Dilated Cardiomyopathy (DCM), Heart Failure
Conditions
Keywords
end-stage dilated cardiomyopathy, FAP immunosuppressive CAR-DC
Brief summary
To study the safety and efficacy of fibroblast activation protein (FAP)-targeted immunosuppressive chimeric antigen receptor-dendritic cell (CAR-DC) in the treatment of end-stage dilated cardiomyopathy and provide a new method for the treatment of end-stage dilated cardiomyopathy.
Detailed description
This study aims to evaluate the safety and efficacy of fibroblast activation protein (FAP)-targeted immunosuppressive chimeric antigen receptor-dendritic cell (iCDC) therapy in patients with end-stage dilated cardiomyopathy, and to provide a novel therapeutic approach for this condition. This is a prospective, single-center, open-label, two-phase clinical study designed to assess the safety and preliminary efficacy of iCDC in patients with end-stage dilated cardiomyopathy. Phase 1 employs a single-arm, 3+3 dose-escalation design. iCDC therapy will be administered at predefined dose levels to evaluate safety, dose-limiting toxicities, treatment-related adverse events, and preliminary efficacy, and to determine the safe and effective dose. Phase 2 will expand enrollment at the safe and effective dose identified in Phase 1. Additional patients will receive iCDC therapy at this dose, and a non-randomized concurrent control group will also be enrolled. Control participants must meet the same eligibility criteria and, after providing informed consent, choose not to receive iCDC therapy but agree to participate in study follow-up. They will not undergo leukapheresis, iCDC manufacturing, or cell infusion, and will continue to receive guideline-directed standard medical therapy. The iCDC treatment group will be assessed for safety and preliminary efficacy. The concurrent control group will be followed using clinically feasible shared assessments, including echocardiography, BNP or NT-proBNP, 6-minute walk distance, NYHA functional class, INTERMACS profile, KCCQ score, worsening heart failure, hospitalization, death, and major cardiovascular events. Cardiac magnetic resonance imaging and cell therapy-specific assessments will be performed exclusively in participants receiving iCDC therapy and will not be included in between-group comparisons with the control group.
Interventions
BIOLOGICALFAP immunosuppressive CAR-DC
Each subject receive FAP immunosuppressive CAR-DC by intravenous infusion
Sponsors
Second Affiliated Hospital, School of Medicine, Zhejiang University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Intervention model description
This is a two-phase interventional study. Phase 1 will employ a modified single-arm 3+3 dose-escalation design to evaluate the safety, dose-limiting toxicities, treatment-related adverse events, and preliminary efficacy of iCDC therapy, and to establish a safe and effective dose for further evaluation. Once the safe and effective dose is determined, enrollment at that dose will be expanded to a total of 8-10 participants in Phase 1 to further assess safety and preliminary efficacy. In Phase 2, the study will be expanded at the safe and effective dose identified in Phase 1. An additional 15 participants will receive iCDC therapy at this dose, and 20 participants will be enrolled as a non-randomized concurrent control group for exploratory comparison.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age between 18 years old and 75 years old, diagnosed with dilated cardiomyopathy. * Able to verbally confirm that he/she understands the risks, benefits and treatment options of the iCDC trial. He/she or his/her legal representative provides written informed consent before participating in the clinical trial. * Diagnosed with Heart Failure with reduced ejection fraction (HFrEF), optimized drug therapy (under maximum tolerance of GDMT) for at least 3 months, left ventricular ejection fraction \<35%, NYHA functional class ⅢB-IV, INTERMACS class 3-6. * Blood test: hematocrit \>30%, lymphocytes \>0.5×10\^9/L, platelets \>60×10\^9/L.
Exclusion criteria
* History of myocardial infarction, unstable angina, stroke or transient ischemic attack within 12 weeks before enrollment. * CRT implanted within 12 weeks before enrollment or intended to implant CRT device. * Previous heart transplantation or implantation of a ventricular assist device or similar device, or planned implantation of a ventricular assist device or similar device. * Heart failure caused by ischemic cardiomyopathy, restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, long-standing hypertension, congenital structural heart disease, or uncorrected primary valvular disease. * Symptomatic bradycardia or second/third degree heart block. * Active autoimmune disease requiring immunosuppressive therapy. * Pulmonary Embolism (PE). * A history of tuberculosis. * History of severe renal failure or need for dialysis, creatinine \>2.5 mg/dl. * Uncorrected thrombocytopenia or systemic coagulopathy (platelet count \< 50,000, INR \> 2.5, or aPTT \> 2.5 times control in the absence of anticoagulation), or active bleeding and uncorrectable coagulopathy. * Aspartate aminotransferase or alanine aminotransferase levels greater than 5.0 times the upper limit of normal (ULN), total bilirubin \>3 mg/dl. * History of concurrent severe infection, hepatobiliary obstruction, or malignancy. * Infections: Active hepatitis B (PCR-detected hepatitis B virus DNA copies \> 1000), hepatitis C, syphilis, or human immunodeficiency virus (HIV) infection at screening; uncontrolled systemic fungal, bacterial, viral, or other pathogen infection. * Severe hemodynamic instability (eg, shock). * Women who are pregnant or may become pregnant. * Contraindications to study drugs or tests.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The proportion of subjects with Dose-limiting toxicity (DLT) | in 14 days after injection | The proportion of participants with treatment-related adverse events as assessed by CTCAE v5.0 |
| Incidence of treatment-emergent adverse events (TEAEs) | in 14 days after injection | Incidence of iCDC treatment-emergent adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Left ventricular ejection fraction (LVEF) | 1, 3, 6, 12 months after injection | The difference of LVEF from baseline. LVEF will be assessed by echocardiography. |
| Enhanced volume (volume%) | 6 , 12 months after injection | The difference of Enhanced volume (volume%) from baseline. Enhanced volume will be assessed by CMR. |
| INTERMACS Profile | 1, 3, 6 , 12 months after injection | Profile 1. Critical cardiogenic shock; Profile 2. Progressive decline on inotropic support; Profile 3. Stable but inotrope dependent; Profile 4. Resting symptoms home on oral therapy; Profile 5. Exertion Intolerant; Profile 6. Exertion Limited; Profile 7. Advanced NYHA Class III symptoms |
| Left ventricular internal diameter end systole (LVIDs) | 1, 3, 6 , 12 months after injection | The difference of LVIDs from baseline. LVIDs will be assessed by echocardiography. |
| Left ventricular internal diameter end diastole (LVIDd) | 1, 3, 6 , 12 months after injection | The difference of LVIDd from baseline. LVIDd will be assessed by echocardiography. |
| Left ventricular end-systolic volume (LVESV) | 6 , 12 months after injection | The difference of LVESV from baseline. LVESV will be assessed by CMR. |
| Left ventricular end-diastolic volume (LVEDV) | 6 , 12 months after injection | The difference of LVEDV from baseline. LVEDV will be assessed by CMR. |
| NT-proBNP | 1, 3, 6 , 12 months after injection | Analysis of differences of NT-proBNP serum level from baseline. |
| 6 minutes walk test (6MWT) | 1, 3, 6 , 12 months after injection | The difference of 6MWT from baseline. |
| assessment of heart failure symptom | 1, 3, 6, 12 months after injection | The difference of heart failure symptom, which will be assessed by NYHA grading and KCCQ score. |
| Incidence of major adverse cardiovascular events (MACE) | 1, 3, 6, 12 months after injection | Incidence of Cardiac death, readmission due to heart failure. |
| incidence of adverse events | 6, 12 months | Incidence of adverse events of heart, nerve system, mental system, digestive system and immune system. |
Countries
China
Contacts
CONTACTJiamin Li, MD
PRINCIPAL_INVESTIGATORXinyang Hu, PhD
2nd Affiliated Hospital, School of Medicine, Zhejiang University, China
Outcome results
None listed