|
Key inclusion & exclusion criteria
|
Inclusion Criteria:
- Subject has a diagnosis of CKD, with Kidney Disease Outcomes Quality Initiative
(KDOQI) Stage 3, 4 or 5, not on dialysis; with an Estimated Glomerular Filtration Rate
(eGFR) <60 mL/min/1.73 m^2 estimated using the abbreviated 4-variable Modification of
Diet in Renal Disease (MDRD) equation.
- The mean of the subject's two most recent (prior to randomization) Hb values during
the screening period, obtained at least 4 days apart, must be less than or equal to
10.5 g/dL, with a difference of less than or equal to 1.0 g/dL. The last Hb value must
be within 10 days prior to randomization.
- Subject is deemed suitable for treatment with Erythropoiesis Stimulating Agent (ESA)
using the criteria specified in the Kidney Disease Improving Global Outcomes (KDIGO)
2012 recommendation considering the rate of fall of Hb concentration, prior response
to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy
and the presence of symptoms attributable to anemia.
- Subject has a serum folate level greater than or equal to lower limit of normal (LLN)
at screening.
- Subject has a serum vitamin B12 level greater than or equal to LLN at screening.
- Subject's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are less
than or equal to 3 x upper limit of normal (ULN), and total bilirubin (TBL) is less
than or equal to 1.5 x ULN.
- Subject's body weight is 45.0 kg to a maximum of 160.0 kg.
- Male subject must not donate sperm starting from screening, throughout the study
period and up to 12 weeks after final study drug administration.
Exclusion Criteria:
- Subject has received any Erythropoiesis Stimulating Agent (ESA) treatment within 12
weeks prior to randomization.
- Subject has received any dose of IV iron within 6 weeks prior to randomization.
- Subject has received a Red Blood Cell (RBC) transfusion within 8 weeks prior to
randomization.
- Subject has a known history of myelodysplastic syndrome or multiple myeloma.
- Subject has a known hereditary hematologic disease such as thalassemia or sickle cell
anemia, pure red cell aplasia, or other known causes for anemia other than Chronic
Kidney Disease (CKD).
- Subject has a known hemosiderosis, hemochromatosis, coagulation disorder, or
hypercoagulable condition.
- Subject has a known chronic inflammatory disease that could impact erythropoiesis
(e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it
is currently in remission.
- Subject is anticipated to undergo elective surgery that is expected to lead to
significant blood loss during the study period or anticipated elective coronary
revascularization.
- Subject has active or chronic gastrointestinal bleeding.
- Subject has received any prior treatment with roxadustat or a Hypoxia-inducible factor
prolyl hydroxylase inhibitor (HIF-PHI).
- Subject has been treated with iron-chelating agents within 4 weeks prior to
randomization.
- Subject has a history of chronic liver disease (e.g., cirrhosis or fibrosis of the
liver).
- Subject has known New York Heart Association Class III or IV congestive heart failure.
- Subject has had a 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.
- Subject has one or more contraindications for treatment with darbepoetin alfa:
- Uncontrolled hypertension, or two or more blood pressure values of SBP greater
than or equal to 160 mmHg or DBP greater than or equal to 95 mmHg (within 2 weeks
prior to randomization).
- Known hypersensitivity to darbepoetin alfa, recombinant human erythropoietin, or
any of the excipients.
- Subject has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F
or higher) of renal cell carcinoma as shown on renal ultrasound within 12 weeks prior
to randomization.
- Subject has a history of malignancy, except for the following: cancers determined to
be cured or in remission for greater than or equal to 5 years, curatively resected
basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic
polyps.
- Subject is positive for any of the following:
- human immunodeficiency virus (HIV).
- hepatitis B surface antigen (HBsAg).
- or anti-hepatitis C virus antibody (anti-HCV Ab).
- Subject has an active clinically significant infection that is manifested by White
Blood Count (WBC) > Upper Limit of Normal (ULN), and/or fever, in conjunction with
clinical signs or symptoms of infection within one week prior to randomization.
- Subject has a known untreated proliferative diabetic retinopathy, diabetic macular
edema, macular degeneration or retinal vein occlusion.
- Subject has had any prior organ transplant (that has not been explanted), subject is
scheduled for organ transplantation, or subject is likely to initiate renal
replacement therapy including dialysis within the first year of the study.
- Subject will be excluded from participation if any of the following apply:
- subject has received investigational therapy within 30 days or 5 half lives or
limit set by national law, whichever is longer, prior to initiation of screening,
or
- any condition which makes the subject unsuitable for study participation.
- Subject has an anticipated use of dapsone in any dose amount or chronic use of
acetaminophen/paracetamol >2.0 g/day during the treatment or follow-up period of the
study.
- Subject has a history of alcohol or drug abuse within 2 years prior to randomization
Age minimum:
18 Years
Age maximum:
N/A
Gender:
All
|
|
Secondary Outcome(s)
|
|
Change from BL in Low Density Lipoprotein (LDL) cholesterol to the average LDL cholesterol
[Time Frame: Baseline and weeks 12 to 28]
|
|
Change from BL to each scheduled measurement in Estimated Glomerular Filtration Rate (eGFR), including eGFR slope over time
[Time Frame: Baseline up to End of Study (EOS) (Up to week 108)]
|
|
Change from BL to each scheduled measurement in low density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio
[Time Frame: Baseline up to End of Study (EOS) (up to week 108)]
|
|
Change from BL to each scheduled measurement in total cholesterol
[Time Frame: Baseline up to End of Study (EOS) (Up to week 108)]
|
|
Number of participants with laboratory value abnormalities and/or adverse events related to treatment
[Time Frame: Up to End of Study (EOS) (Up to week 108)]
|
|
Change from BL to each scheduled measurement in Apolipoproteins B (ApoB)
[Time Frame: Baseline up to End of Study (EOS) (Up to week 108)]
|
|
Occurrence of achieved anti-hypertensive treatment goal (SBP < 130 mmHg and DBP< 80 mmHg) based on the mean SBP and mean DBP calculated over weeks 12 to 28 and 36 to 52 of treatment with study drug
[Time Frame: Up to week 52]
|
|
Hb averaged over weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, without use of rescue therapy within 6 weeks prior to and during this evaluation period
[Time Frame: Up to week 104]
|
|
Change from BL in Short Form 36 (SF-36) Physical Functioning (PF) sub-score to the average PF sub-score
[Time Frame: Baseline and weeks 12 to 28]
|
|
Change from BL to each scheduled measurement in HbA1c
[Time Frame: Baseline up to End of Study (EOS) (Up to week 108)]
|
|
Hb value to each post-dosing time point
[Time Frame: Up to End of Study (EOS) (Up to week 108)]
|
|
Hb change from baseline (BL) to the average Hb, without having received rescue therapy within 6 weeks prior to and during this 8-week evaluation period
[Time Frame: Baseline and weeks 28 to 36]
|
|
Change from BL in mean arterial pressure (MAP) to the average MAP value
[Time Frame: Baseline and weeks 20 to 28]
|
|
Change from BL to each scheduled measurement in ApoB/ApoA1 ratio
[Time Frame: Baseline up to End of Study (EOS) (Up to week 108)]
|
|
Change from BL in SF-36 Vitality (VT) sub-score to the average VT sub-score
[Time Frame: Baseline and weeks 12 to 28]
|
|
Change from BL to each scheduled measurement in fasting blood glucose
[Time Frame: Baseline up to End of Study (EOS) (Up to week 108)]
|
|
Change from BL to each scheduled measurement in Transferrin Saturation (TSAT)
[Time Frame: Baseline up to End of Study (EOS) (Up to week 108)]
|
|
Change from BL to the average value in Work Productivity and Activity Impairment-Anemic Symptoms (WPAI:ANS) score
[Time Frame: Baseline, weeks 12 to 28 and weeks 36 to 52]
|
|
Hb change from BL to each post-dosing time point
[Time Frame: Baseline up to End of Study (EOS) (Up to week 108)]
|
|
Occurrence of prespecified adjudicated cerebrovascular events
[Time Frame: Up to End of Study (EOS) (Up to week 108)]
|
|
Proportion of Hb values within 10.0 to 12.0 g/dL in weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, without use of rescue therapy within 6 weeks prior to and during the 8-week evaluation period
[Time Frame: Up to week 104]
|
|
Number of participants with vital signs abnormalities and/or adverse events related to treatment
[Time Frame: Up to End of Study (EOS) (Up to week 108)]
|
|
Hb response
[Time Frame: Up to week 24]
|
|
Occurrence of prespecified adjudicated cardiovascular events
[Time Frame: Up to End of Study (EOS) (Up to week 108)]
|
|
Change from BL to each scheduled measurement serum ferritin
[Time Frame: Baseline up to End of Study (EOS) (Up to week 108)]
|
|
Change from BL to each scheduled measurement in Urine albumin/creatinine ratio (UACR)
[Time Frame: Baseline up to End of Study (EOS) (Up to week 108)]
|
|
Change from BL to the average value in Anemia Subscale ("Additional Concerns") of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score
[Time Frame: Baseline, weeks 12 to 28 and weeks 36 to 52]
|
|
Occurrence of ESRD
[Time Frame: Up to End of Study (EOS) (Up to week 108)]
|
|
Hb change from BL to the average Hb value regardless of rescue therapy
[Time Frame: Baseline and weeks 28 to 52]
|
|
Number of RBC packs per subject
[Time Frame: Up to End of Treatment (EOT) (Up to week 104)]
|
|
Change from BL to the average value in Total FACT-An Score
[Time Frame: Baseline, weeks 12 to 28 and weeks 36 to 52]
|
|
Hb change from BL to the average Hb value regardless of the use of rescue therapy
[Time Frame: Baseline, weeks 28 to 36, weeks 44 to 52, weeks 72 to 80, weeks 96 to 104]
|
|
Change from BL to the average value in Health Related Quality of Life Questionnaire consisting of Five Levels (EQ-5D 5) visual analogue scale (VAS) Score
[Time Frame: Baseline, weeks 12 to 28 and weeks 36 to 52]
|
|
Safety assessed by nature, frequency, and severity of Treatment Emergent AEs (TEAEs)
[Time Frame: Up to End of Study (EOS) (Up to week 108)]
|
|
Change from BL to the average value in Physical Component Score (PCS) of SF-36
[Time Frame: Baseline, weeks 12 to 28 and weeks 36 to 52]
|
|
Mean monthly intravenous(ly) (IV) iron (mg) use per subject
[Time Frame: Up to week 36]
|
|
Number of subjects having received rescue therapy (composite of red blood cell (RBC) transfusions (all subjects) and darbepoetin alfa use (roxadustat treated subjects only)
[Time Frame: Up to End of Treatment (EOT) (Up to week 104)]
|
|
Number of subjects having received RBC transfusions
[Time Frame: Up to End of Treatment (EOT) (Up to week 104)]
|
|
Occurrence (number) of hospitalization(s)
[Time Frame: Up to End of Treatment (EOT) (Up to week 104)]
|
|
Occurrence of hypertension
[Time Frame: Up to week 36]
|
|
Time to first of occurrence of serum creatinine having doubled during study in comparison with baseline
[Time Frame: Up to End of Study (EOS) (Up to week 108)]
|
|
Patients' Global Impression of Change (PGIC)
[Time Frame: Up to End of Treatment (EOT) (up to Week 104)]
|
|
Change from BL to each scheduled measurement in Apolipoproteins (Apo) A1
[Time Frame: Baseline up to End of Study (EOS) (Up to week 108)]
|
|
Change from BL to each scheduled measurement in non-HDL cholesterol
[Time Frame: Baseline up to End of Study (EOS) (Up to week 108)]
|
|
Number of days of hospitalization
[Time Frame: Up to End of Treatment (EOT) (Up to week 104)]
|
|
Occurrence of mean LDL cholesterol < 100 mg/dL (mean LDL calculated over weeks 12 to 28, and weeks 36 to 52 of treatment)
[Time Frame: Up to week 52]
|
|
Safety assessed by 12- lead electrocardiogram (ECG)
[Time Frame: Up to End of Study (EOS) (Up to week 108)]
|
|
Time (weeks) to achieve the first Hb response as defined by primary endpoint
[Time Frame: Up to week 24]
|
|
Time to occurrence of hypertension
[Time Frame: Up to week 36]
|
|
Volume of RBC transfused per subject
[Time Frame: Up to End of Treatment (EOT) (Up to week 104)]
|