A Randomized, Multicenter, Double-blind, Parallel-group, Active-control Study of the Efficacy and Safety of Sparsentan for the Treatment of Immunoglobulin A Nephropathy
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 406
- 试验地点
- 163
- 主要终点
- Percent Change From Baseline in the Urine Protein/Creatinine (UP/C) at Week 36
研究概览
简要总结
To determine the long-term (approximately 2 years) nephroprotective potential of treatment with sparsentan as compared to an angiotensin receptor blocker in patients with immunoglobulin A nephropathy (IgAN).
详细描述
This is a 114-week,randomized, multicenter, double-blind, parallel-group, active-control study with an open-label extension period of up to 156 weeks, for a total duration of up to 270 weeks in patients with IgAN who have persistent overt proteinuria and remain at high risk of disease progression despite being on a stable dose (or doses) of an angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB) that is (are) a maximum tolerated dose that is at least one half of the maximum labeled dose (MLD) (according to approved labeling. Approximately 380 patients aged ≥18 years will be enrolled in the study globally. The investigational drug (sparsentan) is a dual acting angiotensin receptor blocker and endothelin receptor antagonist. The active control is irbesartan.
The purpose of the study is to evaluate the potential benefit of sparsentan on kidney function by analyzing change in proteinuria (protein in urine) and estimated glomerular filtration rate (eGFR) as compared to current standard treatment.
Patients enrolled in the PROTECT study (Protocol 021IGAN17001) will be those at high risk of progressing to renal failure. They will be randomly assigned in a 1:1 ratio to either sparsentan or irbesartan, as the active control (current standard treatment) at the Day 1 (Randomization) visit. Study medication (sparsentan and irbesartan) will be administered as a single oral morning dose.
The primary analysis is change in proteinuria (urine protein/creatinine ratio) from baseline at Week 36 in sparsentan-treated patients as compared to irbesartan-treated patients.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •for the Double-Blind Period:
- •Age 18 years or older at screening
- •Biopsy-proven primary IgAN
- •Proteinuria of ≥1 g/day at screening
- •eGFR ≥30 mL/min/1.73 m2 at screening
- •Currently on stable dose of ACEI and/or ARB therapy, for at least 12 weeks prior to screening (maximum tolerated dose and at least one-half of the maximum labeled dose)
- •Systolic BP ≤150 mmHg and diastolic BP ≤100 mmHg at screening
- •Willing to undergo change in ACEI and/or ARB and anti-hypertensive medications
- •Agree to contraception
排除标准
- •for the Double-Blind Period:
- •IgAN secondary to another condition
- •Presence of cellular glomerular crescents in >25% of glomeruli on renal biopsy (if biopsy available within 6 months of screening)
- •Chronic kidney disease (CKD) in addition to IgAN
- •History of organ transplantation, with exception of corneal transplants
- •Require any prohibited medications
- •Treatment of systemic immunosuppressive medications (including corticosteroids) for >2 weeks within 3 months of screening
- •History of heart failure or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema
- •Clinically significant cerebrovascular disease or coronary artery disease within 6 months of screening
- •Jaundice, hepatitis, or known hepatobiliary disease or elevations of transaminases (ALT/AST) >2 times upper limit of normal at screening
- •History of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years
- •Hematocrit value <27% (0.27 V/V) or hemoglobin value <9 g/dL (90 g/L) at Screening
- •Potassium >5.5 mEq/L (5.5 mmol/L) at Screening
- •History of alcohol of illicit drug use disorder
- •History of serious side effect or allergic response to any angiotensin II antagonist or endothelin receptor antagonist, including sparsentan or irbesartan, or has a hypersensitivity to any of the excipients in the study medications
- •For female: Pregnancy, or planning to become pregnant during the course of the study, or breastfeeding
- •Participation in a study of another investigational product within 28 days of screening
- •Key Inclusion Criteria for the Open-Label Extension Period based on assessments at the Week 110 visit:
- •Completed participation in the double-blind period, including the Week 114 visit
- •Did not permanently discontinue study medication during the double-blind period
- •Agree to contraception
- •Key Exclusion Criteria for the Open-Label Extension Period based on assessments at the Week 110 and Week 114 visits:
- •Progression to end-stage renal disease (ESRD) requiring renal replacement therapy (RRT)
- •Development of any criteria for discontinuation of study medication or discontinuation from the study, between Week 110 and Week 114
- •Patient was unable to initiate, or developed contraindications to, treatment with RAAS inhibitors between Week 110 and Week 114
- •eGFR ≤20 mL/min/1.73 m2 at Week 110
- •Female patient is pregnant or breastfeeding
- •Key Inclusion Criteria for the OLE Sparsentan + SGLT2 Inhibitor Sub study:
- •Participating in the open-label extension and is willing and able to provide signed informed consent for participation in the open-label extension period Sub study
- •A urine protein excretion value of ≥0.3 g/day.
- •An eGFR of ≥25 mL/min/1.73m2
- •On a stable dose of sparsentan for ≥8 weeks in the open-label extension period that is the maximum tolerated dose.
- •Key Exclusion Criteria for the OLE Sparsentan + SGLT2 Inhibitor Sub study:
- •Progressed to ESRD requiring RRT
- •Initiated or changed dose of a systemic immunosuppressive medication (including systemic steroids) within 12 weeks
- •Taking an SGLT2 inhibitor within 12 weeks
研究组 & 干预措施
dapagliflozin + sparsentan (Sub study)
OLE Sub study: Dapagliflozin will be administered daily as a 5-mg oral tablet, in addition to 400-mg of Sparsentan, for a period of 12 weeks.
干预措施: sparsentan (Drug)
irbesartan
Double-blind: Irbesartan will be administered daily as a 150-mg oral tablet, over-encapsulated (blinded) size 00 capsule for the first 2 weeks of the study following randomization. For patients who tolerate the initial dose of 150 mg after 2 weeks will increase their dose to 300 mg and continue treatment to Week 110.
干预措施: irbesartan (Drug)
sparsentan
Double-blind: Sparsentan will be administered daily as a 200-mg oral tablet, over-encapsulated (blinded) size 00 capsule for the first 2 weeks of the study following randomization. For patients who tolerate the initial dose of 200 mg after 2 weeks will increase their dose to 400- mg and continue treatment to Week 110.
干预措施: sparsentan (Drug)
dapagliflozin + sparsentan (Sub study)
OLE Sub study: Dapagliflozin will be administered daily as a 5-mg oral tablet, in addition to 400-mg of Sparsentan, for a period of 12 weeks.
干预措施: Dapagliflozin (Drug)
sparsentan (Sub Study)
OLE Sub study: Sparsentan will be administered daily as a dose of 400-mg for a period of 12 weeks.
干预措施: sparsentan (Drug)
结局指标
主要结局
Percent Change From Baseline in the Urine Protein/Creatinine (UP/C) at Week 36
时间窗: Baseline (Day 1) and at Week 36
24-hour urine sample was collected for analysis of UP/C via a mixed-model repeated-measures (MMRM) analysis. Missing responses were imputed prior to analysis using multiple imputation. Change from Baseline during the double-blind period in UP/C on the log scale was the dependent variable. Log Baseline UP/C was included as a covariate along with fixed effects for randomized treatment, time (ie, nominal visit in weeks), randomized treatment-by-time interaction, and randomization strata with participants as random effect. Estimates in log scale were back transformed. Baseline was defined as the last non-missing observation on or prior to the start of the dosing. Using Rubin's approach, estimated treatment effects are combined across all imputations to obtain overall estimates.
次要结局
- Annualized Slope of eGFR Following the Initial Acute Effect of Randomized Treatment (Chronic Slope)(From Week 6 to Week 110 post randomization)
- Total Slope of Estimated Glomerular Filtration Rate (eGFR) Over a 110-week Period(From Day 1 to Week 110)