Overview

Phase II clinical study of HRS-9057 injection in patients with heart failure-induced fluid retention

Eligibility

Inclusion Criteria:

1. Aged ≥18 years on the day of signing the informed consent, regardless of gender;
2. Hospitalization due to heart failure within 72 hours prior to randomization.;
3. At screening and prior to randomization, presence of heart failure symptoms (exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, etc.) and at least one sign of fluid retention, including: auscultatory rales in the lungs, pitting edema of the lower extremities, pulmonary congestion confirmed by chest imaging;;
4. NT-proBNP \> 450 pg/mL within 12 hours prior to randomization, or \> 600 pg/mL in patients with atrial fibrillation; or BNP \> 150 pg/mL, or \> 200 pg/mL in patients with atrial fibrillation.
5. Judged to have poor response to loop diuretics before randomisation: presence of symptoms and signs of fluid retention after the administration of a cumulative dose of oral or intravenous loop diuretics equivalent to oral furosemide ≥40 mg (or equivalent doses of other loop diuretics#) within the past 12 hours.

Exclusion Criteria:

1. Occurrence of myocardial infarction, stroke or transient ischemic attack, sustained ventricular tachycardia or ventricular fibrillation within 1 month prior to screening; or severe trauma or major/moderate surgery within 1 month prior to screening;
2. Coronary revascularization (percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)), valve repair/replacement, carotid or peripheral arterial revascularization, mechanical circulatory support device therapy, heart transplantation within 1 month prior to screening or planned during the study; or presence of severe coronary artery disease or cerebrovascular disease without revascularization that may lead to acute events during hospitalization;
3. Fluid retention symptoms and signs determined by the investigator to be caused by non-cardiac diseases; or concomitant with other diseases that cause dyspnea or fluid retention, such as acute exacerbation of chronic obstructive pulmonary disease, severe anemia, decompensated liver cirrhosis, nephrotic syndrome, etc.
4. The investigator determines that this hospitalization is due to acute heart failure requiring initial correction of the underlying cause, including: coronary atherosclerotic heart disease requiring revascularization, active myocarditis, constrictive pericarditis, cardiac tamponade, complex congenital heart disease, or symptomatic severe untreated primary valvular heart disease that may lead to acute events during hospitalization;
5. Previously diagnosed with hypertrophic cardiomyopathy and currently still in the hypertrophic phase (obstructive or non-obstructive), or amyloid cardiomyopathy;
6. Use of cardiac mechanical assist device at the time of screening;
7. Presence of hypovolemia or peripheral hypoperfusion at screening, assessed by the investigator as requiring treatment with vasoconstrictors, positive inotropic agents, or volume resuscitation.
8. Anuria at the time of screening; or urinary difficulties caused by urinary tract obstruction, stones or tumours;
9. Unable to perceive thirst at the time of screening, or any reason causing difficulty in fluid intake;
10. Unable to complete weight measurement or urine collection;
11. Consciousness impairment at the time of screening, or hepatic encephalopathy at the time of screening or a history of hepatic encephalopathy;
12. Any organ system malignancy within the last 5 years requiring ongoing treatment such as chemotherapy, radiotherapy, endocrine therapy, targeted therapy, etc.;
13. History of drug abuse or substance use within 1 year prior to screening.
14. Body mass index (BMI) less than 18.5 or greater than 35 kg/m2;
15. Symptomatic hypotension and/or systolic blood pressure \<90 mmHg;
16. Estimated glomerular filtration rate (eGFR) \<15 mL/min/1.73 m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI2009\] formula based on serum creatinine), or undergoing/planned for haemodialysis or ultrafiltration therapy;
17. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3× the upper limit of normal (ULN), except if assessed by the investigator as due to heart failure;
18. Serum sodium \> ULN or \<125 mmol/L;
19. Serum potassium \> ULN
20. Known or suspected allergy to tolvaptan tablets, OPC-61815 injection, or HRS-9057 injection components;
21. Participation in any drug or medical device clinical trial within 3 months prior to screening, defined as: signing the informed consent and using the investigational product (excluding placebo) or investigational medical device; or still within 5 half-lives of the investigational drug (whichever is longer);
22. Use of tolvaptan tablets, OPC-61815 injection, or thiazide diuretics (including combination formulations) within 5 half-lives before dosing;
23. Use of drugs that may affect tolvaptan metabolism within 2 weeks or 5 half-lives before dosing (whichever is longer), including:

23.1 strong or moderate CYP3A inhibitors: ketoconazole or other strong CYP3A inhibitors (such as clarithromycin, itraconazole, telithromycin, saquinavir, nelfinavir, ritonavir, nefazodone), moderate CYP3A inhibitors (such as erythromycin, fluconazole, aprepitant, diltiazem, verapamil, delavirdine); 23.2 P-glycoprotein inhibitors: such as cyclosporine; 24. Individuals who currently require blood transfusion therapy. 25. Participants with mental incapacity or speech disorders, or unable to fully understand or participate in the trial process, or unable to fully understand potential adverse reactions during the study; 26. Pregnant or breastfeeding women, or participants of childbearing potential unwilling to use protocol-specified contraception during the trial and for 1 week after the last dose; 27. As judged by the investigator, any condition affecting participant safety or otherwise interfering with the evaluation of trial results (medical, psychological, social, or geographical factors, etc.).