Observational Study of Natural History of BAG3 Gene Mutation-Associated Dilated Cardiomyopathy in Chinese Adults

AstraZeneca10 enrolled

Overview

This is a multicentre, prospective cohort study designed to elucidate the natural history of dilated cardiomyopathy (DCM) associated with specific gene mutations in Chinese patients. By establishing a cohort of patients with inherited cardiomyopathy, the study will collect comprehensive data, including demographic characteristics, disease history, clinical features, prior treatments, current treatment patterns, clinical outcomes, and patient-reported outcomes (PROs). The objective is to describe the disease profile, current diagnostic and therapeutic landscape, clinical progression, and prognosis of this specific patient population in China. The data generated will provide a foundational basis for deepening the understanding of disease progression, identifying unmet clinical needs, and exploring potential surrogate endpoints for future clinical trials in drug development. The study plans to enroll 10 eligible patients with BCL-2-associated athanogene 3 (BAG3)-associated inherited DCM from 3 research sites across China.

This is a multicentre, prospective, observational natural history study targeting Chinese adults with BAG3 DCM. Approximately 10 patients with BAG3 DCM will be enrolled from 3 research sites in China. Comprehensive clinical data, including demographic characteristics, medical history, clinical manifestations, treatment records, clinical outcomes, and PROs, will be collected. After completing the informed consent process, eligible patients will undergo screening and enrollment, planned to last 1 year. Patients with a confirmed diagnosis of BAG3 DCM will be directly enrolled; those initially diagnosed only with DCM will undergo genetic testing (e.g., whole-exome sequencing), and carriers of BAG3 mutations will be included upon confirmation. After enrollment, participants will undergo a comprehensive baseline assessment of clinical parameters (including imaging, cardiopulmonary function, and laboratory tests) and enter a subsequent 2-year follow-up evaluation period. Patient follow-up will continue until any of the following events occurs: death, study withdrawal, loss to follow-up (defined as failure to contact via three attempts including telephone, WeChat, medical record review, and contact with family members/treating physicians), early study termination/suspension, or completion of the scheduled 2-year follow-up period. Medical history and cardiomyopathy treatment history at baseline (e.g., medications, surgical procedures, hospitalizations / resuscitation records) will be retrieved from patients' electronic medical records at enrollment. After enrollment, prospective data collection will include information from routine clinical practice, investigator-solicited clinical outcomes, and Patient-reported outcomes (PROs). An Electronic Data Capture (EDC) system will be used for data collection. All enrolled cardiomyopathy patients will be followed at regular intervals until the end of the observation follow-up period. This study will collect electronic medical record data from cardiomyopathy patients at 3 research sites in China. Data sources include hospital electronic health records, medical records, and patient-reported outcome questionnaires. Routine clinical data (including but not limited to baseline information, assessments, and treatment records) will be collected during routine clinical visits or via remote questionnaires. Follow-up frequency is set at baseline (Day 1, V1), Month 3 (V2), Month 6 (V3), Month 12 (V4), Month 18 (V5), and Month 24 (V6). All data will be collected and managed using an EDC system.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Participants must meet all of the following criteria to be eligible for inclusion: 1. Age ≥18 years at screening, male or female; 2. Presence of a BAG3 pathogenic or likely pathogenic mutation interpreted according to the American College of Medical Genetics and Genomics (ACMG) guidelines; 3. Heart failure (HF) Stage B or C, New York Heart Association (NYHA) functional class I-III; 4. LVEF ≤50%. If LVEF is 45%-50% and the participant is classified as Stage B heart failure or NYHA Class I, N-terminal pro-B-type natriuretic peptide (NT-proBNP) must be ≥300 pg/mL. LVEF measurement must be based on echocardiography or cardiac magnetic resonance results within the past 12 months; 5. Willing and able to comply with all scheduled visits, laboratory tests, and other study procedures; 6. Capable of providing signed informed consent, including compliance with the requirements and restrictions listed in the informed consent form and this protocol. Exclusion Criteria: * Participants meeting any of the following criteria will be excluded: 1. Acute decompensated heart failure within 1 month prior to enrollment; 2. Any of the following within 3 months prior to screening: * Myocardial infarction * Cardiac surgical procedures (excluding pacemaker/implantable cardioverter defibrillator/cardiac resynchronization therapy implantation) * Implantable cardioverter defibrillator (ICD) implantation * Acute coronary syndrome * Hospitalization for cardiac arrhythmia 3. History of heart transplantation; 4. Estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73 m² (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula); 5. Active malignancy or malignancy diagnosed within 3 years prior to screening, except for: * Surgically cured in situ malignancies * Surgically cured early-stage cancers (including breast, prostate, skin \[basal cell carcinoma, squamous cell carcinoma\], thyroid, or cervical cancer) * Other early-stage malignancies with an expected 2-year recurrence rate ≤20%, approved by the Medical Monitor 6. Non-cardiac condition limiting life expectancy to \<1 year; 7. Presence of any of the following cardiac conditions: * Other forms of cardiomyopathy contributing to heart failure (e.g., inflammatory or infiltrative cardiomyopathy) * Clinically significant cardiac anatomic abnormalities (e.g., left ventricular aneurysm) * Significant coronary artery disease (e.g., prior revascularization, exercise-induced angina) * Uncorrected, hemodynamically significant (moderate to severe) primary structural valvular disease not due to heart failure (investigator's judgment) 8. Any severe concurrent disease (e.g., active systemic infection) that, in the investigator's judgment, would make the participant unsuitable for study participation; 9. Any medical or psychiatric condition that may increase study risk, including: * Active or recent (within 1 year) suicidal ideation/behavior * Laboratory abnormalities * Other conditions deemed unsuitable by the investigator 10. Administration of any investigational drug within 30 days prior to screening; 11. Prior gene or cell therapy treatment; 12. Anticipated need for cardiac transplantation, left ventricular assist device implantation, or other cardiac surgery within the next 3 months (investigator's assessment); 13. More than 3 first-degree relatives from the same family enrolled concurrently (excluding the participant).

Outcomes

Primary Outcomes

changes in cardiac imaging parameters, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS)

Primary endpoints include changes from baseline in cardiac structure and function parameters, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), at Month 12 and subsequent follow-ups. Changes in the above imaging assessment results are presented as continuous numerical variables and the results of changes expressed as percentages.

Time frame: Baseline (at Day 1 post-enrollment), 12 months and 24 months

changes in cardiac imaging parameters, left ventricular end diastolic diameter (LVEDD)

Primary endpoints include changes from baseline in cardiac structure and function parameters, left ventricular end diastolic diameter (LVEDD), at Month 12 and subsequent follow-ups. Changes in the above imaging assessment results are presented as continuous numerical variables and the results of changes expressed as percentages.

Time frame: Baseline (at Day 1 post-enrollment), 12 months and 24 months

changes in cardiac imaging parameters, left ventricular end systolic volume index (LVESVi) and left ventricular end diastolic volume index (LVEDVi)

Primary endpoints include changes from baseline in cardiac structure and function parameters, left ventricular end systolic volume index (LVESVi) and left ventricular end diastolic volume index (LVEDVi), at Month 12 and subsequent follow-ups. Changes in the above imaging assessment results are presented as continuous numerical variables and the results of changes expressed as percentages.

Time frame: Baseline (at Day 1 post-enrollment), 12 months and 24 months

changes in cardiac imaging parameters, left ventricular mass index (LVMi)

Primary endpoints include changes from baseline in cardiac structure and function parameters, left ventricular mass index (LVMi), at Month 12 and subsequent follow-ups. Changes in the above imaging assessment results are presented as continuous numerical variables and the results of changes expressed as percentages.

Time frame: Baseline (at Day 1 post-enrollment), 12 months and 24 months

Secondary Outcomes

Circulating Biomarkers

Descriptive summaries of High-sensitivity cardiac troponin I (hs-cTnI), High-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro b-type natriuretic peptide (NT-proBNP), and other circulating biomarkers level at baseline and each follow-up visit, including absolute and relative percentage changes from baseline. All of the above test parameters are measured in ng/L, and the changes are treated as continuous numerical variables.

Time frame: Baseline (at Day 1 post-enrollment), 3 months, 6 months, 12 months, 18 months, and 24 months

Peak oxygen capacity (VO₂) measured by cardiopulmonary exercise testing (CPET)

Peak oxygen capacity (VO₂) measured by cardiopulmonary exercise testing (CPET) will be summarized at baseline and each time point, along with absolute and relative changes over time.

Time frame: Baseline (at Day 1 post-enrollment) and 12 months.

Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23)

Changes from baseline in KCCQ-23 overall and domain scores will be described using absolute and relative changes. Raw summary scores are converted to a 0-100 scale, with higher scores indicating better health status.

Time frame: Baseline (at Day 1 post-enrollment), 3 months, 6 months, 12 months, 18 months, and 24 months

EuroQol 5-Dimension 5-Level Health Scale (EQ-5D-5L)

Changes from baseline in EQ-5D-5L overall and domain scores will be described using absolute and relative changes. The EQ-5D was developed by the EuroQol Group to provide a simple, generic measure of health. The EQ-5D primarily consists of two parts: the EQ-5D descriptive system and the EQ-5D visual analogue scale (VAS). The score ranges from \<0 to 1. Higher scores men a better outcome.

Time frame: Baseline (at Day 1 post-enrollment), 3 months, 6 months, 12 months, 18 months, and 24 months

The medical outcomes study 36-item short-form health survey (SF-36)

Changes from baseline in SF-36 overall and domain scores will be described using absolute and relative changes. The questionnaire comprises 8 health domain scales. The raw scores for each health domain scale are converted to a 0-100 scale score and can then be transformed into norm-based T-scores (Mean = 50, Standard Deviation = 10) using scoring software provided by the developer.

The Frequency and Rate of Notable Cardiac Status Changes

The cumulative number and frequency of notable cardiac status events will be reported. Notable cardiac status changes include but are not limited to: new or worsening signs/symptoms of fluid overload (e.g., edema, pulmonary congestion), new or worsening renal impairment (e.g., cardiorenal syndrome, acute renal failure), heart failure (HF) hospitalization, need for unscheduled intravenous diuretics, HF exacerbation, cardiovascular death, myocardial infarction (MI), hospitalization for unstable angina, coronary revascularization, stroke, new or worsening ventricular or supraventricular arrhythmias, sudden cardiac death (SCD), or SCD-equivalent events (e.g., appropriate implantable cardioverter-defibrillator \[ICD\] shock, sustained ventricular arrhythmia). Event rates per 100 patient-years with 95% confidence intervals will be calculated.

Time frame: Baseline (at Day 1 post-enrollment), 3 months, 6 months, 12 months, 18 months, and 24 months

Observational Study of Natural History of BAG3 Gene Mutation-Associated Dilated Cardiomyopathy in Chinese Adults

Overview

Conditions

Interventions

Eligibility

Locations (3)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts