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

• ClinicalTrials.gov Identifier: NCT05321875
• Recruitment Status: Recruiting
• First Posted: April 11, 2022
• Last Update Posted: August 29, 2022
• Sponsor: Cristina Avendaño Solá
• Information provided by (Responsible Party): Cristina Avendaño Solá, Puerta de Hierro University Hospital

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 (Clinical Trial)
• Estimated 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)"
• Actual Study Start Date: June 2, 2022
• Estimated Primary Completion Date: June 2, 2026
• Estimated Study Completion Date: June 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

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 3 years ]

Secondary Outcome Measures :

1. 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. [ Time Frame: 3 years ]
2. 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. [ Time Frame: 3 years ]
3. Changes in LVEF measured by MRI (vs baseline) [ Time Frame: 3 years ]
4. Changes in LVEDV measured by MRI (vs baseline) [ Time Frame: 3 years ]
5. Proportion of individuals who develop DCM (LVEF<50%). [ Time Frame: 3 years ]
6. 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). [ Time Frame: 3 years ]
7. Proportion of treatment discontinuations in the candesartan and placebo groups. [ Time Frame: 3 years ]

Other Outcome Measures:

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 64 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

Contact: Cristina Avendaño-Solá, MD, PhD; +34 91 1916479; cavendano@salud.madrid.org

Contact: Ana Velasco-Iglesias, Msc,PhD; +34 91 1917867; avelasco.idiphim@gmail.com

Locations

Spain

Hospital Universitario Puerta de Hierro-Majadahonda; Recruiting

Majadahonda, Madrid, Spain, 28222

Contact: Cristina Avendaño, MD cavendano@salud.madrid.org

Sponsors and Collaborators

Cristina Avendaño Solá

Investigators

• Study Chair: Pablo García-Pavía, MD, PhD; Hospital Universitario Puerta de Hierro Majadahonda

More Information

• Responsible Party: Cristina Avendaño Solá, Head of Clinical Pharmacology Department, Puerta de Hierro University Hospital
• ClinicalTrials.gov Identifier: NCT05321875
• Other Study ID Numbers: EARLY-GENE; 2021-004577-30 ( EudraCT Number )
• First Posted: April 11, 2022
• Last Update Posted: August 29, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Under agreement, individual or aggregated patient data could be shared with other scientific groups for new scientific projects. Data can be shared only for scientific purposes and in full compliance with Personal Data Protection requirements in the EU
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: After study scientific publication
• Access Criteria: Under request to Study Chair

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Cristina Avendaño Solá, Puerta de Hierro University Hospital:

Dilated Cardiomyopathy; Genetic Mutation Carrier; Randomized Clinical Trial; Genetic Dilated Cardiomyopathy

Additional relevant MeSH terms:

Cardiomyopathies; Cardiomyopathy, Dilated; Heart Diseases; Cardiovascular Diseases; Cardiomegaly; Laminopathies; Genetic Diseases, Inborn; Candesartan; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action