Naoxintong Capsule for Diabetic Nephropathy With Dampness Retention Pattern: A Multicenter, Randomized, Double-Blind, Placebo-Controlled TrialAcronymNXT-DKD

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.

• Naoxintong Capsule (Drug): Naoxintong Capsule is a traditional Chinese medicine formulation composed of 16 herbal and animal-derived ingredients: Astragalus membranaceus (Huangqi), Prunus persica seed (Taoren), Carthamus tinctorius flower (Honghua), Paeonia lactiflora root (Chishao), Angelica sinensis root (Danggui), Ligusticum chuanxiong rhizome (Chuanxiong), Boswellia carterii resin (Ruxiang), Commiphora myrrha resin (Moyao), Salvia miltiorrhiza root (Danshen), Achyranthes bidentata root (Niuxi), Cinnamomum cassia twig (Guizhi), Morus alba twig (Sangzhi), Spatholobus suberectus stem (Jixueteng), Buthus martensii (Quanxie), Pheretima aspergillum (Dilong), and Hirudo nipponica (Shuizhi). Each capsule contains 0.4 g of active ingredients. Dosage: 4 capsules (1.6 g) per dose, taken orally 3 times daily, 30-60 minutes after meals. Manufactured by Shaanxi Buchang Pharmaceutical Co., Ltd. (National Drug Approval No.: Guoyaozhunzi Z20025001). Storage: sealed, at room temperature. Shelf life: 24 months.
• Placebo (Drug): Matching placebo capsules identical in appearance, size, shape, color, weight, packaging, and labeling to Naoxintong Capsules but containing no active pharmaceutical or herbal ingredients. Dosage: 4 capsules per dose, taken orally 3 times daily, 30-60 minutes after meals. Manufactured by Shaanxi Buchang Pharmaceutical Co., Ltd. Storage: sealed, at room temperature. Shelf life: 24 months.

Primary outcomes

• Annual Rate of Decline in Estimated Glomerular Filtration Rate (eGFR) [Baseline to Month 12]: The annual rate of decline in eGFR (ml/min/1.73m\^2/year), calculated as the slope of eGFR over the 12-month treatment period using all available eGFR measurements at each scheduled visit. eGFR is estimated using the CKD-EPI equation. A less negative slope indicates slower disease progression.
• Change in 24-Hour Urinary Protein Excretion From Baseline [Baseline to Month 12]: Change from baseline in 24-hour urinary protein excretion (g/24h), measured at each scheduled visit. A decrease indicates renal protective effect.
• Renal Composite Endpoint: eGFR Decline >30%, ESKD, or MACE [From randomization through Month 12]: Time to first occurrence of: sustained eGFR decline >30% from baseline; end-stage kidney disease; or major adverse cardiovascular event.

Secondary outcomes

• Proportion of Participants With CKD Stage Improvement, Stabilization, or Progression [Baseline to Month 12]: Proportion of participants whose CKD stage (KDIGO eGFR categories) improved, remained stable, or progressed.
• Time to Sustained eGFR Decline of Greater Than 30% From Baseline [From randomization through Month 12]: Time from randomization to first confirmed sustained eGFR decline exceeding 30% from baseline.
• Time to End-Stage Kidney Disease (ESKD) [From randomization through Month 12]: Time from randomization to ESKD: maintenance dialysis, kidney transplantation, or sustained eGFR <15.
• Time to First Unplanned Hospitalization for Heart Failure [From randomization through Month 12]: Time from randomization to first unplanned hospital admission primarily due to heart failure.
• Time to First Non-Fatal Myocardial Infarction [From randomization through Month 12]: Time from randomization to first non-fatal MI per WHO-MONICA criteria.
• Time to First Non-Fatal Ischemic Stroke [From randomization through Month 12]: Time from randomization to first non-fatal ischemic stroke with imaging confirmation.
• Time to Cardiovascular Death or Stroke-Related Death [From randomization through Month 12]: Time from randomization to death attributable to cardiovascular or cerebrovascular causes.
• Time to All-Cause Death [From randomization through Month 12]: Time from randomization to death from any cause.
• Change in TCM Syndrome Score From Baseline [Baseline to Month 12]: Change in TCM syndrome score using a standardized 90-item questionnaire.

Sex: All, ages: 18 Years to any

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).