A Mechanistic Study on the Effect of HTD1801 Versus Placebo on Kidney Function in Patients With Type 2 Diabetes and Chronic Kidney Disease.

A Randomized, Double-blind, Placebo-controlled Mechanistic Study to Evaluate the Effect of HTD1801 in Delaying the Progression of Renal Impairment in Patients With Type 2 Diabetes and Chronic Kidney Disease.

Goal: The goal of this clinical trial is to learn if the investigational drug HTD1801 can slow the progression of kidney damage in adults diagnosed with both Type 2 Diabetes (T2DM) and Chronic Kidney Disease (CKD).

Main Question it Aims to Answer:

▪ Does HTD1801 result in a greater reduction (or a smaller increase) in urine albumin-to-creatinine ratio (UACR) compared to a placebo?

Researchers will compare the group receiving HTD1801 to the group receiving a placebo to see if HTD1801 is more effective in slowing kidney function decline.

Participants will:

• Undergo screening tests to determine eligibility.
• Be randomly assigned to receive either HTD1801 capsules or matching placebo capsules twice daily for 12 weeks.
• Take the study medication twice daily for 12 weeks.
• Attend scheduled clinic visits (weekly for the first 4 weeks, then every 4 weeks) for assessments and check-ups.
• Have their safety monitored through reporting of any health changes and routine lab tests.

Inclusion Criteria:

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Subjects must meet all of the following criteria to be eligible for the study:

1. Male or female, aged between 18 and 75 years (inclusive) at the time of signing the informed consent form.

2. Clinically diagnosed with Type 2 Diabetes (T2DM) and Chronic Kidney Disease (CKD) before screening, evidenced by:

   1. A urine albumin-to-creatinine ratio (UACR) >200 mg/g on at least two separate occasions before screening.
   2. A clinical diagnosis of CKD (KDIGO stage G1 to G3b) for at least 3 months, and an estimated glomerular filtration rate (eGFR) between 30 and 120 ml/min/1.73 m² at screening (using the CKD-EPI creatinine-cystatin C formula).

3. Confirmed diagnosis of T2DM. If on medication for T2DM, the dose must have been stable for at least 3 months before enrollment. At screening, HbA1c must be ≤9%.

4. At screening, on a stable, maximum tolerated or recommended dose of a RAAS inhibitor (e.g., valsartan, irbesartan) for at least 4 weeks. If not on a RAAS inhibitor, must be on at least one other stable, guideline-recommended kidney-protective drug (e.g., GLP-1RA, SGLT-2i, or non-steroidal MRA like finerenone) for at least 4 weeks.

5. Body Mass Index (BMI) at screening between 18.5 kg/m² and 40 kg/m². Weight must be stable (no loss >10% in the 3 months before baseline) with no major lifestyle changes in the 3 months before screening.

6. For women of childbearing potential and sexually active men with partners of childbearing potential: agreement to use highly effective contraception or practice abstinence throughout the study and for 30 days after the last dose.

7. Able to understand, sign the informed consent form, and comply with the study protocol.

Exclusion Criteria:

• Exclusion Criteria Subjects who meet any of the following criteria are excluded from participation in the study. Exclusion criteria based on lab values refer to the most recent results obtained prior to randomization.

Kidney Disease:

1. Congenital or hereditary kidney diseases, including polycystic kidney disease, autoimmune kidney diseases (e.g., glomerulonephritis), or congenital urinary tract malformations.

2. Currently receiving (or within the past 90 days) chronic or intermittent hemodialysis or peritoneal dialysis.

   Liver Disease:

3. Clinically or histologically confirmed liver cirrhosis (Fibrosis Stage 4).

4. History of hepatic decompensation (e.g., ascites, hepatic encephalopathy, or variceal bleeding).

5. Presence of the following acute or chronic liver diseases at screening: autoimmune hepatitis, primary biliary cholangitis, alcoholic liver disease, Wilson's disease, or drug-induced liver injury.

   Gastrointestinal Disease:

6. History of gastric bypass surgery.

7. History of peptic or gastrointestinal ulcer within 12 months prior to randomization.

8. History of clinically active inflammatory bowel disease within 12 months prior to randomization.

9. Severe gastrointestinal disease at screening that affects drug absorption, distribution, metabolism, or excretion, including chronic conditions causing recurrent diarrhea (e.g., irritable bowel syndrome, ulcerative colitis, Crohn's disease).

   Cardiovascular Disease:

10. History of myocardial infarction, stroke, uncontrolled arrhythmia, unstable angina, coronary artery bypass grafting, or percutaneous coronary intervention within 6 months prior to screening.

11. Current or previous history of New York Heart Association (NYHA) Class IV congestive heart failure.

12. Planned coronary, carotid, or peripheral arterial revascularization.

13. Uncontrolled hypertension despite antihypertensive therapy, defined as sustained SBP >150 mmHg and/or DBP >100 mmHg.

    Hematologic Disease:

14. Hematologic disorders or any condition causing hemolysis or red blood cell instability at screening, including but not limited to: glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, hemolytic anemia, iron deficiency anemia, aplastic anemia, chronic malaria, splenectomy, reticulocytopenia.

    Oncology:

15. History of or current malignancy within the past 2 years, except for basal cell carcinoma or excised non-invasive squamous cell carcinoma of the skin.

16. Current, planned, or anticipated treatment with radiotherapy, cytotoxic chemotherapy, or immunomodulators (e.g., interleukins, interferons). Long-term stable use of immunosuppressants is permitted if approved by the investigator.

    Diagnostic Assessments:

17. Clinically significant laboratory abnormalities or ECG changes at screening, including but not limited to:

    1. Platelet count <150,000/mm³.
    2. International Normalized Ratio (INR) >1.3.
    3. Alkaline Phosphatase (ALP) >2 × Upper Limit of Normal (ULN).
    4. Total bilirubin >1.3 × ULN, unless the subject has Gilbert's syndrome.
    5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥5 × ULN.
    6. Corrected QT interval (QTc) >450 ms for males or >470 ms for females (Fridericia's formula).

18. Active severe infection requiring parenteral antibiotic or antifungal therapy within 30 days prior to or at screening.

19. Evidence of the following viral infections at screening:

    1. Human Immunodeficiency Virus (HIV) infection: defined as positive HIV antibody.
    2. Syphilis infection: defined as positive Treponema pallidum antibody (TP-Ab).
    3. Active Hepatitis B Virus (HBV) infection: defined as positive Hepatitis B surface antigen (HBsAg) OR positive Hepatitis B core antibody (HBcAb) with HBV-DNA >500 IU/mL or >2000 copies/mL.
    4. Active Hepatitis C Virus (HCV) infection: defined as positive HCV antibody (HCV-Ab) with HCV-RNA above the ULN.

    Other:

20. Major surgery within 30 days prior to screening.

21. History of solid organ transplantation or being on a waiting list for such transplantation.

22. Blood donation or blood loss ≥400 mL within 3 months prior to screening, or anticipated need for blood transfusion within 12 weeks after randomization.

23. Known exposure to UDCA（Ursodeoxycholic Acid） or BBR（Berberine） within 3 months prior to screening, or known allergy to UDCA or BBR.

24. History or evidence of Type 1 diabetes.

25. Female subjects who are pregnant, breastfeeding, planning pregnancy, or of childbearing potential and not using highly effective contraception.

26. Participation in any clinical study of an approved or investigational product within 30 days prior to screening.

27. Any condition that, in the investigator's judgment, may jeopardize the subject's safety or compliance with the study protocol.