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

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: NCT02174627
Recruitment Status : Completed
First Posted : June 25, 2014
Last Update Posted : November 27, 2018
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
Last Update Posted Date November 27, 2018
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 21, 2018)
  • The primary efficacy endpoint for the US FDA is the mean change from baseline in Hb averaged over week 28 to week 52. [ Time Frame: From week 28 to week 52. ]
    US FDA outcome measure. Hb results obtained from the central laboratory will be used for all Hb efficacy analyses. Baseline Hb is defined as the mean of the three last central laboratory Hb values from the screening and randomization visits.
  • The primary efficacy endpoint for EU health authorities is whether patients achieved Hb response (Yes/No) [ Time Frame: From week 0 to week 24. ]
    EU health authorities outcome measure. Yes is defined as:
    • Hb ≥ 11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL, for subjects with baseline Hb > 8.0 g/dL; or
    • Hb increase from baseline by ≥ 2.0 g/dL, for subjects with baseline Hb ≤ 8.0 g/dL at two consecutive visits [dates] (with available data) separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (RBC transfusion, ESA, or IV iron) prior to Hb response.
  • Time-to-first adjudicated cardiovascular events [ Time Frame: Throughout study, with study duration up to 4 years ]
    Analyses of the adjudicated events are described in a separate pooled statistical analysis plan.
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 Complete list of historical versions of study NCT02174627 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 21, 2018)
  • First secondary efficacy endpoint for FDA is whether patients achieved Hb response (Yes/No) [ Time Frame: From week 0 to week 24. ]
    The EU primary endpoint is the first secondary efficacy endpoint for FDA. Yes is defined as:
    • Hb ≥ 11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL, for subjects with baseline Hb > 8.0 g/dL; or
    • Hb increase from baseline by ≥ 2.0 g/dL, for subjects with baseline Hb ≤ 8.0 g/dL at two consecutive visits [dates] (with available data) separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (RBC transfusion, ESA, or IV iron) prior to Hb response.
  • Mean change in Hb from baseline to the subjects mean level between week 28 to week 52 in subjects with baseline high-sensitivity C-reactive protein (hsCRP) greater than the Upper Limit Normal (ULN) [ Time Frame: From week 28 to week 52. ]
  • Proportion of total time of Hb ≥ 10 g/dL from week 28 to week 52. [ Time Frame: From week 28 to week 52. ]
  • Proportion of total time of Hb within the interval of 10-12 g/dL from week 28 to week 52. [ Time Frame: From week 28 to week 52. ]
  • Mean change in LDL cholesterol from baseline to week 24 [ Time Frame: From randomization to week 24. ]
  • Time-to-first instance of receiving rescue therapy (composite) of any of intravenous (IV) iron, red blood cell (RBC) transfusions, or erythropoietin analogue. [ Time Frame: Throughout the treatment period, with treatment duration up to 4 years. ]
  • Time-to-first instance of receiving red blood cell (RBC) transfusions as rescue therapy. [ Time Frame: Throughout the treatment period, with treatment duration up to 4 years. ]
  • Change from baseline in SF-36 Vitality (VT) sub-score [ Time Frame: From week 12 to week 28. ]
    The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 consists of eight domains of health status: Physical functioning (10 items), Role-physical (4 items), Bodily pain (2 items), General health (5 items), Vitality (4 items), Social functioning (2 items), Role emotional (3 items) and Mental health (5 items). For both the SF-36 domain scores and summary scores, higher scores indicate better health status.
  • Annual rate of eGFR change, calculated as the linear slope of log (eGFR values) to prior to initiation of dialysis/kidney transplant [ Time Frame: Throughout study, with study duration up to 4 years. ]
    eGFR values from randomization to either the end of study or the date initiation of Dialysis/Transplant, whichever comes first, are included in its analysis.
  • Change from baseline in SF-36 Physical Functioning (PF) sub-score [ Time Frame: From week 12 to week 28. ]
    The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 consists of eight domains of health status: Physical functioning (10 items), Role-physical (4 items), Bodily pain (2 items), General health (5 items), Vitality (4 items), Social functioning (2 items), Role emotional (3 items) and Mental health (5 items). For both the SF-36 domain scores and summary scores, higher scores indicate better health status.
  • Adverse events' rate [ Time Frame: Throughout the treatment period, with treatment duration up to 4 years. ]
  • Number of subjects with potentially clinically significant vital sign values [ Time Frame: Throughout the treatment period, with treatment duration up to 4 years. ]
  • Number of subjects with potentially clinically significant electrocardiogram (ECG) values [ Time Frame: Throughout the treatment period, with treatment duration up to 4 years. ]
  • Number of subjects with laboratory value abnormalities [ Time Frame: Throughout the treatment period, with treatment duration up to 4 years. ]
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 2018

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