effect of henagliflozin on renal outcomes in non-dialysis patients with advanced chronic kidney disease : a multicenter prospective, randomized controlled trial（hero -ackd）

Conditions: Chronic Kidney Disease Stage 4

Summary: this is a multicenter, prospective, randomized, controlled study that will enroll approximately 429 subjects. the screening period will last 4-8 weeks. subjects will undergo pre-screening based on egfr and urinary albumin-to-creatinine ratio (uacr). only non-dialysis subjects meeting the following criteria confirmed by local laboratories within 6 months prior to screening will be eligible for central laboratory screening: 10 ml/min/1.73m² ≤ egfr \< 30 ml/min/1.73m² and 150 mg/g (16.95 mg/mmol) ≤ uacr \< 5000 mg/g (565 mg/mmol). unless contraindicated due to intolerance, subjects with 20 ml/min/1.73m² ≤ egfr \< 30 ml/min/1.73m² must receive stable, maximally tolerated labeled daily doses of acei or arb for at least 4 weeks prior to randomization. for subjects with 10 ml/min/1.73m² ≤ egfr \< 20 ml/min/1.73m², investigators will determine acei/arb treatment based on patient condition per kdigo guidelines. other antihypertensive, lipid-lowering, and glucose-lowering therapies should be stabilized for approximately 4 weeks before randomization. investigators are encouraged to maintain stability of medications known to affect serum creatinine levels during screening and approximately 2 weeks prior to any serum chemistry measurements throughout the study. eligible subjects will be randomized in a 1:1:1 ratio to receive henagliflozin (10 mg q.d., 5 mg q.d.) or conventional therapy. thereafter, subjects will undergo laboratory assessments, concomitant medication review, adverse event collection, and clinical endpoint ascertainment at week 4 (day 30), week 12 (day 90), and week 24 (day 180), followed by every 12-week intervals. throughout the study, all subjects will receive glycemic, blood pressure (target sbp \<140 mmhg and dbp \<90 mmhg), and lipid management according to current guidelines. all subjects will complete an end-of-study visit. subjects discontinuing study drug prematurely should continue all subsequent study visits.


Eligibility criteria:
inclusion criteria: * the investigator considers that the participant does not require henagliflozin or any other sglt-2 inhibitor therapy, nor deems such therapy absolutely inappropriate; and based on local laboratory results within 6 months before the screening visit and at the screening visit, the following criteria must be met: 1. 10 ml/min/1.73m² ≤ egfr \< 30 ml/min/1.73m² (ckd-epi equation), and 2. 150 mg/g (16.95 mg/mmol) ≤ urine albumin-to-creatinine ratio (uacr) \< 5000 mg/g (565 mg/mmol) * age ≥ 18 years, male or femal * participants with 20 ml/min/1.73m² ≤ egfr \< 30 ml/min/1.73m² must be on a stable and tolerated dose of an ace inhibitor (acei) or arb for at least 4 weeks, unless intolerant (reasons for intolerance must be documented). participants with 10 ml/min/1.73m² ≤ egfr \< 20 ml/min/1.73m² should have acei/arb use determined by the investigator based on the patient's clinical status and kdigo guideline recommendations; * anticipated time to requiring dialysis is greater than 1 month; * provision of written informed consent (illiterate participants may use a thumbprint in lieu of a signature). exclusion criteria: * received sglt2 inhibitor treatment within 8 weeks prior to enrollment or with a history of sglt2 inhibitor intolerance; * receiving combined therapy with an ace inhibitor (acei) and an arb, or a renin inhibitor combined with acei or arb (based on self-report at screening and randomization visits); * on maintenance dialysis, has a functioning kidney transplant, or is a planned living donor transplant recipient (based on self-report at screening and randomization visits); * polycystic kidney disease, active lupus nephritis, or systemic vasculitis;(5) symptomatic hypotension, or systolic blood pressure \ 180 mmhg at screening; * alt or ast levels \>3 times the upper limit of normal (uln) at screening; * received any intravenous immunosuppressive therapy within the previous 3 months; or any subject who received prednisone \>45 mg/day (or equivalent dose) within the previous 3 months; * current use or use within 12 weeks prior to enrollment of glucagon-like peptide-1 (glp-1) receptor agonist medications (e.g., liraglutide, semaglutide, dulaglutide, etc.) or current participation in another clinical trial of glucose-lowering drugs that may affect kidney or cardiovascular outcomes;(9) severe malnutrition (serum albumin \<25 g/l) and/or severe anemia (hemoglobin \<70 g/l); * known poor adherence to clinical follow-up or medication; * myocardial infarction, unstable angina, or stroke within 12 weeks prior to enrollment; * underwent coronary revascularization (percutaneous coronary intervention \[pci\] or coronary artery bypass grafting \[cabg\]) or valve repair/replacement within 12 weeks prior to enrollment, or plans to undergo any of these procedures after randomization;(13) any disease other than kidney or cardiovascular disease (e.g., but not limited to, malignancy) that, in the investigator's clinical judgment, is associated with a life expectancy of less than 2 years; * active malignancy requiring treatment at the time of the first visit (except for successfully treated basal cell carcinoma, treated squamous cell carcinoma, or thyroid cancer); * currently pregnant, breastfeeding, or a woman of childbearing potential (wocbp) unless using a highly effective method of contraception; * type 1 diabetes;(17) investigator considers the patient unable to understand and/or comply with the study procedures and/or follow-up, or any condition that, in the investigator's opinion, may lead to the patient's inability to complete the study. * additionally, subjects will be excluded at the randomization visit if any of the following occur: 1. did not adhere to the run-in treatment; 2. no longer willing to be randomized and followed for at least 2 years; 3. considered unsuitable for randomization by the local investigator; or experienced ketoacidosis, heart attack (myocardial infarction), stroke, hospitalization for heart failure, hospitalization for urinary tract infection, or acute kidney injury during the run-in period.