Trial to Assess the Efficacy of EMPAgliflozin and Personalized Dietary Counseling for Kidney STONE Prevention (EMPASTONE)

Randomized Placebo-controlled Trial to Assess Efficacies of EMPAgliflozin and Personalized Dietary Counselling for Kidney STONE Prevention in Patients With Calcium Kidney Stones Acronym: EMPASTONE Trial

The aim of this randomized trial with a 2-by-2 factorial design is to test the efficacy of the SGLT2 inhibitor empagliflozin and personalized dietary counseling based on 24-hr urine collection results and dietary assessments for kidney stone recurrence prevention in patients with calcium kidney stones.

Study interventions:

• Empagliflozin 10 mg once daily per os for 36 months
• Personalized dietary counseling for 36 months.

Control interventions:

• Placebo once daily per os for 36 months
• Generic dietary counseling for 36 months.

Study Overview

• Status: Not yet recruiting
• Conditions: Nephrolithiasis; Kidney Stone; Dietary Exposure
• Intervention / Treatment: Behavioral: Personalized dietary counseling; Drug: Placebo; Behavioral: Generic dietary counseling; Drug: Empagliflozin 10 MG

Detailed Description

Background and rationale:

Nephrolithiasis is a highly prevalent kidney disorder causing substantial morbidity, reduced quality of life and enormous healthcare expenditures worldwide, in large part related to their frequent recurrence. Existing pharmacological strategies for recurrence prevention are limited, and non-pharmacological measures, predominantly dietary counseling practices, vary widely. In observational studies and post-hoc analyses of cardiovascular outcome trials, Sodium-Glucose Co-Transporter 2 inhibitor (SGLT2i) use was associated with a 26-49 % reduction in kidney stone events in patients with type 2 diabetes. In our recent randomized phase 2 SWEETSTONE trial (NCT04911660), the SGLT2i empagliflozin reduced the urinary relative supersaturation ratio for calcium phosphate by 36 % compared to placebo in non-diabetic patients with idiopathic calcium kidney stones, by far the most common kidney stone type. The therapeutic value of SGLT2is in prevention of kidney stone recurrence is unknown, and the optimal dietary counseling approach for patients with kidney stones is undefined.

Objectives:

The primary objective of the study is to assess the efficacy of empagliflozin and a personalized dietary counseling strategy in the secondary prevention of calcium kidney stones, assessed as radiologic stone recurrence at 3 years.

The secondary objectives of the study are to assess the effect of the interventions (empagliflozin versus placebo and personalized versus generic dietary counseling) on both the recurrence and cumulative number of symptomatic kidney stones within 3 years.

Methodology:

The investigators will include 400adult (≥ 18 years) patients with recurrent (≥ 2 kidney stone episodes in the last 10 years) calcium kidney stones (containing 50% or more of calcium oxalate, calcium phosphate or a mixture of both). Patients with known secondary causes of kidney stones will be excluded. In this randomized trial with a 2-by-2 factorial design, patients will be allocated to either empagliflozin 10mg or placebo once daily, and to either personalized or generic dietary counselling according to 24-hr urine results. Randomization will be stratified according to the number of kidney stone episodes during the 10 years before enrolment.

The primary endpoint will be radiologic kidney stone recurrence (a composite of stone growth or new stones formed assessed by computed tomography) at 3 years. Secondary endpoints will be symptomatic kidney stone recurrence up to 3 years, and the number of symptomatic recurrences over 3 years. Exploratory endpoints will be changes in blood and urine parameters, vital signs and weight; asymptomatic kidney stone passage; patient-reported pain and quality of life; and kidney stone event-related health care utilization and cost. Safety endpoints assessed will be the frequency of serious adverse events and of pre-defined adverse events of special interest.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Daniel G Fuster, Prof MD; Phone Number: +41 31 632 31 44; Email: daniel.fuster@unibe.ch

Study Locations

• France
  • Amiens, France, 80054
    • University Hospital Amiens-Picardie
    • Contact: Dominique Eladari; Phone Number: +33322667832; Email: dominique.eladari@inserm.fr
  • Paris, France, 75020
    • Hopital Tenon
    • Contact: Emmanuel Letavernier; Phone Number: +33156016774; Email: emmanuel.letavernier@aphp.fr
  • Paris, France, 75908
    • Hôpital Européen Georges Pompidou
    • Contact: Marie Courbebaisse; Phone Number: +33 1 56 09 56 25; Email: marie.courbebaisse@aphp.fr
• Germany
  • Berlin, Germany, 10117
    • Charité University Medicine Berlin
    • Contact: Jan Halbritter; Phone Number: +4930450530405; Email: jan.halbritter@charite.de
• Italy
  • Naples, Italy, 80131
    • Università della Campania "Luigi Vanvitelli"
    • Contact: Giovanna Capolongo; Phone Number: +39 388 730 43 78; Email: giovanna.capolongo@unicampania.it
  • Verona, Italy, 37134
    • Verona University Hospital
    • Contact: Pietro Manuel Ferraro; Phone Number: +390458124652; Email: pietromanuel.ferraro@univr.it
• Switzerland
  • Aarau, Switzerland, 5001
    • Kantonsspital Aarau
    • Contact: Stephan Segerer; Phone Number: +41628389574; Email: Stephan.segerer@ksa.ch
  • Baden, Switzerland, 5404
    • Kantonsspital Baden
    • Contact: Harald Seeger; Phone Number: +41564862707; Email: harald.seeger@ksb.ch
  • Basel, Switzerland, 4031
    • University Hospital Basel
    • Contact: Patrizia Amico; Phone Number: +41 61 265 44 07; Email: patrizia.amico@usb.ch
  • Bern, Switzerland, 3010
    • Inselspital Bern
    • Contact: Daniel Fuster; Phone Number: ++416323144; Email: daniel.fuster@unibe.ch
  • Chur, Switzerland, 7000
    • Kantonsspital Chur
    • Contact: Reto Venzin; Phone Number: +4 812566868; Email: reto.venzin@ksgr.ch
  • Fribourg, Switzerland, 1708
    • Kantonsspital Fribourg
    • Contact: Olivier Bonny; Phone Number: +41263062190; Email: olivier.bonny@h-fr.ch
  • Geneva, Switzerland, 1211
    • University Hospital Geneva (HUG)
    • Contact: Sophie De Seigneux; Phone Number: +41795533220; Email: sophie.deseigneux@hug.ch
  • Lausanne, Switzerland, 1011
    • Lausanne University Hospital (CHUV)
    • Contact: Nora Schwotzer; Phone Number: +41213141131; Email: nora.schwotzer@chuv.ch
  • Lucerne, Switzerland, 6016
    • Kantonsspital Luzern
    • Contact: Urs Odermatt; Phone Number: +41412055150; Email: urs.odermatt@luks.ch
  • Lugano, Switzerland, 6900
    • Regionalspital Lugano
    • Contact: Antonio Bellasi; Phone Number: +41918116166; Email: Antonio.Bellasi@eoc.ch
  • Neuchâtel, Switzerland, 2000
    • Kantonsspital Neuchâtel
    • Contact: Fabien Stucker; Phone Number: +41327133669; Email: fabien.stucker@rhne.ch
  • Olten, Switzerland, 4600
    • Kantonsspital Olten
    • Contact: Stefan Forster; Phone Number: +41326273121; Email: stefan.forster@spital.so.ch
  • Sankt Gallen, Switzerland, 9007
    • Kantonsspital St. Gallen
    • Contact: Alexander Ritter; Phone Number: +41714941244; Email: alexander.ritter@kssg.ch
  • Sion, Switzerland, 1950
    • Kantonsspital Sion
    • Contact: Daniel Teta; Phone Number: +41276034550; Email: daniel.teta@hopitalvs.ch
  • Zurich, Switzerland, 8091
    • Universitatsspital Zurich
    • Contact: Dusan Harmacek; Phone Number: +41442553384; Email: dusan.harmacek@usz.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. Written, informed consent.
2. Age 18 years or older.
3. Recurrent kidney stone disease with 2 or more stone episodes in the last 10 years prior to randomization.
4. Last kidney stone containing 50% or more of CaOx, CaP or a mixture of both.
5. If taking guideline-recommended medications for kidney stone prophylaxis (e.g. citrate salts), patients must have been on a stable regimen for at least 60 days before randomization and willing to remain on this stable regimen for the duration of the study.

Exclusion criteria:

1. Known history of secondary or Mendelian causes of calcium nephrolithiasis
2. Type I diabetes mellitus
3. History of ketoacidosis
4. Chronic Kidney Disease (CKD) stage 4 or 5 (defined as CKD-EPI eGFR <30 mL/min)
5. Kidney transplant recipient
6. History of recurrent urinary tract infections, defined as >3 episodes within the year prior to randomization
7. Heart failure. Symptomatic patients with suspected heart failure must be evaluated before study enrollment
8. Treatment with an SGLT2i within 4 weeks prior to randomization.
9. Active cancer treatment
10. Pregnancy and/or breastfeeding. Women of childbearing potential (i.e., premenopausal women who have not undergone surgical sterilization and are sexually active with a male partner) must have a negative urine or blood pregnancy test prior to enrollment
11. Known allergy to the study drug
12. Inability to understand and follow the study procedures
13. Vulnerable individual, e.g. individual incapable of judgement or currently incarcerated or otherwise institutionalized (priosner), or refugee
14. Concomitant participation in another interventional clinical trial within 4 weeks prior to randomization and during the current trial
15. Prior enrollment in the EMPASTONE trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo and personalized dietary counseling; Placebo once daily per os and personalized dietary counseling for 3 years	Behavioral: Personalized dietary counseling; Personalized dietary counseling based on repeat 24-hr urine collections and dietary assessments for 3 years; Drug: Placebo; Once daily per os for 3 years
Placebo Comparator: Placebo and generic dietary counseling; Placebo once daily per os and generic dietary counseling for 3 years	Drug: Placebo; Once daily per os for 3 years; Behavioral: Generic dietary counseling; Generic dietary counseling based on current guidelines without 24-hr urine collection results and without specific dietary assessments for 3 years
Experimental: Empagliflozin and personalized dietary counseling; Empagliflozin 10 mg once daily per os and personalized dietary counseling for 3 years	Behavioral: Personalized dietary counseling; Personalized dietary counseling based on repeat 24-hr urine collections and dietary assessments for 3 years; Drug: Empagliflozin 10 MG; Once daily per os for 3 years
Experimental: Empagliflozin and generic dietary counseling; Empagliflozin 10 mg once daily per os and generic dietary counseling for 3 years	Behavioral: Generic dietary counseling; Generic dietary counseling based on current guidelines without 24-hr urine collection results and without specific dietary assessments for 3 years; Drug: Empagliflozin 10 MG; Once daily per os for 3 years

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with radiologic stone recurrence	Radiological stone recurrence is defined as a new stone formed or enlargement of a preexisting stone (assessed by low-dose CT of the kidney at the end of the study compared to the low-dose CT of the kidney at the baseline visit).	After 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to symptomatic kidney stone recurrence up to 3 years (time-to-event)	Symptomatic recurrence is defined as the visible passage of a stone with or without accompanying typical symptoms (such as flank or loin pain and hematuria) or as the presence of a symptomatic or asymptomatic stone that was determined to require surgical removal.	From enrollment to the end of treatment at 3 years
Number of symptomatic stone recurrences per patient (cumulative)	Symptomatic recurrence is defined as the visible passage of a stone with or without accompanying typical symptoms (such as flank or loin pain and hematuria) or as the presence of a symptomatic or asymptomatic stone that was determined to require surgical removal.	From enrollment to the end of treatment at 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in blood parameters	Blood parameters will be measured at screening, Month 3, Year 1, Year 2 and Year 3.	From enrollment to the end of treatment at 3 years
Changes in urine parameters	24-hr urine analyses will be done at screening, Month 3, Year 1, Year 2 and Year 3. Note: results of 24-hr urine analyses will be blinded until the end of the study in patients randomized to generic dietary counselling.	From enrollment to the end of treatment at 3 years
Changes in blood pressure	Blood pressure measurements will be done at screening, Month 3, Year 1, Year 2 and Year 3.	From enrollment to the end of treatment at 3 years
Patient-reported kidney stone-related quality of life	Patient-reported kidney stone-related quality of life will be assessed by the Wisconsin Stone-Quality of Life (WSQoL) questionnaire at baseline, Month 3, Year 1, Year 2 and Year 3. Higher scores indicate better quality of life.	From enrollment to the end of treatment at 3 years
Patient-reported health-related quality of life (HRQoL)	Patient-reported HRQoL will be assessed by using the short form-36 version 2 (SF-36v2) questionnaire at baseline, Month 3, Year 1, Year 2 and Year 3. Higher scores indicate higher HRQoL.	From enrollment to the end of treatment at 3 years
Number of patients with asymptomatic kidney stone passage	Asymptomatic passage is defined as a stone present on the baseline CT but not on the end of study CT without causing any symptoms in the patient.	At 3 years
Kidney stone-related cost	Total kidney stone-related cost (direct and indirect).	From enrollment to the end of treatment at 3 years
Changes in weight	Weight, will be measured at screening, Month 3, Year 1, Year 2 and Year 3.	From enrollment to the end of treatment at 3 years
Changes in hip and waist circumference	Hip and waist circumference will be measured at screening, Month 3, Year 1, Year 2 and Year 3	From enrollment to the end of treatment at 3 years
Kidney stone-related health care utilization	Data on health care visits, hospitalizations, and surgical interventions in relation to kidney stone disease	From enrollment to the end of treatment at 3 years
Changes in bone mineral density	Changes in NCCT-based bone mineral density measured at lumbar vertebrae	From enrollment to end of treatment at 3 years
Changes in aortic artery calcification	Changes in NCCT-based aortic artery calcification by the Agaston method	From enrollment to end of treatment at 3 years
Changes in adipose tissue	Changes in NCCT-based visceral, subcutaneous and total adipose tissue (VAT/TAT and VAT/TAT ratios)	From enrollment to end of treatment at 3 years

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Investigators: Principal Investigator: Daniel Fuster, Inselspital, Bern University Hospital

Publications and helpful links

General Publications

• Schietzel S, Bally L, Cereghetti G, Faller N, Moor MB, Vogt B, Rintelen F, Trelle S, Fuster D. Impact of the SGLT2 inhibitor empagliflozin on urinary supersaturations in kidney stone formers (SWEETSTONE trial): protocol for a randomised, double-blind, placebo-controlled cross-over trial. BMJ Open. 2022 Mar 14;12(3):e059073. doi: 10.1136/bmjopen-2021-059073.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): September 1, 2030
• Study Completion (Estimated): September 1, 2030

Study Registration Dates

• First Submitted: October 21, 2024
• First Submitted That Met QC Criteria: October 21, 2024
• First Posted (Actual): October 22, 2024

Study Record Updates

• Last Update Posted (Actual): May 27, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Calculi; Pathological Conditions, Anatomical; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urolithiasis; Urinary Calculi; Pathological Conditions, Signs and Symptoms; Kidney Calculi; Nephrolithiasis; Sodium-Glucose Transporter 2 Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; empagliflozin
• Other Study ID Numbers: EMPASTONE Trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Once results have been published, trial data will be accessible to external researchers and coded datasets corresponding to each publication will be made available. Investigators wishing to replicate the analyses or to do an individual patient meta-analysis may request the data to the Sponsor-Investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No