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A European multicentre and open-label controlled randomized trial to evaluate the efficacy of Sequential treatment with TAcrolimus-Rituximab versus steroids plus cyclophosphamide in patients with primary MEmbranous Nephropathy: the STARMEN study.

ABSTRACT: BACKGROUND:Patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome have a high risk of progression to end-stage renal disease. The Ponticelli protocol (steroids with alkylating agents) is the most effective immunosuppressive therapy for this condition, but it has severe adverse effects. Tacrolimus and rituximab have demonstrated efficacy for remission of nephrotic syndrome in MN with a safer profile. However, the published evidence is largely based on small or short-term observational studies, historical cohorts, comparisons with conservative therapy or clinical trials without appropriate control groups, and there is no head-to-head comparison with the Ponticelli protocol. METHODS:The STARMEN randomized clinical trial will compare the efficacy of sequential tacrolimus-rituximab therapy with a modified Ponticelli protocol (steroids plus cyclophosphamide). The trial will also evaluate the role of antibodies against the M-type phospholipase A2 receptor (anti-PLA2R) and other antibodies as markers of response to treatment and long-term prognosis. RESULTS:The trial has already started with 23 patients having been enrolled as of 1 April 2015, an estimated 21.7% of the estimated sample.

SUBMITTER: Rojas-Rivera J

PROVIDER: S-EPMC4581392 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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A European multicentre and open-label controlled randomized trial to evaluate the efficacy of Sequential treatment with TAcrolimus-Rituximab versus steroids plus cyclophosphamide in patients with primary MEmbranous Nephropathy: the STARMEN study.

Rojas-Rivera Jorge J Fernández-Juárez Gema G Ortiz Alberto A Hofstra Julia J Gesualdo Loreto L Tesar Vladimir V Wetzels Jack J Segarra Alfons A Egido Jesus J Praga Manuel M

Clinical kidney journal 20150924 5

<h4>Background</h4>Patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome have a high risk of progression to end-stage renal disease. The Ponticelli protocol (steroids with alkylating agents) is the most effective immunosuppressive therapy for this condition, but it has severe adverse effects. Tacrolimus and rituximab have demonstrated efficacy for remission of nephrotic syndrome in MN with a safer profile. However, the published evidence is largely based on small or ...[more]

PMID: 26413273

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Project description:Background: Rituximab (RTX) is a monoclonal antibody that selectively targets CD20 and is frequently used in the treatment of membranous nephropathy (MN). Analysis of the therapeutic efficacy and safety of RTX in treating MN in practice and a comparative pharmacoeconomic analysis of the RTX and traditional tacrolimus (TAC) regimens can provide valuable insights to aid decision-making by the government and relevant medical insurance departments. Methods: We conducted a statistical analysis of medical records from patients diagnosed with MN who underwent RTX treatment between 1 January 2019 and 1 January 2023. The TAC data were obtained from the clinical literature. The efficacy rates and incidence of adverse effects (AEs) were calculated to compare the efficacy and safety of RTX and TAC. Based on the patient's disease status, we developed a Markov model to compare the total cost, remission rate, and incremental cost-effectiveness ratio (ICER) of the two regimens. Both univariate and probability sensitivity analyses were performed to validate the stability of the developed model. Results: The RTX group enrolled 53 patients with MN, and the 12-month overall efficacy rate was not significantly different from that of the TAC group with 35 patients (86.79% vs. 71.4%, p = 0.0131); however, the relapse rate was significantly lower in the RTX group (3.77% vs. 22.8%, p = 0.016). The RTX group demonstrated no severe AEs (SAEs), while the TAC group demonstrated six cases of SAEs, including 4 cases of severe pneumonia, 1 case of lung abscess and 1 case of interstitial lung disease, accounting for 7.89% of traditional tacrolimus-treated patients. The baseline analysis results revealed that over a 5-year post-treatment period, RTX increased quality-adjusted life years (QALYs) by 0.058 and costs by ¥7,341. Assuming three times the 2022 domestic gross domestic product as the willingness-to-pay (WTP) threshold per QALY, the ICER of RTX compared to TAC was ¥124,631.14/QALY, which is less than the WTP threshold of ¥257,094/QALY, indicating that RTX treatment is approximately two times more cost-effective compared to TAC. Conclusion: The current analysis indicates that despite the expensive unit price of RTX, it remains a cost-effective treatment option for MN compared to TAC.

Project description:Membranous Nephropathy (MN) is an autoimmune disease associated with antibodies against podocyte proteins: M-type phospholipase A2 receptor (PLA2R1) or thrombospondin type-1 domain-containing 7A (THSD7A) in 70 and 3% of patients, respectively. Antibody titer is correlated with disease activity: rising during active disease and decreasing before remission. Therefore, decreasing PLA2R1-Antibodies titer has become an important goal of therapy. Rituximab a chimeric monoclonal antibody induces remission in 60-80% of primary MN patients. All monoclonal antibodies such as rituximab can elicit antidrug antibodies, which may interfere with therapeutic response. We aim to analyze the relevance of anti-rituximab antibodies on the outcome of MN after a first course of rituximab. Forty-four MN patients were included and treated with two 1 g infusions of rituximab at 2-weeks interval. Anti-rituximab antibodies, CD19 count, and clinical response were analyzed. Then, we (i) analyzed the association of anti-rituximab antibodies at month-6 with response to treatment: remission, relapse and the need for another rituximab course; (ii) confirmed if anti-rituximab antibodies could neutralize rituximab B-cells depletion; and (iii) tested whether anti-rituximab antibodies could cross-inhibit new humanized anti-CD20 therapies. Anti-rituximab antibodies were detected in 10 patients (23%). Seventeen patients received a second rituximab course after a median time of 12 months (7-12), following nine cases of resistance and eight relapses. Anti-rituximab antibodies were significantly associated with faster B-cell reconstitution at month-6 (75 [57-89] vs. 2 [0-41] cells/μl, p = 0.006), higher proteinuria 12 months after rituximab infusion (1.7 [0.7; 5.8] vs. 0.6 [0.2; 3.4], p = 0.03) and before treatment modification (3.5 [1.6; 7.1] vs. 1.7 [0.2; 1.7] p = 0.0004). Remission rate 6 months after rituximab was not different according to anti-rituximab status (p > 0.99) but the rate of relapse was significantly higher for patients with anti-rituximab antibodies (p < 0.001). These patients required more frequently a second course of rituximab infusions (7/10 vs. 10/34, p = 0.03). Anti-rituximab antibodies neutralized rituximab activity in 8/10 patients and cross-reacted with other humanized monoclonal antibodies in only two patients. Three patients with anti-rituximab antibodies were successfully treated with ofatumumab. Anti-rituximab antibodies could neutralize rituximab B cells cytotoxicity and impact clinical outcome of MN patients. Humanized anti-CD20 seems to be a satisfying therapeutic alternative for patients with anti-rituximab antibodies and resistant or relapsing MN.

Dataset Information

A European multicentre and open-label controlled randomized trial to evaluate the efficacy of Sequential treatment with TAcrolimus-Rituximab versus steroids plus cyclophosphamide in patients with primary MEmbranous Nephropathy: the STARMEN study.

Publications

A European multicentre and open-label controlled randomized trial to evaluate the efficacy of Sequential treatment with TAcrolimus-Rituximab versus steroids plus cyclophosphamide in patients with primary MEmbranous Nephropathy: the STARMEN study.

Similar Datasets

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