HYDROchlorothiazide to PROTECT polycystic kidney disease patients and improve their quality of life (HYDRO-PROTECT)

The primary objective of the HYDRO-PROTECT study is to evaluate the long-term effect of co-treatment with **hydrochlorothiazide** (HCT) on the efficacy and tolerability of **tolvaptan** in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). This is clinically relevant as ADPKD leads to progressive renal cyst formation and loss of kidney function, and current treatments are limited by side effects. The study aims to assess the rate of kidney function decline, expressed as the estimated glomerular filtration rate (eGFR) slope, in patients treated with HCT compared to those receiving a placebo. This outcome is crucial for understanding the potential of HCT to enhance the renoprotective efficacy of tolvaptan while mitigating its aquaretic side effects.

Secondary objectives focus on various endpoints related to kidney function, quality of life, tolerability, and safety. These include:

• Changes in eGFR between baseline and end of study (off treatment)
• Incidence of a 30% decrease in eGFR, end-stage kidney disease, or death from renal causes
• Quality of life assessments
• Changes in quality of life-related questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, and SF-12)
• Changes in 24-hour urine volume
• Tolvaptan dose and discontinuation rate
• Changes in serum electrolytes (potassium, sodium, calcium, and phosphate)
• Changes in blood pressure

The clinical trial involves a total of **60 participants** diagnosed with **Autosomal Dominant Polycystic Kidney Disease (ADPKD)**. The study population includes both male and female subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants were selected based on specific criteria, including a confirmed diagnosis of ADPKD according to modified Ravine criteria, an estimated glomerular filtration rate (eGFR) greater than 25 mL/min/1.73m² (or greater than 35 mL/min/1.73m² in Belgium), and stable treatment with the highest tolerated dose of vasopressin 2 receptor antagonists (V2RA) for at least three months. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study aims to evaluate the long-term effects of co-treatment with hydrochlorothiazide on the efficacy and tolerability of tolvaptan in ADPKD patients.

The clinical trial is designed to evaluate the long-term effects of co-treatment with **hydrochlorothiazide** (HCT) on the efficacy and tolerability of **tolvaptan** in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). This study is a randomized, double-blind, placebo-controlled trial, which will assess the primary outcome of the rate of kidney function decline, expressed as the estimated glomerular filtration rate (eGFR) slope, in milliliters per minute per 1.73 square meters per year. The trial will utilize a linear mixed model analysis of all available creatinine values from week 12 until the end of treatment at week 156. Secondary endpoints include changes in eGFR between baseline and end-of-study, incidence of a 30% decrease in eGFR, end-stage kidney disease, or death from renal causes, and changes in quality of life, urine volume, tolvaptan dose, serum electrolytes, and blood pressure.

The trial is expected to last approximately five years, with an estimated recruitment start date of April 1, 2023, and an estimated end date of April 1, 2028. Participants will be involved in the study for a maximum of 156 weeks. The study will begin with an inclusion visit, where participants will be screened based on criteria such as a confirmed diagnosis of ADPKD, age of 18 years or older, and an eGFR greater than 25 mL/min/1.73m². Participants must also be on stable treatment with the highest tolerated dose of vasopressin 2 receptor antagonists for at least three months. Follow-up visits will occur at regular intervals to monitor kidney function, quality of life, and other health parameters. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with study procedures, or if their health status changes in a way that contraindicates continued participation. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **Tolvaptan**, marketed under the name Jinarc, which is provided in tablet form. The pharmaceutical formulation includes 30 mg and 90 mg tablets. The active substance, **Tolvaptan**, is a chemical compound with the synonyms (±)-4’-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-o-tolu-m-toluidide and OPC-41061. The medication is administered orally, with a maximum daily dose of 120 mg and a total maximum dose of 131,400 mg over a treatment period of up to 156 weeks. The product is authorized in the EU and is manufactured by Otsuka Pharmaceutical Netherlands B.V.

**Hydrochlorothiazide** is used as a non-experimental treatment in this study. It is provided in film-coated tablet form and is administered orally. The maximum daily dose is 25 mg, with a total maximum dose of 27,375 mg over a treatment period of up to 1,095 days. The active substance, **Hydrochlorothiazide**, is a chemical compound, and the product is identified by the scientific product code SUB08062MIG.

A placebo is also utilized in the trial, specifically a placebo of **Hydrochlorothiazide**. The placebo is designed to mimic the appearance and administration route of the active medication, ensuring blinding in the study. The pharmaceutical form and specific administration details of the placebo are not provided, but it is implied to be administered in a manner consistent with the active comparator.

The efficacy of the clinical trial titled "HYDROchlorothiazide to PROTECT polycystic kidney disease patients and improve their quality of life (HYDRO-PROTECT)" will be assessed primarily by evaluating the rate of kidney function decline in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). This will be expressed as the **eGFR slope** in mL/min/1.73m² per year. The primary endpoint involves a comparison between patients treated with hydrochlorothiazide (HCT) and those receiving a placebo. The analysis will utilize a linear mixed model to calculate the eGFR slope, incorporating all available creatinine values from week 12 until the end of treatment (week 156).

Secondary endpoints include several parameters: changes in eGFR from baseline to the end of the study, the incidence of a 30% decrease in eGFR, progression to end-stage kidney disease, or death from renal causes. Additionally, changes in quality of life will be measured using validated questionnaires such as TIPS, ADPKD-UIS, EQ-5D-5L, and SF-12. Other secondary measures include changes in 24-hour urine volume, tolvaptan dose and discontinuation rate, serum electrolyte levels (potassium, sodium, calcium, and phosphate), and blood pressure. These assessments will provide a comprehensive evaluation of the treatment's efficacy and its impact on patient quality of life.