Trial Outcomes & Findings for Safety and Efficacy Study of Roxadustat (FG-4592) for the Treatment of Anemia in End-Stage Renal Disease (ESRD) Newly Initiated Dialysis Participants (NCT NCT02052310)

NCT ID: NCT02052310

Last Updated: 2021-10-01

Results Overview

Hb values under the influence of rescue therapy were not censored for the primary analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (erythropoiesis-stimulating agent \[ESA\]) or red blood cell (RBC) transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model, Monotone missing data were imputed by regression from its own treatment group.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1043 participants

Primary outcome timeframe

Baseline (Day 1, Week 0), Week 28 to 52

Results posted on

2021-10-01

Participant Flow

Participants were randomized in a 1:1 ratio to receive either roxadustat or epoetin alfa.

Participant milestones

Participant milestones
Measure	Roxadustat Participants received roxadustat tablets, administered orally 3 times weekly (TIW). Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kilograms (kg)\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 milligrams \[mg\] roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target hemoglobin (Hb) values (10-12 grams \[g\]/deciliter \[dL\]) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa Participants on hemodialysis (HD) received epoetin alfa, administered intravenously (IV) TIW, with starting doses and dose adjustment rules as per United States Package Insert (USPI) or summary of product characteristics (SmPC). Participants on home HD or peritoneal dialysis (PD) received epoetin alfa, administered subcutaneously (SC) as per the country-specific product label (USPI or SmPC) or local standard of care (SOC). The maximum treatment duration was 226.9 weeks.
Overall Study STARTED	522	521
Overall Study Received at Least 1 Dose of Study Drug	522	517
Overall Study COMPLETED	307	309
Overall Study NOT COMPLETED	215	212

Reasons for withdrawal

Reasons for withdrawal
Measure	Roxadustat Participants received roxadustat tablets, administered orally 3 times weekly (TIW). Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kilograms (kg)\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 milligrams \[mg\] roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target hemoglobin (Hb) values (10-12 grams \[g\]/deciliter \[dL\]) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa Participants on hemodialysis (HD) received epoetin alfa, administered intravenously (IV) TIW, with starting doses and dose adjustment rules as per United States Package Insert (USPI) or summary of product characteristics (SmPC). Participants on home HD or peritoneal dialysis (PD) received epoetin alfa, administered subcutaneously (SC) as per the country-specific product label (USPI or SmPC) or local standard of care (SOC). The maximum treatment duration was 226.9 weeks.
Overall Study Death	64	54
Overall Study Withdrawal by Subject	37	49
Overall Study Other than specified	32	29
Overall Study Adverse Event	29	22
Overall Study Kidney Transplant	23	29
Overall Study Physician Decision	14	7
Overall Study Lack of Efficacy	6	1
Overall Study Site Terminated by Sponsor	5	13
Overall Study Lost to Follow-up	4	2
Overall Study Protocol Violation	1	6

Baseline Characteristics

Safety and Efficacy Study of Roxadustat (FG-4592) for the Treatment of Anemia in End-Stage Renal Disease (ESRD) Newly Initiated Dialysis Participants

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Roxadustat n=522 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=521 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.	Total n=1043 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	381 Participants n=5 Participants	391 Participants n=7 Participants	772 Participants n=5 Participants
Age, Categorical >=65 years	141 Participants n=5 Participants	130 Participants n=7 Participants	271 Participants n=5 Participants
Sex: Female, Male Female	213 Participants n=5 Participants	214 Participants n=7 Participants	427 Participants n=5 Participants
Sex: Female, Male Male	309 Participants n=5 Participants	307 Participants n=7 Participants	616 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	99 Participants n=5 Participants	77 Participants n=7 Participants	176 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	423 Participants n=5 Participants	444 Participants n=7 Participants	867 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	415 Participants n=5 Participants	400 Participants n=7 Participants	815 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black/African American	44 Participants n=5 Participants	50 Participants n=7 Participants	94 Participants n=5 Participants
Race/Ethnicity, Customized Race · Asian	43 Participants n=5 Participants	51 Participants n=7 Participants	94 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other	19 Participants n=5 Participants	16 Participants n=7 Participants	35 Participants n=5 Participants
Race/Ethnicity, Customized Race · American Indian/ Alaskan Native	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1, Week 0), Week 28 to 52

Population: The ITT population included all randomized participants.

Outcome measures

Outcome measures
Measure	Roxadustat n=522 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=521 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (ITT Population) Baseline	8.43 g/dL Standard Deviation 1.044	8.46 g/dL Standard Deviation 0.964
US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (ITT Population) Change at Week 28 to 52	2.57 g/dL Standard Deviation 1.269	2.36 g/dL Standard Deviation 1.214

PRIMARY outcome

Timeframe: Baseline (Day 1, Week 0) up to Week 24

Population: The per protocol set (PPS) population included all participants in the full analysis set (FAS) population (all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment) who received at least 8 weeks of treatment and were without major protocol violations.

Hb response was defined, using central laboratory values, as: Hb ≥11.0 g/dL and a Hb increase from baseline by ≥1.0 g/dL in participants whose baseline Hb \>8.0 g/dL, or increase in Hb ≥2.0 g/dL in participants whose baseline Hb ≤8.0 g/dL. Rescue therapy for roxadustat treated participant was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion.

Outcome measures

Outcome measures
Measure	Roxadustat n=490 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=468 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants Who Achieved a Hb Response at 2 Consecutive Visits at Least 5 Days Apart During First 24 Weeks of Treatment, Without Rescue Therapy Within 6 Weeks Prior to the Hb Response (PPS Population)	88.2 percentage of participants	84.4 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day 1, Week 0) up to Week 24

Population: The ITT population included all randomized participants.

Outcome measures

Outcome measures
Measure	Roxadustat n=522 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=521 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
US (FDA Submission): Hb Responder Rate- Percentage of Participants Who Achieved a Hb Response at 2 Consecutive Visits at Least 5 Days Apart During First 24 Weeks of Treatment, Without Rescue Therapy Within 6 Weeks Prior to the Hb Response (ITT Population)	84.3 percentage of participants	79.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day 1, Week 0), Week 28 to 52

Population: The PPS population included all participants in the FAS population (all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment) who received at least 8 weeks of treatment and were without major protocol violations. Here, 'Number analyzed' signifies participants with non-missing data for this outcome measure at specified timepoint.

Hb values under the influence of rescue therapy were censored up to 6 weeks in the analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (ESA or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the MCMC imputation model, Monotone missing data were imputed by regression from its own treatment group.

Outcome measures

Outcome measures
Measure	Roxadustat n=490 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=468 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Ex-US Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (PPS Population) Baseline	8.43 g/dL Standard Deviation 1.043	8.43 g/dL Standard Deviation 0.963
Ex-US Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (PPS Population) Change at Week 28 to 52	2.62 g/dL Standard Deviation 1.292	2.44 g/dL Standard Deviation 1.209

SECONDARY outcome

Timeframe: Baseline (Day 1, Week 0), Week 12 to 24

Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment. Here, 'Number analyzed' signifies participants with non-missing data for this outcome measure at specified timepoints.

Baseline LDL Cholesterol was defined as the mean of values obtained within 6 weeks prior to the first dose of study treatment.

Outcome measures

Outcome measures
Measure	Roxadustat n=522 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=513 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 24 Baseline	109.12 mg/dL Standard Deviation 38.833	109.22 mg/dL Standard Deviation 35.914
Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 24 Change at Weeks 12 to 24	-23.80 mg/dL Standard Deviation 29.996	-5.39 mg/dL Standard Deviation 26.164

SECONDARY outcome

Timeframe: Baseline (Day 1, Week 0), Week 18 to 24

Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Hb values under the influence of rescue therapy were not censored in the analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the MCMC imputation model, Monotone missing data were imputed by regression from its own treatment group.

Outcome measures

Outcome measures
Measure	Roxadustat n=228 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=222 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Mean Change From Baseline in Hb Levels Between Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN) Change at Week 18 to 24	2.34 g/dL Standard Deviation 1.256	2.48 g/dL Standard Deviation 1.271
Mean Change From Baseline in Hb Levels Between Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN) Baseline	8.54 g/dL Standard Deviation 0.968	8.38 g/dL Standard Deviation 0.961

SECONDARY outcome

Timeframe: Weeks 28 to 52

Monthly iron use for each participant = Total IV iron in mg / \[(last dose date - first dose date of study medication in the period)+1\]/ 28.

Outcome measures

Outcome measures
Measure	Roxadustat n=437 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=438 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Median Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52	0.00 mg/PEM Interval 0.0 to 1600.0	26.86 mg/PEM Interval 0.0 to 717.7

SECONDARY outcome

Timeframe: Baseline (Day 1, Week 0) up to last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa)

Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment.

Median time to event (weeks) was calculated using Kaplan Meier Survival Estimates.

Outcome measures

Outcome measures
Measure	Roxadustat n=522 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=513 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Time to First RBC Transfusion	NA weeks Due to smaller number of participants with an event (any use of RBC transfusion), median and 95% CI could not be calculated.	NA weeks Due to smaller number of participants with an event (any use of RBC transfusion), median and 95% CI could not be calculated.

SECONDARY outcome

Timeframe: Baseline (Day 1, Week 0), Weeks 8 to 12

Baseline MAP was defined as the last MAP value prior to the first dose of study treatment.

Outcome measures

Outcome measures
Measure	Roxadustat n=521 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=513 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 8 to 12 Baseline	99.33 millimeters of mercury (mmHg) Standard Deviation 10.146	99.04 millimeters of mercury (mmHg) Standard Deviation 9.874
Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 8 to 12 Change at Weeks 8 to 12	-0.12 millimeters of mercury (mmHg) Standard Deviation 8.018	1.15 millimeters of mercury (mmHg) Standard Deviation 8.729

SECONDARY outcome

Timeframe: Weeks 28 to 52

Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment.

An exacerbation of hypertension was defined as increase from baseline of ≥20 mmHg in systolic blood pressure (sBP) and sBP ≥170 mmHg or an increase from baseline of ≥15 mm Hg in diastolic blood pressure (dBP) and dBP ≥100 mmHg. Median time to event (weeks) was calculated using Kaplan Meier Survival Estimates.

Outcome measures

Outcome measures
Measure	Roxadustat n=522 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=513 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Time to First Exacerbation of Hypertension During Weeks 28 to 52	NA weeks Due to smaller number of participants with an event (exacerbation hypertension), median and 95% CI could not be calculated.	NA weeks Due to smaller number of participants with an event (exacerbation hypertension), median and 95% CI could not be calculated.

SECONDARY outcome

Timeframe: Weeks 28 to 52

Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment.

Percentage of participants with exacerbation of hypertension, meeting at least one of the following criteria are reported: i) Increase in BP: An increase from baseline of ≥ 20 mmHg in sBP and sBP \>170 mmHg, or an increase from baseline of ≥15 mmHg dBP and dBP \>100 mmHg.

Outcome measures

Outcome measures
Measure	Roxadustat n=522 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=513 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Percentage of Participants With Exacerbation of Hypertension During Weeks 28 to 52	14.0 percentage of participants	15.2 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day 1, Week 0) up to Week 24

Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment.

Hb values under the influence of rescue therapy were censored up to 6 weeks in the analysis. Hb response was defined, using central laboratory values, as: Hb ≥11.0 g/dL and a Hb increase from baseline by ≥1.0 g/dL in participants whose baseline Hb \>8.0 g/dL, or increase in Hb ≥2.0 g/dL in participants whose baseline Hb ≤8.0 g/dL. Rescue therapy for roxadustat treated participant was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Median time to event was calculated using Kaplan Meier Survival Estimates.

Outcome measures

Outcome measures
Measure	Roxadustat n=522 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=513 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Time to Achieve the First Hb Response up to Week 24 Censoring for Rescue Therapy	7.1 weeks Interval 6.1 to 8.1	8.1 weeks Interval 8.1 to 9.1

SECONDARY outcome

Timeframe: Weeks 28 to 36 and 28 to 52

Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment.

Outcome measures

Outcome measures
Measure	Roxadustat n=522 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=513 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Percentage of Participants With Hb ≥10.0 g/dL Averaged Over Weeks 28 to 36 and 28 to 52, Regardless of Rescue Therapy Weeks 28 to 36	73.4 percentage of participants	70.8 percentage of participants
Percentage of Participants With Hb ≥10.0 g/dL Averaged Over Weeks 28 to 36 and 28 to 52, Regardless of Rescue Therapy Weeks 28 to 52	73.6 percentage of participants	72.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day 1, Week 0), Week 28 to 36

Outcome measures

Outcome measures
Measure	Roxadustat n=435 Participants Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=439 Participants Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 36), Censoring for Rescue Therapy	2.70 g/dL Standard Deviation 1.423	2.46 g/dL Standard Deviation 1.308

Adverse Events

Roxadustat

Serious events: 234 serious events

Other events: 291 other events

Deaths: 64 deaths

Epoetin Alfa

Serious events: 218 serious events

Other events: 262 other events

Deaths: 54 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Trial Information Desk

FibroGen, Inc.

Phone: 415-978-1200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The multisite consortium can publish any time after the data is collected and analyzed by FibroGen. The investigator can only publish after the multisite consortium publishes (or tries to publish and fails). FibroGen has 60 days to review a publication and can extend the embargo up to an additional 120 days (or 180 total).
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Measure	Roxadustat n=522 participants at risk Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on a tiered, weight-based dosing scheme (low weight \[≤70 kg\] and high weight \[\>70 to 160 kg\] participants received 70 and 100 mg roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target Hb values (10-12 g/dL) was based upon regular monitoring of Hb. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 227.9 weeks.	Epoetin Alfa n=517 participants at risk Participants on HD received epoetin alfa, administered IV TIW, with starting doses and dose adjustment rules as per USPI or SmPC. Participants on home HD or PD received epoetin alfa, administered SC as per the country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 226.9 weeks.
Gastrointestinal disorders Diarrhea	13.8% 72/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	7.4% 38/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Gastrointestinal disorders Nausea	8.6% 45/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	5.8% 30/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Gastrointestinal disorders Constipation	6.7% 35/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	4.4% 23/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Gastrointestinal disorders Vomiting	6.1% 32/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	3.3% 17/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Arteriovenous fistula thrombosis	5.0% 26/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	5.4% 28/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Arteriovenous fistula site complication	5.2% 27/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	8.1% 42/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Injury, poisoning and procedural complications Procedural hypotension	4.8% 25/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	6.0% 31/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Metabolism and nutrition disorders Hyperphosphatemia	10.0% 52/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	6.8% 35/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Metabolism and nutrition disorders Hyperkalemia	4.6% 24/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	5.8% 30/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Musculoskeletal and connective tissue disorders Muscle spasms	11.5% 60/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	7.5% 39/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Musculoskeletal and connective tissue disorders Back pain	3.4% 18/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	5.2% 27/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Nervous system disorders Headache	10.9% 57/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	8.3% 43/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Nervous system disorders Dizziness	5.4% 28/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	4.6% 24/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Respiratory, thoracic and mediastinal disorders Cough	5.4% 28/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	4.1% 21/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Skin and subcutaneous tissue disorders Pruritus	5.7% 30/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	4.3% 22/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Vascular disorders Hypertension	18.4% 96/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	16.8% 87/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.
Vascular disorders Hypotension	9.4% 49/522 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.	6.4% 33/517 • Baseline (Day 1, Week 0) up to 28 days after the last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). Mortality presented is for the timeframe of Baseline (Day 1, Week 0) up to end of treatment (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa). The Safety population included all randomized participants who received at least 1 dose of study medication.