A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study of the Efficacy and Safety of FG-4592 in the Treatment of Anemia in Incident-Dialysis Patients
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- FibroGen
- 入组人数
- 1,043
- 试验地点
- 8
- 主要终点
- US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (ITT Population)
研究概览
简要总结
The purpose of this study is to determine whether roxadustat is safe and effective in the treatment of anemia in participants who have just begun dialysis treatment for ESRD.
详细描述
There is a screening period of up to 6 weeks, a treatment period of a minimum of 52 weeks and a maximum of approximately up to 3 years after last participant is randomized, and a post-treatment follow-up period of 4 weeks. Participants will be randomized in a 1:1 ratio to receive either open-label roxadustat or epoetin alfa (active control).
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
- •Participant has been informed of the investigational nature of this study and has given written informed consent in accordance with institutional, local, and national guidelines.
- •Receiving HD or PD for ESRD for a minimum of 2 weeks and a maximum of 4 months, prior to randomization.
- •Hemodialysis access consisting of an arteriovenous (AV) fistula, AV graft, or tunnelled (permanent) catheter; or PD catheter in use.
- •Mean of the two most recent predialysis Hb values during the Screening Period, obtained at least 2 days apart, must be ≤ 10.0 g/dL, with a difference of ≤ 1.3 g/dL between the highest and the lowest values. The last Hb value must be drawn within 10 days prior to randomization.
- •Ferritin ≥ 100 nanograms (ng)/milliliter (mL) (≥ 220 picomoles (pmol)/L); participants with ferritin level < 100 ng/mL(<220 pmol/L) during screening, qualify after receiving iron supplement (per local standard of care), without the need to retest ferritin prior to randomization.
- •Transferrin saturation ≥ 20%; participants with TSAT level < 20% during screening, qualify after receiving iron supplement (per local standard of care), without the need to retest TSAT prior to randomization.
- •Serum folate level, performed within 8 weeks prior to randomization ≥ lower limit of normal (LLN); participants with serum folate level < LLN during screening, qualify after receiving folate supplement (per local standard of care), without the need to retest folate prior to randomization.
- •Serum vitamin B12 level, performed within 8 weeks prior to randomization ≥ LLN; participants with vitamin B12 level < LLN during screening, qualify after receiving B12 supplement (per local standard of care), without the need to retest B12 prior to randomization.
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3 * upper limit of normal (ULN), and total bilirubin ≤ 1.5 * ULN.
- •Body weight up to 160 kg (HD participants: dry weight).
排除标准
- •Total duration of prior effective ESA use must be ≤3 weeks within the preceding 12 weeks at the time informed consent is obtained.
- •Specific dosing guidance, depending on the type of ESAs, injected IV or SC within 12 weeks prior to start of screening are as follows:
- •i) Short-acting ESAs (EPO-alfa or equivalents) - IV: Up to 9 doses, last EPO dose must be ≥2 days prior to start of screening; SC: Up to 3 doses, last EPO dose must be ≥1 week (7 days) prior to start of screening ii) Darbepoetin - IV: Up to 3 doses, last darbepoetin dose must be ≥1 week (7 days) prior to start of screening; SC: Up to 2 doses, last darbepoetin dose must be ≥2 weeks (14 days) prior to start of screening iii) Continuous erythropoietin receptor activator (CERA) IV and SC: Up to 2 doses; last CERA dose must be ≥2 weeks (14 days) prior to start of screening
- •Intravenous iron: there is no restriction regarding IV iron use during screening, provided it is administered in accordance with local SOC.
- •Red blood cell transfusion within 4 weeks prior to randomization.
- •Active, clinically significant infection that could be manifested by white blood cell (WBC) count > ULN, and/or fever, in conjunction with clinical signs or symptoms of infection at the time of randomization.
- •History of chronic liver disease (for example, chronic infectious hepatitis, chronic auto-immune liver disease, cirrhosis, or fibrosis of the liver).
- •New York Heart Association Class III or IV congestive heart failure at screening.
- •Myocardial infarction, acute coronary syndrome, stroke, seizure, or a thromboembolic event within a major vessel (excluding vascular dialysis access) (for example, deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.
- •Uncontrolled hypertension, in the opinion of the Investigator, (for example, that requires a change in anti-hypertensive medication) within 2 weeks prior to randomization.
- •Renal imaging performed within 12 weeks prior to randomization indicative of a diagnosis or suspicion (for example, complex kidney cyst of Bosniak Category 2 or higher) of renal cell carcinoma.
- •History of malignancy, except for the following: cancers determined to be cured or in remission for ≥ 5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.
- •Positive for any of the following: human immunodeficiency virus (HIV); hepatitis B surface antigen (HBsAg); or anti-hepatitis C virus antibody (anti-HCV Ab).
- •Chronic inflammatory disease that could impact erythropoiesis (for example, systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission.
- •Known, untreated proliferative diabetic retinopathy, diabetic macular edema, macular degeneration, or retinal vein occlusion (participants who are already blind for the above reasons qualify to participate).
- •Known history of myelodysplastic syndrome or multiple myeloma.
- •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).
- •Known hemosiderosis, hemochromatosis, coagulation disorder, or a hypercoagulable condition.
- •Organ transplant: participants with any of the following:
- •Experienced rejection of a transplanted organ within 6 months of transplantation
- •Currently on high doses of immunosuppressive therapy (per discretion of the Investigator)
- •Scheduled for organ transplantation. Note: being on a waiting list for kidney transplant is not exclusionary
- •Anticipated elective surgery, except for vascular access surgery or dialysis catheter placement, that is expected to lead to significant blood loss, or anticipated elective coronary revascularization.
- •Active or chronic gastrointestinal bleeding.
- •Any prior treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI).
- •Use of iron-chelating agents within 4 weeks prior to randomization.
- •Known hypersensitivity reaction to any ESA.
- •Use of an investigational drug or treatment, participation in an investigational study, or presence of an expected carryover effect of an investigational treatment, within 4 weeks prior to randomization.
- •Anticipated use of dapsone or androgens at any dose amount or chronic use of acetaminophen or paracetamol > 2.0 g/day during the study.
- •History of alcohol or drug abuse within 6 months prior to randomization.
- •Females of childbearing potential, unless using contraception as detailed in the protocol; male participants with sexual partners of childbearing potential who are not on birth control unless the male participant agrees to use contraception.
- •Pregnant or breastfeeding females.
- •Any medical condition that, in the opinion of the Investigator, may pose a safety risk to a participant in this study, may confound efficacy or safety assessment, or may interfere with study participation.
研究组 & 干预措施
Roxadustat
Participants will receive roxadustat tablets, administered orally 3 times weekly (TIW). Initial roxadustat dose will be based on a tiered, weight-based dosing scheme (low weight [≤70 kilograms (kg)] and high weight [>70 to 160 kg] participants will receive 70 and 100 milligrams [mg] roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target hemoglobin (Hb) values (10-12 grams [g]/deciliter [dL]) will be based upon regular monitoring of Hb. The maximum roxadustat dose is 3.0 mg/kg per dose or 400 mg per administration (whichever is lower).
干预措施: Roxadustat (Drug)
Epoetin Alfa
Participants on hemodialysis (HD) will receive epoetin alfa, administered intravenously (IV) TIW, with starting doses and dose adjustment rules as per United States Package Insert (USPI) or summary of product characteristics (SmPC). Participants on home HD or peritoneal dialysis (PD) will receive epoetin alfa, administered subcutaneously (SC) as per the country-specific product label (USPI or SmPC) or local standard of care (SOC).
干预措施: Epoetin Alfa (Drug)
结局指标
主要结局
US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (ITT Population)
时间窗: Baseline (Day 1, Week 0), Week 28 to 52
Hb values under the influence of rescue therapy were not censored for the primary analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (erythropoiesis-stimulating agent \[ESA\]) or red blood cell (RBC) transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model, Monotone missing data were imputed by regression from its own treatment group.
Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants Who Achieved a Hb Response at 2 Consecutive Visits at Least 5 Days Apart During First 24 Weeks of Treatment, Without Rescue Therapy Within 6 Weeks Prior to the Hb Response (PPS Population)
时间窗: Baseline (Day 1, Week 0) up to Week 24
Hb response was defined, using central laboratory values, as: Hb ≥11.0 g/dL and a Hb increase from baseline by ≥1.0 g/dL in participants whose baseline Hb \>8.0 g/dL, or increase in Hb ≥2.0 g/dL in participants whose baseline Hb ≤8.0 g/dL. Rescue therapy for roxadustat treated participant was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion.
次要结局
- Ex-US Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (PPS Population)(Baseline (Day 1, Week 0), Week 28 to 52)
- Time to First RBC Transfusion(Baseline (Day 1, Week 0) up to last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa))
- Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 24(Baseline (Day 1, Week 0), Week 12 to 24)
- Time to First Exacerbation of Hypertension During Weeks 28 to 52(Weeks 28 to 52)
- Percentage of Participants With Hb ≥10.0 g/dL Averaged Over Weeks 28 to 36 and 28 to 52, Regardless of Rescue Therapy(Weeks 28 to 36 and 28 to 52)
- US (FDA Submission): Hb Responder Rate- Percentage of Participants Who Achieved a Hb Response at 2 Consecutive Visits at Least 5 Days Apart During First 24 Weeks of Treatment, Without Rescue Therapy Within 6 Weeks Prior to the Hb Response (ITT Population)(Baseline (Day 1, Week 0) up to Week 24)
- Median Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52(Weeks 28 to 52)
- Mean Change From Baseline in Hb Levels Between Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN)(Baseline (Day 1, Week 0), Week 18 to 24)
- Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 8 to 12(Baseline (Day 1, Week 0), Weeks 8 to 12)
- Percentage of Participants With Exacerbation of Hypertension During Weeks 28 to 52(Weeks 28 to 52)
- Time to Achieve the First Hb Response up to Week 24 Censoring for Rescue Therapy(Baseline (Day 1, Week 0) up to Week 24)
- Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 36), Censoring for Rescue Therapy(Baseline (Day 1, Week 0), Week 28 to 36)