Indapamide and Chlorthalidone to Reduce Urine Supersaturation for Kidney Stone Prevention (INDAPACHLOR)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Kidney Stone
• Intervention / Treatment: Drug: Indapamide 2.5 MG; Drug: Hydrochlorothiazide 50Mg; Drug: Chlorthalidone 25mg

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 99
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Daniel G Fuster, M.D.; Phone Number: +41 (0)31 632 31 44; Email: daniel.fuster@insel.ch

Study Locations

• Switzerland
  • Bern, Switzerland, 3010
    • Inselspital, Department of Nephrology and Hypertension

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Indapamide + Hydrochlorothiazide + Chlorthalidone; 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; 1 indapamide 2.5 mg capsule per day for 28 days; Drug: Hydrochlorothiazide 50Mg; 1 hydrochlorothiazide 50 mg capsule per day for 28 days; Drug: Chlorthalidone 25mg; 1 chlorthalidone 25 mg capsule per day for 28 days
Active Comparator: Hydrochlorothiazide + Chlorthalidone + Indapamide; 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; 1 indapamide 2.5 mg capsule per day for 28 days; Drug: Hydrochlorothiazide 50Mg; 1 hydrochlorothiazide 50 mg capsule per day for 28 days; Drug: Chlorthalidone 25mg; 1 chlorthalidone 25 mg capsule per day for 28 days
Active Comparator: Chlorthalidone + Indapamide + Hydrochlorothiazide; 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; 1 indapamide 2.5 mg capsule per day for 28 days; Drug: Hydrochlorothiazide 50Mg; 1 hydrochlorothiazide 50 mg capsule per day for 28 days; Drug: Chlorthalidone 25mg; 1 chlorthalidone 25 mg capsule per day for 28 days
Active Comparator: Hydrochlorothiazide + Indapamide + Chlorthalidone; 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; 1 indapamide 2.5 mg capsule per day for 28 days; Drug: Hydrochlorothiazide 50Mg; 1 hydrochlorothiazide 50 mg capsule per day for 28 days; Drug: Chlorthalidone 25mg; 1 chlorthalidone 25 mg capsule per day for 28 days
Active Comparator: Indapamide + Chlorthalidone + Hydrochlorothiazide; 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; 1 indapamide 2.5 mg capsule per day for 28 days; Drug: Hydrochlorothiazide 50Mg; 1 hydrochlorothiazide 50 mg capsule per day for 28 days; Drug: Chlorthalidone 25mg; 1 chlorthalidone 25 mg capsule per day for 28 days
Active Comparator: Chlorthalidone + Hydrochlorothiazide + Indapamide; 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; 1 indapamide 2.5 mg capsule per day for 28 days; Drug: Hydrochlorothiazide 50Mg; 1 hydrochlorothiazide 50 mg capsule per day for 28 days; Drug: Chlorthalidone 25mg; 1 chlorthalidone 25 mg capsule per day for 28 days

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Collaborators: University of Bern
• Investigators: Principal Investigator: Daniel G Fuster, M.D., Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, Bern Switzerland

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: October 26, 2023
• First Submitted That Met QC Criteria: October 26, 2023
• First Posted (Actual): November 1, 2023

Study Record Updates

• Last Update Posted (Actual): November 1, 2023
• Last Update Submitted That Met QC Criteria: October 26, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Pathological Conditions, Anatomical; Urolithiasis; Urinary Calculi; Calculi; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Calculi; Nephrolithiasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Chloride Symporter Inhibitors; Hydrochlorothiazide; Chlorthalidone; Indapamide
• Other Study ID Numbers: INDAPACHLOR Trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No