A Randomized, Open-label, Two Arm, Parallel Group, Proof-of-concept Clinical Trial to Investigate the Efficacy and Safety of LNP023 Compared With Rituximab in the Treatment of Subjects With Idiopathic Membranous Nephropathy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- Ratio Between Baseline Urine Protein Creatinine Ratio (UPCR) and Urine Protein Creatinine Ratio at 24 Weeks of Treatment (From 24h Urine Collection)
研究概览
简要总结
This was a randomized, open-label, two arm, parallel group, proof-of-concept, nonconfirmatory study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with Idiopathic (primary) membranous nephropathy (iMN) who are at high risk of disease progression defined on the basis of anti- Phospholipase A2 Receptor (PLA2R) antibody titer ≥ 60 RU/mL and proteinuria with urine protein (UP) ≥ 3.5 g/24h.
详细描述
The overall study was planned for a total of 65 weeks and included:
- A screening phase of up to 12 weeks
- A treatment phase of up to 24 weeks
- A post-treatment follow-up period of 29 weeks
As per protocol amendment V01, subjects were randomized 1:1 to LNP023 (investigational drug) or Rituximab (comparator) and followed the below dosing schedule:
- LNP023 50mg orally b.i.d. for 4 weeks followed by 200mg orally b.i.d. for 20 weeks
- Rituximab 1g i.v. infusions on Day 1 and Day 15
Initially, per protocol V00, subjects were planned to be randomized in a 1:1:1 ratio to 3 treatment arms:
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
- None
盲法说明
Open label study for treatment (LNP023 or rituximab).
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
- •Female or male adult (≥18 years) subjects at screening visit with a diagnosis of idiopathic (primary) MN confirmed by renal biopsy within 36 months prior to screening. A renal biopsy may be taken at any time during the run-in period to confirm the diagnosis of MN and facilitate subject eligibility, if the most recent biopsy was performed greater than 36 months prior to the screening visit.
- •Anti-PLA2R antibody titer of ≥ 60 RU/mL at screening visit. If sites opt to use a local laboratory, with prior agreement with sponsor, an anti-PLA2R titer performed within 4 weeks prior to screening visit can be used.
- •Urine protein ≥ 3.5 g/24h at screening and baseline visits
- •≤50% reduction in both anti-PLA2R level and 24h urine protein between screening and baseline
- •Estimated GFR (using the CKD-EPI formula) ≥ 30 mL/min per 1.73 m2 at screening
- •Receiving stable dose at the maximum recommended dose according to local guidelines or maximum tolerated dose of ACEi and/or ARB and/or statins and/or diuretics for at least 8 weeks prior to Day 1
- •Vaccination against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae (in accordance with local guidelines) at least 28 days prior to Day 1 and no longer than 5 years prior to Day 1.
排除标准
- •Secondary causes of MN, e.g. systemic autoimmune diseases, solid or haematological malignancies, infections or chronic intake of drugs (e.g. gold salts, NSAIDs, penicillamines)
- •Diagnostic renal biopsy showing evidence of crescent formation in glomeruli, suggestive of an alternative or additional diagnosis to primary idiopathic MN.
- •Previous treatment with B-cell depleting or B-cell modifying agents such as, but not limited to rituximab, belimumab, daratumomab or bortezomib.
- •Previous treatment with immunosuppressive agents such as cyclophosphamide, chlorambucil, mycophenolate mofetil (or equivalent), cyclosporine, tacrolimus or azathioprine within 90 days prior to Day
- •Low dose systemic corticosteroid therapy is permitted, though the subject should have been on stable dose equivalent to ≤10 mg prednisolone for at least 90 days prior to Day
- •Previous treatment with gemfibrozil or strong CYP2C8 inhibitors such as clopidogrel within 7 days prior to Day 1
- •Presence or suspicion (based on judgment of the investigator) of active infection within 30 days prior to Day 1, or history of severe recurrent bacterial infections
- •Known contra-indications for the use of rituximab, including hypersensitivity to the active substance or to murine proteins, or to any of the excipients (sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for injections). Other contra-indications for the use of rituximab, including active, severe infection, patients in a severely immunocompromised state, severe heart failure (NYHA Class IV) or severe, uncontrolled cardiac disease.
研究组 & 干预措施
LNP023
As per protocol V00, participants took LNP023 10 mg orally b.i.d. for 4 weeks followed by LNP023 50 mg orally b.i.d. for 20 weeks.
As per protocol amendment V01, participants took LNP023 50mg orally b.i.d. for 4 weeks followed by LNP023 200mg for 20 weeks.
干预措施: LNP023 (Drug)
Rituximab
Rituximab 1 g i.v. at Day 1 and Day 15
干预措施: Rituximab (Drug)
结局指标
主要结局
Ratio Between Baseline Urine Protein Creatinine Ratio (UPCR) and Urine Protein Creatinine Ratio at 24 Weeks of Treatment (From 24h Urine Collection)
时间窗: Baseline, Day 113, Day 169
The primary endpoint of this study is the ratio between UPCR at 24 weeks of treatment measured in 24h urine and baseline UPCR . To assess the primary objective, the log-transformed ratio to baseline in UPCR was analyzed using a mixed model for repeated measures (MMRM). The results were back transformed and presented on the original scale.
次要结局
- Pharmacokinetic Parameter AUCtau in Plasma(Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose))
- Change From Baseline in Plasma Levels of Circulating Fragment of Factor B (Bb)(Baseline, Day 15, Day 29, Day 57, Day 113 and Day 169)
- Change From Baseline in Plasma Levels of sC5b-9(Baseline, Day 15, Day 29, Day 57, Day 113, Day 169)
- Pharmacokinetics in Urine: Renal Plasma Clearance Derived From 24 Hour Urine Sample(Day 113)
- Ratio to Baseline of Urine Protein Creatinine Ratio (UPCR) Measured in First Morning Void(Baseline, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169, Day 266 and Day 378)
- Number of Participants by Treatment Response at 24 Weeks of Treatment(Baseline, Day 169)
- Change From Baseline in (eGFR) Estimated Glomerular Filtration Rate Over Time(Baseline, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, Day 169)
- Pharmacokinetic Parameter Tmax in Plasma(Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose))
- Pharmacokinetic Parameter Cmax in Plasma(Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose))
- Pharmacokinetic Parameter AUClast in Plasma(Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose))