Roxadustat in the Treatment of Anemia in Chronic Kidney Disease (CKD) Patients, Not on Dialysis, in Comparison to Darbepoetin Alfa (Dolomites)

A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis

The primary objective of this study was to evaluate the efficacy of roxadustat compared to darbepoetin alfa in the treatment of anemia in nondialysis-dependent chronic kidney disease (NDD CKD) participants.

Study Overview

• Status: Completed
• Conditions: Anemia in Chronic Kidney Disease in Non-dialysis Patients
• Intervention / Treatment: Drug: Roxadustat; Drug: Darbepoetin alfa

Detailed Description

This was a phase 3, multicenter, randomized, open-label, active-controlled study. The study was planned to provide key efficacy and safety data for the approval of roxadustat in the treatment of anemia associated with CKD. Participants assigned to roxadustat treatment were administered roxadustat orally as a combination of tablets of different strengths. Participants assigned to darbepoetin alfa treatment were administered darbepoetin alfa subcutaneously or intravenously.

The study consisted of 3 study periods:

• Screening period: up to 6 weeks
• Treatment period: 104 weeks
• Follow-up period: 4 weeks until planned study end (end of year 2)

• Study Type: Interventional
• Enrollment (Actual): 616
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria
    • Site AT43009
• Belarus
  • Brest, Belarus, 224027
    • Site BY37503
  • Grodno, Belarus, 230017
    • Site BY37501
  • Minsk, Belarus, 220036
    • Site BY37506
  • Minsk, Belarus, 220116
    • Site BY37507
  • Minsk, Belarus, 223040
    • Site BY37505
  • Vitebsk, Belarus, 210037
    • Site BY37502
• Bulgaria
  • Sofia, Bulgaria, 1113
    • Site BG35907
  • Sofia, Bulgaria, 1709
    • Site BG35927
  • Varna, Bulgaria, 9000
    • Site BG35916
• Croatia
  • Karlovac, Croatia, 47000
    • Site HR38505
  • Slavonski Brod, Croatia, 35000
    • Site HR38504
  • Zagreb, Croatia, 10 000
    • Site HR38510
  • Zagreb, Croatia, 10000
    • Site HR38502
  • Zagreb, Croatia, 10000
    • Site HR38509
• Czechia
  • Liberec, Czechia, 46063
    • Site CZ42008
  • Prague, Czechia
    • Site CZ42021
  • CZ
    • Novy Jicin, CZ, Czechia, 741 01
      • Site CZ42018
• Finland
  • Helsinki, Finland, 290
    • Site FI35810
• France
  • Avignon, France, 84900
    • Site FR33004
  • Colmar, France, 68024
    • Site FR33009
  • Grenoble, France
    • Site FR33010
  • Limoges, France, 87042
    • Site FR33062
  • Lyon, France, 69437
    • Site FR33012
  • Saint-Priest-en-Jarez, France, 42270
    • Site FR33007
• Georgia
  • Tbilisi, Georgia, 144
    • Site GE99503
  • Tbilisi, Georgia, 144
    • Site GE99504
  • Tbilisi, Georgia, 159
    • Site GE99502
• Germany
  • Cloppenburg, Germany, 49661
    • Site DE49073
  • Düsseldorf, Germany, 40210
    • Site DE49054
  • Hamburg, Germany, 23397
    • Site DE49065
  • Heilbronn, Germany, 74076
    • Site DE49075
  • Hoyerswerda, Germany, 02977
    • Site DE49057
• Hungary
  • Budapest, Hungary, 1097
    • Site HU36028
  • Budapest, Hungary
    • Site HU36029
  • Kistarcsa, Hungary, 2143
    • Site HU36027
  • Pecs, Hungary, H 7624
    • Site HU36008
  • Velence, Hungary
    • Site HU36046
• Ireland
  • Cork, Ireland
    • Site IE35301
• Israel
  • Be'er Ya'akov, Israel, 70300
    • Site IL97202
  • Haifa, Israel, 34362
    • Site IL97215
• Latvia
  • Riga, Latvia, LV-1002
    • Site LV37101
  • Ventspils, Latvia, LV-3601
    • Site LV37104
• Montenegro
  • Niksic, Montenegro, 81400
    • Site ME38202
  • Podgorica, Montenegro, 81000
    • Site ME38201
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Site NL31005
• North Macedonia
  • Skopje, North Macedonia, 1000
    • Site MK38901
  • Struga, North Macedonia, 6330
    • Site MK38903
• Poland
  • Krakow, Poland, 31-559
    • Site PL48001
  • Pulawy, Poland, 24-100
    • Site PL48066
  • Szczecin, Poland, 70-111
    • Site PL48013
  • Tarnow, Poland, 33-100
    • Site PL48007
  • Warszawa, Poland, 04-749
    • Site PL48004
  • Wroclaw, Poland
    • Site PL48009
  • Zamosc, Poland, 22-400
    • Site PL48059
• Portugal
  • Almada, Portugal, 2801-951
    • Site PT35120
  • Braga, Portugal, 4710-243
    • Site PT35131
  • Carnaxide, Portugal, 2795-523
    • Site PT35112
  • Evora, Portugal, 7000-811
    • Site PT35119
  • Lisboa, Portugal, 1069-166
    • Site PT35118
  • Matosinhos, Portugal, 4464-513
    • Site PT35133
  • Setubal, Portugal, 2910-446
    • Site PT35122
  • Vila Nova de Gaia, Portugal, 4434-502
    • Site PT35132
• Romania
  • Bucharest, Romania, 11234
    • Site RO40003
  • Bucharest, Romania, 22328
    • Site RO40021
  • Bucuresti, Romania, 10825
    • Site RO40012
  • Oradea, Romania, 410469
    • Site RO40004
• Russian Federation
  • Chelyabinsk, Russian Federation, 454047
    • Site RU70024
  • Irkutsk, Russian Federation, 664079
    • Site RU70054
  • Moscow, Russian Federation, 119992
    • Site RU70047
  • Moscow, Russian Federation, 125284
    • Site RU70006
  • Nizhny Novgorod, Russian Federation, 603032
    • Site RU70003
  • Omsk, Russian Federation, 644112
    • Site RU70004
  • Rostov-on-Don, Russian Federation, 344029
    • Site RU70014
  • Saint Petersburg, Russian Federation, 196247
    • Site RU70011
  • Saint Petersburg, Russian Federation, 197089
    • Site RU70002
  • Saratov, Russian Federation, 410039
    • Site RU70060
  • Yaroslavl, Russian Federation, 150000
    • Site RU70057
  • Yaroslavl, Russian Federation, 150062
    • Site RU70001
• Serbia
  • Belgrade, Serbia, 11000
    • Site RS38102
  • Belgrade, Serbia, 11000
    • Site RS38105
  • Belgrade, Serbia, 11080
    • Site RS38103
  • Belgrade, Serbia
    • Site RS38104
  • Krusevac, Serbia, 37000
    • Site RS38117
  • Nis, Serbia, 11070
    • Site RS38101
• Slovakia
  • Kosice, Slovakia, 04001
    • Site SK42109
  • Košice, Slovakia, 04001
    • Site SK42102
  • Puchov, Slovakia, 02001
    • Site SK42113
  • Senica, Slovakia, 905 01
    • Site SK42116
• Slovenia
  • Jesenice, Slovenia, SI-4270
    • Site SI38615
  • Maribor, Slovenia, 2000
    • Site SI38603
  • Slovenj Gradec, Slovenia, SI 2380
    • Site SI38619
  • Šempeter pri Gorici, Slovenia, 5290
    • Site SI38609
• Spain
  • Barcelona, Spain, 08907
    • Site ES34026
  • Cordoba, Spain, 14004
    • Site ES34039
  • Girona, Spain, 17007
    • Site ES34054
  • Jaen, Spain, 23007
    • Site ES34017
  • Madrid, Spain, 28046
    • Site ES34037
  • Madrid, Spain, 28922
    • Site ES34010
  • Majadahonda, Spain, 28222
    • Site ES34030
  • Santiago de Compostela, Spain, 15706
    • Site ES34041
  • A Coruna
    • Ferrol, A Coruna, Spain, 15405
      • Site ES34049
• Ukraine
  • Cherkasy, Ukraine, 18009
    • Site UA38021
  • Dnipropetrovsk, Ukraine, 49005
    • Site UA38006
  • Ivano-Frankivsk, Ukraine, 76018
    • Site UA38016
  • Kharkiv, Ukraine, 61103
    • Site UA38011
  • Kiev, Ukraine, 4053
    • Site UA38017
  • Mykolaiv, Ukraine
    • Site UA38007
  • Odessa, Ukraine, 6500
    • Site UA38008
  • Ternopil, Ukraine, 46002
    • Site UA38001
  • Uzhgorod, Ukraine, 88018
    • Site UA38018
  • Lvivska
    • Lviv, Lvivska, Ukraine, 79010
      • Site UA38009
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Site GB44064
  • Dartford, United Kingdom, DA2 8DA
    • Site GB44099
  • Kings Lynn, United Kingdom, PE30 4ET
    • Site GB44102
  • Leicester, United Kingdom, LE5 4PW
    • Site GB44081
  • London, United Kingdom, E1 1BB
    • Site GB44086
  • London, United Kingdom, SE5 9RS
    • Site GB44006
  • London, United Kingdom, SW17 0QT
    • Site GB44082
  • Nottingham, United Kingdom, NG5 1PB
    • Site GB44097
  • Orpington, United Kingdom, BR6 8ND
    • Site GB44100
  • Preston, United Kingdom, PR2 9HT
    • Site GB44101
  • Stoke-on-Trent, United Kingdom, ST4 6QG
    • Site GB44080
  • Swansea, United Kingdom, SA6 6NL
    • Site GB44001
  • Dorset
    • Dorchester, Dorset, United Kingdom, DT1 2JY
      • Site GB44098

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject has a diagnosis of CKD, with Kidney Disease Outcomes Quality Initiative (KDOQI) Stage 3, 4 or 5, not on dialysis; with an Estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m^2 estimated using the abbreviated 4-variable Modification of Diet in Renal Disease (MDRD) equation.
• The mean of the subject's two most recent (prior to randomization) Hb values during the screening period, obtained at least 4 days apart, must be less than or equal to 10.5 g/dL, with a difference of less than or equal to 1.0 g/dL. The last Hb value must be within 10 days prior to randomization.
• Subject is deemed suitable for treatment with Erythropoiesis Stimulating Agent (ESA) using the criteria specified in the Kidney Disease Improving Global Outcomes (KDIGO) 2012 recommendation considering the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anemia.
• Subject has a serum folate level greater than or equal to lower limit of normal (LLN) at screening.
• Subject has a serum vitamin B12 level greater than or equal to LLN at screening.
• Subject's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are less than or equal to 3 x upper limit of normal (ULN), and total bilirubin (TBL) is less than or equal to 1.5 x ULN.
• Subject's body weight is 45.0 kg to a maximum of 160.0 kg.
• Male subject must not donate sperm starting from screening, throughout the study period and up to 12 weeks after final study drug administration.

Exclusion Criteria:

• Subject has received any Erythropoiesis Stimulating Agent (ESA) treatment within 12 weeks prior to randomization.
• Subject has received any dose of IV iron within 6 weeks prior to randomization.
• Subject has received a Red Blood Cell (RBC) transfusion within 8 weeks prior to randomization.
• Subject has a known history of myelodysplastic syndrome or multiple myeloma.
• Subject has a known hereditary hematologic disease such as thalassemia or sickle cell anemia, pure red cell aplasia, or other known causes for anemia other than Chronic Kidney Disease (CKD).
• Subject has a known hemosiderosis, hemochromatosis, coagulation disorder, or hypercoagulable condition.
• Subject has a known chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission.
• Subject is anticipated to undergo elective surgery that is expected to lead to significant blood loss during the study period or anticipated elective coronary revascularization.
• Subject has active or chronic gastrointestinal bleeding.
• Subject has received any prior treatment with roxadustat or a Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI).
• Subject has been treated with iron-chelating agents within 4 weeks prior to randomization.
• Subject has a history of chronic liver disease (e.g., cirrhosis or fibrosis of the liver).
• Subject has known New York Heart Association Class III or IV congestive heart failure.
• Subject has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.

• Subject has one or more contraindications for treatment with darbepoetin alfa:

  • Uncontrolled hypertension, or two or more blood pressure values of SBP greater than or equal to 160 mmHg or DBP greater than or equal to 95 mmHg (within 2 weeks prior to randomization).
  • Known hypersensitivity to darbepoetin alfa, recombinant human erythropoietin, or any of the excipients.
• Subject has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F or higher) of renal cell carcinoma as shown on renal ultrasound within 12 weeks prior to randomization.
• Subject has a history of malignancy, except for the following: cancers determined to be cured or in remission for greater than or equal to 5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.

• Subject is positive for any of the following:

  • human immunodeficiency virus (HIV).
  • hepatitis B surface antigen (HBsAg).
  • or anti-hepatitis C virus antibody (anti-HCV Ab).
• Subject has an active clinically significant infection that is manifested by White Blood Count (WBC) > Upper Limit of Normal (ULN), and/or fever, in conjunction with clinical signs or symptoms of infection within one week prior to randomization.
• Subject has a known untreated proliferative diabetic retinopathy, diabetic macular edema, macular degeneration or retinal vein occlusion.
• Subject has had any prior organ transplant (that has not been explanted), subject is scheduled for organ transplantation, or subject is likely to initiate renal replacement therapy including dialysis within the first year of the study.

• Subject will be excluded from participation if any of the following apply:

  • subject has received investigational therapy within 30 days or 5 half lives or limit set by national law, whichever is longer, prior to initiation of screening, or
  • any condition which makes the subject unsuitable for study participation.
• Subject has an anticipated use of dapsone in any dose amount or chronic use of acetaminophen/paracetamol >2.0 g/day during the treatment or follow-up period of the study.
• Subject has a history of alcohol or drug abuse within 2 years prior to randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Roxadustat; Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg (milligram) given thrice weekly (TIW) to participants weighing up to 70 kg (kilogram) and 100 mg given TIW to participants weighing more than 70 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL (gram per deciliter) and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat up to a maximum of 104 weeks.	Drug: Roxadustat; Oral tablet.; Other Names: ASP1517
Active Comparator: Darbepoetin alfa; Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 μg/kg (microgram per kilogram), as a single subcutaneous or intravenous (IV) injection once weekly or 0.75 μg/kg, as a single subcutaneous injection once every 2 weeks) as per European Summary of Product Characteristics (EU SmPC) along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.	Drug: Darbepoetin alfa; Subcutaneous or intravenous injection.; Other Names: Aranesp

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With a Hb Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy	Hb response was measured as Yes or No. Response Yes (responders) was defined as: Hb ≥11.0 g/dL and Hb change from baseline by ≥ 1.0 g/dL, for participants with baseline Hb > 8.0 g/dL; or Hb change from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at two consecutive visits with available data separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell [RBC] transfusion for all participants or darbepoetin for roxadustat treated participant).	Baseline to week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Hb to the Average Hb of Weeks 28 to 36 Without Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period	Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose).	Baseline and weeks 28 to 36
Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28	Baseline LDL-C was defined as the LDL-C value on day 1. If this value was missing, the latest value prior to first study drug administration was used.	Baseline and weeks 12 to 28
Time to First Intravenous Iron Use	Participants were analyzed 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 end of treatment (EOT) Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had received more than one intravenous 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. Percentage of participants were reported in this outcome measure.	Weeks 6, 12, 18, 24, 30 and 36
Change From Baseline in Short Form-36 (SF-36) Physical Functioning (PF) Sub-Score to the Average PF Sub Score in 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 measured eight scales: (1) physical functioning; (2) role limitations due to physical health problems; (3) bodily pain; (4) social functioning; (5) general health perceptions; (6) role limitations due to emotional problems; (7) vitality, energy or fatigue; and (8) mental health. Each scale is transformed into 0-100 score, with higher scores indicating better health status. The SF-36 PF consisted of 11 questions that focused on health and ability to do usual activities, with higher scores indicating better health status.	Baseline and weeks 12 to 28
Change From Baseline in SF-36 Vitality (VT) Sub-Score to the Average VT Sub-Score in 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.	Baseline and weeks 12 to 28
Change From Baseline in Mean Arterial Pressure (MAP) to the Average MAP Value in Weeks 20 to 28: Per Protocol Set	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. MAP was derived as: MAP = (2/3)*diastolic blood pressure (DBP) + (1/3)*systolic blood pressure (SBP).	Baseline and weeks 20 to 28
Time to First Occurrence of Hypertension During Weeks 1 to 36: Per Protocol Set	Hypertension was defined as either SBP ≥ 170 mmHg and an increase from baseline ≥ 20 mmHg or as DBP ≥ 110 mmHg and an increase from baseline ≥ 15 mmHg. For participants who had 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. Percentage of participants were reported in this outcome measure.	Weeks 1 to 36
Change From Baseline in MAP to the Average MAP Value in Weeks 20 to 28: Full Analysis Set	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. MAP was derived as: MAP = (2/3)*DBP + (1/3)*SBP.	Baseline and weeks 20 to 28
Time to First Occurrence of Hypertension During Weeks 1 to 36: Full Analysis Set	Hypertension was defined as either SBP ≥ 170 mmHg and an increase from baseline ≥ 20 mmHg or as DBP ≥ 110 mmHg and an increase from baseline ≥ 15 mmHg. For participants who had 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. Percentage of participants were reported in this outcome measure.	Weeks 1 to 36
Change From Baseline in Hb to the Average Hb Value of Weeks 28 to 52 Regardless of Rescue Therapy	Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (pre-dose).	Baseline and weeks 28 to 52
Time to First Hb Response During First 24 Weeks of Treatment Regardless of Administration of Rescue Therapy	Participants were analyzed 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). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure.	Weeks 1 to 24
Time to First Hb Response During First 24 Weeks of Treatment Without Rescue Therapy	Participants were analyzed 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). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure.	Weeks 1 to 24
Hb Level Averaged Over Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104 Without Rescue Therapy	Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose).	Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104
Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy	Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (pre-dose).	Baseline and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104
Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104 Regardless of Use of Rescue Therapy	Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose).	Baseline and weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104
Percentage of Hb Values >=10 g/dL and 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 from the 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.	Weeks 28 to 36, 44 to 52 and 96 to 104
Time to First Hb Rate of Rise > 2 g/dL Within 4 Weeks	Participants were analyzed 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). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.	Year 0.5, 1, 1.5 and 2
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).	Baseline to EOT (up to week 104)
Number of Days of Hospitalization Per Year	The number of days of hospitalization per year was calculated as the sum of the durations of all hospitalizations in days (minimum [date of discharge, end of efficacy of emergent period] - date of admission + 1) / (duration of efficacy emergent period in days / 365.25). 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).	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. 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. Percentage of participants were reported in this outcome measure.	Year 0.5, 1, 1.5 and 2
Time to First Use of RBC Transfusion	Participants were analyzed 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). For participants who had experienced more than one RBC transfusion, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.	Year 0.5, 1, 1.5 and 2
Number of RBC Packs	The number of RBC packs were calculated as the sum of units transfused 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). Participants with no medication records of RBC have their number of RBC packs set to 0.	Baseline to EOT (up to week 104)
Volume of RBC Transfused	The volume of blood transfused was calculated as the sum of blood volume transfused 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). Participants with no medication records of RBC have their volume set to 0.	Baseline to EOT (up to week 104)
Number of Particpants Who Received RBC Transfusions	Participants who received RBC transfusions during the efficacy emergent period were reported. 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).	Baseline to EOT (up to week 104)
Time to First Use of Rescue Therapy	Rescue therapy for participants in the roxadustat group included RBC transfusion or ESA therapy and for participants in the darbepoetin alfa group included RBC transfusion only. Participants were analyzed 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). For participants who have experienced more than one use of rescue therapy (i.e. RBC and ESA), only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.	Year 0.5, 1, 1.5 and 2
Number of Participants Who Received Rescue Therapy (Composite of RBC Transfusions (All Participants) and Darbepoetin Alfa Use (Roxadustat Treated Participants Only)	Rescue therapy for participants in the roxadustat group included RBC transfusion or ESA therapy and for participants in the darbepoetin alfa group included RBC transfusion only. Participants were analyzed 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). For participants who have experienced more than one use of rescue therapy (i.e. RBC and ESA), only their first event was used.	Baseline to EOT (up to week 104)
Mean Monthly Intravenous Iron Per Participant During Weeks 37 to 52 and 53 to 104	Participants with no or missing medication records of IV Iron had their monthly IV Iron use set to 0 mg.	Weeks 37 to 52 and 53 to 104
Time to First Use of IV Iron Supplementation	Participants were analyzed 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). For participants who had 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. Percentage of participants were reported in this outcome measure.	Year 0.5, 1, 1.5 and 2
Percentage of Participants With Oral Iron Use Only	Percentage of participants with oral iron use only were calculated based on total number of participants within 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).	Day 1 to week 36, weeks 37 to 52, weeks 53 to 104, efficacy emergent period (up to week 104)
Change From Baseline to Weeks 8, 28, 52 and 104 in Total 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.	Baseline and weeks 8, 28, 52, 104
Change From Baseline to Weeks 8, 28, 52 and 104 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.	Baseline and weeks 8, 28, 52, 104
Change From Baseline to Weeks 8, 28, 52 and 104 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.	Baseline and weeks 8, 28, 52, 104
Change From Baseline to Weeks 8, 28, 52 and 104 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.	Baseline and weeks 8, 28, 52, 104
Change From Baseline to Weeks 8, 28, 52 and 104 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.	Baseline and weeks 8, 28, 52, 104
Change From Baseline to Weeks 8, 28, 52 and 104 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 regardless of fasting.	Baseline and weeks 8, 28, 52, 104
Number of Participants With Mean LDL Cholesterol < 100 mg/dL	Missing category for fasting only includes non-fasting participants and the participants with missing values.	Weeks 12 to 28 and 36 to 52
Number of Participants Who Had Achieved Antihypertensive Treatment Goal	Achieved antihypertensive treatment goal was defined as SBP < 130 mmHg and DBP < 80 mmHg over an evaluation period defined as the average of available values in weeks 12 to 28 and 36 to 52.	Weeks 12 to 28 and 36 to 52
Change From Baseline to the Average of Weeks 12 to 28 and 36 to 52 in SF-36 Physical Component Score (PCS)	Baseline SF-36 PCS was defined as the SF-36 PCS 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 contains 36 items that measured eight scales: (1) physical functioning; (2) role limitations due to physical health problems; (3) bodily pain; (4) social functioning; (5) general health perceptions; (6) role limitations due to emotional problems; (7) vitality, energy or fatigue; and (8) mental health. Each scale is transformed into 0-100 score, with higher scores indicating better health status. The PCS was calculated based on all 8 scales and ranged from 5.02-79.78. For each of these above scales, higher scores always indicated better health status.	Baseline, weeks 12 to 28 and 36 to 52
Change From Baseline to the Average of Weeks 12 to 28 and 36 to 52 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 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. Higher scores indicated better QoL.	Baseline, weeks 12 to 28 and 36 to 52
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in FACT-An Total 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 well being (PWB) - 7 items, functional well being (FWB) - 7 items, social/family well being (SWB) - 7 items, and emotional well being (EWB) - 6 items. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The total score was obtained by summation of the scores from PWB, SWB, EWB, FWB and AnS. The FACT-An Total Score scale range was 0-188. A higher score indicated better QoL.	Baseline, weeks 12 to 28 and 36 to 52
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in FACT-An Trial Outcome Index (TOI) Score	Baseline FACT-An total TOI Score was defined on day 1. Total FACT-An TOI score is a sum of PWB subscale score, FWB subscale score and Ans scale score. Fact-An TOI scale contains 14 items that cover four dimensions of well-being: PWB -7 items, FWB -7 items, where score range for each PWB subscale and FWB subscale is 0-28. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia, where score range for Ans scale is 0-80. The total score was obtained by summation of the scores from PWB, FWB and AnS. The FACT-An Total TOI score range was 0-136. A higher score indicated better QoL.	Baseline, weeks 12 to 28 and 36 to 52
Change From Baseline to the Average Value 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 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 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.	Baseline and weeks 12 to 28
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in Work Productivity and Activity Impairment-Anemic Symptoms (WPAI:ANS) Score: Percent Work Time Missed	WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Multiply scores by 100 to express in percentages. Percent work time missed due to problem: Q2/(Q2+Q4).	Baseline, weeks 12 to 28 and 36 to 52
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Impairment While Working	WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent impairment while working due to problem: Q5/10.	Baseline, weeks 12 to 28 and 36 to 52
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Overall Work Impairment	WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent overall work impairment due to problem: Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4))x(Q5/10)].	Baseline, weeks 12 to 28 and 36 to 52
Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Activity Impairment	WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent activity impairment due to problem: Q6/10.	Baseline, weeks 12 to 28 and 36 to 52
Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC)	The PGIC is a patient-rated instrument that measured 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 included very much improved, much improved and minimally improved.	Weeks 8, 12, 28, 52, 76, 104, last assessment (week 108)
Change From Baseline to Each Scheduled Measurement 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.	Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104 and end of study (EOS) (up to 108 weeks)
Change From Baseline to Each Scheduled Measurement 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.	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 Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c)	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.	Baseline and weeks 12, 28, 36, 44, 60, 84, 104 and EOS (up to 108 weeks)
Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose	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.	Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, 106 and EOS (up to 108 weeks)
Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR)	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.	Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, 106 and EOS (up to 108 weeks)
Rate of Progression of Chronic Kidney Disease Measured by eGFR Slope Over Time	Annualized eGFR slope over time was estimated by a random slopes and intercepts model using all available eGFR values (one baseline and all post-treatment values up to EOT period or start of dialysis adjusted on baseline Hb, region, CV history at baseline and the interaction terms (baseline eGFR by timepoint and baseline Hb by timepoint). All assessments collected after initiation of dialysis (acute or chronic) were excluded from the analysis. Baseline assessment was the assessment from day 1 visit. If this value was missing, the value from screening visit was used.	Baseline up to EOS (up to week 108)
Change From Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR)	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.	Baseline and weeks 12, 24, 36, 52, 64, 76, 88 and 104
Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline	For participants who had doubled their serum creatinine or had chronic dialysis or renal transplant more than once, only their first occurrence during safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.	Year 0.5, 1, 1.5 and 2
Number of Participants With End Stage Renal Disease (ESRD)	Occurrence of end stage renal disease during the study (i.e from day 1 up to the end of study) was defined as at least one of the following: underwent >30 days dialysis therapy, received kidney transplant, planned kidney transplant, physician recommended renal replacement therapy and participant refused therapy, began dialysis and died < 30 days later.	Baseline up to EOS (up to week 108)
Time to Chronic Kidney Disease Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death)	Chronic kidney disease progression was defined as date of occurrence of chronic dialysis or date of renal transplant or doubled serum creatinine or date of death, whichever came first. For participants who had chronic dialysis or renal transplant or died, only their first occurrence during the safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.	Year 0.5, 1, 1.5 and 2
Time to Chronic Dialysis or Renal Transplant or Death	For participants who had chronic dialysis or renal transplant or died, only their first occurrence during the safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.	Year 0.5, 1, 1.5 and 2
Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant	For participants who had at least 40% decrease in eGFR from baseline, chronic dialysis or renal transplant during the safety emergent period, only their first occurrence was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by kaplan-meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.	Year 0.5, 1, 1.5 and 2
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	An AE was defined as any untoward medical occurrence in a participant who was given the study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. All AEs collected during the safety emergent period were counted as TEAE. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Based on national cancer institute common terminology criteria (NCI-CTCAE), AEs were graded as grade 1=mild, grade 2=moderate, grade 3 =severe or medically significant, grade 4 =life threatening, grade 5 =death related to AE. All reported deaths after the first study drug administration and up to 28 days after the analysis date of last dose were based on last dosing frequency.	From first dose of study drug up to end of study (up to week 108)

Collaborators and Investigators

• Sponsor: Astellas Pharma Europe B.V.
• Collaborators: FibroGen

Publications and helpful links

General Publications

• Natale P, Palmer SC, Jaure A, Hodson EM, Ruospo M, Cooper TE, Hahn D, Saglimbene VM, Craig JC, Strippoli GF. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.

Helpful Links

• Link to results on the Astellas Clinical Study Results website.

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2014
• Primary Completion (Actual): March 23, 2018
• Study Completion (Actual): November 6, 2019

Study Registration Dates

• First Submitted: December 20, 2013
• First Submitted That Met QC Criteria: December 20, 2013
• First Posted (Estimate): December 27, 2013

Study Record Updates

• Last Update Posted (Actual): May 13, 2021
• Last Update Submitted That Met QC Criteria: April 19, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Anemia; Hemoglobin; Chronic Kidney Disease (CKD); Roxadustat; ASP1517; Non-dialysis
• Additional Relevant MeSH Terms: Urologic Diseases; Hematologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Anemia; Hematinics; Darbepoetin alfa
• Other Study ID Numbers: 1517-CL-0610; 2013-000951-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)