An investigator-blinded, randomized, multicenter, active-controlled Phase III study for the treatment of anemia in patients with CKD on hemodialysis

This is an investigator-blinded, randomized, multicenter, active-controlled Phase III study for the treatment of anemia in patients with CKD on hemodialysis. Eligible patients will be randomized to efepoetin alfa or darbepoetin alfa at a ratio of 2:1. An unblinded team will prepare and administer the study drug at the dosages decided by the blinded Investigator.

The study consists of 3 study periods:

• Screening (up to 28 days before Day 1): subjects in screening will continue treatment with epoetin, methoxy polyethylene glycol-epoetin beta, or darbepoetin alfa as per local standard of care.
• Treatment: subjects will discontinue any prior erythropoietin analogue and will be randomized to switch to efepoetin alfa or darbepoetin alfa in a 2:1 ratio.

The aim of the treatment period is to maintain Hb levels between 10.0 g/dL and 12.0 g/dL. It is recommended that study treatment be administered any time after completion of dialysis if dosing is scheduled on a dialysis day to avoid potential bias on study assessments.

• Follow-up (4 weeks) Phone contacts can be done for follow-up for up to Week 56 or at the time of the last patient's Week 56 visit, whichever is shorter.

Inclusion Criteria:

1. Adult males and females ≥ 18 years old.

2. Patient (or patient's legally acceptable representative) has voluntarily signed and dated an informed consent form (ICF), approved by an Ethics Committee (EC) or institutional review board (IRB), after the nature of the study has been explained and the patient has had the opportunity to ask questions.

3. Patient with stage 5 CKD defined by estimated GFR (eGFR, ≤15 mL/min/1.73m2) on adequate HD for a minimum of 12 weeks prior to Day 1. *CKD staging will be based on the five-stage system for classification of CKD based on KDIGO guidelines.

4. Hemodialysis patients with single-pool Kt/V ≥ 1.2 or urea reduction ratio ≥ 65%.

   *Single-pool Kt/V or urea reduction ratio will be based on results measured within 4 weeks prior to screening or during the screening period.

5. Patients must be on stable doses of IV injections of ESA (including biosimilars) for at least 6 weeks prior to Day 1.

   Minimum ESA dose;

   • Epoetin alfa, epoetin beta, and epoetin kappa: ≥1,500 U/week
   • Darbepoetin alfa: ≥20 µg/week
   • Mircera®: ≥30 µg/2 weeks

6. Mean of the 2 most recent local laboratory Hb screening values obtained at least 6 days apart, must be 9.0 g/dL to 12.0 g/dL, inclusive, with a difference of ≤1.5 g/dL between the highest and the lowest value.

7. Patients with serum ferritin ≥100 ng/mL at screening.

8. Patients with transferrin saturation (TSAT) ≥20% at screening.

9. Serum folate concentrations ≥lower limit of normal (LLN) at screening.

10. Serum total vitamin B12 concentrations ≥LLN at screening.

Exclusion Criteria:

1. Active acute or chronic infection, or uncontrolled or symptomatic inflammatory disease other than glomerulonephritis that could impact erythropoiesis (e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac disease), or a C reactive protein level 40> mg/L (high sensitive C-reactive protein level > 10 mg/L).

2. By history or current clinical evidence, patients with active acute hepatitis B virus (HBV) or hepatitis C virus (HCV) infection should be excluded. Routine screening for HBV, HCV, and human immunodeficiency virus (HIV) infection is not required in this protocol. Chronic HBV/HCV infection with liver function tests (LFT) >3 times of normal are excluded. Known HIV positive patients are excluded.

3. History or clinical evidence of cardiovascular, hematologic, hepatic, or any physical conditions that, in the opinion of the Investigator, would compromise participation in the study.

4. Any of the following laboratory abnormalities at screening visit;

   • Alanine transaminase (ALT) >3 x upper limit of normal (ULN)
   • Aspartate aminotransferase (AST) >3 x ULN
   • Total bilirubin >1.5 x ULN

5. Chronic congestive heart failure (New York Heart Association class III or IV).

6. High risk for early withdrawal or interruption of the study (due to myocardial infarction, severe or unstable coronary artery disease, stroke, or severe liver disease) within the 12 weeks before Screening or during Screening.

7. Uncontrolled hypertension defined as a sitting systolic blood pressure ≥170 mmHg and/or diastolic blood pressure ≥100 mmHg.

8. History of active malignancy except for cancers determined to be cured or in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, or in situ cancer at any site.

9. Patients with a history of overt gastrointestinal bleeding or any other bleeding episode associated with a fall in Hb of ≥1 g/dL within the last 8 weeks prior to Screening.

10. Known history of myelodysplastic syndrome, multiple myeloma, hereditary hematologic disease such as thalassemia, sickle cell anemia, pure red cell aplasia, or other known causes for anemia other than CKD, hemosiderosis, hemochromatosis, known coagulation disorder, or hypercoagulable condition.

11. Any prior functioning organ transplant or a scheduled organ transplantation, or anephric state (one or both kidneys).

12. Planned elective surgery that could lead to significant blood loss during the study period.

13. Hypoalbuminemia (Serum albumin <2.5 g/dL) at Screening Visit.

14. Androgen, deferoxamine, deferiprone, or deferasirox therapy within 12 weeks prior to Day 1.

15. Life expectancy of <12 months.

16. Cognitive or psychiatric condition rendering the patient unable to be cooperative with and complete study requirements.

17. Hypersensitivity to any one of the investigational drugs or its excipients.

18. Received a blood transfusion (including RBC transfusion) within the 12 weeks prior to Screening, or blood transfusion is anticipated during the study period (excluding temporary blood transfusion given in case of blood loss due to accident or surgery).

19. Immunosuppressive therapy (tacrolimus/cyclosporine, and other than corticosteroids for a chronic condition) within 12 weeks prior to Day 1.

20. History of alcohol or drug abuse within the past 2 years and inability to avoid consumption of more than >3 alcoholic beverages per day.

21. Use of an investigational medication or treatment, participation in an investigational interventional study, or carryover effect of an investigational treatment expected during the study.

22. Females of childbearing potential or males who are unable/unwilling to take adequate contraceptive precautions defined by the protocol for the duration of the study and for at least 4 months for male subjects and 7 months for female patients after the end of the study. Females with a positive pregnancy test result within 24 hours prior to study entry, are otherwise known to be pregnant, plan to become pregnant in the next 12 months or are currently breastfeeding.

23. Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Sponsor or clinical research organization (CRO) employees directly involved in the conduct of the study.

24. Patients with very limited functional capacity for which a target Hb value of 12 g/dL may have a lower benefit/risk ratio.

25. Any medical condition (patients weighing over 150 kg) that, in the opinion of the Investigator, may pose a safety risk to a patient in this study, may confound efficacy or safety assessment, or may interfere with study participation