A Randomized, Double-blind, Placebo-controlled, Crossover Study of Atrasentan in Subjects With IgA Nephropathy on Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 54
- 试验地点
- 30
- 主要终点
- Change From Baseline in Proteinuria at Week 12 in Both Treatment Periods 1 and 2
研究概览
简要总结
The ASSIST study was a phase 2, double-blind, placebo-controlled crossover study to evaluate the safety and efficacy of atrasentan vs. placebo in subjects with IgA nephropathy (IgAN) while on background standard of care therapy and an SGLT2 inhibitor (SGLT2i).
详细描述
Patients with biopsy-proven IgAN who were on a background SGLT2i and a maximally tolerated and stable dose of a renin-angiotensin system inhibitor (RASi) [such as angiotensin converting enzyme inhibitor (ACEi) or angiotensin-receptor antagonist (ARB)] as part of standard of care, were randomized to either sequence Atrasentan/Placebo or sequence Placebo/Atrasentan in which they received 0.75 mg atrasentan once daily during one period (period A), complete a 12-week washout period, and then received matching placebo during the other period (period B) as determined by the randomization schema.
Subjects who were not on background SGLT2i therapy would first undergo a run-in period of 8 weeks with an SGLT2i with a 24-hour total urine protein of > 0.85 grams/day at screening prior to the run-in period and have 24-hour total urine protein of > 0.5 grams/day at the end of the run-in period to be eligible for randomization.
Subjects remained on their maximally tolerated and stable dose of RASi and stable dose of SGLT2i therapies for the duration of the study following randomization.
The primary objective of the study was to evaluate the efficacy of atrasentan vs. placebo while on background therapy with SGLT2i.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Double-blind
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
- •Legal adults (per local and country specifications) ≥ 18 years of age at the time of signing the informed consent form (ICF) prior to initiation of any study specific activities/procedures.
- •Biopsy-proven IgA nephropathy.
- •Receiving a maximally tolerated and stable dose of a RASi for at least 12 weeks prior to screening. Investigator discretion should be used in determining maximally tolerated and optimized dose.
- •eGFR of at least 30 mL/min/1.73 m^2 at screening based on the 2021 CKD-EPI equation.
- •Willing to agree to highly effective forms of contraception, as specified in the protocol, throughout the study and for up to 1 month afterward. In WOCBP, use of hormonal contraceptive agents must have been started at least 1 month prior to baseline.
- •Willing and able to provide informed consent and comply with all study requirements.
- •Inclusion Criteria for SGLT2i stable subjects
- •Receiving a stable dose of an SGLT2i for at least 8 weeks prior to screening
- •Must have a 24-hour urine protein of >0.5 grams/day.
- •Inclusion Criteria for Run-In Subjects
- •Must have a 24-hour total urine protein of >0.85 grams/day at screening
- •Willing to participate in an 8-week run-in period with an SGLT2i (per Investigator choice)
- •Additional Inclusion Criteria for Run-in Subjects at the end of Run-In
- •Must have completed the 8-week run-in period on a stable and well tolerated dose of an SGLT2i
- •Must have a 24-hour total urine protein of >0.5 grams/day confirmed at the Run-in Week 8 visit.
- •Must have an eGFR of ≥ 30 mL/min/1.73 m^2 based on the CKD-EPI equation at their Run-in Week 8 visit.
排除标准
- •Current diagnosis with another chronic kidney disease, including diabetic kidney disease.
- •History of kidney transplantation or other organ transplantation.
- •Use of systemic immunosuppressant medications, such as steroids, for more than 2 weeks in the past 3 months.
- •Blood pressure above 150 mmHg systolic or 95 mmHg diastolic as evaluated by the Investigator.
- •Known history of heart failure or prior hospital admissions for conditions relating to fluid overload that in the opinion of the Principal Investigator or Sponsor might confound the results of the study or pose additional risk to the participant by their participation in the study.
- •Clinically significant history of liver disease as assessed by the Investigator.
- •Hemoglobin below 9 g/dL as measured by the Investigator or prior history of blood transfusion for anemia within the past 3 months.
- •Malignancy within the past 5 years. Exceptions to this criteria include nonmelanoma skin cancer and curatively treated cervical carcinoma in situ.
- •For women, pregnancy, breast feeding, or intent to become pregnant during the study. and at least 1 month afterward.
- •For men, intent to father a child or donate sperm during the study.
- •Have received any investigational agent or approved treatment for IgAN (other than a RAS inhibitor) including SGLT2i (except for subjects in the SGLT2i stable stratum) within 1 month (or 5 half-lives of the agent, whichever is longer) prior to Screening. If the investigational agent is a cytotoxic or immunosuppressive agent then this washout period is 6 months.
研究组 & 干预措施
Sequence Atrasentan/Placebo
Once daily oral administration of 0.75 mg atrasentan for 12 weeks (Period A) followed by once daily oral administration of placebo for 24 weeks (Period B)
干预措施: Placebo (Drug)
Sequence Placebo/Atrasentan
Once daily oral administration of placebo for 12 weeks (Period B) followed by once daily oral administration of 0.75 mg atrasentan for 24 weeks (Period A)
干预措施: Placebo (Drug)
Sequence Atrasentan/Placebo
Once daily oral administration of 0.75 mg atrasentan for 12 weeks (Period A) followed by once daily oral administration of placebo for 24 weeks (Period B)
干预措施: Atrasentan (Drug)
Sequence Placebo/Atrasentan
Once daily oral administration of placebo for 12 weeks (Period B) followed by once daily oral administration of 0.75 mg atrasentan for 24 weeks (Period A)
干预措施: Atrasentan (Drug)
结局指标
主要结局
Change From Baseline in Proteinuria at Week 12 in Both Treatment Periods 1 and 2
时间窗: Baseline and 12 weeks or approximately 3 months
The change in urine protein: creatinine ratio (UPCR) from baseline to Week 12
Percentage Change in Proteinuria (UPCR From a 24-Hour Urine Collection) From Baseline to Week 12
时间窗: From Baseline to Week 12
Change in proteinuria from Baseline to Week 12 across both periods between atrasentan versus placebo. Proteinuria was assessed using the urine protein to creatinine ratio (UPCR) measured from a 24-hour urine collection.
次要结局
- Change From Baseline in Proteinuria at Week 24 in Treatment Periods 2(Baseline and 24 weeks or approximately 6 months)
- Number of Subjects With Adverse Events (AEs)(From informed consent until end of study, approximately 60 weeks)
- Plasma Concentration of Atrasentan(Treatment Period 1: Pre-dose on Weeks 2, 6 and 12; Treatment Period 2: Pre-dose on Weeks 2, 6, 12 and 24)
- Percentage Change in Proteinuria (UPCR From a 24-Hour Urine Collection) From Baseline to Week 24 in Treatment Period 2.(From Baseline to Week 24 of Treatment Period 2)
- Number of Subjects With TEAE and TEAESI(From first dose of study treatment until end of study, up to 60 weeks)