A Phase 3 Superiority Study Comparing the Safety and Efficacy of SNP-ACTH (1-39) Gel compared to Rituximab and FDA approved biosimilars in Adults with Primary Membranous Nephropathy (PMN) in a Two-Phase Adaptive Trial Design.
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 148
- 试验地点
- 16
- 主要终点
- Phase 3 a - To determine the optimal dose that will be used in the Phase 3b part of the study
研究概览
简要总结
This head-to-head, open-label, 2-phase superiority trial compares SNP-ACTH (1-39) Gel to rituximab in treatment of PMN that commences with an adaptive trial design for dose finding. The trial will be divided into two parts: Phase 3a and Phase 3b.
Dose finding Phase 3a part of the study will enroll 16 patients randomized to 2 different dose levels of SNP-ACTH (1-39) Gel treatment for 12 months. Dose levels will be:
· 8 patients at 3mg SNP-ACTH Gel sc injection 3 times per week;
· 8 patients at 5mg SNP-ACTH Gel sc injection 3 times per week
Data from the Phase 3a part of the study will be assessed at regular intervals (at months 2, 3, 4, 5, 6, 9, 12) and will inform the dose selection for the Phase 3b. The optimal dose will be determined based on a risk/benefit assessment from data obtained from the Phase 3a part of the study, with the earliest assessment being conducted after all patients have completed at least 2 months of therapy.
The Phase 3b part of the study will enroll 132 patients randomized 1:1 to either 12 months of 1g Rituximab therapy (2 treatment cycles at month 1 and month 6) or 12 months of SNP-ACTH (1-39) Gel treatment at the dose level determined in the Phase 3a.
This is an open label adaptive trial. Patients who have been randomized to SNP-ACTH (1-39) Gel who have not demonstrated an improvement in proteinuria levels or anti-PLA2R antibody levels (if applicable) after 4 months of treatment, could, at the option of the treating physician, be removed from the trial and provided an alternative treatment.
The number of randomized patients in the Phase 3b (N=132) was determined by the estimated CR rates of patients after the 12-month treatment period (45% for SNP-ACTH (1-39) Gel vs 18% for rituximab), where the durability of CR is confirmed at month 24 (12-month treatment period plus, for those patients achieving a CR at month 12, a 12-month follow up period to confirm durability of response).
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •To be eligible for the study, an individual must meet all the following criteria:
- •â‰¥ 18 years old
- •Biopsy-proven membranous glomerulonephritis or a diagnosis of MN and a positive anti PLA2R antibody test.
- •Patients classified to be at a High Risk for progressive loss of kidney function, as defined by KDIGO 2021-Glomerular Diseases Guideline a.
- •eGFR of <60 mL/min/1.73 m2 and/or proteinuria >8 g/d for >6 months or b.
- •Normal eGFR, proteinuria >3.5 g/d and no decrease >50% after 6 months of conservative therapy with ACEi / ARB and at least one of the following: PLA2R antibody levels >50 RU/ml, serum albumin <25 g/L, urinary α1-microglobin >40 µg/min, urinary β2-microglobin > 250 mg/d c.
- •Patient meeting above criteria as per PI discretion as High Risk Patient.
- •eGFR by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula ≥40 mL/min/1.73 m2
- •Stable dose of blood pressure (BP) medication for at least 1 month
- •Prophylactic anticoagulation should be employed in patients when the risk of thromboembolism exceeds the estimated patient-specific risks of an anticoagulation
- •Life expectancy > 24 months
- •Vaccinated for coronavirus disease 2019 (Covid-19) before randomization.
- •Vision sufficient to measure a syringe volume or a caretaker who can do the same.
- •Patients who have had CR (Complete Remission) or PR (Partial Remission) in response to immunosuppressive therapy, however if relapsed can participate in the study if they have received high dose glucocorticoids, calcineurin inhibitors, mycophenolate Mofetil (MMF) for more than 3 months since their last dose.
- •Patients who have had CR or PR in response to immunosuppressive therapy, however if relapsed can participate in the study if they have received chlorambucil or CYC (cyclophosphamide) more than 6 months since their last dose.
- •Patients who have had CR or PR in response to immunosuppressive therapy, but then relapsed can participate in the study if it has been more than 12 months since their last dose of Rituximab.
- •If all Inclusion Points are met but patient has not been on a stable dose of ACEi (angiotensin-converting enzyme inhibitor ) or ARB (angiotensin receptor blocker ) for 90 days, he/she will be asked to return for screening once the dose of ACEi or ARB has not changed in 90 days.
排除标准
- •An individual who meets any of the following criteria will not be enrolled in the study:
- •Secondary membranous nephropathy as defined by history, physical exam, kidney biopsy results or serologies.
- •A confirmed diagnosis of diabetes.
- •Patient with fasting blood glucose >126 mg/dL hemoglobin A1C will be tested, If the A1C level is > 6.5% and the patient will be excluded
- •Renal biopsy showing glomerular disease other than MN or clinical manifestations, history, serology, or biopsy findings
- •Patients who have had a 50% or greater decrease in their baseline proteinuria levels within the last year in the absence of IS or cytotoxic therapy
- •Patients who have had a ≥ 50% reduction in serum titers of PLA2R (phospholipase A2 receptor) auto-antibody within 1 year before screening.
- •Patients who were non responders to previous IS treatments
- •Patients who must be initiated on drugs likely to affect renal function
- •Blood serologies suggestive of lupus nephritis or glomerular diseases other than PMN.
- •Active infectious disease either clinically or, serologically, or culture based.
- •Patients with active hepatitis.
- •Past clinical history of Hepatitis B without anti-HBs antibodies.
- •Chronic Hepatitis C (HCV) with no successful virologic curative therapy.
- •History of cancer in remission for < 3 years excluding basal cell skin cancer and squamous cell skin cancer under surveillance by a dermatologist.
- •Scleroderma
- •Osteoporosis
- •Latent tuberculosis or tuberculin positivity as shown by the QuantiFERON Gold test.
- •Ocular herpes simplex present or history thereof.
- •Surgery within 1 month of study entry.
- •Uncompensated congestive heart failure
- •History of sensitivity to proteins of porcine origin.
- •Myasthenia gravis
- •Untreated hypothyroidism
- •Clinical liver disease diagnosed by a health care provider by signs and symptoms or biochemical liver disease manifest 27.
结局指标
主要结局
Phase 3 a - To determine the optimal dose that will be used in the Phase 3b part of the study
时间窗: Phase 3 a - 13.5 month | Phase 3 b - 24 month
This dose finding part of the study will enroll a total of 16 patients randomized to 2 different dose levels of SNP-ACTH (1-39) Gel treatment for up to 12 months. Dose levels will be:
时间窗: Phase 3 a - 13.5 month | Phase 3 b - 24 month
• 8 patients at 3 mg SNP-ACTH Gel sc injection 3 times per week;
时间窗: Phase 3 a - 13.5 month | Phase 3 b - 24 month
• 8 patients at 5 mg SNP-ACTH Gel sc injection 3 times per week;
时间窗: Phase 3 a - 13.5 month | Phase 3 b - 24 month
Phase 3 b - To assess the efficacy of SNP-ACTH (1-39) Gel relative to rituximab in inducing a CR of proteinuria at month 12 and confirming durability of CR at month 24.
时间窗: Phase 3 a - 13.5 month | Phase 3 b - 24 month
次要结局
- 1. To demonstrate the safety and tolerability of SNP-ACTH (1-39) Gel.(2. To assess the efficacy of SNP-ACTH (1-39) Gel relative to rituximab in inducing a CR or PR of proteinuria at month 12.)