Clinical Trial: Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Randomized Controlled Trial of Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy

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-

Detailed Summary:

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, inf
Sponsor: Azienda Ospedaliera Spedali Civili di Brescia

Current Primary Outcome: change in probability of complete remission (proteinuria < 0.3 g/day) Primary Outcome Measures The primary outcome measure is the change in probability of complete remission (proteinuria < 0.3 g/day) at one year (see Design and power considerations). [ Time Frame: 1 year ]

The primary outcome measure is the change in probability of complete remission (proteinuria < 0.3 g/day) at one year


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Change from baseline in proteinuria [ Time Frame: from randomization up to 36 months ]
    Change from baseline in proteinuria at 6,12, 18, 24 and 36 months following treatment
  • CR (Complete Remission) or PR (Partial Remission: Reduction in UP of > 50% plus final UP ≤ 3.5 g but >0.3g ) [ Time Frame: from randomization up to 36 months ]
    CR (Complete Remission) or PR (Partial Remission) at 6, 12, 18, 24, and 36 months
  • Estimated Glomerular filtration rate (MDRD formula) [ Time Frame: from randomization up to 36 months ]
    Estimated Glomerular filtration rate (MDRD formula) at 6, 12, 18, 24, and 36 months
  • Serum creatinine level (mg/dl) [ Time Frame: from randomization up to 36 months ]
    Serum creatinine level (mg/dl) at 6, 12, 18, 24, and 36 months
  • Frequency of and time to relapse of nephrotic syndrome [ Time Frame: up to 36 months ]
    Frequency of and time to relapse of nephrotic syndrome
  • Frequency of auto-antibodies and its relation to therapy and proteinuria response in a subgroup of patients [ Time Frame: baseline and after treatment (day 3, month 1, 3, 6 , 6 and 12) ]
    Frequency of auto-antibodies and its relation to therapy and proteinuria response in a subgroup of patients at baseline and 3 days, 1 month, 3 months, 6 months and 12 months after treatment
  • serious side effects: Death, Life-threatening event, Hospitalization, Disability in the patient's body function/structure or physical activity or quality of life, Congenital anomaly, Intervention to prevent permanent impairment or damage) [ Time Frame: up to 36 months ]
    serious side effects: Death, Life-threatening event, Hospitalization, Disability in the patient's body function/structure or physical activity or quality of life, Congenital anomaly, Intervention to prevent permanent impairment or damage.


Original Secondary Outcome: Same as current

Information By: Azienda Ospedaliera Spedali Civili di Brescia

Dates:
Date Received: January 9, 2017
Date Started: January 2012
Date Completion: December 2019
Last Updated: January 10, 2017
Last Verified: January 2017