A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel Group, Phase III Study to Evaluate the Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 518
- 试验地点
- 23
- 主要终点
- Ratio to baseline in Urine Protein to Creatinine Ratio (sampled from 24h urine collection) at 9 months
研究概览
简要总结
The study is designed as a multicenter, randomized, double-blind, placebo controlled study to demonstrate the superiority of iptacopan (LNP023) at a dose of 200 mg b.i.d. compared to placebo on top of maximally tolerated ACEi or ARB on reduction of proteinuria and slowing renal disease progression in primary IgA Nephropathy patients.
详细描述
The purpose of the study is to evaluate the efficacy and safety of iptacopan (LNP023) compared to placebo on proteinuria reduction and slowing disease progression in primary IgAN patients. The study will be the pivotal trial for registration of LNP023 in IgA Nephropathy patients with the aim to demonstrate a clinically meaningful reduction in proteinuria by LNP023 vs. placebo as assessed by reduction in urine protein to creatinine ratio (UPCR) sampled from a 24 hour urine collection at an IA at 9 months. The trial will continue in a blinded fashion to confirm long-term efficacy based on annualized total slope of eGFR decline over 24 months to provide confirmatory evidence of LNP023 efficacy and safety in treating patients with IgAN. The trial will enroll approximately 470 participants; 430 biopsy-proven IgAN participants with eGFR ≥30 mL /min/1.73m2 (main study population) and up to approximately 40 participants with eGFR 20 to <30 mL/min/1.73m2 (severe renal impairment (SRI) population).
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 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female patients ≥ 18 years of age with an eGFR level and biopsy-confirmed IgA nephropathy as follows:
- •For patients eGFR* ≥ 45ml/min/1.73m2, a qualifying biopsy performed within the last 5 years is required.
- •For patients with eGFR* 30 to <45ml/min/1.73m2, a qualifying biopsy performed within 2 years with < 50% tubulointerstitial fibrosis is required.
- •For patients with eGFR* 20 to <30ml/min/1.73m2, a qualifying biopsy performed at any time.
- •In all cases, if a historical biopsy is not available, one may be performed during screening. *eGFR calculated using the CKD-EPI formula (or modified MDRD formula according to specific ethnic groups and local practice guidelines)
- •Proteinuria due to primary diagnosis of IgA nephropathy as assessed at screening by UPCR ≥1 g/g (113 mg/mmol) sampled from FMV or 24h urine collection, as well as at the completion of the run-in period by UPCR ≥1 g/g (113 mg/mmol) calculated as the (geometric) mean of two 24h urine collections obtained within 14 days of each other at baseline.
- •Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infection is required prior to the start of study treatment. If the patient has not been previously vaccinated, or if a booster is required, vaccine should be given according to local regulations at least 2 weeks prior to first study drug administration. If study treatment has to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment should be initiated.
- •If not previously vaccinated, vaccination against Haemophilus influenzae infections should be given, if available and according to local regulations, at least 2 weeks prior to first study drug administration.
- •All patients must have been on supportive care including stable dose regimen of ACEi or ARB at either the locally approved maximal daily dose or the maximally tolerated dose (per investigators' judgment) for approximately 90 days before first study drug administration. In addition, if patients are taking diuretics, other antihypertensive medication, or other background medication for IgAN, the doses should also be stabilized for approximately 90 days prior to the first dosing of study treatment.
排除标准
- •Any secondary IgAN as defined by the investigator; secondary IgAN can be associated with cirrhosis, celiac disease, Human Immunodeficiency Virus (HIV) infection, dermatitis herpetiformis, seronegative arthritis, small-cell carcinoma, lymphoma, disseminated tuberculosis, bronchiolitis obliterans, and inflammatory bowel disease, familial mediterranean fever, etc.
- •Sitting office SBP >140 mmHg or DBP >90 mmHg at the randomization visit
- •Patients previously treated with immunosuppressive or other immunomodulatory agents such as but not limited to cyclophosphamide, rituximab, infliximab, eculizumab, canakinumab, mycophenolate mofetil (MMF) or mycophenolate sodium (MPS), cyclosporine, tacrolimus, sirolimus, everolimus, or systemic corticosteroids exposure (>7.5 mg/d prednisone/prednisolone equivalent) within 90 days (or 180 days for rituximab) prior to first study drug administration. Participants previously or currently treated with oral budesonide. Participants treated with endothelin (receptor) antagonists within 90 days prior to first study drug administration.
- •Prior use of iptacopan (LNP023) or prior enrollment in any other LNP023 clinical trial where study drug was taken, including matching placebo
- •History of recurrent invasive infections caused by encapsulated organisms, such as meningococcus and pneumococcus.
- •Active systemic bacterial, viral (including COVID-19) or fungal infection within 14 days prior to study drug administration.
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
LNP023 200mg b.i.d
干预措施: LNP023 (Drug)
Placebo to LNP023 200mg b.i.d
干预措施: Placebo (Drug)
结局指标
主要结局
Ratio to baseline in Urine Protein to Creatinine Ratio (sampled from 24h urine collection) at 9 months
时间窗: Baseline and 9 months
Evaluated at interim analysis - To demonstrate superiority of LNP023 vs. placebo in the change of proteinuria at 9 months by measuring Urine Protein to Creatinine Ratio sampled from a 24h urine collection.
Annualized total estimated Glomerular Filtration Rate (eGFR) slope over 24 months).
时间窗: Baseline and 24 months
Evaluated at the final analysis - to demonstrate superiority of LNP023 vs. placebo in slowing IgAN progression measured by the annualized total slope of Estimated Glomerular Filtration Rate (eGFR) change over 24 months.
次要结局
- Proportion of participants reaching Urine Protein To Creatinine Ratio <1g/g without receiving Corticosteroids/Immunosuppressant or other newly approved drugs or initiating new background therapy for treatment of IgAN or Kidney Replacement Therapy (KRT)(Baseline and 9 months)
- Time from randomization to first occurrence of composite kidney failure endpoint event(Up to 24 months)
- Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire.(Baseline and 9 months)
- Ratio to baseline in Urine Protein-To-Creatinine Ratio (sampled from 24h urine collection) at 9 months(Baseline and 9 months)
- Proportion of participants reaching Urine Protein-To-Creatinine Ratio <1g/g without receiving Corticosteroids/Immunosuppressant Therapy or other newly approved drugs or initiating new background therapy for treatment of IgAN or initiating KRT(Baseline and 9 months)
- Change from baseline in estimated glomerular filtration rate at 9 months(Baseline and 9 months)
- Annualized total Estimated Glomerular Filtration Rate slope estimated over 12 months(Baseline and 12 months)
- Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire(Baseline and 9 months)