Obinutuzumab Induced Decreases of PLA2Rab in MN: a Pilot Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Disappearance rate of PLA2R antibodies
研究概览
简要总结
Objective: To assess the disappearance rate (half-life) of anti-PLA2R antibodies in high-risk primary membranous nephropathy (pMN) patients treated with obinutuzumab (OBI), and to evaluate immunological and clinical remission, adverse events, and quality of life.
Design: Open-label, single-center, prospective pilot intervention study conducted at Radboud University Medical Center.
Population: 20 adult patients with high-risk PMN, defined by proteinuria ≥3.5 g/24h despite 6 months of supportive treatment with ACE inhibitors or ARBs.
Intervention: OBI 1000 mg on days 1 and 15, with two additional infusions after 6 months if anti-PLA2R antibody levels remain positive and proteinuria exceeds 2 g/24h.
Follow-up: Patients were monitored at baseline, and at weeks 1, 2, 4, 8, 12, 24, 37, and 52.
详细描述
Rationale:
Primary membranous nephropathy (PMN) is a leading cause of nephrotic syndrome in adults and is characterized by subepithelial immune complex deposits in the glomerular basement membrane. The disease is associated with circulating auto-antibodies targeting the M-type phospholipase A2 receptor (PLA2R), present in 70-80% of patients.
Despite advances in understanding its pathogenesis, the optimal treatment of PMN remains suboptimal; as the response to immunosuppressive therapy is often limited and slow. When considering treatment in PMN, the overall response rate is important, but in high-risk PMN patients the rapidity of response is even more important. As so, ideally we should be able to identify non-responders and slow-responders before or within a few months after start of therapy. A regimen consisting of rituximab (RTX), cyclophosphamide (CP) and steroids (triple therapy) has proven that a rapid immunological and clinical remission in PMN patients is possible. Obinutuzumab (OBI), a next-generation fully humanized anti-CD20 monoclonal antibody, offers enhanced B cell depletion through greater antibody-dependent cytotoxicity and reduced complement activation when compared to RTX. Retrospective studies suggests that OBI demonstrates superior efficacy in the treatment of treatment-refractory PMN patients compared to RTX, while maintaining a similar safety profile. It has been proven effective in the treatment of proliferative lupus nephritis compared to standard-of-care. These studies not only suggested better overall response, but the data also indicated a more rapid onset of remission.
Objective:
The primary objective of this pilot study is to calculate disappearance rate (half-life) of anti-PLA2R antibodies in PMN patients treated with OBI. We hypothesize that OBI monotherapy might be able to induce a rapid immunological response comparable to triple therapy in high-risk PLA2Rab-associated PMN patients. Secondary outcome measures are immunological remission, complete or partial clinical remission, adverse events and quality of life.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years.
- •Diagnosis of PMN, confirmed by:
- •Kidney biopsy or
- •Positive serum PLA2Rab test either by IFT and/or ELISA)
- •Serum PLA2Rab titer > 80 RU/ml
- •Proteinuria ≥ 3.5 g/24h despite supportive treatment for at least 6 months with a maximally tolerated and stable dose of ACE-i or ARB.
- •Serum albumin < 30 g/l measured by BCP assay.
- •eGFR ≥ 30 ml/min/1.73m
- •Treatment with immunosuppression is warranted, as determined by the treating physician.
排除标准
- •Secondary MN (e.g., hepatitis B or C infection, human immunodeficiency virus infection, active infection, systemic lupus erythematosus, sarcoidosis, IgG4-related, drug-induced, malignancy).
- •RTX within 12 months prior to inclusion.
- •CNI within 2 months prior to inclusion.
- •Treatment with other immunosuppressive drugs within 6 months prior to inclusion.
- •Proteinuria must not have decreased by > 50% over 6 months whilst taking ACEi/ARB.
- •Life-threatening nephrotic syndrome resistant to treatment.
- •> 20% increase in serum creatinine not otherwise explained during antiproteinuric supportive treatment.
- •Pregnancy or breastfeeding. Women of childbearing age and male patients with female partners of childbearing potential not willing to use contraception throughout the study and for at least 6 months after the last dose of obinutuzumab.
- •Suspected or known hypersensitivity, allergy, and/or immunogenic reaction history to monoclonal antibodies, corticosteroid, cyclophosphamide, any of their ingredients, and any other drugs from these same pharmacotherapeutic groups.
- •Known active infection of any kind or recent major episode of infection.
- •Any disorder or condition which might pose an unacceptable risk to patient's safety and well-being that might interfere with completion of the study.
- •Inability to understand or comply with the requirements of the study.
- •Incapable of recognizing the nature, significance, and scope of the clinical trial or giving consent even with a legal representative.
- •Use of an investigational agent.
研究组 & 干预措施
Treatment with obinutuzumab.
干预措施: Obinutuzumab administration (Drug)
结局指标
主要结局
Disappearance rate of PLA2R antibodies
时间窗: From baseline to 52 weeks after the first obinutuzumab infusion.
To calculate the disappearance rate (half-life) of anti-PLA2R antibodies. Serum PLA2R antibodies will be measured at baseline, 1, 2, 4, 8, 12, 24 37 and 52 weeks after obinutuzumab infusions.
次要结局
- Immunological remission(From baseline to 52 weeks after the last obinutuzumab infusion.)
- Clinical efficacy(From baseline to 52 weeks after the last obinutuzumab infusion.)
- Adverse events(From baseline to 52 weeks after the last obinutuzumab infusion.)
- Quality of life during treatment(From baseline to 52 weeks after the last obinutuzumab infusion.)