Hydrochlorothiazide for Kidney Stone Recurrence Prevention
Condition: Nephrolithiasis
MeSH terms: Kidney Calculi; Nephrolithiasis
Intervention: Placebo oral capsule; 12.5 mg hydrochlorothiazide; 25.0 mg hydrochlorothiazide; 50.0 mg hydrochlorothiazide
Intervention description: Once daily for 3 years; Once daily for 3 years; Once daily for 3 years; Once daily for 3 years
Intervention MeSH terms: Hydrochlorothiazide
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Enrollment: 416.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: kidney stones; hydrochlorothiazide

Summary:

      The investigators plan to assess the efficacy of standard and low dose HCTZ treatment in the
      recurrence prevention of calcium-containing kidney stones. More specifically, the
      investigators aim to assess the dose-response relationship for three different dosages of
      HCTZ.

      Study intervention: HCTZ 12.5 mg, 25 mg or 50 mg once daily per os for 24 or 36 months. In
      addition, all patients in HCTZ treatment arms will receive state-of-the-art non-pharmacologic
      recommendations for stone prevention according to current guidelines.

      Control intervention: Placebo once daily per os for 24 to 36 months. In addition, all
      patients in the placebo arm will receive state-of-the-art non-pharmacologic recommendations
      for stone prevention according to current guidelines.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Informed Consent as documented by signature

          2. Age 18 years or older

          3. Recurrent kidney stone disease (≥ 2 stone events within the last 10 years prior to
             randomization)

          4. Any past kidney stone containing 50% or more of calcium oxalate, calcium phosphate or
             a mixture of both

        Exclusion Criteria:

          1. Pharmacologic prevention for stone recurrence less than 3 months prior to
             randomization

          2. Patients with secondary causes of recurrent calcareous nephrolithiasis including:

               -  Severe eating disorders (anorexia or bulimia)

               -  Chronic inflammatory bowel disease, bariatric surgery, intestinal surgery with
                  malabsorption or chronic diarrheal status

               -  Sarcoidosis

               -  Primary hyperparathyroidism

               -  Complete distal tubular acidosis

               -  Active malignancy

          3. Patients with the following medications:

               -  Thiazide or loop diuretics

               -  Carbonic anhydrase inhibitors (including topiramate)

               -  Xanthine oxidase inhibitors (febuxostat or allopurinol)

               -  Alkali, including potassium citrate or sodium bicarbonate

               -  Treatment with 1,25-OH Vitamin D (calcitriol)

               -  Calcium supplementation

               -  Bisphosphonates

               -  Denosumab

               -  Teriparatide

               -  Glucocorticoids

          4. Obstructive uropathy, if not treated successfully

          5. Urinary tract infection, if not treated successfully

          6. Chronic kidney disease (defined as CKD-EPI eGFR < 30 mL/min per 1,73 m2 body surface
             area for more than 3 months)

          7. Patients with a kidney transplant

          8. > 3 gout arthritis episodes within one year prior to randomisation or gout arthritis
             requiring uric acid lowering therapy

          9. Cystinuria at screening

         10. Hypokalemia (blood potassium level < 3 mmol/L) at screening

         11. Hyponatremia (blood sodium level < 125 mmol/L) at screening

         12. Pregnant and lactating women [pregnancy test to be performed for women of
             child-bearing potential (defined as women who are not surgically sterilized/
             hysterectomized, and/ or who are postmenopausal for less than 12 months)]

         13. Previous (within 3 months prior to randomization) or concomitant participation in
             another interventional clinical trial

         14. Inability to understand and follow the protocol

         15. Known allergy to the study drug