A Randomized, Multicenter, Double-blind, Parallel, Active-control Study of the Effects of Sparsentan, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, on Renal Outcomes in Patients With Primary FSGS
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 371
- 试验地点
- 227
- 主要终点
- Slope of Estimated Glomerular Filtration Rate (eGFR)
研究概览
简要总结
To determine the long-term nephroprotective potential of treatment with sparsentan as compared to an angiotensin receptor blocker in patients with primary and genetic focal segmental glomerulosclerosis (FSGS).
详细描述
This is a randomized, multicenter, double-blind, parallel, active-control study. Approximately 300 patients aged 8 to 75 years (inclusive) will be enrolled in the study. The study will be conducted in approximately 300 study centers, globally. The investigational drug (sparsentan) is a dual-acting angiotensin receptor blocker and endothelin receptor antagonist. The active control is irbesartan. Patients who meet eligibility criteria will require washout from renin-angiotensin-aldosterone system (RAAS) blockers, if applicable prior to their first dose of study drug.
Patients will be randomly assigned in a 1:1 ratio to receive either sparsentan or active control (irbesartan).
After completing the double-blind portion of the study, patients may participate in the open-label extension for treatment with sparsentan if they meet eligibility criteria.
Primary completion date represents the anticipated completion date of the double-blind portion of the study. Study completion date represents the anticipated completion date of the open-label extension portion of the study.
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
- 8 Years 至 75 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •for the Double-blind Period:
- •Sites within the US and UK: The patient is male or female aged 8 to 75 years, inclusive, weighing ≥20 kg at screening
- •Sites outside the US and UK: The patient is male or female aged 18 to 75 years, inclusive, weighing ≥20 kg at screening
- •Biopsy-proven focal segmental glomerulosclerosis (FSGS) lesion(s) or documentation of a genetic mutation in a podocyte protein associated with FSGS.
- •Urine protein/creatinine (UP/C) ≥1.5 g/g (170 mg/mmol) at screening
- •eGFR ≥30 mL/min/1.73 m2 at screening.
- •Women of childbearing potential must agree to the use of one highly reliable method of contraception from 7 days prior to the first dose of study medication until 90 days after the last dose of study medication, plus one additional barrier method during sexual activity
排除标准
- •for the Double-blind Period:
- •FSGS secondary to another condition
- •Positive serological tests of another primary or secondary glomerular disease not consistent with a diagnosis of primary or genetic FSGS
- •History of type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus, or nonfasting blood glucose >180 mg/dL (10.0 mmol/L)
- •Treated with rituximab, cyclophosphamide, or abatacept within ≤3 months prior to screening; if taking other chronic immunosuppressive medications, the dosage must be stable prior to screening
- •Documented history of heart failure, coronary artery disease, or cerebrovascular disease
- •Significant liver disease
- •Positive at screening for the human immunodeficiency virus or markers indicating acute or chronic hepatitis B virus infection or hepatitis C infection
- •History of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years
- •Screening hematocrit value <27% (0.27 L/L) or hemoglobin value <9 g/dL (90 g/L)
- •Screening potassium value of >5.5 mEq/L (5.5 mmol/L)
- •Extreme obesity (ie, ≥18 years of age with a body mass index (BMI) >40, or is <18 years of age with a BMI in the 99th percentile plus 5 units at screening, in whom there is a causal relationship between obesity and the development of FSGS
- •History of alcohol or illicit drug use disorder
- •History of serious side effect or allergic response to any angiotensin II antagonist or endothelin receptor antagonist
- •Female patient is pregnant, plans to become pregnant during the course of the study, or is breastfeeding.
- •Key Inclusion Criteria for the Open-label Extension Based on assessments at the Week 108 visit:
- •Complete participation in the double-blind period, including the Week 112 visit.
- •Patient received blinded study medication through the duration of the double-blind period (ie, did not permanently discontinue study medication)
- •Key Exclusion Criteria for the Open-label Extension Based on Assessments at Week 108 and 112 visits:
- •Progression to end-stage renal disease requiring replacement therapy
- •The patient developed criteria for discontinuation between Week 108 and Week 112
- •The patient was unable to initiate, or developed contraindications to, treatment with RAAS inhibitors between Week 108 and Week 112
- •eGFR ≤20 mL/min/1.73 m2 at Week 108
研究组 & 干预措施
Irbesartan
Irbesartan will be administered as a single oral dose; an initial dose of 150 mg daily titrating up to a target dose of 300 mg, daily
干预措施: Irbesartan (Drug)
sparsentan for double-blind and open-label extension
Sparsentan will be administered as a single oral dose; an initial dose of 400 mg daily titrating up to a target dose of 800 mg, daily
干预措施: sparsentan (Drug)
结局指标
主要结局
Slope of Estimated Glomerular Filtration Rate (eGFR)
时间窗: From Day 1 to Week 108
The total eGFR slope over 2 years, defined as the slope of eGFR following initiation of randomized treatment (ie, Day 1 to Week 108). Estimates are calculated from a mixed-effects model with treatment, Baseline eGFR, analysis visit, treatment-by-analysis visit, randomization stratification factors as fixed effects, and intercept and slope for each participant as a random effect.
Percentage of Participants Achieving FSGS Partial Remission Endpoint (FPRE)
时间窗: Week 36
Percentage of participants achieving FPRE, defined as urine protein-to-creatinine ratio (UP/C) ≤1.5 grams/gram (g/g) (170 milligrams per millimoles \[mg/mmol\]) and a \>40% reduction from Baseline was analyzed using a generalized linear model to model probability of achieving FPRE. Missing responses were imputed prior to analysis using multiple imputation. A generalized linear model with appropriate link function was implemented with Baseline log (UP/C), treatment, analysis visit, treatment by analysis visit interaction, and randomization strata as fixed effects. For estimates of probability of achieving FPRE, risk difference, and odds ratio, binomial distribution with logit link was used. For relative risk, Poisson distribution with log link was used. Using Rubin's approach, estimated treatment effects are combined across all imputations to obtain overall estimates for probabilities.
次要结局
- Slope of eGFR Following the Initial Acute Effect of Randomized Treatment(From Week 6 to Week 108)
- Change From Baseline in eGFR to 4 Weeks Post-cessation of Randomized Treatment(Baseline (Day 1) to Week 112)