Indapamide and Chlorthalidone to Reduce Urine Supersaturation for Kidney Stone Prevention

Kidney Stone Clinical Trial

— INDAPACHLOR  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06111885
• Other study ID #: INDAPACHLOR Trial
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: April 2024
• Est. completion date: June 2027

Study information

• Verified date: October 2023
• Source: Insel Gruppe AG, University Hospital Bern
• Contact: Daniel G Fuster, M.D.
• Phone: +41 (0)31 632 31 44
• Email: daniel.fuster[@]insel.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 99
• Est. completion date: June 2027
• Est. primary completion date: June 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Kidney Calculi
• Kidney Stone
• Nephrolithiasis

Intervention

Drug:
• Indapamide 2.5 MG
1 indapamide 2.5 mg capsule per day for 28 days
• Hydrochlorothiazide 50Mg
1 hydrochlorothiazide 50 mg capsule per day for 28 days
• Chlorthalidone 25mg
1 chlorthalidone 25 mg capsule per day for 28 days

Locations

Country	Name	City	State
Switzerland	Inselspital, Department of Nephrology and Hypertension	Bern

Sponsors (2)

Lead Sponsor	Collaborator
Insel Gruppe AG, University Hospital Bern	University of Bern

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Abundance of total sodium/chloride co-transporter (SLC12A3) in urinary extracellular vesicles	Abundance of total sodium/chloride co-transporter (SLC12A3) detected by immunoblotting on urinary extracellular vesicles, normalized to the abundance of the urinary extracellular vesicle protein Alix	Data collected at baseline and at day 28 of each active treatment phase
Other	Abundance of phosphorylated sodium/chloride co-transporter (SLC12A3) in urinary extracellular vesicles	Abundance of phosphorylated sodium/chloride co-transporter (SLC12A3) detected by immunoblotting on urinary extracellular vesicles, normalized to the abundance of the urinary extracellular vesicle protein Alix	Data collected at baseline and at day 28 of each active treatment phase
Primary	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	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Venous pH change from baseline	Venous pH measured in pH units	Data collected at baseline and at day 28 of each active treatment phase
Secondary	Venous pCO2 change from baseline	Venous pCO2 measured in mmHg	Data collected at baseline and at day 28 of each active treatment phase
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Urine pH change from baseline	pH measured in pH units	Data collected at baseline and at day 28 of each active treatment phase