Effects of the SGLT2-inhibitor Empagliflozin on Patients With Chronic SIADH - the SANDx Study

Study Overview
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Brief Summary
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Syndrome of inappropriate antidiuresis (SIADH) is characterized by an imbalance of antidiuretic vasopressin (AVP) secretion. The impaired AVP regulation leads to water retention and secondary natriuresis and is a common cause for hyponatremia. Especially chronic (>72h) SIADH is difficult to treat as standard therapeutic options (water restriction, urea, salt tablets) often do not succeed in correction of hyponatremia, making additional therapy necessary. Empagliflozin is a sodium glucose co-transporter 2 (SGLT2)-inhibitor, which is a well-tolerated treatment option for type 2 diabetes mellitus. The inhibition of SGLT2 in the proximal tubule leads to renal excretion of glucose with subsequent osmotic diuresis. This mechanism could result in a therapeutic effect in patients with chronic SIADH, as it resembles the aquaretic effect of urea. The aim of this study is to evaluate whether empagliflozin has an effect on the serum sodium levels of patients with chronic SIADH.

Official Title
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Effects of the SGLT2-inhibitor Empagliflozin on Patients With Chronic SIADH - the SANDx Study

Conditions
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SIAD - Syndrome of Inappropriate Antidiuresis, Hyponatremia

Intervention / Treatment
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* Drug: Empagliflozin 25mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (age ≥ 18 years) with hyponatremia (<133mmol/l) due to chronic (>72h) SIADH defined as serum osmolality <275mosm/kg urine osmolality >100mosm/kg urine sodium >30mmol/l Exclusion Criteria: acute (<72h) or transient hyponatremia severe symptomatic hyponatremia in need of hospital treatment diabetes mellitus type 1 uncontrolled hypothyroidism uncontrolled adrenal insufficiency renal impairment (GFR <45ml/min) cardiac failure symptomatic liver disease / severe hepatic impairment (ALAT / aspartate transaminase (ASAT) > 3x upper limit) treatment with SGLT 2 inhibitors, lithium chloride, urea or glitazone severe immunosuppression pregnancy or breastfeeding palliative situation (end of life care)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Empagliflozin<br>Treatment with empagliflozin 25mg tablets once daily for 28 days | Drug: Empagliflozin 25mg<br>* Treatment with empagliflozin 25mg once daily for 28 days<br>|
| Placebo Comparator: Placebo<br>Treatment with Placebo tablets once daily for 28 days | Drug: Placebo<br>* Treatment with Placebo oral tablet once daily for 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum Sodium concentration | Difference in serum sodium concentration in mmol/l after 28 days of treatment | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum sodium concentration | Serum sodium concentration 1, 2 and 3 weeks of treatment | 21 days | 
| Change in Serum electrolytes | Serum electrolytes after 1, 2, 3 and 4 weeks of treatment | 28 days | 
| Urinary electrolytes | Urinary electrolytes after 1 week of treatment | 7 days | 
| Urinary electrolytes | Urinary electrolytes after 2 weeks of treatment | 14 days | 
| Urinary electrolytes | Urinary electrolytes after 3 weeks of treatment | 21 days | 
| Urinary electrolytes | Urinary electrolytes after 4 weeks of treatment | 28 days | 
| Serum osmolality | Serum osmolality after 1 week of treatment | 7 days | 
| Serum osmolality | Serum osmolality after 2 weeks of treatment | 14 days | 
| Serum osmolality | Serum osmolality after 3 weeks of treatment | 21 days | 
| Serum osmolality | Serum osmolality after 4 weeks of treatment | 28 days | 
| Urinary osmolality | Urinary osmolality after 1 week of treatment | 7 days | 
| Urinary osmolality | Urinary osmolality after 2 weeks of treatment | 14 days | 
| Urinary osmolality | Urinary osmolality after3 weeks of treatment | 21 days | 
| Urinary osmolality | Urinary osmolality after 4 weeks of treatment | 28 days | 
| Serum glucose | Serum glucose after 1 week of treatment | 7 days | 
| Serum glucose | Serum glucose after 2 weeks of treatment | 14 days | 
| Serum glucose | Serum glucose after 3 weeks of treatment | 21 days | 
| Serum glucose | Serum glucose after 4 weeks of treatment | 28 days | 
| Urinary glucose | Urinary glucose after 1 week of treatment | 7 days | 
| Urinary glucose | Urinary glucose after 2 weeks of treatment | 14 days | 
| Urinary glucose | Urinary glucose after 3 weeks of treatment | 21 days | 
| Urinary glucose | Urinary glucose after 4 weeks of treatment | 28 days | 
| Copeptin | Plasma copeptin after 1 week of treatment | 7 days | 
| Copeptin | Plasma copeptin after 2 weeks of treatment | 14 days | 
| Copeptin | Plasma copeptin after3 weeks of treatment | 21 days | 
| Copeptin | Plasma copeptin after 4 weeks of treatment | 28 days | 
| Aldosterone | Plasma aldosterone after 1 week of treatment | 7 days | 
| Aldosterone | Plasma aldosterone after 2 weeks of treatment | 14 days | 
| Aldosterone | Plasma aldosterone after 3 weeks of treatment | 21 days | 
| Aldosterone | Plasma aldosterone after 4 weeks of treatment | 28 days | 
| Renin | Plasma renin after 1 week of treatment | 7 days | 
| Renin | Plasma renin after 2 weeks of treatment | 14 days | 
| Renin | Plasma renin after 3 weeks of treatment | 21 days | 
| Renin | Plasma renin after 4 weeks of treatment | 28 days | 
| MR-proANP | Plasma MR-proANP after 1 week of treatment | 7 days | 
| MR-proANP | Plasma MR-proANP after 2 weeks of treatment | 14 days | 
| MR-proANP | Plasma MR-proANP after 3 weeks of treatment | 21 days | 
| MR-proANP | Plasma MR-proANP after 4 weeks of treatment | 28 days | 
| N terminal (NT)-proBNP | Plasma NT-proBNP after 1 week of treatment | 7 days | 
| NT-proBNP | Plasma NT-proBNP after 2 weeks of treatment | 14 days | 
| NT-proBNP | Plasma NT-proBNP after 3 weeks of treatment | 21 days | 
| NT-proBNP | Plasma NT-proBNP after 4 weeks of treatment | 28 days | 
| P1NP | Plasma P1NP after 1 week of treatment | 7 days | 
| P1NP | Plasma P1NP after 2 weeks of treatment | 14 days | 
| P1NP | Plasma P1NP after 3 weeks of treatment | 21 days | 
| P1NP | Plasma P1NP after 4 weeks of treatment | 28 days | 
| CTx | Plasma CTx after 1 week of treatment | 7 days | 
| CTx | Plasma CTx after 2 weeks of treatment | 14 days | 
| CTx | Plasma CTx after 3 weeks of treatment | 21 days | 
| CTx | Plasma CTx after 4 weeks of treatment | 28 days | 
| Osteocalcin | Plasma Osteocalcin after 1 week of treatment | 7 days | 
| Osteocalcin | Plasma Osteocalcin after 2 weeks of treatment | 14 days | 
| Osteocalcin | Plasma Osteocalcin after 3 weeks of treatment | 21 days | 
| Osteocalcin | Plasma Osteocalcin after 4 weeks of treatment | 28 days | 
| General well being (assessed by VAS) | General well being after 1, 2, 3 and 4 weeks of treatment | 28 days | 
| Headache (assessed by VAS) | Headache after 1, 2, 3 and 4 weeks of treatment | 28 days | 
| Vertigo (assessed by VAS) | vertigo after 1, 2, 3 and 4 weeks of treatment | 28 days | 
| Nausea (assessed by VAS) | Nausea after 1, 2, 3 and 4 weeks of treatment | 28 days | 
| Malaise (assessed by VAS) | Malaise after 1, 2, 3 and 4 weeks of treatment | 28 days | 
| Body weight (kg) | Body weight after 1, 2, 3 and 4 weeks of treatment | 28 days | 
| Blood pressure (mmHg) | Blood pressure after 1, 2, 3 and 4 weeks of treatment | 28 days | 
| Heart rate (bpm) | Heart rate after 1, 2, 3 and 4 weeks of treatment | 28 days | 
| Neurocognitive function (assessed by MOCA) | change in Neurocognitive function (baseline versus after 4 weeks of Treatment) | 28 days | 
| Muscle strength (measured by grip strength test) | Change in Muscle strength (baseline vs after 4 weeks of Treatment) | 28 days | 
| Gait Dynamics (measured by gait Analysis) | Gait dynamics baseline vs after 4 weeks of treatment | 28 days | 
| Hemodynamic Parameters (measured by thoracic electrical bioimpedance) | Hemodynamic parameters baseline vs after 4 weeks of treatment | 28 days | 
| Body fluid volume (measured by bioimpedance spectroscopy) | Body fluid volume baseline vs after 4 weeks of treatment | 28 days | 
| Amount of Fluid intake in ml | Fluid intake after 1, 2, 3 and 4 weeks of treatment | 28 days | 
| Number of Falls | Rate of falls during observation phase | 30 days | 
| number of Fractures | Rate of fractures during observation phase | 30 days | 
| number of Hospital admissions | Rate of Hospital admissions during observation phase | 30 days | 
| Hyponatremia recurrence | Rate of hyponatremia recurrence during 30day follow up | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SGLT2-inhibitor, Treatment