Minimizing Glucocorticoid Administration in Patients With Proliferative Lupus Nephritis

Official title

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

Overview

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

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.

Interventions

• Drug Rituximab
  2 doses of Rituximab 1 g and Methylprednisolone 500 mg on days 1 and 15.
• Drug Mycophenolate Mofetil
  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 Cyclophosphamide
  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 Corticosteroids
  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.

Primary outcome measures

• Percentage of participants with a histological remission [Time frame: 6 months]

Secondary outcome measures (11)

• Percentage of participants with a complete renal response [Time frame: 12 months]
• Percentage of patients with severe infectious episodes effects [Time frame: 24 months]
• Cumulative exposure to glucocorticoids [Time frame: 24 months]
• The proportion of patients who obtained a complete renal response [Time frame: 6, 18 and 24 months]
• The proportion of patients who obtained a partial renal response [Time frame: 6, 12, 18, 24 months]
• The proportion of patients who have developed relapse [Time frame: 24 months]
• Proportion of patients who showed normalization of complement fractions C3, C4 and negative anti-dcDNA antibodies at week 52 [Time frame: 52 weeks]
• Proportion of patients with progression of chronicity score by more than 2 units [Time frame: 6 months]
• Percentage of patients with non-severe infectious episodes [Time frame: 24 months]
• Percentage of patients with severe non-infectious adverse events [Time frame: 24 months]
• Percentage of patients with non-severe non-infectious adverse events [Time frame: 24 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Romania · 1 center

• Fundeni Clinical Institute — Bucharest

Publications

• Parikh SV, Almaani S, Brodsky S, Rovin BH. Update on Lupus Nephritis: Core Curriculum 2020. Am J Kidney Dis. 2020 Aug;76(2):265-281. doi: 10.1053/j.ajkd.2019.10.017. Epub 2020 Mar 24. PMID 32220510
• Pepper R, Griffith M, Kirwan C, Levy J, Taube D, Pusey C, Lightstone L, Cairns T. Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids. Nephrol Dial Transplant. 2009 Dec;24(12):3717-23. doi: 10.1093/ndt/gfp336. Epub 2009 Jul 17. PMID 19617257
• Fanouriakis A, Bertsias G. Changing paradigms in the treatment of systemic lupus erythematosus. Lupus Sci Med. 2019 Feb 8;6(1):e000310. doi: 10.1136/lupus-2018-000310. eCollection 2019. PMID 31168398
• Parikh SV, Rovin BH. Current and Emerging Therapies for Lupus Nephritis. J Am Soc Nephrol. 2016 Oct;27(10):2929-2939. doi: 10.1681/ASN.2016040415. Epub 2016 Jun 9. PMID 27283496
• Catapano F, Chaudhry AN, Jones RB, Smith KG, Jayne DW. Long-term efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus. Nephrol Dial Transplant. 2010 Nov;25(11):3586-92. doi: 10.1093/ndt/gfq256. Epub 2010 May 11. PMID 20466686
• Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, Maciuca R, Zhang D, Garg JP, Brunetta P, Appel G; LUNAR Investigator Group. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012 Apr;64(4):1215-26. doi: 10.1002/art.34359. Epub 2012 Jan 9. PMID 22231479
• Tamirou F, Houssiau FA. Management of Lupus Nephritis. J Clin Med. 2021 Feb 9;10(4):670. doi: 10.3390/jcm10040670. PMID 33572385
• Condon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, Griffith M, Cairns TD, Lightstone L. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis. 2013 Aug;72(8):1280-6. doi: 10.1136/annrheumdis-2012-202844. Epub 2013 Jun 5. PMID 23740227

Identifiers

NCT: NCT05207358 · FundeniCI

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗