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NCT Number: NCT03572166

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

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.

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Key information

Conditions

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

Age range

18 year–95 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Hospital das clinicas Minas Gerais, Belo Horizonte, Brazil

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Arginine infusion

Diagnostic Test

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

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.

    Time frame: 2 days

    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

Secondary outcomes

  1. 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

    Time frame: 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial)

    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. 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

    Time frame: 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial)

    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

  3. 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

    Time frame: 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial)

    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

  4. 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

    Time frame: 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial)

    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

  5. 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

    Time frame: 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial)

  6. Accuracy of the copeptin cut-off of 3.7 pmol/l after 60 minutes and 4.1 after 90 minutes for Arginine Stimulation test

    Time frame: 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial)

  7. Sensitivity of the copeptin cut-off of 3.7 pmol/l after 60 minutes and 4.1 after 90 minutes for Arginine Stimulation test

    Time frame: 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial)

  8. Specificity of the copeptin cut-off of 3.7 pmol/l after 60 minutes and 4.1 after 90 minutes for Arginine Stimulation test

    Time frame: 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial)

  9. Accuracy of the copeptin cut-off of 6.5 pmol/l for Hypertonic Saline Infusion test

    Time frame: 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial)

  10. Sensitivity of the copeptin cut-off of 6.5 pmol/l for Hypertonic Saline Infusion test

    Time frame: 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial)

  11. Specificity of the copeptin cut-off of 6.5 pmol/l for Hypertonic Saline Infusion test

    Time frame: 2 days (1 day for each test, evaluation diagnostic accuracy at end of trial)

  12. Frequency and severity of thirst assessed by visual analogue scale during both tests

    Time frame: 2 days (1 for each test)

    assessed by visual analogue scale from 0 to 10, with 0 indicating no symptoms and 10 indicating severe symptoms.

  13. Frequency and severity of headache assessed by visual analogue scale during both tests

    Time frame: 2 days (1 for each test)

    assessed by visual analogue scale from 0 to 10, with 0 indicating no symptoms and 10 indicating severe symptoms.

  14. Frequency and severity of nausea assessed by visual analogue scale during both tests

    Time frame: 2 days (1 for each test)

    assessed by visual analogue scale from 0 to 10, with 0 indicating no symptoms and 10 indicating severe symptoms.

  15. Frequency and severity of vertigo assessed by visual analogue scale during both tests

    Time frame: 2 days (1 for each test)

    assessed by visual analogue scale from 0 to 10, with 0 indicating no symptoms and 10 indicating severe symptoms.

  16. Frequency and severity of general malaise assessed by visual analogue scale during both tests

    Time frame: 2 days (1 for each test)

    assessed by visual analogue scale from 0 to 10, with 0 indicating no symptoms and 10 indicating severe symptoms.

  17. Subjective burden assessed by visual analogue scale of both tests

    Time frame: 2 days (1 for each test)

    assessed by visual analogue scale from 0 to 10, with 0 indicating no symptoms and 10 indicating severe symptoms.

  18. Health care costs of both tests

    Time frame: 2 days (1 for each test)

  19. Frequency of test preference at follow up visit

    Time frame: 30 days

Sponsors and collaborators

Lead sponsor

University Hospital, Basel, Switzerland

Other

Collaborators

  • 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

Registry information

Acronym: CARGOx

Important dates

Study start
2018
Primary completion
2022
Study completion
2022
First posted
Jun 28, 2018
Registry last updated
Jul 27, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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