This study was conducted to explore a new therapy for anemia in participants with end stage renal disease (ESRD) on dialysis. Anemia is a reduced number of red blood cells or hemoglobin. Hemoglobin (which contains iron) is important for the transport of oxygen in your blood. The purpose of this study was to evaluate if roxadustat is effective and safe in the maintenance treatment of anemia in ESRD participants on stable dialysis. Roxadustat was compared to epoetin alfa and darbepoetin alfa, commercially available medicines for treatment of anemia.
This study consisted of three study periods as follows: * Screening Period: up to 6 weeks * Treatment Period: a minimum of 52 weeks up to a maximum of 104 weeks * Follow-up Period: 4 weeks
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
838
Participants received initial dose of roxadustat orally as a tablet in doses of 100 mg, 150 mg or 200 mg, according to the average weekly dose of epoetin or darbepoetin alfa prior to randomization. Participants' roxadustat dosage was adjusted every 4 weeks to maintain Hb level within the target range 10.0 to 12.0 g/dL. Dose adjustment steps were as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. Oral iron treatment of 200 mg was allowed for supplementation to support erythropoiesis. Treatment with intravenous iron was allowed only if certain protocol criteria were met.
Participants received epoetin alfa via intravenous or subcutaneous injection, once a week, twice a week, or three times a week (TIW). Epoetin alfa dosage was adjusted to maintain Hb level within the target range. Dosing of epoetin alfa was per UK SmPC of Eprex®. Participants received IV iron supplementation according to the standard of care.
Participants received darbepoetin alfa via intravenous or subcutaneous injection, once a week or once every other week. Darbepoetin alfa dosage was adjusted to maintain Hb level within the target range. Dosing of darbepoetin alfa was per EU SmPC of Aranesp®. Participants received IV iron supplementation according to the standard of care.
Oral iron treatment was recommended for supplementation to support erythropoiesis and as first-line treatment for iron deficiency, unless participant was intolerant to this treatment. For participants receiving roxadustat the recommended daily dose was 200 mg of elemental iron. Participants were advised to take roxadustat at least 1 hour before or 1 hour after oral iron. Intravenous iron supplementation for participants receiving roxadustat was allowed if all of the following criteria were met: The participant's Hb level had not responded adequately to roxadustat following two consecutive dose increases or reached the maximum dose limit, and participant's ferritin was \< 100 ng/mL (\< 220 pmol/L) or TSAT \< 20%, or the participant was intolerant of oral iron therapy. For participants treated with epoetin alfa or darbepoetin alfa, IV iron supplementation was given according to standard of care.
Site BE32004
Brussels, Flemish Brabant, Belgium
Site BE32001
Aalst, Belgium
Site BE32019
Antwerp, Belgium
Site BE32002
Antwerp, Belgium
Site BE32012
Baudour, Belgium
Site BE32017
Bonheiden, Belgium
Change From Baseline (BL) to the Average Hemoglobin (Hb) in Weeks 28-36 Without Rescue Therapy [EU (EMA)]
Baseline Hb was defined as the mean of four central laboratory Hb values; four latest Hb values prior or on the same date as the first study drug intake. For participants who did not have an available Hb value during the week 28-36 period, imputation rules were applied. For analyses without rescue therapy, participants who used rescue therapy after the initiation of rescue therapy were set to missing for 6 weeks from the start date of rescue therapy. If no Hb value was available, an imputation technique was used, with the mean of all available values from Day 1 to minimum (End of Efficacy Emergent Period) carried forward.
Time frame: Baseline and weeks 28 to 36
Change From BL to the Average Hb in Weeks 28 to 52 Regardless of Rescue Therapy [US (FDA)]
Baseline Hb was defined as the mean of four central laboratory Hb values: four latest Hb values prior or on the same date as first study drug intake. Change from baseline to the average Hb are observed values. Missing hemoglobin 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 with treatment, baseline hemoglobin, randomization stratification factors and the available non missing hemoglobin for each scheduled week.
Time frame: Baseline and weeks 28 to 52
Percentage of Participants With Hb Response During Weeks 28 to 36
Hb response during weeks 28-36, was defined as mean Hb from 10-12 g/dL without receiving rescue therapy in the 6 weeks prior to, or during, the evaluation period. The percentages and 95% CI were unadjusted, the exact method of Clopper-Pearson was used for 95% CI. The Efficacy Emergent Period was defined as the evaluation period from the Analysis date of first dose intake up to end of treatment (EOT) Visit or last non-missing Hb assessment (for participants who died during the treatment period).
Time frame: Weeks 28 to 36
Change From BL in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28
Baseline LDL was defined as the LDL value on Day 1. If this value was missing, the latest value prior to first study drug administration was used.
Time frame: Baseline and weeks 12 to 28
Mean Monthly Intravenous (IV) Iron Use
Participants with no or missing medication records of IV Iron have their monthly IV Iron use set to 0 mg. For participants who took IV Iron, but without a dosing frequency, the average values were set to missing.
Time frame: Day 1 to week 36
Change From BL in Short Form-36 (SF-36) Health Survey Physical Functioning (PF) Sub-score to the Average of Weeks 12 to 28
Baseline SF-36 PF was defined as the SF-36 PF value on Day 1.The SF-36 is a Quality of Life (QoL) instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 contains 36 items that measure eight scales: (1) physical functioning (PF); (2) role limitations due to physical health problems (RP); (3) bodily pain (BP); (4) social functioning (SF); (5) general health perceptions (GH); (6) role limitations due to emotional problems (RE); (7) vitality, energy or fatigue (VT); and (8) mental health(MH). Each scale is transformed into 0-100 score, with higher scores indicating better health status. The SF-36 PF consists of 11 questions focused on health and ability to do usual activities, with higher scores indicating better health status.
Time frame: Baseline and weeks 12 to 28
Change From BL in SF-36 Vitality (VT) Sub-score to the Average of Weeks 12 to 28
Baseline VT Subscore was defined as the VT value on Day 1. The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 vitality has four questions with score range from 0-100 with higher scores indicating better vitality status.
Time frame: Baseline and weeks 12 to 28
Change From BL in Mean Arterial Pressure (MAP) to the Average of Weeks 20 to 28
Baseline MAP was defined as the MAP value on Day 1. If this value was missing, the latest value prior to first study drug administration was used. Mean Arterial Pressure (MAP) is derived as: MAP = (2/3)\*DBP + (1/3)\*SBP.
Time frame: Baseline and weeks 20 to 28
Time to First Occurrence of an Increase in Blood Pressure
Increase in Blood Pressure was defined as either: Systolic Blood Pressure (SBP) ≥ 170 mmHg and an increase from BL ≥ 20 mmHg, or as: Diastolic Blood Pressure (DBP) ≥ 100 mmHg and an increase from BL ≥ 15 mmHg. For participants who have experienced more than one event, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.
Time frame: Weeks 1 to 36
Change From BL in Mean Arterial Pressure (MAP) to the Average MAP Value of Weeks 20 to 28
Baseline MAP was defined as the MAP value on day 1. If this value was missing, the latest value prior to first study drug administration was used. Mean Arterial Pressure (MAP) is derived as: MAP = (2/3)\*DBP + (1/3)\*SBP.
Time frame: Baseline and weeks 20 to 28
Time to First Occurrence of an Increase in Blood Pressure
Increase in Blood Pressure was defined as either: SBP ≥ 170 mmHg and an increase from BL ≥ 20 mmHg, or as: DBP ≥ 100 mmHg and an increase from BL ≥ 15 mmHg. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.
Time frame: Weeks 1 to 36
Percentage of Participants With a Hb Response During Weeks 28 and 36 Regardless of Use of Rescue Therapy
Hb response was defined as mean Hb during weeks 28 to 36 within the target range of 10.0 to 12.0 g/dL. The percentages and 95% CI are unadjusted, the exact method of Clopper-Pearson was used for 95% CI.
Time frame: Weeks 28 to 36
Change From BL in Hb to Each Postdosing Time Point
Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose).
Time frame: Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18,20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72,76, 80, 84, 88, 92, 96, 100, and 104
Hb Level Averaged Over Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy
Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose). Averaged Hb values over weeks 28-36, weeks 44-52 and weeks 96-104 are observed values.
Time frame: Weeks 28 to 36, 44 to 52, and 96 to 104
Change From BL in Hb to the Average of Weeks 28 to 36, 44 to 52, and 96 to 104 Regardless of the Use of Rescue Therapy
Change from baseline to the average Hb are observed values. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose).
Time frame: Baseline and weeks 28 to 36, 44 to 52, and 96 to 104
Percentage of Hb Values ≥ 10 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy
Percentage for each participant was calculated as Number of Hb values \>= 10.0 g/dL / Total number of Hb values\*100 in weeks 28 to 36, 44 to 52 and 96 to 104 without use of rescue therapy within 6 weeks prior to and during the 8 week evaluation period.
Time frame: Weeks 28-36, 44-52 and 96-104
Percentage of Hb Values Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy
Percentage for each participant was calculated as Number of Hb values within 10.0-12.0 g/dL / Total number of Hb values\*100 in weeks 28 to 36, 44 to 52 and 96 to 104 without use of rescue therapy within 6 weeks prior to and during the 8 week evaluation period.
Time frame: Weeks 28-36, 44-52 and 96-104
Number of Hospitalizations
The number of hospitalizations per participant were calculated during the Efficacy Emergent Period. The Efficacy Emergent Period was defined as the evaluation period from the Analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). It included all Non-Hemodialysis (HD) hospitalizations. The HD days were not counted as hospitalizations, even when performed overnight.
Time frame: Baseline to End of Treatment (EOT) (Up to week 104)
Number of Days of Hospitalization Per Year
The number of days of hospitalizations per year was calculated as the sum of the durations of all non-HD hospitalizations in days (Date of discharge - Date of admission + 1)\] / (duration of efficacy emergent period in days / 365.25). In case of missing dates, the hospitalization duration was imputed by the average duration per stay derived from the participants with non-missing duration within the same treatment group.
Time frame: Baseline to EOT (Up to week 104)
Time to First Hospitalization
Time to first hospitalization in years was defined in years as: (First event date during the Efficacy Emergent Period - Analysis date of First dose intake +1)/365.25, and the 'First event date' was defined as 'Date of first Admission and 'Analysis Date of first dose intake. For participants without hospitalization, the time to censoring was calculated as: (Date of End of Efficacy Emergent Period - Analysis Date of first dose intake + 1) / 365.25. Date of End of Efficacy Emergent Period was defined as as the treatment period up to the EOT visit. For participants who have experienced more than one hospitalization, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.
Time frame: Baseline to EOT (Up to week 104)
Time to First Use of Rescue Therapy
Rescue therapy was defined as red blood cell (RBC) transfusion for both treatment groups and ESA for roxadustat participants. Only rescue medication that was started during the study treatment and up to end of efficacy emergent period was taken into account and considered as use of rescue medication. For participants who have experienced more than one use of rescue therapy, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.
Time frame: Baseline to EOT (Up to week 104)
Time to First RBC Transfusion
For participants who have experienced more than one RBC transfusion, only their first event following study treatment was used. For RBC transfusions, when the number of units was not given but the volume transfused was, the number of units were estimated by volume transfused/250 mL (for transfusion of packed cell units) or volume transfused/500 mL (for transfusion of full blood). Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.
Time frame: Baseline to EOT (Up to week 104)
Mean Monthly Number of RBC Packs Per Participant
During efficacy emergent period, the mean monthly number of RBC packs was calculated as the sum of blood volume and units transfused between the first dose and up to the last dose in the period divided by duration of efficacy emergent period (in days) divided by 28 days. Participants without medication records of RBC have their number of RBC packs and volume set to 0.
Time frame: Baseline to EOT (Up to week 104)
Mean Monthly Volume of RBC Transfusion Per Participant
During Efficacy Emergent Period, the mean monthly volume of blood transfused was calculated as the sum of blood volume and units transfused between the first dose and up to the last dose in the period divided by duration of efficacy emergent period (in days) divided by 28 days. The Efficacy Emergent Period was defined as the evaluation period from the Analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period).
Time frame: Baseline to EOT (Up to week 104)
Time to First Use of IV Iron Supplementation
For participants who have received more than one IV iron, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.
Time frame: Baseline to EOT (Up to week 104)
Mean Monthly Intravenous (IV) Iron Per Participant During Weeks 37-52 and Weeks 53-104
Participants with no or missing medication records of IV Iron had their monthly IV Iron use set to 0 mg.
Time frame: Weeks 37-52 and weeks 53-104
Percentage of Participants With Oral Iron Use Only
Percentage of participants with/without IV iron only was calculated based on total number of participants within the Efficacy Emergent Period. The Efficacy Emergent Period is defined as the evaluation period from the Analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period).
Time frame: Baseline to EOT (Up to week 104)
Change From BL to Each Post-dosing Study Visit in Total Cholesterol
Baseline assessment was the assessment from Day 1 visit. If baseline value was missing, then the latest screening period value was used as the baseline regardless of fasting status.
Time frame: Baseline and weeks 8, 28, 52, 104
Change From BL to Each Post-dosing Study Visit in LDL-C/High-density Lipoprotein Cholesterol (HDL-C) Ratio
Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.
Time frame: Baseline and weeks 8, 28, 52, 104
Change From BL to Each Postdosing Study Visit in Non-HDL Cholesterol
Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.
Time frame: Baseline and weeks 8, 28, 52, 104
Change From BL to Each Postdosing Study Visit in Apolipoproteins A1 (ApoA1)
Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.
Time frame: Baseline and weeks 8, 28, 52, 104
Change From BL to Each Postdosing Study Visit in Apolipoproteins B (ApoB)
Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.
Time frame: Baseline and weeks 8, 28, 52, 104
Change From BL to Each Postdosing Study Visit in ApoB/ApoA1 Ratio
Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used.
Time frame: Baseline and weeks 8, 28, 52, 104
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Over Weeks 12 to 28
Missing category for Fasting Only includes non-fasting participants and the participants with missing values.
Time frame: Weeks 12 to 28
Number of Participants With CKD Who Achieved Antihypertensive Treatment Goal
Achieved antihypertensive treatment goal was defined as SBP \< 140 mmHg and DBP \< 90 mmHg over an evaluation period based on the average of available values in weeks 12-28 (pre-dialysis).
Time frame: Weeks 12 to 28
Change From BL to the Average of Weeks 12 to 28 in SF-36 Physical Component Score (PCS)
Baseline SF-36 PCS was defined as the SF-36 PCS value on Day 1. SF-36 contains 36-item that measures 8 scales with scores ranging from 0-100: physical functioning (PF); role limitations due to physical health problems (RP); bodily pain (BP); social functioning (SF); general health perceptions (GH); role limitations due to emotional problems (RE); vitality, energy or fatigue (VT); and mental health (MH). These scores are normed to the US population (norm-based scoring had very little impact on results when data was collected in Western European countries) to have a mean of 50 and standard deviation of 10. The PCS was calculated based on all 8 scales and ranges from 5.02-79.78. For each of these above scales, higher scores always indicating better health status.
Time frame: Baseline and weeks 12 to 28
Change From BL to the Average of Weeks 12 to 28 in Anemia Subscale (AnS) ("Additional Concerns") of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score
Baseline FACT-An AnS was defined as the FACT-An AnS value on Day 1. Together with the Functional Assessment of Cancer Therapy - General (FACT-G), the Anemia Subscale (AnS) is referred to as the FACT-An Total. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The Anemia AnS score range is 0 to 80. For the above score, a higher score indicates better QoL.
Time frame: Baseline and weeks 12 to 28
Change From BL to the Average Value of Weeks 12 to 28 in Total FACT-An Score
Baseline FACT-An Total Score was defined on Day 1. Total Fact-An score is composed of FACT-G and Ans scales. FACT-G contains 27 items that cover four dimensions of well-being: physical (PWB) - 7 items, functional (FWB) - 7 items, social/family (SWB) - 7 items, and emotional (EWB) - 6 items. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The total score is obtained by summation of the scores from PWB, SWB, EWB, FWB and AnS. The FACT-An Total Score scale range is 0-188. A higher score indicates better QoL.
Time frame: Baseline and weeks 12 to 28
Change From BL to the Average of Weeks 12 to 28 in Euroqol Questionnaire-5 Dimensions 5 Levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score
Baseline assessment was defined as the value on Day 1. The EuroQol Questionnaire -5 Dimensions -5 Levels (EQ-5D-5L) is a self-reported questionnaire, used as a measure of respondents' Health Related Quality of Life (HRQoL) and utility values. The EQ-5D consists of the descriptive system and the visual analogue scale (VAS). The EQ-5D descriptive system comprises 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, extreme problems. The VAS records the respondent's self rated health status on a graduated (0-100) scale, where the endpoints are labeled 'Best imaginable health state' and 'Worst imaginable health state' with higher scores for higher HRQoL.
Time frame: Baseline and weeks 12 to 28
Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC)
The PGIC is a patient-rated instrument that measures change in participant's overall status on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), when compared to the start of treatment. The percentage of participants presented includes very much improved, much improved and minimally improved.
Time frame: Baseline and weeks 8, 12, 28, 36, 52, 76, 104
Change From BL in Serum Hepcidin
Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.
Time frame: Baseline and weeks 4, 12, 20, 36, 52, 104, and End of Study (EOS - up to 108 weeks)
Change From BL in Serum Ferritin
Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.
Time frame: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, and EOS (up to 108 weeks)
Change From BL in Transferrin Saturation (TSAT)
Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.
Time frame: Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104 and EOS (up to 108 weeks)
Change From BL in Glycated Hemoglobin (HbA1c) Level to Weeks 12, 28, 36, 44, 52, 60, 84, 104 and EOS (up to Week 108)
Percentage of change from baseline to each study visit were calculated for HbA1c. Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.
Time frame: Baseline and weeks 12, 28, 36, 44, 52, 60, 84, 104 and EOS (up to 108 weeks)
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Safety was assessed by evaluation of the following variables: (TEAEs; frequency, severity, seriousness, and relationship to study drug), Vital signs (systolic and diastolic blood pressure, pulse, respiratory rate and weight), Clinical laboratory variables (hematology, biochemistry including liver enzymes and total bilirubin, and urinalysis), Physical examination, 12-lead electrocardiogram (ECG) and Vascular Access Thrombosis. All AEs collected during the Safety Emergent Period were counted as TEAE. The TEAE was defined as an adverse event (AE) if it was observed after starting administration of the roxadustat or ESA. Any clinically significant abnormalities were reported as an AEs. All reported deaths after the first study drug administration and up to 28 days after the Analysis Date of Last Dose and considering last dosing frequency.
Time frame: Baseline up to EOS (Up to week 108)
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Site BE32003
Leuven, Belgium
Site BE32013
Liège, Belgium
Site BE32011
Roeselare, Belgium
Site BG35925
Blagoevgrad, Bulgaria
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