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

NCT ID: NCT02021318

Last Updated: 2024-11-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 616 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-03-12
• Study Completion Date: 2019-11-06

Brief Summary

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.

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)

Conditions

Anemia in Chronic Kidney Disease in Non-dialysis Patients

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Oral tablet.

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.

Group Type: ACTIVE_COMPARATOR

Darbepoetin alfa

Intervention Type: DRUG

Subcutaneous or intravenous injection.

Interventions

Roxadustat

Oral tablet.

Intervention Type: DRUG

Darbepoetin alfa

Subcutaneous or intravenous injection.

Intervention Type: DRUG

Other Intervention Names

ASP1517; Aranesp

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

FibroGen

INDUSTRY

Sponsor Role: collaborator

Astellas Pharma Europe B.V.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Monitor

Role: STUDY_DIRECTOR

Astellas Pharma Europe B.V.

Locations

Site AT43009

Vienna, , Austria

Site BY37503

Brest, , Belarus

Site BY37501

Grodno, , Belarus

Site BY37506

Minsk, , Belarus

Site BY37507

Minsk, , Belarus

Site BY37505

Minsk, , Belarus

Site BY37502

Vitebsk, , Belarus

Site BG35907

Sofia, , Bulgaria

Site BG35927

Sofia, , Bulgaria

Site BG35916

Varna, , Bulgaria

Site HR38505

Karlovac, , Croatia

Site HR38504

Slavonski Brod, , Croatia

Site HR38510

Zagreb, , Croatia

Site HR38502

Zagreb, , Croatia

Site HR38509

Zagreb, , Croatia

Site CZ42018

Nový Jičín, CZ, Czechia

Site CZ42008

Liberec, , Czechia

Site CZ42021

Prague, , Czechia

Site FI35810

Helsinki, , Finland

Site FR33004

Avignon, , France

Site FR33009

Colmar, , France

Site FR33010

Grenoble, , France

Site FR33062

Limoges, , France

Site FR33012

Lyon, , France

Site FR33007

Saint-Priest-en-Jarez, , France

Site GE99503

Tbilisi, , Georgia

Site GE99504

Tbilisi, , Georgia

Site GE99502

Tbilisi, , Georgia

Site DE49073

Cloppenburg, , Germany

Site DE49054

Düsseldorf, , Germany

Site DE49065

Hamburg, , Germany

Site DE49075

Heilbronn, , Germany

Site DE49057

Hoyerswerda, , Germany

Site HU36028

Budapest, , Hungary

Site HU36029

Budapest, , Hungary

Site HU36027

Kistarcsa, , Hungary

Site HU36008

Pécs, , Hungary

Site HU36046

Velence, , Hungary

Site IE35301

Cork, , Ireland

Site IL97202

Be’er Ya‘aqov, , Israel

Site IL97215

Haifa, , Israel

Site LV37101

Riga, , Latvia

Site LV37104

Ventspils, , Latvia

Site ME38202

Nikšić, , Montenegro

Site ME38201

Podgorica, , Montenegro

Site NL31005

Utrecht, , Netherlands

Site MK38901

Skopje, , North Macedonia

Site MK38903

Struga, , North Macedonia

Site PL48001

Krakow, , Poland

Site PL48066

Puławy, , Poland

Site PL48013

Szczecin, , Poland

Site PL48007

Tarnów, , Poland

Site PL48004

Warsaw, , Poland

Site PL48009

Wroclaw, , Poland

Site PL48059

Zamość, , Poland

Site PT35120

Almada, , Portugal

Site PT35131

Braga, , Portugal

Site PT35112

Carnaxide, , Portugal

Site PT35119

Evora, , Portugal

Site PT35118

Lisbon, , Portugal

Site PT35133

Matosinhos Municipality, , Portugal

Site PT35122

Setúbal, , Portugal

Site PT35132

Vila Nova de Gaia, , Portugal

Site RO40012

Bucharest, , Romania

Site RO40003

Bucharest, , Romania

Site RO40021

Bucharest, , Romania

Site RO40004

Oradea, , Romania

Site RU70024

Chelyabinsk, , Russia

Site RU70054

Irkutsk, , Russia

Site RU70047

Moscow, , Russia

Site RU70006

Moscow, , Russia

Site RU70003

Nizhny Novgorod, , Russia

Site RU70004

Omsk, , Russia

Site RU70014

Rostov-on-Don, , Russia

Site RU70011

Saint Petersburg, , Russia

Site RU70002

Saint Petersburg, , Russia

Site RU70060

Saratov, , Russia

Site RU70057

Yaroslavl, , Russia

Site RU70001

Yaroslavl, , Russia

Site RS38102

Belgrade, , Serbia

Site RS38105

Belgrade, , Serbia

Site RS38103

Belgrade, , Serbia

Site RS38104

Belgrade, , Serbia

Site RS38117

Kruševac, , Serbia

Site RS38101

Niš, , Serbia

Site SK42102

Košice, , Slovakia

Site SK42109

Košice, , Slovakia

Site SK42113

Púchov, , Slovakia

Site SK42116

Senica, , Slovakia

Site SI38615

Jesenice, , Slovenia

Site SI38603

Maribor, , Slovenia

Site SI38619

Slovenj Gradec, , Slovenia

Site SI38609

Šempeter pri Gorici, , Slovenia

Site ES34049

Ferrol, A Coruna, Spain

Site ES34026

Barcelona, , Spain

Site ES34039

Córdoba, , Spain

Site ES34054

Girona, , Spain

Site ES34017

Jaén, , Spain

Site ES34037

Madrid, , Spain

Site ES34010

Madrid, , Spain

Site ES34030

Majadahonda, , Spain

Site ES34041

Santiago de Compostela, , Spain

Site UA38009

Lviv, Lvivska, Ukraine

Site UA38021

Cherkasy, , Ukraine

Site UA38006

Dnipropetrovsk, , Ukraine

Site UA38016

Ivano-Frankivsk, , Ukraine

Site UA38011

Kharkiv, , Ukraine

Site UA38017

Kiev, , Ukraine

Site UA38007

Mykolaiv, , Ukraine

Site UA38008

Odesa, , Ukraine

Site UA38001

Ternopil, , Ukraine

Site UA38018

Uzhhorod, , Ukraine

Site GB44098

Dorchester, Dorset, United Kingdom

Site GB44064

Birmingham, , United Kingdom

Site GB44099

Dartford, , United Kingdom

Site GB44102

Kings Lynn, , United Kingdom

Site GB44081

Leicester, , United Kingdom

Site GB44086

London, , United Kingdom

Site GB44006

London, , United Kingdom

Site GB44082

London, , United Kingdom

Site GB44097

Nottingham, , United Kingdom

Site GB44100

Orpington, , United Kingdom

Site GB44101

Preston, , United Kingdom

Site GB44080

Stoke-on-Trent, , United Kingdom

Site GB44001

Swansea, , United Kingdom

Countries

Austria; Belarus; Bulgaria; Croatia; Czechia; Finland; France; Georgia; Germany; Hungary; Ireland; Israel; Latvia; Montenegro; Netherlands; North Macedonia; Poland; Portugal; Romania; Russia; Serbia; Slovakia; Slovenia; Spain; Ukraine; United Kingdom

References

Barratt J, Dellanna F, Portoles J, Choukroun G, De Nicola L, Young J, Dimkovic N, Reusch M. Safety of Roxadustat Versus Erythropoiesis-Stimulating Agents in Patients with Anemia of Non-dialysis-Dependent or Incident-to-Dialysis Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies. Adv Ther. 2023 Apr;40(4):1546-1559. doi: 10.1007/s12325-023-02433-0. Epub 2023 Feb 7.

Reference Type: DERIVED

PMID: 36749544 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36005278 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://astellasclinicalstudyresults.com/hcp/study.aspx?ID=401

Link to results on the Astellas Clinical Study Results website.

Other Identifiers

2013-000951-42

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1517-CL-0610

Identifier Type: -

Identifier Source: org_study_id