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

Phase 2

Completed

Conditions: Anemia
End Stage Renal Disease

Interventions: Drug: Epoetin Alfa
Drug: Roxadustat
Other: Placebo

Registration Number: NCT01147666

Lead Sponsor: FibroGen

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 161

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
1. 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
2. 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
3. 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
4. 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
5. 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:

1. 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
2. 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

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort B (Epoetin Alfa)	Epoetin Alfa	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.
Cohort A-8 (Weight Tiered Roxadustat 70-120-200 mg)	Roxadustat	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.
Cohorts A (Epoetin Alfa)	Epoetin Alfa	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.
Cohort A-3 (Roxadustat 2.0 mg/kg TIW)	Roxadustat	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.
Cohort A-9 (Roxadustat 2.0 mg/kg)	Roxadustat	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.
Cohort B (Placebo)	Placebo	Hyporesponsive participants will receive placebo matched to roxadustat, administered orally TIW for 19 weeks.
Cohort A-1 (Roxadustat 1.0 mg/kg TIW)	Roxadustat	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.
Cohort A-2 (Roxadustat 1.5 mg/kg TIW)	Roxadustat	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.
Cohort A-4 (Roxadustat 1.8 mg/kg TIW)	Roxadustat	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.
Cohort A-5 (Roxadustat 1.8 mg/kg TIW)	Roxadustat	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.
Cohort A-7 (Weight Tiered Roxadustat 70-100-150 mg)	Roxadustat	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.
Cohort A-6 (Roxadustat 1.3 mg/kg TIW)	Roxadustat	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.
Cohort A-10 (Weight Tiered Roxadustat 70-120-200 mg)	Roxadustat	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.
Cohort B-1 (Roxadustat 1.5 mg/kg TIW)	Roxadustat	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.
Cohort B-2 (Roxadustat 2.0 mg/kg TIW)	Roxadustat	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Week 7 Hb ≥ Baseline Hb - 0.5 g/dL, Among Normoresponder Participants Treated for 6 Weeks Only	Week 7	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.
Number of Participants With Week 7 Hb ≥ Baseline Hb - 0.5 g/dL, Among Hyporesponsive Participants Treated for at Least 6 Weeks	Week 7	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.
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	Weeks 17, 18, 19, and 20	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.

Secondary Outcome Measures

Name	Time	Method
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)	Weeks 17, 18, 19, and 20	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.
Change From Baseline in Hb at Week 7 for Participants Treated for at Least 6 Weeks	Baseline, Week 7	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.
Change From Baseline in Hb at Weeks 8, 10, 12, 14, 17, 19, and 20 for Participants Treated for 7-19 Weeks	Baseline, Weeks 8, 10, 12, 14, 17, 19, and 20	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.
Number of Participants Who Required Dose Adjustments During the Dosing Period for Participants Treated for 6 Weeks Only	Baseline up to Week 6	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.
Number of Participants Who Required Dose Adjustments During the Dosing Period for Participants Treated for 19 Weeks	Baseline up to Week 19	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.
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
Rate of Change in Hb Levels, Measured by Regression Slopes of the Hb Values During Treatment up to Week 6	Baseline 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.
Trough Plasma Concentration of Roxadustat and Epoetin Alfa	Predose, 4, 8, 12, 24, 48, and 72 hours postdose at Weeks 1 and 6
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)	Weeks 17, 18, 19, and 20	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.
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 Treated for 6 Weeks Only Whose Hb Levels at Week 7 Were Greater Than Their Baseline Level	Week 7	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.
Number of Participants Who Required Rescue Anemia Treatment Due to Hb Levels, Among Participants Treated for 19-Weeks	Baseline up to Week 19	Rescue anemia treatment included any ESA dosing, RBC transfusion, or IV iron.
Number of Participants Who Required Rescue Anemia Treatment Due to Hb Levels, Among Participants Treated for at Least 6 Weeks	Baseline up to Week 6	Rescue anemia treatment included any ESA dosing, RBC transfusion, or IV iron.
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 Treated for 7-19 Weeks Whose Hb Levels at Weeks 8, 10, 12, 14, 17, 19, and 20 Were Greater Than Their Baseline Level	Weeks 8, 10, 12, 14, 17, 19, and 20	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.
Number of Participants Requiring Dose Reduction Secondary to Excessive Erythropoiesis During Dosing Period, Among Participants Treated for 19-Weeks	Baseline up to Week 19

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

Recruitment & Eligibility

Study & Design

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