Copeptin Measurement After Mannitol and Hypertonic Saline for the Diagnosis of Polyuria-polydipsia Syndrome (COMPASS)

The aim of this study is to evaluate whether a new test using mannitol infusion can diagnose the cause of polyuria-polydipsia syndrome as accurately as the current standard test (hypertonic saline infusion) and to compare which test patients prefer. The goal is to identify a simpler and more patient-friendly diagnostic approach.

Study Overview

• Status: Not yet recruiting
• Conditions: Primary Polydipsia; Arginine Vasopressin Deficiency
• Intervention / Treatment: Diagnostic test: Mannitol; Diagnostic test: Hypertonic Saline

Detailed Description

Polyuria-polydipsia syndrome (PPS), characterized by excessive urination and fluid intake, can have different underlying causes, including a deficiency of the hormone vasopressin (AVP-D) or excessive fluid intake without AVP-D (primary polydipsia). Correctly identifying the cause is essential, as the treatments differ and an incorrect diagnosis can negatively impact patient care.

A blood marker called copeptin is used to support the diagnosis, as it reflects vasopressin levels in the body. Currently, the most accurate method involves measuring copeptin after stimulation with hypertonic saline. However, this test is complex, requires close medical monitoring, and can be uncomfortable for patients.

Mannitol is a substance already used in routine clinical care and may offer a simpler way to stimulate copeptin release. Early results suggest that it could provide similar diagnostic accuracy with fewer side effects and better patient comfort.

This study is a randomized, cross-over, multicenter trial in which participants undergo both tests (mannitol and hypertonic saline) in random order. The study compares the diagnostic accuracy and patient preference for both methods, as well as safety and tolerability. In addition, it explores whether other clinical and laboratory measures can further improve the diagnosis of PPS.

• Study Type: Interventional
• Enrollment (Estimated): 144
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Talitha Hildebrandt; Phone Number: +41 61 55 65075; Email: talithanatalja.hildebrandt@usb.ch
• Study Contact Backup: Name: Cemile Bathelt; Phone Number: +41 61 55 65407; Email: cemile.bathelt@usb.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel
    • Principal Investigator: Mirjam Christ-Crain, Prof. Dr.
    • Contact: Talitha Hildebrandt; Phone Number: +41 61 55 65075; Email: talithanatalja.hildebrandt@usb.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years
2. Hypotonic polyuria/polydipsia syndrome defined as polyuria >40ml/kg body weight/24h and polydipsia >3l/24h; and urine osmolality <800mOsm/L or known AVP-D based on accepted criteria

Exclusion Criteria:

1. Polyuria/polydipsia secondary to diabetes mellitus, hypercalcemia, or hypokalemia
2. Diagnosis of AVP-R (Copeptin > 21.4 pmol/L)
3. Evidence of acute illness
4. Epilepsy requiring treatment
5. Uncontrolled arterial hypertension (blood pressure >160/100mmHg at baseline
6. eGFR < 60 ml/min/1,73 m2
7. Cardiac failure (NYHA III-IV)
8. Diagnosis of liver cirrhosis, Child-Pugh Class C
9. Uncorrected adrenal or thyroidal deficiency
10. Pregnancy or breastfeeding
11. Current or unresolved urinary obstruction
12. Enrollment in a clinical trial within the last 30 days
13. Patients refusing or unable to give written informed consent
14. Inability to follow study procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mannitol Infusion; Diagnostic evaluation of polyuria polydipsia syndrome through copeptin measurement after mannitol infusion.	Diagnostic test: Mannitol; Intravenous infusion of 1.5g/kg body weight (max. 120g) mannitol is given over 30 minutes (≙ 7.5ml/kg body weight).
Active Comparator: Hypertonic Saline Infusion (HIS); Diagnostic evaluation of polyuria polydipsia syndrome through copeptin measurement after HIS	Diagnostic test: Hypertonic Saline; Intravenous infusion of NaCl 3% is given first as a bolus of 250ml over 15 minutes, then with an infusion rate of 0.15ml/kg body weight / minute (≙ 9ml/kg body weight/hour).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Diagnostic Accuracy	The overall diagnostic accuracy is defined as the proportion of correct diagnoses out of all diagnoses based on the stimulated copeptin value. Final diagnosis will be made after termination of the study by two endocrine specialists who will be blinded to the copeptin results of the mannitol infusion.	One time assessment at Follow up Visit 2 (10 weeks after baseline)
Patient Test Preference	Patient-reported preference between mannitol infusion and hypertonic saline infusion, assessed using a 5-point Likert scale ranging from -2 (strong preference for hypertonic saline) to +2 (strong preference for mannitol).	1 week after completion of both diagnostic tests

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic Performance Measures for AVP-D	Sensitivity, specificity, positive predictive value, and negative predictive value of mannitol infusion and hypertonic saline infusion for diagnosing AVP deficiency using predefined copeptin cut-offs.	At completion of follow-up, 10 weeks after last diagnostic test
Diagnostic Performance Measures for PP	Sensitivity, specificity, positive predictive value, and negative predictive value of mannitol infusion and hypertonic saline infusion for diagnosing PP using predefined copeptin cut-offs.	At completion of follow-up, 10 weeks after last diagnostic test
Optimal copeptin cut-off after mannitol infusion	Exploratory determination and validation of optimal copeptin cut-off values for differentiating AVP deficiency from primary polydipsia following mannitol stimulation.	At completion of follow-up, 10 weeks after last diagnostic test
Frequency and severity of clinical symptoms	Frequency and severity of symptoms (e.g., thirst, headache, nausea, malaise) assessed using numeric rating scales during mannitol and hypertonic saline tests.	During each test day (baseline to end of monitoring period 90 minutes/ 240 minutes)
Subjective burden of each test assessed by numeric rating scale	Patient-reported burden of each diagnostic test assessed using a numeric rating scale (NRS) (0-10).	Immediately after each test day
Psychopathological assessment (STAI-T)	General anxiety levels is assessed by State-Trait Anxiety Inventory (STAI-T) questionnaire. The total trait score (STAI-T) ranges from 20 to 80, with higher scores indicating more pronounced anxiety.	Baseline
Autistic traits	Autistic traits is assessed by Autism-Spectrum Quotient (AQ) questionnaire. The AQ consists of 50 items, with four choices for each item from "definitely agree" to "definitely disagree" and a total score from 0 to 50. A score above the proposed cut-off of 29 highlights significant traits of autism.	Baseline
Quality of Life in Posterior Pituitary Disease	Currently, no disease-specific tool exists to assess treatment success for either desmopressin or oxytocin (OXT) therapy in patients with arginine vasopressin deficiency (AVP-D). To address this gap, we developed a novel multidimensional questionnaire in close collaboration with patients, patient representatives, and patient advocates. The PP-QoL consists of three parts: Part A assesses symptoms related to AVP-D (15 items), while Parts B (17 items) and C (21 items) focus on domains associated with OXT deficiency.	Baseline and follow-up (10 weeks )
Change in oxytocin/neurophysin I levels	Change in circulating oxytocin and neurophysin I levels before and after each diagnostic test.	Baseline and 90 minutes post-stimulation
Spearman's rank correlation coefficient between psychopathology questionnaires and oxytocin levels	Correlation between psychopathological questionnaires and oxytocin levels will be described using Spearman's rank correlation coefficient.	Baseline and 90 minutes post-stimulation
Spearman's rank correlation coefficient between psychopathology questionnaire and neurophysin I levels	Correlation between psychopathological questionnaires and neurophysin I levels will be described using Spearman's rank correlation coefficient.	Baseline and 90 minutes post-stimulation
Validation of clinical diagnostic score	Validation of a predefined diagnostic score using clinical and basal parameters	After test day 2 and 10 weeks thereafter
Change of urinary copeptin levels	Change in urinary copeptin levels before and after mannitol and hypertonic saline stimulation.	During test day 1 and test day 2 with a maximum of 3 month in between the two test days
Optimal urinary copeptin cut-offs	Exploratory determination of optimal urinary copeptin thresholds for differential diagnosis.	10 weeks after test day 2
Sex-specific copeptin response	Evaluation of sex-specific differences in stimulated copeptin levels and corresponding diagnostic cut-offs.	During test day 1 and test day 2 with a maximum of 3 month in between the two test days and at study completion
Cost-efficiency of diagnostic tests	Exploratory assessment of healthcare costs associated with mannitol infusion versus hypertonic saline infusion.	One time assessment at Follow up Visit 2 (10 weeks after baseline)

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Study Chair: Mirjam Christ-Crain, Prof. Dr., University Hospital of Basel

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): June 1, 2030

Study Registration Dates

• First Submitted: March 30, 2026
• First Submitted That Met QC Criteria: May 4, 2026
• First Posted (Actual): May 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Hypertonic Saline Infusion; Mannitol; Copeptin Measurement; Diagnosis of Polyuria-polydipsia syndrome
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Behavioral Symptoms; Pituitary Diseases; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Polydipsia; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Polydipsia, Psychogenic
• Other Study ID Numbers: 2026-00480;kt25ChristCrain7

Drug and device information, study documents

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