Evaluation of the Effect of Injectable Neucardin on Cardiac Function and Reversal Ventricular Remodeling in Patients With Chronic Systolic Heart Failure

A multicenter, randomized, double-blind, placebo-controlled phase III clinical trial to evaluate the effect of recombinant human Neuregulin-1 for injection on cardiac function and reverse ventricular remodeling in male patients with NT-proBNP ≤ 1700 pg/ml and female patients with NT-proBNP ≤ 4000 pg/ml and New York Heart Association class II-III chronic systolic heart failure, and to confirm its efficacy and safety.

This trial is planned to be conducted simultaneously in multiple clinical study sites nationwide, including 198 subjects, 99 subjects in the treatment group and 99 subjects in the placebo group.

Primary endpoint:

1.Response rate at 35 days of simultaneous reduction of LVESVI and LVEDVI by more than or equal to 20 ml/m2 (The proportion of the subjects achieving this criterion in each treatment group.)

Secondary endpoints:

1. Response rate at 35 day of LVESVI improvement greater than or equal to 25 ml/m2 ;
2. Response rate at 35 day of LVEDVI improvement greater than or equal to 25 ml/m2 ;
3. Change from baseline in LVEF, LVESV, LVEDV, LVESVI and LVEDVI at 35 days ;
4. 90-day response rate of LVESVI improved greater than or equal to 25ml/m2,LVEDVI improved greater than or equal to 25 ml/m2, and LVESVI and LVEDVI improved greater than or equal to 20 ml/m2 at the same time ;
5. Change from baseline in LVEF, LVESV, LVEDV, LVESVI and LVEDVI at 90 days ;
6. Change from baseline in NYHA at 35 and 90 days ;
7. Change from baseline in quality of life at 35 and 90 days ;
8. Mortality during the study period.

Eligibility Criteria:
Inclusion Criteria:

1. 18-75 years, male or female;
2. Definite diagnosis of heart failure for 6 months or more, current stable disease, NYHA class II-III, left ventricular ejection fraction (LVEF) ≤ 40%(echocardiographic modified Simpson's method measurement ≤ 40% at screening, and CMR measurement ≤ 40% at baseline);
3. NT-proBNP ≤1700 pg/ml in males and ≤4000pg/ml in females (detected by Roche kit in central laboratory);
4. Receiving standard basic treatment for heart failure for at least 3 months, and did not change the type and dose of heart failure treatment drugs within 1 month;
5. Understand and sign the informed consent form.

Exclusion Criteria:

1. Unable to receive CMR examination, such as patients with pacemakers, ICDs, CRTs, or other similar devices contraindicated for CMR, claustrophobia, atrial fibrillation during the screening period, or inability to cooperate with air-closed activities required for CMR testing;
2. Hypertrophic cardiomyopathy with left ventricular outflow tract obstruction, constrictive pericarditis, significant and uncorrected valvular heart disease, severe valvular regurgitation or severe stenosis, congenital heart disease requiring surgical treatment but not surgical treatment, primary pulmonary hypertension or secondary severe pulmonary hypertension (≥ 70 mmHg), and right heart failure due to pulmonary disease;
3. Patients suffering from proliferative glands or adenomas with endocrine activity which may affect cardiac function or endocrine function, such as pheochromocytoma, thyromegaly, etc. (patients with euthyroid thyroid nodules do not need to be excluded);
4. LVESVi less than 135 ml/m2 at baseline;
5. Prepare to install pacemaker, ICD, CRT or other similar devices within 6 months;
6. History of heart transplantation, use of ventricular assist devices (VADs) or preparation for heart transplantation, VADs;
7. Diagnosis of peripartum or chemotherapy-induced cardiomyopathy within the past 12 months;
8. Subjects with chronic heart failure with acute hemodynamic disturbance or acute decompensation within the past 1 month (symptoms and signs prove that chronic heart failure is aggravated and intravenous drug therapy is required);
9. Angina pectoris within the past 3 months;
10. Myocardial infarction, cerebrovascular accident, revascularization (PCI or other surgery), cardiac surgery, carotid artery or other large vessel surgery within the past 6 months;
11. Serious ventricular arrhythmias (sustained ventricular tachycardia or other conditions that the investigator considers necessary to exclude);
12. Clinical diagnosis of pericardial effusion, pleural effusion or imaging showed pericardial effusion (greater than 50ml or 3 mm or a small amount or more) or pleural effusion (greater than 200ml or 10 mm);
13. Liver and kidney dysfunction and chronic liver disease may have a potential impact on liver function (such as active chronic hepatitis, etc.), non-heart failure causes of bilirubin or alkaline phosphatase \> 2 times the upper limit of normal, aspartate aminotransferase and/or alanine aminotransferase \> 3 times the upper limit of normal, eGFR calculated using MDRD method \< 30 ml/min/1.73 m2;
14. Systolic blood pressure \< 90 mmHg or \> 160 mmHg;
15. Serum K + \< 3.2 mmol/L or \> 5.5 mmol/L;
16. Women of childbearing potential who plan to become pregnant within 2 years (women of childbearing potential are defined as all women with physical ability to become pregnant), pregnant or lactating women;
17. Previous history of cancer or current cancer, or pathological examination confirmed precancerous lesions (Such as ductal carcinoma in situ of the breast, or atypical hyperplasia of the cervix), or through the examination (physical examination, X-ray examination or B ultrasound examination or other means) found in vivo malignant mass subjects;
18. The investigator judges that the survival time is expected to be less than 6 months;
19. Participated in any drug clinical trials within the first 3 months;
20. Severe neurological disease (Alzheimer's disease, progressive parkinsonism);
21. Subjects who are unable to complete this study or fail to comply with the requirements of this study (due to administrative reasons or other reasons), as judged by the investigator.