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临床试验/NCT02876835
NCT02876835已完成3 期

A Phase 3 Randomized, Open-label (Sponsor-blind), Active-controlled, Parallel-group, Multi-center, Event Driven Study in Non-dialysis Subjects With Anemia Associated With Chronic Kidney Disease to Evaluate the Safety and Efficacy of Daprodustat Compared to Darbepoetin Alfa

GlaxoSmithKline1 个研究点 分布在 1 个国家目标入组 3,872 人开始时间: 2016年9月27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
3,872
试验地点
1
主要终点
Mean Change From Baseline in Hgb Levels Over the Evaluation Period (Week 28 to Week 52)
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 purpose of this multi-center event-driven study in non-dialysis (ND) participants with anemia associated with chronic kidney disease (CKD) is to evaluate the safety and efficacy of daprodustat compared to darbepoetin alfa.

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)
  • •CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3, 4, or 5 defined by electronic eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula.
  • •Erythropoietin-stimulating agents (ESAs)/Hgb: Group 1 (not using ESAs): No ESA use within the 6 weeks prior to screening and no ESA use between screening and randomization (Day 1). Group 2 (ESA users): Use of any approved ESA for the 6 weeks prior to screening and continuing between screening and randomization.
  • •For Group 1 (not using ESAs), Hgb concentration at Week -8 and Week 1 should be 8 to 10 gram per deciliter (g/dL). For Group 2 (ESA users), Hgb concentration at Week -8 should be 8 to 12 g/dL and at Week 1 should be 8 to 11 g/dL.
  • •>=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.

排除标准

  • •Dialysis: On dialysis or clinical evidence of impending need to initiate dialysis within 90 days after study start (Day 1).
  • •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.
  • •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 Q-T 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 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). At screening, this exclusion applies to use of the investigational agent within 30 days or within five half lives (whichever is longer).
  • •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 urine 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.
  • •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 darbepoetin alfa) or prevent understanding of the aims or investigational procedures or possible consequences of the study.

研究组 & 干预措施

Darbepoetin alfa

Active Comparator

Participants will be administered darbepoetin alfa subcutaneously (SC).

干预措施: Placebo (Drug)

Daprodustat

Experimental

Participants will receive oral daprodustat once daily.

干预措施: Daprodustat (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)

Darbepoetin alfa

Active Comparator

Participants will be administered darbepoetin alfa subcutaneously (SC).

干预措施: Darbepoetin alfa (Drug)

Darbepoetin alfa

Active Comparator

Participants will be administered darbepoetin alfa subcutaneously (SC).

干预措施: Iron Therapy (Drug)

结局指标

主要结局

Mean Change From Baseline in Hgb Levels Over the 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 Hgb measurements. Hgb during the evaluation period was defined as the mean of all available post-randomization Hgb values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis missing post-Baseline Hgb 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. Analysis was performed using the Analysis of covariance (ANCOVA) model with terms for treatment, Baseline Hgb, current ESA use and region.

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 4.3 person-years for CV follow-up time period

Time to MACE defined as 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, current erythropoiesis-stimulating agents (ESA) use at randomization 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 \[\*\] 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.

次要结局

  • Time to First Occurrence of Adjudicated MACE During CV Events Follow-up Time Period (Superiority Analysis)(Up to 4.3 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 4.3 person-years for vital status follow-up time period)
  • Change From Baseline in Post-randomization Hgb Levels at Week 52(Baseline (Pre-dose on Day 1) and Week 52)
  • Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria(Day 1 to 51.1 months)
  • 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 Hospitalization for Heart Failure During CV Events Follow-up Time Period(Up to 4.3 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 4.3 person-years for CV follow-up time period)
  • Time to First Occurrence of Kidney Transplant During CV Events Follow-up Time Period(Up to 4.3 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 4.3 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 4.3 person-years for CV follow-up time period)
  • Time to First Occurrence of Chronic Dialysis During CV Events Follow-up Time Period(Up to 4.3 person-years for CV follow-up time period)
  • Percentage of Time With Hgb 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)
  • Number of Participants With at Least One BP Exacerbation Event During Study(Day 1 to end of treatment (51.1 months))
  • Time to First Occurrence of Adjudicated MACE or Thromboembolic Event During CV Events Follow-up Time Period(Up to 4.3 person-years for CV follow-up time period)
  • Time to First Occurrence of Chronic Kidney Disease (CKD) Progression During CV Events Follow-up Time Period(Up to 4.3 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 4.3 person-years for CV follow-up time period)
  • Time to First Occurrence of Adjudicated Stroke (Fatal and Non-Fatal) During CV Events Follow-up Time Period(Up to 4.3 person-years for CV follow-up time period)
  • Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)(Up to 4.3 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 4.3 person-years for CV follow-up time period)
  • Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic Events During CV Events Follow-up Time Period(Up to 4.3 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 4.3 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 4.3 person-years for CV follow-up time period)
  • Time to First Occurrence of Confirmed 40% Decline in eGFR During CV Events Follow-up Time Period(Up to 4.3 person-years for CV follow-up time period)
  • 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 Hgb 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 (4.3 person-years for follow-up time period))
  • Change From Baseline in SBP, DBP, MAP at End of Treatment(Baseline (Week -4) and 51.1 months)
  • 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 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)
  • Percentage of Time With Hgb 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 Maintenance Period (Week 28 to End of Study): Superiority Analysis(Week 28 to end of study (4.3 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)
  • Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years(Day 1 to end of treatment (51.1 months))
  • Change From Baseline in On-treatment EQ Visual Analogue Scale (EQ-VAS) at Week 52(Baseline (Pre-dose on Day 1) and Week 52)
  • 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 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 Post-randomization Estimated Glomerular Filtration Rate (eGFR) at Week 52(Baseline (Pre-dose on Day 1) and Week 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 Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52(Baseline (Day 1) and Weeks 8, 12, 28, 52)

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (1)

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