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Minimizing Glucocorticoid Administration in Patients With Proliferative Lupus Nephritis (GLUREDLUP)

Primary Purpose

Lupus Nephritis

Status
Recruiting
Phase
Phase 4
Locations
Romania
Study Type
Interventional
Intervention
Rituximab
Mycophenolate Mofetil
Cyclophosphamide
Corticosteroids
Sponsored by
Institutul Clinic Fundeni
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lupus Nephritis focused on measuring immunosuppression, glucocorticoids, eurolupus, rituxilup, induction therapy

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Fundeni Clinical InstituteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

RITUXILUP regimen

EUROLUPUS regimen (Standard therapy)

Arm Description

- 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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
Percentage of patients with severe infectious episodes effects
Cumulative exposure to glucocorticoids
The proportion of patients who obtained a complete renal response
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.
The proportion of patients who have developed relapse
Proportion of patients who showed normalization of complement fractions C3, C4 and negative anti-dcDNA antibodies at week 52
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.
Percentage of patients with non-severe infectious episodes
Percentage of patients with severe non-infectious adverse events
Percentage of patients with non-severe non-infectious adverse events

Full Information

First Posted
December 7, 2021
Last Updated
March 2, 2022
Sponsor
Institutul Clinic Fundeni
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1. Study Identification

Unique Protocol Identification Number
NCT05207358
Brief Title
Minimizing Glucocorticoid Administration in Patients With Proliferative Lupus Nephritis
Acronym
GLUREDLUP
Official Title
Minimizing Glucocorticoid Administration in Patients With Proliferative Lupus Nephritis During the Induction of Remission Period-EUROLUPUS vs. RITUXILUP Regimen: A Randomized Study
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Recruiting
Study Start Date
March 2, 2022 (Actual)
Primary Completion Date
December 31, 2028 (Anticipated)
Study Completion Date
December 31, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Institutul Clinic Fundeni

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lupus Nephritis
Keywords
immunosuppression, glucocorticoids, eurolupus, rituxilup, induction therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
RITUXILUP regimen
Arm Type
Experimental
Arm Description
- 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.
Arm Title
EUROLUPUS regimen (Standard therapy)
Arm Type
Other
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Intervention Description
2 doses of Rituximab 1 g and Methylprednisolone 500 mg on days 1 and 15.
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Corticosteroids
Intervention Description
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 Measure Information:
Title
Percentage of participants with a histological remission
Description
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.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Percentage of participants with a complete renal response
Description
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.
Time Frame
12 months
Title
Percentage of patients with severe infectious episodes effects
Time Frame
24 months
Title
Cumulative exposure to glucocorticoids
Time Frame
24 months
Title
The proportion of patients who obtained a complete renal response
Time Frame
6, 18 and 24 months
Title
The proportion of patients who obtained a partial renal response
Description
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.
Time Frame
6, 12, 18, 24 months
Title
The proportion of patients who have developed relapse
Time Frame
24 months
Title
Proportion of patients who showed normalization of complement fractions C3, C4 and negative anti-dcDNA antibodies at week 52
Time Frame
52 weeks
Title
Proportion of patients with progression of chronicity score by more than 2 units
Description
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.
Time Frame
6 months
Title
Percentage of patients with non-severe infectious episodes
Time Frame
24 months
Title
Percentage of patients with severe non-infectious adverse events
Time Frame
24 months
Title
Percentage of patients with non-severe non-infectious adverse events
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Bogdan Obrisca, MD, PhD
Phone
0040721256797
Email
obriscabogdan@yahoo.com
First Name & Middle Initial & Last Name or Official Title & Degree
Alexandra Vornicu, MD
Phone
0040756203773
Email
vornicu.alexandra@yahoo.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gener Ismail, MD, PhD
Organizational Affiliation
Institutul Clinic Fundeni
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fundeni Clinical Institute
City
Bucharest
ZIP/Postal Code
022328
Country
Romania
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bogdan Obrisca, MD, PhD
Phone
0040721256797
Email
obriscabogdan@yahoo.com

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Time Frame
Within 12 months of publishing the results of the primary endpoints of the study
Citations:
PubMed Identifier
32220510
Citation
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.
Results Reference
background
PubMed Identifier
19617257
Citation
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.
Results Reference
background
PubMed Identifier
31168398
Citation
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.
Results Reference
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PubMed Identifier
27283496
Citation
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.
Results Reference
background
PubMed Identifier
20466686
Citation
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.
Results Reference
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PubMed Identifier
22231479
Citation
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.
Results Reference
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PubMed Identifier
33572385
Citation
Tamirou F, Houssiau FA. Management of Lupus Nephritis. J Clin Med. 2021 Feb 9;10(4):670. doi: 10.3390/jcm10040670.
Results Reference
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PubMed Identifier
23740227
Citation
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.
Results Reference
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PubMed Identifier
33147587
Citation
Morales E, Galindo M, Trujillo H, Praga M. Update on Lupus Nephritis: Looking for a New Vision. Nephron. 2021;145(1):1-13. doi: 10.1159/000511268. Epub 2020 Nov 4.
Results Reference
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PubMed Identifier
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Citation
Bajema IM, Wilhelmus S, Alpers CE, Bruijn JA, Colvin RB, Cook HT, D'Agati VD, Ferrario F, Haas M, Jennette JC, Joh K, Nast CC, Noel LH, Rijnink EC, Roberts ISD, Seshan SV, Sethi S, Fogo AB. Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices. Kidney Int. 2018 Apr;93(4):789-796. doi: 10.1016/j.kint.2017.11.023. Epub 2018 Feb 16.
Results Reference
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Minimizing Glucocorticoid Administration in Patients With Proliferative Lupus Nephritis

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