A prospective, randomized, controlled clinical pilot trial investigating the partial down-titration of guideline-directed medical therapy in patients with heart failure in remission

The primary objective is to investigate the safety and feasibility of heart failure therapy down-titration versus therapy continuation in patients with heart failure in remission. This objective addresses the clinically relevant question of whether guideline-directed medical therapy can be safely reduced in patients who have achieved remission, potentially informing management strategies for this specific patient population.

The secondary objectives include:

• To assess differences in all-cause and heart failure-driven hospitalizations, and all-cause and cardiovascular deaths

• To assess the proportion of patients needing therapy re-initiation

• To assess differences in change of natriuretic peptide concentrations, blood pressure, potassium, VO2max, quality of life, other echocardiographic markers of left ventricular function, UACR and eGFR

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consists of **adults aged 18 years and older** of **both male and female gender**. Participants are individuals with **heart failure in remission**, characterized by an improved **ejection fraction** with **left ventricular ejection fraction (LVEF)** above 50%, normalized **left ventricular (LV) volumes**, **NT-proBNP** levels at or below 250 pg/mL, normal functional capacity, and clinical stability. Eligible participants must be receiving at least three **heart failure therapies**, including **ACE inhibitors (ACEi)**, **angiotensin receptor blockers (ARB)**, **angiotensin receptor-neprilysin inhibitors (ARNI)**, **beta-blockers (BB)**, and either **mineralocorticoid receptor antagonists (MRA)** or **sodium-glucose cotransporter-2 inhibitors (SGLT2i)**, in accordance with international heart failure guidelines. Each therapy must have been titrated to the maximally tolerated dose and maintained stable for a minimum of six months prior to screening. The trial does not involve vulnerable populations.

This prospective, randomized, controlled clinical pilot trial investigates the partial down-titration of guideline-directed medical therapy versus therapy continuation in patients with **heart failure in remission**. The study is designed as a low-intervention trial examining the safety and feasibility of withdrawing certain heart failure therapies rather than investigating the efficacy or safety of specific medicinal products. The trial is classified as a therapy withdrawal study and will evaluate patients who have achieved heart failure remission, defined as an improved **ejection fraction** to a left ventricular ejection fraction above 50 percent, normalized left ventricular volumes, **NT-proBNP** levels at or below 250 pg/mL, normal functional capacity, and clinical stability.

Eligible participants must be adults aged 18 years or older who are receiving at least three heart failure therapies, including an **ACE inhibitor**, angiotensin receptor blocker, angiotensin receptor-neprilysin inhibitor, **beta-blocker**, and either a **mineralocorticoid receptor antagonist** or **SGLT2 inhibitor**, consistent with international heart failure guidelines. Each therapy must have been titrated to the maximally tolerated dose and maintained stable for at least six months prior to screening. The investigational medicinal products include **lisinopril** 20 mg tablets administered orally with a maximum daily dose of 40 mg, **empagliflozin** 10 mg film-coated tablets administered orally with a maximum daily dose of 10 mg, **bisoprolol fumarate** 5 mg tablets administered orally with a maximum daily dose of 10 mg, and **spironolactone** 25 mg film-coated tablets administered orally with a maximum daily dose of 50 mg. The maximum treatment period for each product is 24 months.

The primary endpoints of the trial include left ventricular remodeling measured in a core echocardiography laboratory as an increase in **left ventricular end-systolic volume index** of more than 20 percent from baseline, NT-proBNP increase to more than 500 pg/mL, and all-cause mortality. Secondary endpoints comprise time to first occurrence of all-cause mortality or all-cause hospitalizations, change in **KCCQ-12** score, and the proportion of patients requiring heart failure treatment re-initiation or escalation, defined as re-initiation of at least one guideline-directed medical therapy or starting a loop diuretic.

The trial is scheduled to commence recruitment in October 2025 and is estimated to conclude in March 2028, resulting in an overall trial duration of approximately 30 months. Participant involvement will extend up to 24 months during the treatment period, with additional time required for screening and follow-up assessments. Early termination from the study may occur if participants experience significant left ventricular remodeling, substantial increases in NT-proBNP levels, clinical deterioration requiring treatment escalation, or if safety concerns arise that necessitate withdrawal from the trial protocol.

The clinical trial investigates four experimental medicinal products administered orally in patients with heart failure in remission. All investigational medicinal products are classified as test treatments and are administered for a maximum treatment period of 24 weeks.

**Lisinopril** EG 20 mg is supplied as a scored tablet containing **lisinopril** as the active substance of chemical origin. The maximum daily dose is 40 mg, administered via the **oral route**. The maximum total dose per administration is 40 mg. The pharmaceutical form is a tablet, and the product is manufactured by EG LABO LABORATOIRES EUROGENERICS. The medicinal product is authorized in France under marketing authorization number 34009 373 923 7 2.

Jardiance 10 mg is supplied as **film-coated tablets** containing **empagliflozin** as the active substance of chemical origin. The maximum daily dose is 10 mg, administered via the oral route. The maximum total dose per administration is 10 mg. The product is manufactured by BOEHRINGER INGELHEIM INTERNATIONAL GMBH and holds a centralized marketing authorization in the European Union under number EU/1/14/930/010.

Bisoprolol EG 5 mg is supplied as a scored tablet containing **bisoprolol fumarate** as the active substance of chemical origin. The maximum daily dose is 10 mg, administered via the oral route. The maximum total dose per administration is 10 mg. The pharmaceutical form is a tablet, and the product is manufactured by EG LABO LABORATOIRES EUROGENERICS. The medicinal product is authorized in France under marketing authorization number 34009 300 691 8 9.

**Spironolactone** 25 mg is supplied as film-coated tablets containing spironolactone as the active substance of chemical origin. The maximum daily dose is 50 mg, administered via the oral route. The maximum total dose per administration is 50 mg. The product is manufactured by NOUMED LIFE SCIENCES and is authorized in Northern Ireland under marketing authorization number PL 44041/0202.

Efficacy will be assessed through the evaluation of primary and secondary endpoints. The primary endpoints include **left ventricular remodeling**, measured in a core echocardiography laboratory as an increase in left ventricular end-systolic volume index of more than 20% from baseline, **NT-proBNP** increase to more than 500 pg/mL, and all-cause mortality. Secondary endpoints comprise time to first occurrence of all-cause mortality or all-cause hospitalizations, change in KCCQ-12, and the proportion of patients requiring **heart failure** treatment re-initiation or escalation, defined as re-initiation of at least one guideline-directed medical therapy or starting a loop diuretic. The trial will utilize echocardiography performed in a core laboratory for the assessment of cardiac remodeling parameters and biomarker measurements for NT-proBNP levels. Patient-reported outcomes will be captured using the KCCQ-12 instrument.