Evaluation of Patiromer in Facilitating RAAS Inhibitor Optimization in Patients with Stage 3b/4 Chronic Kidney Disease: A Randomized Controlled Trial

The primary objective of this study is to demonstrate that **patiromer**, compared with placebo, more effectively enables the up-titration of RAAS-blocker treatment in patients with **chronic kidney disease** (CKD) stage 3b/4, leading to a significant reduction in albuminuria. This is clinically relevant as albuminuria is a marker of kidney damage and its reduction is associated with improved renal outcomes in CKD patients.

Secondary objectives include evaluating the impact on systolic and diastolic blood pressure through 24-hour ambulatory blood pressure measurement, plasma potassium levels, and kidney function as indicated by the estimated glomerular filtration rate (eGFR) using the combined cystatin C-creatinine-based CKD-EPI formula. Additionally, the study will assess the achieved irbesartan dose and the number of severe adverse events at the end of each study period. These secondary endpoints provide a comprehensive assessment of the treatment's safety and efficacy profile, which is crucial for optimizing therapeutic strategies in CKD management.

The clinical trial involves participants diagnosed with **chronic kidney disease** (CKD) at stages 3b and 4. The study population includes both male and female subjects aged 18 years and older. Participants are generally in a stable health condition, with specific criteria such as an estimated glomerular filtration rate (eGFR) between 15-44 mL/min/1.73 m², an albumin-creatinine ratio greater than 30 mg/mmol, and a serum potassium level between 4.0-5.0 mmol/L. They are either experiencing systolic blood pressure over 130 mmHg or are on one or more antihypertensive medications. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria ensure that participants are on a sub-maximal dose of ACE inhibitors or angiotensin receptor blockers (ARBs). Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **patiromer** in enabling the up-titration of RAAS-blocker treatment in patients with **chronic kidney disease** (CKD) stage 3b/4. This study is a randomized, double-blind, placebo-controlled trial, with an estimated duration from February 2024 to October 2025. Participants will be randomly assigned to receive either patiromer or a placebo, with the primary endpoint being the 24-hour urinary albumin excretion, adjusted for creatinine, at the end of each study period. Secondary endpoints include systolic and diastolic blood pressure, plasma potassium levels, kidney function as measured by the estimated glomerular filtration rate (eGFR), the achieved dose of **irbesartan**, and the number of adverse events.

The trial will commence with a screening visit to confirm eligibility based on criteria such as age (≥18 years), CKD stage, albumin-creatinine ratio, blood pressure, serum potassium levels, and current medication use. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy parameters, including a safety visit one week after the start of treatment. The end-of-study visit will assess the primary and secondary endpoints, ensuring comprehensive data collection for analysis. The expected length of participant involvement is up to 12 months, with conditions for early termination including significant adverse events or non-compliance with the study protocol.

The clinical trial involves the administration of **IRBESARTAN**, a pharmaceutical product containing the active substances **hydrochlorothiazide** and **irbesartan**. This medication is provided in an oral form, with a maximum daily dose of 300 mg. The treatment period is set for a maximum of 12 months. The administration route is oral, and the medication is intended to be used as a standard-of-care therapy in the study. Participant compliance will be monitored throughout the trial to ensure adherence to the dosing schedule.

Additionally, the trial includes the use of **PATIROMER**, a non-absorbed, cation exchange polymer, which is also administered orally. The maximum daily dose for patiromer is 25.2 g, with a treatment period extending up to 12 months. This experimental medication is being evaluated for its efficacy in enabling the up-titration of RAAS-blocker treatment in patients with chronic kidney disease (CKD) stage 3b/4, aiming to achieve a significant reduction in albuminuria.

A placebo, composed of microcrystalline cellulose and xanthan gum, is utilized in the study to serve as a comparator treatment. The placebo is designed to match the experimental medication in appearance and administration route, ensuring blinding of the study. The placebo does not contain any active pharmaceutical ingredients and is used to assess the efficacy of patiromer in comparison to a non-active treatment.

Efficacy in the clinical trial titled "PROMISE: Potassium correction for RAAS Optimization in Chronic Kidney Disease" will be assessed using specific primary and secondary endpoints. The primary endpoint is the 24-hour urinary albumin excretion, adjusted for creatinine, known as the albumin-creatinine ratio (ACR), measured at the end of each study period. This endpoint is crucial for evaluating the effect of the treatment on albuminuria in patients with chronic kidney disease (CKD) stage 3b/4.

Secondary endpoints include systolic and diastolic blood pressure, which will be assessed through a 24-hour ambulatory blood pressure measurement at the end of each study period. Additional secondary endpoints are plasma potassium levels, kidney function as indicated by the estimated glomerular filtration rate (eGFR) using the combined cystatin C-creatinine-based CKD-EPI formula, the achieved dose of **irbesartan**, and the number of severe adverse events recorded at the end of each study period. These endpoints will provide a comprehensive evaluation of the treatment's impact on various aspects of patient health and treatment tolerability.