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Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis

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ClinicalTrials.gov Identifier: NCT02174627
Recruitment Status : Completed
First Posted : June 25, 2014
Results First Posted : December 16, 2019
Last Update Posted : December 16, 2019
Sponsor:
Collaborator:
FibroGen
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE June 24, 2014
First Posted Date  ICMJE June 25, 2014
Results First Submitted Date  ICMJE October 4, 2019
Results First Posted Date  ICMJE December 16, 2019
Last Update Posted Date December 16, 2019
Actual Study Start Date  ICMJE June 26, 2014
Actual Primary Completion Date October 4, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 27, 2019)
Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 [ Time Frame: Baseline (Day 1, Week 0) and Week 28 to Week 52. ]
Baseline Hb was defined as the mean of the last 3 central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to mean value from Week 28 to Week 52 was analyzed using a missing at random (MAR) based multiple imputation analysis of covariance (ANCOVA) model with baseline Hb, baseline estimated glomerular filtration rate (eGFR), cardiovascular (CV) history, geographic region and treatment group as fixed effect covariates. The adjusted least squares (LS) mean estimates of change from baseline to mean during Week 28 to Week 52 are presented.
Original Primary Outcome Measures  ICMJE
 (submitted: June 24, 2014)
Major adverse cardiovascular (CV) events (MACE): Time to first occurrence of all cause mortality, non-fatal myocardial infarction, non-fatal stroke. [ Time Frame: From randomization (~week 6) to end of study (event-driven, anticipate 1-2 years). ]
The number from randomization to the first occurence of any of the components of the primary composit endpoints.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 27, 2019)
  • Percentage of Participants With Hb Response During the First 24 Weeks of Treatment [ Time Frame: Baseline (Day 1, Week 0) up to Week 24. ]
    Hb response was defined as:
    • Hb ≥ 11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL for participants with baseline Hb > 8.0 g/dL; or
    • Hb increase from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at 2 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, erythropoietin analogue, or intravenous [IV] iron) prior to Hb response. The percentage of participants with an Hb response during the first 24 weeks of treatment is presented.
  • Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 in Participants With Baseline High Sensitivity C-Reactive Protein (hsCRP) Greater Than the Upper Limit of Normal (ULN) [ Time Frame: Baseline (Day 1, Week 0) and Week 28 to Week 52. ]
    Baseline hsCRP was quantified from stored biomarker samples obtained at randomization. Baseline Hb was defined as the mean of the last 3 central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to mean value during Week 28 to Week 52 was analyzed using a MAR based multiple imputation ANCOVA model with baseline Hb, baseline eGFR, CV history, geographic region and treatment group as fixed effect covariates. The adjusted LS mean estimates of change from baseline in participants with baseline hsCRP >ULN to mean during Week 28 to Week 52 are presented.
  • Proportion of Total Time of Interpolated Hb Values Greater Than or Equal To 10 g/dL From Week 28 to Week 52 [ Time Frame: Week 28 up to Week 52. ]
    Proportion of total time of interpolated Hb values ≥10 g/dL was calculated as the time the linearly interpolated curve between measurements ≥10 g/dL divided by the time between measurements from Week 28 to Week 52. Proportion of total time was analyzed using an ANCOVA model with baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from Week 28 to Week 52 are presented.
  • Proportion of Total Time of Interpolated Hb Values Within the Interval of 10 to 12 g/dL From Week 28 to Week 52 [ Time Frame: Week 28 up to Week 52. ]
    Proportion of total time of interpolated Hb values within the interval of 10 to 12 g/dL was calculated as the time the linearly interpolated curve between measurements were within 10 to 12 g/dL divided by the time between measurements from Week 28 to Week 52. Proportion of total time was analyzed using an ANCOVA model with baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from Week 28 to Week 52 are presented.
  • Mean Change in Low-Density Lipoprotein (LDL) Cholesterol From Baseline to Week 24 [ Time Frame: Baseline (Day 1, Week 0) and Week 24 ]
    Baseline LDL was defined as the last result obtained prior to randomization. Mean changes in LDL cholesterol from baseline to Week 24 was analyzed using an ANCOVA model with baseline LDL, baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from baseline to Week 24 are presented.
  • Time-To-First Instance of Receiving IV Iron, RBC Transfusion or Erythropoietin Analogue as Rescue Therapy [ Time Frame: Baseline (Day1, Week 0) up to End of Study (EOS) visit (4 weeks after the treatment period) (or up to date of first rescue therapy), with treatment duration up to 4 years. ]
    Time-to-first rescue therapy (IV iron, RBC transfusion or erythropoietin analogue) was calculated as (date of first rescue therapy, or date of censoring if no rescue therapy was taken) minus (date of first dose of IP) +1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events.
  • Time-To-First Instance of Receiving a RBC Transfusion As Rescue Therapy [ Time Frame: Baseline (Day1, Week 0) up to EOS visit (4 weeks after the treatment period) (or up to date of first RBC rescue therapy), with treatment duration up to 4 years. ]
    Time-to-first RBC rescue therapy was calculated as (date of first RBC rescue therapy, or date of censoring if no rescue therapy was taken) minus (date of first dose of IP) +1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events.
  • Mean Change From Baseline in Short Form 36 (SF-36) Vitality Sub-Score From Week 12 to Week 28 [ Time Frame: Baseline (Day 1, Week 0) and Week 12 to Week 28. ]
    SF-36 is a Quality of Life (QoL) scale comprising 8 domains of health status: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. Each domain score is on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Mean change in SF-36 Vitality sub-score from baseline to mean from Week 12 to Week 28 was analyzed using a mixed model for repeated measures (MMRM) with terms for baseline score, treatment group, baseline Hb, baseline eGFR, CV history, geographic region, visit and treatment-by-visit interaction as fixed effects and participant as random effect. The adjusted LS mean estimates of change from baseline to mean score from Week 12 to Week 28 are presented.
  • Annual Rate of eGFR Change From Baseline Prior to the Initiation of Dialysis or Kidney Transplant [ Time Frame: Baseline (Day1, Week 0) up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. ]
    Baseline eGFR was defined as the mean of all available central laboratory values prior to or at randomization. Rate of change in eGFR from baseline during the entire treatment period (in millilitres/minute/1.73 meters squared/years [mL/min/1.73m^2/years]) was estimated using a random effects model using all post-baseline eGFR values prior to initiation of dialysis/transplant. Baseline eGFR, baseline Hb, geographic region, CV history, treatment group and post-baseline eGFR measurement time were used as fixed effects and participant and time (years) as random effects, ie, random intercept and slope.
  • Mean Change From Baseline in SF-36 Physical Functioning Sub-Score From Week 12 to Week 28 [ Time Frame: Baseline (Day 1, Week 0) and Week 12 to Week 28. ]
    SF-36 is a QoL scale comprising 8 domains of health status: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. Each domain score is on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Mean change in SF-36 Physical Functioning sub-score from baseline to mean from Week 12 to Week 28 was analyzed using a MMRM with terms for baseline score, treatment group, baseline Hb, baseline eGFR, CV history, geographic region, visit and treatment-by-visit interaction as fixed effects and participant as random effect. The adjusted LS mean estimates of change from baseline to mean score from Week 12 to Week 28 are presented.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 24, 2014)
  • Mean change in hemoglobin (Hb) from baseline to the end of treatment (EOT) period (~1-2 years). [ Time Frame: From baseline to end of study (event-driven, anticipate 1-2 years). ]
    Mean value of all Hb measurements from week 28 until the end of study will be used.
  • Proportion of total time of Hb measurements within the interval of 11±1 g/dL from week 28 until end of treatment visit (~1-2 years). [ Time Frame: From week 28 until end of study (event-driven, anticipate 1-2 years). ]
    Proportion of total time of Hb values within the interval 11±1 g/dL from week 28 until end of treatment visit.
  • MACE+: Time to first occurrence of all cause mortality, non-fatal myocardial infarction (MI) or non-fatal stroke, heart failure requiring hospitalization or unstable angina leading to hospitalization. [ Time Frame: From randomization (~week 6) to end of study (event-driven, anticipate 1-2 years). ]
    The number from randomization to the first occurence of any of the components of the primary composit endpoints.
  • Time to first occurrence of all cause mortality, non-fatal MI, non-fatal stroke, heart failure requiring hospitalization, unstable angina leading to hospitalization, deep vein thrombosis or pulmonary embolism. [ Time Frame: From randomization (~week 6) to end of study (event-driven, anticipate 1-2 years). ]
    The number from randomization to the first occurence of any of the components of the primary composit endpoints.
  • Changes in anemia symptoms and four disease-specific Health Related Quality of Life (HRQoL) domains as measured by the funtional assessment of cancer therapy-anemia (FACT-An). Measured at visit randomization (~week 6), week 12, 28 and 52. [ Time Frame: Measured at visit randomization (~week 6), week 12, 28 and 52. ]
    The FACT-An has a recall period of the 'past seven days'. Respondents are asked to provide responses (i.e. 'Not at all', 'A little bit', 'Somewhat', 'Quite a bit' and 'Very much'), to a list of statements which are either positively or negatively phrased. For all FACT-An scales, a higher score indicates better HRQoL.
  • Changes in generic HRQoL as measured by the Short Form 36 (SF-36) (vers 2, standard). Measured at visit randomization (~week 6), week 12, 28 and 52. [ Time Frame: Measured at visit randomization (~week 6), week 12, 28 and 52. ]
    The SF-36 version 2, standard is a general HRQoL instrument designed to assess generic health concepts relevant across age, disease and treatment groups.
  • Changes in self-reported health status as measured by the Euroqol Health Utility Index (EQ-5D-5L) measured at baseline, week 12, 28 and 52. [ Time Frame: At baseline, week 12, 28 and 52. ]
    The EQ-5D-5L is a self-reported questionnaire measuring utility values.
  • Time-to-first instance of receiving intravenous (IV) iron, red blood cell (RBC) transfusions or recombinant erythropoietin (EPO) as rescue therapy. [ Time Frame: From randomization (~week 6) to end of study (event-driven, anticipate 1-2 years). ]
    The time from randomization to the first occurence of any of the components of the primary composit endpoints.
  • Change in estimated glomerular filtration rate (eGFR) from baseline to the end of treatment period (~1-2 years). [ Time Frame: From baseline to end of study (event-driven, anticipate 1-2 years). ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis
Official Title  ICMJE A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Roxadustat for the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis
Brief Summary The purpose of the study is to evaluate the safety and efficacy of roxadustat for treatment of anemia in patients with chronic kidney disease not on dialysis
Detailed Description This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study in anemic patients with Stage 3, 4 or 5 chronic kidney disease (CKD) who are not on dialysis.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Anemia
Intervention  ICMJE
  • Drug: Roxadustat
    The initial study drug dose is 70 mg three times a week (TIW). The dose is subsequently adjusted to achieve and maintain Hb 11±1 g/dL.
  • Drug: Placebo
    The initial study drug dose is 70 mg three times a week (TIW). The dose is subsequently adjusted to achieve and maintain Hb 11±1 g/dL.
Study Arms  ICMJE
  • Experimental: Roxadustat
    Intervention: Drug: Roxadustat
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 3, 2018)
2781
Original Estimated Enrollment  ICMJE
 (submitted: June 24, 2014)
5200
Actual Study Completion Date  ICMJE October 4, 2018
Actual Primary Completion Date October 4, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Provision of informed consent prior to any study specific procedures.
  2. Age ≥18 years at screening visit 1
  3. eGFR <60 mL/min/1.73 m2, (calculated by central lab) corresponding to stage 3, 4 or 5CKD according to the Kidney Disease Outcomes Quality Initiative (KDOQI), not receiving dialysis
  4. Mean of 2 most recent central laboratory Hb values during the screening period, obtained at least 7 days apart, must be <10.0 g/dL
  5. Ferritin ≥50 ng/mL at randomization (obtained from screening visit)
  6. TSAT ≥15 % at randomization (obtained from screening visit)
  7. Serum folate level ≥ lower limit of normal (LLN) at randomization (obtained from screening visit)
  8. Serum vitamin B12 level ≥LLN at randomization (obtained from screening visit)
  9. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) and total bilirubin (Tbili) ≤1.5 x ULN at randomization (obtained from screening visit)
  10. Body weight 45 to 160 kg

Exclusion Criteria:

  1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  2. Previous randomization in the present study
  3. Any erythropoietin analogue treatment within 6 weeks of randomization
  4. New York Heart Association Class III or IV congestive heart failure at enrollment
  5. Myocardial infarction (MI), acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization
  6. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic auto- immune liver disease, cirrhosis or fibrosis of the liver)
  7. Known hereditary hematologic disease such as thalassemia, sickle cell anemia, a history of pure red cell aplasia or other known causes for anemia other than CKD
  8. Known and untreated retinal vein occlusion or known and untreated proliferative diabetic retinopathy (risk for retinal vein thrombosis)
  9. Diagnosis or suspicion (e.g. complex kidney cyst of Bosniak Category IIF, III or IV) of renal cell carcinoma on renal ultrasound (or other imaging procedure e.g. CT scan or MRI) conducted at screening or within 12 weeks prior to randomization
  10. Systolic BP ≥160 mmHg or diastolic BP ≥95 mmHg (confirmed by repeated measurement), within 2 weeks prior to randomization. Patients may be rescreened once BP controlled
  11. History of prostate cancer, breast cancer or any other malignancy, except 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
  12. Positive for any of the following: human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus antibody (anti-HCV Ab)
  13. Chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), ankylosing spondylitis, psoriatic arthritis or inflammatory bowel disease that is determined to be the principal cause of anemia
  14. Known hemosiderosis, hemochromatosis or hypercoagulable condition
  15. Any prior organ transplant or a scheduled organ transplantation date
  16. Any red blood cell transfusion (RBC) during the screening period
  17. Any current condition leading to active significant blood loss
  18. Any treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI)
  19. Has received another new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment within at least 1 month of the first administration of IP in this study. (Note: patients consented and screened, but not randomized in this study or a previous study are not excluded)
  20. History of alcohol or drug abuse within 2 years prior to randomization
  21. Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence
  22. Pregnant or breastfeeding females
  23. Known allergy to the investigational product or any of its ingredients
  24. Any medical condition, including active, clinically significant infection, that in the opinion of the investigator or Sponsor may pose a safety risk to a patient in this study, which may confound efficacy or safety assessment or may interfere with study participation
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Brazil,   Bulgaria,   Canada,   Colombia,   Czechia,   Germany,   Hungary,   India,   Korea, Republic of,   Malaysia,   Mexico,   Peru,   Philippines,   Poland,   Puerto Rico,   Romania,   Russian Federation,   Slovakia,   Spain,   Taiwan,   Thailand,   Turkey,   Ukraine,   United States,   Vietnam
Removed Location Countries Czech Republic,   Italy,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT02174627
Other Study ID Numbers  ICMJE D5740C00001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE FibroGen
Investigators  ICMJE
Principal Investigator: Steven Fishbane, MD Chief Division of Kidney Diseases and Hypertension, North Shore University Hospital, Great Neck, NY, USA
Study Director: Mark Houser, MD AZ R&D Gaithersburg, USA
PRS Account AstraZeneca
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP