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    Clinical Trial Results:
    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.

    Summary
    EudraCT number
    		 2013-002753-30
    Trial protocol
    		 EE   BG   LV   PL  
    Global end of trial date
    21 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Oct 2019
    First version publication date
    17 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FGCL-4592-063/CFG13001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02052310
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    FibroGen, Inc.
    Sponsor organisation address
    409 Illinois Street, San Francisco, United States, CA 94158
    Public contact
    Lona Poole, MD (medical monitor), FibroGen, Inc., 415 9781344, lpoole@fibrogen.com
    Scientific contact
    Lona Poole, MD (medical monitor), FibroGen, Inc., 415 9781344, lpoole@fibrogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the efficacy and safety of roxadustat in the treatment of anemia in incident-dialysis subjects, compared with active control.
    Protection of trial subjects
    This trial was conducted in accordance with the ethical principles of Good Clinical Practice, according to the ICH Harmonized Tripartite Guideline and the local law and regularions of the counties of clinical sites. A Data Safety Monitoring Board (DSMB) reviewed safety data periodically in collaboration with the sponsor to ensure subject safety. An Independent Event Review Committee (IERC), blinded to treatment group, adjudicated pre-specified cardiovascular, cerebrovascular, and thromboembolic safety events of interest.
    Background therapy
    		 Oral iron was allowed as first-line iron supplementation without restriction; IV iron was allowed per protocol specification.
    Evidence for comparator
    		 For subjects on HD, doses of epoetin alfa were administered IV three times weekly according to the United States Package Insert (USPI) or Summary of Product Characteristics (SmPC) by appropriately trained personnel. For subjects requiring ultra-low dose of EPO (e.g., ≤1000 IU/per week), the frequency of administration could have been adjusted per local standard of care. For subjects on home-hemodialysis (HHD) or peritoneal dialysis (PD), doses of epoetin alfa were administered by appropriately trained personnel, including the subject or caregiver, according to the USPI, SmPC, or local standard of care. All epoetin alfa was supplied to the study sites from commercial sources. Within the United States (U.S.), sites obtained commercially available epoetin alfa; outside of the U.S., FibroGen provided commercially available epoetin alfa for use by the sites. Epoetin alfa was stored according to the USPI or SmPC.
    Actual start date of recruitment
    04 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Bulgaria: 96
    Country: Number of subjects enrolled
    Latvia: 6
    Country: Number of subjects enrolled
    Argentina: 53
    Country: Number of subjects enrolled
    Belarus: 3
    Country: Number of subjects enrolled
    Brazil: 30
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 34
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Malaysia: 23
    Country: Number of subjects enrolled
    Peru: 6
    Country: Number of subjects enrolled
    Romania: 21
    Country: Number of subjects enrolled
    Russian Federation: 340
    Country: Number of subjects enrolled
    Thailand: 11
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Ukraine: 143
    Country: Number of subjects enrolled
    United States: 252
    Worldwide total number of subjects
    1043
    EEA total number of subjects
    132
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    772
    From 65 to 84 years
    261
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study population consisted of anaemic patients that received hemodialysis (HD) or peritoneal dialysis (PD) for end-stage renal disease (ESRD) for a minimum of 2 weeks and a maximum of 4 months, prior to randomization AND with none or limited (≤ 3 weeks) ESA exposure.

    Pre-assignment
    Screening details
    		 The Screening Period lasted up to 6 weeks. A total of 1043 subjects were randomized to received one of the 2 treatment arms in a 1:1 ratio to receive either open label roxadustat or epoetin alfa.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Automated randomization and treatment assignments were provided by an Interactive Voice and Web Response System (IXRS) for this open label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Roxadustat
    Arm description
    		 Roxadustat was dosed orally 3 times weekly (TIW) throughout the Treatment Period (minimum of 52 weeks, maximum up to approximately 4 years), except if a subject required <20 mg TIW (i.e., <60 mg per week) to maintain Hb levels.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roxadustat
    Investigational medicinal product code
    Other name
    FG 4592
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Roxadustat was orally self-administered by subjects. Roxadustat was dosed TIW throughout the Treatment Period, except if a subject required <20 mg TIW (i.e., <60 mg per week) to maintain Hb levels in the Maintenance Phase, then the dosing frequency could have been reduced in a step-wise fashion (e.g., TIW to BIW, BIW to QW, QW to Q-2 Week [every 2 weeks]). The initial roxadustat dose (per dose amount) was based on a tiered, weight based dosing scheme with a starting dose of 70 mg for subjects who weighed <70 kg or 100 mg for subjects who weighed ≥70 kg at Day 1. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower).

    Arm title
    		 Epoetin Alfa
    Arm description
    		 Epoetin alfa was supplied to the study site from commercial sources. Within the U.S., sites obtained commercially available epoetin alfa; outside of the U.S., FibroGen provided commercially available epoetin alfa for use by the sites. Epoetin alfa was stored according to the USPI or SmPC.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Epoetin alfa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    For subjects on HD, doses of epoetin alfa were administered IV TIW according to the United States Package Insert (USPI) or Summary of Product Characteristics (SmPC) by appropriately trained personnel. For subjects requiring ultra-low dose of EPO (e.g., ≤1000 IU/per week), the frequency of administration could have been adjusted per local standard of care. For subjects on home-hemodialysis (HHD) or PD, doses of epoetin alfa were administered by appropriately trained personnel, including the subject or caregiver, according to the USPI, SmPC, or local standard of care.

    Number of subjects in period 1
    		Roxadustat Epoetin Alfa
    Started
    522
    521
    Completed
    307
    309
    Not completed
    215
    212
         Adverse event, serious fatal
    64
    54
         Consent withdrawn by subject
    37
    49
         Physician decision
    14
    7
         Adverse event, non-fatal
    29
    22
         Lost to follow-up
    4
    2
         Other - subject moved or relocated
    32
    29
         Study/Site Termination by Sponsor
    5
    13
         Kidney transplant
    23
    29
         Lack of efficacy
    6
    1
         Protocol deviation
    1
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Roxadustat
    Reporting group description
    		 Roxadustat was dosed orally 3 times weekly (TIW) throughout the Treatment Period (minimum of 52 weeks, maximum up to approximately 4 years), except if a subject required <20 mg TIW (i.e., <60 mg per week) to maintain Hb levels.

    Reporting group title
    Epoetin Alfa
    Reporting group description
    		 Epoetin alfa was supplied to the study site from commercial sources. Within the U.S., sites obtained commercially available epoetin alfa; outside of the U.S., FibroGen provided commercially available epoetin alfa for use by the sites. Epoetin alfa was stored according to the USPI or SmPC.

    Reporting group values
    		 Roxadustat Epoetin Alfa Total
    Number of subjects
    		 522 521 1043
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 381 391 772
        From 65 to 74
    		 100 94 194
        75 and older
    		 41 36 77
    Age continuous
    Age
    Units: years
        arithmetic mean (standard deviation)
    		 53.8 ( 14.74 ) 54.3 ( 14.55 ) -
    Gender categorical
    Gender
    Units: Subjects
        Female
    		 213 214 427
        Male
    		 309 307 616
    Ethnicity
    Ethnicity
    Units: Subjects
        Non-Hispanic/Non-Latino
    		 423 444 867
        Hispanic/Latino
    		 99 77 176
    Race
    Race
    Units: Subjects
        White
    		 415 400 815
        Black/African American
    		 44 50 94
        Asian
    		 43 51 94
        Other
    		 19 16 35
        American Indian/Alaskan Native
    		 1 4 5
    Region
    Region
    Units: Subjects
        Ex-U.S.
    		 395 396 791
        U.S.
    		 127 125 252
    ESA
    ESA (erythropoiesis-stimulating agent) naïve was defined as never having received ESA or not having received ESA within 12 weeks prior to randomization. Limited ESA use was defined as limited (≤3 weeks) ESA use to prior to screening.
    Units: Subjects
        ESA Naïve
    		 489 489 978
        ESA Limited
    		 33 32 65
    Hemoglobin Group
    Units: Subjects
        ≤8.0 g/dL
    		 166 157 323
        >8.0 g/dL
    		 356 364 720
    CRP
    C-reactive protein
    Units: Subjects
        ≤ULN
    		 289 289 578
        >ULN
    		 228 226 454
        Not recorded
    		 5 6 11
    Ferritin Group
    Units: Subjects
        <100 ng/mL
    		 30 36 66
        100 to <400 ng/mL
    		 266 255 521
        ≥400 ng/mL
    		 226 230 456
    TSAT Group
    Units: Subjects
        <20%
    		 99 89 188
        ≥20% to <40%
    		 347 388 735
        ≥40%
    		 49 44 93
        Not reported
    		 27 0 27
    Iron Repletion Status
    Units: Subjects
        Ferritin ≥100 ng/mL and TSAT ≥20%
    		 406 406 812
        Ferritin <100 ng/mL or TSAT <20%
    		 116 115 231
    History of Cardiovascular, Cerebrovascular, or Thromboembolic Disease Risk Factors as randomization
    Units: Subjects
        Yes
    		 219 224 443
        No
    		 303 297 600
    Cardiovascular, Cerebrovascular Cardiovascular Disease (Excluding Hypertension)
    Units: Subjects
        Cardiovascular
    		 141 149 290
        Cerebrovascular
    		 77 79 156
        Not reported
    		 304 293 597
    Diabetes
    Units: Subjects
        Type 1
    		 22 25 47
        Type 2
    		 183 179 362
        Not reported
    		 317 317 634
    Dialysis Modality
    Units: Subjects
        Hemodialysis
    		 469 462 931
        Peritonaeal Dialysis
    		 53 58 111
        Missing
    		 0 1 1
    Height
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 168.43 ( 9.487 ) 168.25 ( 9.805 ) -
    BMI
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 26.73 ( 5.835 ) 27.01 ( 6.026 ) -
    Hemoglobin
    Hb baseline was defined as the mean of up to 4 of the last central laboratory values prior to the first dose.
    Units: g/dL
        arithmetic mean (standard deviation)
    		 8.43 ( 1.044 ) 8.46 ( 0.964 ) -
    Prior Duration on Dialysis (weeks)
    Units: weeks
        arithmetic mean (standard deviation)
    		 10.13 ( 3.906 ) 10.16 ( 3.621 ) -
    TSAT
    TSAT = transferrin saturation (%). TSAT baselines are defined as the mean of values obtained within 6 weeks prior to the first dose.
    Units: percent
        arithmetic mean (standard deviation)
    		 27.02 ( 9.265 ) 27.56 ( 8.910 ) -
    Ferritin
    Units: ng/mL
        arithmetic mean (standard deviation)
    		 441.38 ( 337.016 ) 437.42 ( 311.359 ) -
    Weight
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    		 76.01 ( 18.499 ) 76.70 ( 19.087 ) -

    End points

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    End points reporting groups
    Reporting group title
    Roxadustat
    Reporting group description
    		 Roxadustat was dosed orally 3 times weekly (TIW) throughout the Treatment Period (minimum of 52 weeks, maximum up to approximately 4 years), except if a subject required <20 mg TIW (i.e., <60 mg per week) to maintain Hb levels.

    Reporting group title
    Epoetin Alfa
    Reporting group description
    		 Epoetin alfa was supplied to the study site from commercial sources. Within the U.S., sites obtained commercially available epoetin alfa; outside of the U.S., FibroGen provided commercially available epoetin alfa for use by the sites. Epoetin alfa was stored according to the USPI or SmPC.

    Primary: Primary Endpoint Analysis-U.S. Submission

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    End point title
    		 Primary Endpoint Analysis-U.S. Submission
    End point description
    The primary efficacy endpoint for the U.S. submission was defined as the Hb change from baseline to the average level from Week 28 until Week 52, regardless of rescue therapy, in the ITT population. (ANCOVA with Multiple Imputation)
    End point type
    Primary
    End point timeframe
    The treatment period is from week 1 up to Week 52. The endpoint is the average of values measured over weeks 28 to 52.
    End point values
    		 Roxadustat Epoetin Alfa
    Number of subjects analysed
    522
    521
    Units: g/dL
        least squares mean (confidence interval 95%)
    2.38 (2.298 to 2.461)
    2.20 (2.115 to 2.278)
    Statistical analysis title
    		 HB change from baseline averaged over w. 28 to 52
    Statistical analysis description
    The primary non-inferiority hypothesis tested for the primary efficacy analysis was: • H0: Hb mean change from baseline to the average level from Week 28 to Week 52 in the roxadustat arm ≤Hb mean change from baseline in the epoetin alfa arm minus 0.75 g/dL versus • H1: Hb mean change from baseline to the average level of Week 28 to Week 52 in the roxadustat arm >Hb mean change from baseline in the epoetin alfa arm minus 0.75 g/dL
    Comparison groups
    Epoetin Alfa v Roxadustat
    Number of subjects included in analysis
    1043
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.0005
    Method
    		 MI ANCOVA
    Parameter type
    		 Least Square Means Difference
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.079
         upper limit
    		 0.287
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.053
    Notes
    [1] - Baseline Hb is defined the mean of up to four last central lab values prior to the first dose of study treatment. A multiple imputation analysis of covariance (MI ANCOVA) model approach was used to analyze the primary endpoint. The method first imputed all intermediate missing values using Markov Chain Monte Carlo (MCMC). The complete observed plus imputed data were analyzed using the analysis of covariance (ANCOVA) model.

    Primary: Primary Endpoint Analysis—Ex-U.S. Submission

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    End point title
    		 Primary Endpoint Analysis—Ex-U.S. Submission
    End point description
    The primary efficacy endpoint for the Ex-U.S. submission was defined as the proportion of subjects who achieved an Hb response at 2 consecutive visits during the first 24 weeks of treatment, censoring for rescue therapy. (PPS population) A 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 subjects whose baseline Hb >8.0 g/dL, or Increase in Hb ≥2.0 g/dL in subjects whose baseline Hb ≤8.0 g/dL.
    End point type
    Primary
    End point timeframe
    First 24 weeks of treatment
    End point values
    		 Roxadustat Epoetin Alfa
    Number of subjects analysed
    490
    468
    Units: subjects
    432
    395
    Statistical analysis title
    		 proportion of subjects who achieved an Hb response
    Statistical analysis description
    A two-sided 95% CI for the difference of 2 responder rates (roxadustat minus epoetin alfa) based on the Miettinen & Nurminen approach adjusting for treatment and other stratification factors was calculated and non-inferiority is reached if the lower bound of the 95% CI is greater than -15%
    Comparison groups
    Roxadustat v Epoetin Alfa
    Number of subjects included in analysis
    958
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 difference in proportions (%)
    Point estimate
    3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 7.7
    Notes
    [2] - To preserve the overall alpha level, the multiple comparison was performed using the fixed sequence testing procedure at a 2-sided significance level of 0.05

    Secondary: The mean Hb (g/dL) change from baseline to the average level during the Evaluation Period, defined as Week 28 until Week 52 for Ex-U.S.

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    End point title
    		 The mean Hb (g/dL) change from baseline to the average level during the Evaluation Period, defined as Week 28 until Week 52 for Ex-U.S.
    End point description
    The mean Hb (g/dL) change from baseline to the average level during the Evaluation Period, defined as Week 28 until Week 52 for Ex-U.S. (in PPS population). To preserve the overall alpha level, the multiple comparison was performed using the fixed sequence testing procedure at a 2-sided significance level of 0.05.
    End point type
    Secondary
    End point timeframe
    Week 28 until Week 52
    End point values
    		 Roxadustat Epoetin Alfa
    Number of subjects analysed
    490
    468
    Units: g/dL
        least squares mean (confidence interval 95%)
    2.49 (2.391 to 2.582)
    2.32 (2.225 to 2.419)
    Statistical analysis title
    		 The mean Hb (g/dL) change from baseline
    Statistical analysis description
    MMRM model which included baseline Hb as covariates and treatment group, visit (a class variable, up to Week 52), interaction of treatment group and visit, and stratification factors as fixed effects. The treatment difference was calculated from an estimate statement based on LSMeans of visits Week 28 to 52 from the MMRM model.
    Comparison groups
    Roxadustat v Epoetin Alfa
    Number of subjects included in analysis
    958
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    		 MMRM Model
    Parameter type
    		 Least Square Means Difference
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.032
         upper limit
    		 0.296
    Notes
    [3] - Non-inferiority of roxadustat versus Epoetin alfa. Non-inferiority was declared when the lower bound of the 95% CI was above -0.75 g/dL.

    Secondary: LDL cholesterol (mg/dL) change from BL to the average of weeks 12 to 24

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    End point title
    		 LDL cholesterol (mg/dL) change from BL to the average of weeks 12 to 24
    End point description
    LDL cholesterol (mg/dL) change from BL to the average of weeks 12 to 24 (in FAS population)
    End point type
    Secondary
    End point timeframe
    over weeks 12 to 24
    End point values
    		 Roxadustat Epoetin Alfa
    Number of subjects analysed
    522
    513
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -25.76 (-28.152 to -23.362)
    -7.42 (-9.828 to -5.007)
    Statistical analysis title
    		 Mean change from baseline in LDL cholesterol
    Statistical analysis description
    The LDL cholesterol averaged over Weeks 12 to 24 was compared between the 2 treatment groups using the MMRM model with baseline LDL cholesterol as a covariate, treatment group, visit, interaction of visit and treatment group baseline LDL cholesterol measurement, and stratification factors of CV/cerebrovascular/thromboembolic medical history (yes versus no) and geographic region (U.S. versus Ex-U.S.) as fixed effects.
    Comparison groups
    Roxadustat v Epoetin Alfa
    Number of subjects included in analysis
    1035
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.0001
    Method
    		 MMRM Model
    Parameter type
    		 Least Square Means Difference
    Point estimate
    -18.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.448
         upper limit
    		 -15.232
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.584
    Notes
    [4] - Superiority of roxadustat versus EPO when p<0.05

    Secondary: Mean change from baseline in Hb (g/dL) levels between Weeks 18 to 24 in patients whose baseline CRP> ULN

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    End point title
    		 Mean change from baseline in Hb (g/dL) levels between Weeks 18 to 24 in patients whose baseline CRP> ULN
    End point description
    Mean change from baseline in Hb (g/dL) levels between Weeks 18 to 24 in patients whose baseline CRP> ULN (in PPS population).
    End point type
    Secondary
    End point timeframe
    over weeks 18 to 24
    End point values
    		 Roxadustat Epoetin Alfa
    Number of subjects analysed
    212
    201
    Units: mg/dL
        least squares mean (confidence interval 95%)
    2.33 (2.168 to 2.477)
    2.33 (2.175 to 2.482)
    Statistical analysis title
    		 Mean Change in Hemoglobin Levels
    Statistical analysis description
    Mean change from baseline in Hb (g/dL) levels between Weeks 18 to 24 in patients whose baseline CRP> ULN.
    Comparison groups
    Roxadustat v Epoetin Alfa
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    		 MI ANCOVA
    Parameter type
    		 Least Square Means Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.194
         upper limit
    		 0.201
    Notes
    [5] - Non-inferiority was declared when the lower bound of the 95% CI was above -0.75 g/dL.

    Secondary: Monthly IV iron (mg per Patient-exposure-month) use per subject during weeks 28 to 52

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    End point title
    		 Monthly IV iron (mg per Patient-exposure-month) use per subject during weeks 28 to 52
    End point description
    Monthly IV iron (mg per Patient-exposure-month) use per subject during weeks 28 to 52 (in FAS population).
    End point type
    Secondary
    End point timeframe
    Weeks 28 to 52
    End point values
    		 Roxadustat Epoetin Alfa
    Number of subjects analysed
    437
    438
    Units: mg per patient-exposure-month
        arithmetic mean (standard deviation)
    59.09 ( 145.179 )
    63.99 ( 98.771 )
    Statistical analysis title
    		 Monthly IV iron use
    Comparison groups
    Roxadustat v Epoetin Alfa
    Number of subjects included in analysis
    875
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.00028
    Method
    		 non-parametric rank ANCOVA
    Confidence interval
    Notes
    [6] - Superiority of roxadustat versus EPO when p<0.05

    Secondary: Time to first RBC transfusion during the treatment

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    End point title
    		 Time to first RBC transfusion during the treatment
    End point description
    Time to first RBC transfusion during the treatment (in PPS population).
    End point type
    Secondary
    End point timeframe
    Treatment period.
    End point values
    		 Roxadustat Epoetin Alfa
    Number of subjects analysed
    490
    468
    Units: events per patient-exposure-year
        number (not applicable)
    4.2
    3.1
    Statistical analysis title
    		 Time to first RBC transfusion
    Statistical analysis description
    Cox proportional hazard regression model.
    Comparison groups
    Roxadustat v Epoetin Alfa
    Number of subjects included in analysis
    958
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.871
         upper limit
    		 2.335
    Notes
    [7] - Non-inferiority of roxadustat versus EPO with Non-inferiority margin of 1.8 for the hazard ratio. Non-inferiority was declared when the upper bound of the 95% CI for the hazard ratio was below 1.8. The endpoint did not met the non-inferiority criteria, and the fixed sequence testing stopped.

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Day 1 through 28 days after last dose.
    Adverse event reporting additional description
    Table “Serious adverse events”: all fatal and serious adverse events in ≥1% of subjects; table “Non-serious adverse events”: both serious and non-serious adverse events in ≥%5 of subjects in either treatment group. One TESAE of transplant rejection in the epoetin alfa arm was found retrospectively, and therefore was not included in the tables.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Epoetin Alfa
    Reporting group description
    		 -

    Reporting group title
    Roxadustat
    Reporting group description
    		 -

    Serious adverse events
    		 Epoetin Alfa Roxadustat
    Total subjects affected by serious adverse events
         subjects affected / exposed
    218 / 517 (42.17%)
    234 / 522 (44.83%)
         number of deaths (all causes)
    59
    63
         number of deaths resulting from adverse events
    59
    63
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Glioblastoma
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 517 (0.58%)
    7 / 522 (1.34%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    12 / 517 (2.32%)
    9 / 522 (1.72%)
         occurrences causally related to treatment / all
    1 / 14
    2 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 517 (0.58%)
    6 / 522 (1.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic rupture
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    4 / 517 (0.77%)
    7 / 522 (1.34%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 4
    0 / 7
    Death
         subjects affected / exposed
    7 / 517 (1.35%)
    2 / 522 (0.38%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 7
    0 / 2
    General physical health deterioration
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 522 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sudden cardiac death
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 517 (0.00%)
    3 / 522 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Social circumstances
    Refusal of treatment by patient
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    6 / 517 (1.16%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 517 (0.77%)
    3 / 522 (0.57%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Pulmonary oedema
         subjects affected / exposed
    5 / 517 (0.97%)
    5 / 522 (0.96%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    4 / 517 (0.77%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Investigations
    Coagulation time prolonged
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    21 / 517 (4.06%)
    39 / 522 (7.47%)
         occurrences causally related to treatment / all
    2 / 27
    5 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carbon monoxide poisoning
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Craniocerebral injury
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory fume inhalation disorder
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Arteriovenous fistula site complication
         subjects affected / exposed
    2 / 517 (0.39%)
    5 / 522 (0.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    7 / 517 (1.35%)
    5 / 522 (0.96%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    11 / 517 (2.13%)
    6 / 522 (1.15%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 9
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    5 / 517 (0.97%)
    3 / 522 (0.57%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Cardiac failure
         subjects affected / exposed
    1 / 517 (0.19%)
    3 / 522 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cardiac failure acute
         subjects affected / exposed
    3 / 517 (0.58%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 517 (0.19%)
    4 / 522 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 522 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 522 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Myocardial ischaemia
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 517 (0.39%)
    5 / 522 (0.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Angina unstable
         subjects affected / exposed
    5 / 517 (0.97%)
    3 / 522 (0.57%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    5 / 517 (0.97%)
    4 / 522 (0.77%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hemorrhagic stroke
         subjects affected / exposed
    6 / 517 (1.16%)
    3 / 522 (0.57%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    Basal ganglia haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain injury
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain stem infarction
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    3 / 517 (0.58%)
    2 / 522 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    2 / 517 (0.39%)
    5 / 522 (0.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    5 / 517 (0.97%)
    4 / 522 (0.77%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Gallbladder necrosis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    2 / 517 (0.39%)
    3 / 522 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Infections and infestations
    Peritonitis
         subjects affected / exposed
    12 / 517 (2.32%)
    12 / 522 (2.30%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    26 / 517 (5.03%)
    30 / 522 (5.75%)
         occurrences causally related to treatment / all
    0 / 30
    0 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    8 / 517 (1.55%)
    13 / 522 (2.49%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 14
         deaths causally related to treatment / all
    0 / 4
    0 / 6
    Device related infection
         subjects affected / exposed
    3 / 517 (0.58%)
    9 / 522 (1.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gangrene
         subjects affected / exposed
    6 / 517 (1.16%)
    6 / 522 (1.15%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    4 / 517 (0.77%)
    7 / 522 (1.34%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 5
    Device related sepsis
         subjects affected / exposed
    2 / 517 (0.39%)
    7 / 522 (1.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    4 / 517 (0.77%)
    6 / 522 (1.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diabetic gangrene
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal wall abscess
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gallbladder empyema
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung infection
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Meningitis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    4 / 517 (0.77%)
    4 / 522 (0.77%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Toxic shock syndrome
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 522 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    5 / 517 (0.97%)
    4 / 522 (0.77%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    12 / 517 (2.32%)
    9 / 522 (1.72%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalemia
         subjects affected / exposed
    6 / 517 (1.16%)
    3 / 522 (0.57%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 522 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Epoetin Alfa Roxadustat
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    441 / 517 (85.30%)
    450 / 522 (86.21%)
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    46 / 517 (8.90%)
    59 / 522 (11.30%)
         occurrences all number
    69
    80
    Arteriovenous fistula site complication
         subjects affected / exposed
    43 / 517 (8.32%)
    31 / 522 (5.94%)
         occurrences all number
    79
    40
    Procedural hypotension
         subjects affected / exposed
    31 / 517 (6.00%)
    26 / 522 (4.98%)
         occurrences all number
    49
    35
    Vascular disorders
    Hypertension
         subjects affected / exposed
    88 / 517 (17.02%)
    99 / 522 (18.97%)
         occurrences all number
    134
    165
    Hypotension
         subjects affected / exposed
    35 / 517 (6.77%)
    54 / 522 (10.34%)
         occurrences all number
    51
    104
    Nervous system disorders
    Headache
         subjects affected / exposed
    44 / 517 (8.51%)
    57 / 522 (10.92%)
         occurrences all number
    66
    88
    Dizziness
         subjects affected / exposed
    24 / 517 (4.64%)
    28 / 522 (5.36%)
         occurrences all number
    32
    39
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    30 / 517 (5.80%)
    45 / 522 (8.62%)
         occurrences all number
    33
    57
    Diarrhoea
         subjects affected / exposed
    38 / 517 (7.35%)
    72 / 522 (13.79%)
         occurrences all number
    56
    112
    Constipation
         subjects affected / exposed
    23 / 517 (4.45%)
    35 / 522 (6.70%)
         occurrences all number
    24
    40
    Vomiting
         subjects affected / exposed
    17 / 517 (3.29%)
    32 / 522 (6.13%)
         occurrences all number
    23
    45
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 517 (4.06%)
    28 / 522 (5.36%)
         occurrences all number
    22
    35
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    22 / 517 (4.26%)
    30 / 522 (5.75%)
         occurrences all number
    26
    36
    Endocrine disorders
    Hyperparathyroidism secondary
         subjects affected / exposed
    27 / 517 (5.22%)
    25 / 522 (4.79%)
         occurrences all number
    32
    26
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    27 / 517 (5.22%)
    18 / 522 (3.45%)
         occurrences all number
    28
    21
    Muscle spasms
         subjects affected / exposed
    39 / 517 (7.54%)
    60 / 522 (11.49%)
         occurrences all number
    65
    106
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    40 / 517 (7.74%)
    42 / 522 (8.05%)
         occurrences all number
    46
    48
    Viral upper respiratory tract infection
         subjects affected / exposed
    25 / 517 (4.84%)
    26 / 522 (4.98%)
         occurrences all number
    42
    52
    Metabolism and nutrition disorders
    Hyperphosphataemia
         subjects affected / exposed
    35 / 517 (6.77%)
    52 / 522 (9.96%)
         occurrences all number
    39
    57
    Fluid overload
         subjects affected / exposed
    28 / 517 (5.42%)
    29 / 522 (5.56%)
         occurrences all number
    39
    42
    Hyperkalaemia
         subjects affected / exposed
    36 / 517 (6.96%)
    26 / 522 (4.98%)
         occurrences all number
    47
    37

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Oct 2014
    Amendment 1 was dated as 20 October 2014 and included the following key changes: • Changed the compound name from FG 4592 to roxadustat. • Increased the total sample size and number of sites to reflect the needs of the global program. • Implemented roxadustat dosing, adjustments to the starting dose, and dose adjustment rules to provide a more conservative dosing and to simplify the dose adjustment rules globally. • Clarified dosing with epoetin alfa: specified use of prefilled syringes in countries other than USA; allowed local standard-of-care EPO dosing for subjects on PD. • Added recommendations for the concomitant use of phosphate binders and statins. • Added more specific instructions, to better standardize supplemental IV iron use. • Modified the language regarding ESA rescue criteria for subjects receiving roxadustat, to allow 1 round of ESA rescue on study. • Clarified that chronic use of paracetamol was prohibited. • Modified eligibility criteria for ferritin, TSAT, and IV iron restrictions, to meet the need of subjects being iron-replete at baseline; modified eligibility to allow for investigator discretion in the exclusion of subjects who had abnormal laboratory parameters that could have posed a safety risk. • Reduced the frequency of the visit schedule without impacting the assessment of safety and efficacy. • Added follow-up requirements for subjects who terminated participation in the study early, until overall study end. • Added additional reasons for subject discontinuation. • Added the following tests and assessments: added creatinine phosphokinase (CPK) at the time of liver function test (LFT) assessment, pregnancy testing every 12 weeks, and weight and ECG every 24 weeks, and changed the Week 28 QOL to Week 36. • Stipulated that archival samples were provided on a voluntary basis. • .......
    24 Nov 2015
    Amendment 2 was implemented in the U.S. only, was dated as 24 November 2015, and included the following key changes: • Changed Exclusion Criterion #1 to allow the total duration of prior effective ESA use to be ≤3 weeks within the preceding 12 weeks at the time of informed consent. • Increased the number of planned subjects from 1000 to 1200. • Increased the number of planned study centers from 300 to 400.
    12 Aug 2016
    Amendment 3 was implemented in the U.S. only, was dated as 12 August 2016, and included the following key changes: • Modified Inclusion Criterion #5 to reduce the number of values from 3 to 2 and the number of days between sample collection from 4 to 2 days; this change was implemented to improve participation of incident dialysis patients with severe anemia by streamlining eligibility assessments without changing the Hb requirement for participation. • Modified Exclusion Criterion #1 language related to CERA dosing guidance to align with the current standard of dosing based on the package insert. • Added text to allow for the participation of subjects receiving HHD and clarified that the administration of epoetin alfa would be according to USPI, SmPC, or local standard of care. • Revised the timeline for reassessment of TSAT and ferritin values after the last dose of IV iron to align with the current clinical practice. • Aligned the Adverse Event Reporting Period with GCP/ICH guidelines for AE reporting. • Added the definition of baseline Hb for subjects in the U.S. who were enrolled under Protocol Amendment 3. • Added guidance for epoetin alfa administration to subjects requiring ultra-low dose therapy.
    20 Sep 2017
    Amendment 4 was dated as 20 September 2017 and included the following key changes: • Allowed the participation of subjects who had restarted dialysis recently after a failed kidney transplant. • Revised the TSAT, ferritin, vitamin B12, folate screening criteria to improve the screening success rate without altering the patient population. • Modified and clarified several exclusion criteria to allow more incident subjects to be eligible for participation, to retain a representative sample of real-life incident dialysis patients. • Updated the duration of the Treatment Period to allow for less than 52 weeks of participation for subjects who were enrolled towards the end of the overall study completion. • Modified the protocol to align it with new standard operating procedures (SOPs) for the handling of incorrectly enrolled subjects, contraception, protocol deviations, and disease progression. • Added instructions for the handling of excessive hematopoiesis, to include the scenario of prolonged dose-hold, and dosing of ultra-low doses. • Loosened IV iron use restrictions. • Clarified that inadvertent administration of ESA therapy or ESA administration as part of standard-of-care did not qualify as ESA rescue. • Reduced screening visits/procedures. • Increased the visit windows to avoid unnecessary protocol deviations. • Added instruction that a central laboratory measurement of Hb was to be performed any time a HemoCue®/CritLine® or other local laboratory Hb measurement was obtained. • Clarified action taken with study drug for AE reporting. • Clarified the reporting requirements in case of pregnancy. • Modified the BP and heart rate measurement guidelines to allow for flexibility with standard clinical practice. • Clarified the sample size determination with regard to the European Medicines Agency (EMA) primary endpoint. • Removed the EMA potential interim analysis. • Clarified and corrected descriptions of the analysis model. .....

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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