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

NCT03572166 | Completed DMC

• 1 other identifier: CARGOx
• Study Type: interventional
• Target: 177
• Locations: 6 countries
• Sites: 7

Brief 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.

Conditions

Diabetes Insipidus; Polydipsia, Primary

Keywords

Copeptin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (19)

• 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

  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

  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

  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

  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)

Study Arms (2)

Arginine Infusion

EXPERIMENTAL

Arginine Stimulation Test

Diagnostic Test: Arginine infusion

Hypertonic saline infusion

ACTIVE COMPARATOR

Hypertonic Saline Infusion Test

Diagnostic Test: Hypertonic saline infusion

Interventions

Arginine infusion DIAGNOSTIC_TEST

Intravenous Infusion of Arginine is given, copeptin measurement will be collected before and 60minutes after start of infusion

Arginine Infusion

Hypertonic saline infusion DIAGNOSTIC_TEST

Intravenous Infusion of hypertonic Saline is given, copeptin measurement will be collected before and once Plasma sodium rises above 149mmol/l

Hypertonic saline infusion

Eligibility Criteria

• Age: 18 Years - 95 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Basel, Switzerland: lead
• University Hospital, Zürich: collaborator
• Wuerzburg University Hospital: collaborator
• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: collaborator
• Erasmus Medical Center: collaborator
• Cambridge University Hospitals NHS Foundation Trust: collaborator
• Federal University of Minas Gerais: collaborator

Study Sites (7)

Hospital das clinicas Minas Gerais

Belo Horizonte, Brazil

Location

University Hospital Würzburg

Würzburg, Germany

Location

Granda Ospedale Maggiore Policlinico Milan

Milan, Italy

Location

Erasmus MC

Rotterdam, Netherlands

Location

University Hospital Basel, Department of Endocrinology

Basel, Canton of Basel-City, 4031, Switzerland

Location

University Hospital Zurich

Zurich, Switzerland

Location

Cambridge University Hospital

Cambridge, United Kingdom

Location

Related Publications (3)

• Atila C, Chifu I, Drummond JB, Vogt DR, Nahum U, Fassnacht M, Winzeler B, Refardt J, Christ-Crain M. A novel diagnostic score for diagnosing arginine vasopressin deficiency (central diabetes insipidus) or primary polydipsia with basal laboratory and clinical parameters: results from two international multicentre prospective diagnostic studies. Lancet Diabetes Endocrinol. 2025 Jun;13(6):505-515. doi: 10.1016/S2213-8587(25)00053-1. Epub 2025 Apr 25.

  PMID: 40294614 DERIVED

• Bizzozero CA, Monnerat S, Chapman FA, Dhaun N, Refardt J, Christ-Crain M. Apelin levels in patients with polyuria-polydipsia syndrome upon copeptin stimulation tests. Eur J Endocrinol. 2024 Oct 29;191(5):491-498. doi: 10.1093/ejendo/lvae138.

  PMID: 39425917 DERIVED

• Refardt J, Atila C, Chifu I, Ferrante E, Erlic Z, Drummond JB, Indirli R, Drexhage RC, Sailer CO, Widmer A, Felder S, Powlson AS, Hutter N, Vogt DR, Gurnell M, Soares BS, Hofland J, Beuschlein F, Fassnacht M, Winzeler B, Christ-Crain M. Arginine or Hypertonic Saline-Stimulated Copeptin to Diagnose AVP Deficiency. N Engl J Med. 2023 Nov 16;389(20):1877-1887. doi: 10.1056/NEJMoa2306263.

  PMID: 37966286 DERIVED

MeSH Terms

Conditions

Diabetes Insipidus; Polydipsia, Psychogenic

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Pituitary Diseases; Endocrine System Diseases; Polydipsia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Behavioral Symptoms; Behavior

Study Officials

• Mirjam Christ-Crain, Prof, MD

  University Hospital, Basel, Switzerland

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Observational randomized cross-over diagnostic international multicenter study

Study Record Dates

• First Submitted: June 4, 2018
• First Posted: June 28, 2018
• Study Start: September 3, 2018
• Primary Completion: September 30, 2022
• Study Completion: December 31, 2022
• Last Updated: July 27, 2023

Record last verified: 2023-07

Locations

NL (1); GB (1); IT (1); DE (1); CH (2); BR (1)