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

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

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

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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


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




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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05321875


Contacts
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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
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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
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Study Chair: Pablo García-Pavía, MD, PhD Hospital Universitario Puerta de Hierro Majadahonda
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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    Key Record Dates
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

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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:
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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