Enteric-coated Mycophenolate Sodium plus hydroxychloroquine therApy versus hydroxychloroquine for the Remission of Proteinuria in IgA Nephropathy (EMSAR-IgAN trial): study protocol for a randomised trial
===========================================================================================================================================================================================================

* Bingjuan Yan
* Xuan Tie
* Lihua Wang
* Xi Qiao
* Xiaole Su

## Abstract

**Introduction** The management of immunoglobulin A (IgA) nephropathy remains a topic of debate. Hydroxychloroquine and mycophenolate mofetil (MMF) are two immunosuppressive agents that have recently garnered increased attention among patients with IgA nephropathy in China. Several studies have shown the comparable efficacy between MMF and enteric-coated mycophenolate sodium (EC-MPS), with lower adverse event rates for EC-MPS. The present study aims to evaluate the efficacy and safety of EC-MPS combined with hydroxychloroquine as an immunosuppressive regimen for patients with high-risk progressive IgA nephropathy, despite receiving routine supportive treatment.

**Methods and analysis** This study is a multicentre, prospective, randomised controlled, open-label, blinded endpoint trial. 96 patients diagnosed with IgA nephropathy and persistent proteinuria from 12 general hospitals in Shanxi Province of China will be recruited and randomly assigned to receive either EC-MPS plus hydroxychloroquine or hydroxychloroquine alone in a 1:1 ratio. We will compare the efficacy and safety of hydroxychloroquine combined with or without oral EC-MPS (720–1080 mg/day for 6 months, and tapered to 360–540 mg/day for another 6 months) on a background of supportive care. All enrolled patients will receive standard basic treatment to achieve optimum blood pressure and the maximum tolerated dose of ACE inhibitors or angiotensin receptor blockers. The primary outcome is the change in 24-hour urine protein at 6 months relative to baseline. Participants will be subject to regular follow-up for a duration of 12 months.

**Ethics and dissemination** This study has received ethical approval from the Ethics Committee of Shanxi Medical University Second Hospital (No. 2024YX-481). A duly signed and dated informed consent form must be obtained from each participant or his/her legal guardian prior to any operational procedures related to the trial. The result of this study will be presented and published at international conferences and in scientific journals.

**Trial registration number** ChiCTR2400093530.

*   Nephrology
*   Glomerulonephritis
*   Randomized Controlled Trial
*   Drug Therapy

### STRENGTHS AND LIMITATIONS OF THIS STUDY

*   The study is a multicentre randomised controlled trial conducted across 12 public hospitals in a less-developed region of China.

*   A superiority hypothesis test was used with a sample size of 96 participants and a 12-month follow-up period to evaluate long-term outcomes.

*   Blinded endpoints reduce evaluation biases and improve research reliability.

*   The study was conducted solely in China, and findings may not be applicable to populations in other regions.

*   The lack of blinding for participants and clinicians may introduce expectancy or response bias.

## Introduction

There is currently no definitive treatment available for IgA nephropathy. According to the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines, patients who continue to be at high risk of chronic kidney disease (CKD) progression despite receiving maximal supportive care should be considered for a 6-month course of corticosteroid therapy.1 The Therapeutic Evaluation of STeroids in IgA Nephropathy Global (TESTING) study revealed that adequate corticosteroids significantly reduced proteinuria and the risk of kidney failure in patients with IgA nephropathy (HR: 0.37, 95% CI: 0.17 to 0.85).2 However, a notable increase in the incidence of serious adverse events (SAEs), primarily infection, was observed with two fatalities resulting from infection (2/126). This represents an almost fivefold elevation in the risk of such serious adverse reaction compared with the control group (risk difference: 11.5%, 95% CI: 4.8% to 18.2%). While the multicentre Supportive versus immunosuppressive Therapy for the treatment Of Progressive IgA Nephropathy (STOP-IgAN) study revealed that the addition of glucocorticoids to adequate supportive care or corticosteroids in combination with cyclophosphamide/azathioprine can reduce proteinuria to a certain extent in patients with persistent proteinuria, it failed to decelerate the decline in glomerular filtration rate (GFR).3 In particular, after up to 10 years of follow-up, immunosuppressive therapy did not demonstrate a decreased risk of ESKD compared with supportive care.4 Therefore, it remains crucial from a clinical standpoint to explore novel strategies for administering safe and effective anti-inflammatory drugs to treat this condition.

Immunoglobulin A (IgA) nephropathy is globally recognised as the predominant primary glomerular disease and a frequent aetiology for end-stage kidney disease (ESKD) among young individuals. The disease gradually progresses to ESKD approximately 10 years after the onset of the condition, affecting around 27% of patients. Moreover, individuals of Pacific Asian descent exhibit a more unfavourable prognosis compared with Western populations.5

Hydroxychloroquine and mycophenolate mofetil (MMF) are two immunosuppressive agents that have recently garnered increased attention among patients with IgA nephropathy in China. Hydroxychloroquine is widely used in the management of rheumatic disorders, such as systemic lupus erythematosus and rheumatoid arthritis. In recent years, clinical studies have also shown good efficacy of hydroxychloroquine in IgA nephropathy. A retrospective cohort study used propensity scores for case matching and revealed that patients administered with hydroxychloroquine sulfate exhibited a notably higher percentage decrease in proteinuria at the 6th month compared with untreated individuals (−43% vs −19%, p=0.01). No significant adverse effects were observed among patients receiving hydroxychloroquine treatment.6 In 2019, a total of 60 patients diagnosed with IgA nephropathy and persistent proteinuria were enrolled in a randomised controlled trial (RCT), and randomly assigned in a 1:1 ratio to either hydroxychloroquine sulfate or placebo. By the 6th month, patients receiving hydroxychloroquine exhibited significantly lower urinary protein compared with the placebo group (0.9 vs 2.0 g/day, p=0.001). Additionally, the likelihood of achieving a 50% decrease in proteinuria was markedly higher in the hydroxychloroquine group (50% vs 15%, p<0.05).7 Based on these findings, hydroxychloroquine has emerged as a novel supportive treatment for IgA nephropathy.1

MMF is a highly effective immunosuppressant that selectively inhibits the proliferation of T and B lymphocytes, releases mycophenolic acid, which induces apoptosis of cytotoxic T lymphocytes and reduces antibody synthesis. In 2002 and 2005, early RCTs initially demonstrated the efficacy of MMF in reducing proteinuria levels in the treatment of IgA nephropathy.8–10 In 2017, a multicentre RCT included 176 patients with active proliferative lesions (cellular and fibrocystic crescents, increased or necrotic capillary endothelial cells) in IgA nephropathy.11 Patients with proteinuria >1.0 g/24 hours and estimated GFR (eGFR) >30 mL/min/1.73 m2 were randomly assigned to two groups: the MMF combined reduced-dose prednisone (0.4–0.6 mg/kg/day) group or the full dose prednisone group (0.8–1.0 mg/kg/day). The complete remission rates were 37% and 38% at 6 months, and 48% and 53% at 12 months, respectively. No statistically significant difference was observed between the two groups. However, the rate of adverse events (AEs) was significantly lower in the MMF plus reduced-dose prednisone group. In a 2022 Korean RCT with 48 patients with progressive IgA nephropathy, the combination of MMF and glucocorticoids showed superiority over supportive therapy alone in relieving proteinuria and delaying the decline in kidney function after a 48-week follow-up period.12

The active ingredient in both enteric-coated mycophenolate sodium (EC-MPS) tablets and MMF capsules is mycophenolic acid, which acts as an inhibitor of inosine monophosphate dehydrogenase. This inhibition effectively hampers the proliferation of T and B cells, leading to the suppression of both cellular and humoral immune responses.13 The clinical efficacy and safety of EC-MPS have been demonstrated in the treatment of autoimmune diseases, such as systemic lupus erythematosus,14 primary systemic vasculitis15 and minimal change nephrotic syndrome.16 A large head-to-head multicentre RCT also revealed comparable efficacy between MMF and EC-MPS in patients who had new kidney transplants. EC-MPS (720 mg two times per day) was comparable with MMF (1000 mg two times per day), with similar efficacy and safety profiles proven in patients with organ transplantation.17 And a comparable efficacy of MMF and EC-MPS treatments was observed in patients who had heart transplantation.18 The pharmacokinetic parameters of MMF and EC-MPS were found to be comparable in a prospective study.19

The intestinal release mechanism of EC-MPS effectively mitigates AEs, particularly those related to the gastrointestinal system, decreasing the occurrence of drug tapering events and improving drug tolerance when compared with MMF. In another multicentre RCT, EC-MPS demonstrated superiority over MMF in terms of AEs. It showed a significantly higher reduction in the occurrence of serious infections compared with MMF.20 A retrospective analysis comparing the efficacy and safety of MMF and EC-MPS in 1709 kidney transplant recipients revealed the following findings: a 2-year incidence of acute kidney rejection (MMF vs EC-MPS: 31.0% vs 24.7%), biopsy-confirmed kidney rejection incidence (30.2% vs 21.9%), forced medication taper incidence (74.4% vs 64.0%), forced drug discontinuation incidence (33.3% vs 27.9%), antidiarrheal drug use (6.5% vs 3.6%) and infection incidence (64.7% vs 59%).21 These findings suggest that the rates of various AEs were higher with MMF compared with EC-MPS, and these differences tended to gradually increase over time.

Administration of MMF seems highly promising in the Chinese population for the treatment of patients with IgA nephropathy due to its potent immunosuppressive properties and favourable toxicity profile. The bioequivalence of EC-MPS and MMF has been established for both systemic exposure to mycophenolic acid and its metabolite, as well as for peak plasma concentrations of mycophenolic acid.22 EC-MPS acts as an alternative form of mycophenolic acid delivery to reduce AEs and improve gastrointestinal tolerability. Therefore, we propose a scientific hypothesis that combining hydroxychloroquine and EC-MPS with standard treatment for a duration of 6 months can effectively reduce proteinuria in patients with high-risk IgA nephropathy. We designed the Enteric-coated Mycophenolate Sodium therApy for the Remission of Proteinuria in IgA Nephropathy (EMSAR-IgAN trial), the first multicentre RCT of EC-MPS for the treatment of IgA nephropathy, to compare the efficacy and safety of hydroxychloroquine combined with standard treatment, with or without EC-MPS.

## Methods and analysis

### Study design

This study is a multicentre, prospective, randomised controlled, open-label, blinded endpoint (Prospective, Randomised, Open-label, Blinded Endpoint (PROBE)) trial, designed to evaluate the efficacy and safety of EC-MPS therapy on a background of routine renin-angiotensin system inhibitor (RASi) therapy and hydroxychloroquine. After randomisation, participants will receive the assigned intervention and be subject to regular follow-up for a duration of 12 months.

During a 4–12 weeks run-in period, participants will be evaluated for compliance with enrolment criteria (figure 1). Patients are administered an ACE inhibitor or angiotensin receptor blocker (ARB) at the maximum tolerated or the maximum dose specified in the instruction, whichever is reached first, according to the KDIGO Clinical Practice Guidelines, and their blood pressure will be controlled within the ideal range of 130/80 mm Hg. In participants whose urinary protein excretion rate remains above 0.5 g per day despite blood pressure control, the dose of RASi will be increased to the tolerable maximum daily dose. For patients who have been on ACE inhibitors or ARBs for more than 8 weeks, the run-in phase will last for 4 weeks; for those who have not received such therapy, the run-in period will be extended to 12 weeks, ensuring that all participants have undergone RAS blockade for a minimum of 3 months prior to study enrolment. Other antihypertensive medicines should be adjusted or added during this stage to achieve the guideline-based goal. Participants will be advised on lifestyle modification to quit smoking, restrict high-salt intake and avoid nephrotoxic drugs. Statins will be used when necessary.

![Figure 1](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/15/4/e098688/F1.medium.gif)

[Figure 1](http://bmjopen.bmj.com/content/15/4/e098688/F1)

Figure 1 
Schematic representation of the study treatment schedule. EC-MPS, enteric-coated mycophenolate sodium; eGFR, estimated glomerular filtration rate; HCQ, hydroxychloroquine.

By the end of the run-in period, participants who have persistent proteinuria, defined as a urinary protein excretion rate above 0.5 g per day, eGFR over 30 mL/min/1.73 m2, and who are willing to participate in the study will enter the 1-year trial phase and will be randomly assigned to EC-MPS plus hydroxychloroquine or to hydroxychloroquine alone. Participants who cannot tolerate RASi (eGFR decline over 30% of baseline or developing hyperkalaemia) during the run-in phase will not undergo randomisation.

### Patient and public involvement

Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

### Study population

#### Inclusion criteria

Participants who satisfy all of the following inclusion criteria will be eligible for this trial: (1) aged 18 years or older; (2) kidney biopsy-confirmed primary IgA nephropathy; (3) proteinuria ≥0.5 g/day while receiving the maximum tolerated dose of RAS blocker therapy; (4) the latest eGFR measurement ≥30 mL/min/1.73 m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation);23 (5) signed informed consent.

#### Exclusion criteria

Subjects meeting any of the following criteria will be excluded from the trial: (1) secondary IgA nephropathy, such as due to lupus, liver cirrhosis or Henoch-Schonlein purpura; (2) indication for immunosuppressive therapy with corticosteroids, such as minimal change renal disease with IgA deposits, and crescents present in >50% of glomeruli on a renal biopsy within the last 12 months; (3) contraindications to immunosuppressive therapy, including active infection, such as hepatitis B virus/hepatitis C virus infection or active tuberculosis; a history of malignant tumours within the last 5 years; current or planned pregnancy or breastfeeding; women of childbearing age who are not able or willing to use adequate contraception, and other situations where clinicians deem it inappropriate to use; (4) administration of systemic glucocorticoids or immunosuppressive agents (including hydroxychloroquine) within the past 3 months; (5) malignant/uncontrolled hypertension, defined as a systolic blood pressure exceeding 160 mm Hg or diastolic blood pressure exceeding 110 mm Hg; (6) other aetiologies of unstable kidney function, such as acute kidney injury resulting from massive haematuria; (7) individuals deemed by investigators as unable to follow the study protocol.

### Randomisation and blinding

Eligible patients meeting inclusion and exclusion criteria and providing informed consent will be stratified according to three parameters: (1) baseline kidney function: eGFR<45 mL/min (yes vs no), (2) baseline proteinuria: 24-hour urinary protein quantity >3 g/day (yes vs no) and (3) whether the patient is newly diagnosed or has relapsing disease. Following stratification, patients will be randomised in a 1:1 ratio to two treatment groups receiving either (A) EC-MPS and hydroxychloroquine or (B) hydroxychloroquine alone via an interactive web response system with a computer-generated random sequence.

This is an open-label study. Both the participant and study personnel, including clinicians, will be aware of the treatment assignment, which may introduce expectancy or response bias. We will employ the blinded endpoint approach to reduce evaluation biases and improve research reliability. An adjudicating committee, whose members will be unaware of patients’ treatment assignments, will review the data to determine which patient has reached study endpoints.

### Study treatments

#### EC-MPS + hydroxychloroquine arm

Given that both EC-MPS and hydroxychloroquine are primarily excreted via the kidneys, impaired renal function may result in drug accumulation, thereby increasing the risk of toxicity. Therefore, the drug dosage will be reduced as the renal function deteriorates to maintain a balance between therapeutic efficacy and safety. For patients with an eGFR >45 mL/min/1.73 m2, the dosage of EC-MPS is 540 mg administered two times per day for a duration of 6 months, followed by a maintenance therapy of 360 mg two times per day for an additional 6 months. The dose of EC-MPS for patients with an eGFR of 30–45 mL/min/1.73 m2 is 360 mg two times per day for the initial 6 months, followed by a maintenance dosage adjustment to 180 mg two times per day for another 6 months. The administration of hydroxychloroquine is identical to that in the hydroxychloroquine group.

#### Hydroxychloroquine arm

Hydroxychloroquine can be taken with meals to reduce the risk of gastrointestinal side effects. For individuals with an eGFR value exceeding 45 mL/min/1.73 m2, initiate treatment with hydroxychloroquine at 200 mg two times per day for 6 months, subsequently transitioning to a lower dosage of 100 mg two times per day for a maintenance period of 6 months. For those with an eGFR between 30 and 45 mL/min/1.73 m², a continuous 12-month course of hydroxychloroquine at a dosage of 100 mg two times per day is prescribed.

#### Other treatment

All enrolled patients should receive standard basic treatment to achieve optimal blood pressure and the maximum tolerated dose of ACE inhibitors or ARB agents. The recommended maximum dose of ACE inhibitors or ARBs from the Kidney Disease Outcome Quality Initiative is summarised in table 1. Other antihypertensive drugs are recommended over adjusting the dose of ACE inhibitors or ARB agents when the blood pressure exceeds the controlled goal during the study process. All subjects should abide by the dietary recommendation criteria for CKD, such as maintaining a daily sodium intake between 3 and 6 g. Participants are also encouraged to quit smoking and to keep their alcohol intake within safe limits.

View this table:
[Table 1](http://bmjopen.bmj.com/content/15/4/e098688/T1)

Table 1 
Recommended doses of ACE inhibitors and ARBs

This study permits the use of traditional Chinese herbal medicine and acupuncture for treatment, but any related treatments must be documented in the database. However, the use of other traditional Chinese medicines containing components of Tripterygium wilfordii Hook F, such as Kunxian capsule, triptolide and celastrol, is strictly prohibited. Sodium-dependent glucose transporters 2 (SGLT2) inhibitors will be recommended during the run-in period. However, the initiation of new SGLT2 inhibitors will be prohibited after randomisation. During the study, all concomitant immunosuppressants are prohibited except for study drugs. Also, the use of live vaccines is prohibited during the study.

### Data collection and management

The ethics committee at each participating centre approved data collection before study initiation. Physical examination will be conducted on the study subjects, and their laboratory findings (blood routine, blood biochemistry and urine test results), histological damage scores, medication records and AEs will be systematically collected in accordance with the study protocol. The data are gathered electronically through case report forms, refraining from including personal names or any other identifying information, using a website-based electronic data capture system.

The independent Data and Safety Monitoring Committee (DSMC), as a standard and conventional procedure in our institution, has been established to review the progress of the study and monitor adherence to the protocol, participant recruitment, outcomes, complications and other issues related to participant safety. They will also monitor the assumptions underlying sample size calculations for the study and alert the investigators if they see substantial departures as the data accumulate. The DSMC consists of physicians and a statistician experienced in clinical studies. The committee will be supported by an unblinded statistician from an independent research group. The independent DSMC will review safety data on an ongoing basis and may recommend stopping or amending the study based on safety concerns.

### Study outcomes

The primary outcome is the alteration in 24-hour urine protein quantification value relative to baseline following a 6-month treatment period. The secondary effect indicators comprise the following: (1) the change in 24-hour urinary protein excretion after 12 months of treatment; (2) the change in urine albumin-to-creatinine ratio at 6 months and 12 months post-treatment compared with the baseline level; (3) the change in eGFR from baseline to 6 and 12 months; and (4) the difference in the rate of eGFR decline at 12 months of treatment. The eGFR calculation will use the CKD-EPI formula.23 Outcomes are adjudicated by a committee blinded to study group assignment.

Safety endpoints include all AEs, SAEs, study drug-related SAEs, AEs leading to study withdrawal and AEs related to the study drug occurring during the study period will be recorded. Special attention should be given to events such as infection at any site of the body, liver impairment, reproductive system damage, haematological system disruption, gastrointestinal tract issues and alterations in vision. According to Good Clinical Practice (GCP) guidelines, SAEs and suspected unexpected serious adverse reactions will be reported to the medical ethics committee.

### Statistical analyses

A superiority hypothesis test was used to calculate the sample size, setting a superiority cut-off (δ) at 0, employing a one-sided test at a significance value of 0.0125, which corresponds to a 90% confidence level. Based on previous studies, we presumed the hydroxychloroquine treatment group with a 30% reduction in proteinuria and a SD of 18%, while the MMF group experienced a 42% decrease with a SD of 20%. Using PASS software, calculations showed that each treatment group should include 40 participants, totalling 96 subjects when considering a 1:1 ratio and allowing for a 20% dropout rate.

The analysis conducted will follow the relevant standard operating procedures. For the result analysis, a two-sided test will be employed, and two-sided CIs will be reported. Statistical analysis for categorical variables will be expressed as the number and percentage of unique patients in each category. For continuous variables, numbers, means, medians, ranges, SD and SE of the mean will be calculated. Geometric means will be calculated for data that are not normally distributed. Results will be presented by treatment group and by stratum for each of the three stratification factors. The assignment of patients to treatment groups is dynamically performed using a minimisation algorithm, aiming to achieve balanced distribution of stratification factors across the treatment groups.

For the subjects who are lost to follow-up or prematurely discontinue the trial, their main reasons will be clarified and summarised, such as patient’s decision, physician’s decision, patient’s voluntary withdrawal, AE, other reasons. The detailed reasons for loss to follow-up or premature discontinuation for each subject will be presented in the lists. For primary and secondary endpoints, missing data will be treated as missing, and no imputations will be performed. Counts of missingness will be reported in the descriptive analysis of categorical variables, and percentages of the non-missing categories will be based on all values. For continuous variables, the number of non-missing values as well as missing values will be reported, but descriptive summaries will be based on the number of non-missing values.

The efficacy endpoints will be analysed using a mixed-effects model for repeated measures, incorporating treatment group, visit, treatment-by-visit interaction and randomisation strata as factors, with baseline serving as the covariate. Patients will be considered as repeated measure units over visits. All randomised subjects will be included in the analyses of both primary and secondary efficacy endpoints, based on the treatment they are assigned to. The same analysis will be performed in those who fully meet the inclusion criteria, adhere to the treatment protocol and undergo outcome evaluation.

The safety analysis will be conducted for all participants on the basis of their actual treatment allocation. The χ² test will be used to compare the differences in the percentages of participants with at least one AE between treatment groups. The Poisson regression method will be performed to compare the rates of AEs between two treatment groups adjusted by study site.

Subgroup analyses will be conducted as exploratory analyses based on: (1) gender (male, female); (2) baseline eGFR (<45 or ≥45 mL/min/1.73 m2); (3) SGLT2 inhibitor use/non-use; (4) primary treatment or not. The Bonferroni correction method will be used for multiplicity adjustment, with the p value set at 0.006. Because of the restricted sample size, there may not be sufficient statistical power to enable us to identify the differences among groups. We expect to perfect and address this issue in subsequent studies.

### Study organisation

EMSAR-IgAN trial, as one of the EMSAR series trials,24 is located in Shanxi Province in North China with a 34.8 million population, which is a less-developed region and ranks 16th out of 31 provinces for gross domestic product per head. 12 hospitals in six different cities of Shanxi Province will take part in the study. They are Shanxi Medical University Second Hospital, Taiyuan Central Hospital, The Hospital of Shanxi University of Chinese Medicine, Xinzhou People’s Hospital, The People’s Hospital of Lvliang, Changzhi People’s Hospital, Heji Hospital Affiliated to Changzhi Medical College, Heping Hospital Affiliated to Changzhi Medical College, Yuncheng Central Hospital, Linfen People’s Hospital, Linfen Central Hospital, Xinzhou Hospital of TCM. 12 centres are all general hospitals with 2000–2500 beds in Shanxi Province. One lead investigator per centre will be responsible for the study conduct and act as coordinator. The study will be managed and coordinated by the clinical trials office at Shanxi Medical University Second Hospital. The trial management committee, the steering committee and the data monitoring committee will be based in the clinical trials office. A study steering committee set up by the office will provide guidance on revisions to the study protocol that may occur during the research and supervise the progress of the study. The clinical events committee arbitrates clinical events at all levels, while the data monitoring committee provides regular data verification and evaluation. Statistical analyses will be performed by the department of statistics at Shanxi Medical University.

## Ethics and dissemination

This clinical trial will be conducted in accordance with the International Ethical Guidelines for Human Biomedical Research, the current GCP, the Declaration of Helsinki and all applicable laws and regulations. The study protocol and informed consent files (online supplemental material 1) have received ethical approval from the Ethics Committee of Shanxi Medical University Second Hospital (No. 2024YX-481). The trial is registered at the Chinese Clinical Trial Registry ([www.chictr.org.cn](http://www.chictr.org.cn)) with identifier ChiCTR2400093530.

### Supplementary data

[[bmjopen-2024-098688supp001.pdf]](pending:yes)

During the study, any modifications to the protocol should be forwarded to the ethics committee, and, if needed, corresponding changes should also be implemented in other research documents, submitted and approved by the committee. The updated protocol must be approved by the committee prior to its implementation. The investigator will provide a comprehensive explanation to each participant regarding the purpose, methods, advantages and potential risks of this clinical trial. A duly signed and dated informed consent form must be obtained from each participant or his/her legal guardian prior to any operational procedures related to the trial, and informed consent should be expressed both orally and in writing.

All medical information pertaining to each subject obtained in this study will be kept in strict confidence. Subjects will only be identified by their assigned clinical trial number in the documents submitted to the sponsor, and the investigator will ensure the preservation of participants’ confidentiality.

This study is presently in the participant recruitment phase and is scheduled to complete randomisation by December 2026. Currently, no subjects have been included in the study. The results of the EMSAR-IgAN study will be presented and published at international conferences and in scientific journals. It is important to note that the response to therapy in patients with IgA nephropathy may vary across populations. While the efficacy of MMF has shown promise in Chinese patients, particularly those with severe features, its efficacy remains unclear in Western populations. Additionally, the research on hydroxychloroquine was also mainly carried out in the Chinese population. Therefore, the results of this study may primarily apply to the Chinese population, and their generalisability to other populations requires further validation.

## Ethics statements

### Patient consent for publication

Not applicable.

## Footnotes

*   Contributors XS and LW contributed to the conception and design of this trial. BY, XQ and XS drafted and revised the manuscript, and gave final approval of the version to be published. XQ and XT provided critical perspective on the manuscript. All authors approved the final manuscript to be published. XQ is the guarantor of this study.

*   Funding This work was supported by grants from the National Science Foundation of China (82000655), ‘Yiluqihang & Shenmingyuanyang' Medical Development and Scientific Research Fund project on kidney diseases (SMYY20220301001), Basic Research Project (Free Exploration) of Shanxi Province (202203021221270) and Shanxi Province Health Commission Science Fund (2022002).

*   Disclaimer The study sponsors were not involved in the design of the study, data collection, analysis and interpretation, report writing or the decision to submit the report for publication.

*   Competing interests None declared.

*   Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

*   Provenance and peer review Not commissioned; externally peer reviewed.

*   Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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