Trial Outcomes & Findings for Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis (NCT NCT02174627)

Last Updated: 2019-12-16

Results Overview

Baseline Hb was defined as the mean of the last 3 central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to mean value from Week 28 to Week 52 was analyzed using a missing at random (MAR) based multiple imputation analysis of covariance (ANCOVA) model with baseline Hb, baseline estimated glomerular filtration rate (eGFR), cardiovascular (CV) history, geographic region and treatment group as fixed effect covariates. The adjusted least squares (LS) mean estimates of change from baseline to mean during Week 28 to Week 52 are presented.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2781 participants

Primary outcome timeframe

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

Results posted on

2019-12-16

Participant Flow

This study was conducted at 385 centers in 25 countries worldwide across the United States, Canada, Latin America, Asia and Europe between 26 June 2014 and 04 October 2018. Participants with chronic kidney disease who were not on dialysis were recruited in this study.

Study had a screening period (up to 6 weeks), treatment period (up to 4 years) and follow-up period (4 weeks after treatment period for those who completed treatment). 2781 participants were randomized, of which 2761 were included in the analysis and 20 were excluded. Only participants included in the analysis are presented in the participant flow.

Participant milestones

Participant milestones
Measure	Roxadustat Participants received roxadustat tablets orally three times a week (TIW). The initial dose was 70 milligram (mg) TIW and was titrated to achieve and maintain haemoglobin (Hb) 11±1 grams per deciliter (g/dL). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Study STARTED	1384	1377
Overall Study Received Treatment	1384	1376
Overall Study Discontinued Treatment	499	801
Overall Study COMPLETED	1300	1247
Overall Study NOT COMPLETED	84	130

Reasons for withdrawal

Reasons for withdrawal
Measure	Roxadustat Participants received roxadustat tablets orally three times a week (TIW). The initial dose was 70 milligram (mg) TIW and was titrated to achieve and maintain haemoglobin (Hb) 11±1 grams per deciliter (g/dL). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Study Missing	0	1
Overall Study Incorrect enrolment before randomization	0	1
Overall Study Participant decision	84	128

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Roxadustat n=1384 Participants Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=1377 Participants Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Total n=2761 Participants Total of all reporting groups
Age, Continuous	60.9 years STANDARD_DEVIATION 14.67 • n=5 Participants	62.4 years STANDARD_DEVIATION 14.14 • n=7 Participants	61.7 years STANDARD_DEVIATION 14.43 • n=5 Participants
Sex: Female, Male Female	820 Participants n=5 Participants	774 Participants n=7 Participants	1594 Participants n=5 Participants
Sex: Female, Male Male	564 Participants n=5 Participants	603 Participants n=7 Participants	1167 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	344 Participants n=5 Participants	357 Participants n=7 Participants	701 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1040 Participants n=5 Participants	1020 Participants n=7 Participants	2060 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 White	623 Participants n=5 Participants	611 Participants n=7 Participants	1234 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	112 Participants n=5 Participants	115 Participants n=7 Participants	227 Participants n=5 Participants
Race/Ethnicity, Customized Asian	544 Participants n=5 Participants	538 Participants n=7 Participants	1082 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	24 Participants n=5 Participants	29 Participants n=7 Participants	53 Participants n=5 Participants
Race/Ethnicity, Customized Other	81 Participants n=5 Participants	82 Participants n=7 Participants	163 Participants n=5 Participants

PRIMARY outcome

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

Outcome measures

Outcome measures
Measure	Roxadustat n=1334 Participants Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=1330 Participants Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52	1.75 g/dL Standard Error 0.033	0.40 g/dL Standard Error 0.034

SECONDARY outcome

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

Population: The Full Analysis Set (FAS) included all participants in the ITT analysis set who received at least 1 dose of IP and had baseline Hb and at least 1 post-dose Hb assessment. Participants from the FAS, with data available for analysis are presented.

Hb response was defined as: * Hb ≥ 11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL for participants with baseline Hb \> 8.0 g/dL; or * Hb increase from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at 2 consecutive visits (with available data) separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell \[RBC\] transfusion, erythropoietin analogue, or intravenous \[IV\] iron) prior to Hb response. The percentage of participants with an Hb response during the first 24 weeks of treatment is presented.

Outcome measures

Outcome measures
Measure	Roxadustat n=1371 Participants Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=1357 Participants Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Percentage of Participants With Hb Response During the First 24 Weeks of Treatment	77.0 Percentage of participants	8.5 Percentage of participants

SECONDARY outcome

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

Population: The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. Only participants who consented to the use of donated biomarker samples and had baseline hsCRP \>ULN were included in the analysis.

Baseline hsCRP was quantified from stored biomarker samples obtained at randomization. Baseline Hb was defined as the mean of the last 3 central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to mean value during Week 28 to Week 52 was analyzed using a MAR based multiple imputation ANCOVA model with baseline Hb, baseline eGFR, CV history, geographic region and treatment group as fixed effect covariates. The adjusted LS mean estimates of change from baseline in participants with baseline hsCRP \>ULN to mean during Week 28 to Week 52 are presented.

Outcome measures

Outcome measures
Measure	Roxadustat n=213 Participants Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=198 Participants Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 in Participants With Baseline High Sensitivity C-Reactive Protein (hsCRP) Greater Than the Upper Limit of Normal (ULN)	1.75 g/dL Standard Error 0.087	0.62 g/dL Standard Error 0.091

SECONDARY outcome

Timeframe: Week 28 up to Week 52.

Population: The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. Participants without any Hb measurements from Week 28 were not included in the analysis.

Proportion of total time of interpolated Hb values ≥10 g/dL was calculated as the time the linearly interpolated curve between measurements ≥10 g/dL divided by the time between measurements from Week 28 to Week 52. Proportion of total time was analyzed using an ANCOVA model with baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from Week 28 to Week 52 are presented.

Outcome measures

Outcome measures
Measure	Roxadustat n=1220 Participants Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=1145 Participants Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Proportion of Total Time of Interpolated Hb Values Greater Than or Equal To 10 g/dL From Week 28 to Week 52	0.82 proportion of total time Standard Error 0.011	0.33 proportion of total time Standard Error 0.011

SECONDARY outcome

Timeframe: Week 28 up to Week 52.

Population: The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. Participants without any Hb measurements from Week 28 were not included in the analysis.

Proportion of total time of interpolated Hb values within the interval of 10 to 12 g/dL was calculated as the time the linearly interpolated curve between measurements were within 10 to 12 g/dL divided by the time between measurements from Week 28 to Week 52. Proportion of total time was analyzed using an ANCOVA model with baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from Week 28 to Week 52 are presented.

Outcome measures

Outcome measures
Measure	Roxadustat n=1220 Participants Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=1145 Participants Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Proportion of Total Time of Interpolated Hb Values Within the Interval of 10 to 12 g/dL From Week 28 to Week 52	0.70 proportion of total time Standard Error 0.010	0.28 proportion of total time Standard Error 0.010

SECONDARY outcome

Timeframe: Baseline (Day 1, Week 0) and Week 24

Baseline LDL was defined as the last result obtained prior to randomization. Mean changes in LDL cholesterol from baseline to Week 24 was analyzed using an ANCOVA model with baseline LDL, baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from baseline to Week 24 are presented.

Outcome measures

Outcome measures
Measure	Roxadustat n=1147 Participants Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=1133 Participants Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Mean Change in Low-Density Lipoprotein (LDL) Cholesterol From Baseline to Week 24	-0.38 millimole per liter Standard Error 0.028	-0.02 millimole per liter Standard Error 0.027

SECONDARY outcome

Timeframe: Baseline (Day1, Week 0) up to End of Study (EOS) visit (4 weeks after the treatment period) (or up to date of first rescue therapy), with treatment duration up to 4 years.

Population: The on-treatment plus 28 days (OT+28) analysis set included all participants who received at least 1 dose of randomized IP, except for those excluded from analysis. Participants were censored 28 days after last intake of IP.

Time-to-first rescue therapy (IV iron, RBC transfusion or erythropoietin analogue) was calculated as (date of first rescue therapy, or date of censoring if no rescue therapy was taken) minus (date of first dose of IP) +1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events.

Outcome measures

Outcome measures
Measure	Roxadustat n=1384 Participants Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=1376 Participants Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Time-To-First Instance of Receiving IV Iron, RBC Transfusion or Erythropoietin Analogue as Rescue Therapy	11.90 Events per 100 participant years	39.76 Events per 100 participant years

SECONDARY outcome

Timeframe: Baseline (Day1, Week 0) up to EOS visit (4 weeks after the treatment period) (or up to date of first RBC rescue therapy), with treatment duration up to 4 years.

Population: The OT+28 analysis set included all participants who received at least 1 dose of randomized IP, except for those excluded from analysis. Participants were censored 28 days after last intake of IP.

Time-to-first RBC rescue therapy was calculated as (date of first RBC rescue therapy, or date of censoring if no rescue therapy was taken) minus (date of first dose of IP) +1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events.

Outcome measures

Outcome measures
Measure	Roxadustat n=1384 Participants Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=1376 Participants Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Time-To-First Instance of Receiving a RBC Transfusion As Rescue Therapy	7.98 Events per 100 participant years	19.61 Events per 100 participant years

SECONDARY outcome

Timeframe: Baseline (Day 1, Week 0) and Week 12 to Week 28.

SF-36 is a Quality of Life (QoL) scale comprising 8 domains of health status: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. Each domain score is on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Mean change in SF-36 Vitality sub-score from baseline to mean from Week 12 to Week 28 was analyzed using a mixed model for repeated measures (MMRM) with terms for baseline score, treatment group, baseline Hb, baseline eGFR, CV history, geographic region, visit and treatment-by-visit interaction as fixed effects and participant as random effect. The adjusted LS mean estimates of change from baseline to mean score from Week 12 to Week 28 are presented.

Outcome measures

Outcome measures
Measure	Roxadustat n=1279 Participants Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=1235 Participants Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Mean Change From Baseline in Short Form 36 (SF-36) Vitality Sub-Score From Week 12 to Week 28	1.59 scores on a scale Standard Error 0.231	1.15 scores on a scale Standard Error 0.233

SECONDARY outcome

Timeframe: Baseline (Day1, Week 0) up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years.

Baseline eGFR was defined as the mean of all available central laboratory values prior to or at randomization. Rate of change in eGFR from baseline during the entire treatment period (in millilitres/minute/1.73 meters squared/years \[mL/min/1.73m\^2/years\]) was estimated using a random effects model using all post-baseline eGFR values prior to initiation of dialysis/transplant. Baseline eGFR, baseline Hb, geographic region, CV history, treatment group and post-baseline eGFR measurement time were used as fixed effects and participant and time (years) as random effects, ie, random intercept and slope.

Outcome measures

Outcome measures
Measure	Roxadustat n=1326 Participants Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=1314 Participants Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Annual Rate of eGFR Change From Baseline Prior to the Initiation of Dialysis or Kidney Transplant	-3.70 eGFR rate (mL/min/1.73m^2/years)	-3.19 eGFR rate (mL/min/1.73m^2/years)

SECONDARY outcome

Timeframe: Baseline (Day 1, Week 0) and Week 12 to Week 28.

SF-36 is a QoL scale comprising 8 domains of health status: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. Each domain score is on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Mean change in SF-36 Physical Functioning sub-score from baseline to mean from Week 12 to Week 28 was analyzed using a MMRM with terms for baseline score, treatment group, baseline Hb, baseline eGFR, CV history, geographic region, visit and treatment-by-visit interaction as fixed effects and participant as random effect. The adjusted LS mean estimates of change from baseline to mean score from Week 12 to Week 28 are presented.

Outcome measures

Outcome measures
Measure	Roxadustat n=1279 Participants Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=1234 Participants Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Mean Change From Baseline in SF-36 Physical Functioning Sub-Score From Week 12 to Week 28	0.14 scores on a scale Standard Error 0.222	-0.39 scores on a scale Standard Error 0.224

Adverse Events

Roxadustat

Serious events: 795 serious events

Other events: 839 other events

Deaths: 284 deaths

Placebo

Serious events: 749 serious events

Other events: 757 other events

Deaths: 245 deaths

Serious adverse events

Other adverse events

Additional Information

Global Clinical Lead

AstraZeneca

Phone: +1 302 885 1180

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Roxadustat n=1384 participants at risk Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.	Placebo n=1377 participants at risk Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Gastrointestinal disorders Constipation	6.6% 91/1384 • Number of events 126 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	6.4% 88/1377 • Number of events 101 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Gastrointestinal disorders Diarrhoea	10.0% 138/1384 • Number of events 190 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	8.5% 117/1377 • Number of events 156 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Gastrointestinal disorders Nausea	9.0% 124/1384 • Number of events 171 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	7.5% 103/1377 • Number of events 127 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Gastrointestinal disorders Vomiting	5.4% 75/1384 • Number of events 90 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	4.9% 67/1377 • Number of events 85 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
General disorders Oedema peripheral	10.4% 144/1384 • Number of events 192 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	7.7% 106/1377 • Number of events 135 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Infections and infestations Bronchitis	5.2% 72/1384 • Number of events 80 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	4.6% 64/1377 • Number of events 76 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Infections and infestations Upper respiratory tract infection	6.9% 95/1384 • Number of events 137 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	5.4% 75/1377 • Number of events 100 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Infections and infestations Urinary tract infection	11.0% 152/1384 • Number of events 205 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	6.8% 94/1377 • Number of events 135 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Infections and infestations Viral upper respiratory tract infection	7.3% 101/1384 • Number of events 159 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	7.7% 106/1377 • Number of events 152 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Metabolism and nutrition disorders Hyperkalaemia	6.2% 86/1384 • Number of events 105 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	5.4% 75/1377 • Number of events 86 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Musculoskeletal and connective tissue disorders Arthralgia	5.3% 73/1384 • Number of events 85 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	3.8% 53/1377 • Number of events 61 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Musculoskeletal and connective tissue disorders Back pain	5.1% 70/1384 • Number of events 87 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	4.1% 57/1377 • Number of events 69 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Nervous system disorders Dizziness	5.3% 74/1384 • Number of events 91 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	6.2% 86/1377 • Number of events 113 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Nervous system disorders Headache	6.7% 93/1384 • Number of events 122 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	6.0% 82/1377 • Number of events 96 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Renal and urinary disorders End stage renal disease	6.7% 93/1384 • Number of events 93 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	6.3% 87/1377 • Number of events 88 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Respiratory, thoracic and mediastinal disorders Cough	7.6% 105/1384 • Number of events 123 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	5.0% 69/1377 • Number of events 91 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.1% 70/1384 • Number of events 85 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	4.6% 64/1377 • Number of events 80 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Skin and subcutaneous tissue disorders Pruritus	4.9% 68/1384 • Number of events 84 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	5.8% 80/1377 • Number of events 89 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
Vascular disorders Hypertension	10.7% 148/1384 • Number of events 190 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.	8.5% 117/1377 • Number of events 151 • From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.