HYDROchlorothiazide versus placebo to PROTECT polycystic kidney disease patients and improve their quality of life: study protocol and rationale for the HYDRO-PROTECT randomized controlled trial

Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor antagonists (V2RA) like tolvaptan are currently the only available renoprotective agents for rapidly progressive ADPKD. However, aquaretic side effects substantially limit their tolerability and therapeutic potential. In a preliminary clinical study, the addition of hydrochlorothiazide (HCT) to tolvaptan decreased 24-h urinary volume and appeared to increase renoprotective efficacy. The HYDRO-PROTECT study will investigate the long-term effect of co-treatment with HCT on tolvaptan efficacy (rate of kidney function decline) and tolerability (aquaresis and quality of life) in patients with ADPKD.

Methods: The HYDRO-PROTECT study is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study is powered to enroll 300 rapidly progressive patients with ADPKD aged ≥ 18 years, with an eGFR of > 25 mL/min/1.73 m², and on stable treatment with the highest tolerated dose of tolvaptan in routine clinical care. Patients will be randomly assigned (1:1) to daily oral HCT 25 mg or matching placebo treatment for 156 weeks, in addition to standard care.

Outcomes: The primary study outcome is the rate of kidney function decline (expressed as eGFR slope, in mL/min/1.73 m² per year) in HCT versus placebo-treated patients, calculated by linear mixed model analysis using all available creatinine values from week 12 until the end of treatment. Secondary outcomes include changes in quality-of-life questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, SF-12) and changes in 24-h urine volume.

Conclusion: The HYDRO-PROTECT study will demonstrate whether co-treatment with HCT can improve the renoprotective efficacy and tolerability of tolvaptan in patients with ADPKD.

Fig. 1

Administration of HCT in tolvaptan-treated ADPKD patients significantly reduces 24-h urine volume compared to baseline and placebo. HCT and placebo treatment were given in random order. BL, baseline visit. ***P < 0.01. Adapted from Kramers et al. [17]

Fig. 2

Schematic presentation of the HYDRO-PROTECT visit schedule. SV, screening visit; BV, baseline visit; EoT, end of treatment; EoS, end of study

Fig. 3

Governance structure. The Core Clinical Trial Working Group (CCTWG) will be responsible for the day-to-day trial management. The steering committee (SC) consists of the CCTWG and the principal investigators of each participating site and is tasked with major decisions regarding the study progress and design. The Data Monitoring Committee (DMC) is responsible for the safety of participants and advises the SC based on the interim analysis. A Patient Advisory Committee has been appointed to advise the SC regarding any patient-related matters. The Clinical Research Office is responsible for, among others, monitoring the trial and for providing safety data that can be assessed by the DMC and be sent to the competent authorities