Study of Roxadustat (FG-4592) in Participants With End-Stage Renal Disease Receiving Maintenance Hemodialysis

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy and safety of roxadustat in participants with end-stage renal disease (ESRD) on maintenance hemodialysis (HD) therapy, previously treated with intravenous (IV) epoetin alfa.

Detailed Description
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Dose ranging study with consecutive cohorts in two participant populations: participants normally responding to current anemia treatment (epoetin alfa) (normoresponders: participants with baseline epoetin alfa dose at study entry 75 to 450 international units [IU]/kilograms [kg]/week) and participants not responding well to current treatment (hyporesponders: participants with maintenance epoetin alfa dose above 450 IU/kg/week). Normoresponders are randomized to study drug roxadustat or epoetin alfa at a ratio of 3:1; hyporesponders are randomized to study drug roxadustat or epoetin alfa or placebo at a ratio of 2:1:1. The study objectives are to demonstrate that roxadustat is effective in maintaining hemoglobin (Hb) levels when converting from epoetin alfa and to establish optimum starting doses and dose adjustment regimens for Hb maintenance.

Official Title
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A Phase 2, Randomized, Open-Label Active-Comparator (Epoetin Alfa) and Single-Blind Placebo-Controlled, Dose-Ranging Safety and Exploratory Efficacy Study of FG-4592 in Subjects With End-Stage Renal Disease Receiving Maintenance Hemodialysis

Conditions
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End Stage Renal Disease, Anemia

Intervention / Treatment
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* Drug: Roxadustat
* Drug: Epoetin Alfa
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: ESRD and receiving maintenance HD TIW for ≥4 months prior to Day 1 Two most recent Hb values obtained during screening period must be within the ranges set below: i) Group A. Normoresponder Criteria: Hb range in the 8 weeks prior to randomization within 9.0 to 13.5 g/dL ii) Group B. Hyporesponder Criteria: Hb range in the 8 weeks prior to randomization within 8.5 to 13.5 g/dL Epoetin alfa, dose requirements: i) Group A. Normoresponder Criteria - Cohorts A-1 to A-12: Stable IV epoetin alfa dose at baseline (that is, no more than a 30% fluctuation in the weekly dose) during the 4 weeks prior to study Day -3 Cohorts A-1 to A-4: Current and previous (past 4 weeks) epoetin alfa dose range 25 to 85 IU/kg/dose, TIW; weekly dose between 75 and 255 IU/kg/week Cohort A-5: Current and previous (past 4 weeks) epoetin alfa dose range ≥85 to 115 IU/kg/dose, TIW; total weekly dose between 255 and 450 IU/kg/week Cohort A-9: Current and previous (past 4 weeks) epoetin alfa dose range ≥85 to 150 IU/kg/dose, TIW; total weekly dose between 255 and 450 IU/kg/week Cohorts A-6 to A-8: Current and previous (past 4 weeks) epoetin alfa dose range 25 to 115 IU/kg/dose, TIW, and two times a week (BIW); total weekly dose between 75 and 345 IU/kg/week Cohorts A-10 to A-12: Optional cohorts to be decided (TBD), dosing frequency and dose range to be determined by sponsor ii) Group B. Hyporesponder Criteria: Cohort B-1 (completed): Current and previous (past 4 weeks) epoetin alfa dose range 125 to 400 IU/kg/dose, TIW; weekly dose between 375 and 1200 IU/kg/week Cohort B-2 to B-4: Current and previous (past 4 weeks) epoetin alfa dose range >115 IU/kg/dose, TIW; total weekly dose >345 IU/kg/week no requirement for stability of epoetin alfa doses Complete Blood Count (CBC), Hematology, liver function blood tests, serum folate and vitamin B12 within acceptable limits Absence of active or chronic gastrointestinal bleeding High sensitivity C-reactive protein (hsCRP) <60 mg/liter for normoresponders Cohorts A-8 through A-12 enrolled under Amendment 3; no hsCRP criteria for hyporesponders Body weight: 40 to 140 kg (dry weight) Body mass index (BMI): 18 to 45 kg/meter square (m^2) Dialysis vascular access via native arteriovenous fistula or synthetic graft, or permanent (tunneled) catheter (not via temporary catheter); permanent and temporary catheters, however, are still prohibited in Cohort A-5 Key Exclusion Criteria: Anticipated change in HD prescription Any clinically significant infection or evidence of an underlying infection Positive for any of the following: Human immunodeficiency virus (HIV); hepatitis B surface antigen (HBsAg); or anti-hepatitis C virus antibody (anti-HCV Ab) History of chronic liver disease New York Heart Association Class III or IV congestive heart failure Chronic inflammatory disease that could impact erythropoiesis (for example, systemic lupus erythematosis, rheumatoid arthritis, celiac disease) even if it is currently in remission History of myelodysplastic syndrome History of hemosiderosis, hemochromatosis, polycystic kidney disease, or anephric Active hemolysis or diagnosis of hemolytic syndrome Known bone marrow fibrosis Uncontrolled or symptomatic secondary hyperparathyroidism Any prior organ transplantation Drug-treated gastroparesis or short-bowel syndrome History of alcohol or drug abuse; or a positive drug screen for a substance that has not been prescribed for the participant Prior treatment with roxadustat Diagnosis or suspicion of renal cell carcinoma Red blood cell (RBC) transfusion within 12 weeks prior to Day 1, or anticipated need for RBC transfusion during the dosing period IV iron supplement within 2 weeks prior to Day 1 and/or unwilling to withhold IV iron during the dosing/treatment period

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A-1 (Roxadustat 1.0 mg/kg TIW)<br>Normoresponsive participants (with baseline epoetin alfa dosage 25-85 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.0 milligrams (mg)/kg, administered orally 3 times weekly (TIW) in the morning of the day after dialysis (interdialytic days) for 6 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 grams [g]/deciliter [dL]) will be based upon regular monitoring of Hb. | Drug: Roxadustat<br>* Roxadustat will be administered per dose and schedule specified in the arms.<br>* Other names: FG-4592;|
| Experimental: Cohort A-2 (Roxadustat 1.5 mg/kg TIW)<br>Normoresponsive participants (with baseline epoetin alfa dosage 25-85 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.5 mg/kg, administered orally TIW for 6 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. | Drug: Roxadustat<br>* Roxadustat will be administered per dose and schedule specified in the arms.<br>* Other names: FG-4592;|
| Experimental: Cohort A-3 (Roxadustat 2.0 mg/kg TIW)<br>Normoresponsive participants (with baseline epoetin alfa dosage 25-85 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 2.0 mg/kg, administered orally TIW for 6 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. | Drug: Roxadustat<br>* Roxadustat will be administered per dose and schedule specified in the arms.<br>* Other names: FG-4592;|
| Experimental: Cohort A-4 (Roxadustat 1.8 mg/kg TIW)<br>Normoresponsive participants (with baseline epoetin alfa dosage 25-85 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.8 mg/kg, administered orally TIW for 6 weeks. Participants who have not completed 6-week treatment at the time of Amendment 2, will continue treatment for up to 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. | Drug: Roxadustat<br>* Roxadustat will be administered per dose and schedule specified in the arms.<br>* Other names: FG-4592;|
| Experimental: Cohort A-5 (Roxadustat 1.8 mg/kg TIW)<br>Normoresponsive participants (with baseline epoetin alfa dosage 85-115 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.8 mg/kg, administered orally TIW for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. | Drug: Roxadustat<br>* Roxadustat will be administered per dose and schedule specified in the arms.<br>* Other names: FG-4592;|
| Experimental: Cohort A-6 (Roxadustat 1.3 mg/kg TIW)<br>Normoresponsive participants (with baseline epoetin alfa dosage 25-115 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.3 mg/kg, administered orally TIW for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. | Drug: Roxadustat<br>* Roxadustat will be administered per dose and schedule specified in the arms.<br>* Other names: FG-4592;|
| Experimental: Cohort A-7 (Weight Tiered Roxadustat 70-100-150 mg)<br>Normoresponsive participants (with baseline epoetin alfa dosage 25-115 IU/kg/dose at study entry) will receive tiered, weight-based initial doses of roxadustat (approximately 1.3 mg/kg/dose TIW). Low weight (40 to 60 kg), medium weight (>60 to 90 kg), and heavy weight (>90 to 140 kg) participants will receive roxadustat 70 mg, 100 mg, and 150 mg, respectively, administered as oral capsules for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. | Drug: Roxadustat<br>* Roxadustat will be administered per dose and schedule specified in the arms.<br>* Other names: FG-4592;|
| Experimental: Cohort A-8 (Weight Tiered Roxadustat 70-120-200 mg)<br>Normoresponsive participants (with baseline epoetin alfa dosage 25-115 IU/kg/dose at study entry) will receive tiered, weight-based initial doses of roxadustat (approximately 1.5 mg/kg/dose TIW). Low weight (40 to 60 kg), medium weight (>60 to 90 kg), and heavy weight (>90 to 140 kg) participants will receive roxadustat 70 mg, 120 mg, and 200 mg, respectively, administered as oral capsules for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. | Drug: Roxadustat<br>* Roxadustat will be administered per dose and schedule specified in the arms.<br>* Other names: FG-4592;|
| Experimental: Cohort A-9 (Roxadustat 2.0 mg/kg)<br>Normoresponsive participants (with baseline epoetin alfa dosage 85-150 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 2.0 mg/kg, administered orally TIW for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. | Drug: Roxadustat<br>* Roxadustat will be administered per dose and schedule specified in the arms.<br>* Other names: FG-4592;|
| Experimental: Cohort A-10 (Weight Tiered Roxadustat 70-120-200 mg)<br>Normoresponsive participants (with baseline epoetin alfa dosage 25-115 IU/kg/dose at study entry) will receive tiered, weight-based initial doses of roxadustat (approximately 1.5 mg/kg/dose TIW). Low weight (40 to 60 kg), medium weight (>60 to 90 kg), and heavy weight (>90 to 140 kg) participants will receive roxadustat 70 mg, 120 mg, and 200 mg, respectively, administered as oral capsules for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. | Drug: Roxadustat<br>* Roxadustat will be administered per dose and schedule specified in the arms.<br>* Other names: FG-4592;|
| Active Comparator: Cohorts A (Epoetin Alfa)<br>Normoresponsive participants will receive IV epoetin alfa treatments on Day 1, at their prestudy dose and according to their prestudy dosing schedule (TIW). Epoetin alfa dosing will occur on dialysis days in each Cohort A. Dose adjustment will be per local standard of care (exclusive of IV iron) for routine maintenance of stable Hb levels on dialysis participants. | Drug: Epoetin Alfa<br>* Epoetin Alfa will be administered per dose and schedule specified in the arms.<br>|
| Experimental: Cohort B-1 (Roxadustat 1.5 mg/kg TIW)<br>Hyporesponsive participants (with baseline epoetin alfa dosage 125-400 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.5 mg/kg, administered orally TIW for 6 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. | Drug: Roxadustat<br>* Roxadustat will be administered per dose and schedule specified in the arms.<br>* Other names: FG-4592;|
| Experimental: Cohort B-2 (Roxadustat 2.0 mg/kg TIW)<br>Hyporesponsive participants (with baseline epoetin alfa dosage >115 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 2.0 mg/kg, administered orally TIW for 6 weeks. Participants who have not completed 6-week treatment at the time of Amendment 2, will continue treatment for up to 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. | Drug: Roxadustat<br>* Roxadustat will be administered per dose and schedule specified in the arms.<br>* Other names: FG-4592;|
| Active Comparator: Cohort B (Epoetin Alfa)<br>Hyporesponsive participants will receive IV epoetin alfa treatments on Day 1, at their prestudy dose and according to their prestudy dosing schedule (TIW). Epoetin alfa dosing will occur on dialysis days in each Cohort B. Dose adjustment will be per local standard of care (exclusive of IV iron) for routine maintenance of stable Hb levels on dialysis participants. | Drug: Epoetin Alfa<br>* Epoetin Alfa will be administered per dose and schedule specified in the arms.<br>|
| Placebo Comparator: Cohort B (Placebo)<br>Hyporesponsive participants will receive placebo matched to roxadustat, administered orally TIW for 19 weeks. | Other: Placebo<br>* Placebo matching to roxadustat will be administered per schedule specified in the arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Week 7 Hb ≥ Baseline Hb - 0.5 g/dL, Among Normoresponder Participants Treated for 6 Weeks Only | Baseline was defined as the mean of the last 3 Hb values obtained prior to the first dose of study treatment, including Day 1 predose. Last observation carried forward (LOCF) method was used to impute missing values. | Week 7 | 
| Number of Participants With Week 7 Hb ≥ Baseline Hb - 0.5 g/dL, Among Hyporesponsive Participants Treated for at Least 6 Weeks | Baseline was defined as the mean of the last 3 Hb values obtained prior to the first dose of study treatment, including Day 1 predose. LOCF method was used to impute missing values. | Week 7 | 
| Number of Participants With a Mean Hb Above 11 g/dL When the Mean Hb Values at Weeks 17, 18, 19, and 20 Were Averaged, Among Participants Treated for 19 Weeks | The average of the mean Hb values that were above 11 g/dL at Weeks 17, 18, 19, and 20 are presented. LOCF method was used to impute missing values. | Weeks 17, 18, 19, and 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Mean of Hb Within 11-13 g/dL (Values Obtained at Weeks 17, 18, 19, and 20 for Participants Dosed for 19 Weeks) | The average of the mean Hb values that were within 11-13 g/dL at Weeks 17, 18, 19, and 20 are presented. LOCF method was used to impute missing values. | Weeks 17, 18, 19, and 20 | 
| Number of Participants With a Mean of Hb Within 10-13 g/dL (Values Obtained at Weeks 17, 18, 19, and 20 for Participants Dosed for 19 Weeks) | The average of the mean Hb values that were within 10-13 g/dL at Weeks 17, 18, 19, and 20 are presented. Because of the small number of hyporesponders enrolled into this study, data for this secondary efficacy analysis as planned per protocol was not collected and summarized for hyporesponder participants. LOCF method was used to impute missing values. | Weeks 17, 18, 19, and 20 | 
| Change From Baseline in Hb at Week 7 for Participants Treated for at Least 6 Weeks | Baseline was defined as the mean of the last 3 Hb values obtained prior to the first dose of study treatment, including Day 1 predose. LOCF method was used to impute missing values. | Baseline, Week 7 | 
| Change From Baseline in Hb at Weeks 8, 10, 12, 14, 17, 19, and 20 for Participants Treated for 7-19 Weeks | Baseline was defined as the mean of the last 3 Hb values obtained prior to the first dose of study treatment, including Day 1 predose. LOCF method was used to impute missing values. | Baseline, Weeks 8, 10, 12, 14, 17, 19, and 20 | 
| Number of Participants Who Required Dose Adjustments During the Dosing Period for Participants Treated for 6 Weeks Only | Number of participants who required dose increase, dose reduce, dose interruption or dose resume were reported. Because of the small number of hyporesponders enrolled into this study, data for this secondary efficacy analysis as planned per protocol was not collected and summarized for hyporesponder participants. | Baseline up to Week 6 | 
| Number of Participants Who Required Dose Adjustments During the Dosing Period for Participants Treated for 19 Weeks | Number of participants who required dose increase, dose reduce, dose interruption or dose resume were reported. Because of the small number of hyporesponders enrolled into this study, data for this secondary efficacy analysis as planned per protocol was not collected and summarized for hyporesponder participants. | Baseline up to Week 19 | 
| Number of Participants Whose Hb Levels Were Maintained at Week 7 to Within ±1 g/dL of Their Mean 4-Week Screening Period Baseline Value for Participants Treated for At Least 6 Weeks |  | Week 7 | 
| Number of Participants Whose Hb Levels Were Maintained at Week 7 to Within ±1 g/dL of Their Mean 4-Week Screening Period Baseline Value for Participants Treated for 19 Weeks |  | Week 7 | 
| Number of Participants Treated for 6 Weeks Only Whose Hb Levels at Week 7 Were Greater Than Their Baseline Level | Baseline was defined as the mean of the last 3 Hb values obtained prior to the first dose of study treatment, including Day 1 predose. LOCF method was used to impute missing values. Because of the small number of hyporesponders enrolled into this study, data for this secondary efficacy analysis as planned per protocol was not collected and summarized for hyporesponder participants. | Week 7 | 
| Number of Participants Treated for 7-19 Weeks Whose Hb Levels at Weeks 8, 10, 12, 14, 17, 19, and 20 Were Greater Than Their Baseline Level | Baseline was defined as the mean of the last 3 Hb values obtained prior to the first dose of study treatment, including Day 1 predose. LOCF method was used to impute missing values. Because of the small number of hyporesponders enrolled into this study, data for this secondary efficacy analysis as planned per protocol was not collected and summarized for hyporesponder participants. | Weeks 8, 10, 12, 14, 17, 19, and 20 | 
| Number of Participants Who Required Rescue Anemia Treatment Due to Hb Levels, Among Participants Treated for at Least 6 Weeks | Rescue anemia treatment included any ESA dosing, RBC transfusion, or IV iron. | Baseline up to Week 6 | 
| Number of Participants Who Required Rescue Anemia Treatment Due to Hb Levels, Among Participants Treated for 19-Weeks | Rescue anemia treatment included any ESA dosing, RBC transfusion, or IV iron. | Baseline up to Week 19 | 
| Number of Participants Requiring Dose Reduction Secondary to Excessive Erythropoiesis During Dosing Period, Among Participants Treated for at Least 6-Weeks |  | Baseline up to Week 6 | 
| Number of Participants Requiring Dose Reduction Secondary to Excessive Erythropoiesis During Dosing Period, Among Participants Treated for 19-Weeks |  | Baseline up to Week 19 | 
| Rate of Change in Hb Levels, Measured by Regression Slopes of the Hb Values During Treatment up to Week 6 | The rate of rise was computed as the slope of the regression line of change in Hb level (in g/dL) vs. time (in weeks) using Random Coefficient Model. Because of the small number of hyporesponders enrolled into this study, data for this secondary efficacy analysis as planned per protocol was not collected and summarized for hyporesponder participants. | Baseline up to Week 6 | 
| Trough Plasma Concentration of Roxadustat and Epoetin Alfa |  | Predose, 4, 8, 12, 24, 48, and 72 hours postdose at Weeks 1 and 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney, End Stage Renal Disease, ESRD, Chronic Kidney Disease, CKD, Renal, Anemia, Oral anemia treatment, Hemoglobin levels, Blood count, Erythropoietin, Hemodialysis, Normoresponder, Hyporesponder