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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 99
- 试验地点
- 2
- 主要终点
- Primary outcome component 1 - calcium oxalate supersaturation in urine
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Hydrochlorothiazide 50Mg (Drug)
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.
干预措施: Indapamide 2.5 MG (Drug)
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.
干预措施: Chlorthalidone 25mg (Drug)
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.
干预措施: Hydrochlorothiazide 50Mg (Drug)
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.
干预措施: Chlorthalidone 25mg (Drug)
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.
干预措施: Chlorthalidone 25mg (Drug)
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.
干预措施: Indapamide 2.5 MG (Drug)
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.
干预措施: Indapamide 2.5 MG (Drug)
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.
干预措施: Indapamide 2.5 MG (Drug)
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.
干预措施: Indapamide 2.5 MG (Drug)
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.
干预措施: Indapamide 2.5 MG (Drug)
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.
干预措施: Hydrochlorothiazide 50Mg (Drug)
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.
干预措施: Hydrochlorothiazide 50Mg (Drug)
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.
干预措施: Hydrochlorothiazide 50Mg (Drug)
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.
干预措施: Hydrochlorothiazide 50Mg (Drug)
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.
干预措施: Chlorthalidone 25mg (Drug)
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.
干预措施: Chlorthalidone 25mg (Drug)
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.
干预措施: Chlorthalidone 25mg (Drug)
结局指标
主要结局
Primary outcome component 1 - calcium oxalate supersaturation in urine
时间窗: 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
时间窗: 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.
次要结局
- Urine potassium excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood sodium level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood glucose level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood urea level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood albumin level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood LDL cholesterol level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood calcium level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood creatinine level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood uric acid level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood HDL cholesterol level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine magnesium excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood potassium level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine creatinine excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood chloride level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood magnesium level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Venous pCO2 change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood total cholesterol level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine sodium excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine calcium excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine uric acid excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood phosphate level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Venous bicarbonate level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Venous pH change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood triglyceride level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Blood haemoglobin A1c level change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine chloride excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine phosphate excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine sulfate excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine ammonium excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine pH change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine citrate excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine urea excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine bicarbonate excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine oxalate excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)
- Urine titratable acidity excretion change from baseline(Data collected at baseline and at day 28 of each active treatment phase)