Treatment effects of Chinese Medicine (Yi-Qi-Qing-Jie Herbal Compound) combined With immunosuppression therapies in patients of IgA Nephropathy with high-risk of ESRD (TCM-WINE): study protocol for a randomized controlled trial

doi:10.21203/rs.2.13775/v1

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Treatment effects of Chinese Medicine (Yi-Qi-Qing-Jie Herbal Compound) combined With immunosuppression therapies in patients of IgA Nephropathy with high-risk of ESRD (TCM-WINE): study protocol for a randomized controlled trial

https://doi.org/10.21203/rs.2.13775/v1

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Background: IgA nephropathy (IgAN) is the most common glomerular disease worldwide. It has a high incidence in Asians and is more likely to progress to end-stage renal disease (ESRD). However, for high-risk IgAN clinically characterized by massive proteinuria and renal dysfunction, there has been no international consensus on treatment options. Compared with other developed countries, Chinese IgAN patients are often found to have severe kidney function loss at the initial diagnosis. Yi-Qi-Qing-Jie Formula Granule (a compound recipe of Chinese medicinal herbs, YQF) has shown potential renal protection in our previous clinical studies. To further confirm the efficacy and safety of YQF in the treatment of high-risk IgAN, we design a prospective double-blind randomized placebo-controlled trial. Methods/Design: The TCM-WINE study is a single-center, prospective, double-blind placebo-randomized controlled trial. We plan to randomize 60 participants with biopsy-proven IgAN to YQF combined group (YQF compound, combined with prednisolone, and cyclophosphamide if necessary) and immunosuppression group (placebo-YQF, combined with prednisolone, and cyclophosphamide if necessary). The two groups will enter 48-week in-trial treatment phase and receive post-trial follow-up till study completion (3-year). All patients will receive optimal supportive care. The primary composite outcome is defined as the first occurrence of a 40% decrease in estimated glomerular filtration rate (eGFR) from the baseline lasting for 3 months, initiating continuous renal replacement treatment or death due to chronic kidney disease (CKD), during the 3-year study phase. Secondary endpoint events are defined as the mean annual eGFR decline rate (eGFR-Slope, ml/min per 1.73 m 2 per year) which is calculated by the eGFR regression curve for each eligible patient, and proteinuria remission (prescribed as proteinuria<0.5g/day) at week 24, 36, 48 during the in-trial phase. Safety monitoring and assessment will be undertaken during the study . Discussion: TCM-WINE study will evaluate effects and safety of YQF combined therapy compared with immunosuppression monotherapy on basis of optimal supportive treatment in high-risk IgAN. The evidence from this study will provide a novel, effective and safe Chinese characteristics therapy for high-risk IgAN patients. Trial registration: Clinicaltrials.gov, identifier: NCT03418779. Registered on 18 June 2018. https://clinicaltrials.gov/show/NCT03418779

Internal Medicine

Integrative & Complementary Medicine

Translational Medicine

IgA nephropathy

Immunosuppressive

High-risk IgAN

Yi-Qi-Qing-Jie Formula

Traditional Chinese Medicine

IgA nephropathy (IgAN) is the most prevalent primary glomerular disease worldwide and accounts for 45% of the primary glomerular disease in China which significantly contributes to the global burden of chronic kidney disease (CKD) [1,2]. Patients with IgAN are often diagnosed as young adults, and about 30% of the patients develop end-stage renal disease (ESRD) in 10–20 years [1,3]. Proteinuria, decreased kidney function and hypertension at diagnosis are the independent risk factors for progression to ESRD. Among them, a persistent proteinuria is the strongest predictor developing ESRD [4–6]. According to the 2016 Oxford Classification of IgAN, mesangial or endocapillary hypercellularity, crescents, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis are pathological indicators of poor renal outcome [7].

Latest Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis recommends angiotensin-converting enzyme inhibitors (ACEI) or angiotensin-receptor blocker (ARB) with up-titration to achieve a maximally tolerated dose, as an initial therapy for progressive IgAN. For those patients with persistent proteinuria>1g per day and estimated glomerular filtration rate (eGFR) >50mL/min/1.73m², a 6-month course of high-dose corticosteroid therapy is suggested despite 3–6 months of optimized supportive care (ACE inhibitor, ARB, or both and blood-pressure control). Intensive immunosuppression [corticosteroid with cyclophosphamide (CTX) or azathioprine] is reserved for patients with crescents in more than half of the glomeruli and a rapidly deteriorating renal function [8]. A meta-analysis has shown that IgAN patients with more serious pathological features may be more resistant to steroid therapy than slight ones according to the earlier outlined Oxford classification system [9].

However, the benefits of systemic immunosuppression have been questioned in recently completed trials. Conflicting results indicate the presence of severe adverse events (SAEs), which imply long-term immunosuppression must be balanced against benefits carefully [10–12]. Other general immunosuppressants, such as mycophenolate mofetil [13,14], calcineurin inhibitors [15], and targeted immunosuppression regimens, like rituximab [16], targeted release formation -budesonide [17], the selective enzyme spleen tyrosine kinase inhibitor fostamatinib which was recently completed in a Phase Ⅱ randomized controlled trial (RCT) (ClinicalTrials.gov, NCT02112838), are waiting for more high-quality trials to access their safety and efficacy. Above all, for high-risk IgAN, a safe, disease-specific therapy remains limited.

Chinese medicine is gradually accumulating evidence-base application in CKD, which has been widely approved for its positive role in the prevention and treatment of IgAN [18–21]. Yi-Qi-Qing-Jie Formula (YQF) was developed from the classical Chinese prescription Yupingfeng San，Yinqiao San and Wuweixiaodu Yin, the main constituents including Astragali radix (HUANG QI), atractylodes rhizome (BAI ZHU), Radix Saposhnikoviae (FANG FENG), oldenlandia diffusa (BAI HUA SHE SHE CAO), Rhizoma Dioscoreae Nipponicae (CHUAN SHAN LONG), and raw rhubarb (DA HUANG). We have conducted an ambispective cohort study [22]. According to serum creatinine, 24h urine total protein (UTP), etc. before treatment, age, sex, and groups, using a propensity score, 34 high-risk IgAN patients with UTP>3g/24h and eGFR<60ml/min/1.73m², who received YQF combined therapy (treatment group) were matched to 34 patients who received immunosuppression monotherapy (control group) from Peking University First Hospital nephrology department, on basis of reninangiotensin system blockade (RASB) (Table 1). In conclusion, YQF combined therapy exhibited a potential renal protective effect during the mean follow-up period of 43 months. 5 patients (14.71%) reached ESRDTable 2 and Figure 1) and there were no SAEs associated with immunosuppressants. In Mitsuiki’s study, which was similar to our treatment protocol, 6 patients (22%) treated with prednisolone and cyclophosphamide reached ESRD during the mean follow-up period of 66.5 months, and 2 patients (7.4%) suffered adverse effects of immunosuppression during treatment [23].

However, the study did not use a standardized clinical study design (cases included were non-contemporaneous), the sample size was small and the observation period was shorter. We will conduct a randomized, prospective, double-blind (placebo) controlled trial to confirm that, compared with immunosuppressive therapy alone, YQF combined with immunosuppressive therapy will be superior in renal function protection and reducing the severe treatment-related adverse effects in patients with high-risk IgA nephropathy.

Study design

This is a single-center, prospective, double-blind, placebo-randomized controlled trial. This clinical trial is reported according to the Standard Protocol Interventions: Recommendations for Interventional Trials (SPIRIT) guidelines [24]study schedule (SPIRIT figure) is outlined in Figure 2, checklist see Additional file 1].

Setting and participants

Sixty high-risk IgAN participants will be followed up until 50% (30 of them) have a composite endpoint or been followed for 3 years. The trial will be conducted at Guang’anmen Hospital, Beijing, China, and was approved by the Ethics Committee of Guang’anmen Hospital (approval number: 2018–055-KY–01) in accordance with the Declaration of Helsinki and the principles outlined in the “Guidelines for Good Clinical Practice” from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Tripartite Guideline (January 1997). The trial will be conducted with all subjects voluntarily and signed informed consent.

Objectives

The trial is aiming to access superiority in renal protection and reducing severe treatment-related adverse events using YQF combined therapy compared with immunosuppression monotherapy based on optimal supportive care in high-risk IgAN.

Rationale of high-risk IgAN

Several high-quality clinical trials mentioned above [11,12] have respectively interpreted the concept of “high-risk” clinically and pathologically while not specific. Drawn from inclusion criteria of above-mentioned trials, this study will define “high-risk” as a persistent heavy proteinuria (≥1g/d despite intensive optimal supportive care) with impaired renal function (eGFR 15–60 ml/min/1.73m²).

Inclusion and exclusion criteria

The inclusion criteria are as follows: (1) in accordance with IgAN pathological diagnosis, renal biopsy within 6 months; (2) a persistent proteinuria≥1g/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 (SCr) increase not more than 30% of baseline, blood pressure control meeting targets, and diet management); (3) eGFR 15 to 60 ml/min/1.73 m², calculated with the use of the CKD-EPI Creatinine Equation 2009; (4) patients who maintain regular follow-up at Guang’anmen Hospital, agree to participate and obtain informed consent. (Additional file 2 shows the Informed Consent Form in more detail)

The exclusion criteria are as follows: (1) secondary IgAN; (2) comorbidity of other primary or secondary glomerular diseases; (3) comorbidity of severe primary diseases such as cardiovascular, hepatic, cerebral, hematopoietic system diseases and mental disorders; (4) allergy or intolerance to the experimental medication (e.g., RAS blockers, prednisolone, cyclophosphamide, YQF compound and its placebo compound) ; (5) contraindications of 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) a history of alcohol or drug abuse; (9) poor compliance, loss to follow-up from the study; (10) participation in another clinical investigation.

Randomization and masking

In the case that the subjects are eligible to participate and have signed informed consent, 30 patients in each group of the YQF group and the control group will be randomly selected according to the 1:1 block by a central stochastic system developed by the Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences. Randomization will be performed by experts using block randomization method with SAS 9.4.3 (SAS Institute, Cary, NC, USA).Block sizes will be hidden from investigators who have no exclusive competence in the randomization system. Relevant personnel have clear division of labor and strict accessing restrictions. Participants, investigators, and other all members with clinical involvement in the trial will be masked to the treatment allocation which contained in opaque, sealed and stapled envelopes, for the duration of the trial. The masking will be removed only if the participant occurs severe side effects which need to terminate the trial.

Interventions

Run-in period (pre-trial, 4 weeks)

Eligible participants will enter a run-in period for 4 weeks, during which they will receive an optimized basic treatment, including living behavior management (smoking cessation, alcohol restriction, weight control, low-salt and proper protein diet), maximum tolerated dose of ACEI or ARB, blood pressure control to a target below 130/80mmHg, controlling glycated hemoglobin≤7% by using insulin or oral hypoglycemic agents in diabetics, reaching targets in serum uric acid (UA) (<420umol/L in male, <360umol/L in female) by uric acid-lowering medications in hyperuricemia, and stopping other Chinese medicine treatments.

Treatment period (in-trail, 48 weeks)

At the end of the run-in period, participants who fulfill all eligibility criteria and no exclusion criteria with persistent proteinuria of at least 1g/d, will be randomized to either the YQF combined immunosuppression therapy (YQF group) or matching placebo combined with immunosuppression therapy (control group) in a double-blind fashion with a total treatment period of 48 weeks. Both group will continue their basic treatment as above mentioned in the pre-trial phase.

Immunosuppression therapy: oral prednisolone (0.5–0.8 mg/kg/d, exact dose decided by the investigator, maximum dose not exceeding 60 mg/d) for 8 weeks, then tapered by 5~10 mg/d every 4 weeks, with a total treatment period of 24–32 weeks. Participants with persistent proteinuria≥1g/d after 8-weeks corticosteroid monotherapy, will receive 0.8–1.0g of intravenous cyclophosphamide (CTX) every 4 weeks, for a total dose of not exceeding 8g (exact dose decided by the site Investigator). If severe CTX-related adverse events occur, such as alanine transaminase (ALT) exceeded the upper limit of 2 times, infections requiring hospitalization, granulocytes<3.0×10⁹/L and platelets (PLT) < 50.0×10⁹/L, stop using CTX, symptomatic treatment, and record adverse events. The frequency of detection is increased to once every 2 weeks, and the trial is terminated if persistent infection and myelosuppression occur.

YQF Formula Granule: obtained from Sichuan Xinlvyao Co. (Chengdu, Sichuan, China), manufacturing process complying with Chinese GMP. The compounds are blends of individual herbal extract from YQF formula (consist of:astragalus membranaceus, saposhnikovia divaricata(turcz.) schischk, Flos Lonicerae, Angelica Sinensis, Dioscorea Nipponica, hedyotis diffusa willd, rhubarb, Spatholobus Suberectus.), dissolving in 150ml boiled water and taking it orally twice a day.

YQF placebo: major component: malt dextrine, with similar appearance and the packaging, dissolving in 150ml boiled water and taking it orally twice a day.

Follow-up period (post-trial)

All participants will continue their previous basic treatment agents.

Follow-up assessments

Participants will be visited at regular intervals, for a planned mean of at least3 years until the end point occurs. In run-in period and treatment period, study visits occur every 4 weeks until week 24, and every 12 weeks face-to-face or by telephone in consideration of choice of the participants and investigators, till the end of the trial. The measurements will be performed at qualified laboratories during the follow-up period.

Laboratory measurements including: (1) urine tests: 24h urine total protein (UTP) measured using biuret method, albumin/creatinine ratio (ACR); (2) blood tests: serum creatinine, albumin (Alb), blood urea nitrogen (BUN), uric acid (UA), blood glucose (GLU), total cholesterol (CHO), electrolyte (K, Na, Cl), triglyceride (TG), alanine transaminase (ALT), aspartate aminotransferase (AST), hemoglobin (HGB), white blood cell count (WBC), and PLT.

General condition inspection includes body weight, appetite, excretory functions, stamina, mobility, sleep, etc. Vital signs inspection includes temperature, respiration, pulse and blood pressure.

The final follow-up duration will be continued until the occurrence of primary end point or keeping visit up to 3 years (Figure 3).

Outcome measures definition

The primary composite end point is defined as the first occurrence of a 40% decrease in eGFR from the baseline eGFR, the progression to continuous renal replacement, or death due to a renal disease.

Secondary composite end points are defined as (1) main outcome measure: the mean annual reduction in eGFR based on SCr (eGFR-slope); (2) proteinuria remission (prescribed as proteinuria <0.5g/d) at week 24, 36, 48 in treatment period, and month 6, 12, 24, or 36 if possible.

Adverse events and safety

Adverse events and SAEs will be inspected at each follow up, including infections requiring hospitalization, thromboembolic events, hepatic dysfunction, hematopoietic disorders, fracture or osteonecrosis and new onset diabetes. SAEs are defined according to the definitions of Good Clinical Practice (GCP) by the China Food and Drug Administration (CFDA).

Termination and withdrawal

Participants will be withdrawn from the trial in any of the following situations: (1) SAEs related with immunosuppression: severe infections (e.g., pulmonary infection requiring ventilatory support), serious granulocytopenia/thrombocytopenia (e.g., WBC<2.0×10⁹/L, PLT<20×10⁹/L); (2) participants or investigators fail to obey the study protocol; (3) participants behave poor compliance, experimental medications are taken less than 30%.

Sample size calculation

Based on our recent trial from above [22] of which the primary end point was eGFR-Slope after 12-month treatment, we define δ = (μ1-μ2)/σ, σ as the pooled standard deviation (sample size calculation, see Additional file 4), where μ is the treated mean, respectively. We calculate δ = 0.994 which can be approximately equivalent as 1.0, according to the look-up table of counts (Medical Statistics Method, PH Jin, Shanghai Medical College Press, see Additional file 3), using α = 0.05 and β = 0.1, we require a sample size of 46 participants. Assuming 25% dropout adaptation and in view of n = 30 as a rule of thumb for a small size clinical trial, we plan to recruit 60 patients for this study (30 patients per group).

Statistical analysis

Investigators will fill the Case Report Forms as making follow-up observations. Data analysis of treatment effect and safety follows the intention-to-treat principle. The endpoint events will be described by Kaplan-Meier method and the between-group difference will be compared using log-rank test. Chi-square test will be used to compare the rates, t-test or variance analysis will be used for comparison between data sets. The eGFR-slope will be calculated as the individual slopes obtained from individual linear regressions of eGFR during the follow-up period. All analyses were performed using SPSS software version 23.0 (IBM Analytics). Differences were considered to indicate statistically significant for 2-sided P < 0.05.

Quality control Data monitoring

The Clinical Pharmacological Research Base, Scientific Research Department and the Ethics Committee of Guang’anmen Hospital will review the study data regularly and monitor compliance with the protocol until completion. The Clinical Pharmacological Research Base will assess that participants receive good clinical care and that safety concerns are interpreted and addressed appropriately.

Intention-to-treat analysis will be used for subjects who dropout or withdraw from the study which includes every subject who is randomized according to randomized treatment assignment regardless of whether they receive the treatment of this group or not, should finally be included in the assigned group for statistical analysis of efficacy.

Last observation carried forward method will be applied in missing data of longitudinal observations.

IgAN is considered to be an autoimmune disease, it is logical that immunosuppression therapy may be effective [10,26]. As the therapeutic benefits of intensive supportive care show, it’s the cornerstone of treatment in IgAN. Recently completed high-profile RCTs with rigorous standardization and optimization of supportive management have focused on outcomes of additional immunosuppression. STOP-IgAN trial [11] showed that the additional immunosuppression therapy (oral corticosteroids plus CTX and azathioprine) did not exert substantial renal protection for those with eGFR 30–59 ml/min/1.73m², including one death due to sepsis related to steroids. However, the trial excluded patients with 24hUTP >3.5g, eGFR <30 ml/min/1.73m², or eGFR decreased more than 30% at the end of 6-month run-in phase which often underlies relatively high risk in disease progression and a better response to steroids. In TESTING study [12], after a 3-month run-in phase of optimal supportive treatment, recruiting participants with 24hUTP >1g and eGFR of 20–120 ml/min/1.73m², was terminated because of two deaths of infection and excess SAEs in methylprednisolone group. Early results could not demonstrate definite treatment efficacy in steroid therapy though they have shown indication in short-term potential renal benefits. Both trials highlight the safety concerns about immunosuppression and necessary to seek for alternative, safe and effective approach for high-risk IgAN.

Traditional Chinese medicine has initiative proved promising effects regarding safety and renoprotection with some RCTs in chronic kidney diseases, for instance, Abelmoschus manihot [27], however, it is notable that this trial excluded patients with impaired renal function (eGFR <60 ml/min/1.73m²) and nephrotic syndrome. Therefore, we conduct TCM-WINE, a prospective, double-blind, single-dummy, randomized controlled trial, aiming to evaluate safety and long-term outcomes with YQF herbal compound compared to immunosuppression monotherapy in treating high-risk IgAN. In conclusion, the results of TCM-WINE will provide clinical evidence for the efficacy and safety of YQF compound, moreover, this trial will serve as an important step toward new era of treatment in high-risk IgAN.

Trial status

Recruitment for this study began on 4July 2019 (protocol version 02, 28 March 2018). It’s estimated that recruitment will be completed in August 2020.

ACEI: Angiotensin-converting enzyme inhibitor; ACR: Albumin/creatinine ratio; ALT: Alanine transaminase; Alb: Albumin; ARB: Angiotensin-receptor blocker; AST: Aspartate aminotransferase; BUN: Blood urea nitrogen; CFDA: China Food and Drug Administration; CHO: Total cholesterol; CKD: Chronic kidney disease; CTX: Cyclophosphamide; eGFR: Estimated glomerular filtration rate; ESRD: End-stage renal disease; GCP: Good Clinical Practice; GLU: Blood glucose; HGB: Hemoglobin; IgAN: Immunoglobulin A nephropathy; KDIGO: Kidney Disease: Improving Global Outcomes; PLT: Platelets; RASB: Reninangiotensin system blockade; RASB: Reninangiotensin system blockade; RCT: Randomized controlled trial; SAE: Severe adverse event; SCr: Serum creatinine; SPIRIT: Standard Protocol Interventions: Recommendations for Interventional Trials; TG: Triglyceride; UA: Uric acid; UTP: Urine total protein; WBC: White blood cell count; YQF: Yi-Qi-Qing-Jie Formula Granule.

Funding

This study is supported by the Beijing Municipal Science & Technology Commission (grant number: Z181100001718123) and the special research projects of national traditional Chinese medicine clinical research demonstration base of Guang’anmen Hospital (grant number: 2017S379).

Acknowledgements

We are grateful to Professor Ji-cheng Lv, Renal Division, Department of Medicine, Peking University First Hospital for advice on trial design, Dr. Li-yun He, Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences and her team for randomization by their central stochastic system. The authors are also grateful to the Beijing Municipal Science & Technology Commission and Guang’anmen Hospital for funding this study.

Availability of data and material

The datasets generated or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

Shen Li and Ji-cheng Lv discussed and designed the trial. Shen Li and Jin-pu Li drafted and finalized the manuscript. Shen Li reviewed the final version. All authors approved the final version of the manuscript.

Competing interests

No competing interests.

Consent for publication

Not applicable.

Ethics approval and the consent

This study has been approved by the Ethics Committee of Guang’anmen Hospital (approval number: 2018–055-KY–01). Patients who agree to participate and sign the informed consent will be involved.

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Table 1 Baseline characteristics of participants in our former ambispective cohort study

	Treatment group (N =34)	Control group (N =34)	P
Age, y	38.50 ±11.62	38.21 ± 13.05	0.92
Male, N (%)	64.71	55.88	0.31
SBP (mmHg)	126.18±11.68	124.94±13.64	0.69
DBP (mmHg)	74.71±14.35	77.97±10.06	0.28
UTP (g/24h)	3.85【3.19 - 4.89】	3.82【2.36 - 5.89】	0.78
SCr (umol/L)	154.82 ± 70.58	175.53 ± 80.01	0.26
eGFR (ml/min/1.73m²)	47.43 ±14.75	46.52 ± 22.61	0.84
Alb (g/L)	35.29 ±3.37	34.71 ± 6.68	0.64

Values for continuous variables are given as mean ± standard deviation. The non-normal variables are presented as median and【interquartile range】. Alb=albumin, DBP=diastolic pressure, eGFR=estimated glomerular filtration rate, N=intention-to-treat patients number, SBP=systolic pressure, SCr=serum creatinine, UTP=urine total protein.

Table 2 Renal function and proteinuria changes at the end of the in-trial phase

	Treatment group (N =34)	Control group (N =34)	Odds Ratio (95%CI)	P
ΔeGFR (ml/min/1.73m²)
6m	14.16±11.55	-0.45±13.97	4.70	0.00
12m	16.67±18.09	-2.72±16.34	4.52	0.00
eGFR-Slope (ml/min/1.73m² per month)	1.39±1.51	-0.26±1.39	4.69	0.00
Proteinuria reduction(g/24h)
6m	1.93【1.54 - 2.74】	1.60【0.97 - 2.97】	0.85	0.39
12m	2.48【1.70 - 3.38】	1.81【1.29 - 3.90】	0.16	0.87
Proteinuria complete remission, N (%)	5 (14.71)	9 (26.47)	2.09（0.62-7.05）	0.37

M=month, N=number of patients in the respective population, ΔeGFR=[after-treatment]-[before-treatment], proteinuria complete remission was defined as proteinuria<0.5g/d after treatment.

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Editorial decision: Major revision
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Treatment effects of Chinese Medicine (Yi-Qi-Qing-Jie Herbal Compound) combined With immunosuppression therapies in patients of IgA Nephropathy with high-risk of ESRD (TCM-WINE): study protocol for a randomized controlled trial

Status:

Journal Publication

Version 1

Abstract

Figures

Background

Methods/Design

Study design

Setting and participants

Objectives

Rationale of high-risk IgAN

Inclusion and exclusion criteria

Randomization and masking

Interventions

Run-in period (pre-trial, 4 weeks)

Treatment period (in-trail, 48 weeks)

Follow-up period (post-trial)

Follow-up assessments

Outcome measures definition

Adverse events and safety

Termination and withdrawal

Sample size calculation

Statistical analysis

Quality control Data monitoring

Discussion

Trial status

Abbreviations

Declarations

Funding

Acknowledgements

Availability of data and material

Authors’ contributions

Competing interests

Consent for publication

Ethics approval and the consent

References

Tables

Supplementary Files

Status:

Journal Publication

Version 1