Change in copeptin values | Measured at 0 (baseline), 30, 60, 90, 120, 150 and 180 minutes after injection | 
| Maximum copeptin time: the time from baseline to the maximum copeptin value | Maximum copeptin time: the time from baseline to the maximum copeptin value | Within three hours after the injection | 
| Change in growth hormone (GH) | Change in growth hormone (GH) | Measured at 0 (baseline), 30, 60, 90, 120, 150 and 180 minutes after injection | 
| Change in prolactin | Change in prolactin | Measured at 0 (baseline), 30, 60, 90, 120, 150 and 180 minutes after injection | 
| Change in plasma sodium | Change in plasma sodium | Measured at 0 (baseline), 30, 60, 90, 120, 150 and 180 minutes after injection | 
| Change in plasma osmolality | Change in plasma osmolality | Measured at 0 (baseline), 30, 60, 90, 120, 150 and 180 minutes after injection | 
| Change in oxytocin | Change in oxytocin | Measured at 0 (baseline), 30, 60, 90, 120, 150 and 180 minutes after injection | 
| Maximal Change in GH | Maximal Change in GH | Within three hours after the injection | 
| Maximal Change in prolactin | Maximal Change in prolactin | Within three hours after the injection | 
| Maximal Change in plasma osmolality | Maximal Change in plasma osmolality | Within three hours after the injection | 
| Maximal Change in oxytocin | Maximal Change in oxytocin | Within three hours after the injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Copeptin, Glucagon, central diabetes insipidus, primary polydipsia, hypothalamo-pituitary-adrenal axis, posterior pituitary gland, polyuria-polydipsia syndrome