Kidney Stone
Conditions
Keywords
Nephrolithiasis, Kidney stones, Thiazide, Hydrochlorothiazide, Indapamide, Chlorthalidone
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.
Interventions
DRUGIndapamide 2.5 MG
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
Sponsors
Department of clinical research, Bern
Insel Gruppe AG, University Hospital Bern
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Indapamide, hydrochlorothiazide and chlorthalidone will be provided in identically looking bottles containing identically looking capsules. All trial personnel that is involved in recruitment and care of patients, trial assessment, monitoring and statistical analyses will be blinded to the assigned trial arm.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary outcome component 1 - calcium oxalate supersaturation in urine | Calcium oxalate supersaturation will be determined at day 28 of each active treatment phase | 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. |
| Primary outcome component 2 - calcium phosphate supersaturation in urine | Calcium phosphate supersaturation will be determined at day 28 of each active treatment phase | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood sodium level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Sodium level measured in mmol/l |
| Blood potassium level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Potassium level measured in mmol/l |
| Blood chloride level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Chloride level measured in mmol/l |
| Blood calcium level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Calcium level measured in mmol/l |
| Blood magnesium level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Magnesium level measured in mmol/l |
| Blood phosphate level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Phosphate level measured in mmol/l |
| Venous bicarbonate level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Venous bicarbonate level measured in mmol/l |
| Venous pH change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Venous pH measured in pH units |
| Venous pCO2 change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Venous pCO2 measured in mmHg |
| Blood glucose level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Glucose level measured in mmol/l |
| Blood creatinine level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Creatinine level measured in μmol/l |
| Blood urea level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urea level measured in mmol/l |
| Blood uric acid level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Uric acid level measured in μmol/l |
| Blood albumin level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Albumin level measured in g/l |
| Blood total cholesterol level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Total cholesterol level measured in mmol/l |
| Blood HDL cholesterol level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | HDL cholesterol level measured in mmol/l |
| Blood triglyceride level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Triglycerides level measured in mmol/l |
| Blood haemoglobin A1c level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Haemoglobin A1c activity level measured in mU/l |
| Urine sodium excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine sodium excretion measured in mmol/24 h |
| Urine potassium excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine potassium excretion measured in mmol/24 h |
| Urine chloride excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine chloride excretion measured in mmol/24 h |
| Urine calcium excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine calcium excretion measured in mmol/24 h |
| Urine phosphate excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine phosphate excretion measured in mmol/24 h |
| Urine urea excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine urea excretion measured in mmol/24 h |
| Urine creatinine excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine creatinine excretion measured in μmol/24 h |
| Urine uric acid excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine uric acid excretion measured in μmol/24 h |
| Urine citrate excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine citrate excretion measured in mmol/24 h |
| Urine sulfate excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine sulfate excretion measured in mmol/24 h |
| Urine oxalate excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine oxalate excretion measured in μmol/24 h |
| Urine ammonium excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine ammonium excretion measured in mmol/24 h |
| Urine bicarbonate excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine bicarbonate excretion measured in mmol/24 h |
| Urine titratable acidity excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine titratable acidity excretion measured in mEq/24 h |
| Urine pH change from baseline | Data collected at baseline and at day 28 of each active treatment phase | pH measured in pH units |
| Blood LDL cholesterol level change from baseline | Data collected at baseline and at day 28 of each active treatment phase | LDL cholesterol level measured in mmol/l |
| Urine magnesium excretion change from baseline | Data collected at baseline and at day 28 of each active treatment phase | Urine magnesium excretion measured in mmol/24 h |
Other
| Measure | Time frame | Description |
|---|---|---|
| Abundance of total sodium/chloride co-transporter (SLC12A3) in urinary extracellular vesicles | Data collected at baseline and at day 28 of each active treatment phase | 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 |
| Abundance of phosphorylated sodium/chloride co-transporter (SLC12A3) in urinary extracellular vesicles | Data collected at baseline and at day 28 of each active treatment phase | 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 |
Countries
Switzerland
Contacts
Primary ContactDaniel G Fuster, M.D.
Outcome results
None listed