Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis.

• ClinicalTrials.gov Identifier: NCT02174731
• Recruitment Status: Completed
• First Posted: June 25, 2014
• Last Update Posted: November 27, 2018
• Sponsor: AstraZeneca
• Collaborator: FibroGen
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: June 24, 2014
• First Posted Date: June 25, 2014
• Last Update Posted Date: November 27, 2018
• Actual Study Start Date: July 1, 2014
• Actual Primary Completion Date: September 26, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 21, 2018)

• US FDA: 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. The primary efficacy endpoint is the mean change from baseline in Hb averaged over week 28 to week 52. 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.
• EU health authorities: The EU (EMA) primary efficacy endpoint is change in Hb from BL to the average level during the evaluation period, without having received rescue therapy within 6 weeks prior to and during this 8-week evaluation period. [ Time Frame: From week 28 to week 36. ]
  EU health authorities outcome measure. Evaluation period is defined as week 28 until week 36. Rescue therapy is defined as RBC transfusion for all subjects or ESA for subjects treated with roxadustat.
• 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 (submitted: June 24, 2014)

Major adverse cardiovascular (CV) events (MACE): Time to first occurrence of death from any cause, non-fatal myocardial infarction or non-fatal stroke. [ Time Frame: From randomization (~week 6) to end of study (event-driven, anticipate 1-2 years). ]

Time from randomization to the first occurence of any of the components of the primary composit endpoint.

• Change History: Complete list of historical versions of study NCT02174731 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: November 21, 2018)

• Change in Hb from BL to the average level during the evaluation period, without having received rescue therapy within 6 weeks prior to and during this 8-week evaluation period. [ Time Frame: From week 28 to week 36. ]
  The EU primary endpoint is the first secondary efficacy endpoint for FDA. Evaluation period is defined as week 28 until week 36. Rescue therapy is defined as RBC transfusion for all subjects or ESA for subjects treated with roxadustat.
• Mean change from baseline in LDL cholesterol from baseline to week 24. [ Time Frame: From randomization to week 24. ]
• 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. ]
• Average monthly IV iron use [ Time Frame: From week 36 through study completion (with study duration up to 4 years) ]
• Time-to-first administration of red blood cell (RBC) transfusion as rescue therapy. [ Time Frame: Throughout the treatment period, with treatment duration up to 4 years. ]
• 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 (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.
• Major adverse CV events+ (MACE+): Time to first occurrence of death from any cause, non-fatal myocardial infarction (MI), 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). ]
  Time from randomization to the first occurence of any of the components of the primary composit endpoint.
• Time to first occurrence of death from any cause, non-fatal MI, non-fatal stroke, heart failure requiring hospitalization, unstable angina leading to hospitalization, vascular access thrombosis, deep vein thrombosis or pulmonary embolism. [ Time Frame: From randomization (~week 6) to end of study (event-driven, anticipate 1-2 years). ]
  Time from randomization to the first occurence of any of the components of the primary composit endpoints.
• Changes in self-reported health status as measured by the EuroQol Health Utility Index (EQ-5D-5L) during roxadustat or EPO treatment. 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 rescue therapy (composite) of intravenous (IV) iron, red blood cell (RBC) transfusion, or recombinant erythropoietin (for Roxadustat patients only) as rescue therapy. [ Time Frame: From randomization (~week 6) to end of study (event-driven, anticipate 1-2 years). ]
  Time from randomization to the first occurence of any of the three types of rescue therapy; IV iron, RBC transfusion, or EPO.
• Adverse events (AEs), serious adverse events (SAEs) Changes in vital signs, electrocardiogram (ECG) and laboratory values. Measured at randomization (~week 6) to end of study (event-driven, anticipate 1-2 years). [ Time Frame: From randomization (~week 6) to end of study (event-driven, anticipate 1-2 years). ]
  To evaluate the safety and tolerability of Roxadustat.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis.
• Official Title: A Phase 3, Multicenter, Randomized, Open-label, Active-Controlled Study of the Safety and Efficacy of Roxadustat in the Treatment of Anemia in Dialysis Patients
• Brief Summary: The purpose of this study is to evaluate the efficacy and safety of roxadustat compared to epoetin alfa for the treatment of anemia in chronic kidney disease patients on dialysis
• Detailed Description: This is a Phase 3, multicenter, randomized, open-label, active-controlled study to evaluate the efficacy and safety of roxadustat compared to epoetin alfa for the treatment of anemia in dialysis patients. Patients on hemodialysis (HD) or peritoneal dialysis (PD) who have been treated with an erythropoietin analogue or have an indication for treatment with an erythropoietin analogue will be evaluated for eligibility and randomized at a 1:1 ratio to treatment with roxadustat (with discontinuation of prior erythropoietin analogue therapy) or to an active-control group treated with epoetin alfa
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Anemia

Intervention

• Drug: Roxadustat
  Roxadustat will be administered orally three times a week (TIW) to achieve an Hb level of 11 g/dL and maintain a Hb level of 11±1 g/dL.
• Drug: Epoetin alfa
  Epoetin alfa will be administered TIW consistent with approved prescribing information for epoetin alfa to achieve an Hb level of 11 g/dL and maintain a Hb level of 11±1 g/dL.

Study Arms

• Experimental: Roxadustat
  Intervention: Drug: Roxadustat
• Active Comparator: Epoetin alfa
  Intervention: Drug: Epoetin alfa

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 23, 2018): 2133
• Original Estimated Enrollment (submitted: June 24, 2014): 2850
• Actual Study Completion Date: September 26, 2018
• Actual Primary Completion Date: September 26, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

1. Provision of Informed Consent prior to any study specific procedures
2. Age ≥18 years at screening visit 1

3. Previous versions of the protocol prior to US amendment ver 6.0 and outside of US amendment ver 7.0:

   Receiving or initiating hemodialysis or peritoneal dialysis for treatment of native kidney end-stage renal disease (ESRD) at least 30 days prior to visit 1. Patients treated with hemodialysis must have access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) catheter. Patients on peritoneal dialysis must have a functioning peritoneal dialysis catheter in place.

   Starting with US amendment ver. 6.0 and outside of US amendment ver 7.0 (changed to recruit incident dialysis patients only):

   Receiving or initiating hemodialysis or peritoneal dialysis for treatment of native kidney end-stage renal disease (ESRD) for a minimum of 2 weeks and a maximum of 4 months prior to randomization. Patients treated with hemodialysis must have access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) catheter. Patients on peritoneal dialysis must have a functioning peritoneal dialysis catheter in place.

4. Two central laboratory Hb values during the screening period, obtained at least 7 days apart, must be <12 g/dL in patients currently treated with an erythropoietin analogue or <10 g/dL in patients not currently treated with an erythropoietin analogue. Patients are considered not currently treated if they have not received either Mircera® for at least 8 weeks or any other erythropoietin analogue for at least 4 weeks prior to visit 1.
5. Ferritin ≥100 ng/mL at randomization (obtained from screening visit)
6. TSAT ≥20% 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) ≤3x 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 (prescribed dry weight)

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 randomisation in the present study
3. New York Heart Association Class III or IV congestive heart failure at enrolment
4. 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
5. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic auto-immune liver disease, cirrhosis or fibrosis of the liver)
6. 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
7. Known and untreated retinal vein occlusion or known and untreated proliferative diabetic retinopathy (risk for retinal vein thrombosis)
8. 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.
9. Uncontrolled hypertension at the time of randomization (defined as systolic BP ≥180 mmHg or diastolic BP ≥100 mmHg on repeated measurement post-dialysis in hemodialysis patients or at any time in peritoneal dialysis patients), contraindication to epoetin alfa treatment (e.g., pure red cell aplasia, hypersensitivity or know inability to tolerate epoetin alfa)
10. 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.
11. Positive for any of the following: human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus antibody (anti-HCV Ab)
12. Chronic inflammatory diseases such as rheumatoid arthritis, SLE, ankylosing spondylitis, psoriatic arthritis or inflammatory bowel disease that is determined to be the principal cause of anemia
13. Known hemosiderosis, hemochromatosis or hypercoagulable condition
14. Any prior organ transplant with the exception of an autologous renal transplant or a renal transplant that was subsequently removed ("explanted") or scheduled organ transplantation date
15. Any red blood cell (RBC) transfusion during the screening period
16. Any current condition leading to active significant blood loss
17. Any prior treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI)
18. 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 the month preceding 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)
19. History of alcohol or drug abuse within 2 years prior to randomization
20. Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence (see Section 3.8)
21. Pregnant or breastfeeding females
22. Known allergy to the investigational product or any of its ingredients
23. 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

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Bulgaria, Canada, Czechia, Hungary, India, Mexico, Peru, Philippines, Poland, Russian Federation, Slovakia, Spain, Sweden, Thailand, Ukraine, United States, Vietnam
• Removed Location Countries: Argentina, Brazil, Czech Republic, Romania

Administrative Information

• NCT Number: NCT02174731
• Other Study ID Numbers: D5740C00002
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: AstraZeneca
• Study Sponsor: AstraZeneca
• Collaborators: FibroGen

Investigators

• 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