Clinical trial NCT05321875: Early Treatment With Candesartan vs Placebo in Genetic Carriers of Dilated Cardiomyopathy (EARLY-GENE Trial)
Official title: Early Treatment With Candesartan vs Placebo in Asymptomatic Genetic Carriers of Dilated Cardiomyopathy (EARLY-GENE Trial)"
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Cardiomyopathy, Dilated
Keywords: Dilated Cardiomyopathy
Genetic Mutation Carrier
Randomized Clinical Trial
Genetic Dilated Cardiomyopathy
Lead sponsor: Puerta de Hierro University Hospital
Sponsor class: OTHER
First posted: 2022-04-11
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Prospective, multicenter, randomized, placebo-controlled, double-blind clinical trial to evaluate safety and efficacy of candesartan in the prevention of the development of Dilated Cardiomyopathy (DCM) in genetic carriers of a DCM-causing variant without disease expression (asymptomatic)

Detailed description: Prospective, multicenter, randomized, placebo-controlled, double-blind clinical trial to evaluate safety and efficacy of early administration of candesartan in the prevention of the development of Dilated Cardiomyopathy (DCM) in genetic carriers of a DCM-causing variant without disease expression (asymptomatic).

Randomization will be 1:1 and patients are allocated to candesartan or matching placebo.

Patients will be followed for a 3 years period and efficacy will be demonstrated if candesartan (compared to placebo) prevents either a significant Left ventricular ejection fraction (LVEF) decline of ≥10%, or a ventricular dilatation (left ventricular end-diastolic volume, LVEDV) increase of ≥10% within a 3-years period of follow-up

Eligibility criteria: Inclusion Criteria:

* Age: 18-64 (both included), both sexes
* Carrier of a pathogenic or likely pathogenic DCM genetic variant1 according to modified American College of Medical Genetics (ACMG) criteria.
* Baseline LVEF ≥ 50% measured by MRI1 and evaluated by the eligibility study committee. Carriers with myocardial fibrosis, detected by late gadolinium enhancement in magnetic resonance imaging, are valid.
* Baseline creatinine ≤1.3 mg/dL, potassium ≤ 5.3 mEq/L and an estimated Glomerular Filtration Rate (eGFR)≥ 60 ml/min/1.73 m2 calculated by CKD-EPI formula.
* Able to understand and accept the study constraints and to provide informed consent.

Exclusion Criteria:

* Hypotension (systolic arterial pressure \<100 mmHg (measured following a standardized methodology).
* Prior ventricular dysfunction (LVEF ≤ 50% at any time prior to study inclusion)
* Candidates who are expected or highly likely to receive an implantable cardioverter defibrillator (ICD) in the following 12 months after inclusion in the trial
* Preexisting hypertension requiring pharmacological treatment.
* Uncontrolled arterial hypertension (i.e., repeatedly systolic arterial pressure \> 140 mmHg).
* Carriers of TTN-truncating variants (TTNtv) who are \< 35 years old.
* Known clinically significant coronary artery disease (e.g., ≥70% stenosis in any epicardial artery or ≥50% of left main coronary artery), valvular disease (≥ moderate in severity) or ventricular arrhythmias.
* Ongoing treatment with ACEI, ARB, ARNI or MRA.
* Prior intolerance to ACE inhibitors or ARB.
* Presence of any contraindications to receive candesartan treatment, including severe liver failure and/or cholestasis
* Known bilateral renal artery stenosis.
* Uncontrolled concomitant severe disease (e.g., with expected survival inferior to the duration of the study follow-up)
* Participation in any other clinical trial using an investigational medicinal product or device in the 30 days previous to the inclusion in the study.
* Current pregnancy, breastfeeding or women of childbearing age who are not willing to practice an adequate birth control during the entire duration of the study (a negative pregnancy test result must be confirmed at the time of enrolment)\*.
* Drug or alcohol abuse (current).
* Inability to comply with study procedures and treatments.
* Carriers of MRI incompatible internal devices (ICD, pacemakers, aneurysm clips, etc.), with known intolerance to MRI studies or presenting any contraindications to perform cardiac MRI studies.
* Any circumstances that in the investigator's opinion compromise the participant's ability to participate in the clinical trial.

Primary outcomes:
measure: Proportion of participants that progress to either a LVEF or LVEDV deterioration of ≥10% with respect to the baseline value at the end of follow-up as measured by MRI
timeFrame: 3 years
Secondary outcomes:
measure: Proportion of participants that progress to a LVEF deterioration of ≥10% compared to baseline value at the end of follow-up as measured by MRI.
timeFrame: 3 years
measure: Proportion of participants that progress to a LVEDV deterioration of ≥10% compared to baseline value at the end of follow-up as measured by MRI.
timeFrame: 3 years
measure: Changes in LVEF measured by MRI (vs baseline)
timeFrame: 3 years
measure: Changes in LVEDV measured by MRI (vs baseline)
timeFrame: 3 years
measure: Proportion of individuals who develop DCM (LVEF<50%).
timeFrame: 3 years
measure: Proportion of participants in each treatment group developing Serious Adverse Events (SAEs), Grade 3-4 adverse events (AEs), Adverse Reactions, or AEs of Special Interest (AESIs).
timeFrame: 3 years
measure: Proportion of treatment discontinuations in the candesartan and placebo groups.
timeFrame: 3 years
Other outcomes:
measure: Proportion of participants developing new cardiac fibrosis and its extent measured by MRI in the candesartan and placebo groups.
timeFrame: 3 years
Locations:
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro-Majadahonda
state: Madrid
Study officials:
affiliation: Hospital Universitario Puerta de Hierro Majadahonda
name: Pablo García-Pavía, MD, PhD
role: STUDY_CHAIR
References: