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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02021318
Recruitment Status : Completed
First Posted : December 27, 2013
Last Update Posted : March 10, 2020
Sponsor:
Collaborator:
FibroGen
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Europe B.V. )

Study Description
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Brief Summary:
This study is conducted to explore a new therapy for anemia in patients with chronic kidney disease. 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 the study is to see if Roxadustat is effective and safe to treat anemia in patients with chronic kidney disease. Roxadustat will in this study be compared to darbepoetin alfa, a commercially available medicine for treatment of anemia (tradename Aranesp).

Condition or disease Intervention/treatment Phase
Anemia in Chronic Kidney Disease in Non-dialysis Patients Drug: Roxadustat Drug: darbepoetin alfa Phase 3

Detailed Description:

This study will consist of three study periods as follows:

  • Screening Period: from 2 up to 6 weeks
  • Treatment Period: 104 weeks
  • Follow-up Period: 4 weeks
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 616 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 12, 2014
Actual Primary Completion Date : March 23, 2018
Actual Study Completion Date : November 6, 2019

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Roxadustat
Study drug Roxadustat will be dosed three times weekly (TIW) during correction period, and TIW during the maintenance period. Dose adjustments are allowed during the study
 Drug: Roxadustat
oral
Other Name: ASP1517
Active Comparator: darbepoetin alfa
darbepoetin alfa will be dosed per European Summary of Product Characteristics (SmPC)
 Drug: darbepoetin alfa
subcutaneous or intravenous injection
Other Name: Aranesp


Outcome Measures
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Primary Outcome Measures :
  1. Hemoglobin (Hb) response to treatment with Roxadustat without the use of rescue therapy [ Time Frame: Up to week 24 ]

Secondary Outcome Measures :
  1. Hb change from baseline (BL) to the average Hb, without having received rescue therapy within 6 weeks prior to and during this 8-week evaluation period [ Time Frame: Baseline and weeks 28 to 36 ]
  2. Change from BL in Low Density Lipoprotein (LDL) cholesterol to the average LDL cholesterol [ Time Frame: Baseline and weeks 12 to 28 ]
  3. Mean monthly intravenous(ly) (IV) iron (mg) use per subject [ Time Frame: Up to week 36 ]
    Monthly is defined as a period of 4 weeks

  4. Change from BL in Short Form 36 (SF-36) Physical Functioning (PF) sub-score to the average PF sub-score [ Time Frame: Baseline and weeks 12 to 28 ]
  5. Change from BL in SF-36 Vitality (VT) sub-score to the average VT sub-score [ Time Frame: Baseline and weeks 12 to 28 ]
  6. Change from BL in mean arterial pressure (MAP) to the average MAP value [ Time Frame: Baseline and weeks 20 to 28 ]
  7. Occurrence of hypertension [ Time Frame: Up to week 36 ]
    Defined as either Systolic Blood Pressure (SBP) >170 mmHg and an increase from BL of greater than or equal to 20 mmHg SBP or Diastolic Blood Pressure (DBP) >110 mmHg and an increase from BL of greater than or equal to 15 mmHg DBP on 2 consecutive visits

  8. Time to occurrence of hypertension [ Time Frame: Up to week 36 ]
  9. Hb change from BL to the average Hb value regardless of rescue therapy [ Time Frame: Baseline and weeks 28 to 52 ]
  10. Time (weeks) to achieve the first Hb response as defined by primary endpoint [ Time Frame: Up to week 24 ]
  11. Hb response [ Time Frame: Up to week 24 ]
    Hb response defined as: Hb greater than or equal to 11.0 g/dL and a Hb increase from BL Hb by greater than or equal to 1.0 g/dL in any subject with BL Hb > 8.0 g/dL, or an increase from BL Hb by greater than or equal to 2.0 g/dL in any subject with BL Hb less than or equal to 8.0 g/dL as measured at 2 consecutive visits separated by at least 5 days, during the first 24 weeks of treatment regardless of administration of rescue therapy prior to Hb response

  12. Hb averaged over weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, without use of rescue therapy within 6 weeks prior to and during this evaluation period [ Time Frame: Up to week 104 ]
  13. Hb value to each post-dosing time point [ Time Frame: Up to End of Study (EOS) (Up to week 108) ]
  14. Hb change from BL to each post-dosing time point [ Time Frame: Baseline up to End of Study (EOS) (Up to week 108) ]
  15. Hb change from BL to the average Hb value regardless of the use of rescue therapy [ Time Frame: Baseline, weeks 28 to 36, weeks 44 to 52, weeks 72 to 80, weeks 96 to 104 ]
  16. Proportion of Hb values within 10.0 to 12.0 g/dL in weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, without use of rescue therapy within 6 weeks prior to and during the 8-week evaluation period [ Time Frame: Up to week 104 ]
  17. Occurrence (number) of hospitalization(s) [ Time Frame: Up to End of Treatment (EOT) (Up to week 104) ]
  18. Number of days of hospitalization [ Time Frame: Up to End of Treatment (EOT) (Up to week 104) ]
  19. Number of subjects having received rescue therapy (composite of red blood cell (RBC) transfusions (all subjects) and darbepoetin alfa use (roxadustat treated subjects only) [ Time Frame: Up to End of Treatment (EOT) (Up to week 104) ]
  20. Number of subjects having received RBC transfusions [ Time Frame: Up to End of Treatment (EOT) (Up to week 104) ]
  21. Number of RBC packs per subject [ Time Frame: Up to End of Treatment (EOT) (Up to week 104) ]
  22. Volume of RBC transfused per subject [ Time Frame: Up to End of Treatment (EOT) (Up to week 104) ]
  23. Change from BL to each scheduled measurement in total cholesterol [ Time Frame: Baseline up to End of Study (EOS) (Up to week 108) ]
  24. Change from BL to each scheduled measurement in low density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio [ Time Frame: Baseline up to End of Study (EOS) (up to week 108) ]
  25. Change from BL to each scheduled measurement in non-HDL cholesterol [ Time Frame: Baseline up to End of Study (EOS) (Up to week 108) ]
  26. Change from BL to each scheduled measurement in Apolipoproteins (Apo) A1 [ Time Frame: Baseline up to End of Study (EOS) (Up to week 108) ]
  27. Change from BL to each scheduled measurement in Apolipoproteins B (ApoB) [ Time Frame: Baseline up to End of Study (EOS) (Up to week 108) ]
  28. Change from BL to each scheduled measurement in ApoB/ApoA1 ratio [ Time Frame: Baseline up to End of Study (EOS) (Up to week 108) ]
  29. Occurrence of mean LDL cholesterol < 100 mg/dL (mean LDL calculated over weeks 12 to 28, and weeks 36 to 52 of treatment) [ Time Frame: Up to week 52 ]
  30. Occurrence of achieved anti-hypertensive treatment goal (SBP < 130 mmHg and DBP< 80 mmHg) based on the mean SBP and mean DBP calculated over weeks 12 to 28 and 36 to 52 of treatment with study drug [ Time Frame: Up to week 52 ]
  31. Change from BL to the average value in Physical Component Score (PCS) of SF-36 [ Time Frame: Baseline, weeks 12 to 28 and weeks 36 to 52 ]
  32. Change from BL to the average value in Anemia Subscale ("Additional Concerns") of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score [ Time Frame: Baseline, weeks 12 to 28 and weeks 36 to 52 ]
  33. Change from BL to the average value in Total FACT-An Score [ Time Frame: Baseline, weeks 12 to 28 and weeks 36 to 52 ]
  34. Change from BL to the average value in Health Related Quality of Life Questionnaire consisting of Five Levels (EQ-5D 5) visual analogue scale (VAS) Score [ Time Frame: Baseline, weeks 12 to 28 and weeks 36 to 52 ]
  35. Change from BL to the average value in Work Productivity and Activity Impairment-Anemic Symptoms (WPAI:ANS) score [ Time Frame: Baseline, weeks 12 to 28 and weeks 36 to 52 ]
  36. Patients' Global Impression of Change (PGIC) [ Time Frame: Up to End of Treatment (EOT) (up to Week 104) ]
  37. Change from BL to each scheduled measurement serum ferritin [ Time Frame: Baseline up to End of Study (EOS) (Up to week 108) ]
  38. Change from BL to each scheduled measurement in Transferrin Saturation (TSAT) [ Time Frame: Baseline up to End of Study (EOS) (Up to week 108) ]
  39. Change from BL to each scheduled measurement in HbA1c [ Time Frame: Baseline up to End of Study (EOS) (Up to week 108) ]
    Hemoglobin A1c glycated hemoglobin (HbA1c) level

  40. Change from BL to each scheduled measurement in fasting blood glucose [ Time Frame: Baseline up to End of Study (EOS) (Up to week 108) ]
  41. Change from BL to each scheduled measurement in Estimated Glomerular Filtration Rate (eGFR), including eGFR slope over time [ Time Frame: Baseline up to End of Study (EOS) (Up to week 108) ]
  42. Change from BL to each scheduled measurement in Urine albumin/creatinine ratio (UACR) [ Time Frame: Baseline up to End of Study (EOS) (Up to week 108) ]
  43. Time to first of occurrence of serum creatinine having doubled during study in comparison with baseline [ Time Frame: Up to End of Study (EOS) (Up to week 108) ]
  44. Occurrence of ESRD [ Time Frame: Up to End of Study (EOS) (Up to week 108) ]
    End Stage Renal Disease (ESRD)

  45. Safety assessed by nature, frequency, and severity of Treatment Emergent AEs (TEAEs) [ Time Frame: Up to End of Study (EOS) (Up to week 108) ]
  46. Number of participants with laboratory value abnormalities and/or adverse events related to treatment [ Time Frame: Up to End of Study (EOS) (Up to week 108) ]
  47. Number of participants with vital signs abnormalities and/or adverse events related to treatment [ Time Frame: Up to End of Study (EOS) (Up to week 108) ]
  48. Safety assessed by 12- lead electrocardiogram (ECG) [ Time Frame: Up to End of Study (EOS) (Up to week 108) ]
    Local 12-lead ECGs will be performed on all subjects at specific time points

  49. Occurrence of prespecified adjudicated cardiovascular events [ Time Frame: Up to End of Study (EOS) (Up to week 108) ]
  50. Occurrence of prespecified adjudicated cerebrovascular events [ Time Frame: Up to End of Study (EOS) (Up to week 108) ]

Eligibility Criteria
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Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02021318


Locations
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Sponsors and Collaborators
Astellas Pharma Europe B.V.
FibroGen
Investigators
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Study Director: Medical Monitor Astellas Pharma Europe B.V.
More Information
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Responsible Party: Astellas Pharma Europe B.V.
ClinicalTrials.gov Identifier: NCT02021318    
Other Study ID Numbers: 1517-CL-0610
2013-000951-42 ( EudraCT Number )
First Posted: December 27, 2013    Key Record Dates
Last Update Posted: March 10, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
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.
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.
URL: https://www.clinicalstudydatarequest.com/
Keywords provided by Astellas Pharma Inc ( Astellas Pharma Europe B.V. ):
Non-dialysis
Roxadustat
ASP1517
 Chronic Kidney Disease (CKD)
Anemia
Hemoglobin
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Anemia
Hematologic Diseases
 Urologic Diseases
Renal Insufficiency
Darbepoetin alfa
Hematinics