Phase II Clinical Study of HRS-9057 Injection in Patients With Heart Failure-induced Fluid Retention

Exclusion Criteria32

• Myocardial infarction, stroke or transient cerebral ischaemic attack, sustained ventricular tachycardia or ventricular fibrillation within 1 month prior to screening; or severe infection, major trauma or undergoing major or medium-sized surgery within 1 month prior to screening;
• Coronary revascularisation (percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)), atrial flutter/fibrillation ablation, pacemaker implantation, valve repair/replacement, carotid or peripheral artery revascularisation, cardiac mechanical assist device therapy, heart transplantation within 1 month prior to screening or planned during the trial; or current severe coronary artery disease or cerebrovascular disease without revascularisation;
• Fluid retention symptoms and signs judged by the investigator to be caused by non-cardiac diseases; or concomitant conditions causing dyspnoea or fluid retention, such as acute exacerbation of chronic obstructive pulmonary disease, pulmonary heart disease, severe anaemia, decompensated liver cirrhosis, nephrotic syndrome, etc.;
• Acute heart failure requiring primary correction of the underlying cause as determined by the investigator, due to the following conditions: coronary atherosclerotic heart disease requiring revascularisation, active myocarditis, constrictive pericarditis, cardiac tamponade, complex congenital heart disease, untreated severe primary valvular heart disease, etc.;
• Previously diagnosed hypertrophic cardiomyopathy (obstructive or non-obstructive), amyloid cardiomyopathy;
• Use of cardiac mechanical assist device at the time of screening;
• Hypovolaemia or peripheral perfusion insufficiency at the time of screening, requiring vasoactive drugs, positive inotropic drugs or volume expansion therapy as assessed by the investigator;
• Anuria at the time of screening; or urinary difficulties caused by urinary tract obstruction, stones or tumours;
• Unable to perceive thirst at the time of screening, or any reason causing difficulty in fluid intake;
• Unable to complete weight measurement or urine collection;
• Consciousness impairment at the time of screening, or hepatic encephalopathy at the time of screening or a history of hepatic encephalopathy;
• Poorly controlled diabetes at the time of screening, with fasting blood glucose ≥11.1mmol/L;
• Any organ system malignancy within the last 5 years requiring ongoing treatment such as chemotherapy, radiotherapy, endocrine therapy, targeted therapy, etc.;
• History of drug abuse or substance use within 1 year prior to screening.
• Body mass index (BMI) less than 18.5 or greater than 35 kg/m2;
• Symptomatic hypotension and/or systolic blood pressure \<90 mmHg;
• 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;
• 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;
• Serum sodium \> ULN or \<130 mmol/L;
• Serum potassium \> ULN or serum potassium still \< lower limit of normal (LLN) after treatment;
• Concurrent active hepatitis B (hepatitis B surface antigen \[HBsAg\] positive and peripheral blood hepatitis B virus DNA positive) or any one of human immunodeficiency virus antibodies (HIV-Ab), Treponema pallidum antibodies (Anti-TP), hepatitis C virus antibodies (HCV-Ab) positive.
• Known or suspected allergy to tolvaptan tablets, OPC-61815 injection, or HRS-9057 injection components;
• 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);
• Use of tolvaptan tablets, OPC-61815 injection, or thiazide diuretics (including combination formulations) within 5 half-lives before dosing;
• Use of drugs that may affect tolvaptan metabolism within 2 weeks or 5 half-lives before dosing (whichever is longer), includin
• ⅰ 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);
• ⅱ CYP3A inducers: rifampicin or other inducers (such as rifabutin, rifapentine, barbiturates, phenytoin, carbamazepine, forsythia);
• ⅲ P-glycoprotein inhibitors: such as cyclosporine;
• History of blood donation or blood loss ≥400 mL within 3 months prior to screening, or blood transfusion within 2 months;
• 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;
• 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;
• 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.).