Clinical trial NCT06111885: Indapamide and Chlorthalidone to Reduce Urine Supersaturation for Kidney Stone Prevention
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Kidney Stone
Keywords: Nephrolithiasis
Kidney stones
Thiazide
Hydrochlorothiazide
Indapamide
Chlorthalidone
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: Department of clinical research, Bern
First posted: 2023-11-01
Enrollment: 99
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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.
Primary purpose: PREVENTION

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Primary outcome component 1 - calcium oxalate supersaturation in urine
timeFrame: Calcium oxalate supersaturation will be determined at day 28 of each active treatment phase
measure: Primary outcome component 2 - calcium phosphate supersaturation in urine
timeFrame: Calcium phosphate supersaturation will be determined at day 28 of each active treatment phase
Secondary outcomes:
measure: Blood sodium level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood potassium level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood chloride level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood calcium level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood magnesium level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood phosphate level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Venous bicarbonate level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Venous pH change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Venous pCO2 change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood glucose level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood creatinine level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood urea level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood uric acid level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood albumin level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood total cholesterol level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood HDL cholesterol level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood LDL cholesterol level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood triglyceride level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Blood haemoglobin A1c level change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine sodium excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine potassium excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine chloride excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine calcium excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine phosphate excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine magnesium excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine urea excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine creatinine excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine uric acid excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine citrate excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine sulfate excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine oxalate excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine ammonium excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine bicarbonate excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine titratable acidity excretion change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Urine pH change from baseline
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
Other outcomes:
measure: Abundance of total sodium/chloride co-transporter (SLC12A3) in urinary extracellular vesicles
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
measure: Abundance of phosphorylated sodium/chloride co-transporter (SLC12A3) in urinary extracellular vesicles
timeFrame: Data collected at baseline and at day 28 of each active treatment phase
Locations:
city: Bern
country: Switzerland
facility: Inselspital, Department of Nephrology and Hypertension
Study officials:
affiliation: Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, Bern Switzerland
name: Daniel G Fuster, M.D.
role: PRINCIPAL_INVESTIGATOR
References: