Outcome-targeted Therapy: Principle and Outcome Evaluation: Clinical Study and Phenotype-genotype Correlation

NCT ID: NCT06632834

Last Updated: 2024-10-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 230 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-15
• Study Completion Date: 2025-01-19

Brief Summary

Brief Summary(Use lay language. Include a statement of the study hypothesis.):

Dilated cardiomyopathy (DCM) is the most common childhood cardiomyopathy and is associated with significant early morbidity and mortality. Those who fail to improve within the first year of diagnosis usually deteriorated even upon aggressive anti-congestive medications. Investigators had conducted precision-medicine-based approach to provide strategic approach as drug repurposing to identify new treatments. Investigators have identified the beneficial effects from a statin, simvastatin, to restore the cardiac contractility in the human induced pluripotent stem cell lines derived from a DCM proband and the proband's father. The mutant mouse consequently confirmed the beneficial effects. The initial experience in the proband is promising. This clinical trial is to find out if simvastatin will benefit the cardiac function of DCM patients.

Detailed Description

Dilated cardiomyopathy (DCM) is the most common childhood cardiomyopathy and is associated with significant early morbidity and mortality. About half of patients die or require heart transplantation within 5 years of diagnosis. The survival advantage from transplantation is limited, particularly in DCM infants.The medical therapy for DCM with heart failure includes anti-congestive medications and antiplatelet therapy. Those who fail to improve within the first year of diagnosis usually deteriorated even upon aggressive anti-congestive medications. Investigators have conducted precision-medicine-based approach to provide strategic approach as drug repurposing to identify new treatments. Investigators have identified the beneficial effects from a statin, simvastatin, to restore the cardiac contractility in the human induced pluripotent stem cell lines derived from a DCM proband and the proband's father. The mutant mouse consequently confirmed the beneficial effects. The initial experience in the proband is promising. The proband was diagnosed as DCM with severe heart failure during infancy. Family screening identified that the proband's father had dilated left ventricle (LV) and low LV ejection fraction (LVEF). Genetic examination of this DCM family revealed that the proband and the proband's father had heterogeneous missense mutation. About 2 years after the disease onset, participants growth was slow, the LVEF remained poor and the NT-pro BNP level was high under aggressive anti-congestive medications. Because of the beneficial effects of simvastatin from in vitro study and in vivo animal study, off-label use of simvastatin was initiated after obtaining the parents' agreement. Participants general condition and cardiac condition 4 years after the disease onset and 1.5 years after the simvastatin therapy improved without adverse effects. The LVEF increased from 17.5% to 39.2% and the NT-pro BNP level dropped from 1200 to 363 pg/ml. Simvastatin is effective in lowing LDL and cholesterol, thereby to improve the outcome of patients with coronary arterial disease, familiar hypercholesterolemia, etc. For children, though the dosage range and the indication remain unclear, it had been used in children with various diseases. Simvastatin had been given in a small cohort of adult DCM. Patients treated with simvastatin had a lower New York Heart Association functional class compared with those receiving placebo. The LVEF also improved in the simvastatin group. This clinical trial is to find out if simvastatin will benefit the cardiac function of DCM patients.

Conditions

Dilated Cardiomyopathy

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Simvastatin

Simvastatin added with baseline anti-congestive medication in dilated cardiomyopathy patient.

Group Type: EXPERIMENTAL

simvastatin therapy

Intervention Type: DRUG

Simvastatin should be administered initially with the dose of 10 mg once daily for adult and 0.25 mg/Kg once daily for children. Dose of simvastatin will be increased to the dose of 20 mg once daily for adult and 0.5 mg/Kg once daily for children after the check at 3 months without adverse effects.

Interventions

simvastatin therapy

Simvastatin should be administered initially with the dose of 10 mg once daily for adult and 0.25 mg/Kg once daily for children. Dose of simvastatin will be increased to the dose of 20 mg once daily for adult and 0.5 mg/Kg once daily for children after the check at 3 months without adverse effects.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Patients diagnosed as dilated cardiomyopathy, classified as NYHA functional class II or III and still have a low left ventricular ejection fraction (LVEF) (LVEF < 45% and the Z score of the LV end-diastolic diameter > 2.0) will be enrolled, if they have normal or high level of cholesterol and triglyceride and fulfill any of the following criteria:

1. Patients who have already received anti-congestive medications for at least three months and still have poor LV function (LVEF < 45% and the Z score of the LV end-diastolic diameter > 2.0).

2. Patients who have persistent or even worsening heart failure after one month of anti-congestive medications.

3. Patients who have positive family history of dilated cardiomyopathy and have received anti-congestive medications for one month.

4. Patients or their parents must sign an informed consent form.

Exclusion Criteria

Patients who fulfill any of the following criteria will be excluded from the trial:

1. Patients who underwent prior cardiac surgery. Those who received DCM related surgery, such as mitral valve plasy, for longer than a year are not subject to this restriction.

2. Patients who had active liver / renal dysfunction.

3. Concomitant use with gemfibrozil, cyclosporine, danazol, strong CYP3A4 inhibitors (eg, boceprevir, clarithromycin, erythromycin, HIV protease inhibitors, itraconazole, ketoconazole, nefazodone, posaconazole, telaprevir, telithromycin, voriconazole), or cobicistat-containing products

4. Patients who are pregnant or plan to pregnancy in the period of study.

5. Patients who are intolerance to simvastatin therapy.

• Minimum Eligible Age: 0 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Taiwan University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Wei-Chieh Tseng, MD

Role: PRINCIPAL_INVESTIGATOR

Principal Investigator

Locations

National Taiwan University Hospital

Taipei County, Zhongzheng District, Taiwan

Site Status: RECRUITING

Countries

Taiwan

Central Contacts

Wei-Chieh Tseng

Role: CONTACT

littlecardiologist@gmail.com

0972652584

Facility Contacts

Wei-Chieh Tseng, MD

Role: primary

littlecardiologist@gmail.com

0972652584

Other Identifiers

201912067MINB

Identifier Type: -

Identifier Source: org_study_id