Efficacy and Safety of Enteric-coated Mycophenolate Sodium in Combination With Two Corticosteroid Regimens for the Treatment of Lupus Nephritis Flare

Study Overview
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Brief Summary
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The study will investigate the efficacy and safety of enteric-coated mycophenolate sodium in combination with two different corticosteroid (CS) regimes for the induction of remission of a lupus nephritis flare. Patients will be randomly allocated to standard CS regimen (group I) or to a reduced dose CS regimen (group II)

Official Title
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A Randomized, Multicenter, Open-label, 6-month Study to Explore the Efficacy and Safety of Enteric-coated Mycophenolate Sodium in Combination With Two Corticosteroid Regimens for the Treatment of Lupus Nephritis Flare

Conditions
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Lupus Nephritis

Intervention / Treatment
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* Drug: Mycophenolate sodium
* Drug: Prednisone
* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Male or female patients with systemic lupus erythematosus (SLE)(at least 4 classification criteria) Aged ≥18 years, Proliferative lupus nephritis classified as ISN/RPS class III or IV Renal biopsy within the last 24-month preceding the study entry Proteinuria defined as >0.5 gram urine protein per gram urine creatinine at screening and baseline Clinical activity defined by one or more of the following changes in renal function: Serum creatinine >1.0 mg/dl (88.4 μmol/l) Microscopic hematuria defined as >5 red cells per high power field Presence of cellular casts Exclusion criteria Patients with calculated creatinine clearance <30 ml/min (using the Cockcroft-Gault formula) Patients having received an intravenous (i.v.) corticosteroid bolus during the last 3 months, Patients having received oral or i.v. cyclophosphamide during the last 3 month Patients having received mycophenolate mofetil (MMF) within the preceding 3 months Use of any antibody therapy within the past 6 months Pregnant or nursing (lactating) women or women of child-bearing potential who are planning to become pregnant, or are not willing to use effective means of contraception throughout the study and during one month after the end of the study. Use of other investigational drugs within 1 month of enrollment (except for antibodies: within 6 months of enrollment History of hypersensitivity to any of the study drugs or to drugs with similar chemical structures, History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard dose<br>Mycophenolate sodium was administered orally in combination with a standard dose of corticosteroids (CS) administered as prednisone or prednisone equivalent (PRED). Mycophenolate sodium was administered in divided doses at a daily dose of 1440 mg during the first 2 weeks of the study and then at 2160 mg daily for the next 22 weeks. The dose of Prednisone was started at 1 mg per kg body weight and subsequently tapered according to the patient's weight. The planned treatment duration was 24 weeks. | Drug: Mycophenolate sodium<br>* Mycophenolate sodium as administered orally for 2 weeks at 1440mg daily and then increased to 2160mg daily for 22 weeks.<br>* Other names: Myfortic;Drug: Prednisone<br>* Oral prednisone or prednisone equivalent was started on Day 4 and subsequently tapered every 2 weeks according to the patient's weight.<br>Drug: Methylprednisolone<br>* All patients received bolus therapy with 0.5 g of intravenous Methylprednisolone per day for 3 consecutive days.<br>|
| Active Comparator: Low dose<br>Mycophenolate sodium was administered in combination with a reduced dose of corticosteroids (CS) administered as prednisone or prednisone equivalent (PRED). Mycophenolate sodium was administered in divided doses at a daily dose of 1440 mg during the first 2 weeks of the study and then at 2160 mg daily for the next 22 weeks. The dose of Prednisone was started at 0.5 mg per kg body weight and subsequently tapered according to the patient's weight. The planned treatment duration was 24 weeks. | Drug: Mycophenolate sodium<br>* Mycophenolate sodium as administered orally for 2 weeks at 1440mg daily and then increased to 2160mg daily for 22 weeks.<br>* Other names: Myfortic;Drug: Prednisone<br>* Oral prednisone or prednisone equivalent was started on Day 4 and subsequently tapered every 2 weeks according to the patient's weight.<br>Drug: Methylprednisolone<br>* All patients received bolus therapy with 0.5 g of intravenous Methylprednisolone per day for 3 consecutive days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Complete Remission | Complete remission was defined as urine protein/urine creatinine ratio < 0.5 gram urine protein per gram urine creatinine, urine sediment normalized (no cellular casts, < 5 red cells per high power field), and serum creatinine within 10% of normal range according to local lab. | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Complete Remission | Complete remission was defined as urine protein/urine creatinine ratio < 0.5 gram urine protein per gram urine creatinine, urine sediment normalized (no cellular casts, < 5 red cells per high power field), and serum creatinine within 10% of normal value. | 12 Weeks | 
| Number of Patients With Partial Remission | Partial remission was defined as urine protein/creatinine ratio reduced by at least 50% from baseline and stable serum creatinine within 10% of baseline value) or improved. | Baseline to 12 and 24 weeks | 
| Cumulative Dose of Prednisone Equivalent Corticosteroids (CS) | Corticosteroid use was measured as cumulative dose until 12 and 24 weeks of treatment as well as daily doses at baseline, 12 and 24 weeks. | 12 Weeks and 24 Weeks | 
| Number of Patients With Moderate to Severe Flares | A moderate to severe flare was defined as the occurrence of increased lupus activity after partial or complete remission, based on the presence of 1 BILAG A score or >=3 BILAG B scores. British Isles Lupus Assessment Group (BILAG) index divides lupus activity in 8 organs/systems which are each given a score of A to E. A=disease sufficiently active to need disease modifying treatment; B=problems requiring symptomatic treatment; C=mild stable disease; D=previously affected but currently inactive system; E=the system or organ has never been involved. BILAG score: A=9, B=3, C=1, D/E=0; range(0-72) | 12 and 24 weeks | 
| Duration of Exposure to Study Medication | The duration of exposure was calculated as the date of the last Mycophenolate sodium dose minus the date of the last Mycophenolate sodium dose +1. | 24 weeks | 
| Number of Patients With Adverse Events and Infections | Safety assessments included collecting all adverse events (AEs), serious adverse events (SAEs), with their severity and relationship to study drug. According to FDA 21CFR 314.80, a serious adverse event (SAE) is described as any adverse event that leads to death, is life threatening ( NIH criteria Grade 4), causes or prolongs hospitalization, results in a congenital anomaly, or any other important medical event not described above. | 24 weeks | 
| Number of Patients With Treatment Failure | Treatment failure was defined as no therapeutic response (without complete or partial remission) or premature discontinuation during the first 24 weeks from study medication or the study for any reason except complete or partial remission. | 12 Weeks and 24 Weeks | 
| Change From Baseline in Overall Disease Activity With Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) | SLEDAI stands for Systemic Lupus Erythematosus Disease Activity Index and was a well established global score index based on assessment of 24 items measuring a disease activity in the 10-day period prior to the assessment. SLEDAI item weights range from 1 for fever to 8 for seizures. A maximum theoretical score is 105. Total score range from 1 to 105. A flare has been defined as a SLEDAI score increase of 3 or more to a level of 8 or higher. During flares SLEDAI scores of 25 to 30 are common. | From Baseline to week 4, week 12 and week 24 | 
| Change From Baseline in Overall Disease Activity With British Isles Lupus Assessment Group (BILAG) | BILAG (British Isles Lupus Assessment Group) index divides lupus activity into 8 organs/systems and was based on the principle of the physician's intention to treat, assessing activity in the previous one month. Each organ or system was given a score of A to E, where A = disease that is sufficiently active to require disease modifying treatment; a B = problems requiring symptomatic treatment; C = stable mild disease; D = previously affected but currently inactive system; and E = the system or organ has never been involved. [A=9, B=3, C=1, D/E=0 the score range for each patient will be 0-72]. | From Baseline to week 4, week 12 and week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lupus Nephritis, enteric-coated mycophenolate sodium, EC-MPS, Myfortic