HYDROchlorothiazide to PROTECT Polycystic Kidney Disease Patients and Improve Their Quality of Life (HYDRO-PROTECT)

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive formation of renal cysts which ultimately lead to a loss of renal function.

Tolvaptan (a V2R antagonist) is currently the only effective treatment for preserving renal function in ADPKD. However, side-effects such as polyuria limit its tolerability and thereby the therapeutic potential. This study will test whether co-administration with hydochlorothiazide can improve V2RA efficacy (slowing kidney function decline) and tolerability (quality of life) in ADPKD. Approximately 300 patients will be enrolled.

Study Overview

• Status: Recruiting
• Conditions: ADPKD
• Intervention / Treatment: Drug: Hydrochlorothiazide 25 mg; Drug: Placebo

Detailed Description

Aims: The main objectives of the current study are to prospectively test whether HCT co-treatment can improve V2RA efficacy (slowing kidney function decline) and tolerability (quality of life) in PKD.

Study design: Investigator driven randomized placebo-controlled multicenter trial

Study population: 300 ADPKD patients of ≥18 years, with an eGFR of > 25 mL/min/1.73m2, on stable treatment with the highest tolerated dose of V2RA

Intervention: Oral HCT 25 mg once daily or matching placebo for a total of 156 weeks. The randomization ratio will be 1:1.

Study visit schedule: study measurements will be performed during 12-weekly visits (which is routine care for V2RA treated patients), except for one additional study visit (or telephone call) 2 weeks after the start of treatment

Primary study outcome: Slope of kidney function decline (measured by eGFR)

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Dr. E Meijer; Phone Number: +31 50 3616161; Email: esther.meijer@umcg.nl
• Study Contact Backup: Name: T. Bais, MD; Email: t.bais@umcg.nl

Study Locations

• Belgium
  • Brussels, Belgium
    • Recruiting
    • Cliniques Universitaires Saint-Luc
    • Contact: Prof. Nathalie Demoulin
  • Leuven, Belgium
    • Recruiting
    • University Hospital Leuven
    • Contact: Prof dr. B. Bammens
• France
  • Brest, France
    • Recruiting
    • Hospital La Cavale Blanche
    • Contact: Prof. dr. E. Cornec-Le Gall
  • Paris, France
    • Recruiting
    • Necker-Enfants Malades Hospital
    • Contact: Prof dr. B. Knebelmann
• Germany
  • Berlin, Germany
    • Recruiting
    • Charite University Hospital
    • Contact: Prof J. Halbritter
  • Cologne, Germany
    • Recruiting
    • University Hospital Cologne
    • Contact: Prof. dr. R.U. Müller
  • Dresden, Germany
    • Recruiting
    • Med. Klinik und Poliklinik III, Universitätsklinikum Dresden.
    • Contact: Alexander Paliege
• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • Amsterdam University Medical Center
    • Contact: Prof dr. M. van Ittersum
  • Groningen, Netherlands
    • Recruiting
    • University Medical Center Groningen
    • Contact: dr. E. Meijer; Phone Number: +31 50 3616161; Email: esther.meijer@umcg.nl
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus University Medical Center
    • Contact: dr. M. Salih
• Spain
  • Barcelona, Spain
    • Recruiting
    • Fundacion Puigvert
    • Contact: Prof. dr. R. Torra
  • Madrid, Spain
    • Recruiting
    • La Fundación Jiménez Díaz
    • Contact: María Vanessa Pérez Gómez

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ADPKD diagnosis (modified Ravine criteria)
• ≥18 years old
• eGFR > 25 mL/min/1.73m2
• On stable treatment with the highest tolerated dose of V2RA for a minimum of 3 months

Exclusion Criteria:

• Known intolerance to hydrochlorothiazide
• Use of any diuretic
• Orthostatic hypotension complaints or blood pressure <105/65mmHg during screening visit
• Uncontrolled hypertension (blood pressure >160/100mmHg)
• Hypokalemia (<3.5 mmol/L)
• History of active gout on maintenance preventive treatment for gout (allopurinol, desuric and/or colchicine), defined as ≥2 episodes during the last year
• History of skin cancer (basal cell, squamous cell and melanoma)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hydrochlorothiazide; Oral hydrochlorothiazide 25mg, once daily, for a total of 156 weeks	Drug: Hydrochlorothiazide 25 mg; An oral capsule containing 25mg of hydrochlorothiazide
Placebo Comparator: Placebo; Matching oral placebo, once daily, for a total of 156 weeks. The placebo is inert.	Drug: Placebo; A matching oral capsule containing placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in kidney function decline	The primary outcome is the change in kidney function decline (assessed as eGFR slope, in ml/min/1.73 m2 per year), calculated with linear mixed models, using all available creatinine values from week 12 until end of treatment between the tolvaptan/placebo and tolvaptan/HCT group.	156 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in eGFR from baseline compared to end of study (12 weeks after End of Treatment)	A secondary outcome is the change in eGFR from baseline compared to end of study (12 weeks after end of treatment)	168 weeks
Incidence of 30% decrease in eGFR, end stage kidney disease (EKSD) or renal death	A secondary outcome is the incidence of a 30% decrease in eGFR, occurrence of end stage kidney disease (EKSD) or renal death during the entire study period (until the end of study (12 weeks after end of treatment)	168 weeks
Changes in 24-hour urine volume	A secondary outcome is the change in 24-hour urine volume, measured at baseline, week 12, week 48, week 96 and week 156 (end of treatment)	156 weeks
Quality of life, assessed by the TIPS questionnaire	Changes in Quality of Life measured by the Tolvaptan Impact of Polyuria Scale questionnaire (TIPS) at baseline, week 12, week 48, week 96 and week 156 (end of treatment)	156 weeks
Quality of life, assessed by the ADPKD-UIS questionnaire	Changes in Quality of Life measured by the ADPKD-Urinary Impact Scale questionnaire (ADPKD-UIS) at baseline, week 12, week 48, week 96 and week 156 (end of treatment)	156 weeks
Quality of life, assessed by the SF-12 questionnaire	Changes in Quality of Life measured by the Short Form 12 questionnaire (SF-12) at baseline, week 12, week 48, week 96 and week 156 (end of treatment)	156 weeks
Quality of life, assessed by the EQ-5D questionnaire	Changes in Quality of Life measured by the EuroQol-5 Dimension questionnaire (EQ-5D) at baseline, week 12, week 48, week 96 and week 156 (end of treatment)	156 weeks
Change in V2RA dose	V2RA dose during each study visit and compared at the end of study visit (12 weeks after end of treatment) between tolvaptan/placebo and tolvaptan/hydrochlorothiazide group	168 weeks
Change in V2RA discontinuation rate	The V2RA discontinuation rate will be compared at the end of study visit (12 weeks after end of treatment) between tolvaptan/placebo and tolvaptan/hydrochlorothiazide group	168 weeks
Changes in serum sodium concentration	Changes in serum sodium concentration between tolvaptan/placebo and tolvaptan/hydrochlorothiazide group, measured from baseline until the end of study (12 weeks after end of treatment)	168 weeks
Changes in serum potassium concentration	Changes in serum potassium concentration between tolvaptan/placebo and tolvaptan/hydrochlorothiazide group, measured from baseline until the end of study (12 weeks after end of treatment)	168 weeks
Changes in plasma serum calcium concentration	Changes in plasma serum calcium concentration between tolvaptan/placebo and tolvaptan/hydrochlorothiazide group, measured from baseline until the end of study (12 weeks after end of treatment)	168 weeks
Changes in serum phosphate concentration	Changes in serum phosphate concentration between tolvaptan/placebo and tolvaptan/hydrochlorothiazide group, measured from baseline until the end of study (12 weeks after end of treatment)	168 weeks
Incidence of (serious) adverse events	Incidence of (serious) adverse events from baseline until the end of study (12 weeks after end of treatment)	168 weeks

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Investigators: Principal Investigator: Prof. dr. R.T. Gansevoort, University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2024
• Primary Completion (Estimated): July 1, 2030
• Study Completion (Estimated): July 1, 2031

Study Registration Dates

• First Submitted: April 28, 2022
• First Submitted That Met QC Criteria: May 10, 2022
• First Posted (Actual): May 13, 2022

Study Record Updates

• Last Update Posted (Actual): February 25, 2026
• Last Update Submitted That Met QC Criteria: February 23, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Quality of Life; ADPKD; Side effects; Tolvaptan; Hydrochlorothiazide; Polyuria
• Additional Relevant MeSH Terms: Ciliopathies; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genetic Diseases, Inborn; Urination Disorders; Urological Manifestations; Congenital Abnormalities; Abnormalities, Multiple; Kidney Diseases, Cystic; Polycystic Kidney Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Polycystic Kidney, Autosomal Dominant; Polyuria; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Sulfonamides; Sulfones; Chlorothiazide; Benzothiadiazines; Thiazides; Hydrochlorothiazide
• Other Study ID Numbers: 202100714; 2021-005612-61 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No