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

Study Overview
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Brief Summary
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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.

Detailed Description
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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)

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

Conditions
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ADPKD

Intervention / Treatment
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* Drug: Hydrochlorothiazide 25 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: An investigator driven, multicenter, placebo-controlled, randomized clinical trial.
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADPKD, Tolvaptan, Hydrochlorothiazide, Quality of Life, Side effects, Polyuria