Phase 2, Randomized, Open-Label, Active-Controlled, Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics Study of Oral Vadadustat for the Treatment of Anemia in Hemodialysis Subjects Converting From Epoetin Alfa (FO2RWARD-2)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 175
- 试验地点
- 3
- 主要终点
- Mean Change in Hemoglobin (Hb) Between Baseline and the Primary Evaluation Period (PEP)
研究概览
简要总结
This is a Phase 2 open-label efficacy, safety, and pharmacokinetic/pharmacodynamic (PK/PD) study to evaluate oral Vadadustat for the treatment of anemia in hemodialysis participants converting from Epoetin Alfa therapy.
详细描述
This is a Phase 2, randomized, open-label study to evaluate efficacy and safety of oral Vadadustat for the treatment of anemia in hemodialysis participants converting from Epoetin Alfa therapy. The study will be conducted in two parts running in parallel: Part 1, Main Study in a hemodialysis population on maintenance treatment with Epoetin Alfa; Part 2 is in a hemodialysis population that are erythropoiesis-stimulating agent (ESA) hyporesponders on maintenance treatment with Epoetin Alfa. For all participants (Main and ESA hyporesponder parallel study), the study will include a Screening Period, a Treatment Period, and a Safety Follow-Up Period. PK and PD sampling will be done throughout the study. The aim is to achieve and maintain hemoglobin (Hb) levels within the target range of 10.0 to 11.0 grams per deciliter (g/dL), inclusive, while targeting the middle of the range and minimizing excursions outside the target range.
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
- •≥18 years of age, providing informed consent
- •Receiving chronic, outpatient in-center hemodialysis (TIW) for end-stage renal disease for at least 12 weeks prior to Screening
- •Maintained on intravenous Epoetin Alfa therapy for 8 weeks prior to and including Screening through Screening Visit 2 (SV2)
- •Eligibility in the Main study and erythropoiesis-stimulating agent (ESA) hyporesponder parallel study is based on the following mean weekly Epoetin Alfa doses:
- •Main study: Mean weekly Epoetin Alfa dose <300 Units per kilogram per week (U/kg/week) for 8 weeks prior to SV2;
- •ESA hyporesponder parallel study: Mean weekly Epoetin Alfa dose ≥300 U/kg/week for 8 weeks prior to SV2
- •Two Hb values measured by the central laboratory at least 4 days apart between Screening Visit 1 (SV1) and SV2 as indicated:.
- •Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive;
- •ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 grams per deciliter (g/dL), inclusive
- •Serum ferritin ≥100 nanograms per milliliter (ng/mL) and transferrin saturation (TSAT) ≥20% during Screening
- •Folate and vitamin B12 measurements ≥ lower limit of normal during Screening
- •Hemodialysis adequacy as indicated by single-pool Kt/Vurea ≥1.2 using the most recent historical measurement within 8 weeks prior to or during Screening
- •Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure
排除标准
- •Anemia due to a cause other than chronic kidney disease (e.g., sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell aplasia)
- •Active bleeding or recent blood loss within 8 weeks prior to randomization
- •Red blood cell (RBC) transfusion within 8 weeks prior to randomization
- •Anticipated to discontinue hemodialysis during the study
- •Judged by the Investigator that the participant is likely to need rescue therapy (ESA administration or RBC transfusion) immediately after enrollment in the study
- •History of chronic liver disease (e.g., chronic infectious hepatitis, chronic autoimmune liver disease, cirrhosis or fibrosis of the liver)
- •Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total bilirubin >1.5 x upper limit of normal (ULN) during Screening. Participants with a history of Gilbert's syndrome are not excluded.
- •Current uncontrolled hypertension as determined by the Investigator that would contraindicate the use of Epoetin Alfa
- •Acute coronary syndrome (hospitalization for unstable angina or myocardial infarction), surgical or percutaneous intervention for coronary, cerebrovascular or peripheral artery disease (aortic or lower extremity), surgical or percutaneous valvular replacement or repair, sustained ventricular tachycardia, hospitalization for heart failure (HF) or New York Heart Association Class IV HF, or stroke within 12 weeks prior to or during Screening
- •History of new or recurrent malignancy within 2 years prior to and during Screening or currently receiving treatment or suppressive therapy for cancer. Participants with treated basal cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, or cervical carcinoma in situ are not excluded.
- •History of deep vein thrombosis or pulmonary embolism within 12 weeks prior to or during Screening
- •History of hemosiderosis or hemochromatosis
- •History of prior organ transplantation (participants with a history of failed kidney transplant or corneal transplants are not excluded)
- •Scheduled organ transplant from a living donor and participants on the kidney transplant wait-list who are expected to receive a transplant within 6 months
- •History of a prior hematopoietic stem cell or bone marrow transplant (stem cell therapy for knee arthritis is not excluded)
- •Known hypersensitivity to Vadadustat, Epoetin Alfa, or any of their excipients
- •Any prior use of a hypoxia-inducible factor prolyl-hydroxylase (HIF-PH) inhibitor or any use of an investigational medication within 30 days or 5 half-lives of the investigational medication (whichever is longer), prior to randomization
- •For female participants of non-childbearing potential:
- •inability to confirm surgical sterility (e.g., hysterectomy, bilateral tubal ligation, bilateral oophorectomy) at least 1 month prior to Screening;
- •not considered post-menopausal (no menses for >1 year with follicle stimulating hormone >40 U/Liter at Screening)
- •For female participants of childbearing potential:
- •lack of confirmation of the use of acceptable forms of contraception* for a minimum of one complete menstrual cycle prior to Screening;
- •positive serum pregnancy test at SV2;
- •unwilling to use two acceptable forms of contraception* (at least one of which must be a barrier method) starting Baseline/Day 1, throughout the Treatment Period and for 30 days after the final study drug administration
- •Breastfeeding during Screening or throughout the Treatment Period and for 30 days after the final study drug administration
- •Donation of ova starting at Screening, throughout the Treatment Period, and for 30 days after the final study drug administration
- •Male participants who have not had a vasectomy and do not agree to the following: use of an acceptable form of contraception* during the study and for 30 days after the last dose of the study drug; to not donate semen during the study and for at least 30 days after the last dose of Vadadustat
- •Participants with bilateral native nephrectomy
- •Any other reason, which in the opinion of the Investigator, would make the participant not suitable for participation in the study
- •Acceptable forms of contraception include:
- •Established use of oral, injected or implanted hormonal methods of contraception;
- •Placement of an intrauterine device or intrauterine system;
- •Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
研究组 & 干预措施
Epoetin Alfa
Epoetin Alfa
干预措施: Epoetin Alfa (Drug)
Vadadustat
The initial dose of Vadadustat (300, 450, or 600 milligrams [mg]) will be based upon the dose of Epoetin Alfa dose participants had received prior to Vadadustat treatment
干预措施: Vadadustat (Drug)
Vadadustat TIW
Participants randomized to Vadadustat (Main and erythropoiesis-stimulating agent [ESA] hyporesponder parallel studies) who complete a once-daily dosing regimen treatment period and meet eligibility criteria for transition to three times weekly (TIW) dosing will switch to TIW dosing
干预措施: Vadadustat TIW (Drug)
结局指标
主要结局
Mean Change in Hemoglobin (Hb) Between Baseline and the Primary Evaluation Period (PEP)
时间窗: Baseline; Week 10 to Week 12
Change from Baseline in Hb value was calculated as the PEP Hb value minus the Baseline Hb value. The PEP value was the average Hb value from Week 10 to Week 12. The Baseline Hb value was defined as the average of the final two Hb values prior to start of dosing on Day 1.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
时间窗: Up to Week 24
An adverse event (AE) was defined as any untoward medical occurrence (including a clinically significant abnormal laboratory finding) that occurred in the protocol-specified AE reporting period. An AE included medical conditions, signs, and symptoms not previously observed in the participant that emerged during the protocol-specified AE reporting period, including signs or symptoms associated with pre-existing underlying conditions that were not present prior to the AE reporting period. TEAEs, defined as AEs that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, are reported.
Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameter Values
时间窗: Up to Week 24
Parameters assessed for laboratory values included hematology (excluding the primary and secondary efficacy endpoint results related to Hb), clinical chemistry, lipid profiles, and glucose. The investigator was responsible for reviewing laboratory results for clinically significant changes.
Number of Participants With Clinically Significant Changes From Baseline in Vital Sign Values
时间窗: Up to Week 24
Parameters assessed for vital signs included sitting (at rest for a minimum of 5 minutes) heart rate, respiratory rate, body temperature, and blood pressure. The investigator was responsible for reviewing vital sign values for clinically significant changes.
Number of Participants Classified as Hb Outliers
时间窗: Weeks 13 - 20
The target range for Hb was from 10.0 to 11.0 grams per deciliter (g/dL). Hb outliers included participants with a Hb increase of more than 12.0 g/dL or \<8.0 g/dL and decline in Hb ≥0.5 g/dL from Baseline, and a Hb increase to more than 1.0 g/dL within any 2-week interval during the Study Period.
次要结局
- Number of Participants With a Mean Increase in Hb From Baseline to the PEP ≥0.5 g/dL or With Hb Values Within the Target Range at the PEP(Week 10 to Week 12)
- Mean Change From Baseline in Iron Concentration(Baseline; Week 4, Week 8, Week 12, Week 16, and Week 20)
- Mean Change From Baseline in Ferritin Concentration(Baseline; Week 4, Week 8, Week 12, Week 16, and Week 20)
- Mean Change From Baseline in Total Iron Binding Capacity(Baseline; Week 4, Week 8, Week 12, Week 16, and Week 20)
- Mean Change From Baseline in Hepcidin Concentration(Baseline; Week 12 and Week 20)
- Geometric Mean Maximum Observed Plasma Concentration (Cmax) of Vadadustat Following a Single Dose(Day 1; Week 1, Week 1 +1 (Day 8), Week 11, Week 13: pre-dose, 2 hours (h), 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose)
- Geometric Mean Area Under the Concentration-time Curve (AUC) From Time 0 to 24 Hours (AUC0-24) of Vadadustat Following a Single Dose(Day 1; Week 1, Week 1 +1 (Day 8), Week 11: pre-dose, 2h, 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose)
- Median Terminal Half-life (t1/2) of Vadadustat Following a Single Dose(Day 1; Week 1, Week 1 +1 (Day 8), Week 11, Week 13: pre-dose, 2 hours (h), 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose)
- Median Time to Reach Cmax (Tmax) of Vadadustat Following a Single Dose(Day 1; Week 1, Week 1 +1 (Day 8), Week 11, Week 13: pre-dose, 2 hours (h), 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose)
- Geometric Mean Elimination Rate Constant (λz) of Vadadustat Following a Single Dose(Day 1; Week 1, Week 1 +1 (Day 8), Week 11, Week 13: pre-dose, 2 hours (h), 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose)
- Geometric Mean Apparent Total Body Clearance (CLss/F) of Vadadustat Following a Single Dose(Day 1; Week 1, Week 1 +1 (Day 8), Week 11: pre-dose, 2h, 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose)
- Number of Participants With Hb Values Within the Target Range at the PEP(Week 10 to Week 12)
- Number of Participants With a Mean Increase in Hb From Baseline to the SEP ≥0.5 g/dL or With Hb Values Within the Target Range at the SEP(Week 18 to Week 20)
- Mean Change in Hb From the PEP to the Secondary Evaluation Period (SEP) in Participants Who Transitioned to Three Times Per Week (TIW) Vadadustat Dosing After Week 12(Week 10 to Week 12; Week 18 to Week 20)
- Number of Participants Requiring Red Blood Cell (RBC) Transfusion(Up to Week 20)
- Mean Change in Hb Between Baseline and the SEP(Baseline; Week 18 to Week 20)
- Number of Participants With Hb Values Within the Target Range at the SEP(Week 18 to Week 20)
- Number of Participants With Hb Values Within the Target Range at the SEP in Participants Who Transitioned to TIW Vadadustat Dosing(Week 18 to Week 20)
- Number of Participants Requiring at Least One Intravenous (IV) Elemental Iron Supplementation(Up to Week 20)
- Number of Participants Requiring Erythropoiesis-stimulating Agent (ESA) Rescue(Up to Week 20)
- Mean Change From Baseline in Reticulocyte Count(Baseline; Week 1, Week 4, Week 8, Week 11, Week 12, Week 13, Week 16, and Week 20)
- Mean Serum Concentration of Erythropoietin (EPO) for Vadadustat Treatment Groups by Strata of Epoetin Alfa Dose Group(Baseline; Week 1 (pre-dose), Week 1 +1 (Day 8; pre-dose), Week 11 (pre-dose), and Week 13 (pre-dose))
- Geometric Mean Apparent Volume of Distribution (Vz/F) of Vadadustat Following a Single Dose(Day 1; Week 1, Week 1 +1 (Day 8), Week 11: pre-dose, 2h, 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose)