This is a Phase IV, randomized, active-controlled, open-label, parallel design, multicenter prospective study to evaluate the effect of roxadustat versus rHuEPO treatment on the gastrointestinal (GI) iron absorption in patients with anemia of Stage 4 and Stage 5 CKD.

This is an open-label study, after eligibility confirmation patients will be randomized in a 1:1 ratio to either roxadustat or rHuEPO arms for 2 weeks.

The study will enroll eligible dialysis and non-dialysis patients ≥18 years of age, who have anemia of CKD, and are either dialysis-dependent (DD) and on a stable dose of rHuEPO within 4 weeks prior to screening, or are non-dialysis-dependent (NDD) and are being treated with rHuEPO (ie, on a stable dose of rHuEPO within 4 weeks prior to screening), or are rHuEPO -naïve at the time of screening.

Each patient will be contacted before the first Screening Visit (Visit 1) for the symptoms of coronavirus disease of 2019 (COVID-19) and for any contact with COVID-19 positive person within the past 14 days.

For each patient, the duration of participation in the study will be approximately 8 to 9 weeks divided into 3 periods: Screening Period (approximately 2-3 weeks); Treatment Period (2 weeks) and Post-Treatment Follow-up Period (4 weeks).

Inclusion Criteria:

Informed consent • Provision of signed and dated, written informed consent form (ICF) prior to any mandatory study specific procedures, sampling, and analyses.

Type of patient and disease characteristics

At Visit 1 prior to screening

Dialysis patients:

• Patients receiving hemodialysis (HD) or peritoneal dialysis (PD) for treatment of end-stage renal disease (ESRD) for at least 12 weeks. Patients treated with HD must have access consisting of an arteriovenous (AV) fistula, AV graft, or tunneled (permanent) catheter. Patients on PD must have a functioning PD catheter in place.
• Hemodialysis patients should be on 3x/week dialysis with evidence of achievement of adequate dialysis as defined by standardized Kt/V ≥2.1 in HD, and total (renal + PD) weekly Kt/V ≥1.7 in PD documented twice during the 16 weeks preceding screening for the study.
• Patients should be on a stable rHuEPO dose as defined by change in rHuEPO dose, not exceeding 20% within 4 weeks prior to screening.

Non-dialysis patients:

• Patients with estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m^2, corresponding to Stage 4 or Stage 5 CKD according to the Kidney Disease Outcomes Quality Initiative (KDOQI), and not receiving dialysis.
• Patients should either be on a stable dose of rHuEPO for 4 weeks before screening or be rHuEPO-naïve.

Dialysis and non-dialysis patients:

• Patients agree not to take any new traditional Chinese medicine (TCM) and not to change, dose, schedule or brand of any TCM from beginning of the Screening Period through the end of the Follow-up Period.

At Visit 1 (screening)

• Ferritin ≥50 ng/mL and transferrin saturation (TSAT) ≥15% in non-dialysis patients
• Ferritin ≥100 ng/mL and TSAT ≥20% in dialysis patients.
• Dry body weight should be 45 to 100 kg.

During the Screening Period:

• Dialysis patients must have a mean Hb level of ≥ 9 to ≤ 12 g/dL based on the mean of the 2 most recent central laboratory Hb values within 0.50 g/dL on 2 assays taken at least 7 days apart during the Screening Period.
• Non-dialysis patients must have a mean Hb level of ≥ 9 to ≤ 12 g/dL for rHuEPO-user patients and ≥ 7 and ≤ 10 g/dL for rHuEPO-naïve patients, based on the mean of the 2 most recent central laboratory Hb values within 0.50 g/dL on 2 assays taken at least 7 days apart during the Screening Period.

At Visit 1 Screening:

• Serum folate level ≥ lower limit of normal (LLN).
• Serum vitamin B12 level ≥ LLN.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3 x ULN and total bilirubin (TBL) ≤ 1.5 x ULN.
• Negative test results on the swab test to rule out active COVID-19 infection. If according to site procedures the test for COVID-19 infection cannot be performed at the first Screening Visit, the test should be performed as soon as possible thereafter but must be performed before the patient returns for the next study visit. Any patient who has had confirmed COVID-19 infection in the past, has fully recovered from symptoms at least 14 days prior to Screening, and has a negative swab test result for COVID-19 infection at Screening, may be included in the study.

Reproduction:

• Serum pregnancy test should be negative for female of childbearing potential at the start of the Screening Period.
• Female patients of childbearing potential and male patients (non-surgically sterile) with a female partner of childbearing potential must, if not practicing complete sexual abstinence, agree to practice a dual method of contraception.

Contraceptive methods must be practiced upon being randomized to the study and through 7 days after the last dose of study treatment. Male patients must not donate or bank sperm during this same time period.

Exclusion Criteria:

Medical conditions

• New York Heart Association Class III or IV congestive heart failure (CHF) at screening.
• Acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (eg, deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.
• History of severe, chronic, end-stage, or uncontrolled autoimmune liver disease with ALT 3 x ULN, or AST > 3 × ULN, or total bilirubin > 1.5 × ULN.
• 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.
• Known and untreated retinal vein occlusion or known and untreated proliferative diabetic retinopathy.
• Systolic BP ≥160 mmHg or diastolic BP ≥95 mmHg (confirmed by repeated measurement), within 2 weeks prior to randomization. Patients may be rescreened once BP is controlled.
• History of prostate cancer, breast cancer, renal cell carcinoma 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.
• Chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythromatosus (SLE), ankylosing spondylitis, psoriatic arthritis or active inflammatory bowel disease that is determined to be the principal cause of anemia.
• Known hemosiderosis, hemochromatosis or hypercoagulable condition.
• Any prior organ transplant or a scheduled organ transplantation date.
• Any current condition leading to active significant blood loss.
• Known allergy to the study treatment or any of its ingredients.
• 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 safety or efficacy assessment or may interfere with study participation.
• Intolerance of oral iron in the past as defined by stomach upset, nausea, vomiting, or diarrhea.
• Active GI bleed.
• Hospitalizations within the 12 weeks preceding study randomization for GI bleeding or Congestive heart failure.
• Life expectancy <6 months.
• Patients who are likely to be initiated on dialysis within the next 3 months per Investigator's assessment at the time of screening.
• Previous bowel resection.
• Coeliac disease.
• Gastroenteritis in the 4 weeks prior to randomization.
• Cognitive disabilities, physical or psychiatric disease that in the opinion of the Investigator/clinician influence the patient's adherence and successful completion of the study.

Prior/concomitant therapy:

• Any treatment with roxadustat or a Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors (HIF-PHI).
• Any red blood cells transfusion within 6 weeks prior to the first Screening Visit, or during the Screening Period.
• Has received another new chemical entity (defined as a compound which has not been approved for marketing) within the 12 weeks prior to Screening Visit.
• Exposure to IV iron or use of TRIFERIC® in dialysate during the Screening Period (ie, 2 weeks before randomization [Day 1]).
• Exposure to iron-chelating agent (eg, deferoxamine/desferrioxamine, deferiprone or deferaxirox therapy) within the 6 weeks prior to the first Screening Visit.

Prior/concurrent clinical study experience:

• Participation in any other clinical study that included drug treatment within at least 4 weeks of screening.

Other exclusions:

• Involvement in the planning and/or conduct of the study (applies to AstraZeneca and FibroGen staff and/or staff at the study site).
• Patient non-adherence to medications or missing >1 dialysis treatments/month per the Investigator's knowledge.
• Previous randomization in the present study.
• History of alcohol or drug abuse within 2 years prior to randomization.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

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