The aim of this study is to test the efficacy of the two long-acting thiazide-like diuretics indapamide and chlorthalidone in reducing urine supersaturation for calcium oxalate and calcium phosphate compared to the short-acting thiazide diuretic hydrochlorothiazide for the prevention of calcium-containing kidney stones.

Background and Rationale:

Kidney stones are the most common condition affecting the kidney. Both prevalence and incidence are increasing rapidly, driven by global warming, urbanization, dietary habits and occupational changes. Kidney stones are highly recurrent, associated with increased mortality, significant morbidity and reduced quality of life, and result in enormous health care expenditures. Hence, effective preventive measures are an undisputed medical need. Thiazide and thiazide-like diuretics ("thiazides") have been the cornerstone of pharmacologic recurrence prevention since >50 years. The NOSTONE trial (NCT03057431), the only state-of-the-art trial ever performed for pharmacologic recurrence prevention, recently revealed that the most widely prescribed and best studied thiazide, hydrochlorothiazide, is not effectively preventing kidney stone recurrence. If these results also apply to the two more potent and long-acting thiazide-like diuretics indapamide and chlorthalidone is currently unknown. No head-to-head comparison of different thiazides for prevention of kidney stone recurrence has ever been performed. Thus, the role of thiazides in the prevention of kidney stone recurrence remains unclear. This poses the urgent need for a clinical trial that addresses this critical knowledge gap.

Objective:

The investigators plan to conduct a single-center, prospective, randomized, double-blind, crossover trial (INDAPACHLOR) to assess if indapamide and chlorthalidone are superior to hydrochlorothiazide in reducing urine supersaturations of calcium oxalate and calcium phosphate, the two best validated biochemical indicators of kidney stone recurrence risk.

Methodology:

Patients will be allocated to indapamide 2.5 mg once daily, chlorthalidone 25 mg once daily and hydrochlorothiazide 50 mg once daily in a random sequence. The three consecutive active treatment periods of 4 weeks each will be separated by wash-out periods of 4 weeks. The investigators will include 99 adult (>18 years old) patients with recurrent (≥ 2 stone episodes in the last 10 years) calcium-containing kidney stones (containing ≥ 50% of calcium oxalate, calcium phosphate or a mixture of both). All patients will receive a state-of-the art concomitant non-pharmacologic intervention to prevent stone recurrence according to current guidelines. The primary outcome will be reduction of urine supersaturations of calcium oxalate and calcium phosphate at 4 weeks with indapamide or chlorthalidone compared to hydrochlorothiazide. Secondary outcomes will be changes in 24-hour urine and blood parameters, ambulatory blood pressure and adverse events elicited by indapamide or chlorthalidone compared to hydrochlorothiazide. In an exploratory outcome, the abundance of the thiazide target, the sodium/chloride co-transporter, will be analyzed in urinary extracellular vesicles at 4 weeks.

Expected significance:

INDAPACHLOR will provide long-sought evidence on the comparative efficacy of commonly used thiazides in lowering urine supersaturations and is thus expected to have a strong guideline-changing impact, which will transform patient care for this very common disease.

Inclusion criteria:

• Written, informed consent.
• Age 18 years or older.
• Recurrent kidney stone disease (≥2 kidney stone episodes in the last 10 years prior to randomisation).
• Past kidney stone containing ≥50 % CaOx, CaP, or a mixture of both.

Exclusion criteria:

• Patients with secondary causes of recurrent calcium kidney stones including severe eating disorders (anorexia or bulimia), chronic bowel disease, intestinal or bariatric surgery, sarcoidosis, primary hyperparathyroidism, chronic urinary tract infection.
• Patients with the following medications: Thiazide or loop diuretics, carbonic anhydrase inhibitors (including topiramate), xanthine oxidase inhibitors, alkali, active vitamin D (calcitriol or similar), calcium supplementation, bisphosphonates, denusomab, teriparatide, sodium-glucose co-transporter 2 (SGLT2) inhibitors, strong CYP3A4 inhibitors or inducers (may affect indapamide metabolism), lithium (To be eligible for study participation, patients taking any of the above listed medications at screening must be willing to discontinue these medications at least 28 days before randomization).
• Patients with chronic kidney disease (defined as CKD-EPI eGFR <30 mL/min).
• Patients with glomerulonephritis.
• Patients with the following biochemical imbalances: severe hypercalcemia (>2.8 mmol/L), therapy-resistant hypokalemia or conditions with increased potassium loss, severe hyponatremia (<130 mmol/L), symptomatic hyperuricemia.
• Patients with hepatic encephalopathy or severe liver insufficiency.
• Patients with severe cardiac insufficiency.
• Patient with a recent cerebrovascular event.
• Patients with a solid organ transplant.
• Pregnant and lactating women (A urine pregnancy test must 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).
• Previous (within 3 months prior to randomization) or concomitant participation in another interventional clinical trial.
• Previous participation in INDAPACHLOR.
• Inability to understand and follow the protocol.
• Allergy to any one of the study drugs.

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.

Indapamide, hydrochlorothiazide and chlorthalidone will be provided in identically looking bottles containing identically looking capsules. All trial personnel that is involved in recruitment and care of patients, trial assessment, monitoring and statistical analyses will be blinded to the assigned trial arm.