Mannitol-induced Release of Copeptin in Healthy Adults and Patients With Polyuria-Polydipsia Syndrome (MARS Study) (MARS)

Mannitol-induced Release of Copeptin in Healthy Adults and Patients With Polyuria-Polydipsia Syndrome: a Double-blind, Randomized Crossover Proof-of-concept and Open-label Single Arm Pilot Study (MARS Study)

The aims of this study are to investigate whether mannitol stimulates copeptin (part 1: proof-of-concept) and whether the copeptin levels upon mannitol infusion differ in primary polydipsia and arginine vasopressin deficiency (part 2: pilot study).

Study Overview

• Status: Completed
• Conditions: Polyuria-polydipsia Syndrome; Primary Polydipsia; Arginine Vasopressin Deficiency
• Intervention / Treatment: Diagnostic test: Mannitol Infusion (blinded); Diagnostic test: Placebo Infusion (blinded); Diagnostic test: Mannitol Infusion (open label)

Detailed Description

Diagnosing polyuria-polydipsia syndrome, which includes arginine vasopressin (AVP) deficiency (AVP-D, formerly central diabetes insipidus) and primary polydipsia (PP), is challenging but essential. Currently, the most accurate test currently involves measuring copeptin after osmotic stimulation with hypertonic saline, but this test is rarely used due to the need for close sodium monitoring and the discomfort it can cause.

Mannitol has been shown to stimulate AVP release, but no study has tested copeptin levels after mannitol stimulation in healthy adults or patients with AVP-D or PP.

This single-center study is conducted in two consecutive parts. Part 1 is a double-blind, randomized cross-over proof-of-concept study in healthy adults to investigate if mannitol infusion stimulates copeptin release. Part 2 is an open-label, single arm case-control pilot study in adults with diagnosed PP or AVP-D to see if copeptin levels after mannitol stimulation differ in PP and AVP-D.

The results of this study aim to demonstrate if mannitol infusion has the potential to be used as an alternative to hypertonic saline infusion.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Part 1: Proof of Concept in Healthy adults

• Age ≥ 18 years
• Healthy with no medication except hormonal contraception

Part 2: Pilot Study in Patients with primary polydipsia (PP) or arginine vasopressin deficiency (AVP-D)

• Age ≥ 18 years
• Evidence of polyuria > 40-50 ml/kg body weight per 24 hours and polydipsia > 3 Liter per 24 hours or regular desmopressin medication corresponding to a diagnosis of PP or AVP-D

Exclusion Criteria:

Part 1: Proof of Concept in Healthy adults

• Participation in a trial with investigational drugs within 30 days
• Evidence of disordered drinking habits and diuresis defined as polyuria > 40-50 ml/kg body weight per 24 hours and polydipsia > 3 Liter per 24 hours.
• Estimated Glomerular Filtration Rate (eGFR) < 60 ml/min/1,73 m2
• Glucose > 11.1 mmol/L corresponding to the diagnosis of an uncontrolled diabetes mellitus
• History of urinary tract obstruction
• Problems with urination
• Pregnancy or breastfeeding
• Multiple allergies (≥ 3)
• Evidence of acute illness

Part 2: Pilot Study in Patients with PP or AVP-D

• Participation in a trial with investigational drugs within 30 days
• Pregnancy or breastfeeding
• Evidence of acute illness
• eGFR < 60 ml/min/1,73 m2
• Glucose > 11.1 mmol/L corresponding to the diagnosis of uncontrolled diabetes mellitus
• History of urinary tract obstruction
• Problems with urination
• Therapy with diuretics
• Multiple allergies (≥ 3)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy adults; Part 1 of the study is conducted with healthy adults.	Diagnostic test: Mannitol Infusion (blinded); 1 g of mannitol per kg body weight is infused in 30 minutes (≙ 5 ml/kg body weight), with an upper limit of 80 g, equivalent to a body weight of 80 kg or a volume of 400 ml. The solution used for infusion is 20% mannitol in water for injection and is administered at a rate of 0.17 ml/kg/min.; Diagnostic test: Placebo Infusion (blinded); 0.9% saline will be administered in the same amount as the mannitol dose infusion (= 5 ml/kg body weight), with a rate of 0.17 ml/kg/min in 30 minutes, with an upper limit of 400 ml (equivalent to a body weight of 80 kg).
Experimental: Primary polydipsia (PP) patients; Part 2 of the study is conducted with PP patients.	Diagnostic test: Mannitol Infusion (open label); 1.5 g of mannitol per kg body weight is infused in 30 minutes (≙ 7.5 ml/kg body weight), with an upper limit of 120 g, equivalent to a body weight of 80 kg or a volume of 600 ml. The solution used for infusion is 20% mannitol in water for injection.
Experimental: Arginine vasopressin deficiency (AVP-D) patients; Part 2 of the study is conducted with AVP-D patients.	Diagnostic test: Mannitol Infusion (open label); 1.5 g of mannitol per kg body weight is infused in 30 minutes (≙ 7.5 ml/kg body weight), with an upper limit of 120 g, equivalent to a body weight of 80 kg or a volume of 600 ml. The solution used for infusion is 20% mannitol in water for injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in copeptin levels	The difference in copeptin levels at 90 minutes following a 30-minute infusion of mannitol, part 1: compared to placebo in healthy adults and part 2: between patients with (primary polydipsia) PP and arginine vasopressin deficiency (AVP-D)	Part 1: At 90 min post infusion, Part 2: at 30 min post infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of copeptin levels	Changes in copeptin levels compared to baseline.	Part 1: At baseline, 30, 45, 60, 90, and 150 min after infusion, Part 2: At baseline, 30 and 90 minutes
Maximum copeptin levels	The maximum copeptin level after infusion is determined.	Part 1: At baseline, 30, 45, 60, 90, and 150 min after infusion, Part 2: At baseline, 30 and 90 minutes
Assessment of hormone level	To determine the change in hormone levels, an assessment of hormones (e.g. Adrenocorticotropic hormone, Growth hormone, Insulin-like growth factor 1) is performed.	Part 1: At baseline, 30, 45, 60, 90, and 150 min after infusion, Part 2: At baseline, 30 and 90 minutes
Assessment of serum electrolytes	To determine the change in electrolytes, an assessment of electrolytes (e.g. sodium potassium, chloride) in the serum is performed.	Part 1: At baseline, 30, 45, 60, 90, and 150 min after infusion, Part 2: At baseline, 30 and 90 minutes
Assessment of plasma osmolality	To determine the change in parameters associated with fluid balance/ kidney function, an assessment of plasma osmolality (mOsm/kg) is performed.	Part 1: At baseline, 30, 45, 60, 90, and 150 min after infusion, Part 2: At baseline, 30 and 90 minutes
Assessment of urea	To determine the change in parameters associated with fluid balance/ kidney function, an assessment of ureal levels (mmol/L) is performed.	Part 1: At baseline, 30, 45, 60, 90, and 150 min after infusion, Part 2: At baseline, 30 and 90 minutes
Assessment of uric acid	To determine the change in parameters associated with fluid balance/ kidney function, an assessment of uric acid levels (umol/L) is performed.	Part 1: At baseline, 30, 45, 60, 90, and 150 min after infusion, Part 2: At baseline, 30 and 90 minutes
Assessment of creatinine	To determine the change in parameters associated with fluid balance/ kidney function, an assessment of creatinine levels (umol/L) is performed.	Part 1: At baseline, 30, 45, 60, 90, and 150 min after infusion, Part 2: At baseline, 30 and 90 minutes
Assessment of glucose	To determine the change in parameters associated with fluid balance/ kidney function, an assessment of glucose levels (mmol/L) is performed.	Part 1: At baseline, 30, 45, 60, 90, and 150 min after infusion, Part 2: At baseline, 30 and 90 minutes
Assessment of urine parameters	To determine the change in urine parameters, an assessment of parameters (e.g. sodium, osmolality, creatinine) in the urine is performed.	Part 1: At baseline, 90 and 150 min after infusion, Part 2: At baseline, 30 and 90 min after infusion
Assessment of blood pressure	To determine the change of vital parameters, the blood pressure (systolic and diastolic) is assessed.	Part 1: At baseline, 30, 45, 60, 90, and 150 min after infusion, Part 2: At baseline, 30 and 90 minutes
Assessment of heart rate	To determine the change of vital parameters, the heart rate is assessed.	Part 1: At baseline, 30, 45, 60, 90, and 150 min after infusion, Part 2: At baseline, 30 and 90 minutes
Assessment of adverse effects	The incidence of adverse effects, such as nausea, headache, fatigue, dizziness, thirst, is assessed using the numeric rating scale from 0 to 10, where 0 represents "no pain" and 10 represents "the worst possible pain."	Part 1: At baseline, 30, 45, 60, 90, and 150 min after infusion, Part 2: At baseline, 30 and 90 minutes
Diagnostic accuracy of copeptin after mannitol Infusion for differentiating AVP-D from PP	Assessment of the diagnostic accuracy of stimulated copeptin levels measured after mannitol infusion to distinguish patients AVP-D from those with PP. The outcome will compare post-infusion copeptin concentrations between the two groups.	Part 2: At 30 min post infusion
Assessment of changes in ECG QTc Interval	Assessment of the change in the corrected QT (QTc) interval on a standard ECG	Part 2: at Baseline and 90 min after infusion
Assessment of changes in ECG Heart rate	Assessment of the change in Heart rate on a standard ECG	Part 2: at Baseline and 90 min after infusion
Assessment of changes in ECG Cardiac rhythm	Assessment of the change in Cardiac rhythm on a standard ECG	Part 2: at Baseline and 90 min after infusion
Assessment of changes in ECG QRS morphology	Assessment of the change in QRS morphology on a standard ECG	Part 2: at Baseline and 90 min after infusion
Assessment of changes in ECG P- and T wave morphology	Assessment of the change in P- and T wave morphology on a standard ECG	Part 2: at Baseline and 90 min after infusion

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Mirjam Christ-Crain, Prof. Dr. med., University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2024
• Primary Completion (Actual): July 22, 2025
• Study Completion (Actual): July 22, 2025

Study Registration Dates

• First Submitted: July 26, 2024
• First Submitted That Met QC Criteria: August 2, 2024
• First Posted (Actual): August 7, 2024

Study Record Updates

• Last Update Posted (Actual): December 15, 2025
• Last Update Submitted That Met QC Criteria: December 8, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Copeptin; Mannitol; Hypertonic saline infusion
• 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; Physiological Effects of Drugs; Diuretics; Natriuretic Agents; Diuretics, Osmotic; Mannitol
• Other Study ID Numbers: 2024-01214; kt24ChristCrain

Drug and device information, study documents

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