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Study to Evaluate the Efficacy and Safety of Roxadustat in the Treatment of Anemia in Participants With ESRD on Stable Dialysis

Sponsor
FibroGen (Industry)
Overall Status
Completed
CT.gov ID
NCT02273726
Collaborator
Astellas Pharma Europe B.V. (Industry), AstraZeneca (Industry)
741
Enrollment
76
Locations
2
Arms
44.1
Actual Duration (Months)
9.8
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the efficacy and safety of roxadustat compared with active control (epoetin alfa) for the maintenance treatment of anemia in participants with ESRD on dialysis.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

This study will consist of three study periods as follows:

  1. Screening Period of up to 6 weeks (8 weeks if on Mircera)

  2. Treatment Period: a minimum of 52 weeks, a maximum of up to 3 years from the date last participant is randomized. Minimum study duration for participants enrolled under Protocol Amendment 1 or 2 may be less than 52 weeks

  3. A Follow-up period of 4 weeks.

Participants will be randomized in a 1:1 ratio to receive either roxadustat or epoetin alfa (active control) in an open-label manner.

Study Design

Study Type:
Interventional
Actual Enrollment :
741 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 3, Open-Label, Randomized, Active-Controlled Study of the Efficacy and Safety of Roxadustat (FG-4592) in the Maintenance Treatment of Anemia in Subjects With End Stage Renal Disease (ESRD) on Stable Dialysis
Actual Study Start Date :
Jan 15, 2015
Actual Primary Completion Date :
Sep 19, 2018
Actual Study Completion Date :
Sep 19, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Roxadustat

Participants will receive roxadustat tablets, administered orally 3 times weekly (TIW). Initial roxadustat dose will be based on the participant's average prescribed erythropoietin stimulating agent (ESA) dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments will be permitted to maintain a hemoglobin (Hb) level of approximately 11 grams (g)/deciliter (dL). The maximum roxadustat dose is 3.0 milligrams (mg)/kilogram (kg) per dose or 400 mg per administration (whichever is lower).

Drug: Roxadustat
Roxadustat will be administered per dose and schedule specified in the arm.
Other Names:
  • FG-4592

    		•
    Active Comparator: Epoetin Alfa

    Participants on hemodialysis (HD) will receive epoetin alfa, administered intravenously (IV) TIW and participants on home HD or peritoneal dialysis (PD) will receive epoetin alfa, administered subcutaneously (SC). Initial epoetin alfa dose will be based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa will be determined by the investigator per local standard of care (SOC). Dose adjustments will follow the recommendations as per the approved country-specific product label (United States Package Insert [USPI] or Summary of Product Characteristics [SmPC]) or local SOC.

    Drug: Epoetin Alfa
    Epoetin alfa will be administered per dose and schedule specified in the arm.

    Outcome Measures

    Primary Outcome Measures

    1. US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Weeks 28 to 52), Regardless of Rescue Therapy [Baseline (Day 1, Week 0), Weeks 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 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.

    2. Ex-U.S. Submission: Mean Hb Change From Baseline to the Average Weeks 28 to 36, Without Having Received Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period for Participants Enrolled Under the Original Protocol [Baseline (Day 1, Week 0), Weeks 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.

    Secondary Outcome Measures

    1. US (FDA Submission): Hb Responder Rate- Percentage of Participants With Mean Hb Level ≥10.0 g/dL Averaged Over Weeks 28 to 52, Regardless of Rescue Therapy [Weeks 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.

    2. Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants With Mean Hb 10.0 to 12.0 g/dL Averaged Over Weeks 28 to 36, Censoring for Rescue Therapy [Weeks 28 to 36]

      Hb values under the influence of a 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.

    3. Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28 [Baseline (Day 1, Week 0), Weeks 12 to 28]

      Baseline LDL Cholesterol was defined as the last available value prior to the first dose of study treatment.

    4. Change From Baseline in Hb Levels Averaged Over 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), Weeks 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.

    5. Average 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.

    6. Time to First RBC Transfusion [Baseline (Day 1, Week 0) up to last dose of study drug (maximum treatment duration was 183.7 weeks for roxadustat and 180.4 weeks for epoetin alfa)]

      Median time to event (weeks) was calculated using Kaplan Meier Survival Estimates.

    7. Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28 [Baseline (Day 1, Week 0), Weeks 20 to 28]

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

    8. 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 mmHg in diastolic blood pressure (dBP) and dBP ≥100 mmHg. Median time to event (weeks) was calculated using Kaplan Meier Survival Estimates.

    9. Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28 [Baseline (Day 1, Week 0), Weeks 12 to 28]

      The SF-36 V2 consists of 36 questions covering 8 health domains: physical functioning (10 items), bodily pain (2 items), role limitations due to physical problems (4 items), role limitations due to emotional problems (3 items), general health perceptions (5 items), mental health (5 items), social function (2 items), and vitality (4 items). The physical functioning subscore and vitality subscore are reported. Each scale was transformed into 0-100 score, with higher scores indicating better health status. Baseline score was defined as the last physical functioning value or vitality value, as applicable, prior to the first dose of study drug.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Center Phoenix Arizona United States 85012
    2 Research Center Pine Bluff Arkansas United States 71603
    3 Research Center Chula Vista California United States 91910
    4 Research Center Chula Vista California United States 91915
    5 Research Center La Mesa California United States 91942
    6 Research Center Long Beach California United States 90806
    7 Research Center Long Beach California United States 90813
    8 Research Center Los Angeles California United States 90057
    9 Research Center Northridge California United States 91324
    10 Research Center Ontario California United States 91762
    11 Research Center Roseville California United States 95661
    12 Research Center San Diego California United States 92111
    13 Research Center San Dimas California United States 91773
    14 Research Center San Gabriel California United States 91776
    15 Research Center Whittier California United States 90603
    16 Research Center Coral Springs Florida United States 33071
    17 Research Center Lauderdale Lakes Florida United States 33313
    18 Research Center Miami Florida United States 33143
    19 Research Center Miami Florida United States 33173
    20 Research Center Pembroke Pines Florida United States 33028
    21 Research Center Tampa Florida United States 33614
    22 Research Center Albany Georgia United States 31701
    23 Research Center Meridian Idaho United States 83642
    24 Research Center Shreveport Louisiana United States 71101
    25 Research Center Springfield Massachusetts United States 01107
    26 Research Center Detroit Michigan United States 48202
    27 Research Center Detroit Michigan United States 48236
    28 Research Center Pontiac Michigan United States 48341
    29 Research Center Brookhaven Mississippi United States 39601
    30 Research Center Columbus Mississippi United States 39705
    31 Research Center Gulfport Mississippi United States 39501
    32 Research Center Tupelo Mississippi United States 38801
    33 Research Center Creve Coeur Missouri United States 63141
    34 Research Center Kansas City Missouri United States 64131
    35 Research Center Saint Ann Missouri United States 63074
    36 Research Center Saint Louis Missouri United States 63110
    37 Research Center Portsmouth New Hampshire United States 03885
    38 Research Center North Brunswick New Jersey United States 08902
    39 Research Center Albuquerque New Mexico United States 87109
    40 Research Center Gallup New Mexico United States 87301
    41 Research Center College Point New York United States 11356
    42 Research Center New York New York United States 11355
    43 Research Center Charlotte North Carolina United States 28204
    44 Research Center Durham North Carolina United States 27704
    45 Research Center Greenville North Carolina United States 27834
    46 Research Center New Bern North Carolina United States 28562
    47 Research Center Raleigh North Carolina United States 27609
    48 Research Center Rocky Mount North Carolina United States 27804
    49 Research Center Columbus Ohio United States 43210
    50 Research Center Columbus Ohio United States 43215
    51 Research Center Aiken South Carolina United States 29803
    52 Research Center Columbia South Carolina United States 29203
    53 Research Center Orangeburg South Carolina United States 29118
    54 Research Center Sumter South Carolina United States 29150
    55 Research Center Knoxville Tennessee United States 37923
    56 Research Center Knoxville Tennessee United States 37924
    57 Research Center Nashville Tennessee United States 37205
    58 Research Center Nashville Tennessee United States 37232
    59 Research Center Arlington Texas United States 76015-2368
    60 Research Center Edinburg Texas United States 78539
    61 Research Center Fort Worth Texas United States 76104
    62 Research Center Fort Worth Texas United States 76105
    63 Research Center Fort Worth Texas United States 76112
    64 Research Center Fort Worth Texas United States 76133
    65 Research Center Fort Worth Texas United States 76164
    66 Research Center Grand Prairie Texas United States 75050
    67 Research Center Houston Texas United States 77054
    68 Research Center Houston Texas United States 77099
    69 Research Center Lubbock Texas United States 79430
    70 Research Center Mansfield Texas United States 76063
    71 Research Center San Antonio Texas United States 78202
    72 Research Center San Antonio Texas United States 78221
    73 Research Center Alexandria Virginia United States 20735
    74 Research Center Shorewood Wisconsin United States 53226
    75 Research Center Caguas Puerto Rico 00725
    76 Research Center San Juan Puerto Rico 00926

    Sponsors and Collaborators

    • FibroGen
    • Astellas Pharma Europe B.V.
    • AstraZeneca

    Investigators

    • Study Director: Meraf Eyassu, FibroGen

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    FibroGen
    ClinicalTrials.gov Identifier:
    NCT02273726
    Other Study ID Numbers:
    • FGCL-4592-064
    First Posted:
    Oct 24, 2014
    Last Update Posted:
    Oct 29, 2021
    Last Verified:
    Sep 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by FibroGen
    Anemia
    Chronic Kidney Disease
    Dialysis
    hemodialysis
    peritoneal dialysis
    hemoglobin
    End stage renal disease
    Stable Dialysis
    erythropoietins
    erythropoiesis stimulating agent
    Additional relevant MeSH terms:
    Anemia
    Epoetin Alfa

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Participants were randomized in a 1:1 ratio to receive either roxadustat or epoetin alfa.
    Arm/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally 3 times weekly (TIW). Initial roxadustat dose was based on the participant's average prescribed erythropoietin stimulating agent (ESA) dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a hemoglobin (Hb) level of approximately 11 grams (g)/deciliter (dL). The maximum roxadustat dose was 3.0 milligrams (mg)/kilogram (kg) per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on hemodialysis (HD) received epoetin alfa, administered intravenously (IV) TIW and participants on home HD or peritoneal dialysis (PD) received epoetin alfa, administered subcutaneously (SC). Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local standard of care (SOC). Dose adjustments followed the recommendations as per the approved country-specific product label (United States Package Insert [USPI] or Summary of Product Characteristics [SmPC]) or local SOC. The maximum treatment duration was 180.4 weeks.
    Period Title: Overall Study
    STARTED 370 371
    Received at Least 1 Dose of Study Drug 370 370
    COMPLETED 127 183
    NOT COMPLETED 243 188

    Baseline Characteristics

    Arm/Group Title Roxadustat Epoetin Alfa Total
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks. Total of all reporting groups
    Overall Participants 370 371 741
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    253
    68.4%
    246
    66.3%
    499
    67.3%
    >=65 years
    117
    31.6%
    125
    33.7%
    242
    32.7%
    Sex: Female, Male (Count of Participants)
    Female
    183
    49.5%
    156
    42%
    339
    45.7%
    Male
    187
    50.5%
    215
    58%
    402
    54.3%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    137
    37%
    129
    34.8%
    266
    35.9%
    Not Hispanic or Latino
    233
    63%
    242
    65.2%
    475
    64.1%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    White
    165
    44.6%
    184
    49.6%
    349
    47.1%
    Black/African American
    158
    42.7%
    156
    42%
    314
    42.4%
    Asian
    21
    5.7%
    15
    4%
    36
    4.9%
    American Indian/Alaskan Native
    10
    2.7%
    7
    1.9%
    17
    2.3%
    Native Hawaiian or Other Pacific Islander
    1
    0.3%
    3
    0.8%
    4
    0.5%
    Other
    15
    4.1%
    6
    1.6%
    21
    2.8%

    Outcome Measures

    1. Primary Outcome
    Title US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Weeks 28 to 52), Regardless of Rescue Therapy
    Description 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 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), Weeks 28 to 52

    Outcome Measure Data

    Analysis Population Description
    ITT Population included all randomized participants.
    Arm/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks.
    Measure Participants 370 371
    Baseline
    10.30
    (0.661)
    10.31
    (0.656)
    Change at Weeks 28 to 52
    0.39
    (0.934)
    -0.09
    (0.838)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
    Comments 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, ESA dependent incident dialysis within ≤4 months vs. >4 months of starting dialysis when randomized, and other randomization stratification factors except mean qualifying screening hemoglobin (≤10.5 vs. >10.5 g/dL) as fixed effects.
    Type of Statistical Test Non-Inferiority
    Comments Non-inferiority was established if the 2-sided 95% confidence interval (CI) for the treatment difference in least square (LS) means from MI ANCOVA model between the 2 treatment groups lay entirely above -0.75 g/dL.
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments ANCOVA with MI
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.48
    Confidence Interval (2-Sided) 95%
    0.365 to 0.591
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.058
    Estimation Comments
    2. Primary Outcome
    Title Ex-U.S. Submission: Mean Hb Change From Baseline to the Average Weeks 28 to 36, Without Having Received Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period for Participants Enrolled Under the Original Protocol
    Description 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 Frame Baseline (Day 1, Week 0), Weeks 28 to 36

    Outcome Measure Data

    Analysis Population Description
    Per protocol set (PPS) population included all participants in 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. 'Overall number of participants analyzed'=participants evaluable for this outcome measure. 'Number analyzed'=participants evaluable at specified timepoint.
    Arm/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks.
    Measure Participants 303 324
    Baseline
    10.33
    (0.639)
    10.35
    (0.614)
    Change at Weeks 28 to 36
    0.54
    (1.022)
    -0.03
    (0.897)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
    Comments Treatment comparison was made using a mixed model of repeated measures (MMRM) with baseline Hb as a covariate, and treatment, visit, visit-by-treatment interaction, ESA dependent incident dialysis within ≤4 months vs. >4 months of starting dialysis when randomized, and randomization stratification factors except mean qualifying screening Hb (≤10.5 vs. >10.5 g/dL) as fixed effects.
    Type of Statistical Test Non-Inferiority
    Comments The non-inferiority was established when the 2-sided 95% CI for the difference of LS means between the 2 treatment groups using the MMRM model lay entirely above -0.75 g/dL.
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.55
    Confidence Interval (2-Sided) 95%
    0.404 to 0.687
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.072
    Estimation Comments
    3. Secondary Outcome
    Title US (FDA Submission): Hb Responder Rate- Percentage of Participants With Mean Hb Level ≥10.0 g/dL Averaged Over Weeks 28 to 52, Regardless of Rescue Therapy
    Description 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.
    Time Frame Weeks 28 to 52

    Outcome Measure Data

    Analysis Population Description
    FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment.
    Arm/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks.
    Measure Participants 369 370
    Number [percentage of participants]
    66.1
    17.9%
    58.6
    15.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
    Comments For the difference of responder rates between 2 treatment groups, the CI analyzed was from the Miettinen & Nurminen approach adjusting for randomization stratification factors.
    Type of Statistical Test Non-Inferiority
    Comments Non-inferiority was established if the lower bound of the 2-sided 95% CI for the treatment difference for the responder rates (roxadustat minus epoetin alfa) calculated based on the Miettinen & Nurminen approach, adjusting for stratification factors, was greater than -15%.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Responder Rate Difference
    Estimated Value 7.6
    Confidence Interval (2-Sided) 95%
    0.9 to 14.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants With Mean Hb 10.0 to 12.0 g/dL Averaged Over Weeks 28 to 36, Censoring for Rescue Therapy
    Description Hb values under the influence of a 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.
    Time Frame Weeks 28 to 36

    Outcome Measure Data

    Analysis Population Description
    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, had at least 1 valid postdose Hb assessment and were without major protocol violations.
    Arm/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks.
    Measure Participants 334 352
    Number [percentage of participants]
    64.1
    17.3%
    60.8
    16.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
    Comments For the difference of responder rates between 2 treatment groups, the CI analyzed was from the Miettinen & Nurminen approach adjusting for randomization stratification factors.
    Type of Statistical Test Non-Inferiority
    Comments Non-inferiority was established if the lower bound of the 2-sided 95% CI for the treatment difference for the responder rates (roxadustat minus epoetin alfa) calculated based on the Miettinen & Nurminen approach, adjusting for stratification factors, was greater than -15%.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Responder Rate Difference
    Estimated Value 2.7
    Confidence Interval (2-Sided) 95%
    -4.3 to 9.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28
    Description Baseline LDL Cholesterol was defined as the last available value prior to the first dose of study treatment.
    Time Frame Baseline (Day 1, Week 0), Weeks 12 to 28

    Outcome Measure Data

    Analysis Population Description
    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 evaluable for this outcome measure at specified timepoint.
    Arm/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks.
    Measure Participants 369 370
    Baseline
    84.53
    (34.009)
    84.45
    (34.124)
    Change at Weeks 12 to 28
    -13.70
    (23.068)
    1.23
    (22.389)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
    Comments Treatment comparison was made using a MMRM with baseline as a covariate, and treatment, visit, visit-by-treatment interaction, ESA dependent incident dialysis within ≤4 months vs. >4 months of starting dialysis when randomized, and randomization stratification factors as fixed effects.
    Type of Statistical Test Superiority
    Comments Superiority was declared if the upper bound of the 2-sided 95% CI of the difference between roxadustat and epoetin alfa (roxadustat - epoetin alpha) was less than 0.
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value -14.67
    Confidence Interval (2-Sided) 95%
    -17.640 to -11.695
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.514
    Estimation Comments
    6. Secondary Outcome
    Title Change From Baseline in Hb Levels Averaged Over Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN)
    Description 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), Weeks 18 to 24

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks.
    Measure Participants 189 176
    Baseline
    10.30
    (0.616)
    10.24
    (0.630)
    Change at Weeks 18-24
    0.61
    (1.020)
    -0.03
    (0.940)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
    Comments Treatment comparison was made using the MI strategy by combining the results of ANCOVA model with baseline Hb as a covariate, and treatment, ESA dependent incident dialysis within ≤4 months vs. >4 months of starting dialysis when randomized, and other randomization stratification factors except mean qualifying screening Hb (≤10.5 vs. >10.5 g/dL) as fixed effects.
    Type of Statistical Test Non-Inferiority
    Comments The non-inferiority margin was fixed as a difference of -0.75.
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance at 0.05 level.
    Method ANCOVA
    Comments ANCOVA with MI
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.69
    Confidence Interval (2-Sided) 95%
    0.503 to 0.869
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.093
    Estimation Comments
    7. Secondary Outcome
    Title Average Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks.
    Measure Participants 286 319
    Mean (Standard Deviation) [mg/PEM]
    17.07
    (53.375)
    37.02
    (106.778)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
    Comments Treatment comparison was made using an ANCOVA model with baseline iron repletion status, treatment, ESA dependent incident dialysis within ≤4 months vs. >4 months of starting dialysis when randomized, and randomization stratification factors as fixed effects.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.00091
    Comments Threshold for significance at 0.05 level.
    Method Rank ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -20.14
    Confidence Interval (2-Sided) 95%
    -33.842 to -6.445
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 6.975
    Estimation Comments
    8. Secondary Outcome
    Title Time to First RBC Transfusion
    Description Median time to event (weeks) was calculated using Kaplan Meier Survival Estimates.
    Time Frame Baseline (Day 1, Week 0) up to last dose of study drug (maximum treatment duration was 183.7 weeks for roxadustat and 180.4 weeks for epoetin alfa)

    Outcome Measure Data

    Analysis Population Description
    FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment.
    Arm/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks.
    Measure Participants 369 370
    Median (95% Confidence Interval) [weeks]
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
    Comments Analysis was done using a Cox Proportional Hazards model adjusting for baseline Hb and other stratification factors except mean qualifying screening Hb (≤10.5 vs. >10.5 g/dL) as fixed effects.
    Type of Statistical Test Non-Inferiority
    Comments The non-inferiority margin for the difference between groups was 1.8.
    Statistical Test of Hypothesis p-Value 0.0337
    Comments
    Method Cox Proportional Hazards model
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.67
    Confidence Interval (2-Sided) 95%
    0.466 to 0.970
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28
    Description Baseline MAP 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), Weeks 20 to 28

    Outcome Measure Data

    Analysis Population Description
    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 evaluable for this outcome measure at specified timepoints.
    Arm/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks.
    Measure Participants 369 370
    Baseline
    101.41
    (12.591)
    100.34
    (12.350)
    Change at Weeks 20 to 28
    0.46
    (10.933)
    0.04
    (10.489)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Roxadustat, Epoetin Alfa
    Comments Treatment comparison was made using MMRM with baseline as a covariate, and treatment, visit, visit-by-treatment interaction, ESA dependent incident dialysis within ≤4 months vs. >4 months of starting dialysis when randomized, and randomization stratification factors as fixed effects.
    Type of Statistical Test Superiority
    Comments Superiority was declared if the upper bound of the 2-sided 95% CI of the difference between roxadustat and epoetin alfa (roxadustat - epoetin alpha) was less than 0.
    Statistical Test of Hypothesis p-Value 0.3500
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.69
    Confidence Interval (2-Sided) 95%
    -0.760 to 2.142
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.739
    Estimation Comments
    10. Secondary Outcome
    Title Time to First Exacerbation of Hypertension During Weeks 28 to 52
    Description 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 mmHg in diastolic blood pressure (dBP) and dBP ≥100 mmHg. Median time to event (weeks) was calculated using Kaplan Meier Survival Estimates.
    Time Frame Weeks 28 to 52

    Outcome Measure Data

    Analysis Population Description
    FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment.
    Arm/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks.
    Measure Participants 369 370
    Median (95% Confidence Interval) [weeks]
    NA
    NA
    11. Secondary Outcome
    Title Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28
    Description The SF-36 V2 consists of 36 questions covering 8 health domains: physical functioning (10 items), bodily pain (2 items), role limitations due to physical problems (4 items), role limitations due to emotional problems (3 items), general health perceptions (5 items), mental health (5 items), social function (2 items), and vitality (4 items). The physical functioning subscore and vitality subscore are reported. Each scale was transformed into 0-100 score, with higher scores indicating better health status. Baseline score was defined as the last physical functioning value or vitality value, as applicable, prior to the first dose of study drug.
    Time Frame Baseline (Day 1, Week 0), Weeks 12 to 28

    Outcome Measure Data

    Analysis Population Description
    FAS Population included all randomized/enrolled participants who received at least 1 dose of study drug and had baseline and at least 1 postdose Hb assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable for this outcome measure at specified timepoint.
    Arm/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks.
    Measure Participants 368 369
    Physical functioning subscore: Baseline
    38.55
    (11.202)
    39.63
    (11.368)
    Physical functioning subscore: Change at Weeks 12 to 28
    -0.15
    (7.443)
    -0.20
    (6.380)
    Vitality subscore: Baseline
    51.65
    (10.111)
    51.27
    (9.841)
    Vitality subscore: Change at Weeks 12 to 28
    -0.92
    (7.007)
    0.30
    (7.041)

    Adverse Events

    Time Frame Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 183.7 weeks for roxadustat and 180.4 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 183.7 weeks for roxadustat and 180.4 weeks for epoetin alfa).
    Adverse Event Reporting Description The Safety population included all randomized participants who received at least 1 dose of study medication.
    Arm/Group Title Roxadustat Epoetin Alfa
    Arm/Group Description Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks.
    All Cause Mortality
    Roxadustat Epoetin Alfa
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 70/370 (18.9%) 62/370 (16.8%)
    Serious Adverse Events
    Roxadustat Epoetin Alfa
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 242/370 (65.4%) 248/370 (67%)
    Blood and lymphatic system disorders
    Anaemia 16/370 (4.3%) 20/370 (5.4%)
    Haemorrhagic anaemia 1/370 (0.3%) 6/370 (1.6%)
    Coagulopathy 1/370 (0.3%) 0/370 (0%)
    Disseminated intravascular coagulation 1/370 (0.3%) 0/370 (0%)
    Haemolysis 1/370 (0.3%) 0/370 (0%)
    Iron deficiency anaemia 0/370 (0%) 1/370 (0.3%)
    Leukocytosis 0/370 (0%) 2/370 (0.5%)
    Nephrogenic anaemia 0/370 (0%) 1/370 (0.3%)
    Neutropenia 1/370 (0.3%) 0/370 (0%)
    Pancytopenia 0/370 (0%) 1/370 (0.3%)
    Thrombocytopenia 2/370 (0.5%) 1/370 (0.3%)
    Cardiac disorders
    Acute myocardial infarction 31/370 (8.4%) 26/370 (7%)
    Cardiac failure congestive 23/370 (6.2%) 23/370 (6.2%)
    Cardiac arrest 20/370 (5.4%) 23/370 (6.2%)
    Coronary artery disease 11/370 (3%) 12/370 (3.2%)
    Atrial fibrillation 9/370 (2.4%) 11/370 (3%)
    Cardiorespiratory arrest 8/370 (2.2%) 9/370 (2.4%)
    Angina unstable 7/370 (1.9%) 3/370 (0.8%)
    Myocardial infarction 5/370 (1.4%) 3/370 (0.8%)
    Angina pectoris 4/370 (1.1%) 6/370 (1.6%)
    Bradycardia 4/370 (1.1%) 4/370 (1.1%)
    Pulseless electrical activity 4/370 (1.1%) 1/370 (0.3%)
    Cardiogenic shock 4/370 (1.1%) 0/370 (0%)
    Acute coronary syndrome 0/370 (0%) 2/370 (0.5%)
    Acute left ventricular failure 1/370 (0.3%) 1/370 (0.3%)
    Aortic valve incompetence 0/370 (0%) 1/370 (0.3%)
    Arrhythmia 1/370 (0.3%) 0/370 (0%)
    Atrial flutter 0/370 (0%) 3/370 (0.8%)
    Atrioventricular block second degree 0/370 (0%) 1/370 (0.3%)
    Bundle branch block left 1/370 (0.3%) 0/370 (0%)
    Cardiac failure 0/370 (0%) 2/370 (0.5%)
    Cardiac failure acute 0/370 (0%) 1/370 (0.3%)
    Cardiopulmonary failure 0/370 (0%) 2/370 (0.5%)
    Cardiovascular disorder 1/370 (0.3%) 1/370 (0.3%)
    Chronic left ventricular failure 1/370 (0.3%) 0/370 (0%)
    Coronary artery stenosis 0/370 (0%) 1/370 (0.3%)
    Hypertensive heart disease 1/370 (0.3%) 0/370 (0%)
    Ischaemic cardiomyopathy 1/370 (0.3%) 0/370 (0%)
    Mitral valve incompetence 0/370 (0%) 1/370 (0.3%)
    Mitral valve stenosis 0/370 (0%) 1/370 (0.3%)
    Myocardial ischaemia 2/370 (0.5%) 2/370 (0.5%)
    Palpitations 0/370 (0%) 1/370 (0.3%)
    Pericarditis 1/370 (0.3%) 1/370 (0.3%)
    Sinus bradycardia 1/370 (0.3%) 2/370 (0.5%)
    Sinus tachycardia 1/370 (0.3%) 1/370 (0.3%)
    Supraventricular extrasystoles 1/370 (0.3%) 0/370 (0%)
    Supraventricular tachycardia 1/370 (0.3%) 3/370 (0.8%)
    Tachyarrhythmia 0/370 (0%) 1/370 (0.3%)
    Ventricular arrhythmia 0/370 (0%) 1/370 (0.3%)
    Ventricular fibrillation 1/370 (0.3%) 1/370 (0.3%)
    Ventricular tachycardia 2/370 (0.5%) 2/370 (0.5%)
    Congenital, familial and genetic disorders
    Arteriovenous malformation 0/370 (0%) 1/370 (0.3%)
    Ear and labyrinth disorders
    Deafness 1/370 (0.3%) 0/370 (0%)
    Endocrine disorders
    Hyperparathyroidism 1/370 (0.3%) 1/370 (0.3%)
    Hyperparathyroidism secondary 1/370 (0.3%) 2/370 (0.5%)
    Hyperparathyroidism tertiary 2/370 (0.5%) 1/370 (0.3%)
    Hypothyroidism 1/370 (0.3%) 0/370 (0%)
    Gastrointestinal disorders
    Gastrointestinal haemorrhage 10/370 (2.7%) 16/370 (4.3%)
    Colitis 4/370 (1.1%) 1/370 (0.3%)
    Upper gastrointestinal haemorrhage 2/370 (0.5%) 4/370 (1.1%)
    Small intestinal obstruction 1/370 (0.3%) 4/370 (1.1%)
    Gastric ulcer 0/370 (0%) 4/370 (1.1%)
    Abdominal hernia 1/370 (0.3%) 0/370 (0%)
    Abdominal pain 3/370 (0.8%) 1/370 (0.3%)
    Abdominal pain upper 0/370 (0%) 2/370 (0.5%)
    Ascites 0/370 (0%) 3/370 (0.8%)
    Colitis ischaemic 2/370 (0.5%) 0/370 (0%)
    Constipation 0/370 (0%) 2/370 (0.5%)
    Diabetic gastroparesis 2/370 (0.5%) 2/370 (0.5%)
    Diarrhoea 1/370 (0.3%) 2/370 (0.5%)
    Diverticulum 1/370 (0.3%) 0/370 (0%)
    Diverticulum intestinal 1/370 (0.3%) 0/370 (0%)
    Duodenal ulcer 1/370 (0.3%) 1/370 (0.3%)
    Dyspepsia 1/370 (0.3%) 0/370 (0%)
    Dysphagia 0/370 (0%) 1/370 (0.3%)
    Enterocutaneous fistula 0/370 (0%) 1/370 (0.3%)
    Erosive duodenitis 0/370 (0%) 1/370 (0.3%)
    Faecaloma 1/370 (0.3%) 1/370 (0.3%)
    Gastric ulcer haemorrhage 0/370 (0%) 2/370 (0.5%)
    Gastritis 2/370 (0.5%) 1/370 (0.3%)
    Gastritis erosive 1/370 (0.3%) 0/370 (0%)
    Gastroduodenitis 0/370 (0%) 1/370 (0.3%)
    Gastrointestinal necrosis 0/370 (0%) 1/370 (0.3%)
    Gastrooesophageal reflux disease 1/370 (0.3%) 2/370 (0.5%)
    Haematemesis 0/370 (0%) 1/370 (0.3%)
    Haemorrhagic erosive gastritis 1/370 (0.3%) 0/370 (0%)
    Haemorrhoidal haemorrhage 1/370 (0.3%) 1/370 (0.3%)
    Haemorrhoids 2/370 (0.5%) 0/370 (0%)
    Hiatus hernia 0/370 (0%) 1/370 (0.3%)
    Ileus 1/370 (0.3%) 0/370 (0%)
    Impaired gastric emptying 1/370 (0.3%) 2/370 (0.5%)
    Incarcerated umbilical hernia 1/370 (0.3%) 0/370 (0%)
    Irritable bowel syndrome 1/370 (0.3%) 0/370 (0%)
    Large intestine perforation 0/370 (0%) 1/370 (0.3%)
    Lower gastrointestinal haemorrhage 0/370 (0%) 2/370 (0.5%)
    Mallory-Weiss syndrome 1/370 (0.3%) 0/370 (0%)
    Melaena 1/370 (0.3%) 0/370 (0%)
    Mesenteric vein thrombosis 1/370 (0.3%) 0/370 (0%)
    Oesophageal polyp 1/370 (0.3%) 0/370 (0%)
    Oesophagitis 2/370 (0.5%) 1/370 (0.3%)
    Pancreatitis 3/370 (0.8%) 0/370 (0%)
    Pancreatitis acute 3/370 (0.8%) 3/370 (0.8%)
    Peptic ulcer 1/370 (0.3%) 0/370 (0%)
    Reactive gastropathy 0/370 (0%) 1/370 (0.3%)
    Rectal haemorrhage 1/370 (0.3%) 3/370 (0.8%)
    Small intestinal haemorrhage 0/370 (0%) 2/370 (0.5%)
    Tongue dysplasia 1/370 (0.3%) 0/370 (0%)
    Umbilical hernia 1/370 (0.3%) 1/370 (0.3%)
    Uraemic gastropathy 0/370 (0%) 1/370 (0.3%)
    Vomiting 0/370 (0%) 2/370 (0.5%)
    General disorders
    Non-cardiac chest pain 17/370 (4.6%) 10/370 (2.7%)
    Asthenia 3/370 (0.8%) 7/370 (1.9%)
    Death 1/370 (0.3%) 4/370 (1.1%)
    Chest pain 3/370 (0.8%) 2/370 (0.5%)
    Complication associated with device 3/370 (0.8%) 1/370 (0.3%)
    Drowning 0/370 (0%) 1/370 (0.3%)
    Generalised oedema 1/370 (0.3%) 1/370 (0.3%)
    Hypothermia 1/370 (0.3%) 0/370 (0%)
    Impaired healing 0/370 (0%) 1/370 (0.3%)
    Influenza like illness 1/370 (0.3%) 0/370 (0%)
    Multiple organ dysfunction syndrome 3/370 (0.8%) 0/370 (0%)
    Oedema peripheral 2/370 (0.5%) 1/370 (0.3%)
    Pain 0/370 (0%) 1/370 (0.3%)
    Pelvic mass 0/370 (0%) 1/370 (0.3%)
    Peripheral swelling 2/370 (0.5%) 0/370 (0%)
    Pyrexia 3/370 (0.8%) 1/370 (0.3%)
    Sudden cardiac death 2/370 (0.5%) 0/370 (0%)
    Hepatobiliary disorders
    Acute hepatic failure 1/370 (0.3%) 0/370 (0%)
    Bile duct stone 1/370 (0.3%) 0/370 (0%)
    Cholecystitis 0/370 (0%) 1/370 (0.3%)
    Cholecystitis acute 3/370 (0.8%) 0/370 (0%)
    Cholelithiasis 2/370 (0.5%) 2/370 (0.5%)
    Hepatic cirrhosis 1/370 (0.3%) 0/370 (0%)
    Hepatic failure 1/370 (0.3%) 1/370 (0.3%)
    Hepatosplenomegaly 0/370 (0%) 1/370 (0.3%)
    Hyperbilirubinaemia 2/370 (0.5%) 0/370 (0%)
    Ischaemic hepatitis 0/370 (0%) 2/370 (0.5%)
    Jaundice 1/370 (0.3%) 0/370 (0%)
    Immune system disorders
    Anaphylactic reaction 1/370 (0.3%) 0/370 (0%)
    Anaphylactic shock 0/370 (0%) 1/370 (0.3%)
    Kidney transplant rejection 1/370 (0.3%) 0/370 (0%)
    Infections and infestations
    Pneumonia 30/370 (8.1%) 39/370 (10.5%)
    Sepsis 18/370 (4.9%) 23/370 (6.2%)
    Septic shock 10/370 (2.7%) 7/370 (1.9%)
    Cellulitis 9/370 (2.4%) 15/370 (4.1%)
    Urinary tract infection 8/370 (2.2%) 6/370 (1.6%)
    Gastroenteritis 8/370 (2.2%) 3/370 (0.8%)
    Arteriovenous fistula site infection 7/370 (1.9%) 1/370 (0.3%)
    Influenza 6/370 (1.6%) 6/370 (1.6%)
    Staphylococcal bacteraemia 6/370 (1.6%) 6/370 (1.6%)
    Osteomyelitis 3/370 (0.8%) 12/370 (3.2%)
    Gangrene 4/370 (1.1%) 8/370 (2.2%)
    Diverticulitis 4/370 (1.1%) 6/370 (1.6%)
    Bronchitis 4/370 (1.1%) 4/370 (1.1%)
    Bacteraemia 3/370 (0.8%) 6/370 (1.6%)
    Arteriovenous graft site infection 3/370 (0.8%) 4/370 (1.1%)
    Clostridium difficile colitis 3/370 (0.8%) 4/370 (1.1%)
    Device related infection 2/370 (0.5%) 5/370 (1.4%)
    Staphylococcal sepsis 2/370 (0.5%) 4/370 (1.1%)
    Abdominal abscess 2/370 (0.5%) 0/370 (0%)
    Abscess limb 1/370 (0.3%) 1/370 (0.3%)
    Abscess oral 0/370 (0%) 1/370 (0.3%)
    Abscess soft tissue 0/370 (0%) 1/370 (0.3%)
    Appendicitis 3/370 (0.8%) 3/370 (0.8%)
    Appendicitis perforated 1/370 (0.3%) 1/370 (0.3%)
    Arthritis bacterial 0/370 (0%) 1/370 (0.3%)
    Arthritis infective 0/370 (0%) 1/370 (0.3%)
    Atypical pneumonia 1/370 (0.3%) 0/370 (0%)
    Beta haemolytic streptococcal infection 0/370 (0%) 1/370 (0.3%)
    Cardiac valve vegetation 0/370 (0%) 1/370 (0.3%)
    Cellulitis staphylococcal 0/370 (0%) 1/370 (0.3%)
    Citrobacter sepsis 1/370 (0.3%) 0/370 (0%)
    Cystitis 1/370 (0.3%) 0/370 (0%)
    Device related sepsis 2/370 (0.5%) 1/370 (0.3%)
    Endocarditis 1/370 (0.3%) 1/370 (0.3%)
    Endocarditis bacterial 1/370 (0.3%) 1/370 (0.3%)
    Enterococcal bacteraemia 1/370 (0.3%) 0/370 (0%)
    Enterococcal sepsis 1/370 (0.3%) 0/370 (0%)
    Escherichia bacteraemia 0/370 (0%) 1/370 (0.3%)
    Escherichia infection 1/370 (0.3%) 0/370 (0%)
    Escherichia sepsis 1/370 (0.3%) 0/370 (0%)
    Extradural abscess 1/370 (0.3%) 0/370 (0%)
    Eye infection 1/370 (0.3%) 0/370 (0%)
    Furuncle 0/370 (0%) 1/370 (0.3%)
    Gastroenteritis clostridial 1/370 (0.3%) 0/370 (0%)
    Gastroenteritis viral 2/370 (0.5%) 1/370 (0.3%)
    Graft infection 2/370 (0.5%) 0/370 (0%)
    Haemophilus infection 0/370 (0%) 1/370 (0.3%)
    Implant site infection 0/370 (0%) 1/370 (0.3%)
    Infected seroma 1/370 (0.3%) 1/370 (0.3%)
    Infectious colitis 1/370 (0.3%) 0/370 (0%)
    Infectious pleural effusion 0/370 (0%) 1/370 (0.3%)
    Intervertebral discitis 1/370 (0.3%) 1/370 (0.3%)
    Klebsiella bacteraemia 0/370 (0%) 1/370 (0.3%)
    Klebsiella sepsis 0/370 (0%) 1/370 (0.3%)
    Localised infection 3/370 (0.8%) 1/370 (0.3%)
    Ludwig angina 1/370 (0.3%) 0/370 (0%)
    Necrotising fasciitis 1/370 (0.3%) 0/370 (0%)
    Osteomyelitis acute 0/370 (0%) 2/370 (0.5%)
    Osteomyelitis bacterial 0/370 (0%) 1/370 (0.3%)
    Osteomyelitis bacterial 1/370 (0.3%) 1/370 (0.3%)
    Pelvic abscess 1/370 (0.3%) 1/370 (0.3%)
    Perirectal abscess 1/370 (0.3%) 0/370 (0%)
    Peritonitis 2/370 (0.5%) 3/370 (0.8%)
    Pharyngitis streptococcal 1/370 (0.3%) 0/370 (0%)
    Pneumonia bacterial 1/370 (0.3%) 3/370 (0.8%)
    Postoperative wound infection 0/370 (0%) 2/370 (0.5%)
    Proteus infection 1/370 (0.3%) 0/370 (0%)
    Pseudomonal bacteraemia 0/370 (0%) 1/370 (0.3%)
    Pyelonephritis 1/370 (0.3%) 1/370 (0.3%)
    Pyelonephritis acute 0/370 (0%) 1/370 (0.3%)
    Respiratory syncytial virus bronchitis 1/370 (0.3%) 0/370 (0%)
    Septic embolus 1/370 (0.3%) 0/370 (0%)
    Septic phlebitis 0/370 (0%) 1/370 (0.3%)
    Sinusitis 1/370 (0.3%) 0/370 (0%)
    Staphylococcal infection 1/370 (0.3%) 3/370 (0.8%)
    Streptococcal bacteraemia 1/370 (0.3%) 0/370 (0%)
    Streptococcal infection 1/370 (0.3%) 0/370 (0%)
    Subacute endocarditis 1/370 (0.3%) 0/370 (0%)
    Subcutaneous abscess 0/370 (0%) 1/370 (0.3%)
    Tracheobronchitis 1/370 (0.3%) 0/370 (0%)
    Urinary tract infection enterococcal 0/370 (0%) 1/370 (0.3%)
    Urinary tract infection fungal 0/370 (0%) 1/370 (0.3%)
    Vascular access site infection 0/370 (0%) 1/370 (0.3%)
    Viral infection 1/370 (0.3%) 0/370 (0%)
    Viral upper respiratory tract infection 1/370 (0.3%) 0/370 (0%)
    Vulval abscess 1/370 (0.3%) 0/370 (0%)
    Vulval cellulitis 1/370 (0.3%) 0/370 (0%)
    Wound infection 0/370 (0%) 1/370 (0.3%)
    Wound infection staphylococcal 1/370 (0.3%) 1/370 (0.3%)
    Wound sepsis 1/370 (0.3%) 1/370 (0.3%)
    Gun shot wound 1/370 (0.3%) 0/370 (0%)
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis 11/370 (3%) 11/370 (3%)
    Arteriovenous graft thrombosis 10/370 (2.7%) 7/370 (1.9%)
    Arteriovenous fistula site complication 8/370 (2.2%) 1/370 (0.3%)
    Fall 4/370 (1.1%) 7/370 (1.9%)
    Arteriovenous fistula site haemorrhage 3/370 (0.8%) 4/370 (1.1%)
    Femur fracture 2/370 (0.5%) 8/370 (2.2%)
    Accidental overdose 1/370 (0.3%) 1/370 (0.3%)
    Anastomotic ulcer 0/370 (0%) 1/370 (0.3%)
    Ankle fracture 0/370 (0%) 1/370 (0.3%)
    Arteriovenous fistula aneurysm 1/370 (0.3%) 1/370 (0.3%)
    Arteriovenous fistula site haematoma 1/370 (0.3%) 0/370 (0%)
    Arteriovenous graft site haematoma 0/370 (0%) 1/370 (0.3%)
    Arteriovenous graft site haemorrhage 2/370 (0.5%) 2/370 (0.5%)
    Arteriovenous graft site stenosis 0/370 (0%) 1/370 (0.3%)
    Complications of transplanted kidney 0/370 (0%) 1/370 (0.3%)
    Concussion 1/370 (0.3%) 1/370 (0.3%)
    Craniocerebral injury 0/370 (0%) 1/370 (0.3%)
    Femoral neck fracture 2/370 (0.5%) 1/370 (0.3%)
    Foot fracture 1/370 (0.3%) 1/370 (0.3%)
    Graft thrombosis 0/370 (0%) 2/370 (0.5%)
    Head injury 1/370 (0.3%) 0/370 (0%)
    Hip fracture 1/370 (0.3%) 3/370 (0.8%)
    Humerus fracture 3/370 (0.8%) 1/370 (0.3%)
    Injury 1/370 (0.3%) 0/370 (0%)
    Jaw fracture 0/370 (0%) 1/370 (0.3%)
    Joint dislocation 0/370 (0%) 2/370 (0.5%)
    Laceration 1/370 (0.3%) 0/370 (0%)
    Ligament injury 0/370 (0%) 1/370 (0.3%)
    Limb injury 2/370 (0.5%) 0/370 (0%)
    Lower limb fracture 1/370 (0.3%) 1/370 (0.3%)
    Pelvic fracture 1/370 (0.3%) 1/370 (0.3%)
    Pneumothorax traumatic 0/370 (0%) 1/370 (0.3%)
    Post procedural haematoma 1/370 (0.3%) 0/370 (0%)
    Postoperative ileus 0/370 (0%) 1/370 (0.3%)
    Postoperative wound complication 1/370 (0.3%) 0/370 (0%)
    Procedural hypotension 1/370 (0.3%) 1/370 (0.3%)
    Rib fracture 1/370 (0.3%) 0/370 (0%)
    Road traffic accident 2/370 (0.5%) 1/370 (0.3%)
    Seroma 0/370 (0%) 1/370 (0.3%)
    Shunt thrombosis 1/370 (0.3%) 0/370 (0%)
    Spinal column injury 1/370 (0.3%) 0/370 (0%)
    Spinal fracture 0/370 (0%) 1/370 (0.3%)
    Subdural haematoma 2/370 (0.5%) 2/370 (0.5%)
    Subdural haemorrhage 0/370 (0%) 1/370 (0.3%)
    Thermal burn 0/370 (0%) 1/370 (0.3%)
    Tibia fracture 1/370 (0.3%) 1/370 (0.3%)
    Upper limb fracture 0/370 (0%) 1/370 (0.3%)
    Vascular access malfunction 2/370 (0.5%) 0/370 (0%)
    Vascular access site haemorrhage 0/370 (0%) 1/370 (0.3%)
    Vascular access site pseudoaneurysm 0/370 (0%) 1/370 (0.3%)
    Vascular graft complication 1/370 (0.3%) 2/370 (0.5%)
    Vascular graft occlusion 1/370 (0.3%) 1/370 (0.3%)
    Vascular graft thrombosis 1/370 (0.3%) 0/370 (0%)
    Wound 1/370 (0.3%) 0/370 (0%)
    Wrist fracture 0/370 (0%) 1/370 (0.3%)
    Investigations
    Activated partial thromboplastin time prolonged 1/370 (0.3%) 0/370 (0%)
    Troponin increased 2/370 (0.5%) 0/370 (0%)
    Metabolism and nutrition disorders
    Hyperkalaemia 25/370 (6.8%) 25/370 (6.8%)
    Fluid overload 24/370 (6.5%) 27/370 (7.3%)
    Hypoglycaemia 7/370 (1.9%) 9/370 (2.4%)
    Diabetic ketoacidosis 3/370 (0.8%) 4/370 (1.1%)
    Hypervolaemia 1/370 (0.3%) 4/370 (1.1%)
    Calciphylaxis 1/370 (0.3%) 1/370 (0.3%)
    Dehydration 2/370 (0.5%) 1/370 (0.3%)
    Diabetes mellitus inadequate control 1/370 (0.3%) 0/370 (0%)
    Hyperglycaemia 3/370 (0.8%) 1/370 (0.3%)
    Hyperglycaemic hyperosmolar nonketotic syndrome 0/370 (0%) 1/370 (0.3%)
    Hypokalaemia 0/370 (0%) 1/370 (0.3%)
    Hyponatraemia 1/370 (0.3%) 1/370 (0.3%)
    Hypovolaemia 1/370 (0.3%) 0/370 (0%)
    Lactic acidosis 1/370 (0.3%) 0/370 (0%)
    Metabolic acidosis 1/370 (0.3%) 1/370 (0.3%)
    Obesity 0/370 (0%) 1/370 (0.3%)
    Type 1 diabetes mellitus 1/370 (0.3%) 0/370 (0%)
    Musculoskeletal and connective tissue disorders
    Back pain 4/370 (1.1%) 2/370 (0.5%)
    Musculoskeletal chest pain 2/370 (0.5%) 4/370 (1.1%)
    Arthralgia 1/370 (0.3%) 0/370 (0%)
    Brown tumour 1/370 (0.3%) 0/370 (0%)
    Cervical spinal stenosis 0/370 (0%) 1/370 (0.3%)
    Costochondritis 0/370 (0%) 2/370 (0.5%)
    Intervertebral disc protrusion 1/370 (0.3%) 0/370 (0%)
    Joint effusion 0/370 (0%) 1/370 (0.3%)
    Mobility decreased 0/370 (0%) 1/370 (0.3%)
    Muscular weakness 1/370 (0.3%) 3/370 (0.8%)
    Musculoskeletal pain 1/370 (0.3%) 0/370 (0%)
    Myositis 1/370 (0.3%) 1/370 (0.3%)
    Osteoarthritis 0/370 (0%) 3/370 (0.8%)
    Pain in extremity 0/370 (0%) 1/370 (0.3%)
    Rhabdomyolysis 0/370 (0%) 1/370 (0.3%)
    Rotator cuff syndrome 0/370 (0%) 1/370 (0.3%)
    Spinal column stenosis 0/370 (0%) 1/370 (0.3%)
    Tendonitis 1/370 (0.3%) 0/370 (0%)
    Uraemic myopathy 1/370 (0.3%) 0/370 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign pleural neoplasm 0/370 (0%) 1/370 (0.3%)
    Carcinoid tumour of the stomach 1/370 (0.3%) 0/370 (0%)
    Cholangiocarcinoma 0/370 (0%) 1/370 (0.3%)
    Colorectal cancer 0/370 (0%) 1/370 (0.3%)
    Gastrointestinal stromal tumour 0/370 (0%) 1/370 (0.3%)
    Large granular lymphocytosis 0/370 (0%) 1/370 (0.3%)
    Malignant neoplasm of thorax 0/370 (0%) 1/370 (0.3%)
    Metastases to bone 1/370 (0.3%) 0/370 (0%)
    Metastatic renal cell carcinoma 1/370 (0.3%) 0/370 (0%)
    Myelodysplastic syndrome 0/370 (0%) 3/370 (0.8%)
    Nasopharyngeal neoplasm benign 1/370 (0.3%) 0/370 (0%)
    Oesophageal carcinoma 0/370 (0%) 1/370 (0.3%)
    Pancreatic carcinoma 1/370 (0.3%) 0/370 (0%)
    Parathyroid tumour benign 0/370 (0%) 1/370 (0.3%)
    Pericardial effusion malignant 0/370 (0%) 1/370 (0.3%)
    Plasma cell myeloma 0/370 (0%) 1/370 (0.3%)
    Prostate cancer 2/370 (0.5%) 0/370 (0%)
    Renal cell carcinoma 1/370 (0.3%) 1/370 (0.3%)
    Squamous cell carcinoma 0/370 (0%) 1/370 (0.3%)
    Nervous system disorders
    Syncope 7/370 (1.9%) 12/370 (3.2%)
    Seizure 7/370 (1.9%) 8/370 (2.2%)
    Encephalopathy 6/370 (1.6%) 5/370 (1.4%)
    Cerebrovascular accident 4/370 (1.1%) 5/370 (1.4%)
    Metabolic encephalopathy 5/370 (1.4%) 11/370 (3%)
    Hypoxic-ischaemic encephalopathy 0/370 (0%) 5/370 (1.4%)
    Allodynia 1/370 (0.3%) 0/370 (0%)
    Altered state of consciousness 1/370 (0.3%) 1/370 (0.3%)
    Ataxia 1/370 (0.3%) 0/370 (0%)
    Brain injury 0/370 (0%) 1/370 (0.3%)
    Brain oedema 0/370 (0%) 1/370 (0.3%)
    Cerebellar stroke 0/370 (0%) 1/370 (0.3%)
    Cerebral haemorrhage 2/370 (0.5%) 1/370 (0.3%)
    Cerebral infarction 1/370 (0.3%) 0/370 (0%)
    Cervical radiculopathy 1/370 (0.3%) 0/370 (0%)
    Dementia Alzheimer's type 1/370 (0.3%) 0/370 (0%)
    Dizziness 1/370 (0.3%) 2/370 (0.5%)
    Facial paralysis 1/370 (0.3%) 2/370 (0.5%)
    Haemorrhagic cerebral infarction 1/370 (0.3%) 0/370 (0%)
    Haemorrhagic stroke 0/370 (0%) 1/370 (0.3%)
    Hemiparesis 0/370 (0%) 1/370 (0.3%)
    Hepatic encephalopathy 0/370 (0%) 1/370 (0.3%)
    Hypoaesthesia 0/370 (0%) 1/370 (0.3%)
    Intracranial aneurysm 2/370 (0.5%) 0/370 (0%)
    Ischaemic cerebral infarction 1/370 (0.3%) 1/370 (0.3%)
    Ischaemic strok 1/370 (0.3%) 0/370 (0%)
    Parkinson's disease 1/370 (0.3%) 0/370 (0%)
    Posterior reversible encephalopathy syndrome 0/370 (0%) 1/370 (0.3%)
    Presyncope 3/370 (0.8%) 3/370 (0.8%)
    Sciatica 2/370 (0.5%) 0/370 (0%)
    Thalamic infarction 0/370 (0%) 1/370 (0.3%)
    Thoracic outlet syndrome 0/370 (0%) 1/370 (0.3%)
    Transient ischaemic attack 2/370 (0.5%) 3/370 (0.8%)
    Tremor 0/370 (0%) 1/370 (0.3%)
    Psychiatric disorders
    Mental status changes 5/370 (1.4%) 8/370 (2.2%)
    Acute psychosis 1/370 (0.3%) 0/370 (0%)
    Anxiety 0/370 (0%) 1/370 (0.3%)
    Anxiety disorder 1/370 (0.3%) 0/370 (0%)
    Delirium 2/370 (0.5%) 0/370 (0%)
    Psychotic disorder 0/370 (0%) 1/370 (0.3%)
    Suicide attempt 0/370 (0%) 1/370 (0.3%)
    Depression 1/370 (0.3%) 3/370 (0.8%)
    Major depression 0/370 (0%) 1/370 (0.3%)
    Renal and urinary disorders
    Azotaemia 3/370 (0.8%) 2/370 (0.5%)
    End stage renal disease 1/370 (0.3%) 2/370 (0.5%)
    Haematuria 1/370 (0.3%) 1/370 (0.3%)
    Hydronephrosis 1/370 (0.3%) 1/370 (0.3%)
    Nephrolithiasis 0/370 (0%) 2/370 (0.5%)
    Renal haemorrhage 0/370 (0%) 1/370 (0.3%)
    Renal impairment 0/370 (0%) 1/370 (0.3%)
    Renal mass 1/370 (0.3%) 1/370 (0.3%)
    Urinary retention 0/370 (0%) 1/370 (0.3%)
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 0/370 (0%) 1/370 (0.3%)
    Menometrorrhagia 0/370 (0%) 1/370 (0.3%)
    Postmenopausal haemorrhage 0/370 (0%) 1/370 (0.3%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 15/370 (4.1%) 26/370 (7%)
    Pleural effusion 4/370 (1.1%) 12/370 (3.2%)
    Asthma 4/370 (1.1%) 1/370 (0.3%)
    Pneumonia aspiration 4/370 (1.1%) 3/370 (0.8%)
    Respiratory failure 4/370 (1.1%) 2/370 (0.5%)
    Pulmonary oedema 3/370 (0.8%) 15/370 (4.1%)
    Dyspnea 2/370 (0.5%) 7/370 (1.9%)
    Chronic obstructive pulmonary disease 2/370 (0.5%) 6/370 (1.6%)
    Acute pulmonary oedema 0/370 (0%) 6/370 (1.6%)
    Bronchitis chronic 1/370 (0.3%) 0/370 (0%)
    Bronchospasm 0/370 (0%) 1/370 (0.3%)
    Chronic respiratory failure 0/370 (0%) 1/370 (0.3%)
    Cough 1/370 (0.3%) 0/370 (0%)
    Haemoptysis 2/370 (0.5%) 1/370 (0.3%)
    Hypoxia 2/370 (0.5%) 1/370 (0.3%)
    Lung infiltration 0/370 (0%) 1/370 (0.3%)
    Mediastinal haemorrhage 1/370 (0.3%) 0/370 (0%)
    Pneumothorax 1/370 (0.3%) 0/370 (0%)
    Pulmonary congestion 0/370 (0%) 1/370 (0.3%)
    Pulmonary embolism 2/370 (0.5%) 2/370 (0.5%)
    Pulmonary hypertension 2/370 (0.5%) 2/370 (0.5%)
    Skin and subcutaneous tissue disorders
    Diabetic foot 3/370 (0.8%) 4/370 (1.1%)
    Angioedema 2/370 (0.5%) 1/370 (0.3%)
    Dermatitis bullous 1/370 (0.3%) 0/370 (0%)
    Hypersensitivity vasculitis 0/370 (0%) 1/370 (0.3%)
    Panniculitis 0/370 (0%) 2/370 (0.5%)
    Skin ulcer 1/370 (0.3%) 0/370 (0%)
    Vascular disorders
    Hypotension 18/370 (4.9%) 19/370 (5.1%)
    Deep vein thrombosis 9/370 (2.4%) 5/370 (1.4%)
    Hypertension 6/370 (1.6%) 4/370 (1.1%)
    Peripheral ischaemia 5/370 (1.4%) 0/370 (0%)
    Hypertensive crisis 4/370 (1.1%) 3/370 (0.8%)
    Aortic stenosis 0/370 (0%) 4/370 (1.1%)
    Accelerated hypertension 2/370 (0.5%) 2/370 (0.5%)
    Arteriosclerosis 2/370 (0.5%) 0/370 (0%)
    Brachiocephalic vein occlusion 0/370 (0%) 1/370 (0.3%)
    Dry gangrene 1/370 (0.3%) 3/370 (0.8%)
    Essential hypertension 1/370 (0.3%) 2/370 (0.5%)
    Extremity necrosis 0/370 (0%) 1/370 (0.3%)
    Haemorrhage 0/370 (0%) 1/370 (0.3%)
    Hypertensive emergency 3/370 (0.8%) 3/370 (0.8%)
    Hypovolaemic shock 0/370 (0%) 2/370 (0.5%)
    Iliac vein occlusion 0/370 (0%) 1/370 (0.3%)
    Intermittent claudication 0/370 (0%) 1/370 (0.3%)
    Malignant hypertension 0/370 (0%) 2/370 (0.5%)
    Orthostatic hypotension 1/370 (0.3%) 1/370 (0.3%)
    Pelvic venous thrombosis 1/370 (0.3%) 0/370 (0%)
    Peripheral arterial occlusive disease 0/370 (0%) 1/370 (0.3%)
    Peripheral artery occlusion 0/370 (0%) 1/370 (0.3%)
    Peripheral artery stenosis 0/370 (0%) 1/370 (0.3%)
    Peripheral embolism 1/370 (0.3%) 0/370 (0%)
    Peripheral vascular disorder 2/370 (0.5%) 3/370 (0.8%)
    Secondary hypertension 0/370 (0%) 1/370 (0.3%)
    Shock 1/370 (0.3%) 0/370 (0%)
    Shock haemorrhagic 2/370 (0.5%) 2/370 (0.5%)
    Steal syndrome 2/370 (0.5%) 0/370 (0%)
    Superior vena cava stenosis 0/370 (0%) 1/370 (0.3%)
    Superior vena cava syndrome 0/370 (0%) 1/370 (0.3%)
    Venous stenosis 1/370 (0.3%) 0/370 (0%)
    Venous thrombosis limb 0/370 (0%) 1/370 (0.3%)
    Other (Not Including Serious) Adverse Events
    Roxadustat Epoetin Alfa
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 286/370 (77.3%) 292/370 (78.9%)
    Blood and lymphatic system disorders
    Anaemia 28/370 (7.6%) 41/370 (11.1%)
    Cardiac disorders
    Tachycardia 20/370 (5.4%) 19/370 (5.1%)
    Bradycardia 11/370 (3%) 19/370 (5.1%)
    Gastrointestinal disorders
    Nausea 63/370 (17%) 60/370 (16.2%)
    Vomiting 60/370 (16.2%) 55/370 (14.9%)
    Diarrhoea 54/370 (14.6%) 69/370 (18.6%)
    Constipation 44/370 (11.9%) 48/370 (13%)
    Abdominal pain 32/370 (8.6%) 30/370 (8.1%)
    Abdominal pain upper 19/370 (5.1%) 16/370 (4.3%)
    General disorders
    Non-cardiac chest pain 24/370 (6.5%) 32/370 (8.6%)
    Pyrexia 32/370 (8.6%) 33/370 (8.9%)
    Asthenia 25/370 (6.8%) 15/370 (4.1%)
    Oedema peripheral 22/370 (5.9%) 34/370 (9.2%)
    Peripheral swelling 16/370 (4.3%) 26/370 (7%)
    Face oedema 10/370 (2.7%) 19/370 (5.1%)
    Infections and infestations
    Upper respiratory tract infection 43/370 (11.6%) 40/370 (10.8%)
    Pneumonia 19/370 (5.1%) 22/370 (5.9%)
    Urinary tract infection 24/370 (6.5%) 26/370 (7%)
    Viral upper respiratory tract infection 26/370 (7%) 26/370 (7%)
    Bronchitis 22/370 (5.9%) 25/370 (6.8%)
    Injury, poisoning and procedural complications
    Arteriovenous fistula site complication 53/370 (14.3%) 71/370 (19.2%)
    Arteriovenous fistula thrombosis 29/370 (7.8%) 32/370 (8.6%)
    Fall 36/370 (9.7%) 53/370 (14.3%)
    Arteriovenous graft thrombosis 24/370 (6.5%) 27/370 (7.3%)
    Contusion 14/370 (3.8%) 20/370 (5.4%)
    Vascular graft complication 9/370 (2.4%) 22/370 (5.9%)
    Metabolism and nutrition disorders
    Hyperkalaemia 38/370 (10.3%) 43/370 (11.6%)
    Fluid overload 17/370 (4.6%) 25/370 (6.8%)
    Hypoglycaemia 20/370 (5.4%) 21/370 (5.7%)
    Iron deficiency 12/370 (3.2%) 23/370 (6.2%)
    Musculoskeletal and connective tissue disorders
    Pain in extremity 49/370 (13.2%) 58/370 (15.7%)
    Back pain 37/370 (10%) 39/370 (10.5%)
    Arthralgia 26/370 (7%) 37/370 (10%)
    Muscle spasms 17/370 (4.6%) 25/370 (6.8%)
    Musculoskeletal pain 15/370 (4.1%) 20/370 (5.4%)
    Nervous system disorders
    Headache 42/370 (11.4%) 40/370 (10.8%)
    Dizziness 24/370 (6.5%) 30/370 (8.1%)
    Psychiatric disorders
    Anxiety 16/370 (4.3%) 20/370 (5.4%)
    Insomnia 15/370 (4.1%) 25/370 (6.8%)
    Respiratory, thoracic and mediastinal disorders
    Cough 49/370 (13.2%) 69/370 (18.6%)
    Dyspnoea 56/370 (15.1%) 64/370 (17.3%)
    Skin and subcutaneous tissue disorders
    Pruritus 22/370 (5.9%) 21/370 (5.7%)
    Vascular disorders
    Hypertension 59/370 (15.9%) 44/370 (11.9%)
    Hypotension 27/370 (7.3%) 27/370 (7.3%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The multisite consortium can publish any time after the data is collected and analyzed by FibroGen. The investigator can only publish after the multisite consortium publishes (or tries to publish and fails). FibroGen has 60 days to review a publication and can extend the embargo up to an additional 120 days (or 180 total).

    Results Point of Contact

    Name/Title Clinical Trial Information Desk
    Organization FibroGen, Inc.
    Phone 415-978-1441
    Email 064study@fibrogen.com
    Responsible Party:
    FibroGen
    ClinicalTrials.gov Identifier:
    NCT02273726
    Other Study ID Numbers:
    • FGCL-4592-064
    First Posted:
    Oct 24, 2014
    Last Update Posted:
    Oct 29, 2021
    Last Verified:
    Sep 1, 2021