Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3, Multicenter, Randomized, Open-label, Active-Controlled Study of the Safety and Efficacy of Roxadustat in the Treatment of Anemia in Dialysis Patients
Brief Summary: The purpose of this study is to evaluate the efficacy and safety of roxadustat compared to epoetin alfa for the treatment of anemia in chronic kidney disease patients on dialysis.


Options:
A: Inclusion Criteria:

* Receiving chronic, outpatient three times weekly (TIW) in-center hemodialysis for end-stage renal disease for at least 12 weeks prior to 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
* Use of any approved erythropoiesis-stimulating agents (ESAs) for at least the 8 weeks prior to Screening Visit 2
* Two hemoglobin (Hb) values, at least 4 days apart, measured by the central laboratory during Screening within the following prespecified ranges:

  1. Hb values between 8.0 and 11.0 grams per deciliter (g/dL) (inclusive) in the United States;
  2. Hb values between 9.0 and 12.0 g/dL (inclusive) in Europe
* 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

Exclusion Criteria:

* Women of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of investigational medicinal product (IMP). If employing birth control, 2 of the following precautions must be used: vasectomy of partner, tubal ligation, vaginal diaphragm, intrauterine device, or birth control.
* 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
* Women who are breast feeding and/or who have a positive pregnancy test result prior to receiving IMP
* Participants with contraindication to required trial assessment
* Participants who, is in opinion of the investigator or medical monitor, have a medical history or medical findings inconsistent with safety or trial compliance
* 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)
* Participants meeting cut-off of the following equivalent mean weekly doses calculated over 8 weeks prior to Screening Visit 2

  1. Methoxy polyethylene glycol-epoetin beta \> 50 micrograms (µg)/week;
  2. Darbepoetin alfa \> 100 µg/week;
  3. Epoetin analogues \> 23000 International Units (IU)/week
* Active bleeding or recent blood loss within 8 weeks prior to randomization
* Red blood cell transfusion within 8 weeks prior to randomization
* Anticipated to discontinue hemodialysis during the trial
* Judged by the investigator that the participant is likely to need rescue therapy (ESA administration or red blood cell \[RBC\] transfusion) immediately after enrollment in the trial
* 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 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 an ESA
* 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 a new or recurrent episode 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 subjects 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, darbepoetin alfa, or any of their excipients
* Use of an investigational medication within 30 days or 5 half-lives of the investigational medication (whichever is longer), prior to screening or during screening and any prior use of a hypoxia-inducible factor prolyl hydroxylase inhibitor. Participants may participate in another concurrent trial only if that trial is a non-interventional, observational investigation.
* Participants with bilateral native nephrectomy
* Treated with probenecid within the 28-day Screening Period prior to randomization or during the study treatment duration
* Any other reason, which in the opinion of the investigator, would make the participant not suitable for participation in the trial
B: Inclusion Criteria:

* Receiving HD or PD for native kidney end-stage renal disease (ESRD) for 2 weeks to 4 months, prior to randomization
* Mean of the 2 most recent Hb values during the screening period, obtained at least 7 days apart, must be \<10.0 grams (g)/deciliter (dL), with a difference of ≤1.0 g/dL between the 2 values
* Body weight 40 to 140 kilograms (kg)

Exclusion Criteria:

* Previously received erythropoiesis-stimulating agents
* Received IV iron within 4 weeks of randomization
* Received red blood cell transfusion within 8 weeks prior to randomization or anticipated need for transfusion during the treatment period
* Positive for any of the following: human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus antibody (anti-HCV Ab)
* History of chronic liver disease
* Clinically significant infection
* New York Heart Association Class III or IV congestive heart failure
* History of 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
* Chronic inflammatory disease that could impact erythropoiesis (for example, systemic lupus erythematosis, rheumatoid arthritis, celiac disease) even if it is currently in remission
* History of other blood disorders
* Active hemolysis or diagnosis of hemolytic syndrome
* Known bone marrow fibrosis
* Uncontrolled or symptomatic secondary hyperparathyroidism
* History of alcohol or drug abuse within a year prior to randomization, or anticipated inability to avoid consumption of more than 3 alcoholic beverages per day
* History of allergy or sensitivity to oral or IV iron therapy
* Seizure disorder or receiving anti-epilepsy medication for seizure disorder within 12 weeks prior to randomization
* Pregnant or breast-feeding females
C: 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
D: Inclusion Criteria:

1. Age 18 to 75 years
2. Subject has voluntarily signed and dated an informed consent form
3. Chronic Kidney Disease, not receiving dialysis
4. Hemoglobin (Hb) values in 4 screening visits and the mean Hb must be \<10g/dL
5. Aminotransferase levels (alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\]) and total bilirubin must be ≤ upper limit of normal (ULN) during the screening period
6. Serum alkaline phosphatase (ALP) ≤2x ULN during screening period. Subjects with serum ALP values between 1 x and 2 x ULN may be included only if bone-specific ALP (BSAP) is also elevated \> ULN
7. Total bilirubin values must be ≤ULN during screening period
8. Serum folate and vitamin B12 levels above the lower limit of normal (LLN)
9. Body weight: 40 to 100 kg (dry weight) inclusive
10. Body mass index (BMI): 16 to 38 kg/m2 inclusive

Exclusion Criteria:

1. Received any erythropoiesis-stimulating agent (ESA) other than epoetin alfa within 12 weeks prior to Day 1
2. Any clinically significant infection or evidence of an underlying infection such as a white blood cell count (WBC) \> ULN during screening on two separate occasions,
3. Positive for any of the following: human immunodeficiency virus (HIV); hepatitis B surface antigen (HBsAg); anti-hepatitis C virus antibody (anti-HCV Ab)
4. History of chronic liver disease
5. New York Heart Association Class III or IV congestive heart failure
6. Chronic inflammatory disease other than glomerulonephritis that could impact erythropoiesis (e.g., systemic lupus erythematosis, rheumatoid arthritis, celiac disease) even if it is currently in remission
7. Active or chronic gastrointestinal bleeding, or a known coagulation disorder
8. Hemoglobinopathy (e.g., homozygous sickle-cell disease, thalassemia of all types, etc.)
9. Hematological disorders, including myelodysplastic syndrome, multiple myeloma, or pure red cell aplasia
10. History of hemosiderosis, hemochromatosis, polycystic kidney disease, or anephric
11. Active hemolysis or diagnosis of hemolytic syndrome
12. Known bone marrow fibrosis
13. Uncontrolled or symptomatic secondary hyperparathyroidism (PTH\>600ng/L)
14. Any prior organ transplantation
15. Drug-treated gastroparesis, short-bowel syndrome, or any other gastrointestinal condition that may lead to reduced absorption of study drug
16. Serum albumin \<3 g/dL
17. History of alcohol or drug abuse; or a positive drug screen for a substance that has not been prescribed for the subject
18. Prior treatment with FG-4592
19. Use of an investigational medication or treatment, or carryover effect of an investigational treatment expected, during the screening visit, treatment and follow-up period.
20. Use of traditional Chinese medicines (TCM) during the screening visit to Day 1 or plans to use TCM during the study unless approved in advance by the Medical Monitor

Answer: C