Evaluation of Peritoneal Ultrafiltration with PolyCore in Patients with Congestive Heart Failure and Cardio Renal Syndrome: Impact on Mortality and Condition Worsening

The primary objective of this study is to evaluate the impact of **Peritoneal Ultrafiltration** with PolyCore on the composite endpoint of patient mortality or worsening of the patient's condition in individuals with **Congestive Heart Failure**. This is clinically relevant as it aims to address the critical outcomes of mortality and disease progression in a population with significant morbidity and mortality risks.

Secondary objectives include evaluating:

• The improvement of patients' conditions
• Changes in the Quality of Life
• Changes in the use of hospital resources
• Changes in NYHA class
• Changes in kidney function
• Urine output and urine sodium preservation
• Changes in the sympathetic nerve tone
• The need for loop diuretics
• Hospitalization requirements
• PolyCore safety

The clinical trial focuses on evaluating the impact of Peritoneal Ultrafiltration with PolyCore on patients with **Congestive Heart Failure**. The study population includes both male and female adult patients, with an age range corresponding to categories 3 and 4, which typically represent middle-aged to older adults. The trial does not involve a vulnerable population. Participants were selected based on specific inclusion criteria, such as having a left ventricular ejection fraction of 60% or less, a New York Heart Association (NYHA) Classification of III-IV, and persistency of right ventricular failure due to afterload mismatch. Additional criteria include cava vein enlargement, decreased kidney function with a measured glomerular filtration rate (mGFR) between 15 and 60 ml/min/1.73m², and elevated NT pro-BNP or BNP plasma concentrations. Participants must have experienced at least one episode of pulmonary or systemic congestion requiring high-dose intravenous diuretics in the six months prior to enrollment and be appropriate candidates for the PUF technique. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the impact of **peritoneal ultrafiltration** using PolyCore on the composite endpoint of patient mortality or worsening of the patient's condition in individuals with **congestive heart failure**. This is a Phase II/III, randomized, double-blind, controlled trial. The trial is expected to commence on April 1, 2024, and conclude by April 1, 2027. Participants will be involved for a maximum treatment period of 12 months, with the study drug administered intraperitoneally. The trial will include several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. The screening visit will confirm eligibility based on criteria such as age, left ventricular ejection fraction, and NT pro-BNP plasma concentration. Follow-up visits will assess primary and secondary endpoints, including patient mortality, hospitalization for cardiovascular causes, and changes in renal function. The end-of-study visit will evaluate the overall outcomes and safety, including adverse events and laboratory parameters. Participants may be terminated early from the study if they experience significant adverse effects or fail to comply with the study protocol. The primary endpoint focuses on a composite of patient mortality and hospitalization for cardiovascular causes, while secondary endpoints include quality of life assessments and changes in NYHA class. The trial aims to provide valuable insights into the efficacy and safety of PolyCore in managing congestive heart failure.

The clinical trial involves the administration of **PolyCore**, an experimental medication formulated as a **solution for peritoneal dialysis**. PolyCore is designed for **intraperitoneal use** and is administered at a maximum daily dose of 2 liters, with a total maximum dose of 2 liters over a treatment period of up to 12 weeks. The solution contains a combination of active substances, including **levocarnitine**, **magnesium chloride hexahydrate**, **sodium chloride**, **calcium chloride dihydrate**, **lactic acid**, **xylitol**, and **polydextrose**. These components are of chemical, mixture, and polymer origins, respectively, and are provided by IPERBOREAL PHARMA S.R.L.

Levocarnitine is a chemical substance included in the formulation to support metabolic processes. Magnesium chloride hexahydrate, also known as E511, is utilized for its electrolyte properties. Sodium chloride serves as a fundamental electrolyte, while calcium chloride dihydrate, synonymous with Calcii Chloridum Dihydricum, contributes to the solution's ionic balance. Lactic acid, a mixture, is incorporated for its role in maintaining pH balance. Xylitol, a chemical, is included for its osmotic properties, and polydextrose, a polymer known as E 1200, is used for its bulking and stabilizing effects.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The administration of PolyCore is monitored to ensure participant compliance with the dosing schedule, and the impact of the treatment on the composite endpoint of patient mortality or worsening of the patient's condition is evaluated. The trial aims to assess the efficacy of peritoneal ultrafiltration with PolyCore in preventing heart failure exacerbation in patients with cardio-renal syndrome.

Efficacy in the clinical trial titled "Peritoneal Ultrafiltration in Cardio Renal Syndrome to Prevent Heart Failure Exacerbation (PURE)" will be assessed using a combination of primary and secondary endpoints. The primary endpoint is a composite measure that includes patient mortality, hospitalization for cardiovascular causes (including the need for intravenous diuretics and/or hemofiltration), the necessity to increase the initial daily dose of loop diuretics by at least 30%, and worsening renal function defined as a decrease in estimated glomerular filtration rate (eGFR) by 10 ml/min/1.73 m².

Secondary endpoints will include assessments such as the 6-minute walking distance, quality of life measured by the Kansas City Cardiomyopathy Questionnaire, and a decrease in NT pro-BNP levels by at least 25% or BNP levels by at least 40%. Changes in the New York Heart Association (NYHA) class, hospitalization for intravenous therapy with loop diuretics, and the requirement for other treatment methods like peritoneal ultrafiltration (PUF) or hemodialysis will also be evaluated. Additional secondary endpoints include hospitalization for all causes, worsening of renal function as indicated by the percentage change in glomerular filtration rate (GFR), changes in the cumulative daily dosage of loop diuretics, and the use of hospital resources for cardiovascular causes. Safety will be monitored through adverse events, vital signs, physical examinations, ECG, and laboratory parameters.

These efficacy parameters will be measured at various timepoints throughout the trial, including visits V1, V3, V4, V5, V6, V7, V8, V9, and during long-term follow-up. The tools and instruments used for these assessments include validated scales and questionnaires, laboratory tests, and patient-reported outcomes. The trial is designed to evaluate the impact of treatment with PolyCore, a solution for peritoneal dialysis, on the composite endpoint of patient mortality or worsening of the patient's condition.