Early Treatment With Candesartan vs Placebo in Genetic Carriers of Dilated Cardiomyopathy (EARLY-GENE Trial)

Study Overview
=================
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

Official Title
-----------------
Early Treatment With Candesartan vs Placebo in Asymptomatic Genetic Carriers of Dilated Cardiomyopathy (EARLY-GENE Trial)

Conditions
-----------------
Cardiomyopathy, Dilated

Intervention / Treatment
-----------------
* Drug: Candesartan


Participation Criteria
=================
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. 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 (either themselves or a legal representative). Exclusion Criteria: Hypotension (systolic arterial pressure <100 mmHg as the mean value after 3 consecutive reads 5 minutes apart). 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 (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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Candesartan<br>Candesartan, 16 mg oral tablets. Target dose 32 mg or maximum tolerated dose after dose escalation from 16 mg | Drug: Candesartan<br>* 3 years treatment with candesartan target dose: 32 mg or maximum tolerated dose after dose escalation from 16 mg<br>|
| Placebo Comparator: Placebo<br>Matching placebo. Target dose 2 tablets or maximum tolerated dose after dose escalation from 1 tablet | Drug: Candesartan<br>* 3 years treatment with candesartan target dose: 32 mg or maximum tolerated dose after dose escalation from 16 mg<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. |  | 3 years | 
| 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. |  | 3 years | 
| Changes in LVEF measured by MRI (vs baseline) |  | 3 years | 
| Changes in LVEDV measured by MRI (vs baseline) |  | 3 years | 
| Proportion of individuals who develop DCM (LVEF<50%). |  | 3 years | 
| 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). |  | 3 years | 
| Proportion of treatment discontinuations in the candesartan and placebo groups. |  | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dilated Cardiomyopathy, Genetic Mutation Carrier, Randomized Clinical Trial, Genetic Dilated Cardiomyopathy