Effectiveness of Mycophenolate Mofetil Combined With Tacrolimus for Steroid Tapering in Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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The goal of this clinical trial is to determine whether mycophenolate mofetil(MMF) combined with tacrolimus(TAC) can maintain remission in patients with lupus nephritis (LN) who have reached treatment targets after steroid tapering. The main question[s] it aims to answer are: The efficacy, safety and tolerability of MMF combined with TAC regimen in the treatment of LN patients in the maintenance period. The influence of low-dose steroid on carotid intima thickness (CIMT). The omics and cell-free RNA (cfRNA) spectral differences related to lupus flare. The differences in health economics between steroid tapering and steroid maintenance patients. Participants will be randomly assigned into 2 groups. In the steroid tapering group, participants will take MMF+TAC treatment without steroid for 1 year, and participants who stop steroid treatment without lupus flare will be randomly assigned to monotherapy with MMF or TAC. In the steroid maintenance group, participants will take MMF+TAC+steroid for 1 year, and participants without lupus flare will be randomly assigned to therapy with MMF + steroid or TAC + steroid.

Detailed Description
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According to the references, with the maintenance of steroid, 1-year lupus flare rate is 7%. Investigators plan to take a 2-year follow-up for participants, so the proportion of patients without flare in steroid maintenance group should be 86%. As this is a non-inferiority study, investigators hypothesize that in steroid tapering group, the proportion of patients without flare is also 86%. Investigators set α=0.05 (two-sided), 1-β=0.90, non-inferiority value = 15%, the dropout rate = 20%. The sample size of each group should be 110, the 220 in total.

Official Title
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Effectiveness of Mycophenolate Mofetil Combined With Tacrolimus for Steroid Tapering in Systemic Lupus Erythematosus: A Prospective, Random Control, Open-label, Single Center Clinical Trial

Conditions
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Systemic Lupus Erythematosus, Lupus Nephritis

Intervention / Treatment
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* Drug: Mycophenolate Mofetil
* Drug: Tacrolimus
* Drug: Glucocorticoid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Systemic lupus erythematosus participants diagnosed with 2019 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria, fulfilled with American College of Rheumatology (ACR) lupus nephritis definition, and have reached treatment target (accord with lupus nephritis clinical remission and DORIS) for at least 6 months. The target is defined as: (1)24h urine protein ≤0.5g/d；(2)stable of improved renal function (baseline creatinine ±10% or decrease 15%)；(3)clinical SLE Disease Activity Index (cSLEDAI) =0 (all scores are required zero, except hypocomplementemia and anti-dsDNA antibody positivity)；(4)PGA score (Physician Global Assessment)<0.5; (5)prednisone or equivalent steroid dose≤5mg/d；(6)stable use of immunosuppressants and antimalarial drugs; (7)no use of biological agents. According to the physician, the participant can accept this treatment. The participant is willing to join this clinical trial, has good compliance, and could understand and sign the informed consent before the study begins. Exclusion Criteria: SLE complicated with important organ dysfunction, including consciousness disorder, cognitive disorder, renal dysfunction, heart dysfunction (NYHA class 3, 4), pulmonary arterial hypertension, and interstitial lung disease. SLE with active vital organ disease (not satisfied with DORIS), including but not limited to active neuropsychiatric systemic lupus erythematosus, lupus nephritis, thrombocytopenia, hemolytic anemia, myocardial involvement, gastrointestinal involvement, etc. Participants who are allergic to or intolerant with mycophenolate mofetil or tacrolimus. Participants with acute and chronic infections requiring anti-infective treatment, including but not limited to tuberculosis infection, Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection, Human Immunodeficiency Virus (HIV) infection, and Cytomegalovirus (CMV) infection. Participants who are pregnant or planning to become pregnant. Participants who have used biological agents within 6 months before enrollment. The researcher considers any condition that may cause the participant to be unable to complete the study or bring an obvious risk to the participant.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: First, participants are randomly assigned into 2 groups: steroid tapering group and steroid maintenance group. In steroid tapering group, participants without flare will be assigned into 2 groups: mycophenolate mofetil group and tacrolimus group. In steroid maintenance group, participants without flare will be assigned into 2 groups: mycophenolate mofetil + steroid (1 pill/d) group and tacrolimus + steroid (1 pill/d) group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: steroid tapering group<br>0 6th month: mycophenolate mofetil (1g/d) + tacrolimus (2.0mg/d) + steroid (1 pill/d) 6th 18th month: mycophenolate mofetil (1g/d) + tacrolimus (2.0mg/d) 18th 30th month: Participants who stop steroid treatment and do not flare will be randomly assigned to monotherapy with mycophenolate mofetil or tacrolimus | Drug: Mycophenolate Mofetil<br>* During the first 18 months, participants will take MMF+TAC. After 18 months, participants without lupus flare will randomly stop MMF or TAC.<br>* Other names: MMF;Drug: Tacrolimus<br>* During the first 18 months, participants will take MMF+TAC. After 18 months, participants without lupus flare will randomly stop MMF or TAC.<br>* Other names: TAC;Drug: Glucocorticoid<br>* Participants in steroid tapering group will stop taking glucocorticoid after the first 6 months. Participants in steroid maintenance group will consistently take glucocorticoid.<br>|
| Active Comparator: steroid maintenance group<br>0 18th month: mycophenolate mofetil (1g/d) + tacrolimus (2.0mg/d) + steroid (1 pill/d) 18th 30th month: Participants who do not flare will be randomly assigned to therapy with mycophenolate mofetil + steroid (1 pill/d) or tacrolimus + steroid (1 pill/d) | Drug: Mycophenolate Mofetil<br>* During the first 18 months, participants will take MMF+TAC. After 18 months, participants without lupus flare will randomly stop MMF or TAC.<br>* Other names: MMF;Drug: Tacrolimus<br>* During the first 18 months, participants will take MMF+TAC. After 18 months, participants without lupus flare will randomly stop MMF or TAC.<br>* Other names: TAC;Drug: Glucocorticoid<br>* Participants in steroid tapering group will stop taking glucocorticoid after the first 6 months. Participants in steroid maintenance group will consistently take glucocorticoid.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The 1-year flare rate of lupus nephritis participants who reach the treatment target and accept MMF+TAC remedy tapering steroid in the maintenance period. | If the DORIS (Definition of Remission In SLE) is not sustained, the patient is considered to have lupus flare. Lupus flare can be further evaluated according to SELENA-SLEDAI Flare Index (SFI). Lupus nephritis flare can be further evaluated as flare of proteinuria and flare of nephritis. | 6th 18th month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The 1-year flare rate of lupus nephritis participants who accept MMF or TAC monotherapy. | If the DORIS (Definition of Remission In SLE) is not sustained, the patient is considered to have lupus flare. | 18th 30th month | 
| Lupus flare (as assessed by SLEDAI and PGA) in SLE patients during the maintenance period after steroid tapering. |  | 6th 30th month | 
| The changes of serum activity markers (anti-dsDNA antibody and C3 level) in SLE patients after steroid tapering. |  | 6th 30th month | 
| Proportion of SLE patients with irreversible organ damage (assessed by SLICC/SDI) after steroid tapering. |  | 6th 30th month | 
| Changes in carotid intima-media thickness after steroid tapering. |  | 6th 30th month | 
| Differences in medical charges between steroid tapering and steroid maintenance patients. | Obtain the information by questionnaire. | 6th 30th month | 
| Differences in health-related quality of life between steroid tapering and steroid maintenance patients. | Evaluate health-related quality of life by Short-Form Six-Dimension (SF-6D) health index. SF-6D includes 6 dimensions: physical functioning, role limitations, social functioning, pain, mental health, and vitality. The minimum total value is 0. The maximum total value is 1. Higher scores mean a better outcome. | 6th 30th month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mycophenolate mofetil, tacrolimus, steroid tapering, systemic lupus erythematosus, lupus nephritis