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临床试验/NCT02021318
NCT02021318已完成3 期

A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis

Astellas Pharma Europe B.V.125 个研究点 分布在 17 个国家目标入组 616 人开始时间: 2014年3月12日最近更新:
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适应症
干预措施
相关药物

试验速览

阶段
3 期
状态
已完成
入组人数
616
试验地点
125
主要终点
Percentage of Participants With a Hb Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

The primary objective of this study was to evaluate the efficacy of roxadustat compared to darbepoetin alfa in the treatment of anemia in nondialysis-dependent chronic kidney disease (NDD CKD) participants.

详细描述

This was a phase 3, multicenter, randomized, open-label, active-controlled study. The study was planned to provide key efficacy and safety data for the approval of roxadustat in the treatment of anemia associated with CKD. Participants assigned to roxadustat treatment were administered roxadustat orally as a combination of tablets of different strengths. Participants assigned to darbepoetin alfa treatment were administered darbepoetin alfa subcutaneously or intravenously.

The study consisted of 3 study periods:

  • Screening period: up to 6 weeks
  • Treatment period: 104 weeks
  • Follow-up period: 4 weeks until planned study end (end of year 2)

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

  • •Subject has a diagnosis of CKD, with Kidney Disease Outcomes Quality Initiative (KDOQI) Stage 3, 4 or 5, not on dialysis; with an Estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m^2 estimated using the abbreviated 4-variable Modification of Diet in Renal Disease (MDRD) equation.
  • •The mean of the subject's two most recent (prior to randomization) Hb values during the screening period, obtained at least 4 days apart, must be less than or equal to 10.5 g/dL, with a difference of less than or equal to 1.0 g/dL. The last Hb value must be within 10 days prior to randomization.
  • •Subject is deemed suitable for treatment with Erythropoiesis Stimulating Agent (ESA) using the criteria specified in the Kidney Disease Improving Global Outcomes (KDIGO) 2012 recommendation considering the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anemia.
  • •Subject has a serum folate level greater than or equal to lower limit of normal (LLN) at screening.
  • •Subject has a serum vitamin B12 level greater than or equal to LLN at screening.
  • •Subject's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are less than or equal to 3 x upper limit of normal (ULN), and total bilirubin (TBL) is less than or equal to 1.5 x ULN.
  • •Subject's body weight is 45.0 kg to a maximum of 160.0 kg.
  • •Male subject must not donate sperm starting from screening, throughout the study period and up to 12 weeks after final study drug administration.

排除标准

  • •Subject has received any Erythropoiesis Stimulating Agent (ESA) treatment within 12 weeks prior to randomization.
  • •Subject has received any dose of IV iron within 6 weeks prior to randomization.
  • •Subject has received a Red Blood Cell (RBC) transfusion within 8 weeks prior to randomization.
  • •Subject has a known history of myelodysplastic syndrome or multiple myeloma.
  • •Subject 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).
  • •Subject has a known hemosiderosis, hemochromatosis, coagulation disorder, or hypercoagulable condition.
  • •Subject has a known chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission.
  • •Subject is anticipated to undergo elective surgery that is expected to lead to significant blood loss during the study period or anticipated elective coronary revascularization.
  • •Subject has active or chronic gastrointestinal bleeding.
  • •Subject has received any prior treatment with roxadustat or a Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI).
  • •Subject has been treated with iron-chelating agents within 4 weeks prior to randomization.
  • •Subject has a history of chronic liver disease (e.g., cirrhosis or fibrosis of the liver).
  • •Subject has known New York Heart Association Class III or IV congestive heart failure.
  • •Subject has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.
  • •Subject has one or more contraindications for treatment with darbepoetin alfa:
  • •Uncontrolled hypertension, or two or more blood pressure values of SBP greater than or equal to 160 mmHg or DBP greater than or equal to 95 mmHg (within 2 weeks prior to randomization).
  • •Known hypersensitivity to darbepoetin alfa, recombinant human erythropoietin, or any of the excipients.
  • •Subject has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F or higher) of renal cell carcinoma as shown on renal ultrasound within 12 weeks prior to randomization.
  • •Subject has a history of malignancy, except for the following: cancers determined to be cured or in remission for greater than or equal to 5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.
  • •Subject is positive for any of the following:
  • •human immunodeficiency virus (HIV).
  • •hepatitis B surface antigen (HBsAg).
  • •or anti-hepatitis C virus antibody (anti-HCV Ab).
  • •Subject has an active clinically significant infection that is manifested by White Blood Count (WBC) > Upper Limit of Normal (ULN), and/or fever, in conjunction with clinical signs or symptoms of infection within one week prior to randomization.
  • •Subject has a known untreated proliferative diabetic retinopathy, diabetic macular edema, macular degeneration or retinal vein occlusion.
  • •Subject has had any prior organ transplant (that has not been explanted), subject is scheduled for organ transplantation, or subject is likely to initiate renal replacement therapy including dialysis within the first year of the study.
  • •Subject will be excluded from participation if any of the following apply:
  • •subject has received investigational therapy within 30 days or 5 half lives or limit set by national law, whichever is longer, prior to initiation of screening, or
  • •any condition which makes the subject unsuitable for study participation.
  • •Subject has an anticipated use of dapsone in any dose amount or chronic use of acetaminophen/paracetamol >2.0 g/day during the treatment or follow-up period of the study.
  • •Subject has a history of alcohol or drug abuse within 2 years prior to randomization

研究组 & 干预措施

Roxadustat

Experimental

Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg (milligram) given thrice weekly (TIW) to participants weighing up to 70 kg (kilogram) and 100 mg given TIW to participants weighing more than 70 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL (gram per deciliter) and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat up to a maximum of 104 weeks.

干预措施: Roxadustat (Drug)

Darbepoetin alfa

Active Comparator

Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 μg/kg (microgram per kilogram), as a single subcutaneous or intravenous (IV) injection once weekly or 0.75 μg/kg, as a single subcutaneous injection once every 2 weeks) as per European Summary of Product Characteristics (EU SmPC) along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.

干预措施: Darbepoetin alfa (Drug)

结局指标

主要结局

Percentage of Participants With a Hb Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy

时间窗: Baseline to week 24

Hb response was measured as Yes or No. Response Yes (responders) was defined as: Hb ≥11.0 g/dL and Hb change from baseline by ≥ 1.0 g/dL, for participants with baseline Hb \> 8.0 g/dL; or Hb change from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at two consecutive visits with available data separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell \[RBC\] transfusion for all participants or darbepoetin for roxadustat treated participant).

次要结局

  • Time to First Intravenous Iron Use(Weeks 6, 12, 18, 24, 30 and 36)
  • Change From Baseline in Mean Arterial Pressure (MAP) to the Average MAP Value in Weeks 20 to 28: Per Protocol Set(Baseline and weeks 20 to 28)
  • Time to First Hb Response During First 24 Weeks of Treatment Without Rescue Therapy(Weeks 1 to 24)
  • Change From Baseline 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 Baseline in Short Form-36 (SF-36) Physical Functioning (PF) Sub-Score to the Average PF Sub Score in Weeks 12 to 28(Baseline and weeks 12 to 28)
  • Time to First Occurrence of Hypertension During Weeks 1 to 36: Per Protocol Set(Weeks 1 to 36)
  • Change From Baseline in Hb to the Average Hb Value of Weeks 28 to 52 Regardless of Rescue Therapy(Baseline and weeks 28 to 52)
  • Hb Level Averaged Over Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104 Without Rescue Therapy(Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104)
  • Number of Participants Who Had Achieved Antihypertensive Treatment Goal(Weeks 12 to 28 and 36 to 52)
  • Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in FACT-An Trial Outcome Index (TOI) Score(Baseline, weeks 12 to 28 and 36 to 52)
  • Change From Baseline in MAP to the Average MAP Value in Weeks 20 to 28: Full Analysis Set(Baseline and weeks 20 to 28)
  • Percentage of Hb Values >=10 g/dL and 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 to 36, 44 to 52 and 96 to 104)
  • Time to First Hb Rate of Rise > 2 g/dL Within 4 Weeks(Year 0.5, 1, 1.5 and 2)
  • Number of Days of Hospitalization Per Year(Baseline to EOT (up to week 104))
  • Change From Baseline in Hb to the Average Hb of Weeks 28 to 36 Without Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period(Baseline and weeks 28 to 36)
  • Change From Baseline in SF-36 Vitality (VT) Sub-Score to the Average VT Sub-Score in Weeks 12 to 28(Baseline and weeks 12 to 28)
  • Time to First Occurrence of Hypertension During Weeks 1 to 36: Full Analysis Set(Weeks 1 to 36)
  • Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104 Regardless of Use of Rescue Therapy(Baseline and weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104)
  • Percentage of Participants With Oral Iron Use Only(Day 1 to week 36, weeks 37 to 52, weeks 53 to 104, efficacy emergent period (up to week 104))
  • Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein Cholesterol (HDL-C) Ratio(Baseline and weeks 8, 28, 52, 104)
  • Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1)(Baseline and weeks 8, 28, 52, 104)
  • Time to First Hb Response During First 24 Weeks of Treatment Regardless of Administration of Rescue Therapy(Weeks 1 to 24)
  • Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy(Baseline and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104)
  • Number of Participants Who Received Rescue Therapy (Composite of RBC Transfusions (All Participants) and Darbepoetin Alfa Use (Roxadustat Treated Participants Only)(Baseline to EOT (up to week 104))
  • Mean Monthly Intravenous Iron Per Participant During Weeks 37 to 52 and 53 to 104(Weeks 37 to 52 and 53 to 104)
  • Time to First Use of IV Iron Supplementation(Year 0.5, 1, 1.5 and 2)
  • Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol(Baseline and weeks 8, 28, 52, 104)
  • Change From Baseline to the Average of Weeks 12 to 28 and 36 to 52 in Anemia Subscale (AnS) (Additional Concerns) of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score(Baseline, weeks 12 to 28 and 36 to 52)
  • Rate of Progression of Chronic Kidney Disease Measured by eGFR Slope Over Time(Baseline up to EOS (up to week 108))
  • Time to First Use of RBC Transfusion(Year 0.5, 1, 1.5 and 2)
  • Number of Hospitalizations(Baseline to EOT (up to week 104))
  • Time to First Hospitalization(Year 0.5, 1, 1.5 and 2)
  • Number of RBC Packs(Baseline to EOT (up to week 104))
  • Volume of RBC Transfused(Baseline to EOT (up to week 104))
  • Number of Particpants Who Received RBC Transfusions(Baseline to EOT (up to week 104))
  • Time to First Use of Rescue Therapy(Year 0.5, 1, 1.5 and 2)
  • Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in Work Productivity and Activity Impairment-Anemic Symptoms (WPAI:ANS) Score: Percent Work Time Missed(Baseline, weeks 12 to 28 and 36 to 52)
  • Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol(Baseline and weeks 8, 28, 52, 104)
  • Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB)(Baseline and weeks 8, 28, 52, 104)
  • Number of Participants With Mean LDL Cholesterol < 100 mg/dL(Weeks 12 to 28 and 36 to 52)
  • Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in FACT-An Total Score(Baseline, weeks 12 to 28 and 36 to 52)
  • Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline(Year 0.5, 1, 1.5 and 2)
  • Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant(Year 0.5, 1, 1.5 and 2)
  • Change From Baseline to Weeks 8, 28, 52 and 104 in ApoB/ApoA1 Ratio(Baseline and weeks 8, 28, 52, 104)
  • Change From Baseline to the Average of Weeks 12 to 28 and 36 to 52 in SF-36 Physical Component Score (PCS)(Baseline, weeks 12 to 28 and 36 to 52)
  • Change From Baseline to Each Scheduled Measurement 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 Baseline to Each Scheduled Measurement in Fasting Blood Glucose(Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, 106 and EOS (up to 108 weeks))
  • Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR)(Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, 106 and EOS (up to 108 weeks))
  • Number of Participants With End Stage Renal Disease (ESRD)(Baseline up to EOS (up to week 108))
  • Time to Chronic Dialysis or Renal Transplant or Death(Year 0.5, 1, 1.5 and 2)
  • Change From Baseline to the Average Value 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)
  • Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Activity Impairment(Baseline, weeks 12 to 28 and 36 to 52)
  • Change From Baseline to Each Scheduled Measurement in Serum Ferritin(Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104 and end of study (EOS) (up to 108 weeks))
  • Change From Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR)(Baseline and weeks 12, 24, 36, 52, 64, 76, 88 and 104)
  • Time to Chronic Kidney Disease Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death)(Year 0.5, 1, 1.5 and 2)
  • Number of Participants With Treatment Emergent Adverse Events (TEAEs)(From first dose of study drug up to end of study (up to week 108))
  • Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Impairment While Working(Baseline, weeks 12 to 28 and 36 to 52)
  • Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Overall Work Impairment(Baseline, weeks 12 to 28 and 36 to 52)
  • Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC)(Weeks 8, 12, 28, 52, 76, 104, last assessment (week 108))
  • Change From Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c)(Baseline and weeks 12, 28, 36, 44, 60, 84, 104 and EOS (up to 108 weeks))

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (125)

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