Use of Copeptin Measurement After Arginine Infusion for the Differential Diagnosis of Diabetes Insipidus - the CARGOx Study

Study Overview
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Brief Summary
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The differential diagnosis of central diabetes insipidus (cDI) is difficult and the current test with the highest diagnostic accuracy is copeptin measurement after hypertonic saline infusion (HIS). Although the HIS improved diagnostic accuracy compared to the standard water deprivation test used for decades before, it still comprises great discomfort for patients due to the rise in serum sodium levels above 149mmol/l and requires the presence of medical staff at all times to guarantee safety of the test. The arginine stimulation test is routinely used to stimulate growth hormone. Own data in 52 patients with polyuria / polydipsia syndrome showed that arginine infusion is a potent stimulator of the neurohypophysis and provides a new diagnostic tool in the differential diagnosis of cDI. Copeptin measurements upon arginine stimulation (CAS) discriminated patients with diabetes insipidus vs. patients with primary polydipsia with a high diagnostic accuracy of 94%. To validate these results and to compare them against the HIS a large multicenter trial is needed, where the diagnostic accuracy of the CAS is compared to the HIS.

Official Title
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Use of Copeptin Measurement After Arginine Infusion for the Differential Diagnosis of Diabetes Insipidus - the CARGOx Study

Conditions
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Diabetes Insipidus, Polydipsia, Primary

Intervention / Treatment
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* Diagnostic Test: Arginine infusion
* Diagnostic Test: Hypertonic saline infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Hypotonic polyuria / polydipsia syndrome defined as: polyuria >50ml/kg body weight/24h and polydipsia >3l /24h or known diabetes insipidus under treatment with DDAVP Urine-Osmolality <800mOsm/L Exclusion Criteria: Polyuria / polydipsia secondary to diabetes mellitus, hypercalcemia or hypokalemia Nephrogenic diabetes insipidus (defined as baseline copeptin level >21.4pmol/L) Evidence of any acute illness Epilepsy requiring treatment Uncontrolled arterial hypertension (blood pressure >160/100mmHg at baseline) Cardiac failure (NYHA III-IV) Liver cirrhosis (Child B-C) Uncorrected adrenal or thyroidal deficiency Patients refusing or unable to give written informed consent Pregnancy or breast feeding End of life care

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 95 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: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Observational randomized cross-over diagnostic international multicenter study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arginine Infusion<br>Arginine Stimulation Test | Diagnostic Test: Arginine infusion<br>* Intravenous Infusion of Arginine is given, copeptin measurement will be collected before and 60minutes after start of infusion<br>|
| Active Comparator: Hypertonic saline infusion<br>Hypertonic Saline Infusion Test | Diagnostic Test: Hypertonic saline infusion<br>* Intravenous Infusion of hypertonic Saline is given, copeptin measurement will be collected before and once Plasma sodium rises above 149mmol/l<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome is the overall diagnostic accuracy - defined as the proportion of correct diagnoses - of each diagnostic procedure in differentiating patients with central diabetes insipidus from patients with primary polydipsia. | For Arginine stimulation the copeptin cut-off to differentiate between diabetes insipidus and primary polydipsia will be 3.8 pmol/l after 60 minutes, for hypertonic saline stimulation it will be the copeptin cut-off 4.9 pmol/l taken at the end of the test | 2 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity of both diagnostic procedures for each diagnosis (Primary polydipsia, partial and complete central Diabetes insipidus) according to recommended diagnostic test criteria and previously generated cutoff values | Copeptin cut-offs used: Arginine stimulation: Copeptin level at 60 minutes < 2.4 pmol/l = complete central diabetes insipidus Copeptin level at 60 minutes 2.4 - 3.8 pmol/l = partial central diabetes insipidus Copeptin level at 60 minutes > 3.8 pmol/l = primary polydipsia Hypertonic saline stimulation: Copeptin level < 2.7 pmol/l = complete central diabetes insipidus Copeptin level 2.7 - 4.9 pmol/l = partial central diabetes insipidus Copeptin level > 4.9 pmol/l = primary polydipsia | 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial) | 
| Specificity of both diagnostic procedures for each diagnosis (Primary polydipsia, partial and complete central Diabetes insipidus) according to recommended diagnostic test criteria and previously generated cutoff values | Copeptin cut-offs used: Arginine stimulation: Copeptin level at 60 minutes < 2.4 pmol/l = complete central diabetes insipidus Copeptin level at 60 minutes 2.4 - 3.8 pmol/l = partial central diabetes insipidus Copeptin level at 60 minutes > 3.8 pmol/l = primary polydipsia Hypertonic saline stimulation: Copeptin level < 2.7 pmol/l = complete central diabetes insipidus Copeptin level 2.7 - 4.9 pmol/l = partial central diabetes insipidus Copeptin level > 4.9 pmol/l = primary polydipsia | 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial) | 
| Positive predictive value of both diagnostic procedures for each diagnosis (Primary polydipsia, partial and complete central Diabetes insipidus) according to recommended diagnostic test criteria and previously generated cutoff values | Copeptin cut-offs used: Arginine stimulation: Copeptin level at 60 minutes < 2.4 pmol/l = complete central diabetes insipidus Copeptin level at 60 minutes 2.4 - 3.8 pmol/l = partial central diabetes insipidus Copeptin level at 60 minutes > 3.8 pmol/l = primary polydipsia Hypertonic saline stimulation: Copeptin level < 2.7 pmol/l = complete central diabetes insipidus Copeptin level 2.7 - 4.9 pmol/l = partial central diabetes insipidus Copeptin level > 4.9 pmol/l = primary polydipsia | 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial) | 
| Negative predictive value of both diagnostic procedures for each diagnosis (Primary polydipsia, partial and complete central Diabetes insipidus) according to recommended diagnostic test criteria and previously generated cutoff values | Copeptin cut-offs used: Arginine stimulation: Copeptin level at 60 minutes < 2.4 pmol/l = complete central diabetes insipidus Copeptin level at 60 minutes 2.4 - 3.8 pmol/l = partial central diabetes insipidus Copeptin level at 60 minutes > 3.8 pmol/l = primary polydipsia Hypertonic saline stimulation: Copeptin level < 2.7 pmol/l = complete central diabetes insipidus Copeptin level 2.7 - 4.9 pmol/l = partial central diabetes insipidus Copeptin level > 4.9 pmol/l = primary polydipsia | 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial) | 
| Best fit diagnostic copeptin cut-off values for differentiation between each diagnosis (Primary polydipsia, partial and complete central Diabetes insipidus) upon arginine stimulation and hypertonic saline infusion stimulation |  | 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial) | 
| Accuracy of the copeptin cut-off of 3.7 pmol/l after 60 minutes and 4.1 after 90 minutes for Arginine Stimulation test |  | 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial) | 
| Sensitivity of the copeptin cut-off of 3.7 pmol/l after 60 minutes and 4.1 after 90 minutes for Arginine Stimulation test |  | 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial) | 
| Specificity of the copeptin cut-off of 3.7 pmol/l after 60 minutes and 4.1 after 90 minutes for Arginine Stimulation test |  | 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial) | 
| Accuracy of the copeptin cut-off of 6.5 pmol/l for Hypertonic Saline Infusion test |  | 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial) | 
| Sensitivity of the copeptin cut-off of 6.5 pmol/l for Hypertonic Saline Infusion test |  | 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial) | 
| Specificity of the copeptin cut-off of 6.5 pmol/l for Hypertonic Saline Infusion test |  | 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial) | 
| Frequency and severity of thirst assessed by visual analogue scale during both tests | assessed by visual analogue scale from 0 to 10, with 0 indicating no symptoms and 10 indicating severe symptoms. | 2 days (1 for each test) | 
| Frequency and severity of headache assessed by visual analogue scale during both tests | assessed by visual analogue scale from 0 to 10, with 0 indicating no symptoms and 10 indicating severe symptoms. | 2 days (1 for each test) | 
| Frequency and severity of nausea assessed by visual analogue scale during both tests | assessed by visual analogue scale from 0 to 10, with 0 indicating no symptoms and 10 indicating severe symptoms. | 2 days (1 for each test) | 
| Frequency and severity of vertigo assessed by visual analogue scale during both tests | assessed by visual analogue scale from 0 to 10, with 0 indicating no symptoms and 10 indicating severe symptoms. | 2 days (1 for each test) | 
| Frequency and severity of general malaise assessed by visual analogue scale during both tests | assessed by visual analogue scale from 0 to 10, with 0 indicating no symptoms and 10 indicating severe symptoms. | 2 days (1 for each test) | 
| Subjective burden assessed by visual analogue scale of both tests | assessed by visual analogue scale from 0 to 10, with 0 indicating no symptoms and 10 indicating severe symptoms. | 2 days (1 for each test) | 
| Health care costs of both tests |  | 2 days (1 for each test) | 
| Frequency of test preference at follow up visit |  | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Copeptin