Safety and Efficacy Study of Roxadustat (FG-4592) for the Treatment of Anemia in End-Stage Renal Disease (ESRD) Newly Initiated Dialysis Participants
Condition: Anemia in Incident Dialysis Patients
MeSH terms: Anemia
Intervention: Roxadustat; Epoetin Alfa
Intervention description: Roxadustat will be administered per dose and schedule specified in the arm.; Epoetin alfa will be administered TIW according to the epoetin alfa USPI or SmPC, or local SOC.
Intervention MeSH terms: Epoetin Alfa
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1043.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Anemia; Chronic Kidney Disease; Hemoglobin; End-Stage Renal Disease; Incident-Dialysis; Erythropoieitin; Erythropoieisis stimulating-agent; Roxadustat; AZD9941; ASP1517; FG4592

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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).

        Exclusion Criteria:

          -  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:

               1. Experienced rejection of a transplanted organ within 6 months of transplantation

               2. Currently on high doses of immunosuppressive therapy (per discretion of the
                  Investigator)

               3. 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.