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

Primary Purpose

SIAD - Syndrome of Inappropriate Antidiuresis, Hyponatremia

Status
Completed
Phase
Phase 2
Locations
Switzerland
Study Type
Interventional
Intervention
Empagliflozin 25mg
Placebo
Sponsored by
University Hospital, Basel, Switzerland
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for SIAD - Syndrome of Inappropriate Antidiuresis focused on measuring SGLT2-inhibitor, Treatment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • University Hospital Basel

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Empagliflozin

Placebo

Arm Description

Treatment with empagliflozin 25mg tablets once daily for 28 days

Treatment with Placebo tablets once daily for 28 days

Outcomes

Primary Outcome Measures

Change in Serum Sodium concentration
Difference in serum sodium concentration in mmol/l after 28 days of treatment

Secondary Outcome Measures

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

Full Information

First Posted
June 27, 2017
Last Updated
December 10, 2021
Sponsor
University Hospital, Basel, Switzerland
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1. Study Identification

Unique Protocol Identification Number
NCT03202667
Brief Title
Effects of the SGLT2-inhibitor Empagliflozin on Patients With Chronic SIADH - the SANDx Study
Acronym
SANDx
Official Title
Effects of the SGLT2-inhibitor Empagliflozin on Patients With Chronic SIADH - the SANDx Study
Study Type
Interventional

2. Study Status

Record Verification Date
December 2021
Overall Recruitment Status
Completed
Study Start Date
December 15, 2017 (Actual)
Primary Completion Date
August 26, 2021 (Actual)
Study Completion Date
December 6, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Basel, Switzerland

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
SIAD - Syndrome of Inappropriate Antidiuresis, Hyponatremia
Keywords
SGLT2-inhibitor, Treatment

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
17 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Empagliflozin
Arm Type
Active Comparator
Arm Description
Treatment with empagliflozin 25mg tablets once daily for 28 days
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Treatment with Placebo tablets once daily for 28 days
Intervention Type
Drug
Intervention Name(s)
Empagliflozin 25mg
Intervention Description
Treatment with empagliflozin 25mg once daily for 28 days
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Treatment with Placebo oral tablet once daily for 28 days
Primary Outcome Measure Information:
Title
Change in Serum Sodium concentration
Description
Difference in serum sodium concentration in mmol/l after 28 days of treatment
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Change in Serum sodium concentration
Description
Serum sodium concentration 1, 2 and 3 weeks of treatment
Time Frame
21 days
Title
Change in Serum electrolytes
Description
Serum electrolytes after 1, 2, 3 and 4 weeks of treatment
Time Frame
28 days
Title
Urinary electrolytes
Description
Urinary electrolytes after 1 week of treatment
Time Frame
7 days
Title
Urinary electrolytes
Description
Urinary electrolytes after 2 weeks of treatment
Time Frame
14 days
Title
Urinary electrolytes
Description
Urinary electrolytes after 3 weeks of treatment
Time Frame
21 days
Title
Urinary electrolytes
Description
Urinary electrolytes after 4 weeks of treatment
Time Frame
28 days
Title
Serum osmolality
Description
Serum osmolality after 1 week of treatment
Time Frame
7 days
Title
Serum osmolality
Description
Serum osmolality after 2 weeks of treatment
Time Frame
14 days
Title
Serum osmolality
Description
Serum osmolality after 3 weeks of treatment
Time Frame
21 days
Title
Serum osmolality
Description
Serum osmolality after 4 weeks of treatment
Time Frame
28 days
Title
Urinary osmolality
Description
Urinary osmolality after 1 week of treatment
Time Frame
7 days
Title
Urinary osmolality
Description
Urinary osmolality after 2 weeks of treatment
Time Frame
14 days
Title
Urinary osmolality
Description
Urinary osmolality after3 weeks of treatment
Time Frame
21 days
Title
Urinary osmolality
Description
Urinary osmolality after 4 weeks of treatment
Time Frame
28 days
Title
Serum glucose
Description
Serum glucose after 1 week of treatment
Time Frame
7 days
Title
Serum glucose
Description
Serum glucose after 2 weeks of treatment
Time Frame
14 days
Title
Serum glucose
Description
Serum glucose after 3 weeks of treatment
Time Frame
21 days
Title
Serum glucose
Description
Serum glucose after 4 weeks of treatment
Time Frame
28 days
Title
Urinary glucose
Description
Urinary glucose after 1 week of treatment
Time Frame
7 days
Title
Urinary glucose
Description
Urinary glucose after 2 weeks of treatment
Time Frame
14 days
Title
Urinary glucose
Description
Urinary glucose after 3 weeks of treatment
Time Frame
21 days
Title
Urinary glucose
Description
Urinary glucose after 4 weeks of treatment
Time Frame
28 days
Title
Copeptin
Description
Plasma copeptin after 1 week of treatment
Time Frame
7 days
Title
Copeptin
Description
Plasma copeptin after 2 weeks of treatment
Time Frame
14 days
Title
Copeptin
Description
Plasma copeptin after3 weeks of treatment
Time Frame
21 days
Title
Copeptin
Description
Plasma copeptin after 4 weeks of treatment
Time Frame
28 days
Title
Aldosterone
Description
Plasma aldosterone after 1 week of treatment
Time Frame
7 days
Title
Aldosterone
Description
Plasma aldosterone after 2 weeks of treatment
Time Frame
14 days
Title
Aldosterone
Description
Plasma aldosterone after 3 weeks of treatment
Time Frame
21 days
Title
Aldosterone
Description
Plasma aldosterone after 4 weeks of treatment
Time Frame
28 days
Title
Renin
Description
Plasma renin after 1 week of treatment
Time Frame
7 days
Title
Renin
Description
Plasma renin after 2 weeks of treatment
Time Frame
14 days
Title
Renin
Description
Plasma renin after 3 weeks of treatment
Time Frame
21 days
Title
Renin
Description
Plasma renin after 4 weeks of treatment
Time Frame
28 days
Title
MR-proANP
Description
Plasma MR-proANP after 1 week of treatment
Time Frame
7 days
Title
MR-proANP
Description
Plasma MR-proANP after 2 weeks of treatment
Time Frame
14 days
Title
MR-proANP
Description
Plasma MR-proANP after 3 weeks of treatment
Time Frame
21 days
Title
MR-proANP
Description
Plasma MR-proANP after 4 weeks of treatment
Time Frame
28 days
Title
N terminal (NT)-proBNP
Description
Plasma NT-proBNP after 1 week of treatment
Time Frame
7 days
Title
NT-proBNP
Description
Plasma NT-proBNP after 2 weeks of treatment
Time Frame
14 days
Title
NT-proBNP
Description
Plasma NT-proBNP after 3 weeks of treatment
Time Frame
21 days
Title
NT-proBNP
Description
Plasma NT-proBNP after 4 weeks of treatment
Time Frame
28 days
Title
P1NP
Description
Plasma P1NP after 1 week of treatment
Time Frame
7 days
Title
P1NP
Description
Plasma P1NP after 2 weeks of treatment
Time Frame
14 days
Title
P1NP
Description
Plasma P1NP after 3 weeks of treatment
Time Frame
21 days
Title
P1NP
Description
Plasma P1NP after 4 weeks of treatment
Time Frame
28 days
Title
CTx
Description
Plasma CTx after 1 week of treatment
Time Frame
7 days
Title
CTx
Description
Plasma CTx after 2 weeks of treatment
Time Frame
14 days
Title
CTx
Description
Plasma CTx after 3 weeks of treatment
Time Frame
21 days
Title
CTx
Description
Plasma CTx after 4 weeks of treatment
Time Frame
28 days
Title
Osteocalcin
Description
Plasma Osteocalcin after 1 week of treatment
Time Frame
7 days
Title
Osteocalcin
Description
Plasma Osteocalcin after 2 weeks of treatment
Time Frame
14 days
Title
Osteocalcin
Description
Plasma Osteocalcin after 3 weeks of treatment
Time Frame
21 days
Title
Osteocalcin
Description
Plasma Osteocalcin after 4 weeks of treatment
Time Frame
28 days
Title
General well being (assessed by VAS)
Description
General well being after 1, 2, 3 and 4 weeks of treatment
Time Frame
28 days
Title
Headache (assessed by VAS)
Description
Headache after 1, 2, 3 and 4 weeks of treatment
Time Frame
28 days
Title
Vertigo (assessed by VAS)
Description
vertigo after 1, 2, 3 and 4 weeks of treatment
Time Frame
28 days
Title
Nausea (assessed by VAS)
Description
Nausea after 1, 2, 3 and 4 weeks of treatment
Time Frame
28 days
Title
Malaise (assessed by VAS)
Description
Malaise after 1, 2, 3 and 4 weeks of treatment
Time Frame
28 days
Title
Body weight (kg)
Description
Body weight after 1, 2, 3 and 4 weeks of treatment
Time Frame
28 days
Title
Blood pressure (mmHg)
Description
Blood pressure after 1, 2, 3 and 4 weeks of treatment
Time Frame
28 days
Title
Heart rate (bpm)
Description
Heart rate after 1, 2, 3 and 4 weeks of treatment
Time Frame
28 days
Title
Neurocognitive function (assessed by MOCA)
Description
change in Neurocognitive function (baseline versus after 4 weeks of Treatment)
Time Frame
28 days
Title
Muscle strength (measured by grip strength test)
Description
Change in Muscle strength (baseline vs after 4 weeks of Treatment)
Time Frame
28 days
Title
Gait Dynamics (measured by gait Analysis)
Description
Gait dynamics baseline vs after 4 weeks of treatment
Time Frame
28 days
Title
Hemodynamic Parameters (measured by thoracic electrical bioimpedance)
Description
Hemodynamic parameters baseline vs after 4 weeks of treatment
Time Frame
28 days
Title
Body fluid volume (measured by bioimpedance spectroscopy)
Description
Body fluid volume baseline vs after 4 weeks of treatment
Time Frame
28 days
Title
Amount of Fluid intake in ml
Description
Fluid intake after 1, 2, 3 and 4 weeks of treatment
Time Frame
28 days
Title
Number of Falls
Description
Rate of falls during observation phase
Time Frame
30 days
Title
number of Fractures
Description
Rate of fractures during observation phase
Time Frame
30 days
Title
number of Hospital admissions
Description
Rate of Hospital admissions during observation phase
Time Frame
30 days
Title
Hyponatremia recurrence
Description
Rate of hyponatremia recurrence during 30day follow up
Time Frame
30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mirjam Christ-Crain, Prof. Dr. MD
Organizational Affiliation
University Hopsital Basel
Official's Role
Study Director
Facility Information:
Facility Name
University Hospital Basel
City
Basel
ZIP/Postal Code
4031
Country
Switzerland

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
36396331
Citation
Refardt J, Imber C, Nobbenhuis R, Sailer CO, Haslbauer A, Monnerat S, Bathelt C, Vogt DR, Berres M, Winzeler B, Bridenbaugh SA, Christ-Crain M. Treatment Effect of the SGLT2 Inhibitor Empagliflozin on Chronic Syndrome of Inappropriate Antidiuresis: Results of a Randomized, Double-Blind, Placebo-Controlled, Crossover Trial. J Am Soc Nephrol. 2023 Feb 1;34(2):322-332. doi: 10.1681/ASN.2022050623. Epub 2022 Nov 17.
Results Reference
derived

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

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