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

Sponsor

Cristina Avendaño Solá (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05321875

Collaborator

(none)

320

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

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)

Condition or Disease	Intervention/Treatment	Phase
Cardiomyopathy, Dilated	Drug: Candesartan	Phase 3

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

320 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Identical placebo tablets manufactured by the same Manufacturer of active marketed Candesartan (KERN PHARMA). Double-blind labelling specific for the study.

Primary Purpose:

Prevention

Official Title:

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

Anticipated Study Start Date :

May 2, 2022

Anticipated Primary Completion Date :

May 2, 2026

Anticipated Study Completion Date :

May 2, 2026

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Candesartan

Candesartan, 16 mg oral tablets. Target dose 32 mg or maximum tolerated dose after dose escalation from 16 mg

Drug: Candesartan

3 years treatment with candesartan target dose: 32 mg or maximum tolerated dose after dose escalation from 16 mg

Placebo Comparator: Placebo

Matching placebo. Target dose 2 tablets or maximum tolerated dose after dose escalation from 1 tablet

Drug: Candesartan

3 years treatment with candesartan target dose: 32 mg or maximum tolerated dose after dose escalation from 16 mg

Outcome Measures

Primary Outcome Measures

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

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]

Other Outcome Measures

Proportion of participants developing new cardiac fibrosis and its extent measured by MRI in the candesartan and placebo groups. [3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 64 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.