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

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).

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.

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)