Evaluation of Candesartan Cilexetil Versus Placebo in Asymptomatic Genetic Carriers of Dilated Cardiomyopathy-Causing Variants

The primary objective of the EARLY-GENE trial is to evaluate whether early administration of **candesartan** compared to placebo can prevent a significant decline in left ventricular ejection fraction (LVEF) of ≥10% or an increase in left ventricular end-diastolic volume (LVEDV) of ≥10% in genetic carriers of a dilated cardiomyopathy (DCM)-causing variant who do not yet express the disease. This is clinically relevant as it aims to intervene before the onset of symptomatic DCM, potentially altering the disease course and improving long-term cardiac outcomes.

Secondary objectives include:

• Assessing if early administration of candesartan reduces or prevents any signs of progression to DCM, such as LVEF decline, LVEDV increase, or LVEF <50%, as assessed by MRI, in genetic carriers of a DCM-causing variant without disease expression.
• Evaluating the safety and tolerability of candesartan compared to placebo in the study population.

The clinical trial involves **genetic carriers** of dilated cardiomyopathy causing variants, specifically targeting individuals aged 18 to 64 years, inclusive of both males and females. The study population is characterized by a baseline left ventricular ejection fraction (LVEF) of at least 50%, as measured by MRI, and includes carriers with myocardial fibrosis detected by late gadolinium enhancement. Participants are required to have baseline potassium levels of 5.3 mEq/L or lower, creatinine levels of 1.3 mg/dL or lower, and an estimated glomerular filtration rate (eGFR) of 60 ml/min/1.73 m² or higher. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria ensure that participants are carriers of a pathogenic or likely pathogenic DCM genetic variant according to modified American College of Medical Genetics (ACMG) criteria. Participants must be able to understand and accept the study constraints and provide informed consent. No specific lifestyle considerations such as diet or physical activity are highlighted in the trial details.

The clinical trial is designed to evaluate the efficacy of **candesartan cilexetil** in preventing significant cardiac changes in genetic carriers of dilated cardiomyopathy (DCM) causing variants. This study is a randomized, double-blind, placebo-controlled trial, with participants receiving either candesartan or a placebo. The trial is expected to run from May 2022 to June 2028, with the primary objective of assessing whether early administration of candesartan can prevent a decline in left ventricular ejection fraction (LVEF) or an increase in left ventricular end-diastolic volume (LVEDV) by 10% or more, as measured by MRI.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, genetic variant status, and baseline cardiac function. Follow-up visits will be scheduled periodically to monitor participants' cardiac health and any adverse events. The end-of-study visit will evaluate the primary and secondary endpoints, including changes in LVEF and LVEDV, the development of DCM, and the incidence of adverse events. The expected length of participant involvement is up to 36 months, depending on the treatment group assignment.

Conditions that may lead to early termination from the study include significant adverse reactions, non-compliance with study procedures, or withdrawal of consent. The trial aims to provide valuable insights into the potential benefits of early intervention with candesartan in asymptomatic genetic carriers of DCM, contributing to the understanding of preventive strategies in this population.

The clinical trial involves the administration of **Candesartan Kern Pharma 16 mg tablets**, which contain the active substance **candesartan cilexetil**. This medication is provided in tablet form and is administered orally. The maximum daily dose is 32 mg, with a total maximum dose of 32.25 grams over the treatment period. The treatment duration is set for a maximum of 36 months. The tablets are manufactured by Kern Pharma, S.L., and are not formulated for pediatric use. The active substance is of chemical origin, and the medication is classified under the ATC code C09CA06, indicating its use as an angiotensin II receptor antagonist.

Another experimental medication used in the trial is **Candesartan Kern Pharma 8 mg tablets**, also containing **candesartan cilexetil**. These tablets are similarly administered orally, with a maximum daily dose of 16 mg and a total maximum dose of 672 mg over the treatment period. The treatment duration for this dosage is limited to 6 months. Like the 16 mg formulation, these tablets are produced by Kern Pharma, S.L., and are not intended for pediatric use. The active substance is chemically derived, and the medication shares the same ATC classification as the 16 mg tablets.

The trial also includes a **placebo** treatment, which is designed to mimic the composition of the 16 mg candesartan tablets but contains no active substance. This placebo is used to provide a comparator for evaluating the efficacy of the active treatment. The placebo is not associated with any specific pharmaceutical form or route of administration, as it is intended to match the appearance and administration method of the active treatment without providing therapeutic effects.

The efficacy of the clinical trial titled "EARLY treatment with Candesartan vs Placebo in asymptomatic GENEtic carriers of Dilated Cardiomyopathy (EARLY-GENE trial)" will be assessed through both primary and secondary endpoints. The primary endpoint is the proportion of participants who experience a deterioration of at least 10% in either **Left Ventricular Ejection Fraction (LVEF)** or left ventricular end-diastolic volume (LVEDV) compared to baseline, as measured by MRI at the end of the follow-up period. Secondary endpoints include the proportion of participants with a 10% deterioration in LVEF or LVEDV, changes in LVEF and LVEDV from baseline, the proportion of individuals developing Dilated Cardiomyopathy (DCM) defined as LVEF less than 50%, and the incidence of serious adverse events, grade 3-4 adverse events, adverse reactions, or adverse events of special interest. Additionally, the trial will evaluate the proportion of treatment discontinuations in the candesartan and placebo groups.