Randomized, Double-Blind Trial Comparing Fentanyl Continuous Infusion Versus Morphine Bolus for Refractory Dyspnea in Acute Heart Failure Hospitalizations

The primary objective of this clinical trial is to evaluate the **effectiveness** and **tolerability** of **fentanyl** administered in continuous parenteral perfusion, compared with the administration of **morphine** on demand, for the treatment of refractory **dyspnea** in patients hospitalized for acute decompensation of **heart failure**. This objective is clinically relevant as it aims to determine the optimal management strategy for alleviating severe dyspnea, a common and distressing symptom in heart failure patients, potentially improving patient outcomes and quality of life.

Secondary objectives include evaluating the effectiveness and tolerability of fentanyl in continuous parenteral perfusion compared with the administration of morphine on demand for the treatment of refractory dyspnea in the same patient population. These secondary objectives will provide additional insights into the comparative benefits and risks of these two opioid treatments, further informing clinical decision-making in the management of refractory dyspnea in acute heart failure.

The clinical trial involves participants who are **hospitalized** for acute decompensation of heart failure (HF) and are experiencing refractory dyspnea. The study population includes both male and female subjects aged 18 years and older. Participants are selected based on their hospitalization at the Mútua Terrassa University Hospital in the internal medicine units and complex chronic patient unit due to HF decompensation of any etiology. The trial does not involve a vulnerable population. Participants are required to have refractory dyspnea that persists despite treatment and must have received two or more doses of 3 mg of subcutaneous morphine on demand for dyspnea in the previous 24 hours. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include the ability to provide informed consent or have a family member or primary caregiver do so, and the expectation that the participant or their caregiver can complete questionnaires on the effectiveness and tolerability of the drugs administered.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the effectiveness and tolerability of **fentanyl** in continuous parenteral perfusion compared to on-demand bolus administration of morphine for the treatment of refractory dyspnea in patients hospitalized due to acute decompensation of heart failure. The trial is expected to span from March 2021 to November 2028, with participant involvement lasting up to 36 months. The study will include several key visits: an initial screening visit to assess eligibility, multiple follow-up visits to monitor treatment efficacy and safety, and a final end-of-study visit to conclude participation.

Participants will be required to meet specific inclusion criteria, such as being 18 years or older, hospitalized for heart failure decompensation, and experiencing refractory dyspnea despite optimized treatment. They must have received at least two doses of 3 mg of subcutaneous morphine for dyspnea in the previous 24 hours. Informed consent is mandatory, either from the patient or a family member if the patient is unable to provide it. The primary endpoint is the reduction in the average daily intensity of dyspnea, assessed using a Verbal Numerical Scale and a Visual Analogue Scale at various intervals (0h, 24h, 48h, and 72h).

Participants may be withdrawn from the study if they experience adverse effects that compromise safety, fail to comply with the study protocol, or withdraw consent. The trial aims to provide valuable insights into the comparative effectiveness of **fentanyl** and morphine in managing refractory dyspnea, potentially influencing future treatment guidelines for patients with acute heart failure decompensation.

The clinical trial involves the administration of **Fentanyl**, a potent opioid analgesic, as the experimental medication. **Fentanyl** is provided in the form of a **solution for injection/infusion**. The pharmaceutical preparation is administered via **intravenous use**. The maximum daily dose is set at 3 g/ml, with a total maximum dose of 3 g/ml over the treatment period. The treatment duration is capped at 36 days. The solution is not formulated for pediatric use, and the active substance is of chemical origin. The trial aims to evaluate the effectiveness and tolerability of **Fentanyl** in continuous parenteral perfusion for the treatment of refractory dyspnea in patients hospitalized for acute decompensation of heart failure.

In addition to the experimental treatment, the study includes a comparator treatment involving the administration of **morphine** on demand. This standard-of-care therapy serves as a control to assess the relative effectiveness and tolerability of **Fentanyl**. The trial is designed as a randomized, double-blind, comparative study to ensure unbiased results. Participant compliance with the dosing schedule is monitored throughout the trial to maintain the integrity of the data collected.

The efficacy of the clinical trial will be assessed by evaluating the reduction in the average daily intensity of **dyspnea**. This primary endpoint will be measured using two scales: the Verbal Numerical Scale (EVN) and the Visual Analogue Scale (VAS) of dyspnea. Patients will self-evaluate their dyspnea intensity at the initial evaluation (0 hours) and subsequently at 24, 48, and 72 hours. The effectiveness of the treatment will be determined by comparing the scores from these timepoints to the baseline measurements. The trial aims to assess the effectiveness and tolerability of fentanyl in continuous parenteral perfusion compared to on-demand bolus administration of morphine for treating refractory dyspnea in patients hospitalized for acute decompensation of heart failure.