Minimizing Glucocorticoid Administration in Patients With Proliferative Lupus Nephritis

Study Overview
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Brief Summary
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The aim of the study is to evaluate the efficacy of a therapeutic regimen which decreases glucocorticoid exposure compared with standard therapy in patients with proliferative lupus nephritis during remission induction by evaluating the histological and clinical remission.

Detailed Description
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After an initial screening phase during which a first kidney biopsy is performed, all patients that meet the inclusion criteria will be randomized to one of the treatment arms: EUROLUPUS regimen: 3 daily pulses of 750 mg of intravenous Methylprednisolone, followed by oral corticosteroid therapy starting with a dose of 0.5 mg / kg / day for 4 weeks, then decreased by 2.5 mg of Prednisolone / day each 2 weeks. A low dose of glucocorticoid (5-7.5 mg / day) is maintained until 24 months after enrollment. All patients will receive Cyclophosphamide intravenously starting day 1, 6 pulses at a fixed dose of 500 mg given at 2 weeks. After 3 months, Azathioprine (2 mg / kg / day) is initiated 2 weeks after the last administration of Cyclophosphamide and maintained for the next 21 months. RITUXILUP regimen: 2 doses of Rituximab 1 g and Methylprednisolone 500 mg on days 1 and 15. Patients will receive Mycophenolate Mofetil, initially 500 mg twice daily, titrated to a maximum of 1.5 g twice daily, depending on leukocyte count and digestive tolerance, which will be maintained 24 months. Second kidney biopsy will be performed 6 months after the start of the treatment phase.

Official Title
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Minimizing Glucocorticoid Administration in Patients With Proliferative Lupus Nephritis During the Induction of Remission Period-EUROLUPUS vs. RITUXILUP Regimen: A Randomized Study

Conditions
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Lupus Nephritis

Intervention / Treatment
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* Drug: Rituximab
* Drug: Mycophenolate Mofetil
* Drug: Cyclophosphamide
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of the patient between 18 and 80 years, Patients diagnosed with systemic lupus erythematosus according to ACR 1997 or SLICC-2012 criteria Diagnosis of proliferative lupus nephritis class III, IV +/- V (confirmed by renal biopsy and classified according to ISN / RPS); Estimated glomerular filtration rate by CKD-EPI> 30 ml / min / 1.73 sqm Estimated glomerular filtration rate by CKD-EPI <30 ml / min / 1.73 sqm but> 15 ml / min / 1.73 sqm with chronicity index (according to NIH score) <6 Absence of contraindications to the use of Methylprednisolone, Mycophenolate mofetil, oral corticosteroids or Rituximab Ability to provide informed consent Exclusion Criteria: The patient's age under 18 years Patients with life-threatening complications (e.g. Cerebritis) Estimated glomerular filtration rate by CKD-EPI <30 ml / min / 1.73 sqm Estimated glomerular filtration rate by CKD-EPI <30 ml / min / 1.73 sqm but> 15 ml / min / 1.73 sqm with chronicity index (according to NIH score)> 6 Presence of pregnancy / lactation Patients who have received more than 2 g of Methylprednisolone intravenously in the last 4 weeks Use in the last 3 months of biological therapy Use of intravenous immunoglobulins / plasmapheresis in the last 6 months The presence of an active infection History of neoplasia Comorbidities requiring systemic corticosteroid therapy Non-adhesion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: RITUXILUP regimen<br>- 2 doses of Rituximab 1 g and Methylprednisolone 500 mg on days 1 and 15. Patients will receive Mycophenolate Mofetil, initially 500 mg twice daily, titrated to a maximum of 1.5 g twice daily, depending on leukocyte count and digestive tolerance, which will be maintained 24 months. | Drug: Rituximab<br>* 2 doses of Rituximab 1 g and Methylprednisolone 500 mg on days 1 and 15.<br>Drug: Mycophenolate Mofetil<br>* Patients will receive Mycophenolate Mofetil, initially 500 mg twice daily, titrated to a maximum of 1.5 g twice daily, depending on leukocyte count and digestive tolerance, which will be maintained 24 months.<br>|
| Other: EUROLUPUS regimen (Standard therapy)<br>3 daily pulses of 750 mg of intravenous Methylprednisolone, followed by oral corticosteroid therapy starting with a dose of 0.5 mg / kg / day for 4 weeks, then decreased by 2.5 mg of Prednisolone / day each 2 weeks. A low dose of glucocorticoid (5-7.5 mg / day) is maintained until 24 months after enrollment. All patients will receive Cyclophosphamide intravenously starting day 1, 6 pulses at a fixed dose of 500 mg given at 2 weeks. After 3 months, Azathioprine (2 mg / kg / day) is initiated 2 weeks after the last administration of Cyclophosphamide and maintained for the next 21 months. | Drug: Cyclophosphamide<br>* All patients will receive Cyclophosphamide intravenously starting day 1, 6 pulses at a fixed dose of 500 mg given at 2 weeks. After 3 months, Azathioprine (2 mg / kg / day) is initiated 2 weeks after the last administration of Cyclophosphamide and maintained for the next 21 months.<br>Drug: Corticosteroids<br>* 3 daily pulses of 750 mg of intravenous Methylprednisolone, followed by oral corticosteroid therapy starting with a dose of 0.5 mg / kg / day for 4 weeks, then decreased by 2.5 mg of Prednisolone / day each 2 weeks. A low dose of glucocorticoid (5-7.5 mg / day) is maintained until 24 months after enrollment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with a histological remission | The primary endpoint is to evaluate the histologic remission at 6 months after initiation of induction treatment assessed by the change in the individual active lesions and in the activity modified NIH score. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with a complete renal response | Complete renal response is defined by the combination of a decrease in proteinuria below 500 mg / g Creatinine, an inactive urinary sediment and a return of serum Creatinine to baseline. | 12 months | 
| Percentage of patients with severe infectious episodes effects |  | 24 months | 
| Cumulative exposure to glucocorticoids |  | 24 months | 
| The proportion of patients who obtained a complete renal response |  | 6, 18 and 24 months | 
| The proportion of patients who obtained a partial renal response | Partial renal response is defined as a 50% decrease in proteinuria (if the proteinuria was nephrotic the decrease is defined as a 50% reduction in proteinuria to values <3000 mg / g) and stabilization (+/- 25%) or decrease, but not normalization of serum Creatinine. | 6, 12, 18, 24 months | 
| The proportion of patients who have developed relapse |  | 24 months | 
| Proportion of patients who showed normalization of complement fractions C3, C4 and negative anti-dcDNA antibodies at week 52 |  | 52 weeks | 
| Proportion of patients with progression of chronicity score by more than 2 units | Evaluation of the histologic progression at 6 months after initiation of induction treatment assessed by the change in the individual chronic lesions and in the chronicity modified NIH score. | 6 months | 
| Percentage of patients with non-severe infectious episodes |  | 24 months | 
| Percentage of patients with severe non-infectious adverse events |  | 24 months | 
| Percentage of patients with non-severe non-infectious adverse events |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunosuppression, glucocorticoids, eurolupus, rituxilup, induction therapy