Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III, Double Blind, Confirmatory Study of MT-6548 Compared to Darbepoetin Alfa in Hemodialysis Subjects With Anemia Associated With Chronic Kidney Disease in Japan
Brief Summary: For hemodialysis subjects currently receiving ESAs with anemia associated with chronic kidney disease, demonstrate non-inferiority of MT-6548 compared to darbepoetin alfa using Hb value and evaluate long-term safety of MT-6548.


Options:
A: Inclusion Criteria:

* Subjects who were diagnosed with non-dialysis Chronic Kidney Disease and who are considered not to require renal replacement therapy during the study period
* Subjects with renal anemia who have been receiving erythropoiesis stimulating agent (ESA) by subcutaneous injection and whose Hb values are considered stable.
* Mean of the subject's two most recent Hb values before randomization during the Screening Period must be ≥10.0 g/dL and ≤12.0 g/dL
* Either transferrin saturation ≥ 20% or serum ferritin ≥ 100 ng/mL
* Female subject must either:

Be of non-childbearing potential:

* post-menopausal, or
* documented surgically sterile Or, if of childbearing potential,
* Agree not to try to become pregnant during the study and for 28 days after the final study drug administration
* And have a negative urine pregnancy test at pre-screening
* And, if heterosexually active, agree to consistently use two forms of highly effective birth control\* (at least one of which must be a barrier method) starting at pre-screening and throughout the study period and continued for 28 days after the final study drug administration.

  * Female subject must agree not to breastfeed starting at pre-screening and throughout the study period, and continued for 28 days after the final study drug administration.
  * Female subject must not donate ova starting at pre-screening and throughout the study period, and continued for 28 days after the final study drug administration.
  * Male subject and their female spouse/partners who are of childbearing potential must be using two forms of highly effective birth control (at least one of which must be a barrier method) starting at pre-screening and continue throughout the study period, and for 12 weeks after the final study drug administration
  * Male subject must not donate sperm starting at pre-screening and throughout the study period and, for 12 weeks after the final study drug administration

Exclusion Criteria:

* Concurrent retinal neovascular lesion untreated or macular edema untreated, and patients with any condition that significantly compromises the ability to visualize the retina
* Concurrent autoimmune disease with inflammation that could impact erythropoiesis
* History of gastric/intestinal resection considered influential on the absorption of drugs in the gastrointestinal tract (excluding resection of gastric or colon polyps) or concurrent gastro-paresis
* Uncontrolled hypertension
* Concurrent congestive heart failure (NYHA Class III or higher)
* History of hospitalization for treatment of stroke, myocardial infarction, or pulmonary embolism within 12 weeks before the pre-screening assessment
* Positive for hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV) antibody at the pre-screening assessment, or positive for human immunodeficiency virus (HIV) in a past test
* Concurrent other form of anemia than renal anemia
* History of pure red cell aplasia
* Having received treatment with protein anabolic hormone, testosterone enanthate, or mepitiostane within 6 weeks before the pre-screening assessment
* Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), or total bilirubin that is greater than the criteria, or previous or concurrent another serious liver disease at pre-screening assessment
* Previous or current malignant tumor (no recurrence for at least 5 years is eligible.)
* Having undergone red blood transfusion and/or a surgical procedure consider to promote anemia and/or ophthalmological surgery within 4 weeks before the pre-screening assessment
* Having undergone a kidney transplantation
* History of serious drug allergy including anaphylactic shock
* Having a previous history of treatment with ASP1517 or participation in this study
* Participation in another clinical study or post-marketing clinical study (including that of a medical device) within 12 weeks before informed consent acquisition
B: 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.
C: Inclusion Criteria:

* Diagnosis of CKD
* Receiving hemodialysis or hemodiafiltration 3 times a week for more than 12 weeks prior to the screening period, excluding receiving home dialysis or combination of peritoneal dialysis.
* Being treated with ESAs for the recent 8 weeks prior to the screening period
* Mean of the two screening Hb levels closest in time to the baseline visit is ≥9.5 g/dL and ≤12.0 g/dL
* Fluctuation between the two Hb levels closest in time to the baseline visit during the screening period less than 1.5 g/dL
* Serum ferritin ≥ 100 ng/mL, or TSAT ≥20% during the screening period
* Folate and vitamin B12 ≥ lower limit of normal during the screening period

Exclusion Criteria:

* Anemia due to a main cause other than CKD: sickle cell disease, myelodysplastic syndrome, bone marrow fibrosis, hematologic malignancy, hemolytic anemia, thalassemia, or pure red cell aplasia
* Active bleeding or recent blood loss within 8 weeks prior to the screening period
* RBC transfusion within 8 weeks prior to the screening period
* Received testosterone enanthate or mepitiostane within 8 weeks prior to the screening period
* AST, ALT, or total bilirubin \>2.5 x upper limit of normal during the screening period
* Uncontrolled hypertension (diastolic blood pressure \>110 mm Hg or systolic blood pressure \>180 mm Hg) at the first day of the screening period and Day 1
* Ophthalmic examinations during the screening period correspond to either of the following criteria;

  * No available fundal findings
  * Findings indicating the presence of active fundal disease
* Severe heart failure (New York Heart Association Class IV)
* Cerebrovascular disorder or acute coronary syndrome (hospitalization due to unstable angina or myocardial infarction), requiring hospitalization due to urgent percutaneous intervention for coronary or heart failure within 12 weeks prior to the screening period
* Current or history of malignancy. History of malignancy with no recurrence for the recent 5 years is not an exclusion criterion
* New onset or recurrent event of deep vein thrombosis or pulmonary embolism within 12 weeks prior to the screening period
* Current or history of hemosiderosis or hemochromatosis
* History of prior organ transplantation or scheduled organ transplant, or prior transplantation of hematopoietic stem cell or bone marrow
* Males and females of childbearing potential who are unwilling to use an acceptable method of contraception during the designated period (Males: during the study and 90 days after the last dose, females: during study and 30 days after the last dose)
* Females who are pregnant or breast feeding, or are predicted to be pregnant
D: Inclusion criteria:

1. Provision of Informed Consent prior to any study specific procedures
2. Age ≥18 years at screening visit 1
3. Previous versions of the protocol prior to US amendment ver 6.0 and outside of US amendment ver 7.0:

   Receiving or initiating hemodialysis or peritoneal dialysis for treatment of native kidney end-stage renal disease (ESRD) at least 30 days prior to visit 1. Patients treated with hemodialysis must have access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) catheter. Patients on peritoneal dialysis must have a functioning peritoneal dialysis catheter in place.

   Starting with US amendment ver. 6.0 and outside of US amendment ver 7.0 (changed to recruit incident dialysis patients only):

   Receiving or initiating hemodialysis or peritoneal dialysis for treatment of native kidney end-stage renal disease (ESRD) for a minimum of 2 weeks and a maximum of 4 months prior to randomization. Patients treated with hemodialysis must have access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) catheter. Patients on peritoneal dialysis must have a functioning peritoneal dialysis catheter in place.
4. Two central laboratory Hb values during the screening period, obtained at least 7 days apart, must be \<12 g/dL in patients currently treated with an erythropoietin analogue or \<10 g/dL in patients not currently treated with an erythropoietin analogue. Patients are considered not currently treated if they have not received either Mircera® for at least 8 weeks or any other erythropoietin analogue for at least 4 weeks prior to visit 1.
5. Ferritin ≥100 ng/mL at randomization (obtained from screening visit)
6. TSAT ≥20% at randomization (obtained from screening visit)
7. Serum folate level ≥ lower limit of normal (LLN) at randomization (obtained from screening visit)
8. Serum vitamin B12 level ≥ LLN at randomization (obtained from screening visit)
9. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3x upper limit of normal (ULN), and total bilirubin (Tbili) ≤1.5 x ULN at randomization (obtained from screening visit)
10. Body weight 45 to 160 kg (prescribed dry weight)

Exclusion criteria:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
2. Previous randomisation in the present study
3. New York Heart Association Class III or IV congestive heart failure at enrolment
4. Myocardial infarction, acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization
5. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic auto-immune liver disease, cirrhosis or fibrosis of the liver)
6. Known hereditary hematologic disease such as thalassemia, sickle cell anemia, a history of pure red cell aplasia or other known causes for anemia other than CKD
7. Known and untreated retinal vein occlusion or known and untreated proliferative diabetic retinopathy (risk for retinal vein thrombosis)
8. Diagnosis or suspicion (e.g. complex kidney cyst of Bosniak Category IIF, III or IV) of renal cell carcinoma on renal ultrasound (or other imaging procedure e.g. CT scan or MRI) conducted at screening or within 12 weeks prior to randomization.
9. Uncontrolled hypertension at the time of randomization (defined as systolic BP ≥180 mmHg or diastolic BP ≥100 mmHg on repeated measurement post-dialysis in hemodialysis patients or at any time in peritoneal dialysis patients), contraindication to epoetin alfa treatment (e.g., pure red cell aplasia, hypersensitivity or know inability to tolerate epoetin alfa)
10. History of prostate cancer, breast cancer or any other malignancy, except 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.
11. Positive for any of the following: human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus antibody (anti-HCV Ab)
12. Chronic inflammatory diseases such as rheumatoid arthritis, SLE, ankylosing spondylitis, psoriatic arthritis or inflammatory bowel disease that is determined to be the principal cause of anemia
13. Known hemosiderosis, hemochromatosis or hypercoagulable condition
14. Any prior organ transplant with the exception of an autologous renal transplant or a renal transplant that was subsequently removed ("explanted") or scheduled organ transplantation date
15. Any red blood cell (RBC) transfusion during the screening period
16. Any current condition leading to active significant blood loss
17. Any prior treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI)
18. Has received another new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment within the month preceding the first administration of IP in this study. (Note: patients consented and screened, but not randomized in this study or a previous study are not excluded)
19. History of alcohol or drug abuse within 2 years prior to randomization
20. Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence (see Section 3.8)
21. Pregnant or breastfeeding females
22. Known allergy to the investigational product or any of its ingredients
23. Any medical condition, including active, clinically significant infection, that in the opinion of the investigator or Sponsor may pose a safety risk to a patient in this study, which may confound efficacy or safety assessment, or may interfere with study participation

Answer: C