Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Parallel Group, Open-label, Multicenter Study to Investigate the Efficacy and Safety of Oral BAY85-3934 and Active Comparator (Darbepoetin Alfa) in the Maintenance Treatment of Anemia in Pre-dialysis Subjects With Chronic Kidney Disease on Darbepoetin Treatment in Europe and Asia Pacific
Brief Summary: Anaemia is a condition in which blood has a lower than normal number of red blood cells. It can also occur if red blood cells do not contain enough haemoglobin, an oxygen carrying part of blood. Anaemia is common in patients with chronic kidney disease. Healthy kidneys produce a hormone called erythropoietin, which stimulates the bone marrow to produce the proper number of red blood cells needed to carry oxygen to vital organs. Chronic kidney disease is a general term that means that the kidneys are not functioning to their full potential. The study drug, BAY85-3934, is being evaluated as a drug to increase the body's ability to produce erythropoietin.

The purpose of this study is to find out if the study drug, a tablet taken orally, is safe and effective for the treatment of anaemia associated with chronic kidney disease.

The study will enroll 120 patients at multiple locations in Europe, Asia and Australia. Participation will involve a screening visit and between 12 and 15 study visits scheduled over a period of approximately 5 to 7 months. The estimated total duration of study treatment will be 16 weeks. During these scheduled visits patients will undergo a number of procedures to confirm efficacy and safety of the study drug, including measurement of heart rate and blood pressure, physical examination, Electrocardiogram and blood/urine sample collection for laboratory tests.

The study will be conducted at 3 hospitals in the UK. Bayer HealthCare AG is funding this research.


Options:
A: Inclusion Criteria:

* Receiving dialysis for ESRD for ≥3 months. Incident dialysis participants (under Amendment 1 and 2) receiving dialysis for ESRD for ≥ 2 weeks but ≤ 4 months at the time of randomization
* Participants must be on ESA for ≥ 8 weeks prior to screening; incident dialysis participants must be on ESA for ≥ 4 weeks prior to screening.
* Mean of the 3 most recent central lab Hb values during the Screening Period must be ≥ 9.0 g/dL and ≤ 12.0 g/dL (for incident dialysis participants, mean of the 2 most recent Hb values must be ≥ 8.5 g/dL and ≤ 12.0 g/dL); with an absolute difference of ≤ 1.3 g/dL between the highest and the lowest value. Samples are obtained at least 4 days apart (2 days under Amendment 2) and the last Hb value must be within 10 days prior to the randomization visit
* Participants with ferritin level ≥ 100 nanograms (ng)/milliliter (mL) (\<100 ng/mL under Amendment 2) or transferrin saturation (TSAT) ≥ 20% (\<20% under Amendment 2) at screening may qualify upon receiving iron supplement (per local standard of care)
* Participants with a serum folate and Vitamin B12 ≥ lower limit of normal (LLN) (\< LLN under Amendment 2) at screening may qualify upon receiving supplement (per local standard of care)
* Participant's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤3x the upper limit of normal (ULN), and total bilirubin (TBL) is ≤1.5x ULN at screening
* Participant's body weight is 45 kilograms (kg) to 160 kg.

Exclusion Criteria:

* Participant has received an red blood cell (RBC) transfusion within 8 weeks (4 weeks under Amendment 2) prior to randomization
* Participant has known history of myelodysplastic syndrome or multiple myeloma
* Participant has known inherited disease such as thalassemia or sickle cell anemia or other known causes for anemia other than chronic kidney disease.
* Participant has known hemosiderosis, hemochromatosis, coagulation disorder,or hypercoagulable condition
* Participant has known chronic inflammatory disease that could cause anemia
* Participant has anticipated surgery that is expected to cause blood loss
* Participant has known gastrointestinal bleeding
* Participant has history of chronic liver disease (for example, chronic infectious hepatitis,chronic auto-immune liver disease,cirrhosis, or fibrosis of the liver)
* Participant with New York Heart Association (NYHA) Class III or IV congestive heart failure
* Participant has had a heart attack, stroke, seizure, or a thrombotic/thromboembolic event (for example, deep vein thrombosis or pulmonary embolism) within 12 weeks prior to participating in the study
* Participant has uncontrolled high blood pressure within 2 weeks prior to participating in the study
* Participant has a history of malignancy, except for the following: cancers determined to be cured or in remission for ≥2 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.)
* Participant is positive for human immunodeficiency virus (HIV), Hepatitis B surface antigen, or anti-hepatitis C virus antibody
* Participant with prior organ transplant who experience rejection within 6 months or on high doses of immunosuppressive therapy
* Participant has any of the following known untreated conditions; proliferative diabetic retinopathy, diabetic macular edema, macular degeneration or retinal vein occlusion.
B: Inclusion Criteria

* Age (informed consent): \>=20 years of age
* Dialysis: On HD or hemodiafiltration (HDF) given three times weekly for at least 12 weeks prior to screening
* ESAs: Use of one and the same ESA for 10 weeks prior to screening
* ESA dose: Darbepoetin alfa 10 to 60 μg per week, epoetin (including biosimilars) \<=9000 international units (IU) per week, or epoetin beta pegol \<=250 μg per 4 weeks
* Hgb:\>=9.5 g/dL and \<=12.5 g/dL. Determined at the site using an Hgb analyzer
* Iron parameters: Ferritin \>100 nanogram (ng)/millilitre (mL) or transferrin saturation (TSAT) \>20 percent (screening verification only)
* Gender (screening verification only): Female or male

Females: Not pregnant \[demonstrated to be negative for human chorionic gonadotropin (hCG) in serum\], not breast-feeding, and meet at least one of the following:

• Females of non-childbearing potential are defined as follows:

Pre-menopausal with at least one of the following and no plans to utilise assisted reproductive techniques (e.g., in vitro fertilisation or donor embryo transfer):

* History of bilateral tubal ligation or salpingectomy
* History of hysteroscopic tubal occlusion and postoperatively documented bilateral tubal obstruction
* History of hysterectomy
* History of bilateral oophorectomy Postmenopausal defined as A) females 60 years of age or older or B) In females \< 60 years of age, 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with postmenopausal follicle stimulating hormone (FSH) and estradiol concentrations is confirmatory (see separately specified reference ranges)\]. Females on hormone replacement therapy (HRT) whose menopausal status is in doubt will be required to use one of the most effective contraception methods if they wish to continue their HRT during the study. Otherwise they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.

  • Females of childbearing potential must agree to comply with one of the contraception methods listed as requirements in "GlaxoSmithKline (GSK) Listing of Most Effective Contraceptive Methods for Females of Childbearing Potential from 28 days prior to the first dose of study medication until the completion of the follow-up visit.
* Informed consent: Written informed consent, including adherence to the requirements and conditions specified in the consent form and the protocol, must be obtained from each subject.

Exclusion Criteria

CKD-related criteria

* Kidney transplant: Planned living-related kidney transplant during the study

Anemia-related criteria

* Aplasia: History of bone-marrow hypoplasia or pure red cell aplasia
* Other causes of anemia: pernicious anemia, thalassemia, sickle cell anemia, or myelodysplastic syndromes
* Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease OR clinically significant GI bleeding within 10 weeks prior to screening or during a period from screening to Day 1

Cardiovascular disease-related criteria

* Myocardial infarction, acute coronary syndrome, stroke, or transient ischemic attack: Diagnosed within 10 weeks prior to screening or during a period from screening to Day 1
* Heart failure: Chronic Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system
* Corrected QT (QTc) Interval (screening verification only): QTc \>500 milliseconds (msec); or QTc \>530 msec in subjects with bundle branch block Note: QT interval corrected using the Bazett's formula (QTcB) will be used, and electrocardiogram (ECG) can be mechanically or manually read

Other disease-related criteria:

* Liver disease (if any of the following occurs):

  * Alanine transaminase (ALT) \>2 upper limit of normal (ULN)
  * Bilirubin \>1.5×ULN (isolated bilirubin \>1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin is \<35 percent)
  * Current unstable active liver or biliary disease (generally defined by the onset of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, persistent jaundice, or cirrhosis)
* Malignancy: History of malignancy within 2 years prior to screening, currently receiving treatment for cancer, or complex kidney cyst \>3 centimeters (cm) (II F, III or IV based on the Bosniak classification)

Concomitant medication and other study treatment-related criteria

* Iron: Planned use of intravenous iron during the screening phase or during a period from Day 1 to Week 4
* Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.
* Drugs and supplements: Use or planned use of any prescription or non-prescription drugs or dietary supplements that are prohibited during the study period \[prohibited medications: strong inducers and inhibitor of Cytochrome P450 (CYP) 2C8\].
* Prior investigational product exposure: Use of an investigational agent within 30 days or five half lives of the investigational agent (whichever is longer)
* Prior treatment with daprodustat: Any prior treatment with daprodustat for a treatment duration of \>30 days

General health-related criteria

* Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the investigator (or subinvestigator) considers would put the subject at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.
C: Inclusion Criteria:

* Male or female subjects ≥ 18 years of age with anemia of chronic kidney disease (CKD) at screening
* Estimated glomerular filtration rate (eGFR) of \< 60 mL/min/1.73 m2 (Modification of Diet in Renal Disease or the formula according to Matsuo, et al.)
* Not on dialysis and not expected to begin dialysis during the treatment period of the study (at least 16 weeks from randomization)
* Treated with darbepoetin via intravenous (IV) or subcutaneous (SC) route with a weekly, bi-weekly, or monthly dose, having had no more than one dose change within 8 weeks prior to randomization
* At least one kidney
* Mean screening hemoglobin (Hb) concentration of 10.0 to 12.0 g/dL
* Men who agree to use adequate contraception when sexually active or women without childbearing potential

Exclusion Criteria:

* Subjects with significant acute or chronic bleeding, such as overt gastrointestinal bleeding
* Active hemolysis or diagnosis of hemolytic syndrome
* History of myelodysplastic syndrome, multiple myeloma, marrow fibrosis, or pure red-cell aplasia (PRCA)
* History of hemosiderosis or hemochromatosis
* Hereditary hemoglobinopathies (such as sickle cell disease and thalassemia major)
* Aplastic anemia
* Chronic lymphoproliferative diseases
* Proliferative choroidal or retinal disease, such as neovascular age-related macular degeneration or proliferative diabetic retinopathy that is likely to require invasive treatment (intraocular injections or laser photocoagulation) during the study
* Chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosis, rheumatoid arthritis, celiac disease) even if it is currently in remission
* Known hypersensitivity to the study drugs (active substances or excipients of the preparations)
* Uncontrolled and symptomatic hyperparathyroidism
* Uncontrolled active infection
* Previous or concurrent cancer except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, and T1) or any cancer curatively treated \> 3 years prior to randomization
* Any allograft (including renal allograft) in place and on immunosuppressive therapy or a scheduled kidney transplant within the next 16 weeks (being on a waiting list does not exclude the subject)
D: Key Inclusion Criteria:

* 18 to 79 years of age, inclusive
* Chronic Kidney Disease (eGFR \<60 mL/min), not yet on dialysis
* Hemoglobin (Hgb) ≤ 10.5 g/dL
* Transferring saturation ≥ 20%
* Ferritin ≥ 50 ng/mL

Key Exclusion Criteria:

* Body mass index \>42
* Red blood cell transfusion within 12 weeks
* Androgen therapy within the previous 21 days prior to study dosing
* Therapy with any approved or experimental erythropoiesis stimulating agent (ESA) within the 11 weeks prior to the Screening visit
* Participants meeting the criteria of ESA resistance within the previous 4 months
* Individual doses of intravenous iron of greater than 250 mg within the past 21 days
* Aspartate aminotransferase or alanine aminotransferase \>1.8x upper limit of normal (ULN)
* Alkaline phosphatase \>2x ULN
* Total bilirubin \>1.5x ULN
* Uncontrolled hypertension
* New York Heart Association Class III or IV congestive heart failure
* Myocardial infarction, acute coronary syndrome, or stroke within 6 months prior to dosing

Answer: C