Diabetic nephropathy (DN) is a leading cause of end-stage kidney disease worldwide and is associated with a high risk of cardiovascular events and mortality. Despite current standard therapies including renin-angiotensin system inhibitors (ACEI/ARB), glycemic control, and blood pressure management, disease progression remains inadequately controlled in many patients.

Naoxintong Capsule is a traditional Chinese medicine formulation composed of 16 herbal ingredients (Astragalus membranaceus, Prunus persica seed, Carthamus tinctorius, Paeonia lactiflora, Angelica sinensis, Ligusticum chuanxiong, Boswellia carterii, Commiphora myrrha, Salvia miltiorrhiza, Achyranthes bidentata, Cinnamomum cassia, Morus alba, Spatholobus suberectus, Buthus martensii, Pheretima aspergillum, and Hirudo nipponica). It has been widely used in China for cardiovascular and cerebrovascular diseases, with demonstrated effects on endothelial protection, anti-inflammation, anti-thrombosis, and plaque stabilization.

This multicenter, randomized, double-blind, placebo-controlled trial aims to evaluate the efficacy and safety of Naoxintong Capsule added to standard conventional therapy in slowing the progression of diabetic nephropathy and providing cardiovascular protection. A total of 410 patients with Type 2 diabetic nephropathy will be randomized (1:1) to receive either Naoxintong Capsules (4 capsules, 3 times daily) or matching placebo, in addition to standard therapy, for 12 months. The primary outcome is the annual rate of decline in estimated glomerular filtration rate (eGFR). Secondary outcomes include changes in proteinuria, CKD stage progression, time to end-stage kidney disease, major adverse cardiovascular events, TCM syndrome scores, and quality of life measures.

BACKGROUND AND RATIONALE

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in economically developed countries. China has the largest diabetic population globally, and DN now accounts for approximately 30% of new dialysis patients. Despite the beneficial effects of ACE inhibitors (ACEI) and Angiotensin II receptor blockers (ARB) in the microalbuminuric stage, landmark trials (RENNAL, IDNT, VA NEPHRON-D) have shown that these agents alone or in combination fail to significantly reduce cardiovascular events and all-cause mortality in advanced DN. There is an urgent need for novel therapeutic approaches to slow DN progression and improve survival.

Naoxintong Capsule (National Drug Approval No.: Guoyaozhunzi Z20025001) is a well-established traditional Chinese medicine formulation that has been widely used in China for cardiovascular and cerebrovascular diseases. It comprises 16 herbal and animal-derived ingredients that collectively exert effects through endothelial protection, anti-inflammatory activity, inhibition of thrombosis, and plaque stabilization. Based on the integrative medicine concept of brain-heart-kidney co-treatment and the shared pathophysiological mechanisms underlying DN progression and cardiovascular complications, Naoxintong Capsule represents a promising adjunctive therapy for DN.

STUDY DESIGN AND OBJECTIVES

This is a multicenter, randomized, double-blind, placebo-controlled clinical trial designed to provide high-level evidence for the efficacy and safety of Naoxintong Capsule in treating DN. The study will enroll 410 adult patients with confirmed Type 2 diabetic nephropathy across approximately 20 clinical centers in China.

The primary objective is to evaluate whether adding Naoxintong Capsule to standard conventional therapy can slow the annual rate of eGFR decline compared with standard therapy alone (with placebo). Secondary objectives include assessing effects on proteinuria, CKD stage progression, time to ESKD, cardiovascular events, traditional Chinese medicine (TCM) syndrome scores, and health-related quality of life.

PARTICIPANT POPULATION

Eligible participants are adults (age >= 18 years) with confirmed Type 2 diabetic nephropathy, 24-hour urinary protein excretion between 0.5 and 3.5 g, eGFR >= 45 mL/min/1.73m2, and on stable ACEI/ARB therapy for at least 8 weeks prior to enrollment. Patients must discontinue all other traditional Chinese medicine products for a washout period of at least 4 weeks before randomization.

INTERVENTION

Participants will be randomized (1:1) to receive either Naoxintong Capsules or matching placebo capsules, both administered as 4 capsules per dose, 3 times daily, taken orally 30 to 60 minutes after meals. All participants continue to receive standard conventional therapy for DN, including glycemic control, blood pressure management, lipid-lowering therapy, dietary management, and treatment of CKD-related complications as clinically indicated. The treatment duration is 12 months.

FOLLOW-UP AND ASSESSMENTS

Following randomization at Visit 1 (V1), participants will attend scheduled visits at Month 1 (V2), Month 3 (V3), Month 6 (V4), Month 9 (V5), and Month 12 (V6). At each visit, clinical assessments include physical examination, laboratory tests (urinalysis, 24-hour urine protein, urine albumin-to-creatinine ratio, complete blood count, blood biochemistry including renal function, HbA1c, lipid profile, hs-CRP, IL-6), ECG, TCM syndrome scoring, and adverse event monitoring. At selected visits (V1, V6), additional imaging studies (chest X-ray/CT, renal ultrasound) and optional fundoscopy are performed. Biological samples (blood, urine, stool) are collected at V1, V4, and V6 for exploratory analyses including gut microbiota and metabolomics.

SAMPLE SIZE

The sample size of 410 (205 per group) was calculated based on detecting a clinically meaningful difference of 1.0 mL/min/1.73m2/year in eGFR annual decline slope between groups (expected: -3.0 vs. -2.0 mL/min/1.73m2/year), with a pooled standard deviation of 3.2, at a two-sided alpha of 0.05 and 80% power, allowing for a 20% dropout rate.

STATISTICAL ANALYSIS

Efficacy analyses will be conducted on both the Full Analysis Set (FAS, intention-to-treat) and the Per-Protocol Set (PPS). The primary analysis will use a mixed-effects model for the eGFR slope, adjusting for center effect. Time-to-event outcomes will be analyzed using Kaplan-Meier methods and Cox proportional hazards models. Safety analyses will be performed on the FAS.

Inclusion Criteria:

1. Age >= 18 years.

2. Meets the diagnostic criteria for Type 2 diabetic nephropathy, defined as:

   1. Confirmed diagnosis of Type 2 diabetes mellitus; AND
   2. At least one of the following: urinary albumin-to-creatinine ratio (UACR) >= 30 mg/g, or eGFR < 60 mL/min/1.73m^2, confirmed by repeat testing (interval >= 3 months), after excluding transient factors such as acute kidney injury, dehydration, infection, or heart failure; OR
   3. Renal biopsy confirmed as isolated diabetic nephropathy; AND
   4. Exclusion of other primary or secondary kidney diseases.

3. 24-hour urinary protein excretion >= 0.5 g and < 3.5 g.

4. Estimated glomerular filtration rate (eGFR) >= 45 mL/min/1.73m^2.

5. On a stable dose of ACE inhibitor (ACEI) or Angiotensin II receptor blocker (ARB) therapy for at least 8 weeks prior to enrollment. If SGLT2 inhibitors, mineralocorticoid receptor antagonists (MRA), or GLP-1 receptor agonists are being used, the dose must have been stable for at least 4 weeks prior to enrollment and remain unchanged during the study period. Patients not currently using these agents must not initiate them during the study.

6. Signed informed consent form.

Exclusion Criteria:

1. Type 1 diabetes mellitus or other types of diabetes mellitus (e.g., secondary diabetes, maturity-onset diabetes of the young).
2. Coexisting systemic autoimmune or immune-mediated disease where the clinical assessment suggests a non-diabetic nephropathy etiology.
3. Decline in eGFR of > 30% within the past 3 months.
4. Persistent serum potassium > 5.5 mmol/L.
5. Diagnosis of hemorrhagic cardiovascular or cerebrovascular disease within the past 3 months.
6. Known allergy or hypersensitivity to any component of Naoxintong Capsule or placebo; pregnant or lactating women.
7. Participation in another drug or medical device clinical trial within the past 6 months.
8. Any other condition that, in the investigator's judgment, renders the patient unsuitable for participation in the clinical trial (e.g., severe hepatic dysfunction, life expectancy < 1 year).

De-identified individual participant data (IPD) may be shared with qualified researchers upon reasonable request, subject to a data use agreement, following publication of the primary results.

After publication of primary results

Via reasonable request with data use agreement

This is a double-blind study. Both the participants and the investigators are blinded to treatment assignment. Naoxintong Capsules and matching placebo capsules are identical in appearance, size, color, packaging, and labeling. The randomization code is maintained by the central data management center and will not be disclosed to investigators or participants until database lock, except in emergency situations requiring unblinding for safety reasons. Emergency unblinding envelopes are provided to each study site.