Study of Vadadustat in Hemodialysis Participants With Anemia Switching From Epoetin Alfa
Condition: Anemia; Dialysis-dependent Chronic Kidney Disease
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia
Intervention: Vadadustat; Epoetin Alfa; Vadadustat TIW
Intervention description: Vadadustat Tablets 150 mg; Epoetin Alfa; Oral Vadadustat
Intervention MeSH terms: Epoetin Alfa; Glycine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized, Open-Label, Active-Controlled
Masking: None (Open Label)
Enrollment: 175.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Vadadustat; AKB-6548; Anemia; Chronic kidney disease (CKD); erythropoietin

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  ≥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:

               1. Main study: Mean weekly Epoetin Alfa dose <300 Units per kilogram per week
                  (U/kg/week) for 8 weeks prior to SV2;

               2. 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:.

               1. Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive;

               2. 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

        Exclusion Criteria:

          -  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:

               1. inability to confirm surgical sterility (e.g., hysterectomy, bilateral tubal
                  ligation, bilateral oophorectomy) at least 1 month prior to Screening;

               2. not considered post-menopausal (no menses for >1 year with follicle stimulating
                  hormone >40 U/Liter at Screening)

          -  For female participants of childbearing potential:

               1. lack of confirmation of the use of acceptable forms of contraception* for a
                  minimum of one complete menstrual cycle prior to Screening;

               2. positive serum pregnancy test at SV2;

               3. 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.