Enteric-coated Mycophenolate Sodium therApy versus cyclophosphamide for induction of Remission in Microscopic PolyAngiitis (EMSAR-MPA trial): study protocol for a randomised controlled trial

Abstract

Introduction

Several studies have demonstrated that mycophenolate mofetil (MMF) may be an excellent alternative to cyclophosphamide (CYC) or rituximab for the induction of remission in non-life-threatening anti-neutrophil cytoplasmic antibodies associated vasculitis because of its strong immunosuppressive potency and low toxicity profile. Enteric-coated mycophenolate sodium (EC-MPS) was introduced to reduce gastrointestinal adverse reactions of MMF. This study will evaluate the efficacy and safety of EC-MPS combined with glucocorticoid in patients with active and non-life-threatening microscopic polyangiitis (MPA).

Methods and analysis

This study is a multicentre, open-label, randomised controlled, non-inferiority trial. A total of 110 patients with active and non-life-threatening MPA from 11 hospitals in Shanxi Province of China will be recruited and randomised in a 1:1 ratio to receive either EC-MPS or CYC. All patients will receive the same glucocorticoid plan. We will compare oral EC-MPS (720–1440 mg/day) with intravenous pulsed CYC (7.5–15 mg/kg) administered for 3–6 months. All patients will be switched from their assigned treatment (EC-MPS or CYC) to oral azathioprine (2 mg/kg/day) after remission has been achieved, between 3 and 6 months. Azathioprine will be continued until the study ends at 18 months. The primary end point of efficacy is the remission rate at 6 months. Follow-up will continue for 18 months in order to detect an influence of induction regimen on subsequent relapse rates.

Ethics and dissemination

This study has received approval from the Ethics Committee of the Second Hospital of Shanxi Medical University (2022YX-026). All participants are required to provide written informed consent and no study-related procedures will be performed until consent is obtained. The results of this trial will be published in peer-reviewed journals and presented at conferences.

Trial registration number

ChiCTR2200063823.

Strengths and limitations of this study.

• The trial design is multicentre, open-label, randomised controlled, non-inferiority, with a large sample size of 110.

• This trial is the first randomised controlled trial to evaluate the efficacy and safety of mycophenolate sodium enteric-coated tablets compared with cyclophosphamide for remission induction therapy in patients with active and non-life-threatening microscopic polyangiitis (MPA).

• The planned study will provide a new therapeutic option for remission induction therapy in patients with MPA .

• The subjects are unable to perform blind methods due to limitations in the characteristics of the study, which may lead to performance and detection bias.

Introduction

Anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV), which includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA), is a group of multisystem autoimmune diseases and the most commonly involved organs are the kidneys and lungs.¹ The studies on prevalence showed that the overall incidence was approximately 10–20 per million/year and the peak age of onset was 65–74 years in European countries.² The incidence of GPA is 10–12 per million/year and the incidence of MPA is 3–10 per million/year in Northern Europe, while EGPA is much less common than GPA or MPA, with an incidence of 0.5–2.0 per million/year.³ Compared with Caucasian patients, myeloperoxidase (MPO)-ANCA, rather than proteinase 3-ANCA, is the major ANCA target antigen in Chinese patients,⁴ even in patients with a clinical picture of GPA, 60% of them with ANCA specificity for MPO.^{5 6} The striking preponderance of MPA is an epidemiological characteristic of Chinese patients with AAV, constituting about 80% of patients with AAV.⁷

Prior to the availability of effective treatment, the prognosis was extremely poor with a 2-year mortality rate of 80%.⁸ In the early 1970s, with the introduction of glucocorticoids and cyclophosphamide (CYC), AAV achieved a complete response rate of 80%–90% and a 5-year survival rate of 60%–80%.⁹ However, many patients have suffered treatment-related serious adverse events. Therapy causes severe adverse events in 25%–45% of patients in the first year, irreversible damage in over 50% of patients and is the major cause of death in the first 5 years.¹⁰ Toxicity of CYC includes the increased risk of malignancy and irreversible reproductive toxicity, most of which are related to cumulative dosage.¹¹ Serious infection after using CYC combined with glucocorticoid has also become an important problem for clinicians to make treatment plans. In a prospective cohort that enrolled 524 patients with AAV, 56 patients died in the first year of follow-up. Therapy-associated adverse events, especially infection, resulted in many more deaths than active vasculitis (28 vs 8 cases).¹² In another retrospective cohort including 398 patients with AAV, 83 patients died in the first year of follow-up after diagnosis. Secondary infection was the leading cause of death (39 cases) and an independent predictor of death in patients diagnosed with AAV.¹³ In order to address the issue of drug toxicity, newer therapies with better safety profiles but equivalent immunosuppressive potency are required urgently to achieve disease remission. In recent years, rituximab has been concluded similar remission induction rates with CYC but its high medical costs also greatly limit its use. Another study found that rituximab may be associated with hypoalbuminaemia in patients with AAV.¹⁴ Rituximab also has a high risk of severe infection.¹⁵

Therefore, it is advisable to consider disease stage and activity when selecting remission induction therapy for patients with AAV. According to the suggestion of the European Vasculitis Research Group (EUVAS), AAV has been divided into the following clinical subtypes: localised, early systemic, systemic, severe kidney disease and refractory disease.¹⁶ For those patients with non-life-threatening AAV, the European Union for Rheumatology (EULAR) recommends mycophenolate mofetil (MMF) in combination with glucocorticoids, although the level of evidence is requiring further studies.¹⁷

Since 2005, several observational studies have used MMF for the induced remission treatment of AAV. Two small randomised controlled studies (RCTs) in 2008¹ and in 2011¹⁸ have suggested that MMF has efficacy for remission induction in AAV, particularly in MPO-ANCA disease. Based on these studies, the EUVAS conducted a randomised trial (MYCYC study) and the results concluded MMF was non-inferior to pulsed CYC during remission induction in AAV.¹⁹ Of note, the MYCYC study excluded patients on dialysis or with life-threatening diseases. This study provides evidence that MMF is a potential alternative to CYC for remission induction in non-life-threatening AAV, particularly in patients with low predicted relapse risk, such as the elderly who are MPO positive. Another multicentre RCT that included 84 participants with relapsed AAV showed that MMF could be an alternative to CYC for the treatment of selected patients with non-life-threatening relapses.²⁰

The prodrug MMF is converted into 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.²¹ The occurrence of gastrointestinal intolerance is a frequently encountered dose-limiting adverse effect, often resulting in therapy interruptions.²² Enteric-coated mycophenolate sodium (EC-MPS) was introduced to reduce gastrointestinal adverse reactions of MMF. EC-MPS (720 mg two times per day) was comparable with MMF (1000 mg two times per day), with similar profiles of efficacy and safety proven in patients with organ transplantation.^23–25 The clinical efficacy and safety of EC-MPS have been demonstrated in the treatment of autoimmune diseases, such as systemic lupus erythematosus,²⁶ primary systemic vasculitis,²⁷ minimal change nephrotic syndrome²⁸ and progressive IgA nephritis.²⁹

The use of MMF as an alternative to CYC for inducing remission in non-life-threatening AAV seems highly promising due to its potent immunosuppressive properties and favourable toxicity profile. The bioequivalence of EC-MPS and MMF has been confirmed for both mycophenolate and metabolite exposure, as well as for maximum plasma mycophenolate concentrations.³⁰ EC-MPS acts as an alternative form of mycophenolic acid delivery to improve gastrointestinal tolerability. Pilot studies in AAV using EC-MPS as induction of remission suggested that EC-MPS was beneficial.²⁷ Therefore, we propose a new hypothesis that EC-MPS-based induction regimen is as effective as a standard intravenous CYC regimen for the remission induction treatment in non-life-threatening MPA. To test this hypothesis, we designed the Enteric-coated Mycophenolate Sodium therApy for the induction of Remission and tolerance trial in Microscopic PolyAngiitis (EMSAR-MPA trial) as the first RCT to compare the efficacy and safety of EC-MPS combined with glucocorticoids as remission induction therapy to CYC combined with glucocorticoids.

Methods and analysis

Study design

This study is a multicentre, open-label, randomised controlled, non-inferiority trial using a parallel arm designed to evaluate the efficacy and safety of oral EC-MPS in patients with active and non-life-threatening MPA. The primary end point of efficacy is the remission rate at 6 months. Follow-up will continue for 18 months in order to detect the influence of the induction regimen on subsequent relapse rates.

The EMSAR trial has three phases (figure 1):

Figure 1.

Schematic representation of the study treatment schedule. AZA, azathioprine; BVAS, Birmingham Vasculitis Activity Score; CYC, cyclophosphamide; EC-MPS, enteric-coated mycophenolate sodium.

1. Screening and baseline: Participants will undergo procedures to establish inclusion/exclusion criteria and will sign the informed consent form. Baseline values of Birmingham Vasculitis Activity Score (BVAS)³¹ for the efficacy outcome and other outcomes of interest will immediately be established after randomisation but before receiving study medications.

2. Remission induction phase (day 1 through month 6): Eligible participants will be randomised in a 1:1 ratio to the EC-MPS arm or the CYC arm. Each participant in the EC-MPS arm will receive the maximum tolerated dose between 720 and 1440 mg/day orally in two times per day doses. Each participant in the CYC arm will receive the intravenous CYC 7.5–15 mg/kg at weeks 0, 2, 4, 6 and every 3 weeks thereafter. Participants will receive either EC-MPS or CYC for a minimum of 3 months. Once the investigator determines that a participant has entered clinical remission, BVAS=0 twice (the interval >1 month), the participant will be switched to maintenance therapy.

3. Remission maintenance phase (month 7 through month 18): Participants will switch from daily EC-MPS or intravenous CYC to daily azathioprine (AZA) (2 mg/kg/day). They will be followed up until 18 months visit.

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

Patients aged 18 years or older are eligible for inclusion when meeting all of the following criteria: (1) newly diagnosed or relapsed MPA according to Chapel Hill Consensus Conference definitions; (2) MPO-ANCA positivity; (3) active disease (defined by at least one major or three minor BVAS 2003 items, see table 1); (4) non-life-threatening MPA and (5) have signed informed consent (see online supplemental material 1).

Table 1.

Features of limited and severe AAV

Severe (major) BVAS items*	Limited (minor) BVAS items†
Cutaneous gangrene Scleritis Retinal exudates/haemorrhage Sensorineural hearing loss Mesenteric ischaemia Alveolar haemorrhage Red blood cell urinary casts Rise in serum creatinine 30% over baseline Aseptic meningitis Spinal cord lesions Cerebrovascular accident caused by vasculitis Cranial nerve palsy Sensory peripheral neuropathy Motor mononeuritis multiplex	Arthralgia/arthritis Fever (>38℃) Purpura Skin ulcers Mouth ulcers Conjunctivitis/episcleritis Orbital mass/proptosis Uveitis Bloody nasal discharge/nasal crusting Sinus involvement Swollen salivary gland Subglottic inflammation Conductive deafness Pericarditis Pleurisy Pulmonary nodules or cavities Other pulmonary infiltrates secondary to vasculitis Endobronchial lesions Haematuria

*Any of these items must be attributable to the underlying disease.

†Minor items with significant risk of morbidity may be classified as severe (BVAS=3).

AAV, anti-neutrophil cytoplasmic antibodies associated vasculitis; BVAS, Birmingham Vasculitis Activity Score.

Exclusion criteria

Patients will be excluded if any of the following criteria were met: (1) imminently life-threatening vasculitis (diffuse alveolar haemorrhage, intestinal perforation or major haemorrhage, cerebral vasculitis and cardiac vasculitis); (2) rapidly progressive glomerulonephritis and declining renal function. Defined as estimated glomerular filtration rate (eGFR) (by using Cockcroft-Gault Formula) fall >20% in previous 2 weeks; (3) eGFR<15 mL/min at entry or on dialysis; (4) limited disease that would not normally be treated with CYC; (5) previous treatment with: MMF/EC-MPS (more than 2 weeks within the last 2 months), CYC (more than 2 weeks daily oral or more than 1 pulse of intravenous CYC within the last 3 months) or rituximab (within the last 12 months); (6) active infection, including hepatitis B, C, HIV and tuberculosis; (7) known hypersensitivity to EC-MPS, AZA or CYC; (8) cancer or an individual history of cancer; (9) any other multi-system autoimmune diseases including EGPA, GPA, systemic lupus erythematosus, anti-glomerular basement membrane disease and cryoglobulinaemia; (10) severe digestive system diseases (eg, inflammatory bowel disease, gastrointestinal haemorrhage); (11) white blood cell count with less than 3500/mm³; platelet with less than 1 20 000/mm³; alanine transaminase or aspartate transaminase level greater than two times the upper limit of normal that cannot be attributed to underlying AAV disease; (12) females who are pregnant, breast feeding or at risk of pregnancy and not using a medically acceptable form of contraception; and (13) any condition judged by the investigator that would cause the study to be detrimental to the patient.

Randomisation and blinding

Participants will be randomly assigned (1:1) to the EC-MPS arm or CYC arm via an interactive web response system with a computer-generated random sequence. Randomisation will be stratified by eGFR<30 mL/min (yes vs no) by Cockcroft-Gault, planned additional therapy at entry with methylprednisolone ≥0.5 g or plasma exchange (yes vs no) and age >60 years (yes vs no). Given the observed variations in adherence to guidelines and awareness of new clinical research among different hospitals, plasma exchange was included as a stratification factor, despite current recommendations suggesting its consideration only in cases of severe life-threatening AAV.

Due to the differences in routes administration of CYC (intravenous) and EC-MPS (oral), the trial is not blinded but clinical event assessors are blinded to assignment.

Study treatments

EC-MPS arm

Participants randomised to the EC-MPS arm will receive 1440 mg/day of oral EC-MPS or a maximum tolerated dose between 720 and 1440 mg/day. EC-MPS is given in divided doses two times a day as remission induction therapy for 3–6 months until remission (BVAS=0 for two consecutive study assessments), then switch to AZA maintenance regimen. Reductions will be performed according to renal function and age (table 2). For persistent disease in adults at 4 weeks, dose increase up to a maximum of 2160 mg/day is allowed. The dose increase is only permitted if 1440 mg/day is tolerated without moderate/severe side effects. Persistent disease is defined as the persistence (not worsening) of major or minor BVAS items present at entry.

Table 2.

Pulsed EC-MPS dose reduction for renal function and age

Age (year)	CrCl* >50 mL/min	CrCl 30–50 mL/min
<60	1440 mg/day (four tablets, two times per day)	720 mg/day (two tablets, two times per day)
>60	1080 mg/day (three tablets, two times per day)	720 mg/day (two tablets, two times per day)

*Use Cockcroft-Gault formula to evaluate creatinine clearance (CrCl):

EC-MPS, enteric-coated mycophenolate sodium.

CYC arm

Participants in the CYC arm will receive intravenous pulsed CYC (15 mg/kg) at weeks 0, 2, 4 and 6 and then every 3 weeks as given in the CYCLOPS trial³² until the remission is reached at 3–6 months from the start of therapy (maximum 10 doses and minimum six doses). Reductions will be performed according to renal function and age (table 3). Maximum CYC pulse is 1 g. CYC may be stopped from 3 months onwards provided the patient is in remission (BVAS=0 for two consecutive study assessments). After completion of CYC, AZA will be commenced.

Table 3.

Pulsed CYC dose reduction for renal function and age

Age (years)	CrCl* >50 mL/min	CrCl 30–50 mL/min
<60	15 mg/kg/pulse	12.5 mg/kg/pulse
60–70	12.5 mg/kg/pulse	10 mg/kg/pulse
>70	10 mg/kg/pulse	7.5 mg/kg/pulse

*Use Cockcroft-Gault formula to evaluate creatinine clearance (CrCl):

CYC, cyclophosphamide.

Glucocorticoids

All included participants will receive prednisone orally (1 mg/kg/day, not to exceed 60 mg/day). The prednisone will then be tapered, and the dose should be reduced to 40 mg/day by the end of 1 month. The dose of 40 mg/day will be maintained for 2 weeks. Subsequently, the dose will be reduced in a stepwise fashion every 2 weeks to 30, 20, 15, 10, 7.5, 5 and 2.5 mg/day, until the participant is completely off prednisone. The entire tapering process will require 20 weeks. The goal of prednisone tapering is to cease prednisone treatment completely no later than 6 months after randomisation. Flexibility in dose is ±12.5% from the above protocol in the first 12 weeks and 25% thereafter. Oral prednisone may substitute for prednisolone at the same dose. In the event of a limited flare that requires restarting prednisone, the new prednisone dose must be maintained 1 month before tapering. Intravenous methylprednisolone may be given at entry (maximum 3 g total) before randomisation; however, intention to use methylprednisolone must be stated pre-randomisation.

Azathioprine

All patients will be switched from their assigned study treatment (EC-MPS or CYC) to oral AZA 2 mg/kg/day (maximum 200 mg/day) after remission has been achieved, between 3 and 6 months. AZA will be continued until the study ends at 18 months. The dose will be reduced by 25% in patients with age >60 years and be reduced by 50% in patients with age>75 years.

Other treatments

All patients, unless allergic, will receive a once every other day administration of sulfamethoxazole/trimethoprim 480 mg until the completion of the study. If myelosuppression occurs, the administration of sulfamethoxazole/trimethoprim will be discontinued, and monitoring will continue until recovery. In case of persistent non-recovery, it will be classified as the adverse event associated with EC-MPS/CYC. Oral calcium and/or vitamin D are recommended but not mandatory according to local practice. Plasma exchange is allowed before randomisation. During the study, all concomitant immunosuppressants are prohibited except for study drugs. Also, the use of live vaccines is prohibited during the study.

Study evaluations

Participant assessments, including clinical, biochemical, BVAS and patient-reported outcomes, will be performed at 0, 2, 4, 6, 9, 12, 15, 18, 21 and 24 weeks and 7, 9, 12, 15 and 18 months after entry and at the time of relapse. The maximum duration of the study for any individual is 18 months. Data will be collected on paper case report forms and entered into an electronic database.

Progressive disease is defined as the persistence or worsening of a major BVAS item present at entry or a new major BVAS item, not present at entry. Patients with progressive disease should be considered a ‘treatment failure’ and should be treated according to clinical practice, including intravenous methylprednisolone, immunoglobulin or plasma exchange. Disease response is defined as a reduction of at least one in the BVAS compared with the baseline measure and no new disease manifestation. Severe flare is defined as a BVAS>3 or the occurrence of at least one major item listed in table 1 following a period in which the BVAS had improved. Limited flare is defined as the new occurrence or worsening of one or more minor BVAS items (see table 1) following a period of improvement.

Treatment failure is defined as any one of the following: (1) failure to achieve disease response by the week 4 study visit; (2) a severe disease flare that occurs after disease response; (3) a limited flare within the first 6 months after randomisation that cannot be controlled by increasing the prednisone dose and (4) intractable adverse effects related to study medications leading to permanent discontinuation of study medications. Participants who are considered treatment failures before the month 6 study visit will be crossed over to the opposite treatment arm or will be treated according to the best medical judgement.

Study outcomes

The primary outcome is the proportion of patients achieving remission by 6 months. Remission is defined as the absence of disease activity with BVAS 2003 of zero on two consecutive occasions at least 1 month apart and adherence to the prednisolone taper.^{19 33 34} BVAS V.3 represents a robust and useful tool for standard assessment of systemic vasculitis.^{31 35} The secondary endpoints are as follows: the adverse event rate; the time to remission; the percentage of participants with complete remission (BVAS of 0 and being off prednisone) at 6, 12 and 18 months after randomisation; the number of limited and/or severe flares (as defined above) in participants at 6, 12 and 18 months; the time to limited and/or severe flare; cumulative glucocorticoid dosing; change in eGFR and quality of life of patients. Outcomes were adjudicated by a committee blinded to study group assignment.

The adverse events will be assessed and recorded, including but not limited to infections, end-stage renal disease, death, malignancy, infusion reactions, cardiovascular, serious hypersensitivity, thromboembolic and serious disease-related events. According to Good Clinical Practice guidelines, serious adverse events and suspected unexpected serious adverse reaction will be reported to the medical ethics committee. Quality of life will be assessed by the AAV-Patient-Reported Outcome questionnaire,³⁶ Vasculitis Impact on Daily Life³⁷ and the Sino-Nasal Outcome Test-22 questionnaires.³⁸

Planned subgroup analyses will include the effect of eGFR, age, BVAS, newly diagnosed or relapsed disease and additional intravenous methylprednisolone and/or plasma exchange before randomisation on remission.

Statistical analyses

The sample size estimate was based on a non-inferiority design. Based on the data from the MYCYC trial,¹⁹ the sample size was calculated assuming that 80% of the participants who receive CYC and MMF will attain remission during the first 6 months after randomisation and that there will be a non-inferiority limit of 20% on the difference in the remission percentage between EC-MPS and CYC. If we also assume a 10% dropout rate that is equally distributed between treatment groups, a sample size of 55 participants per arm will yield 80% power to conclude non-inferiority using a one-sided 0.05-level test. The non-inferiority limit of 20% is chosen based on the assumption that 0% of untreated participants would attain remission and that, with this bound, EC-MPS would still be considered an effective treatment.

A differentiation in analysis will be made according to the intent-to-treat (ITT) sample and the per-protocol (PP) sample. The ITT sample will include all randomised participants and be used in the analysis of efficacy endpoints according to the treatment to which they are assigned and not which they actually received. The PP sample will exclude participants with major protocol deviations and will be used as a supporting analysis to the ITT analysis. The safety sample will include all participants who received at least one dose of any study drug (EC-MPS, CYC and AZA) and will be analysed according to the actual received treatments. The safety sample will be used for safety analysis. Continuous data will be summarised using mean, SD, median, minimum and maximum. For categorical data, the number and percentage of participants in each arm will be presented.

For the primary and secondary remission outcomes, the absolute risk difference of remission with corresponding two-sided 90% CIs will be calculated according to the Consolidated Standards of Reporting Trials extension for reporting of non-inferiority trials.³⁹ If the lower bound is above −20%, a conclusion that EC-MPS is non-inferior to CYC will be made. In this case, if the observed primary efficacy endpoint of the EC-MPS group is lower than that of the CYC group, the observed primary efficacy endpoint of the CYC group must be at least 40% to conclude the non-inferiority of EC-MPS. If the lower bound of the above CI for the difference is greater than 0 and the lower bound of the two-sided 95% CI of the primary efficacy endpoint for EC-MPS group is greater than or equal to 50%, a conclusion that EC-MPS is superior to CYC will be made. Descriptive statistics will be compared using the two-sample t-test or Wilcoxon rank-sum test depending on the normality of the response. The χ² test will be used to compare the binary outcomes. A log-rank test and Kaplan-Meier curves will be performed in time-to-event comparisons. Multivariable-adjusted Cox regression models will be used to account for the possible confounding factors. The rates of relapse and adverse events will be compared using a Poisson regression model.

Study organisation

EMSAR trial is located in Shanxi Province in North China with a 34.8 million population, which is a less-developed region and ranks 17th out of 31 provinces for gross domestic product per head. Eleven hospitals in six different cities of Shanxi Province will take part in the study. Eleven centres are all general hospitals with 2000–2500 beds in Shanxi Province. One lead investigator per centre will be responsible for the study and conduct and act as coordinator. The study will be coordinated at the clinical trials office in Shanxi Medical University. The trial management committee, the steering committee and the data monitoring committee will be based on the clinical trials office. The steering committee will ensure investigators receive training at meetings and will meet every 6 months to review the progress of the study. A data monitoring committee will meet annually to review drug safety and protocol compliance reports provided by the trial management committee.

Ethics and dissemination

This protocol and the informed consent documents have received ethical approval from the Ethics Committee of Shanxi Medical University Second Hospital (no 2022YX-026). Any amendments to the protocol or consent materials will also be approved before they are implemented. This study will be conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice guidelines in China. The trial is registered at the Chinese Clinical Trial Registry (www.chictr.org.cn) with identifier ChiCTR2200063823.

All participants (or their legally acceptable representative) must read, sign and date a consent form prior to participation in the study, taking study drug and/or undergoing any study-specific procedures. Potential participants will be informed that their involvement is voluntary and that they may withdraw from the study at any time for any reason. A participant’s privacy and confidentiality will be respected throughout the study. Each participant will be assigned a sequential identification number; these numbers rather than names will be used to collect, store and report participant information. Clinical trial insurance is available for patients who suffer harm from trial participation.

Enrolment will be started in April 2023, and thus randomisation will be complete by the end of March 2025. The study is currently in the phase of recruiting participants, and as of 1 December 2023, a total of 13 patients who meet the enrolment criteria have been enrolled. The final results of the EMSAR-MPA trial will be reported in relevant peer-reviewed publications in 2027. The key findings will be presented at national and international conferences. This protocol complies with the Standard Protocol Items: Recommendations for Interventional Trials recommendations for protocol reporting. Final findings will be reported according to the Consolidated Standards of Reporting Trials guidelines. The funder will have no role in the data collection process, data-analysis and interpretation of the trial results.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).