Randomized Interventional Trial of Spironolactone and Eplerenone in Heart Failure with Preserved Ejection Fraction Patients

The primary objective of the Spironolactone Initiation Registry Randomized Interventional Trial in **Heart Failure with Preserved Ejection Fraction** (SPIRRIT-HFpEF) is to evaluate whether the initiation of **spironolactone** or **eplerenone** in conjunction with standard care, as opposed to standard care alone, can reduce the incidence rate of total heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction. This is assessed using a pragmatic Registry-based Randomized Clinical Trial methodology. The clinical relevance of this objective lies in its potential to inform treatment strategies that could improve patient outcomes by reducing hospitalizations and mortality associated with heart failure with preserved ejection fraction.

The secondary objectives include studying the secondary endpoints and the primary and secondary endpoints in pre-specified sub-groups. These objectives aim to provide a comprehensive understanding of the treatment effects across different patient populations, which could further refine therapeutic approaches and enhance personalized medicine in this patient cohort.

The clinical trial involves a total of **387 participants** diagnosed with **heart failure with preserved ejection fraction** (HFpEF). The study population includes both male and female subjects, aged 50 years and older, who are in a stable condition of heart failure as determined by symptoms and signs evaluated by local investigators. Participants were selected based on specific criteria, including a left ventricular ejection fraction of 40% or higher and elevated natriuretic peptide levels. The trial does not involve a vulnerable population. Participants are required to be regular users of loop diuretics, defined as daily or most days of the week, and fall within the New York Heart Association (NYHA) Class II-IV. The selection process ensures that the study population is representative of individuals with HFpEF, allowing for a comprehensive assessment of the trial's primary objective.

The clinical trial is designed to evaluate the efficacy of **spironolactone** or eplerenone in combination with standard care compared to standard care alone in reducing the incidence of total heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction (HFpEF). The study employs a randomized, double-blind, controlled trial design, utilizing the pragmatic Registry-based Randomized Clinical Trial (RRCT) methodology. The trial is expected to span a duration from November 27, 2017, to December 31, 2027, with participant involvement lasting up to 120 days.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, heart failure stability, left ventricular ejection fraction, natriuretic peptide levels, and regular use of loop diuretics. Follow-up visits will be scheduled to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will conclude the participant's involvement, assessing the primary endpoint of heart failure hospitalizations or cardiovascular death incidence.

Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination, such as withdrawal of consent, significant protocol deviations, or adverse events that compromise safety. The trial's primary endpoint is the incidence rate of total heart failure hospitalizations or cardiovascular death, with no secondary endpoints specified. The trial is not categorized as low intervention and is classified as a Phase 3 study.

The clinical trial involves the administration of **spironolactone**, a pharmaceutical product with the active substance **cinnarizine**. The medication is provided in an oral form, identified by the pharmaceutical form code PHF00245MIG. The maximum daily dose is 50 mg, with a total maximum dose of 50 mg over a treatment period of up to 120 days. The administration route is oral, and the medication is of chemical origin. The trial aims to evaluate the efficacy of spironolactone in reducing heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction (HFpEF).

Another experimental treatment in the trial is **eplerenone**, which contains the active substances **altizide** and **micronised spironolactone**. This medication is also administered orally, with the same pharmaceutical form code PHF00245MIG. The dosing regimen mirrors that of spironolactone, with a maximum daily dose of 50 mg and a total maximum dose of 50 mg over a 120-day period. The active substances are of chemical origin, with micronised spironolactone classified under Specified Substance Group 1. The trial evaluates the combination of eplerenone with standard care against standard care alone in the context of HFpEF.

Both spironolactone and eplerenone are tested in conjunction with standard-of-care therapy, which serves as the comparator treatment. The trial does not include a placebo group. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. The primary objective is to determine the impact of these treatments on the incidence of heart failure hospitalizations and cardiovascular mortality in the target patient population.

Efficacy in the clinical trial titled "Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction SPIRRIT-HFpEF" will be assessed by evaluating the primary endpoint, which is the incidence rate for total **heart failure (HF)** hospitalizations or cardiovascular (CV) death. This trial aims to determine whether the initiation of spironolactone or eplerenone, in addition to standard care, reduces these incidence rates compared to standard care alone in patients with HFpEF. The study employs a pragmatic Registry-based Randomized Clinical Trial (RRCT) methodology to achieve its objectives. The trial will collect data on hospitalizations and CV deaths, which will be analyzed to assess the efficacy of the treatment interventions. The trial is expected to conclude by December 31, 2027.