Indapamide or chlorthalidone to reduce urine supersaturation for secondary prevention of kidney stones: protocol for a randomised, double-blind, cross-over trial (INDAPACHLOR).

introductionKidney stones constitute a major global healthcare problem and are characterised by high recurrence rates. Thiazide and thiazide-like diuretics (thiazides) have been the standard medical treatment for the prevention of kidney stone recurrence. This clinical routine has recently been challenged by the findings of the large NOSTONE trial that failed to show superiority of hydrochlorothiazide at doses up to 50 mg daily over placebo in preventing a composite of clinical or radiological recurrence in patients at high risk of kidney stone recurrence. If these results also apply to the longer-acting and more potent thiazides indapamide and chlorthalidone remains unknown. No head-to-head comparison of different thiazides for kidney stone recurrence prevention or for the established proxies of recurrence risk, urine relative supersaturation ratios, has ever been conducted. METHODS AND ANALYSIS: INDAPACHLOR is a single-centre, randomised, double-blind, cross-over trial evaluating the efficacy of indapamide or chlorthalidone compared with hydrochlorothiazide in lowering urine relative supersaturation ratios for calcium oxalate and calcium phosphate in individuals with idiopathic calcium kidney stones. Participants 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 28 days each will be separated by wash-out periods of 28 days. Inclusion criteria are age ≥18 years and ≥2 stone episodes in the last 10 years with calcium-containing kidney stones (containing ≥50% of calcium oxalate, calcium phosphate or a mixture of both). Patients with secondary causes of calcium kidney stones are excluded. The primary outcomes are the changes in the relative supersaturation ratios of calcium oxalate and calcium phosphate from baseline to day 28 of each treatment period. Secondary outcomes include changes in 24 hours urine and blood parameters from baseline to day 28 of each treatment period. The study targets enrolment of 99 participants to achieve 80% power for detecting a 20% reduction in the relative supersaturation ratios of calcium oxalate and calcium phosphate when treated with indapamide or chlorthalidone and hydrochlorothiazide. ETHICS AND DISSEMINATION: The study was approved by the Ethics Commission Bern, Switzerland, and the Competent Authority Swissmedic. Results will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov (NCT06111885) and Swiss National Clinical Trials Portal (SNCTP000006156). PROTOCOL VERSION: Version 4.0, 29 November 2024.