NCT02879305已完成3 期
A Phase 3 Randomized, Open-label (Sponsor-blind), Active-controlled, Parallel-group, Multi-center, Event Driven Study in Dialysis Subjects With Anemia Associated With Chronic Kidney Disease to Evaluate the Safety and Efficacy of Daprodustat Compared to Recombinant Human Erythropoietin, Following a Switch From Erythropoietin-stimulating Agents
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
- 2,964
- 试验地点
- 1
- 主要终点
- Time to First Occurrence of Adjudicated Major Adverse Cardiovascular Event (MACE) During Cardiovascular (CV) Events Follow-up Time Period: Non-inferiority Analysis
研究概览
简要总结
The purpose of this multi-center event-driven study in participants with anemia associated with chronic kidney disease (CKD) to evaluate the safety and efficacy of daprodustat.
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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: 18 to 99 years of age (inclusive).
- •Erythropoietin-stimulating agents (ESAs): Use of any approved ESA for at least the 6 weeks prior to screening and between screening and randomization.
- •Hgb concentration: On Week -8: Hgb 8 to 12 grams per deciliter (g/dL). On randomization (Day 1): Hgb 8 to 11 g/dL and receiving at least the minimum ESA dose. Hgb >11 g/dL to 11.5 g/dL and receiving greater than the minimum ESA dose.
- •Dialysis: On dialysis >90 days prior to screening and continuing on the same mode of dialysis from screening (Week -8) through to randomization (Day 1).
- •Frequency of Dialysis: Hemodialysis (HD) >=2 times/week and peritoneal dialysis (PD) >=5 times/week. Home hemodialysis >=2 times/week.
- •Compliance with placebo [randomization (Day 1) only]: >=80% and <=120% compliance with placebo during run-in period.
- •Informed consent (screening only): capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
排除标准
- •Kidney transplant: Planned living-related or living-unrelated kidney transplant within 52 weeks after study start (Day 1).
- •Ferritin: <=100 nanograms (ng)/milliliter (mL) (<=100 micrograms/liter [L]) at screening.
- •Transferrin saturation (TSAT) (screening only): <=20%.
- •Aplasias: History of bone marrow aplasia or pure red cell aplasia.
- •Other causes of anemia: Untreated Pernicious anemia, thalassemia major, sickle cell disease or myelodysplastic syndrome.
- •Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant GI bleeding <=4 weeks prior to screening through to randomization (Day 1).
- •MI or acute coronary syndrome: <=4 weeks prior to screening through to randomization (Day 1).
- •Stroke or transient ischemic attack: <=4 weeks prior to screening through to randomization (Day 1).
- •Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart Association (NYHA) functional classification system.
- •Current uncontrolled hypertension: Current uncontrolled hypertension as determined by the investigator that would contraindicate the use of recombinant human erythropoietin (rhEPO).
- •Bazett's corrected QT interval (QTcB) (Day 1): QTcB >500 millisecond (msec), or QTcB >530 msec in subjects with bundle branch block. There is no QT Interval Corrected for Heart Rate (QTc) exclusion for subjects with a predominantly ventricular paced rhythm.
- •Alanine transaminase (ALT): >2x upper limit of normal (ULN) at screening.
- •Bilirubin: >1.5xULN at screening.
- •Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
- •Malignancy: History of malignancy within the 2 years prior to screening through to randomization (Day 1) or currently receiving treatment for cancer, or complex kidney cyst (example [e.g.] Bosniak Category II F, III or IV) > 3 centimeter (cm); with the exception of localized squamous cell or basal cell carcinoma of the skin that has been definitively treated >=4 weeks prior to screening.
- •Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product, or epoetin alfa or darbepoetin alfa.
- •Drugs and supplements: Use of strong inhibitors of Cytochrome P4502C8 (CYP2C8) (e.g., gemfibrozil) or strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
- •Other study participation: Use of other investigational agent or device prior to screening through to randomization (Day 1).
- •Prior treatment with daprodustat: Any prior treatment with daprodustat for treatment duration of >30 days.
- •Females only: Subject is pregnant [as confirmed by a positive serum human chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) only], subject is breastfeeding, or subject is of reproductive potential and does not agree to follow one of the contraceptive options listed in the List of Highly Effective Methods for Avoiding Pregnancy.
- •Other Conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the subject at unacceptable risk, which may affect study compliance (e.g., intolerance to rhEPO) or prevent understanding of the aims or investigational procedures or possible consequences of the study.
研究组 & 干预措施
Daprodustat
Experimental
Participants will receive oral daprodustat once daily.
干预措施: Daprodustat (Drug)
rhEPO
Active Comparator
Participants on peritoneal dialysis (PD) will be administered darbepoetin alfa subcutaneously (SC) and participants on hemodialysis (HD) will be administered epoetin alfa intravenously (IV).
干预措施: Iron therapy (Drug)
Daprodustat
Experimental
Participants will receive oral daprodustat once daily.
干预措施: Placebo (Drug)
Daprodustat
Experimental
Participants will receive oral daprodustat once daily.
干预措施: Iron therapy (Drug)
rhEPO
Active Comparator
Participants on peritoneal dialysis (PD) will be administered darbepoetin alfa subcutaneously (SC) and participants on hemodialysis (HD) will be administered epoetin alfa intravenously (IV).
干预措施: rhEPO (Drug)
rhEPO
Active Comparator
Participants on peritoneal dialysis (PD) will be administered darbepoetin alfa subcutaneously (SC) and participants on hemodialysis (HD) will be administered epoetin alfa intravenously (IV).
干预措施: Placebo (Drug)
结局指标
主要结局
Time to First Occurrence of Adjudicated Major Adverse Cardiovascular Event (MACE) During Cardiovascular (CV) Events Follow-up Time Period: Non-inferiority Analysis
时间窗: Up to 3.9 person-years for CV follow-up time period
Time to MACE defined as the time to first occurrence of Clinical Events Committee (CEC) adjudicated MACE (composite of all-cause mortality, non-fatal myocardial infarction \[MI\] and non-fatal stroke) was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) plus (+) 1. The incidence rate per 100 person years calculated as (100 multiplied by \[\*\] number of participants with at least 1 event) divided by \[/\] first event person-years) is presented along with 95 percent (%) confidence interval (CI). First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.
Mean Change From Baseline in Hemoglobin (Hgb) Levels During Evaluation Period (Week 28 to Week 52)
时间窗: Baseline (Pre-dose on Day 1) and evaluation period (Week 28 to Week 52)
Blood samples were collected from participants for hemoglobin measurements. Hemoglobin during the evaluation period was defined as the mean of all available post-randomization hemoglobin values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis, missing post-Baseline hemoglobin values were imputed using pre-specified multiple imputation methods. Change from Baseline was defined as post-Baseline value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
次要结局
- Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic Events During CV Events Follow-up Time Period(Up to 3.9 person-years for CV follow-up time period)
- Time to First Occurrence of Adjudicated Hospitalization for Heart Failure During CV Events Follow-up Time Period(Up to 3.9 person-years for CV follow-up time period)
- Change From Baseline in Post-randomization Hemoglobin Levels at Week 52(Baseline (Pre-dose on Day 1) and Week 52)
- Number of Hgb Responders in the Hgb Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)(Week 28 to Week 52)
- Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Non-inferiority Analysis(Week 28 to Week 52)
- Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Superiority Analysis(Week 28 to Week 52)
- Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of Study): Non-inferiority Analysis(Week 28 to end of study (3.9 person-years for follow-up time period))
- Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of Study): Superiority Analysis(Week 28 to end of study (3.9 person-years for follow-up time period))
- Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52(Baseline (Week -4) and Week 52)
- Change From Baseline in SBP, DBP, MAP at End of Treatment(Baseline (Week -4) and 45.1 months)
- Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years(Day 1 to end of study (3.9 person-years for follow-up time period))
- Number of Participants With at Least One BP Exacerbation Event During Study(Day 1 to end of study (3.9 person-years for follow-up time period))
- Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria(Day 1 to 45.1 months)
- Change From Baseline in On-Treatment Physical Component Score (PCS) Using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52(Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52)
- Change From Baseline in On-Treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52(Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52)
- Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52(Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52)
- Change From Baseline in On-Treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52(Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52)
- Change From Baseline in On-Treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52(Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52)
- Change From Baseline in On-Treatment Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52(Baseline (Pre-dose on Day 1) and Week 52)
- Change From Baseline in On-Treatment EuroQol Visual Analogue Scale (EQ-VAS) at Week 52(Baseline (Pre-dose on Day 1) and Week 52)
- Change From Baseline in On-Treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52(Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52)
- Time to First Occurrence of Adjudicated MACE or Thromboembolic Event During CV Events Follow-up Time Period(Up to 3.9 person-years for CV follow-up time period)
- Mean Average Monthly On-treatment IV Iron Dose Per Participant(Day 1 to Week 52)
- Time to First Occurrence of Adjudicated Stroke (Fatal and Non-Fatal) During CV Events Follow-up Time Period(Up to 3.9 person-years for CV follow-up time period)
- Time to First Occurrence of All-Cause Hospitalization During CV Events Follow-up Time Period(Up to 3.9 person-years for CV follow-up time period)
- Time to First Occurrence of All-Cause Hospital Re-admission Within 30 Days During CV Events Follow-up Time Period(Up to 3.9 person-years for CV follow-up time period)
- Time to First Occurrence of Adjudicated Thromboembolic Events During CV Events Follow-up Time Period(Up to 3.9 person-years for CV follow-up time period)
- Time to First Occurrence of Adjudicated MACE During CV Events Follow-up Time Period: Superiority Analysis(Up to 3.9 person-years for CV follow-up time period)
- Time to First Occurrence of Adjudicated All-Cause Mortality During Vital Status for Follow-up Time Period(Up to 3.9 person-years for vital status follow-up time period)
- Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure During CV Events Follow-up Time Period(Up to 3.9 person-years for CV follow-up time period)
- Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)(Up to 3.9 person-years for CV follow-up time period)
- Time to First Occurrence of Adjudicated CV Mortality During CV Events Follow-up Time Period(Up to 3.9 person-years for CV follow-up time period)
- Time to First Occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) During CV Events Follow-up Time Period(Up to 3.9 person-years for CV follow-up time period)
- Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI During CV Events Follow-up Time Period(Up to 3.9 person-years for CV follow-up time period)
研究者
研究点 (1)
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