Effects of Empagliflozin an SGLT2-Inhibitor on Healthy Volunteers With Induced Hypotonic Hyponatremia - the DIVE Study (DIVE)

Empagliflozin (Jardiance)® is a sodium glucose co-transporter 2 (SGLT2)-Inhibitor, which is a new treatment option developed for patients with diabetes mellitus type 2. The SGLT2 is expressed in the proximal tubule and reabsorbs approximately 90 percent of the filtered glucose. The inhibition of SGLT2 results in renal excretion of glucose with subsequent osmotic diuresis. This mechanism could result in a therapeutic effect in patients with hypotonic hyponatremia as in the syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIAD). Because patients with SIAD usually have several comorbidities and different medications, studies investigating the physiological effects are difficult to interpret. Therefore a model to study the possible physiological effect of SGLT2-inhibitors in hypotonic hyponatremia as in SIAD is needed.

The aim of this study is to evaluate whether empagliflozin (Jardiance)® has an effect on serum sodium levels of healthy volunteers with induced hypotonic hyponatremia.

Study Overview

• Status: Completed
• Conditions: Inappropriate ADH Syndrome
• Intervention / Treatment: Other: Induced hypotonic hyponatremia - SIAD model; Drug: Empagliflozin 25mg Tbl; Drug: Placebo P-Tablet

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • Department Endocrinology University Hospital Basel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Informed consent as documented by signature
• Age 18 to 65 years
• serum sodium level 135-145mmol/l
• clinically euvolemic status

Exclusion Criteria:

• Known or suspected allergy to trial product or related products
• Pregnancy or breast feeding
• Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant
• Participation in another study with investigational drug within the 30 days preceding and during the present study
• Enrolment of the investigator, his/her family members, employees and other dependent persons
• untreated hypothyroidism
• cortisol deficiency
• history of heart failure
• liver cirrhosis at any stage
• kidney disease (GFR <60ml/min)
• epileptic seizures within the last year
• uncontrolled hypertension (systolic blood pressure >160mmHg)
• Diabetes mellitus type 1 or 2
• BMI <18 or >29kg/m2
• other severe disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Empagliflozin 25mg Tbl; Induced hypotonic hyponatremia - SIAD model: Hypotonic hyponatremia will be induced in healthy volunteers through oral overhydration and parenteral administration of desmopressin (Minirin)® 4ug. After administration of the study drug, the artificial SIAD will be sustained with infusion of hypotonic sodium-solution (NaCl 0.45%) over two hours.	Other: Induced hypotonic hyponatremia - SIAD model; Other Names: Induced hypotonic hyponatremia; Drug: Empagliflozin 25mg Tbl
Placebo Comparator: Placebo P-Tablet; Induced hypotonic hyponatremia - SIAD model: Hypotonic hyponatremia will be induced in healthy volunteers through oral overhydration and parenteral administration of desmopressin (Minirin)® 4ug. After administration of the study drug, the artificial SIAD will be sustained with infusion of hypotonic sodium-solution (NaCl 0.45%) over two hours.	Other: Induced hypotonic hyponatremia - SIAD model; Other Names: Induced hypotonic hyponatremia; Drug: Placebo P-Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary outcome is the area under the curve (AUC) of the serum sodium concentration between time points 2 and 8 hours after administration of the study drug.	concentration measured every hour within 8 hours after drug administration on both study days

Secondary Outcome Measures

Outcome Measure	Time Frame
Serum sodium concentration at every time point of the study	every hour for twelve hours on each of the two study days
Amount of urinary excretion	every 2 hours for twelve hours on each of the two study days
Serum osmolality at every time point of the study	every hour for twelve hours on each of the two study days
Serum glucose at every time point of the study	every hour for twelve hours on each of the two study days
Urinary osmolality	every two hours for twelve hours on each of the two study days
Urinary glucose	every 2 hours for twelve hours on each of the two study days
Serum electrolytes at time point -1, 0, 2 and 8	1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day
Urinary electrolytes at time point -1, 0, 2 and 8	1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day
Plasma level of Copeptin at time point -1, 0, 2 and 8	1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day
Plasma level of Aldosterone at time point -1, 0, 2 and 8	1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day
Plasma level of Renin at time point -1, 0, 2 and 8	1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day
Plasma Level of atrial natriuretic peptide (ANP) at time point -1, 0, 2 and 8	1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day
Plasma levels of brain natriuretic peptide (BNP) at time point -1, 0, 2 and 8	1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day
Body weight at every time point of the study	every hour during 12 hours on each of the two study days
Blood pressure at every time point of the study	every hour during 12 hours on each of the two study days
Heart rate at every time point of the study	every hour during 12 hours on each of the two study days
Symptoms of hyponatremia assessed by visual analogue scale (VAS) at every time point of the study	every hour during 12 hours on each of the two study days
Urinary sodium level	every 2 hours for twelve hours on each of the two study days

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Mirjam Christ-Crain, Prof., Deputy chief division endocrinology university hospital basel

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: March 24, 2016
• First Submitted That Met QC Criteria: March 31, 2016
• First Posted (Estimate): April 6, 2016

Study Record Updates

• Last Update Posted (Estimate): August 10, 2016
• Last Update Submitted That Met QC Criteria: August 9, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Hyponatremia; SGLT2 inhibitor
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Hypothalamic Diseases; Pituitary Diseases; Water-Electrolyte Imbalance; Hyponatremia; Inappropriate ADH Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 2015-00024