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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
99
1 indapamide 2.5 mg capsule per day for 28 days
1 hydrochlorothiazide 50 mg capsule per day for 28 days
1 chlorthalidone 25 mg capsule per day for 28 days
Inselspital, Department of Nephrology and Hypertension
Bern, Switzerland
RECRUITINGPrimary outcome component 1 - calcium oxalate supersaturation in urine
The trial has two primary outcomes that will be assessed separately. Change from baseline urine calcium oxalate supersaturation to end of treatment. Calcium oxalate supersaturation will be calculated by the Equil2 program.
Time frame: Calcium oxalate supersaturation will be determined at day 28 of each active treatment phase
Primary outcome component 2 - calcium phosphate supersaturation in urine
The trial has two primary outcomes that will be assessed separately. Change from baseline urine calcium phosphate supersaturation to end of treatment. Calcium phosphate supersaturation will be calculated by the Equil2 program.
Time frame: Calcium phosphate supersaturation will be determined at day 28 of each active treatment phase
Blood sodium level change from baseline
Sodium level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood potassium level change from baseline
Potassium level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood chloride level change from baseline
Chloride level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood calcium level change from baseline
Calcium level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
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Blood magnesium level change from baseline
Magnesium level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood phosphate level change from baseline
Phosphate level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Venous bicarbonate level change from baseline
Venous bicarbonate level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Venous pH change from baseline
Venous pH measured in pH units
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Venous pCO2 change from baseline
Venous pCO2 measured in mmHg
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood glucose level change from baseline
Glucose level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood creatinine level change from baseline
Creatinine level measured in μmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood urea level change from baseline
Urea level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood uric acid level change from baseline
Uric acid level measured in μmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood albumin level change from baseline
Albumin level measured in g/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood total cholesterol level change from baseline
Total cholesterol level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood HDL cholesterol level change from baseline
HDL cholesterol level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood LDL cholesterol level change from baseline
LDL cholesterol level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood triglyceride level change from baseline
Triglycerides level measured in mmol/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Blood haemoglobin A1c level change from baseline
Haemoglobin A1c activity level measured in mU/l
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine sodium excretion change from baseline
Urine sodium excretion measured in mmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine potassium excretion change from baseline
Urine potassium excretion measured in mmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine chloride excretion change from baseline
Urine chloride excretion measured in mmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine calcium excretion change from baseline
Urine calcium excretion measured in mmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine phosphate excretion change from baseline
Urine phosphate excretion measured in mmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine magnesium excretion change from baseline
Urine magnesium excretion measured in mmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine urea excretion change from baseline
Urine urea excretion measured in mmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine creatinine excretion change from baseline
Urine creatinine excretion measured in μmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine uric acid excretion change from baseline
Urine uric acid excretion measured in μmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine citrate excretion change from baseline
Urine citrate excretion measured in mmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine sulfate excretion change from baseline
Urine sulfate excretion measured in mmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine oxalate excretion change from baseline
Urine oxalate excretion measured in μmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine ammonium excretion change from baseline
Urine ammonium excretion measured in mmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine bicarbonate excretion change from baseline
Urine bicarbonate excretion measured in mmol/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine titratable acidity excretion change from baseline
Urine titratable acidity excretion measured in mEq/24 h
Time frame: Data collected at baseline and at day 28 of each active treatment phase
Urine pH change from baseline
pH measured in pH units
Time frame: Data collected at baseline and at day 28 of each active treatment phase