Indapamide and Chlorthalidone to Reduce Urine Supersaturation for Kidney Stone Prevention

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Randomized, Double-blind, Crossover Trial Assessing the Efficacy of Indapamide and Chlorthalidone Compared to Hydrochlorothiazide for the Reduction of Urine Supersaturation for Kidney Stone Prevention

Conditions
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Kidney Stone

Intervention / Treatment
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* Drug: Indapamide 2.5 MG
* Drug: Hydrochlorothiazide 50Mg
* Drug: Chlorthalidone 25mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written, informed consent. Age 18 years or older. Recurrent kidney stone disease (2 or more stone episodes in the last 10 years). Past kidney stone containing 50% or more of calcium oxalate, calcium phosphate 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, denosumab, teriparatide, sodium-glucose co-transporter 2 (SGLT2) inhibitors, strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers (may affect indapamide metabolism) Patients with chronic kidney disease, defined as estimated GFR (eGFR) according to CKD-EPI formula < 30ml/min). Patients with a kidney transplant Pregnant and lactating women. Previous (within 3 months prior to randomization) or concomitant participation in another interventional clinical trial. Inability to understand and follow the protocol. Allergy to study drugs.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Eligible individuals will be randomly allocated to one of six treatment sequences with indapamide 2.5 mg, chlorthalidone 25 mg or hydrochlorothiazide 50 mg once daily per os in the morning. Active treatment phases will be 28 days each, separated by wash out periods of 28 days. Active treatment periods can be extended by a maximum of one week, wash out periods can be extended to a maximum of eight weeks.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Indapamide + Hydrochlorothiazide + Chlorthalidone<br>1 capsule containing 2.5 mg indapamide per day for 28 days, followed by a 28 days wash out phase, followed by a second treatment phase with 1 capsule containing 50 mg hydrochlorothiazide per day for 28 days, followed by a 28 days wash out phase, followed by a third treatment phase with 1 capsule containing 25 mg chlorthalidone per day for 28 days. | Drug: Indapamide 2.5 MG<br>* 1 indapamide 2.5 mg capsule per day for 28 days<br>Drug: Hydrochlorothiazide 50Mg<br>* 1 hydrochlorothiazide 50 mg capsule per day for 28 days<br>Drug: Chlorthalidone 25mg<br>* 1 chlorthalidone 25 mg capsule per day for 28 days<br>|
| Active Comparator: Hydrochlorothiazide + Chlorthalidone + Indapamide<br>1 capsule containing 50 mg hydrochlorothiazide per day for 28 days, followed by a 28 days wash out phase, followed by a second treatment phase with 1 capsule containing 25 mg chlorthalidone per day for 28 days, followed by a 28 days wash out phase, followed by a third treatment phase with 1 capsule containing 2.5 mg indapamide per day for 28 days. | Drug: Indapamide 2.5 MG<br>* 1 indapamide 2.5 mg capsule per day for 28 days<br>Drug: Hydrochlorothiazide 50Mg<br>* 1 hydrochlorothiazide 50 mg capsule per day for 28 days<br>Drug: Chlorthalidone 25mg<br>* 1 chlorthalidone 25 mg capsule per day for 28 days<br>|
| Active Comparator: Chlorthalidone + Indapamide + Hydrochlorothiazide<br>1 capsule containing 25 mg chlorthalidone per day for 28 days, followed by a 28 days wash out phase, followed by a second treatment phase with 1 capsule containing 2.5 mg indapamide per day for 28 days, followed by a 28 days wash out phase, followed by a third treatment phase with 1 capsule containing 50 mg hydrochlorothiazide per day for 28 days. | Drug: Indapamide 2.5 MG<br>* 1 indapamide 2.5 mg capsule per day for 28 days<br>Drug: Hydrochlorothiazide 50Mg<br>* 1 hydrochlorothiazide 50 mg capsule per day for 28 days<br>Drug: Chlorthalidone 25mg<br>* 1 chlorthalidone 25 mg capsule per day for 28 days<br>|
| Active Comparator: Hydrochlorothiazide + Indapamide + Chlorthalidone<br>1 capsule containing 50 mg hydrochlorothiazide per day for 28 days, followed by a 28 days wash out phase, followed by a second treatment phase with 1 capsule containing 2.5 mg indapamide per day for 28 days, followed by a 28 days wash out phase, followed by a third treatment phase with 1 capsule containing 25 mg chlorthalidone per day for 28 days. | Drug: Indapamide 2.5 MG<br>* 1 indapamide 2.5 mg capsule per day for 28 days<br>Drug: Hydrochlorothiazide 50Mg<br>* 1 hydrochlorothiazide 50 mg capsule per day for 28 days<br>Drug: Chlorthalidone 25mg<br>* 1 chlorthalidone 25 mg capsule per day for 28 days<br>|
| Active Comparator: Indapamide + Chlorthalidone + Hydrochlorothiazide<br>1 capsule containing 2.5 mg indapamide per day for 28 days, followed by a 28 days wash out phase, followed by a second treatment phase with 1 capsule containing 25 mg chlorthalidone per day for 28 days, followed by a 28 days wash out phase, followed by a third treatment phase with 1 capsule containing 50 mg hydrochlorothiazide per day for 28 days. | Drug: Indapamide 2.5 MG<br>* 1 indapamide 2.5 mg capsule per day for 28 days<br>Drug: Hydrochlorothiazide 50Mg<br>* 1 hydrochlorothiazide 50 mg capsule per day for 28 days<br>Drug: Chlorthalidone 25mg<br>* 1 chlorthalidone 25 mg capsule per day for 28 days<br>|
| Active Comparator: Chlorthalidone + Hydrochlorothiazide + Indapamide<br>1 capsule containing 25 mg chlorthalidone per day for 28 days, followed by a 28 days wash out phase, followed by a second treatment phase with 1 capsule containing 50 mg hydrochlorothiazide per day for 28 days, followed by a 28 days wash out phase, followed by a third treatment phase with 1 capsule containing 2.5 mg indapamide per day for 28 days. | Drug: Indapamide 2.5 MG<br>* 1 indapamide 2.5 mg capsule per day for 28 days<br>Drug: Hydrochlorothiazide 50Mg<br>* 1 hydrochlorothiazide 50 mg capsule per day for 28 days<br>Drug: Chlorthalidone 25mg<br>* 1 chlorthalidone 25 mg capsule per day for 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary 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. | 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. | Calcium phosphate supersaturation will be determined at day 28 of each active treatment phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood sodium level change from baseline | Sodium level measured in mmol/l | 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 | 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 | 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 | Data collected at baseline and at day 28 of each active treatment phase | 
| Blood magnesium level change from baseline | Magnesium level measured in mmol/l | 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 | 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 | Data collected at baseline and at day 28 of each active treatment phase | 
| Venous pH change from baseline | Venous pH measured in pH units | Data collected at baseline and at day 28 of each active treatment phase | 
| Venous pCO2 change from baseline | Venous pCO2 measured in mmHg | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | Data collected at baseline and at day 28 of each active treatment phase | 
| Urine pH change from baseline | pH measured in pH units | Data collected at baseline and at day 28 of each active treatment phase |