Arginine Vasopressin Deficiency, Primary Polydipsia
Conditions
Keywords
Copeptin Measurement, Diagnosis of Polyuria-polydipsia syndrome, Mannitol, Hypertonic Saline Infusion
Brief summary
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.
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.
Interventions
DIAGNOSTIC_TESTMannitol
Intravenous infusion of 1.5g/kg body weight (max. 120g) mannitol is given over 30 minutes (≙ 7.5ml/kg body weight).
DIAGNOSTIC_TESTHypertonic 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).
Sponsors
University Hospital, Basel, Switzerland
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
NONE
Intervention model description
Randomized open-label cross-over diagnostic multicenter study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Diagnostic Accuracy | One time assessment at Follow up Visit 2 (10 weeks after baseline) | 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. |
| Patient Test Preference | 1 week after completion of both diagnostic tests | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Diagnostic Performance Measures for AVP-D | At completion of follow-up, 10 weeks after last diagnostic test | 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. |
| Diagnostic Performance Measures for PP | At completion of follow-up, 10 weeks after last diagnostic test | Sensitivity, specificity, positive predictive value, and negative predictive value of mannitol infusion and hypertonic saline infusion for diagnosing PP using predefined copeptin cut-offs. |
| Optimal copeptin cut-off after mannitol infusion | At completion of follow-up, 10 weeks after last diagnostic test | Exploratory determination and validation of optimal copeptin cut-off values for differentiating AVP deficiency from primary polydipsia following mannitol stimulation. |
| Frequency and severity of clinical symptoms | During each test day (baseline to end of monitoring period 90 minutes/ 240 minutes) | Frequency and severity of symptoms (e.g., thirst, headache, nausea, malaise) assessed using numeric rating scales during mannitol and hypertonic saline tests. |
| Subjective burden of each test assessed by numeric rating scale | Immediately after each test day | Patient-reported burden of each diagnostic test assessed using a numeric rating scale (NRS) (0-10). |
| Psychopathological assessment (STAI-T) | Baseline | 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. |
| Autistic traits | Baseline | 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. |
| Quality of Life in Posterior Pituitary Disease | Baseline and follow-up (10 weeks ) | 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. |
| Change in oxytocin/neurophysin I levels | Baseline and 90 minutes post-stimulation | Change in circulating oxytocin and neurophysin I levels before and after each diagnostic test. |
| Spearman's rank correlation coefficient between psychopathology questionnaires and oxytocin levels | Baseline and 90 minutes post-stimulation | Correlation between psychopathological questionnaires and oxytocin levels will be described using Spearman's rank correlation coefficient. |
| Spearman's rank correlation coefficient between psychopathology questionnaire and neurophysin I levels | Baseline and 90 minutes post-stimulation | Correlation between psychopathological questionnaires and neurophysin I levels will be described using Spearman's rank correlation coefficient. |
| Validation of clinical diagnostic score | After test day 2 and 10 weeks thereafter | Validation of a predefined diagnostic score using clinical and basal parameters |
| Change of urinary copeptin levels | During test day 1 and test day 2 with a maximum of 3 month in between the two test days | Change in urinary copeptin levels before and after mannitol and hypertonic saline stimulation. |
| Optimal urinary copeptin cut-offs | 10 weeks after test day 2 | Exploratory determination of optimal urinary copeptin thresholds for differential diagnosis. |
| Sex-specific copeptin response | During test day 1 and test day 2 with a maximum of 3 month in between the two test days and at study completion | Evaluation of sex-specific differences in stimulated copeptin levels and corresponding diagnostic cut-offs. |
| Cost-efficiency of diagnostic tests | One time assessment at Follow up Visit 2 (10 weeks after baseline) | Exploratory assessment of healthcare costs associated with mannitol infusion versus hypertonic saline infusion. |
Countries
Switzerland
Contacts
CONTACTTalitha Hildebrandt
CONTACTCemile Bathelt
STUDY_CHAIRMirjam Christ-Crain, Prof. Dr.
University Hospital of Basel
Outcome results
None listed