Belimumab and Rituximab Compared to Rituximab Alone for the Treatment of Primary Membranous Nephropathy (ITN080AI)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 58
- 试验地点
- 40
- 主要终点
- Proportion of Participants in Complete or Partial Remission (CR or PR) at Week 104.
研究概览
简要总结
The primary objective of this study is to evaluate the effectiveness of belimumab and intravenous rituximab co-administration at inducing a complete or partial remission (CR or PR) compared to rituximab alone in participants with primary membranous nephropathy.
Background:
Primary membranous nephropathy (MN) is among the most common causes of nephrotic syndrome in adults. MN affects individuals of all ages and races. The peak incidence of MN is in the fifth decade of life.
Primary MN is recognized to be an autoimmune disease, a disease where the body's own immune system causes damage to kidneys. This damage can cause the loss of too much protein in the urine.
Drugs used to treat MN aim to reduce the attack by one's own immune system on the kidneys by blocking inflammation and reducing the immune system's function. These drugs can have serious side effects and often do not cure the disease. There is a need for new treatments for MN that are better at improving the disease while reducing fewer treatment associated side effects.
In this study, researchers will evaluate if treatment with a combination of two different drugs, belimumab and rituximab, is effective at blocking the immune attacks on the kidney compared to rituximab alone. Rituximab works by decreasing a type of immune cell, called B cells. B cells are known to have a role in MN. Once these cells are removed, disease may become less active or even inactive. However, after stopping treatment, the body will make new B cells which may cause disease to become active again.
Belimumab works by decreasing the new B cells produced by the body and, may even change the type of new B cells subsequently produced. Belimumab is approved by the US Food and Drug Administration (FDA) to treat systemic lupus erythematosus (also referred to as lupus or SLE). Rituximab is approved by the FDA to treat some types of cancer, rheumatoid arthritis, and vasculitis. Neither rituximab nor belimumab is approved by the FDA to treat MN. Treatment with a combination of belimumab and rituximab has not been studied in individuals with MN, but has been tested in other autoimmune diseases, including lupus nephritis and Sjögren's syndrome.
详细描述
This trial is a two-part study (Part A and Part B) of adults with primary membranous nephropathy (MN), ages 18-75 inclusive. The study will be conducted at multiple sites in the United States and Canada.
Part A: Open-label Phase
Part A is an open-label, PK study to compare belimumab exposure between participants who have "low" proteinuria (≥ 4 to < 8 g/day) and "high" proteinuria (≥ 8 g/day) at Visit -1.
Initially Part A planned to enroll 20 individuals with primary MN: 10 individuals with low proteinuria and 10 individuals with high proteinuria. All Part A participants received 200 mg subcutaneous belimumab weekly, the initially approved dose of belimumab in SLE, for 52 doses (weeks 0-51). Trough serum belimumab levels would be obtained weekly following the first 4 doses of belimumab. All participants would receive rituximab 1000 mg IV at weeks 4 and 6, and are followed after the 52 week treatment period on no study medication until week 156.
Belimumab trough levels were to be analyzed after all 20 participants received the first 4 doses to compare the belimumab exposure between the low and high proteinuria groups. If the belimumab exposure was not comparable between the high and low proteinuria groups, the belimumab dose would be doubled to 400 mg/weekly for participants with high proteinuria in Part B. Dose determination for participants with high proteinuria in Part B would be made by an adjudication committee comprised of the Protocol Chair, NIAID Medical Monitor, ITN Clinical Trial Physician, and Rho Scientist, in consultation with the belimumab PK expert at GSK.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects must meet all of the following criteria to be eligible for this study-
- •Age 18 to 75 years inclusive
- •Diagnosis of one of the following:
- •Primary MN confirmed by a kidney biopsy within the past 5 years
- •Primary MN that is relapsing following a CR (Section 3.3.1) or PR (Section 3.3.2), confirmed by a kidney biopsy within the past 7 years
- •Nephrotic syndrome with eGFR > 60 mL/min/1.73m2 and no history of immunosuppressant treatment (e.g. glucocorticoids, cyclophosphamide, cyclosporine A, tacrolimus, B-cell depleting agent) for nephrotic syndrome, and without evidence of a secondary cause of nephrotic syndrome
- •Nephrotic syndrome and a contraindication to kidney biopsy (e.g., anticoagulation, solitary kidney, body habitus that increases the risk of biopsy, or other contraindication in the opinion of the investigator), and without evidence of a secondary cause of nephrotic syndrome
- •Serum anti-PLA2R positive
- •eGFR ≥ 30 mL/min/1.73m2 while on maximally tolerated RAS blockade
- •Proteinuria:
- •≥ 4 and < 8 g/day that has persisted for at least the previous 3 months while on maximally tolerated RAS blockade. Documentation of persistent proteinuria may be from a 24-hour collection or calculated from a spot urine collection. Or,
- •≥ 8 g/day while on maximally tolerated RAS blockade
- •Blood pressure while on maximally tolerated RAS blockade:
- •Systolic blood pressure ≤ 140 mmHg
- •Diastolic blood pressure ≤ 90 mmHg
排除标准
- •Subjects meeting any of the following criteria will not be eligible for this study-
- •Secondary cause of MN (e.g., SLE, drug, infection, malignancy) suggested by review of the patient's medical history and/or clinical presentation
- •Rituximab use within the previous 12 months
- •Rituximab use > 12 months ago:
- •With an undetectable CD19 B cell count, or
- •Did not result in a CR (Section 3.3.1) or PR (Section 3.3.2) with rituximab treatment alone (e.g., without other immunosuppressive or immunomodulatory therapy)
- •Use of anti-B cell therapy other than rituximab within the previous 12 months (or 5 half-lives, whichever is greater)
- •Cyclophosphamide use within the past 3 months
- •Use of other immunosuppressive medications such as cyclosporine or tacrolimus within the past 30 days
- •Use of systemic corticosteroids within the past 30 days
- •Use of any biologic investigational agent (defined as any drug not approved for sale in the country it is used) in the previous 12 months
- •Use of any non-biologic investigational agent in the past 30 days (or 5 half-lives, whichever is greater)
- •Poorly controlled diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥ 9.0%
- •Patients with diabetic glomerulopathy on renal biopsy that is:
- •Greater than Class I diabetic glomerulopathy, or
- •Class I diabetic glomerulopathy with a history of poor diabetic control (e.g., HbA1c ≥ 9.0%) since time of biopsy
- •Unstable kidney function defined as > 20% decrease in eGFR during the previous 3 months due to primary MN, as determined by the site investigator in consultation with the protocol chair
- •Decrease in proteinuria by 50% or more during the previous 12 months
- •WBC count < 3.0 x 103/μl
- •Absolute neutrophil count < 1.5 x 103/μl
- •Moderately severe anemia (hemoglobin < 9 g/dL)
- •History of primary immunodeficiency
- •Serum IgA < 10 mg/dL
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2x the upper limit of normal (ULN)
- •Positive HIV serology
- •Positive HCV serology, unless treated with anti-viral therapy with achievement of a sustained virologic response (undetectable viral load 24 weeks after cessation of therapy)
- •Evidence of current or prior infection with hepatitis B, as indicated by positive HBsAg or positive HBcAb
- •Positive QuantiFERON - TB Gold test results. PPD tuberculin test may be substituted for QuantiFERON - TB Gold test
- •History of lung disease with FVC < 70% predicted, DLCO < 70% predicted, or requiring supplemental oxygen
- •History of malignant neoplasm within the last 5 years except for basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the uterine cervix treated locally and with no evidence of metastatic disease for 3 years
- •Absence of individualized, age-appropriate cancer screening
- •Women of child-bearing potential who are pregnant, nursing, or unwilling to be sexually inactive or use FDA-approved contraception until week 104
- •Acute or chronic infection, including current use of suppressive therapy for chronic infection, hospitalization for treatment of infection in the past 60 days, or parenteral anti-microbial (including anti-bacterial, anti-viral, or anti-fungal agents) use in the past 60 days for infection
- •History of an anaphylactic reaction or known sensitivity or intolerance to parenteral administration of contrast agents, human or murine proteins, or monoclonal antibodies, including rituximab or belimumab
- •Evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months, or who in the investigator's judgment, poses a significant suicide risk
- •Evidence of current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence in the past 12 months
- •Vaccination with a live vaccine within the past 30 days
- •Other diseases or conditions or other clinically significant abnormal laboratory value which in the opinion of the investigator would put the patient at risk or confound the results of the study
- •Inability to comply with study and follow-up procedures
研究组 & 干预措施
Part A :High Proteinuria Group - Belimumab and Rituximab
Open-label pharmacokinetics (PK) phase.
Participants with high proteinuria classification will receive belimumab weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6.
High proteinuria classification: The excretion of ≥8 g/day of protein by the kidneys in adults. (Normal in adults: 0.15 g/day).
干预措施: Belimumab (Drug)
Part A: Low Proteinuria Group - Belimumab and Rituximab
Open-label pharmacokinetics (PK) phase.
Participants with low proteinuria classification will receive belimumab weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6.
Low proteinuria classification: The excretion of ≥4 to <8 g/day of protein by the kidneys in adults. (Normal in adults: 0.15 g/day).
干预措施: Belimumab (Drug)
Part A :High Proteinuria Group - Belimumab and Rituximab
Open-label pharmacokinetics (PK) phase.
Participants with high proteinuria classification will receive belimumab weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6.
High proteinuria classification: The excretion of ≥8 g/day of protein by the kidneys in adults. (Normal in adults: 0.15 g/day).
干预措施: Rituximab (Drug)
Part B: Placebo and Rituximab
Participants in the low proteinuria classification stratification, based upon Part A, and randomized to this arm, will receive subcutaneous belimumab placebo 400 mg (two 200 mg injections) once weekly from weeks 0-3, and then 200 mg once weekly from weeks 4-51. Participants will receive rituximab infusions at Weeks 4 and 6.
At week 30, participants will be assessed for a response to study treatment. Participants who meet at least two out of the following three criteria at week 30 will be considered to have an inadequate response to study treatment and receive a second course of rituximab (defined as 1000 mg IV given at weeks 34 and 36):
- Anti-PLA2R level is ≥ 25% of baseline
- Proteinuria is ≥ 50% of baseline
- Serum albumin is < 2.8 g/dL
干预措施: Placebo for Belimumab (Drug)
Part A: Low Proteinuria Group - Belimumab and Rituximab
Open-label pharmacokinetics (PK) phase.
Participants with low proteinuria classification will receive belimumab weekly subcutaneous injections (52 doses administered Week 0 to Week 51) and rituximab infusions at Weeks 4 and 6.
Low proteinuria classification: The excretion of ≥4 to <8 g/day of protein by the kidneys in adults. (Normal in adults: 0.15 g/day).
干预措施: Rituximab (Drug)
Part B: Belimumab and Rituximab
Participants in the low proteinuria classification stratification, based upon Part A, and randomized to this arm, will receive subcutaneous belimumab 400 mg (two 200 mg injections) once weekly from weeks 0-3, and then 200 mg once weekly from weeks 4-51. Participants will receive rituximab infusions at Weeks 4 and 6.
At week 30, participants will be assessed for a response to study treatment. Participants who meet at least two out of the following three criteria at week 30 will be considered to have an inadequate response to study treatment and receive a second course of rituximab (defined as 1000 mg IV given at weeks 34 and 36):
- Anti-PLA2R level is ≥ 25% of baseline
- Proteinuria is ≥ 50% of baseline
- Serum albumin is < 2.8 g/dL
干预措施: Belimumab (Drug)
Part B: Belimumab and Rituximab
Participants in the low proteinuria classification stratification, based upon Part A, and randomized to this arm, will receive subcutaneous belimumab 400 mg (two 200 mg injections) once weekly from weeks 0-3, and then 200 mg once weekly from weeks 4-51. Participants will receive rituximab infusions at Weeks 4 and 6.
At week 30, participants will be assessed for a response to study treatment. Participants who meet at least two out of the following three criteria at week 30 will be considered to have an inadequate response to study treatment and receive a second course of rituximab (defined as 1000 mg IV given at weeks 34 and 36):
- Anti-PLA2R level is ≥ 25% of baseline
- Proteinuria is ≥ 50% of baseline
- Serum albumin is < 2.8 g/dL
干预措施: Rituximab (Drug)
Part B: Placebo and Rituximab
Participants in the low proteinuria classification stratification, based upon Part A, and randomized to this arm, will receive subcutaneous belimumab placebo 400 mg (two 200 mg injections) once weekly from weeks 0-3, and then 200 mg once weekly from weeks 4-51. Participants will receive rituximab infusions at Weeks 4 and 6.
At week 30, participants will be assessed for a response to study treatment. Participants who meet at least two out of the following three criteria at week 30 will be considered to have an inadequate response to study treatment and receive a second course of rituximab (defined as 1000 mg IV given at weeks 34 and 36):
- Anti-PLA2R level is ≥ 25% of baseline
- Proteinuria is ≥ 50% of baseline
- Serum albumin is < 2.8 g/dL
干预措施: Rituximab (Drug)
结局指标
主要结局
Proportion of Participants in Complete or Partial Remission (CR or PR) at Week 104.
时间窗: Week 104
. CR is defined as proteinuria of ≤ 0.3 g/day with a serum albumin ≥ 3.5 g/dL. PR is defined as a 50% or greater decrease in proteinuria compared to baseline and proteinuria \< 3.5 g/day glomerular filtration rate (eGFR) from baseline.
次要结局
- Proportion of Participants in Complete or Partial Remission (CR or PR) at Week 52 and Week 156.(Week 52, Week 156)
- Proportion of Participants in Complete Remission (CR) at Week 52, Week 104 and Week 156.(Week 52, Week 104, Week 156)
- Proportion of Participants in PR but not CR at Week 52, Week 104, Week 156.(Week 52, Week 104, Week 156)
- Time to Relapse for Participants who Achieved CR or PR.(Up to 156 Weeks (3 Years))
- Level of Proteinuria at Week 52, Week 104 and Week 156.(Week 52, Week 104, Week 156)
- Proportion of participants meeting criteria for a second course of rituximab at week 30(Week 30)
- Proportion of Participants in CR or PR and Anti-PLA2R Negative at week 52, 104, and 156(Week 52, Week 104, Week 156)
- Proportion of Participants in PR and Anti-PLA2R Negative at week 52, 104, and 156(Week 52, Week 104, Week 156)
- Proportion of participants in PR but not CR and who are anti-PLA2R negative at week 52, 104, and 156(Week 52, Week104, Week 156)
- Proportion of Participants who are Anti-PLA2R Negative at week 52, 104, and 156(Week 52, Week104, Week 156)
- Quality of life at weeks 52, 104, and 156(Week 52, Week104, Week 156)
- Incidence of Adverse Events (AEs).(Week 0 to Week 52)
- Incidence of Grade 3 or Higher Infectious Adverse Events (AEs): By Treatment Group(Week 0 to Week 52)
- Incidence of Arterial Thromboembolic Events: By Treatment Group(Week 0 to Week 52)
- Incidence of Venous Thromboembolic Events: By Treatment Group(Week 0 to Week 52)