A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of Roxadustat in the Maintenance Treatment of Anemia in End Stage Renal Disease Patients on Stable Dialysis
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 838
- 试验地点
- 143
- 主要终点
- Change From Baseline (BL) to the Average Hemoglobin (Hb) in Weeks 28-36 Without Rescue Therapy [EU (EMA)]
研究概览
简要总结
This study was conducted to explore a new therapy for anemia in participants with end stage renal disease (ESRD) on dialysis. Anemia is a reduced number of red blood cells or hemoglobin. Hemoglobin (which contains iron) is important for the transport of oxygen in your blood. The purpose of this study was to evaluate if roxadustat is effective and safe in the maintenance treatment of anemia in ESRD participants on stable dialysis. Roxadustat was compared to epoetin alfa and darbepoetin alfa, commercially available medicines for treatment of anemia.
详细描述
This study consisted of three study periods as follows:
- Screening Period: up to 6 weeks
- Treatment Period: a minimum of 52 weeks up to a maximum of 104 weeks
- Follow-up Period: 4 weeks
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
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
- •Main Inclusion:
- •Participant is on stable hemodialysis (HD), hemodiafiltration (HDF) or peritoneal dialysis (PD) treatment with the same mode of dialysis for ≥4 months prior to randomization.
- •Participant is on IV or SC epoetin or IV or SC darbepoetin alfa treatment for ≥8 weeks prior to randomization with stable weekly doses (during 4 weeks prior to randomization).
- •Mean of the participant's three most recent Hb values, as measured by central laboratory, during the Screening Period.
- •Participant's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤3 x upper limit of normal (ULN), and total bilirubin (TBL) is ≤1.5 x ULN
排除标准
- •Main Exclusion:
- •Participant has received a red blood cell (RBC) transfusion within 8 weeks prior to randomization.
- •Participant has a known hereditary hematologic disease such as thalassemia or sickle cell anemia, pure red cell aplasia, or other known causes for anemia other than Chronic Kidney Disease (CKD).
- •Participant has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a thrombotic/thrombo-embolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.
- •Participant has had uncontrolled hypertension, in the opinion of the investigator, within 2 weeks prior to randomization.
- •Participant has a history of malignancy, except for the following: cancers determined to be cured or in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.
- •Participant has had any prior organ transplant (that has not been explanted), or participant is scheduled for organ transplantation.
研究组 & 干预措施
Roxadustat
Participants received roxadustat three times a week (TIW) for at least 52 weeks up to a maximum of 104 weeks. Participants received initial dose of roxadustat in doses of 100 mg, 150 mg or 200 mg, according to the average weekly dose of epoetin or darbepoetin alfa prior to randomization. Participants' roxadustat dosage was adjusted every 4 weeks to maintain Hb level within the target range 10.0 to 12.0 g/dL. Dose adjustment steps were as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. Oral iron treatment of 200 mg was allowed for supplementation to support erythropoiesis. Treatment with intravenous iron was allowed only if certain protocol criteria were met.
干预措施: Roxadustat (Drug)
Roxadustat
Participants received roxadustat three times a week (TIW) for at least 52 weeks up to a maximum of 104 weeks. Participants received initial dose of roxadustat in doses of 100 mg, 150 mg or 200 mg, according to the average weekly dose of epoetin or darbepoetin alfa prior to randomization. Participants' roxadustat dosage was adjusted every 4 weeks to maintain Hb level within the target range 10.0 to 12.0 g/dL. Dose adjustment steps were as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. Oral iron treatment of 200 mg was allowed for supplementation to support erythropoiesis. Treatment with intravenous iron was allowed only if certain protocol criteria were met.
干预措施: Iron (Drug)
ESA (Erythropoiesis Stimulating Agent) treatment
Participants received epoetin alfa once weekly, twice weekly or TIW and darbepoetin alfa once a week or once every other week. Participants were treated for at least 52 weeks up to a maximum of 104 weeks. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant's Hb levels between 10.0 to 12.0 g/dL. Participants were not allowed to switch from the epoetin alfa to darbepoetin alfa or vice versa.
干预措施: Epoetin alfa (Drug)
ESA (Erythropoiesis Stimulating Agent) treatment
Participants received epoetin alfa once weekly, twice weekly or TIW and darbepoetin alfa once a week or once every other week. Participants were treated for at least 52 weeks up to a maximum of 104 weeks. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant's Hb levels between 10.0 to 12.0 g/dL. Participants were not allowed to switch from the epoetin alfa to darbepoetin alfa or vice versa.
干预措施: Darbepoetin alfa (Drug)
ESA (Erythropoiesis Stimulating Agent) treatment
Participants received epoetin alfa once weekly, twice weekly or TIW and darbepoetin alfa once a week or once every other week. Participants were treated for at least 52 weeks up to a maximum of 104 weeks. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant's Hb levels between 10.0 to 12.0 g/dL. Participants were not allowed to switch from the epoetin alfa to darbepoetin alfa or vice versa.
干预措施: Iron (Drug)
结局指标
主要结局
Change From Baseline (BL) to the Average Hemoglobin (Hb) in Weeks 28-36 Without Rescue Therapy [EU (EMA)]
时间窗: Baseline and weeks 28 to 36
Baseline Hb was defined as the mean of four central laboratory Hb values; four latest Hb values prior or on the same date as the first study drug intake. For participants who did not have an available Hb value during the week 28-36 period, imputation rules were applied. For analyses without rescue therapy, participants who used rescue therapy after the initiation of rescue therapy were set to missing for 6 weeks from the start date of rescue therapy. If no Hb value was available, an imputation technique was used, with the mean of all available values from Day 1 to minimum (End of Efficacy Emergent Period) carried forward.
Change From BL to the Average Hb in Weeks 28 to 52 Regardless of Rescue Therapy [US (FDA)]
时间窗: Baseline and weeks 28 to 52
Baseline Hb was defined as the mean of four central laboratory Hb values: four latest Hb values prior or on the same date as first study drug intake. Change from baseline to the average Hb are observed values. Missing hemoglobin data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model with treatment, baseline hemoglobin, randomization stratification factors and the available non missing hemoglobin for each scheduled week.
次要结局
- Percentage of Participants With Hb Response During Weeks 28 to 36(Weeks 28 to 36)
- Change From BL in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28(Baseline and weeks 12 to 28)
- Change From BL in Mean Arterial Pressure (MAP) to the Average MAP Value of Weeks 20 to 28(Baseline and weeks 20 to 28)
- Percentage of Participants With a Hb Response During Weeks 28 and 36 Regardless of Use of Rescue Therapy(Weeks 28 to 36)
- Change From BL in Hb to Each Postdosing Time Point(Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18,20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72,76, 80, 84, 88, 92, 96, 100, and 104)
- Hb Level Averaged Over Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy(Weeks 28 to 36, 44 to 52, and 96 to 104)
- Change From BL in Hb to the Average of Weeks 28 to 36, 44 to 52, and 96 to 104 Regardless of the Use of Rescue Therapy(Baseline and weeks 28 to 36, 44 to 52, and 96 to 104)
- Percentage of Hb Values ≥ 10 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy(Weeks 28-36, 44-52 and 96-104)
- Percentage of Hb Values Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy(Weeks 28-36, 44-52 and 96-104)
- Number of Hospitalizations(Baseline to End of Treatment (EOT) (Up to week 104))
- Mean Monthly Intravenous (IV) Iron Use(Day 1 to week 36)
- Time to First Hospitalization(Baseline to EOT (Up to week 104))
- Time to First Use of Rescue Therapy(Baseline to EOT (Up to week 104))
- Time to First RBC Transfusion(Baseline to EOT (Up to week 104))
- Change From BL in Short Form-36 (SF-36) Health Survey Physical Functioning (PF) Sub-score to the Average of Weeks 12 to 28(Baseline and weeks 12 to 28)
- Change From BL in SF-36 Vitality (VT) Sub-score to the Average of Weeks 12 to 28(Baseline and weeks 12 to 28)
- Change From BL in Mean Arterial Pressure (MAP) to the Average of Weeks 20 to 28(Baseline and weeks 20 to 28)
- Time to First Occurrence of an Increase in Blood Pressure(Weeks 1 to 36)
- Number of Days of Hospitalization Per Year(Baseline to EOT (Up to week 104))
- Mean Monthly Number of RBC Packs Per Participant(Baseline to EOT (Up to week 104))
- Mean Monthly Volume of RBC Transfusion Per Participant(Baseline to EOT (Up to week 104))
- Time to First Use of IV Iron Supplementation(Baseline to EOT (Up to week 104))
- Mean Monthly Intravenous (IV) Iron Per Participant During Weeks 37-52 and Weeks 53-104(Weeks 37-52 and weeks 53-104)
- Percentage of Participants With Oral Iron Use Only(Baseline to EOT (Up to week 104))
- Change From BL to Each Post-dosing Study Visit in Total Cholesterol(Baseline and weeks 8, 28, 52, 104)
- Change From BL to Each Post-dosing Study Visit in LDL-C/High-density Lipoprotein Cholesterol (HDL-C) Ratio(Baseline and weeks 8, 28, 52, 104)
- Change From BL to Each Postdosing Study Visit in Non-HDL Cholesterol(Baseline and weeks 8, 28, 52, 104)
- Change From BL to Each Postdosing Study Visit in Apolipoproteins A1 (ApoA1)(Baseline and weeks 8, 28, 52, 104)
- Change From BL to Each Postdosing Study Visit in Apolipoproteins B (ApoB)(Baseline and weeks 8, 28, 52, 104)
- Change From BL to Each Postdosing Study Visit in ApoB/ApoA1 Ratio(Baseline and weeks 8, 28, 52, 104)
- Number of Participants With Mean LDL Cholesterol < 100 mg/dL Over Weeks 12 to 28(Weeks 12 to 28)
- Number of Participants With CKD Who Achieved Antihypertensive Treatment Goal(Weeks 12 to 28)
- Change From BL to the Average of Weeks 12 to 28 in SF-36 Physical Component Score (PCS)(Baseline and weeks 12 to 28)
- Change From BL to the Average of Weeks 12 to 28 in Anemia Subscale (AnS) ("Additional Concerns") of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score(Baseline and weeks 12 to 28)
- Change From BL to the Average Value of Weeks 12 to 28 in Total FACT-An Score(Baseline and weeks 12 to 28)
- Change From BL to the Average of Weeks 12 to 28 in Euroqol Questionnaire-5 Dimensions 5 Levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score(Baseline and weeks 12 to 28)
- Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC)(Baseline and weeks 8, 12, 28, 36, 52, 76, 104)
- Change From BL in Serum Hepcidin(Baseline and weeks 4, 12, 20, 36, 52, 104, and End of Study (EOS - up to 108 weeks))
- Change From BL in Serum Ferritin(Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, and EOS (up to 108 weeks))
- Change From BL in Transferrin Saturation (TSAT)(Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104 and EOS (up to 108 weeks))
- Change From BL in Glycated Hemoglobin (HbA1c) Level to Weeks 12, 28, 36, 44, 52, 60, 84, 104 and EOS (up to Week 108)(Baseline and weeks 12, 28, 36, 44, 52, 60, 84, 104 and EOS (up to 108 weeks))
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs)(Baseline up to EOS (Up to week 108))