Safety and Efficacy Study of Roxadustat (FG-4592) for the Treatment of Anemia in End-Stage Renal Disease (ESRD) Newly Initiated Dialysis Participants

A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study of the Efficacy and Safety of FG-4592 in the Treatment of Anemia in Incident-Dialysis Patients

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02052310

Acronym

Himalayas

Enrollment

1043

Registered

2014-02-03

Start date

2014-02-11

Completion date

2018-09-21

Last updated

2021-10-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Anemia in Incident Dialysis Patients

Keywords

Anemia, Chronic Kidney Disease, Hemoglobin, End-Stage Renal Disease, Incident-Dialysis, Erythropoieitin, Erythropoieisis stimulating-agent, Roxadustat, AZD9941, ASP1517, FG4592

Brief summary

The purpose of this study is to determine whether roxadustat is safe and effective in the treatment of anemia in participants who have just begun dialysis treatment for ESRD.

Detailed description

There is a screening period of up to 6 weeks, a treatment period of a minimum of 52 weeks and a maximum of approximately up to 3 years after last participant is randomized, and a post-treatment follow-up period of 4 weeks. Participants will be randomized in a 1:1 ratio to receive either open-label roxadustat or epoetin alfa (active control).

Interventions

DRUGRoxadustat

Roxadustat will be administered per dose and schedule specified in the arm.

DRUGEpoetin Alfa

Epoetin alfa will be administered TIW according to the epoetin alfa USPI or SmPC, or local SOC.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Participant has been informed of the investigational nature of this study and has given written informed consent in accordance with institutional, local, and national guidelines. * Receiving HD or PD for ESRD for a minimum of 2 weeks and a maximum of 4 months, prior to randomization. * Hemodialysis access consisting of an arteriovenous (AV) fistula, AV graft, or tunnelled (permanent) catheter; or PD catheter in use. * Mean of the two most recent predialysis Hb values during the Screening Period, obtained at least 2 days apart, must be ≤ 10.0 g/dL, with a difference of ≤ 1.3 g/dL between the highest and the lowest values. The last Hb value must be drawn within 10 days prior to randomization. * Ferritin ≥ 100 nanograms (ng)/milliliter (mL) (≥ 220 picomoles (pmol)/L); participants with ferritin level \< 100 ng/mL(\<220 pmol/L) during screening, qualify after receiving iron supplement (per local standard of care), without the need to retest ferritin prior to randomization. * Transferrin saturation ≥ 20%; participants with TSAT level \< 20% during screening, qualify after receiving iron supplement (per local standard of care), without the need to retest TSAT prior to randomization. * Serum folate level, performed within 8 weeks prior to randomization ≥ lower limit of normal (LLN); participants with serum folate level \< LLN during screening, qualify after receiving folate supplement (per local standard of care), without the need to retest folate prior to randomization. * Serum vitamin B12 level, performed within 8 weeks prior to randomization ≥ LLN; participants with vitamin B12 level \< LLN during screening, qualify after receiving B12 supplement (per local standard of care), without the need to retest B12 prior to randomization. * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3 \* upper limit of normal (ULN), and total bilirubin ≤ 1.5 \* ULN. * Body weight up to 160 kg (HD participants: dry weight).

Exclusion criteria

* Total duration of prior effective ESA use must be ≤3 weeks within the preceding 12 weeks at the time informed consent is obtained. Specific dosing guidance, depending on the type of ESAs, injected IV or SC within 12 weeks prior to start of screening are as follows: i) Short-acting ESAs (EPO-alfa or equivalents) - IV: Up to 9 doses, last EPO dose must be ≥2 days prior to start of screening; SC: Up to 3 doses, last EPO dose must be ≥1 week (7 days) prior to start of screening ii) Darbepoetin - IV: Up to 3 doses, last darbepoetin dose must be ≥1 week (7 days) prior to start of screening; SC: Up to 2 doses, last darbepoetin dose must be ≥2 weeks (14 days) prior to start of screening iii) Continuous erythropoietin receptor activator (CERA) IV and SC: Up to 2 doses; last CERA dose must be ≥2 weeks (14 days) prior to start of screening * Intravenous iron: there is no restriction regarding IV iron use during screening, provided it is administered in accordance with local SOC. * Red blood cell transfusion within 4 weeks prior to randomization. * Active, clinically significant infection that could be manifested by white blood cell (WBC) count \> ULN, and/or fever, in conjunction with clinical signs or symptoms of infection at the time of randomization. * History of chronic liver disease (for example, chronic infectious hepatitis, chronic auto-immune liver disease, cirrhosis, or fibrosis of the liver). * New York Heart Association Class III or IV congestive heart failure at screening. * Myocardial infarction, acute coronary syndrome, stroke, seizure, or a thromboembolic event within a major vessel (excluding vascular dialysis access) (for example, deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization. * Uncontrolled hypertension, in the opinion of the Investigator, (for example, that requires a change in anti-hypertensive medication) within 2 weeks prior to randomization. * Renal imaging performed within 12 weeks prior to randomization indicative of a diagnosis or suspicion (for example, complex kidney cyst of Bosniak Category 2 or higher) of renal cell carcinoma. * History of malignancy, except for 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. * Positive for any of the following: human immunodeficiency virus (HIV); hepatitis B surface antigen (HBsAg); or anti-hepatitis C virus antibody (anti-HCV Ab). * Chronic inflammatory disease that could impact erythropoiesis (for example, systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission. * Known, untreated proliferative diabetic retinopathy, diabetic macular edema, macular degeneration, or retinal vein occlusion (participants who are already blind for the above reasons qualify to participate). * Known history of myelodysplastic syndrome or multiple myeloma. * 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). * Known hemosiderosis, hemochromatosis, coagulation disorder, or a hypercoagulable condition. * Organ transplant: participants with any of the following: 1. Experienced rejection of a transplanted organ within 6 months of transplantation 2. Currently on high doses of immunosuppressive therapy (per discretion of the Investigator) 3. Scheduled for organ transplantation. Note: being on a waiting list for kidney transplant is not exclusionary * Anticipated elective surgery, except for vascular access surgery or dialysis catheter placement, that is expected to lead to significant blood loss, or anticipated elective coronary revascularization. * Active or chronic gastrointestinal bleeding. * Any prior treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). * Use of iron-chelating agents within 4 weeks prior to randomization. * Known hypersensitivity reaction to any ESA. * Use of an investigational drug or treatment, participation in an investigational study, or presence of an expected carryover effect of an investigational treatment, within 4 weeks prior to randomization. * Anticipated use of dapsone or androgens at any dose amount or chronic use of acetaminophen or paracetamol \> 2.0 g/day during the study. * History of alcohol or drug abuse within 6 months prior to randomization. * Females of childbearing potential, unless using contraception as detailed in the protocol; male participants with sexual partners of childbearing potential who are not on birth control unless the male participant agrees to use contraception. * Pregnant or breastfeeding females. * Any medical condition that, in the opinion of the Investigator, may pose a safety risk to a participant in this study, may confound efficacy or safety assessment, or may interfere with study participation.

Design outcomes

Primary

Measure	Time frame	Description
US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (ITT Population)	Baseline (Day 1, Week 0), Week 28 to 52	Hb values under the influence of rescue therapy were not censored for the primary analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (erythropoiesis-stimulating agent \[ESA\]) or red blood cell (RBC) transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model, Monotone missing data were imputed by regression from its own treatment group.
Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants Who Achieved a Hb Response at 2 Consecutive Visits at Least 5 Days Apart During First 24 Weeks of Treatment, Without Rescue Therapy Within 6 Weeks Prior to the Hb Response (PPS Population)	Baseline (Day 1, Week 0) up to Week 24	Hb response was defined, using central laboratory values, as: Hb ≥11.0 g/dL and a Hb increase from baseline by ≥1.0 g/dL in participants whose baseline Hb \>8.0 g/dL, or increase in Hb ≥2.0 g/dL in participants whose baseline Hb ≤8.0 g/dL. Rescue therapy for roxadustat treated participant was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion.

Secondary

Measure	Time frame	Description
US (FDA Submission): Hb Responder Rate- Percentage of Participants Who Achieved a Hb Response at 2 Consecutive Visits at Least 5 Days Apart During First 24 Weeks of Treatment, Without Rescue Therapy Within 6 Weeks Prior to the Hb Response (ITT Population)	Baseline (Day 1, Week 0) up to Week 24	Hb response was defined, using central laboratory values, as: Hb ≥11.0 g/dL and a Hb increase from baseline by ≥1.0 g/dL in participants whose baseline Hb \>8.0 g/dL, or increase in Hb ≥2.0 g/dL in participants whose baseline Hb ≤8.0 g/dL. Rescue therapy for roxadustat treated participant was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion.
Ex-US Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (PPS Population)	Baseline (Day 1, Week 0), Week 28 to 52	Hb values under the influence of rescue therapy were censored up to 6 weeks in the analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (ESA or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the MCMC imputation model, Monotone missing data were imputed by regression from its own treatment group.
Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 24	Baseline (Day 1, Week 0), Week 12 to 24	Baseline LDL Cholesterol was defined as the mean of values obtained within 6 weeks prior to the first dose of study treatment.
Mean Change From Baseline in Hb Levels Between Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN)	Baseline (Day 1, Week 0), Week 18 to 24	Hb values under the influence of rescue therapy were not censored in the analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the MCMC imputation model, Monotone missing data were imputed by regression from its own treatment group.
Median Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52	Weeks 28 to 52	Monthly iron use for each participant = Total IV iron in mg / \[(last dose date - first dose date of study medication in the period)+1\]/ 28.
Time to First RBC Transfusion	Baseline (Day 1, Week 0) up to last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa)	Median time to event (weeks) was calculated using Kaplan Meier Survival Estimates.
Percentage of Participants With Exacerbation of Hypertension During Weeks 28 to 52	Weeks 28 to 52	Percentage of participants with exacerbation of hypertension, meeting at least one of the following criteria are reported: i) Increase in BP: An increase from baseline of ≥ 20 mmHg in sBP and sBP \>170 mmHg, or an increase from baseline of ≥15 mmHg dBP and dBP \>100 mmHg.
Time to Achieve the First Hb Response up to Week 24 Censoring for Rescue Therapy	Baseline (Day 1, Week 0) up to Week 24	Hb values under the influence of rescue therapy were censored up to 6 weeks in the analysis. Hb response was defined, using central laboratory values, as: Hb ≥11.0 g/dL and a Hb increase from baseline by ≥1.0 g/dL in participants whose baseline Hb \>8.0 g/dL, or increase in Hb ≥2.0 g/dL in participants whose baseline Hb ≤8.0 g/dL. Rescue therapy for roxadustat treated participant was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Median time to event was calculated using Kaplan Meier Survival Estimates.
Percentage of Participants With Hb ≥10.0 g/dL Averaged Over Weeks 28 to 36 and 28 to 52, Regardless of Rescue Therapy	Weeks 28 to 36 and 28 to 52	Hb values under the influence of rescue therapy were not censored in the analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment.
Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 36), Censoring for Rescue Therapy	Baseline (Day 1, Week 0), Week 28 to 36	Hb values under the influence of rescue therapy were censored up to 6 weeks in the analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment.
Time to First Exacerbation of Hypertension During Weeks 28 to 52	Weeks 28 to 52	An exacerbation of hypertension was defined as increase from baseline of ≥20 mmHg in systolic blood pressure (sBP) and sBP ≥170 mmHg or an increase from baseline of ≥15 mm Hg in diastolic blood pressure (dBP) and dBP ≥100 mmHg. Median time to event (weeks) was calculated using Kaplan Meier Survival Estimates.
Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 8 to 12	Baseline (Day 1, Week 0), Weeks 8 to 12	Baseline MAP was defined as the last MAP value prior to the first dose of study treatment.

Countries

Argentina, Bulgaria, Chile, Colombia, Latvia, Malaysia, Mexico, Poland, Romania, Russia, South Korea, Taiwan, Thailand, Ukraine, United States

Participant flow

Pre-assignment details

Participants were randomized in a 1:1 ratio to receive either roxadustat or epoetin alfa.

Participants by arm

Arm	Count
Roxadustat Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	522
Epoetin Alfa Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.	521
Total	1,043

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	29	22
Overall Study	Death	64	54
Overall Study	Kidney Transplant	23	29
Overall Study	Lack of Efficacy	6	1
Overall Study	Lost to Follow-up	4	2
Overall Study	Other than specified	32	29
Overall Study	Physician Decision	14	7
Overall Study	Protocol Violation	1	6
Overall Study	Site Terminated by Sponsor	5	13
Overall Study	Withdrawal by Subject	37	49

Baseline characteristics

Characteristic	Roxadustat	Epoetin Alfa	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	141 Participants	130 Participants	271 Participants
Age, Categorical Between 18 and 65 years	381 Participants	391 Participants	772 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	99 Participants	77 Participants	176 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	423 Participants	444 Participants	867 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Race American Indian/ Alaskan Native	1 Participants	4 Participants	5 Participants
Race/Ethnicity, Customized Race Asian	43 Participants	51 Participants	94 Participants
Race/Ethnicity, Customized Race Black/African American	44 Participants	50 Participants	94 Participants
Race/Ethnicity, Customized Race Other	19 Participants	16 Participants	35 Participants
Race/Ethnicity, Customized Race White	415 Participants	400 Participants	815 Participants
Sex: Female, Male Female	213 Participants	214 Participants	427 Participants
Sex: Female, Male Male	309 Participants	307 Participants	616 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	64 / 522	54 / 517
other Total, other adverse events	291 / 522	262 / 517
serious Total, serious adverse events	234 / 522	218 / 517

Outcome results

Primary

Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants Who Achieved a Hb Response at 2 Consecutive Visits at Least 5 Days Apart During First 24 Weeks of Treatment, Without Rescue Therapy Within 6 Weeks Prior to the Hb Response (PPS Population)

Hb response was defined, using central laboratory values, as: Hb ≥11.0 g/dL and a Hb increase from baseline by ≥1.0 g/dL in participants whose baseline Hb \>8.0 g/dL, or increase in Hb ≥2.0 g/dL in participants whose baseline Hb ≤8.0 g/dL. Rescue therapy for roxadustat treated participant was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion.

Time frame: Baseline (Day 1, Week 0) up to Week 24

Population: The per protocol set (PPS) population included all participants in the full analysis set (FAS) population (all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment) who received at least 8 weeks of treatment and were without major protocol violations.

Arm	Measure	Value (NUMBER)
Roxadustat	Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants Who Achieved a Hb Response at 2 Consecutive Visits at Least 5 Days Apart During First 24 Weeks of Treatment, Without Rescue Therapy Within 6 Weeks Prior to the Hb Response (PPS Population)	88.2 percentage of participants
Epoetin Alfa	Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants Who Achieved a Hb Response at 2 Consecutive Visits at Least 5 Days Apart During First 24 Weeks of Treatment, Without Rescue Therapy Within 6 Weeks Prior to the Hb Response (PPS Population)	84.4 percentage of participants

Comparison: For the difference of responder rates between 2 treatment groups, the CI was analyzed from the Miettinen \& Nurminen approach adjusting for randomization stratification factors.95% CI: [-0.7, 7.7]

Primary

US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (ITT Population)

Hb values under the influence of rescue therapy were not censored for the primary analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (erythropoiesis-stimulating agent \[ESA\]) or red blood cell (RBC) transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model, Monotone missing data were imputed by regression from its own treatment group.

Time frame: Baseline (Day 1, Week 0), Week 28 to 52

Population: The ITT population included all randomized participants.

Arm	Measure	Group	Value (MEAN)	Dispersion
Roxadustat	US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (ITT Population)	Baseline	8.43 g/dL	Standard Deviation 1.044
Roxadustat	US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (ITT Population)	Change at Week 28 to 52	2.57 g/dL	Standard Deviation 1.269
Epoetin Alfa	US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (ITT Population)	Baseline	8.46 g/dL	Standard Deviation 0.964
Epoetin Alfa	US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (ITT Population)	Change at Week 28 to 52	2.36 g/dL	Standard Deviation 1.214

Comparison: Treatment comparison was made using the multiple imputation (MI) strategy by combining the results of analysis of covariance (ANCOVA) model with baseline Hb as a covariate, and treatment, region and cardiovascular/cerebrovascular/thromboembolic medical history (yes vs. no) as factors.p-value: 0.000595% CI: [0.079, 0.287]ANCOVA

Secondary

Ex-US Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (PPS Population)

Hb values under the influence of rescue therapy were censored up to 6 weeks in the analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (ESA or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the MCMC imputation model, Monotone missing data were imputed by regression from its own treatment group.

Time frame: Baseline (Day 1, Week 0), Week 28 to 52

Population: The PPS population included all participants in the FAS population (all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment) who received at least 8 weeks of treatment and were without major protocol violations. Here, 'Number analyzed' signifies participants with non-missing data for this outcome measure at specified timepoint.

Arm	Measure	Group	Value (MEAN)	Dispersion
Roxadustat	Ex-US Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (PPS Population)	Baseline	8.43 g/dL	Standard Deviation 1.043
Roxadustat	Ex-US Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (PPS Population)	Change at Week 28 to 52	2.62 g/dL	Standard Deviation 1.292
Epoetin Alfa	Ex-US Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (PPS Population)	Baseline	8.43 g/dL	Standard Deviation 0.963
Epoetin Alfa	Ex-US Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (PPS Population)	Change at Week 28 to 52	2.44 g/dL	Standard Deviation 1.209

Comparison: Treatment comparison was made using mixed model for repeated measures (MMRM) with baseline Hb as a covariate, and treatment, visit, visit-by-treatment interaction and randomization stratification factors except mean qualifying screening hemoglobin (≤8.0 vs. \>8.0 g/dL) as fixed effects.p-value: 0.014895% CI: [0.032, 0.296]Mixed Models Analysis

Secondary

Mean Change From Baseline in Hb Levels Between Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN)

Hb values under the influence of rescue therapy were not censored in the analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the MCMC imputation model, Monotone missing data were imputed by regression from its own treatment group.

Time frame: Baseline (Day 1, Week 0), Week 18 to 24

Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Arm	Measure	Group	Value (MEAN)	Dispersion
Roxadustat	Mean Change From Baseline in Hb Levels Between Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN)	Baseline	8.54 g/dL	Standard Deviation 0.968
Roxadustat	Mean Change From Baseline in Hb Levels Between Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN)	Change at Week 18 to 24	2.34 g/dL	Standard Deviation 1.256
Epoetin Alfa	Mean Change From Baseline in Hb Levels Between Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN)	Baseline	8.38 g/dL	Standard Deviation 0.961
Epoetin Alfa	Mean Change From Baseline in Hb Levels Between Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN)	Change at Week 18 to 24	2.48 g/dL	Standard Deviation 1.271

Comparison: Treatment comparison was made using the multiple imputation strategy by combining the results of ANCOVA model with baseline Hb as a covariate, and treatment, region and cardiovascular/cerebrovascular/thromboembolic medical history (yes vs. no) as factors.p-value: 0.817895% CI: [-0.171, 0.217]ANCOVA

Secondary

Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 24

Baseline LDL Cholesterol was defined as the mean of values obtained within 6 weeks prior to the first dose of study treatment.

Time frame: Baseline (Day 1, Week 0), Week 12 to 24

Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment. Here, 'Number analyzed' signifies participants with non-missing data for this outcome measure at specified timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Roxadustat	Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 24	Baseline	109.12 mg/dL	Standard Deviation 38.833
Roxadustat	Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 24	Change at Weeks 12 to 24	-23.80 mg/dL	Standard Deviation 29.996
Epoetin Alfa	Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 24	Baseline	109.22 mg/dL	Standard Deviation 35.914
Epoetin Alfa	Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 24	Change at Weeks 12 to 24	-5.39 mg/dL	Standard Deviation 26.164

Comparison: Treatment comparison was made using a MMRM with baseline LDL cholesterol as a covariate, and treatment, visit, visit-by-treatment interaction and randomization stratification factors as fixed effects.p-value: <0.000195% CI: [-21.448, -15.232]Mixed Models Analysis

Secondary

Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 8 to 12

Baseline MAP was defined as the last MAP value prior to the first dose of study treatment.

Time frame: Baseline (Day 1, Week 0), Weeks 8 to 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Roxadustat	Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 8 to 12	Baseline	99.33 millimeters of mercury (mmHg)	Standard Deviation 10.146
Roxadustat	Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 8 to 12	Change at Weeks 8 to 12	-0.12 millimeters of mercury (mmHg)	Standard Deviation 8.018
Epoetin Alfa	Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 8 to 12	Baseline	99.04 millimeters of mercury (mmHg)	Standard Deviation 9.874
Epoetin Alfa	Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 8 to 12	Change at Weeks 8 to 12	1.15 millimeters of mercury (mmHg)	Standard Deviation 8.729

Secondary

Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 36), Censoring for Rescue Therapy

Time frame: Baseline (Day 1, Week 0), Week 28 to 36

Arm	Measure	Value (MEAN)	Dispersion
Roxadustat	Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 36), Censoring for Rescue Therapy	2.70 g/dL	Standard Deviation 1.423
Epoetin Alfa	Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 36), Censoring for Rescue Therapy	2.46 g/dL	Standard Deviation 1.308

Secondary

Median Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52

Monthly iron use for each participant = Total IV iron in mg / \[(last dose date - first dose date of study medication in the period)+1\]/ 28.

Time frame: Weeks 28 to 52

Arm	Measure	Value (MEDIAN)
Roxadustat	Median Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52	0.00 mg/PEM
Epoetin Alfa	Median Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52	26.86 mg/PEM

Comparison: Treatment comparison was made using an ANCOVA model with baseline iron repletion status, treatment, and randomization stratification factors as fixed effects.p-value: 0.00028Rank ANCOVA

Secondary

Percentage of Participants With Exacerbation of Hypertension During Weeks 28 to 52

Percentage of participants with exacerbation of hypertension, meeting at least one of the following criteria are reported: i) Increase in BP: An increase from baseline of ≥ 20 mmHg in sBP and sBP \>170 mmHg, or an increase from baseline of ≥15 mmHg dBP and dBP \>100 mmHg.

Time frame: Weeks 28 to 52