THINK - intensification of blood pressure lowering Therapeutics based on diuretics versus usual management for uncontrolled Hypertension IN patients with moderate to severe chronic Kidney disease: an open label, cluster randomized controlled, phase 3 trial

The primary objective of this study is to evaluate the **efficacy** of an algorithm based on diuretic agents in patients with moderate to severe chronic kidney disease and uncontrolled hypertension. The focus is on reducing the incidence of end-stage kidney disease, chronic kidney disease progression, cardiovascular events, and mortality. This is clinically relevant as it addresses critical outcomes in a population with significant morbidity and mortality risks.

Secondary objectives include assessing the efficacy of the strategy on various health parameters:

• End-stage kidney disease
• Chronic kidney disease progression
• Cardiovascular events
• All-cause mortality
• Systolic and diastolic blood pressure
• Hypertension control
• Renal function changes
• Proteinuria
• Use of diuretics
• Quality of life
• Safety (clinical and biological)

The clinical trial focuses on **uncontrolled hypertension** in patients with moderate to severe chronic kidney disease. The study population includes both male and female participants aged 18 years and older, with a clinical frailty score of 5 or less for those over 80 years of age. Participants are required to have advanced or moderate chronic kidney disease, with an estimated glomerular filtration rate (eGFR) between 15.0 to 44.9 ml/min/1.73m², and must be undergoing treatment for arterial hypertension with at least one blood pressure-lowering drug therapy, specifically blockers of the renin-angiotensin system, at the maximum tolerated dosage. The trial does not involve a vulnerable population. Participants must have uncontrolled office blood pressure confirmed by home or ambulatory monitoring. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of a diuretic-based algorithm in patients with **uncontrolled hypertension** and moderate to severe **chronic kidney disease**. This is an open-label, cluster randomized controlled, phase 3 trial. The trial aims to assess the reduction in the incidence of end-stage kidney disease, progression of chronic kidney disease, cardiovascular events, and mortality. The study will involve a series of visits, starting with an inclusion visit where participants will be screened based on specific criteria, including age, clinical frailty score, and existing treatment for hypertension. Participants must have uncontrolled blood pressure confirmed by home or ambulatory monitoring.

The trial will be conducted over an estimated duration from March 2023 to March 2029, with a maximum treatment period of 36 months for each participant. The trial will include follow-up visits at months 3 and 6, and then every 6 months, to monitor changes in blood pressure, glomerular filtration rate, and proteinuria. The primary endpoint is the time to a composite event, including end-stage kidney disease, significant decline in eGFR, cardiovascular events, and all-cause mortality. Secondary endpoints include time to individual events, changes in blood pressure and kidney function, and quality of life assessments.

Participants will be involved in the study for up to 36 months, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with the study protocol. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged. The trial will utilize **indapamide**, **amiloride hydrochloride**, **hydrochlorothiazide**, and **furosemide**, administered orally, with specific dosing regimens tailored to each participant's needs. The study is categorized as a low-intervention trial, ensuring minimal risk to participants while providing valuable insights into the management of hypertension in chronic kidney disease.

The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in patients with moderate to severe chronic kidney disease and uncontrolled hypertension. The first medication is **Indapamide**, provided in the form of a film-coated tablet. The maximum daily dose is 2.5 mg, with a total maximum dose of 22.44 g over the treatment period. Indapamide is administered orally, and the treatment duration is up to 36 months. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

Another experimental medication used in the trial is **Amiloride Hydrochloride**, available as a tablet. The maximum daily dose for this medication is 5 mg, with a total maximum dose of 5.47 g over the course of the study. Like Indapamide, Amiloride Hydrochloride is administered orally, and the treatment period extends up to 36 months. Compliance monitoring is conducted to ensure participants adhere to the prescribed dosing regimen.

The trial also includes a prolonged-release formulation of **Indapamide**, provided as a prolonged-release film-coated tablet. The maximum daily dose for this formulation is 1.5 mg, with a total maximum dose of 1.64 g. This medication is administered orally, with a treatment period of up to 36 months. Participant adherence to the dosing schedule is closely monitored throughout the trial.

**Hydrochlorothiazide** is another medication used in the study, available in tablet form. The maximum daily dose is 25 mg, with a total maximum dose of 27.37 g over the treatment period. This medication is administered orally, and the treatment duration is up to 36 months. Compliance with the dosing schedule is monitored to ensure participant adherence.

Lastly, **Furosemide** is included in the trial, provided as a tablet. The maximum daily dose is 120 mg, with a total maximum dose of 131.4 g over the course of the study. Furosemide is administered orally, and the treatment period extends up to 36 months. Participant compliance is monitored to ensure adherence to the prescribed dosing regimen.

All medications in the trial are administered orally, and the treatment period for each medication is up to 36 months. Compliance monitoring is an integral part of the study to ensure participants adhere to the dosing schedules. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is on evaluating the efficacy of these diuretic agents in reducing the incidence of end-stage kidney disease, chronic kidney disease progression, cardiovascular events, and mortality.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is a composite measure that includes the time to event outcome, specifically focusing on the incidence of end-stage kidney disease, a decline in estimated glomerular filtration rate (eGFR) by 40% or more, cardiovascular events such as myocardial infarction, heart failure hospitalization, stroke, and all-cause mortality. These events will be tracked to determine the effectiveness of the diuretic-based algorithm in patients with moderate to severe chronic kidney disease and uncontrolled hypertension.

Secondary endpoints will provide additional insights into the efficacy of the treatment. These include the time to end-stage kidney disease, time to a 40% decrease in eGFR, time to the first cardiovascular event, and all-cause mortality. Changes from baseline in systolic and diastolic blood pressure will be measured at months 3 and 6, and then every 6 months, using both home blood pressure monitoring and office measurements. The proportion of patients achieving controlled blood pressure at 2 years will also be evaluated. Furthermore, changes from baseline in eGFR, proteinuria, and quality of life, assessed by the PROMIS-29 survey, will be monitored at specified intervals. Safety parameters such as volume depletion, dyskalemia, hyponatremia, acute kidney injury, gout, and orthostatic hypotension will also be assessed.