Clinical trial NCT06653738: Trial to Assess the Efficacy of EMPAgliflozin and Personalized Dietary Counseling for Kidney STONE Prevention
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Kidney Stone
Nephrolithiasis
Dietary Exposure
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2024-10-22
Enrollment: 380
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Patients will be allocated to either empagliflozin 25 or placebo once daily, and to either personalized or generic dietary counseling (2x2 factorial design).
Primary purpose: PREVENTION

Brief summary: 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 25 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.

Detailed description: Background:

Nephrolithiasis is a highly prevalent kidney disorder that causes substantial morbidity, reduced quality of life and enormous healthcare expenditures worldwide. Kidney stones recur frequently, with 10-year recurrence rates of up to 80 %. Existing pharmacological strategies for the prevention of kidney stone recurrence are limited, and dietary counselling practices for patients with kidney stones vary widely. In observational studies and post-hoc analyses of cardiovascular outcome trials, sodium-glucose cotransporter 2 inhibitor (SGLT2i) use was associated with a reduction in kidney stone events in patients with type 2 diabetes. In the recent randomized phase 2 trial SWEETSTONE (NCT04911660), the SGLT2i empagliflozin significantly improved the urinary lithogenic risk profile compared to placebo in non-diabetic patients with calcium kidney stones, by far the most common kidney stone type.

Rationale:

The efficacy of SGLT2is in the prevention of kidney stone recurrence in patients with kidney stones is unknown. Furthermore, the optimal dietary counseling approach for individuals with kidney stones remains unclear.

Objective:

The investigators plan to conduct a 3-year multicentric, double-blind, placebo-controlled factorial trial to assess the efficacy of empagliflozin with either a personalized or generic dietary counselling strategy for recurrence prevention in patients with calcium kidney stones.

Methodology:

The investigators will include 380 adult (≥ 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 25 mg 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.

Eligibility criteria: Inclusion criteria:

1. Written, informed consent.
2. Age 18 years or older.
3. Recurrent kidney stone disease (2 or more stone episodes in the last 10 years).
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. Patients with a known history of secondary or Mendelian causes of calcium nephrolithiasis
2. Type I diabetes mellitus
3. History of ketoacidosis
4. Treatment with SGLT2 Inhibitor
5. CKD (defined as CKD-EPI eGFR \<30 mL/min)
6. Kidney transplant recipient
7. History of recurrent urinary tract infections (\>3 episodes/year)
8. Active cancer treatment
9. Less than 3-year life expectancy
10. Pregnancy and breastfeeding
11. Inability to understand and follow the study protocol
12. Known allergy to the study drug
13. Concomitant participation in another interventional clinical trial

Primary outcomes:
measure: Number of patients with radiologic stone recurrence
timeFrame: After 3 years
Secondary outcomes:
measure: Time to symptomatic kidney stone recurrence up to 3 years (time-to-event)
timeFrame: From enrollment to the end of treatment at 3 years
measure: Number of symptomatic stone recurrences per patient (cumulative)
timeFrame: From enrollment to the end of treatment at 3 years
Other outcomes:
measure: Changes in blood parameters
timeFrame: From enrollment to the end of treatment at 3 years
measure: Changes in urine parameters
timeFrame: From enrollment to the end of treatment at 3 years
measure: Changes in blood pressure
timeFrame: From enrollment to the end of treatment at 3 years
measure: Changes in weight
timeFrame: From enrollment to the end of treatment at 3 years
measure: Patient-reported kidney stone-related quality of life
timeFrame: From enrollment to the end of treatment at 3 years
measure: Patient-reported health-related quality of life (HRQoL)
timeFrame: From enrollment to the end of treatment at 3 years
measure: Number of patients with asymptomatic kidney stone passage
timeFrame: At 3 years
measure: Kidney stone-related health care utilization
timeFrame: From enrollment to the end of treatment at 3 years
measure: Kidney stone-related cost
timeFrame: From enrollment to the end of treatment at 3 years
Locations:
city: Amiens
country: France
facility: University Hospital Amiens-Picardie
city: Paris
country: France
facility: Hôpital Tenon
city: Berlin
country: Germany
facility: Charité University Medicine Berlin
city: Verona
country: Italy
facility: Verona University Hospital
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Baden
country: Switzerland
facility: Kantonsspital Baden
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bellinzona
country: Switzerland
facility: Regionalspital Bellinzona e Valli
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Chur
country: Switzerland
facility: Kantonsspital Chur
city: Fribourg
country: Switzerland
facility: Kantonsspital Fribourg
city: Geneva
country: Switzerland
facility: University Hospital Geneva (HUG)
city: Lausanne
country: Switzerland
facility: Lausanne University Hospital (CHUV)
city: Lugano
country: Switzerland
facility: Regionalspital Lugano
city: Luzern
country: Switzerland
facility: Kantonsspital Luzern
city: Neuchâtel
country: Switzerland
facility: Kantonsspital Neuchâtel
city: Olten
country: Switzerland
facility: Kantonsspital Olten
city: Sion
country: Switzerland
facility: Kantonsspital Sion
city: Solothurn
country: Switzerland
facility: Kantonsspital Solothurn
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich
Study officials:
affiliation: Inselspital, Bern University Hospital
name: Daniel Fuster
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.