Treatment Effects of Chinese Medicine (Yi-Qi-Qing-Jie Herbal Compound) Combined With Immunosuppression Therapies in IgA Nephropathy Patients With High-risk of ESRD

NCT ID: NCT03418779

Last Updated: 2024-09-25

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-07-04
• Study Completion Date: 2024-12-31

Brief Summary

The TCM-WINE study is a single-center, prospective, double-blind randomized placebo-controlled trial. Based on optimal supportive care, the trial is aiming to assess superiority with regard to renal protection and reduction of severe treatment-related adverse events of Yi-Qi-Qing-Jie formula (YQF) combined therapy compared with immunosuppression monotherapy in high-risk IgAN.

Detailed Description

The investigators plan to randomize 60 participants with biopsy-proven IgAN to a YQF combined group (YQF compound combined with prednisolone, and cyclophosphamide if necessary) or an immunosuppression group (placebo-YQF combined with prednisolone, and cyclophosphamide if necessary). The two groups will enter a 48-week in-trial treatment phase and receive post-trial follow-up until 50% (30/60) have a composite endpoint or have been followed for 3 years (study completion). All patients will receive optimal supportive care.

Conditions

IgA Nephropathy at High Risk of Developing ESRD

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Control Group

Optimized supportive care, YQF placebo (oral granule), immunosuppression therapy comprises oral prednisolone plus intravenous cyclophosphamide.

Group Type: EXPERIMENTAL

Immunosuppressants

Intervention Type: DRUG

Immunosuppression therapy comprises oral prednisolone (0.5-0.8 mg/kg/day; exact dose decided by the investigator, maximum dose not exceeding 60 mg/day) for 8 weeks, then tapered by 5-10 mg/day every 4 weeks, with a total treatment period of 24-32 weeks. Participants with persistent proteinuria ≥ 1 g/day after 8 weeks of corticosteroid monotherapy will receive 0.8-1.0 g of intravenous cyclophosphamide (CTX) every 4 weeks, total dose of not exceeding 8 g (exact dose decided by the site investigator). If severe CTX-related adverse events occur, such as alanine transaminase (ALT) exceeding the upper limit of two times, infections requiring hospitalization, granulocytes \< 3.0 × 109/L and platelets \< 50.0 × 109/L, CTX will stop being administered, symptoms will be treated, and adverse events recorded. Also, the frequency of detection will be increased to once every 2 weeks and the affected participant will be withdrawn if persistent infection or myelosuppression occurs.

Optimized Supportive Care

Intervention Type: OTHER

The optimized supportive care included:

1. Lifestyle: low-salt, restricted protein dietary with sufficient calorie supply, smoking cessation, moderate alcohol consumption and keeping a healthy weight

2. The use of renin-angiotensin system blockade: lowering blood pressure to a target below 135/85 mmHg, during which treatment was adjusted to ensure that patients were receiving the maximum labelled or tolerated dose of RAS blockade

3. Patients with Diabetes Mellitus received insulin or oral hypoglycemic agents to achieve HbA1c≤ 7.0%

4. Received uricosuric agents or xanthine oxidase inhibitors as necessary to achieve serum uric acid <6 mg/dL in female, <7 mg/dL in male

Yi-Qi-Qing-Jie herbal compound placebo

Intervention Type: OTHER

Patients will receive Yi-Qi-Qing-Jie herbal compound placebo instead for the duration of the treatment and follow-up phases. The major component of the placebo is malt dextrin which looks, smells and tastes like YQF compound, and it comes in packaging with a similar appearance to YQF compound; it is also dissolved in 150 ml boiled water and taken orally twice a day.

YQF Group

Optimized supportive care, YQF (oral granule), immunosuppression therapy comprises oral prednisolone plus intravenous cyclophosphamide.

Group Type: EXPERIMENTAL

The Yi-Qi-Qing-Jie herbal compound

Intervention Type: DRUG

The compounds are blends of individual herbal extracts from YQF (consisting of Astragalus membranaceus, Saposhnikovia divaricata (turcz.) Schischk, Flos lonicerae, Angelica sinensis, Dioscorea nipponica, Hedyotis diffusa Willd, rhubarb, Spatholobus suberectus, with the effect of reinforcing Qi and activating blood, clearing away heat and poison, dissolving dampness and downbearing turbid) dissolved in 150 ml boiled water and taken orally twice a day for the duration of the treatment and follow-up phases.

Immunosuppressants

Intervention Type: DRUG

Immunosuppression therapy comprises oral prednisolone (0.5-0.8 mg/kg/day; exact dose decided by the investigator, maximum dose not exceeding 60 mg/day) for 8 weeks, then tapered by 5-10 mg/day every 4 weeks, with a total treatment period of 24-32 weeks. Participants with persistent proteinuria ≥ 1 g/day after 8 weeks of corticosteroid monotherapy will receive 0.8-1.0 g of intravenous cyclophosphamide (CTX) every 4 weeks, total dose of not exceeding 8 g (exact dose decided by the site investigator). If severe CTX-related adverse events occur, such as alanine transaminase (ALT) exceeding the upper limit of two times, infections requiring hospitalization, granulocytes \< 3.0 × 109/L and platelets \< 50.0 × 109/L, CTX will stop being administered, symptoms will be treated, and adverse events recorded. Also, the frequency of detection will be increased to once every 2 weeks and the affected participant will be withdrawn if persistent infection or myelosuppression occurs.

Optimized Supportive Care

Intervention Type: OTHER

The optimized supportive care included:

1. Lifestyle: low-salt, restricted protein dietary with sufficient calorie supply, smoking cessation, moderate alcohol consumption and keeping a healthy weight

2. The use of renin-angiotensin system blockade: lowering blood pressure to a target below 135/85 mmHg, during which treatment was adjusted to ensure that patients were receiving the maximum labelled or tolerated dose of RAS blockade

3. Patients with Diabetes Mellitus received insulin or oral hypoglycemic agents to achieve HbA1c≤ 7.0%

4. Received uricosuric agents or xanthine oxidase inhibitors as necessary to achieve serum uric acid <6 mg/dL in female, <7 mg/dL in male

Interventions

The Yi-Qi-Qing-Jie herbal compound

The compounds are blends of individual herbal extracts from YQF (consisting of Astragalus membranaceus, Saposhnikovia divaricata (turcz.) Schischk, Flos lonicerae, Angelica sinensis, Dioscorea nipponica, Hedyotis diffusa Willd, rhubarb, Spatholobus suberectus, with the effect of reinforcing Qi and activating blood, clearing away heat and poison, dissolving dampness and downbearing turbid) dissolved in 150 ml boiled water and taken orally twice a day for the duration of the treatment and follow-up phases.

Intervention Type: DRUG

Immunosuppressants

Immunosuppression therapy comprises oral prednisolone (0.5-0.8 mg/kg/day; exact dose decided by the investigator, maximum dose not exceeding 60 mg/day) for 8 weeks, then tapered by 5-10 mg/day every 4 weeks, with a total treatment period of 24-32 weeks. Participants with persistent proteinuria ≥ 1 g/day after 8 weeks of corticosteroid monotherapy will receive 0.8-1.0 g of intravenous cyclophosphamide (CTX) every 4 weeks, total dose of not exceeding 8 g (exact dose decided by the site investigator). If severe CTX-related adverse events occur, such as alanine transaminase (ALT) exceeding the upper limit of two times, infections requiring hospitalization, granulocytes \< 3.0 × 109/L and platelets \< 50.0 × 109/L, CTX will stop being administered, symptoms will be treated, and adverse events recorded. Also, the frequency of detection will be increased to once every 2 weeks and the affected participant will be withdrawn if persistent infection or myelosuppression occurs.

Intervention Type: DRUG

Optimized Supportive Care

The optimized supportive care included:

1. Lifestyle: low-salt, restricted protein dietary with sufficient calorie supply, smoking cessation, moderate alcohol consumption and keeping a healthy weight

2. The use of renin-angiotensin system blockade: lowering blood pressure to a target below 135/85 mmHg, during which treatment was adjusted to ensure that patients were receiving the maximum labelled or tolerated dose of RAS blockade

3. Patients with Diabetes Mellitus received insulin or oral hypoglycemic agents to achieve HbA1c≤ 7.0%

4. Received uricosuric agents or xanthine oxidase inhibitors as necessary to achieve serum uric acid <6 mg/dL in female, <7 mg/dL in male

Intervention Type: OTHER

Yi-Qi-Qing-Jie herbal compound placebo

Patients will receive Yi-Qi-Qing-Jie herbal compound placebo instead for the duration of the treatment and follow-up phases. The major component of the placebo is malt dextrin which looks, smells and tastes like YQF compound, and it comes in packaging with a similar appearance to YQF compound; it is also dissolved in 150 ml boiled water and taken orally twice a day.

Intervention Type: OTHER

Other Intervention Names

prednisolone; cyclophosphamide

Eligibility Criteria

Inclusion Criteria

1. patients who maintain regular follow-ups at Guang'anmen Hospital, agree to participate, and provide informed consent;

2. biopsy-proven IgA nephropathy, with recent progression to high-risk IgAN*;

3. eGFR 15 to 60 ml/min/1.73 m2, calculated with the use of CKD-EPI Creatinine Equation 2009.

• High-risk IgAN: persistent proteinuria ≥ 1 g/d despite at least 8 weeks of optimal supportive care [maximally tolerated RAS blocker which refers to no symptomatic hypotension, no hyperkalemia, and serum creatinine increased by not more than 30% of baseline, blood pressure control meeting targets (135/85 mmHg or lower), and dietary management (sodium intake less than 6 g/d, protein intake of 0.6-0.8 g/kg/day, and low-fat diet)], the mean annual eGFR decline rate (eGFR-slope) >10 ml/min per 1.73 m2 per year, while needing to restart immunosuppressive therapy; or eGFR<60 ml/min/1.73 m2 at the first diagnosis.

Exclusion Criteria

1. secondary IgAN;

2. comorbidity of other primary or secondary glomerular diseases;

3. comorbidity of severe primary diseases such as cardiovascular, hepatic, cerebral, and hematopoietic system diseases or mental disorders;

4. allergy or intolerance to the experimental medication (e.g., RAS blockers, prednisolone, cyclophosphamide, YQF compound and its placebo compound);

5. contraindications to immunosuppression therapy-acute and chronic infectious diseases, malignancies, leukopenia, thrombocytopenia, gastrointestinal hemorrhage, ulcers of stomach or duodenum, post-transplantation;

6. pregnant or lactating women;

7. unwilling to participate in this study, failure to accept or tolerate Chinese medicine compound;

8. history of alcohol or drug abuse;

9. poor compliance, loss to follow-up;

10. participation in another clinical investigation.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

China Academy of Chinese Medical Sciences

OTHER

Sponsor Role: collaborator

Guang'anmen Hospital of China Academy of Chinese Medical Sciences

OTHER

Sponsor Role: lead

Responsible Party

Li Shen

Professor & MD.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jie Wang

Role: STUDY_CHAIR

Guang anmen Hospital, China Academy of Chinese Medical Sciences

Locations

Guang anmen Hospital, China Academy of Chinese Medical Sciences

Beijing, Beijing Municipality, China

Countries

China

References

Tunnicliffe DJ, Reid S, Craig JC, Samuels JA, Molony DA, Strippoli GF. Non-immunosuppressive treatment for IgA nephropathy. Cochrane Database Syst Rev. 2024 Feb 1;2(2):CD003962. doi: 10.1002/14651858.CD003962.pub3.

Reference Type: DERIVED

PMID: 38299639 (View on PubMed)

Li S, Li JP. Treatment effects of Chinese medicine (Yi-Qi-Qing-Jie herbal compound) combined with immunosuppression therapies in IgA nephropathy patients with high-risk of end-stage renal disease (TCM-WINE): study protocol for a randomized controlled trial. Trials. 2020 Jan 6;21(1):31. doi: 10.1186/s13063-019-3989-9.

Reference Type: DERIVED

PMID: 31907076 (View on PubMed)

Other Identifiers

TCMWINE

Identifier Type: -

Identifier Source: org_study_id