Ignite Creation Date:
2024-05-06 @ 9:35 AM
Last Modification Date:
2024-10-26 @ 12:16 PM
Study NCT ID:
NCT03018535
Status:
UNKNOWN
Last Update Posted:
2019-05-20
First Post:
2017-01-09
Brief Title:
Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy
Sponsor:
Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
Organization:
Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
Study Overview
Official Title:
A Randomized Controlled Trial of Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy
Status:
UNKNOWN
Status Verified Date:
2019-05
Last Known Status:
ACTIVE_NOT_RECRUITING
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:
RI-CYCLO
Brief Summary:
Idiopathic Membranous nephropathy IMN is an auto-immune glomerular disease Recent studies suggest that circulating auto-antibodies against the podocyte surface antigens phospholipase A2 receptor1 PLA2R1 and thrombospondin type 1 domain-containing 7A THSD7A cause the disease in the majority of the patients Additional autoantibodies directed to podocyte neo-expressed cytoplasm proteins have been described including aldose reductase AR Mn-superoxide dismutase SOD2 and alpha-enolase alpha-ENO
The commonest presentation of IMN is nephrotic syndrome Data from placebo arms of interventional studies show that 30-40 of the untreated patients with persistent nephrotic syndrome NS progress to end-stage renal disease ESRD
The best-validated treatment regimen of IMN is combination therapy with steroids and cyclophosphamide capable to induce remission of protenuria in two-third of the patients
Despite this evidence of efficacy there are concerns about the use of cyclophosphamide since it may be associated with adverse events including bone marrow suppression gonadal toxicity infections and oncogenic effects Thus the availability of alternative therapies highly effective but with a greater safety profile is desirable
Given the key role of IgG antibodies in IMN B cell depletion may favourably impact the glomerular disease The anti-CD20 monoclonal antibody Rituximab is a selective B cell depleting agent There is evidence that Rituximab is effective in the treatment of other diseases in which B cells play a key role such as ANCA-related vasculitis Observational studies in IMN provided encouraging data in addition the drug seems well tolerated
Head-to-head comparisons between Rituximab and steroid plus ciclophosphamide in randomized clinical trials are missing
The investigators propose this study in order to test in a randomized controlled trial the hypothesis that Rituximab is more effective than cyclical steroidalkylating-agent therapy in inducing remission in patients with IMN and NS undergoing the initial treatment In addition the levels of the above-mentioned pathogenetic autoantibodies will be measured at baseline and during treatment Finally the study will compare the safety profile of steroid plus cyclophosphamide and Rituximab by evaluating the rate and severity of adverse events
The commonest presentation of IMN is nephrotic syndrome Data from placebo arms of interventional studies show that 30-40 of the untreated patients with persistent nephrotic syndrome NS progress to end-stage renal disease ESRD
The best-validated treatment regimen of IMN is combination therapy with steroids and cyclophosphamide capable to induce remission of protenuria in two-third of the patients
Despite this evidence of efficacy there are concerns about the use of cyclophosphamide since it may be associated with adverse events including bone marrow suppression gonadal toxicity infections and oncogenic effects Thus the availability of alternative therapies highly effective but with a greater safety profile is desirable
Given the key role of IgG antibodies in IMN B cell depletion may favourably impact the glomerular disease The anti-CD20 monoclonal antibody Rituximab is a selective B cell depleting agent There is evidence that Rituximab is effective in the treatment of other diseases in which B cells play a key role such as ANCA-related vasculitis Observational studies in IMN provided encouraging data in addition the drug seems well tolerated
Head-to-head comparisons between Rituximab and steroid plus ciclophosphamide in randomized clinical trials are missing
The investigators propose this study in order to test in a randomized controlled trial the hypothesis that Rituximab is more effective than cyclical steroidalkylating-agent therapy in inducing remission in patients with IMN and NS undergoing the initial treatment In addition the levels of the above-mentioned pathogenetic autoantibodies will be measured at baseline and during treatment Finally the study will compare the safety profile of steroid plus cyclophosphamide and Rituximab by evaluating the rate and severity of adverse events
Detailed Description:
Idiopathic Membranous nephropathy IMN is an immune-mediated glomerular disease characterized by deposition of IgG4 antibodies in the subepithelial area of the glomerular basement membrane GBM Proteinuria is the hallmark of the disease The commonest presentation of IMN is nephrotic syndrome with preserved kidney function The natural course of the disease can be variable and may be punctuated with spontaneous remissions and relapses In about 20 of patients there is spontaneous complete remission of the nephrotic syndrome and another 15-20 undergo partial remission about 30 of patients may remain with fluctuating proteinuria and about 30 may progress to end-stage renal disease ESRD However data from natural history studies and placebo arms of intervention studies with follow-up lasting more than 10 years show that about 30-40 of the untreated patients with persistent nephrotic syndrome progress to ESRD
Complete remission of nephrotic syndrome predicts excellent long-term kidney and patient survival and partial remission also significantly reduces the risk of progression to ESRD Therefore persisting remission of the nephrotic state is an acceptable surrogate end-point to assess efficacy of treatment The primary aims of treatment therefore are to induce a lasting reduction in proteinuria The best-validated regimen is combination therapy with corticosteroids and cyclophosphamide Ponticelli regimen This treatment is superior to supportive therapy alone in inducing remissions and preventing long-term decline of kidney function in patients with idiopathic MN and persisting nephrotic syndrome However there are concerns about the use of cyclophosphamide since its use may be associated with adverse events leading to treatment interruption in about 9 of patients These adverse events include bone marrow suppression gonadal toxicity infections and oncogenic effects
Thus the availability of alternative therapies highly effective but with a greater safety profile is desirable
Recent human studies confirmed that MN is an autoimmune disease suggesting that the disease may be triggered by isotype specific autoantibodies directed against podocyte enzymes and podocyte receptors that are recognized as antigens including M-type phospholipase-2 receptorsPLA2R1 and thrombospondin type 1 domain-containing 7A THSD7A The podocyte expression of these autoantigens can trigger the production of specific antibodies and in situ deposits of immune complexes with consequent activation of complement cascade oxygen radicals and other inflammatory pathways leading to tissue injury and fibrosis Additional autoantibodies directed to podocyte neo-expressed cytoplasm proteins have been described including aldose reductase AR Mn-superoxide dismutase SOD2 and alpha-enolase alpha-ENO
However the mechanisms eliciting the expression of these neoantigens on podocytes and regulating the deposition of the auto-antibodies on the subepithelial surface of the glomerular basement membrane is not known
Considering the potential role of IgG antibodies in the pathogenesis of IMN B cell depletion may favourably impact the glomerular disease as reflected by a reduction in proteinuria The anti-CD20 monoclonal antibody Rituximab is a selective B cell depleting agent capable to maintain B cells undetectable for 3-12 months There is evidence that this strategy is effective in the treatment of other diseases in which B cells play a key role such as ANCA-related vasculitis and humoral allograft rejection Preliminary studies in IMN are promising with observational studies providing encouraging data in addition the drug seems well tolerated with minimal adverse events
Head-to-head comparisons between Rituximab and steroid plus ciclophosphamide in randomized clinical trials are missing
The investigators propose this study in order to test in a randomized controlled trial the hypothesis that selective B lymphocyte depletion obtained with Rituximab is more effective than cyclical corticosteroidalkylating-agent therapy in inducing long-term remission of proteinuria in patients undergoing the initial treatment of with IMN and nephrotic syndrome In addition since specific assay for the above-mentioned autoantibodies are now available the levels of these pathogenetic autoantibodies will be measured at baseline and during treatment Finally the study will compare the safety profile of steroid plus cyclophosphamide and Rituximab by evaluating the rate and severity of adverse events
Design and Power Considerations
The investigators hypothesized that the remission probability in the RTX arm will be greater than in the active comparator group superiority design Available data Ponticelli 1998 suggest that the probability of complete remission with standard therapy is 15 at one year
The investigators plan to enroll 70 patients in this pilot RCT This sample size will be able to detect with a power of 80 and a two-sided P of 005 an odds ratio of 3 ie change in probability from 015 to 045 - a very optimistic effect Smaller and likely more reasonable effects would require larger studies
The study will provide an estimate of this true effect if it exists
Adverse effects
Patients will be directly questioned every two weeks during the drug exposure and then at monthly intervals during follow-up In addition a contact number will be provided to the subjects to call if they experience any adverse affect or if they suspect adverse effect at any time between specific visits
Definition Of Proteinuric Status
UP urinary protein g24h
Complete remission CR UP 03 g
Partial remission PR Reduction in UP of 50 plus final UP 35 g but 03g
Non-response NR Reduction in UP of 50 includes increase in UP 50
Neither CR nor PR
Progression Proteinuria S creatinine increases by 50 over the baseline
Complete remission of nephrotic syndrome predicts excellent long-term kidney and patient survival and partial remission also significantly reduces the risk of progression to ESRD Therefore persisting remission of the nephrotic state is an acceptable surrogate end-point to assess efficacy of treatment The primary aims of treatment therefore are to induce a lasting reduction in proteinuria The best-validated regimen is combination therapy with corticosteroids and cyclophosphamide Ponticelli regimen This treatment is superior to supportive therapy alone in inducing remissions and preventing long-term decline of kidney function in patients with idiopathic MN and persisting nephrotic syndrome However there are concerns about the use of cyclophosphamide since its use may be associated with adverse events leading to treatment interruption in about 9 of patients These adverse events include bone marrow suppression gonadal toxicity infections and oncogenic effects
Thus the availability of alternative therapies highly effective but with a greater safety profile is desirable
Recent human studies confirmed that MN is an autoimmune disease suggesting that the disease may be triggered by isotype specific autoantibodies directed against podocyte enzymes and podocyte receptors that are recognized as antigens including M-type phospholipase-2 receptorsPLA2R1 and thrombospondin type 1 domain-containing 7A THSD7A The podocyte expression of these autoantigens can trigger the production of specific antibodies and in situ deposits of immune complexes with consequent activation of complement cascade oxygen radicals and other inflammatory pathways leading to tissue injury and fibrosis Additional autoantibodies directed to podocyte neo-expressed cytoplasm proteins have been described including aldose reductase AR Mn-superoxide dismutase SOD2 and alpha-enolase alpha-ENO
However the mechanisms eliciting the expression of these neoantigens on podocytes and regulating the deposition of the auto-antibodies on the subepithelial surface of the glomerular basement membrane is not known
Considering the potential role of IgG antibodies in the pathogenesis of IMN B cell depletion may favourably impact the glomerular disease as reflected by a reduction in proteinuria The anti-CD20 monoclonal antibody Rituximab is a selective B cell depleting agent capable to maintain B cells undetectable for 3-12 months There is evidence that this strategy is effective in the treatment of other diseases in which B cells play a key role such as ANCA-related vasculitis and humoral allograft rejection Preliminary studies in IMN are promising with observational studies providing encouraging data in addition the drug seems well tolerated with minimal adverse events
Head-to-head comparisons between Rituximab and steroid plus ciclophosphamide in randomized clinical trials are missing
The investigators propose this study in order to test in a randomized controlled trial the hypothesis that selective B lymphocyte depletion obtained with Rituximab is more effective than cyclical corticosteroidalkylating-agent therapy in inducing long-term remission of proteinuria in patients undergoing the initial treatment of with IMN and nephrotic syndrome In addition since specific assay for the above-mentioned autoantibodies are now available the levels of these pathogenetic autoantibodies will be measured at baseline and during treatment Finally the study will compare the safety profile of steroid plus cyclophosphamide and Rituximab by evaluating the rate and severity of adverse events
Design and Power Considerations
The investigators hypothesized that the remission probability in the RTX arm will be greater than in the active comparator group superiority design Available data Ponticelli 1998 suggest that the probability of complete remission with standard therapy is 15 at one year
The investigators plan to enroll 70 patients in this pilot RCT This sample size will be able to detect with a power of 80 and a two-sided P of 005 an odds ratio of 3 ie change in probability from 015 to 045 - a very optimistic effect Smaller and likely more reasonable effects would require larger studies
The study will provide an estimate of this true effect if it exists
Adverse effects
Patients will be directly questioned every two weeks during the drug exposure and then at monthly intervals during follow-up In addition a contact number will be provided to the subjects to call if they experience any adverse affect or if they suspect adverse effect at any time between specific visits
Definition Of Proteinuric Status
UP urinary protein g24h
Complete remission CR UP 03 g
Partial remission PR Reduction in UP of 50 plus final UP 35 g but 03g
Non-response NR Reduction in UP of 50 includes increase in UP 50
Neither CR nor PR
Progression Proteinuria S creatinine increases by 50 over the baseline
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None