A Phase 3 Randomized, Double-blind, Active-controlled, Parallel-group, Multi-center Study in Hemodialysis Participants With Anemia of Chronic Kidney Disease to Evaluate the Efficacy, Safety and Pharmacokinetics of Three-times Weekly Dosing of Daprodustat Compared to Recombinant Human Erythropoietin, Following a Switch From Recombinant Human Erythropoietin or Its Analogs
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 407
- 试验地点
- 1
- 主要终点
- Mean Change From Baseline in Hemoglobin Levels Over the Evaluation Period (Week 28 to Week 52)
研究概览
简要总结
This Phase 3 study in hemodialysis-dependent subjects with anemia will evaluate the efficacy and safety of daprodustat administered three-times weekly compared to epoetin alfa, the current standard of care. This study includes a 4 week Screening Period, a 52 week Treatment Period and a 4 to 6 week follow-up period. Each subject will remain in the study for up to 62 weeks. Approximately 402 subjects will be randomized to receive either daprodustat three times weekly or epoetin alfa three-times weekly or once weekly, depending on dose level.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
This is a double-blind study, in which the subject, investigator, site staff and the sponsor will remain blinded to each subjects study treatment assignment throughout the course of the study, with the exception of a limited number of unblinded site staff who are necessary to maintain the blind, as well as a limited number of sponsor staff.
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
- •Subject must be 18 to 99 years of age inclusive, at the time of signing the informed consent.
- •Use of any approved rhEPO or analog for at least 8 weeks prior to the screening visit and continuing during the screening period until randomization (Day 1).
- •Hgb concentration (measured by HemoCue) within the following range: Week -4: Hgb 8 to 11.5 grams/deciliter (5 to 7.1 millimoles/liter). If Hgb is 11.6 to 11.9 grams/deciliter (7.2 to 7.4 millimoles/liter), up to two retests are allowed; the retest value must be between 8 to 11.5 grams/deciliter (5 to 7.1 millimoles/liter). Day 1: Hgb 8 to 11 grams/deciliter (5 to 6.8 millimoles/liter) and receiving at least the minimum rhEPO or analog dose
- •Hgb>11 to 11.5 grams/deciliter (6.8 to 7.1 millimoles/liter) and receiving greater than the minimum rhEPO or analog dose
- •On hemodialysis (including hemofiltration or hemodiafiltration) >90 days prior to screening and continuing during the screening period.
- •On hemodialysis (in-center) >=3 times per week.
- •Male and female subjects are eligible. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP), or A WOCBP who agrees to follow the contraceptive guidance from at least 28 days prior to first dose of study treatment and for at least 28 days after the last dose of study treatment.
- •Capable of giving signed informed consent.
- •In France, a subject will be eligible for inclusion in this study if he or she is either affiliated to or beneficiary of a social security category.
排除标准
- •Planned living-related or living-unrelated kidney transplant within 52 weeks after randomization (Day 1).
- •Ferritin: <=100 nanograms/milliliter (<=100 micrograms/liter), at screening.
- •Transferrin saturation (TSAT): <=20 percent, at screening. If TSAT is 18 to 20 percent, then a retest using a new blood sample can be obtained within 7 days of the final laboratory report; the final retest value must be >20 percent to confirm eligibility.
- •Aplasias: History of bone marrow aplasia or pure red cell aplasia.
- •Conditions, other than anemia of CKD, which can affect erythropoiesis.
- •Myocardial infarction (MI) or acute coronary syndrome within 8 weeks prior to screening through to randomization (Day 1).
- •Stroke or transient ischemic attack within 8 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 as determined by the investigator that would contraindicate the use of rhEPO.
- •Bazett's correction of QTc interval (QTcB): at Day 1: QTcB >500 milliseconds, or QTcB >530 milliseconds in subjects with bundle branch block. There is no QTc (corrected QT) exclusion for subjects with a predominantly ventricular paced rhythm.
- •Liver Disease: presence of any one of the following liver-related laboratory values or conditions, at screening, is exclusionary: ALT >2x upper limit of normal (ULN); Bilirubin >1.5x ULN; or Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
- •Evidence of actively bleeding gastric, duodenal or esophageal ulcer disease OR clinically significant gastro intestinal bleeding <= 8 weeks prior to screening through to randomization (Day 1).
- •History of malignancy within 2 years prior to screening through to randomization (Day 1), currently receiving treatment for cancer, or complex kidney cyst (e.g., Bosniak Category IIF, III or IV) >3 centimeters.
- •Use of a strong inhibitor of Cytochrome P4502C8 [CYP2C8] (e.g. gemfibrozil) or a strong inducer of CYP2C8 (e.g. rifampin/rifampicin).
- •History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product (daprodustat) or epoetin alfa.
- •Use of another investigational agent within 30 days or within five half-lives of the investigational agent (whichever is longer) or currently participating in a study of an investigational device prior to screening through to randomization (Day 1).
- •Any prior treatment with daprodustat for treatment duration of >30 days.
- •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
Subjects randomized to this arm will receive daprodustat tablets titrated doses from 2 to 48 milligrams orally three-times weekly along with saline by IV route for the 52 weeks treatment period.
干预措施: Daprodustat tablets (Drug)
Daprodustat
Subjects randomized to this arm will receive daprodustat tablets titrated doses from 2 to 48 milligrams orally three-times weekly along with saline by IV route for the 52 weeks treatment period.
干预措施: Saline vials or bags (Drug)
Epoetin alfa
Subjects randomized to this arm will receive matching placebo tablets to daprodustat orally three-times weekly and Epoetin alfa by IV route for the 52 weeks treatment period.
干预措施: Matching placebo tablets (Drug)
Epoetin alfa
Subjects randomized to this arm will receive matching placebo tablets to daprodustat orally three-times weekly and Epoetin alfa by IV route for the 52 weeks treatment period.
干预措施: Epoetin alfa vials (Drug)
结局指标
主要结局
Mean Change From Baseline in Hemoglobin 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 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, the missing post-Baseline hemoglobin values were imputed using pre-specified multiple imputations. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline was defined as the average of post-randomization values during the evaluation period minus Baseline value. Analysis was performed using the Analysis of Covariance (ANCOVA) model with terms for treatment, Baseline hemoglobin, and region.
次要结局
- Mean Average Monthly On-treatment Intravenous (IV) Iron Dose Per Participant(Day 1 to Week 52)
- Change From Baseline in Hemoglobin Levels at Week 52(Baseline (Pre-dose on Day 1) and Week 52)
- Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) Over Evaluation Period (Week 28 to Week 52)(Week 28 to Week 52)
- Number of Hemoglobin Responders in the Hemoglobin Analysis Range (10 to 11.5 Grams/Deciliter) Over Evaluation Period (Week 28 to Week 52)(Week 28 to Week 52)
- Percentage of Participants Permanently Stopping Study Treatment Due to Meeting Rescue Criteria(Up to Week 52)
- Change From Baseline in SBP, DBP and MAP at End of Treatment(Baseline (Week -4) and end of treatment (last on-treatment value until Week 52))
- Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years(Up to 52 weeks)
- Change From Baseline at Weeks 8, 12, 28 and 52 in Patient Global Impression of Severity (PGI-S)(Baseline (Pre-dose on Day 1) and Weeks 8, 12, 28, 52)
- Pre-dose Trough Concentration (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13)(Pre-dose on Day 1; Pre-dose and at 0.5, 1, 2, 3 hours post-dose on any one post-Baseline visit day between Week 8 and Week 52)
- Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) at Week 52(Baseline (Week -4 ) and Week 52)
- Number of Participants With at Least One BP Exacerbation Event During the Study(Up to 52 weeks)
- Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13)(Pre-dose on Day 1; Pre-dose and at 0.5, 1, 2, 3 hours post-dose on any one post-Baseline visit day between Week 8 and Week 52)