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

Diabetes Insipidus Clinical Trial

— CARGOx  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03572166
• Other study ID #: CARGOx
• Status: Completed
• Phase: N/A
• Start date: September 3, 2018
• Est. completion date: December 31, 2022

Study information

• Verified date: July 2023
• Source: University Hospital, Basel, Switzerland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 177
• Est. completion date: December 31, 2022
• Est. primary completion date: September 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 95 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Insipidus
• Diabetes Mellitus
• Polydipsia
• Polydipsia, Primary

Intervention

Diagnostic Test:
• Arginine infusion
Intravenous Infusion of Arginine is given, copeptin measurement will be collected before and 60minutes after start of infusion
• Hypertonic saline infusion
Intravenous Infusion of hypertonic Saline is given, copeptin measurement will be collected before and once Plasma sodium rises above 149mmol/l

Locations

Country	Name	City	State
Brazil	Hospital das clinicas Minas Gerais	Belo Horizonte
Germany	University Hospital Würzburg	Würzburg
Italy	Granda Ospedale Maggiore Policlinico Milan	Milan
Netherlands	Erasmus MC	Rotterdam
Switzerland	University Hospital Basel, Department of Endocrinology	Basel	Basel Stadt
Switzerland	University Hospital Zurich	Zürich
United Kingdom	Cambridge University Hospital	Cambridge

Sponsors (7)

Lead Sponsor	Collaborator
University Hospital, Basel, Switzerland	Cambridge University Hospitals NHS Foundation Trust, Erasmus Medical Center, Federal University of Minas Gerais, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University Hospital, Zürich, Wuerzburg University Hospital

Countries where clinical trial is conducted

Brazil,  Germany,  Italy,  Netherlands,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Health care costs of both tests		2 days (1 for each test)
Secondary	Frequency of test preference at follow up visit		30 days