Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial

Nasser A Dhayat, Nicolas Faller, Olivier Bonny, Nilufar Mohebbi, Alexander Ritter, Lisa Pellegrini, Giulia Bedino, Carlo Schönholzer, Reto M Venzin, Carina Hüsler, Irene Koneth, Rosaria Del Giorno, Luca Gabutti, Patrizia Amico, Michael Mayr, Urs Odermatt, Florian Buchkremer, Thomas Ernandez, Catherine Stoermann-Chopard, Daniel Teta, Felix Rintelen, Marie Roumet, Irina Irincheeva, Sven Trelle, Luca Tamò, Beat Roth, Bruno Vogt, Daniel G Fuster, Nasser A Dhayat, Nicolas Faller, Olivier Bonny, Nilufar Mohebbi, Alexander Ritter, Lisa Pellegrini, Giulia Bedino, Carlo Schönholzer, Reto M Venzin, Carina Hüsler, Irene Koneth, Rosaria Del Giorno, Luca Gabutti, Patrizia Amico, Michael Mayr, Urs Odermatt, Florian Buchkremer, Thomas Ernandez, Catherine Stoermann-Chopard, Daniel Teta, Felix Rintelen, Marie Roumet, Irina Irincheeva, Sven Trelle, Luca Tamò, Beat Roth, Bruno Vogt, Daniel G Fuster

Abstract

Background: Nephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women. Given the high cost of medical treatments and surgical interventions as well as the morbidity related to symptomatic stone disease, medical prophylaxis for stone recurrence is an attractive approach. Thiazide diuretics have been the cornerstone of pharmacologic metaphylaxis for more than 40 years. However, evidence for benefits and harms of thiazides in the prevention of calcium containing kidney stones in general remains unclear. In addition, the efficacy of the currently employed low dose thiazide regimens to prevent stone recurrence is not known.

Methods: The NOSTONE trial is an investigator-initiated 3-year prospective, multicenter, double-blind, placebo-controlled trial to assess the efficacy of standard and low dose hydrochlorothiazide treatment in the recurrence prevention of calcium containing kidney stones. We plan to include 416 adult (≥ 18 years) 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). Patients will be randomly allocated to 50 mg or 25 mg or 12.5 mg hydrochlorothiazide or placebo. The primary outcome will be incidence of stone recurrence (a composite of symptomatic or radiologic recurrence). Secondary outcomes will be individual components of the composite primary outcome, safety and tolerability of hydrochlorothiazide treatment, changes in urinary biochemistry elicited by hydrochlorothiazide treatment and impact of baseline disease severity, biochemical abnormalities and stone composition on treatment response.

Discussion: The NOSTONE study will provide long-sought information on the efficacy of hydrochlorothiazide in the recurrence prevention of calcium containing kidney stones. Strengths of the study include the randomized, double-blind and placebo-controlled design, the large amount of patients studied, the employment of high sensitivity and high specificity imaging and the exclusive public funding support.

Trial registration: ClinicalTrials.gov, NCT03057431 . Registered on February 20 2017.

Keywords: Hydrochlorothiazide; Kidney stones; Nephrolithiasis; Prevention; Recurrence.

Conflict of interest statement

Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent will be obtained from all study participants. The study was approved by the lead ethics committee in Bern, Switzerland (EK BE) on October 25 2016 and subsequently by all other ethics committees in Switzerland (EK NZ, EK OS, EK VD, EK GE, EK TI, EK ZH) with EK approval # 2016_01475. Approval for the study investigational product was obtained from Swissmedic on February 24 2017 with Swissmedic approval # 2017DR3035.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Flow diagram of the NOSTONE trial

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