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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Insipidus; Polydipsia, Primary
• Intervention / Treatment: Diagnostic test: Arginine infusion; Diagnostic test: Hypertonic saline infusion

• Study Type: Interventional
• Enrollment (Actual): 177
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Brazil
  • Belo Horizonte, Brazil
    • Hospital das clinicas Minas Gerais
• Germany
  • Würzburg, Germany
    • University Hospital Würzburg
• Italy
  • Milan, Italy
    • Granda Ospedale Maggiore Policlinico Milan
• Netherlands
  • Rotterdam, Netherlands
    • Erasmus MC
• Switzerland
  • Zürich, Switzerland
    • University Hospital Zurich
  • Basel Stadt
    • Basel, Basel Stadt, Switzerland, 4031
      • University Hospital Basel, Department of Endocrinology
• United Kingdom
  • Cambridge, United Kingdom
    • Cambridge university hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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
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)
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
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)
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)

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: Erasmus Medical Center; Cambridge University Hospitals NHS Foundation Trust; Federal University of Minas Gerais; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico; University Hospital, Zürich; Wuerzburg University Hospital
• Investigators: Principal Investigator: Mirjam Christ-Crain, Prof, MD, University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2018
• Primary Completion (Actual): September 30, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: June 4, 2018
• First Submitted That Met QC Criteria: June 27, 2018
• First Posted (Actual): June 28, 2018

Study Record Updates

• Last Update Posted (Actual): July 27, 2023
• Last Update Submitted That Met QC Criteria: July 24, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Copeptin
• Additional Relevant MeSH Terms: Behavioral Symptoms; Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Kidney Diseases; Urologic Diseases; Neurobehavioral Manifestations; Endocrine System Diseases; Pituitary Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Mellitus; Diabetes Insipidus; Polydipsia; Polydipsia, Psychogenic
• Other Study ID Numbers: CARGOx

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No