Roxadustat in the Treatment of Anemia in End Stage Renal Disease (ESRD) Patients on Stable Dialysis

A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of Roxadustat in the Maintenance Treatment of Anemia in End Stage Renal Disease Patients on Stable Dialysis

Sponsors

Lead Sponsor: Astellas Pharma Europe B.V.

Collaborator: FibroGen

Source Astellas Pharma Inc
Brief Summary

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.

Detailed Description

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

Overall Status Completed
Start Date November 21, 2014
Completion Date July 6, 2018
Primary Completion Date June 8, 2017
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Change From Baseline (BL) to the Average Hemoglobin (Hb) in Weeks 28-36 Without Rescue Therapy [EU (EMA)] 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 and weeks 28 to 52
Secondary Outcome
Measure Time Frame
Percentage of Participants with Hb Response During Weeks 28 to 36 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 and weeks 12 to 28
Mean Monthly Intravenous (IV) Iron Use 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 and weeks 12 to 28
Change From BL in SF-36 Vitality (VT) Sub-score to the Average of Weeks 12 to 28 Baseline and weeks 12 to 28
Change From BL in Mean Arterial Pressure (MAP) to the Average of Weeks 20 to 28 Baseline and weeks 20 to 28
Time to First Occurrence of an Increase in Blood Pressure Weeks 1 to 36
Change From BL in Mean Arterial Pressure (MAP) to the Average MAP Value of Weeks 20 to 28 Weeks 20 to 28
Time to First Occurrence of an Increase in Blood Pressure Weeks 1 to 36
Percentage of Participants with a Hb Response During Weeks 28 and 36 Regardless of Use of Rescue Therapy Weeks 28 to 36
Change From BL in Hb to Each Postdosing Time Point 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 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 Baseline and weeks 28 to 36, 44 to 52, 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 Weeks 28-36, 44-52 and 96-104
Number of Hospitalizations Baseline to End of Treatment (EOT) (Up to week 104)
Number of Days of Hospitalization per Year Baseline to EOT (Up to week 104)
Time to First Hospitalization Baseline to EOT (Up to week 104)
Time to First Use of Rescue Therapy Baseline to EOT (Up to week 104)
Time to First RBC Transfusion Baseline to EOT (Up to week 104)
Mean Monthly Number of RBC Packs Per Participant Baseline to EOT (Up to week 104)
Mean Monthly Volume of RBC Transfusion Per Participant Baseline to EOT (Up to week 104)
Time to First Use of IV Iron Supplementation Baseline to EOT (Up to week 104)
Mean Monthly Intravenous (IV) Iron per Participant During Weeks 37-52 and Weeks 53-104 Weeks 37-52 and weeks 53-104
Percentage of Participants with Oral Iron Use Only Baseline to EOT (Up to week 104)
Change From BL to Each Post-dosing Study Visit in Total Cholesterol 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 and weeks 8, 28, 52, 104
Change From BL to Each Postdosing Study Visit in Non-HDL Cholesterol Baseline and weeks 8, 28, 52, 104
Change From BL to Each Postdosing Study Visit in Apolipoproteins A1 (ApoA1) Baseline and weeks 8, 28, 52, 104
Change From BL to Each Postdosing Study Visit in Apolipoproteins B (ApoB) Baseline and weeks 8, 28, 52, 104
Change From BL to Each Postdosing Study Visit in ApoB/ApoA1 Ratio Baseline and weeks 8, 28, 52, 104
Number of Participants with Mean LDL Cholesterol < 100 mg/dL Over Weeks 12 to 28 Weeks 12 to 28
Number of Participants with CKD Who Achieved Antihypertensive Treatment Goal Weeks 12 to 28
Change From BL to the Average of Weeks 12 to 28 in SF-36 Physical Component Score 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 and weeks 12 to 28
Change From BL to the Average Value of Weeks 12 to 28 in Total FACT-An Score 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 and weeks 12 to 28
Percentage of Participants with Improvements Measured by Patients' Global Impression of Change (PGIC) Baseline and weeks 8, 12, 28, 36, 52, 76, 104
Change From BL in Serum Hepcidin 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 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 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 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) Baseline up to EOS (Up to week 108)
Enrollment 838
Condition
Intervention

Intervention Type: Drug

Intervention Name: Roxadustat

Description: 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.

Arm Group Label: Roxadustat

Intervention Type: Drug

Intervention Name: Epoetin alfa

Description: 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.

Arm Group Label: ESA (Erythropoiesis Stimulating Agent) treatment

Other Name: Eprex

Intervention Type: Drug

Intervention Name: Darbepoetin alfa

Description: 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.

Arm Group Label: ESA (Erythropoiesis Stimulating Agent) treatment

Other Name: Aranesp

Eligibility

Criteria:

Inclusion Criteria:

Main Inclusion:

- Participant is on stable hemodialysis (HD), hemodiafiltration (HDF) or peritoneal dialysis (PD) treatment with the same mode of dialysis for ≥4 months prior to randomization.

- Participant is on IV or SC epoetin or IV or SC darbepoetin alfa treatment for ≥8 weeks prior to randomization with stable weekly doses (during 4 weeks prior to randomization).

- Mean of the participant's three most recent Hb values, as measured by central laboratory, during the Screening Period.

- Participant's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤3 x upper limit of normal (ULN), and total bilirubin (TBL) is ≤1.5 x ULN

Exclusion Criteria:

Main Exclusion:

- Participant has received a red blood cell (RBC) transfusion within 8 weeks prior to randomization.

- Participant 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).

- Participant has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a thrombotic/thrombo-embolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.

- Participant has had uncontrolled hypertension, in the opinion of the investigator, within 2 weeks prior to randomization.

- Participant has a history of malignancy, except for the following: cancers determined to be cured or in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.

- Participant has had any prior organ transplant (that has not been explanted), or participant is scheduled for organ transplantation.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Study Physician Study Director Astellas Pharma Europe B.V.
Location
Facility:
Site BE32004 | Brussels, Flemish Brabant, 1200, Belgium
Site BE32001 | Aalst, 9300, Belgium
Site BE32019 | Antwerpen, 2020, Belgium
Site BE32002 | Antwerp, 2060, Belgium
Site BE32012 | Baudour, 7331, Belgium
Site BE32017 | Bonheiden, 2820, Belgium
Site BE32003 | Leuven, 3000, Belgium
Site BE32013 | Liege, 4000, Belgium
Site BE32011 | Roeselare, 8800, Belgium
Site BG35925 | Blagoevgrad, 2700, Bulgaria
Site BG35931 | Haskovo, 6300, Bulgaria
Site BG35915 | Pleven, 5800, Bulgaria
Site BG35909 | Plovdiv, 4000, Bulgaria
Site BG35919 | Plovdiv, 4003, Bulgaria
Site BG35920 | Rousse, 7002, Bulgaria
Site BG35938 | Shumen, 9700, Bulgaria
Site BG35924 | Sofia, 1309, Bulgaria
Site BG35906 | Sofia, 1431, Bulgaria
Site BG35921 | Sofia, 1527, Bulgaria
Site BG35907 | Stara Zagora, 6000, Bulgaria
Site BG35916 | Varna, 9000, Bulgaria
Site BG35918 | Varna, 9010, Bulgaria
Site BG35903 | Veliko Tarnovo, 5000, Bulgaria
Site BG35937 | Yambol, 8600, Bulgaria
Site HR38509 | Zagreb, Grad Zagreb, 10000, Croatia
Site HR38508 | Cakovec, 40000, Croatia
Site HR38505 | Karlovac, 47000, Croatia
Site HR38507 | Osijek, 31 000, Croatia
Site HR38506 | Rijeka, 51000, Croatia
Site HR38504 | Slavonski Brod, 35000, Croatia
Site HR38501 | Zadar, 23 000, Croatia
Site CZ42008 | Liberec, 46063, Czechia
Site CZ42021 | Praha 6, 169 00, Czechia
Site CZ42015 | Rakovnik, 26929, Czechia
Site FR33005 | Amiens cedex 1, 80054, France
Site FR33010 | La Tronche, 38701, France
Site FR33055 | Saint Ouen, 93400, France
Site FR33007 | Saint Priez En Jarez, 42270, France
Site FR33056 | Valenciennes, 59300, France
Site GE99503 | Tbilisi, 0144, Georgia
Site GE99504 | Tbilisi, 0144, Georgia
Site GE99508 | Tbilisi, 159, Georgia
Site DE49056 | Dormagen, Nordrhein-Westfalen, 41540, Germany
Site DE49067 | Berlin, 10117, Germany
Site DE49073 | Cloppenburg, 49661, Germany
Site DE49008 | Dresden, 01307, Germany
Site DE49054 | Dusseldorf, 40210, Germany
Site DE49020 | Frankfurt am Main, 60590, Germany
Site DE49065 | Hamburg, 23397, Germany
Site DE49075 | Heilbronn, 74076, Germany
Site DE49001 | Kaiserslautern, 67655, Germany
Site DE49070 | Muenchen, 81695, Germany
Site DE49002 | Solingen, 42653, Germany
Site DE49071 | Villingen-Schwenningen, 78052, Germany
Site HU36033 | Baja, 6500, Hungary
Site HU36036 | Esztergom, 2500, Hungary
Site HU36031 | Gyor, 9002, Hungary
Site HU36026 | Kaposvar, H 7400, Hungary
Site HU36027 | Kistarcsa, 2143, Hungary
Site HU36032 | Pecs, 7624, Hungary
Site HU36035 | Pecs, 7633, Hungary
Site HU36034 | Salgotarjan, 3100, Hungary
Site HU36004 | Szeged, 6724, Hungary
Site HU36046 | Szekesfehervar, 8000, Hungary
Site HU36006 | Szombathely, H 9700, Hungary
Site HU36003 | Zalsaegerszeg, 8900, Hungary
Site IT39028 | Prato, Frazione Di Galciana, 59100, Italy
Site IT39039 | Cremona, Lombardia, 26100, Italy
Site IT39014 | Mestre, Venezia, 30174, Italy
Site IT39010 | Brescia, 25123, Italy
Site IT39008 | Lecco, 23900, Italy
Site IT39006 | Milano, 20162, Italy
Site IT39037 | Modena, 41124, Italy
Site IT39022 | Padova, 35128, Italy
Site IT39036 | Pavia, 27100, Italy
Site IT39005 | Roma, 122, Italy
Site IT39035 | Torino, 10126, Italy
Site IT39032 | Trieste, 34142, Italy
Site PL48002 | Katowice, 40 027, Poland
Site PL48001 | Krakow, 30 501, Poland
Site PL48013 | Szczecin, 70-111, Poland
Site PL48005 | Warszawa, 00 507, Poland
Site PL48006 | Wroclaw, 50-556, Poland
Site PL48009 | Wroclaw, 51 124, Poland
Site PL48014 | Zamosc, 20-400, Poland
Site PT35121 | Almada, 2800-455, Portugal
Site PT35127 | Aveiro, 3800-266, Portugal
Site PT35139 | Cascais, 2750-663, Portugal
Site PT35117 | Faro, 8005-546, Portugal
Site PT35128 | Gaeiras, 2510-702, Portugal
Site PT35114 | Leiria, 2400-441, Portugal
Site PT35102 | Porto, 4099-001, Portugal
Site PT35122 | Setubal, 2900-655, Portugal
Site RO40018 | Bucharest, 011794, Romania
Site RO40015 | Bucharest, Romania
Site RO40019 | Bucharest, Romania
Site RO40003 | Bucuresti, 22328, Romania
Site RO40004 | Oradea, 410562, Romania
Site RU70008 | Kaluga, 248007, Russian Federation
Site RU70051 | Moscow, 119992, Russian Federation
Site RU70005 | Moscow, 125284, Russian Federation
Site RU70003 | Nizhny Novgorod, 603032, Russian Federation
Site RU70004 | Omsk, 644112, Russian Federation
Site RU70014 | Rostov-on-Don, 344029, Russian Federation
Site RU70072 | Saint Petersburg, 190103, Russian Federation
Site RU70002 | Saint Petersburg, 197089, Russian Federation
Site RU70011 | Saint-Petersburg, 196247, Russian Federation
Site RU70050 | Saint-Petersburg, 197374, Russian Federation
Site RU70030 | Sankt-Peterburg, 197110, Russian Federation
Site RU70006 | Smolensk, 214006, Russian Federation
Site RU70037 | Volgograd, 404120, Russian Federation
Site RU70001 | Yaroslavl, 150062, Russian Federation
Site RS38102 | Belgrade, 11000, Serbia
Site RS38105 | Belgrade, 11000, Serbia
Site RS38120 | Belgrade, 11000, Serbia
Site RS38104 | Belgrade, Serbia
Site RS38117 | Krusevac, 37000, Serbia
Site RS38101 | Nis, Serbia
Site RS38116 | Zrenjanin, Serbia
Site SK42102 | Koshice, 04001, Slovakia
Site SK42119 | Levice, 93401, Slovakia
Site SK42120 | Lučenec, 984 01, Slovakia
Site SK42113 | Puchov, 020 01, Slovakia
Site SK42116 | Senica, 90501, Slovakia
Site ES34041 | Santiago de Compostela, A Coruna, 15706, Spain
Site ES34009 | El Ejido, Almeria, 04700, Spain
Site ES34010 | Alcorcon, Madrid, 28922, Spain
Site ES34030 | Majadahonda, Madrid, 28222, Spain
Site ES34011 | Galdakao, Vizcaya, 48960, Spain
Site ES34002 | Badalona-Barcelona, 8916, Spain
Site ES34008 | Barcelona, 08025, Spain
Site ES34006 | Barcelona, 08035, Spain
Site ES34017 | Jaen, 23007, Spain
Site ES34037 | Madrid, 28046, Spain
Site ES34052 | Valencia, 46017, Spain
Site GB44087 | Brighton, EastSussex, BN2 5BD, United Kingdom
Site GB44011 | Canterbury, Kent, CT1 3NG, United Kingdom
Site GB44080 | Stoke on Trent, Staffordshire, ST4 6QG, United Kingdom
Site GB44008 | Cambridge, CB2 0QQ, United Kingdom
Site GB44010 | Hull, HU3 2JZ, United Kingdom
Site GB44081 | Leicester, LE5 4PW, United Kingdom
Site GB44079 | Liverpool, L9 7AL, United Kingdom
Site GB44001 | Swansea, SA6 6NL, United Kingdom
Location Countries

Belgium

Bulgaria

Croatia

Czechia

France

Georgia

Germany

Hungary

Italy

Poland

Portugal

Romania

Russian Federation

Serbia

Slovakia

Spain

United Kingdom

Verification Date

February 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Roxadustat

Type: Experimental

Description: Participants received roxadustat three times a week (TIW) for at least 52 weeks up to a maximum of 104 weeks. Participants received initial dose of roxadustat 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.

Label: ESA (Erythropoiesis Stimulating Agent) treatment

Type: Active Comparator

Description: Participants received epoetin alfa once weekly, twice weekly or TIW and darbepoetin alfa once a week or once every other week. Participants were treated for at least 52 weeks up to a maximum of 104 weeks. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant's Hb levels between 10.0 to 12.0 g/dL. Participants were not allowed to switch from the epoetin alfa to darbepoetin alfa or vice versa.

Acronym Pyrenees
Patient Data Yes
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov