Evaluation of Combined Diuretic Therapy with Acetazolamide and Metolazone on Exercise Capacity and Euvolemia in Chronic Congestive Heart Failure Patients

The primary objective of this study is to compare two distinct treatment strategies in patients with **chronic heart failure**. The control arm will be treated with loop diuretics and potassium-sparing diuretics, while the experimental arm will combine these therapies with acetazolamide and a free-dose of metolazone. This comparison is clinically relevant as it aims to determine the efficacy of combined diuretic therapy in managing chronic heart failure, potentially leading to improved patient outcomes.

Secondary objectives include:

• Assessing the degree of congestion and volemia through body weight changes and vector impedance measurement (BIVA) between patients treated with standard versus combined diuretic therapy.
• Evaluating differences in functional capacity using cardiopulmonary exercise testing (CPET) with VO2 max measurement and alveolar-capillary diffusion between the two treatment groups.
• Assessing differences in the trend of subjective health perception using the Kansas City Cardiomyopathy Questionnaire.
• Evaluating differences in neurohormonal response by measuring NT-proBNP levels.

The clinical trial involves participants diagnosed with **congestive heart failure**, specifically targeting individuals aged 18 to 80 years. Both male and female subjects are included in the study, with no vulnerable populations being selected. The trial population was chosen based on specific criteria, including patients with chronic heart failure, either with reduced or preserved ejection fraction, who have been discharged after hospitalization for acute heart failure, having experienced at least a second episode of decompensation in the past 12 months. Participants are required to be on loop diuretics at a dosage equivalent to or higher than furosemide 40 mg at the time of admission. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. Key inclusion criteria include the necessity for written informed consent. The study does not focus on any specific lifestyle considerations beyond the medical treatment regimen.

The clinical trial is designed to evaluate the effects of combined diuretic therapy on exercise capacity, alveolar-capillary diffusion, and maintenance of euvolemia in patients with **congestive heart failure**. This study employs a randomized, double-blind, controlled design to compare two treatment strategies: a control arm treated with loop diuretics and potassium-sparing diuretics, and an experimental arm that combines this therapy with **acetazolamide** and free-dose **metolazone**. The trial is expected to run until January 31, 2027, with recruitment starting on December 21, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-80 years), diagnosis of chronic heart failure, and current treatment with loop diuretics. Following the screening, participants will be randomized into one of the two treatment arms. The study will include regular follow-up visits to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The primary endpoint is to evaluate differences in the trend of short- to medium-term re-hospitalizations between the two groups. The end-of-study visit will assess the overall outcomes and gather final data.

The expected length of participant involvement is up to three months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial aims to provide valuable insights into the efficacy of combined diuretic therapy in managing chronic heart failure, potentially influencing future treatment guidelines.

The clinical trial involves the administration of **Zaroxolyn 5 mg** tablets, which contain the active substance **metolazone**. This medication is provided in tablet form and is intended for **oral use**. The maximum daily dose is 5 mg, with a total treatment period not exceeding three weeks. The tablets are manufactured by TEOFARMA S.R.L. and are chemically derived. Participants are required to adhere to the prescribed dosing schedule to ensure compliance and accurate assessment of the treatment's efficacy.

Another experimental medication used in the trial is **Zaroxolyn 10 mg** tablets, also containing **metolazone** as the active ingredient. Similar to the 5 mg formulation, these tablets are administered orally. The maximum daily dose is 5 mg, and the treatment duration is limited to three weeks. The pharmaceutical form remains consistent as a tablet, and the chemical origin of the active substance is maintained. Compliance with the dosing regimen is monitored throughout the trial to ensure participant adherence.

The trial also includes the administration of **DIAMOX 250 mg** tablets, which contain **acetazolamide** as the active substance. These tablets are designed for **oral use** and have a maximum daily dose of 750 mg. The treatment period is capped at three weeks. The tablets are produced by TEOFARMA S.R.L. and are of chemical origin. Participant compliance with the dosing schedule is crucial for evaluating the treatment's impact on chronic heart failure.

In addition to the experimental medications, the trial includes a control arm where participants receive standard-of-care therapy consisting of loop diuretics and potassium-sparing diuretics. This comparator treatment serves as a baseline to evaluate the efficacy of the experimental arm, which combines the standard therapy with acetazolamide and a free-dose regimen of metolazone. The trial's objective is to assess the effects of these combined diuretic therapies on exercise capacity, alveolar-capillary diffusion, and the maintenance of euvolemia in patients with chronic congestive heart failure.

Efficacy in this clinical trial will be assessed by evaluating the primary endpoint, which is the difference in the trend of short- to medium-term re-hospitalizations between patients with chronic heart failure treated with standard diuretic therapy (control arm) and those receiving combination diuretic therapy (experimental arm). The trial aims to compare two treatment strategies: the control arm treated with loop diuretics and potassium-sparing diuretics, and the experimental arm that combines this therapy with **acetazolamide** and free-dose **metolazone**. The assessment will focus on the ability of these treatment strategies to maintain euvolemia and improve exercise capacity and alveolar-capillary diffusion in patients with chronic congestive heart failure. The trial is designed to provide insights into the efficacy of the combination therapy over a specified treatment period, with the primary endpoint being a critical measure of success in reducing re-hospitalization rates.