HYDROchlorothiazide to PROTECT Polycystic Kidney Disease Patients and Improve Their Quality of Life

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)

• Hydrochlorothiazide 25 mg (Drug): An oral capsule containing 25mg of hydrochlorothiazide
• Placebo (Drug): A matching oral capsule containing placebo

Primary outcomes

• Changes in kidney function decline [156 weeks]: 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.

Secondary outcomes

• Changes in eGFR from baseline compared to end of study (12 weeks after End of Treatment) [168 weeks]: A secondary outcome is the change in eGFR from baseline compared to end of study (12 weeks after end of treatment)
• Incidence of 30% decrease in eGFR, end stage kidney disease (EKSD) or renal death [168 weeks]: 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)
• Changes in 24-hour urine volume [156 weeks]: 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)
• Quality of life, assessed by the TIPS questionnaire [156 weeks]: 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)
• Quality of life, assessed by the ADPKD-UIS questionnaire [156 weeks]: 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)
• Quality of life, assessed by the SF-12 questionnaire [156 weeks]: 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)
• Quality of life, assessed by the EQ-5D questionnaire [156 weeks]: 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)
• Change in V2RA dose [168 weeks]: 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
• Change in V2RA discontinuation rate [168 weeks]: 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
• Changes in serum sodium concentration [168 weeks]: 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)
• Changes in serum potassium concentration [168 weeks]: 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)
• Changes in plasma serum calcium concentration [168 weeks]: 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)
• Changes in serum phosphate concentration [168 weeks]: 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)
• Incidence of (serious) adverse events [168 weeks]: Incidence of (serious) adverse events from baseline until the end of study (12 weeks after end of treatment)

Sex: All, ages: 18 Years to 80 Years

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)

• Prof. dr. R.T. Gansevoort, Principal investigator, University Medical Center Groningen