Effect of Henagliflozin on Renal Outcomes in Non-dialysis Patients With Advanced Chronic Kidney Disease : A Multicenter Prospective, Randomized Controlled Trial（HERO -aCKD）

A Multicenter, Prospective, Randomized, Controlled Study Evaluating the Progression of Renal Function in Patients With Late-Stage Chronic Kidney Disease Treated With Henagliflozin

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.

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 <90 mmHg or >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.