Ignite Creation Date:
2024-05-06 @ 6:29 PM
Last Modification Date:
2024-10-26 @ 2:49 PM
Study NCT ID:
NCT05679336
Status:
RECRUITING
Last Update Posted:
2024-05-07
First Post:
2022-11-28
Brief Title:
Rituximab Cyclophosphamide and Corticosteroids in Primary Membranous Nephropathy
Sponsor:
St Petersburg State Pavlov Medical University
Organization:
St Petersburg State Pavlov Medical University
Study Overview
Official Title:
Rituximab Cyclophosphamide and Corticosteroids at Low Cumulative Doses to Induce Remission in Primary Membranous Nephropathy
Status:
RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This exploratory study aims to assess the efficacy safety of the experimental treatment based on a combination of rituximab RTX intravenous IV cyclophosphamide CYC and corticosteroids S administrated at lower cumulative doses RCP for the induction of early remission in subjects with anti-PLA2R antibody-positive primary membranous nephropathy PMN having nephrotic syndrome NS
Detailed Description:
BACKGROUND
PMN is a glomerular disease associated with autoantibodies targeting podocyte antigens mostly the phospholipase A2 receptor anti-PLA2R The formation of subepithelial immune complexes and complement-mediated injury to podocyte and glomerular basement membrane leads in most cases to the development of NS and the risk of its life-threatening complications thromboembolic infectious and metabolic Standard renoprotective approaches are not sufficient for many patients with PMN and persistent NS In randomized clinical trials of immunosuppressive therapies up to 68 of patients failed to achieve remission during the first 12 months without substantial differences in efficacy between immunosuppressive regimens Treatment failures are increased in high-risk patients including those with heavier proteinuria and higher serum anti-PLA2R levels As a result a significant proportion of patients remain for a long time at high risk of severe complications due to persistent high-level proteinuria and NS and disease progression
PROPOSED NEW TREATMENT APPROACH
Collectively in the past decades no significant progress has been achieved in the treatment of patients with PMN and up to 40 of the patients still progress to dialysis In this context therapies that may result in a higher response and lower relapse rates at an acceptable rate of adverse effects are warranted Particularly developing of treatment approaches to rapid induction of remission is critically important to prevent life-threatening NS complications stop disease progression and improve long-term prognosis especially in high-risk patients
We conducted a pilot open-label trial in 14 patients mean age 5112 years men - 70 with PMN and NS and high serum level of anti-PLA2R treated with RTX CYC and S The overall remission was achieved in 100 of cases of which complete remissions CR in 214 with the median time-to-remission of 25 10 35 months The most commonly observed side effects were infusion related flu-like symptoms chillsrigors fever fatigue headache hypotension and typically responded to antihistamines No patient except one had a major drug-related adverse event in 157 patient-years This adverse event was transient elevation of transaminases in induction phase leading to several days delay in administration of next dose of CYC and prolongation of hospital stay Thus according to these results the use of multi-targeted therapy with RTX CYC and S at low dosages seems to be an effective approach for the rapid induction of PMN remission and prevention of NS complications
The study population will comprise of adult male and female subjects aged 18 - 75 years with a biopsy-proven PMN positive for serum anti-PLA2R antibodies Biopsy-proven PMN defined upon the exclusion of any significant concomitant disease infectious autoimmune neoplastic by careful clinical work-up at the time of kidney biopsy Most of patients are expected to have high or very high risk of disease progression according to current KDIGO guidelines
STUDY DESIGN
This exploratory single-center study aims to assess the efficacy safety of treatment based on a combination of RTX IV CYC and S administrated at lower cumulative doses RCP for the induction of early remission in subjects with anti-PLA2R antibody-positive PMN having NS and high risk of progression Subjects meeting the inclusion criteria and agreed to experimental treatment will be treated with the RCP regimen and will be prospectively followed During the study we plan to do an interim analysis to confirm an expected efficacy and safety of the experimental treatment Besides analyzing the experimental treatment group itself regarding primary and secondary end-points we plan to compare to the RCP group two age- and gender-matched historic control groups Control group 1 will include patients treated with Cyclosporine CSA in combination with S and control group 2 will include patients with treatment based on RTX infusions either as monotherapy or in combination with CSA Both controls will have to fulfill same eligibility criteria These comparisons will allow to assess whether the RCP protocol may have an advantage over standard treatments based on RTX or CSA in primary and secondary efficacy criteria early remission rate the time to clinical and immunological remissions and the change in proteinuria serum albumin and estimated GFR by CKD-EPI equation eGFR
PMN is a glomerular disease associated with autoantibodies targeting podocyte antigens mostly the phospholipase A2 receptor anti-PLA2R The formation of subepithelial immune complexes and complement-mediated injury to podocyte and glomerular basement membrane leads in most cases to the development of NS and the risk of its life-threatening complications thromboembolic infectious and metabolic Standard renoprotective approaches are not sufficient for many patients with PMN and persistent NS In randomized clinical trials of immunosuppressive therapies up to 68 of patients failed to achieve remission during the first 12 months without substantial differences in efficacy between immunosuppressive regimens Treatment failures are increased in high-risk patients including those with heavier proteinuria and higher serum anti-PLA2R levels As a result a significant proportion of patients remain for a long time at high risk of severe complications due to persistent high-level proteinuria and NS and disease progression
PROPOSED NEW TREATMENT APPROACH
Collectively in the past decades no significant progress has been achieved in the treatment of patients with PMN and up to 40 of the patients still progress to dialysis In this context therapies that may result in a higher response and lower relapse rates at an acceptable rate of adverse effects are warranted Particularly developing of treatment approaches to rapid induction of remission is critically important to prevent life-threatening NS complications stop disease progression and improve long-term prognosis especially in high-risk patients
We conducted a pilot open-label trial in 14 patients mean age 5112 years men - 70 with PMN and NS and high serum level of anti-PLA2R treated with RTX CYC and S The overall remission was achieved in 100 of cases of which complete remissions CR in 214 with the median time-to-remission of 25 10 35 months The most commonly observed side effects were infusion related flu-like symptoms chillsrigors fever fatigue headache hypotension and typically responded to antihistamines No patient except one had a major drug-related adverse event in 157 patient-years This adverse event was transient elevation of transaminases in induction phase leading to several days delay in administration of next dose of CYC and prolongation of hospital stay Thus according to these results the use of multi-targeted therapy with RTX CYC and S at low dosages seems to be an effective approach for the rapid induction of PMN remission and prevention of NS complications
The study population will comprise of adult male and female subjects aged 18 - 75 years with a biopsy-proven PMN positive for serum anti-PLA2R antibodies Biopsy-proven PMN defined upon the exclusion of any significant concomitant disease infectious autoimmune neoplastic by careful clinical work-up at the time of kidney biopsy Most of patients are expected to have high or very high risk of disease progression according to current KDIGO guidelines
STUDY DESIGN
This exploratory single-center study aims to assess the efficacy safety of treatment based on a combination of RTX IV CYC and S administrated at lower cumulative doses RCP for the induction of early remission in subjects with anti-PLA2R antibody-positive PMN having NS and high risk of progression Subjects meeting the inclusion criteria and agreed to experimental treatment will be treated with the RCP regimen and will be prospectively followed During the study we plan to do an interim analysis to confirm an expected efficacy and safety of the experimental treatment Besides analyzing the experimental treatment group itself regarding primary and secondary end-points we plan to compare to the RCP group two age- and gender-matched historic control groups Control group 1 will include patients treated with Cyclosporine CSA in combination with S and control group 2 will include patients with treatment based on RTX infusions either as monotherapy or in combination with CSA Both controls will have to fulfill same eligibility criteria These comparisons will allow to assess whether the RCP protocol may have an advantage over standard treatments based on RTX or CSA in primary and secondary efficacy criteria early remission rate the time to clinical and immunological remissions and the change in proteinuria serum albumin and estimated GFR by CKD-EPI equation eGFR
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None