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

• ClinicalTrials.gov Identifier: NCT02729766
• Recruitment Status: Completed
• First Posted: April 6, 2016
• Last Update Posted: August 10, 2016
• Sponsor: University Hospital, Basel, Switzerland
• Information provided by (Responsible Party): University Hospital, Basel, Switzerland

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Inappropriate ADH Syndrome	Other: Induced hypotonic hyponatremia - SIAD model; Drug: Empagliflozin 25mg Tbl; Drug: Placebo P-Tablet	Phase 2; Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of Empagliflozin an SGLT2-Inhibitor on Healthy Volunteers With Induced Hypotonic Hyponatremia - the DIVE Study
• Study Start Date: March 2016
• Actual Primary Completion Date: July 2016
• Actual Study Completion Date: August 2016

Arms and Interventions

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 Name: 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 Name: Induced hypotonic hyponatremia; Drug: Placebo P-Tablet

Outcome Measures

Primary Outcome Measures :

1. 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. [ Time Frame: concentration measured every hour within 8 hours after drug administration on both study days ]

Secondary Outcome Measures :

1. Serum sodium concentration at every time point of the study [ Time Frame: every hour for twelve hours on each of the two study days ]
2. Amount of urinary excretion [ Time Frame: every 2 hours for twelve hours on each of the two study days ]
3. Serum osmolality at every time point of the study [ Time Frame: every hour for twelve hours on each of the two study days ]
4. Serum glucose at every time point of the study [ Time Frame: every hour for twelve hours on each of the two study days ]
5. Urinary osmolality [ Time Frame: every two hours for twelve hours on each of the two study days ]
6. Urinary glucose [ Time Frame: every 2 hours for twelve hours on each of the two study days ]
7. Serum electrolytes at time point -1, 0, 2 and 8 [ Time Frame: 1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day ]
8. Urinary electrolytes at time point -1, 0, 2 and 8 [ Time Frame: 1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day ]
9. Plasma level of Copeptin at time point -1, 0, 2 and 8 [ Time Frame: 1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day ]
10. Plasma level of Aldosterone at time point -1, 0, 2 and 8 [ Time Frame: 1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day ]
11. Plasma level of Renin at time point -1, 0, 2 and 8 [ Time Frame: 1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day ]
12. Plasma Level of atrial natriuretic peptide (ANP) at time point -1, 0, 2 and 8 [ Time Frame: 1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day ]
13. Plasma levels of brain natriuretic peptide (BNP) at time point -1, 0, 2 and 8 [ Time Frame: 1 hour before induction of siad, at baseline, 2 hours and 8 hours after administration of study medication on each study day ]
14. Body weight at every time point of the study [ Time Frame: every hour during 12 hours on each of the two study days ]
15. Blood pressure at every time point of the study [ Time Frame: every hour during 12 hours on each of the two study days ]
16. Heart rate at every time point of the study [ Time Frame: every hour during 12 hours on each of the two study days ]
17. Symptoms of hyponatremia assessed by visual analogue scale (VAS) at every time point of the study [ Time Frame: every hour during 12 hours on each of the two study days ]
18. Urinary sodium level [ Time Frame: every 2 hours for twelve hours on each of the two study days ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

Switzerland

Department Endocrinology University Hospital Basel

Basel, Switzerland, 4031

Sponsors and Collaborators

University Hospital, Basel, Switzerland

Investigators

• Principal Investigator: Mirjam Christ-Crain, Prof.; Deputy chief division endocrinology university hospital basel

More Information

• Responsible Party: University Hospital, Basel, Switzerland
• ClinicalTrials.gov Identifier: NCT02729766
• Other Study ID Numbers: 2015-00024
• First Posted: April 6, 2016
• Last Update Posted: August 10, 2016
• Last Verified: August 2016

Keywords provided by University Hospital, Basel, Switzerland:

Hyponatremia; SGLT2 inhibitor

Additional relevant MeSH terms:

Inappropriate ADH Syndrome; Hyponatremia; Water-Electrolyte Imbalance; Metabolic Diseases; Pituitary Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Empagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Physiological Effects of Drugs