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Impact of the SGLT2 Inhibitor Empagliflozin on Urinary Supersaturations in Kidney Stone Formers (SWEETSTONE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04911660
Recruitment Status : Recruiting
First Posted : June 3, 2021
Last Update Posted : October 29, 2021
Sponsor:
Collaborators:
Boehringer Ingelheim
University of Bern
Information provided by (Responsible Party):
University Hospital Inselspital, Berne

Brief Summary:
The aim of this study is to test the effect of a new drug on the composition of the urine in kidney stone patients. This new drug (Jardiance®, substance: empagliflozin) is currently approved in Switzerland for the treatment of patients with diabetes. Data from previous studies with and without diabetes suggest that it may have a beneficial effect on the composition of the urine and thereby reduce the risk of developing kidney stones.

Condition or disease Intervention/treatment Phase
Kidney Stone Drug: Empagliflozin 25 MG Other: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Eligible individuals will be randomized in equal proportions to 25 mg empagliflozin or placebo, taken once daily per os in the morning. Placebo will be administered to individuals randomized to that treatment in a form identical to empagliflozin. Patients will remain on the assigned IMP for 14 days. The following 14 days (days 15 - 28) will be a wash out period without IMP intake; this wash out time can be extended to up to 6 weeks if necessary. On day 29 of the study (or later according to the length of the wash out phase), a second 14 days period with IMP intake starts (empagliflozin or placebo, whichever was not received initially).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Empagliflozin and placebo will be provided in identically looking bottles. Besides the consecutive number, packs and pack content will look identical. Therefore, all trial personnel that is involved in recruitment and care of patients, trial assessment, monitoring and analyses will be blinded to the assigned trial arm.
Primary Purpose: Prevention
Official Title: Randomized, Double-blind, Placebo-controlled Crossover Trial Assessing the Impact of the SGLT2 Inhibitor Empagliflozin on Urinary Supersaturations in Kidney Stone Formers
Actual Study Start Date : August 25, 2021
Estimated Primary Completion Date : June 30, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Stones

Arm Intervention/treatment
Active Comparator: Empagliflozin + Placebo
1 capsule containing 25 mg empagliflozin per day for 14 days, followed by a 14-42 days wash-out phase and a second treatment phase with 1 capsule containing placebo for 14 days.
Drug: Empagliflozin 25 MG
1 empagliflozin 25 mg capsule per day for 14 days

Other: Placebo
1 placebo capsule per day for 14 days

Placebo Comparator: Placebo + Empagliflozin
1 capsule containing placebo per day for 14 days, followed by a 14-42 days wash-out phase and a second treatment phase with 1 capsule containing 25 mg empagliflozin for 14 days.
Drug: Empagliflozin 25 MG
1 empagliflozin 25 mg capsule per day for 14 days

Other: Placebo
1 placebo capsule per day for 14 days




Primary Outcome Measures :
  1. Primary outcome component 1 - calcium oxalate supersaturation in urine (empagliflozin treatment) [ Time Frame: Oxalate supersaturation will be determined at baseline and after 14 days treatment with empagliflozin ]

    The primary endpoint is composed of three primary outcomes that will be assessed separately.

    1) change in calcium oxalate supersaturation after empagliflozin treatment

    Calcium oxalate supersaturation will be calculated by the Equil-2 program from the oxalate concentration in urine.


  2. Primary outcome component 1 - calcium oxalate supersaturation in urine (placebo treatment) [ Time Frame: Oxalate supersaturation will be determined at baseline and after 14 days treatment with placebo ]

    The primary endpoint is composed of three primary outcomes that will be assessed separately.

    1) change in calcium oxalate supersaturation after placebo treatment as a comparator for empagliflozin treatment

    Calcium oxalate supersaturation will be calculated by the Equil-2 program from the oxalate concentration in urine.


  3. Primary outcome component 2 - calcium phosphate supersaturation in urine (empagliflozin treatment) [ Time Frame: Calcium phosphate supersaturation will be determined at baseline and after 14 days treatment with empagliflozin ]

    The primary endpoint is composed of three primary outcomes that will be assessed separately.

    2) change in calcium phosphate supersaturation after empagliflozin treatment

    Calcium phosphate supersaturation will be calculated by the Equil-2 program from the calcium phosphate concentration in urine.


  4. Primary outcome component 2 - calcium phosphate supersaturation in urine (placebo treatment) [ Time Frame: Calcium phosphate supersaturation will be determined at baseline and after 14 days treatment with placebo ]

    The primary endpoint is composed of three primary outcomes that will be assessed separately.

    2) change in calcium phosphate supersaturation after placebo treatment as a comparator for empagliflozin treatment

    Calcium phosphate supersaturation will be calculated by the Equil-2 program from the calcium phosphate concentration in urine.


  5. Primary outcome component 3 - uric acid supersaturation in urine (empagliflozin treatment) [ Time Frame: Uric acid supersaturation will be determined at baseline and after 14 days treatment with empagliflozin ]

    The primary endpoint is composed of three primary outcomes that will be assessed separately.

    3) change in uric acid supersaturation after empagliflozin treatment

    Uric acid supersaturation will be calculated by the Equil-2 program from the uric acid concentration in urine.


  6. Primary outcome component 3 - uric acid supersaturation in urine (placebo treatment) [ Time Frame: Uric acid supersaturation will be determined at baseline and after 14 days treatment with placebo ]

    The primary endpoint is composed of three primary outcomes that will be assessed separately.

    3) change in uric acid supersaturation after placebo treatment as a comparator for empagliflozin treatment

    Uric acid supersaturation will be calculated by the Equil-2 program from the uric acid concentration in urine.



Secondary Outcome Measures :
  1. Blood sodium level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Sodium level measured in mmol/l

  2. Blood potassium level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Potassium level measured in mmol/l

  3. Blood chloride level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Chloride level measured in mmol/l

  4. Blood total calcium level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Total calcium level measured in mmol/l

  5. Blood ionized calcium level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Ionized calcium level measured in mmol/l

  6. Blood phosphate level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Phosphate level measured in mmol/l

  7. Blood magnesium level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Magnesium level measured in mmol/l

  8. Venous bicarbonate level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Venous bicarbonate level measured in mmol/l

  9. Blood glucose level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Blood glucose level measured in mmol/l

  10. Blood urea level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Urea level measured in mmol/l

  11. Blood total cholesterol level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Total cholesterol level measured in mmol/l

  12. Blood HDL cholesterol level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    HDL cholesterol level measured in mmol/l

  13. Blood LDL cholesterol level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    LDL cholesterol level measured in mmol/l

  14. Blood triglycerides level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Triglycerides level measured in mmol/l

  15. Blood osmolality change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Osmolality measured in mmol/l

  16. Blood creatinine level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Creatinine level measured in μmol/l

  17. Blood uric acid level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Uric acid level measured in μmol/l

  18. Blood 25-OH vitamine D level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    25-OH vitamine D level measured in nmol/l

  19. Blood 1,25-OH vitamine D level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    1,25-OH vitamine D level measured in pmol/l

  20. Venous pCO2 change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Venous pCO2 measured in mmHg

  21. Venous pH change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Venous pH measured in pH units

  22. Blood albumin level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Albumin level measured in g/l

  23. Blood parathormone level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Parathormone level measured in pg/ml

  24. Blood FGF23 level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    FGF23 level measured in pg/ml

  25. Blood alcaline phosphatase activity change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Alcaline phosphatase activity level measured in U/l

  26. Blood TSH activity change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    TSH activity level measured in mU/l

  27. Blood haemoglobin A1c level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Haemoglobin A1c activity level measured in mU/l

  28. Urine sodium level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Urine sodium level measured in mmol/l

  29. Urine potassium level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Urine potassium level measured in mmol/l

  30. Urine chloride level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Chloride level measured in mmol/l

  31. Urine calcium level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Calcium level measured in mmol/l

  32. Urine phosphate level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Phosphate level measured in mmol/l

  33. Urine magnesium level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Magnesium level measured in mmol/l

  34. Urine glucose level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Glucose level measured in mmol/l

  35. Urine urea level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Urea level measured in mmol/l

  36. Urine osmolality level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Osmolality level measured in mmol/l

  37. Urine citrate level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Citrate level measured in mmol/l

  38. Urine sulfate level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Sulfate level measured in mmol/l

  39. Urine oxalate level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Oxalate level measured in μmol/l

  40. Urine ammonia level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Ammonia level measured in μmol/l

  41. Urine creatinine level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Creatinine level measured in μmol/l

  42. Urine uric acid level change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Uric acid level measured in μmol/l

  43. Urine pH change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    pH measured in pH units

  44. Urine pCO2 change from baseline [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    pCO2 measured in mmHg

  45. Calculated outcomes 1: estimated glomerular filtration rate (eGFR) (Blood) [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    eGFR will be derived from the serum creatinine concentration, age and sex using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation

  46. Calculated outcomes 2: titratable acid (urine) [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]
    Titratable acid will be calculated in g/100 ml with the Equil-2 program.

  47. Calculated outcomes 3: bicarbonate (urine) [ Time Frame: Data collected at baseline, after 1st 14 days treatment and after 2nd 14 days treatment expected to be 6-10 weeks from baseline. ]

    Urine bicarbonate in mmol/l will be calculated with the Henderson-Hasselbalch equation using urine pH and urine pCO2

    HCO-3= 0.0309 x pCO2 x 10pH-6.1




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 74 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Informed Consent as documented by signature
  • Age between 18 and 74 years old
  • One or more kidney stone event(s) in the past
  • Any past kidney stone containing ≥ 80 % of calcium or ≥ 80 % of uric acid
  • HbA1c < 6.5 %

Exclusion Criteria:

  • Patients with secondary causes of recurrent nephrolithiasis:
  • Severe eating disorders (anorexia or bulimia)
  • Chronic bowel disease, past intestinal or bariatric surgery
  • Sarcoidosis
  • Primary hyperparathyroidism
  • Complete distal tubular acidosis
  • Patients with the following medications:
  • Anti-diabetic treatment (insulin and non-insulin agents)
  • Patients not able or not willing to stop the following medication during the period of participation in the trial (including a time window of 4 weeks wash out prior to randomization):
  • Diuretics (thiazide and loop diuretics)
  • Carbonic anhydrase inhibitors (including topiramate)
  • Xanthine oxidase inhibitors
  • Alkali, including potassium citrate or sodium bicarbonate
  • Treatment with 1,25-OH Vitamin D (calcitriol)
  • Calcium supplementation
  • Bisphosphonates, Denosumab, Teriparatide
  • Glucocorticoids
  • Obstructive uropathy, if not treated successfully
  • Genito-urinary infection, if not treated successfully
  • Chronic kidney disease (defined as CKD-EPI eGFR < 60 mL/min per 1.73 m2 body surface area)
  • Kidney transplant
  • Pregnant and lactating women [urine pregnancy test to be performed for women of childbearing potential (defined as women who are not surgically sterilized/ hysterectomized, and/ or who are postmenopausal for less than 12 months)] or women of childbearing potential that refuse to use an effective contraceptive method (birth control pill or IUD).
  • Inability to understand and follow the protocol
  • Known allergy to the study drug
  • Participation in another interventional clinical trial within 4 weeks prior to baseline and during the current trial

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04911660


Contacts
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Contact: Daniel Fuster, MD +41 (0)31 632 31 44 daniel.fuster@insel.ch

Locations
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Switzerland
Inselspital, Department of Nephrology and Hypertension Recruiting
Bern, Switzerland, 3010
Contact: Daniel Fuster, MD    +41 (0)31 632 31 44    daniel.fuster@insel.ch   
Sponsors and Collaborators
University Hospital Inselspital, Berne
Boehringer Ingelheim
University of Bern
Investigators
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Principal Investigator: Daniel Fuster, MD University Hospital Inselspital, Berne
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier: NCT04911660    
Other Study ID Numbers: 2020-02679
First Posted: June 3, 2021    Key Record Dates
Last Update Posted: October 29, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital Inselspital, Berne:
Kidney stones
Empagliflozin
Supersaturation
Additional relevant MeSH terms:
Layout table for MeSH terms
Kidney Calculi
Nephrolithiasis
Calculi
Pathological Conditions, Anatomical
Kidney Diseases
Urologic Diseases
Urolithiasis
Urinary Calculi
Empagliflozin
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs