Evaluation of Acetazolamide and SGLT2 Inhibitors in Managing Volume Overload in Acute Heart Failure Patients

The primary objective of this study is the **improvement in natriuresis** in patients with volume overload and acute heart failure. This is clinically relevant as enhancing natriuresis can help manage fluid balance and reduce symptoms associated with acute heart failure, potentially improving patient outcomes. Secondary objectives include:

• Improvement in diuresis, which is important for reducing fluid retention and alleviating symptoms of congestion.
• Changes in different indices of congestion, providing insights into the effectiveness of the treatment in managing heart failure symptoms.
• Weight change, which can be an indicator of fluid status and overall treatment efficacy in heart failure management.

The clinical trial focuses on individuals diagnosed with **Acute Heart Failure**, aiming to assess the improvement in natriuresis. The study population includes both male and female participants aged 18 years and older. Participants are required to be on maintenance therapy with loop diuretics, specifically at least 40mg of furosemide or its equivalents, and must be deemed volume overloaded by their treating cardiologist, necessitating the addition of SGLT2 inhibitors and intravenous loop diuretic therapy. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are receiving consistent treatment for heart failure, which is crucial for the study's objective. The trial population was selected based on these specific medical and therapeutic criteria to ensure the relevance and accuracy of the study outcomes.

The clinical trial is designed to evaluate the efficacy of **acetazolamide** in combination with SGLT2 inhibitors in patients with volume overload and **acute heart failure**. This study is a randomized, double-blind, controlled trial aimed at improving natriuresis. The trial will involve the administration of **empagliflozin**, **dapagliflozin**, and **acetazolamide** in their respective pharmaceutical forms: film-coated tablets for oral administration and powder for solution for injection for intravenous use. The trial is expected to commence recruitment on January 22, 2024, and conclude by December 31, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as being 18 years or older, having heart failure, and being on maintenance therapy with loop diuretics. The primary endpoint is the measurement of 24-hour sodium excretion, while secondary endpoints include 24-hour volume output, weight change, and changes in plasma volume and neurohormonal stimulation. Follow-up visits will be scheduled to monitor these parameters and ensure participant safety. The end-of-study visit will conclude the trial, where final assessments will be conducted.

The expected length of participant involvement is approximately one year, with conditions for early termination including adverse events or withdrawal of consent. Participants will be monitored closely throughout the trial to ensure compliance with the protocol and to address any safety concerns promptly. The trial's design and procedures are structured to maintain scientific rigor and ensure the reliability of the results.

The clinical trial involves the administration of **Jardiance** 10 mg film-coated tablets, which contain the active substance **empagliflozin**. This medication is provided in the form of film-coated tablets and is administered orally. The dosage is set at 10 mg per day, with a maximum treatment period of one day. The tablets are manufactured by Boehringer Ingelheim International GmbH and are chemically derived. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another experimental medication used in the trial is **Forxiga** 10 mg film-coated tablets, containing the active substance **dapagliflozin**. Similar to Jardiance, Forxiga is also administered orally in the form of film-coated tablets. The dosage is 10 mg per day, with a maximum treatment period of one day. This medication is produced by AstraZeneca AB and is of chemical origin. Compliance with the administration schedule will be closely monitored.

The trial also includes the administration of **DIAMOX** parenteraal 500 mg poeder voor injectievloeistof, which contains the active substance **acetazolamide**. This medication is provided as a powder for solution for injection and is administered intravenously. The dosage is 500 mg per day, with a maximum treatment period of one day. Manufactured by Amdipharm Limited, this medication is chemically derived. Monitoring of participant compliance with the dosing schedule will be conducted throughout the trial.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for this study. The trial focuses on the combination of these medications to assess their efficacy in patients with volume overload and acute heart failure, with the main objective being the improvement in natriuresis.

The clinical trial aims to assess the efficacy of **acetazolamide** in combination with SGLT2 inhibitors in patients experiencing volume overload and acute heart failure. The primary endpoint for evaluating efficacy is the 24-hour sodium excretion. Secondary endpoints include 24-hour volume output, weight change, congestion assessment according to the ADVOR protocol, plasma volume changes, changes in neurohormonal stimulation (renin, aldosterone), and changes in POCUS (Heart, IVC, lung, abdomen, JVP).

Measurements for these endpoints will be collected and analyzed at specified intervals throughout the trial. The trial is designed to ensure that data collection is systematic and consistent, utilizing validated methods and tools appropriate for each parameter. The trial is scheduled to commence recruitment on January 22, 2024, with an estimated end date of December 31, 2025. The trial will involve the administration of acetazolamide and SGLT2 inhibitors, with the treatment period for each product being one day, administered orally or intravenously as appropriate.