2024-515857-93-00招募中2 期
Obinutuzumab for primary membranous nephropathy: a pilot study in patients with rituximab-resistant or rituximab-dependent nephrotic syndrome and in patients intolerant to rituximab (the ORION study)
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Incidence of complete or partial remission of nephrotic syndrome at 12 months from Obinutuzumab treatment in (1) Rituximab-Intolerant patients and (2) Rituximab-Resistant and Rituximab-Dependent patients considered separately and as a whole.
研究概览
简要总结
To evaluate whether rescue therapy with Obinutuzumab may induce remission of MN-related nephrotic syndrome in (1) Rituximab-Intolerant patients and in (2) Rituximab-Resistant or Rituximab-Dependent patients, and whether this drug is safe and well tolerated in these cohorts.
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 否
入选标准
- •Adults (≥18 years old) on the day of signing informed consent.
- •Compliance with an effective contraception without interruption, from 28 days before treatment start up to 18 months after treatment discontinuation, agreeing not to donate semen during treatment and for 18 months after discontinuation (if the patient is male), or to undergo pregnancy test during the course of the study (if the patient is female). (According to 2014 CTFG “Recommendations related to contraception and pregnancy testing in clinical trials”).
- •Biopsy-proven primary membranous nephropathy.
- •Availability of a recent (over the last six months) diagnostic kidney biopsy to confirm the diagnosis of membranous nephropathy and quantify the severity of chronic changes and the number of glomerular podocytes.
- •High-risk of progression to end-stage kidney disease due to persistent nephrotic-range proteinuria (urinary protein excretion > 3.5 g/24-hours as a median of three consecutive measurements) despite background treatment with RASinhibitors (ACEi and/or ARBs) at the maximum tolerated doses for at least six months before inclusion.
- •Failure to definitively and effectively respond to rituximab therapy because of RITUXIMAB-INTOLERANCE: i.e. any previous severe hypersensitivity reaction to rituximab (acute grade III or IV adverse reactions requiring advanced care, or late reactions including delayed serum sickness syndrome) that, independent of response to treatment, preclude further exposure to the drug
- •Failure to definitively and effectively respond to rituximab therapy because of RITUXIMAB-RESISTANCE: no evidence of nephrotic syndrome complete remission (24-hour proteinuria < 0.3 g/day, normal serum albumin and stable renal function) or partial remission (24-hour proteinuria < 3.5 g/day with > 50% decrease from baseline, normal serum albumin and stable renal function) along with detectable circulating CD19+ lymphocytes for at least 6 months after rituximab administration
- •Failure to definitively and effectively respond to rituximab therapy because of RITUXIMAB-DEPENDENCE: frequently-relapsing nephrotic syndrome (≥ 2 relapses) with nephrotic-range proteinuria for ≥ 50% of time in the 24 months preceding enrolment in patients who achieved initial remission after rituximab administration
- •Estimated GFR/eGFR) ≥30 mL/min/1.73 m2 (calculated using the CKD-EPI equation) or qualified endogenous creatinine clearance ≥30 mL/min/1.73 m2 based on 24-hour urine collection during screening.
- •Ability to understand and provide a valid written consent to the study according to the guidelines of the Declaration of Helsinki.
排除标准
- •Secondary forms of membranous nephropathy (associated with systemic lupus erythematosus, active hepatitis B, malignancy, drugs such as gold salts and penicillamine, and others).
- •Known history of drug induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extra-hepatic obstruction caused by cholelithiasis, cirrhosis of the liver or portal hypertension.
- •Pregnancy or breast-feeding.
- •Childbearing potential and unwillingness or impossibility to comply with a scientifically acceptable birth-control method (According to 2014 CTFG “Recommendations related to contraception and pregnancy testing in clinical trials”).
- •Legal incapacity, limited legal capacity, intellectual disability, uncooperative attitude or any other evidence that the patient will not be able to understand the study aims and procedures.
- •Rituximab treatment or any other prolonged (i.e. for more than two weeks) immunosuppressive treatment in the 6 months preceding anti-CD20 infusion.
- •Uncontrolled hypertension (systolic BP ≥160 and/or diastolic BP >90 mmHg despite therapy).
- •Active bacterial, viral and/or fungal infections.
- •Seropositivity for HIV, regardless of viral load.
- •Active or recent (< 5 years before enrolment) history of malignancy.
- •Known hypersensitivity or allergy to any of the medicaments under investigation.
- •Any other serious medical condition, uncontrolled intercurrent illness or laboratory abnormality that, according to the investigator’s judgement, would constitute an unacceptable risk of premature discontinuation from the study.
- •Patients with previous hepatitis B virus infection (seropositive for anti-HBcAb), planning a vaccination with live virus vaccines.
结局指标
主要结局
Incidence of complete or partial remission of nephrotic syndrome at 12 months from Obinutuzumab treatment in (1) Rituximab-Intolerant patients and (2) Rituximab-Resistant and Rituximab-Dependent patients considered separately and as a whole.
Incidence of complete or partial remission of nephrotic syndrome at 12 months from Obinutuzumab treatment in (1) Rituximab-Intolerant patients and (2) Rituximab-Resistant and Rituximab-Dependent patients considered separately and as a whole.
Incidence of serious and non-serious adverse events (in particular, infusion-related reactions (IRRs)) during and after Obinutuzumab treatment in (1) Rituximab-Intolerant patients and (2) Rituximab-Resistant and Rituximab- Dependent patients considered separately and as a whole.
Incidence of serious and non-serious adverse events (in particular, infusion-related reactions (IRRs)) during and after Obinutuzumab treatment in (1) Rituximab-Intolerant patients and (2) Rituximab-Resistant and Rituximab- Dependent patients considered separately and as a whole.
次要结局
- To evaluate, in the both cohorts, the incidence of complete or partial remission of nephrotic syndrome at 6 and 24 months from Obinutuzumab treatment.
- To evaluate, in the both cohorts, the incidence and time to nephrotic syndrome relapse in patients who previously achieved complete or partial remission during the study.
- To evaluate, in the both cohorts, the incidence and time to complete immunologic remission (defined as anti-PLA2R levels below the positivity threshold of the assay) in anti-PLA2R positive patients during the whole follow- up period.
- To evaluate, in the both cohorts, the change in proteinuria and serum anti-PLA2R antibody levels (in anti-PLA2R positive patients) considered as continuous variables at each time point during the follow-up as compared to baseline.
- To evaluate, in the both cohorts, the change in measured GFR, albumin and IgG fractional clearances at 6 and 12, 18 and 24 months from treatment as compared to baseline.
- To evaluate, in the both cohorts, the safety parameters including clinical and laboratory tests evaluated at each time point during the follow-up and any intercurrent serious and non-serious adverse event.
- To evaluate, in the both cohorts, the changes in peripheral leukocyte subpopulations (B, T, NK cells) and BAFF levels at every time point included in the study flow-chart.
- To evaluate, in both the cohorts, the changes in the number of podocytes lost in the urine (podocituria) evaluated at each time point, and relationships between podocituria and proteinuria or the number of glomerular podocytes in baseline and repeat, optional patients’ renal biopsies.
- To evaluate, in the both cohorts, patient health-related quality of life as measured by means of the SF-12 questionnaire.
研究者
orion@marionegri.it
Scientific
Istituto Di Ricerche Farmacologiche Mario Negri
研究点 (2)
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