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Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo Controlled Study of the Efficacy and Safety of Roxadustat for the Treatment of Anemia in Chronic Kidney Disease Patients not on Dialysis

Summary
EudraCT number	2012-005180-27
Trial protocol	GB BE HU IT ES BG PL EE GR
Global end of trial date	01 Nov 2017

Results information
Results version number	v3(current)
This version publication date	17 Apr 2021
First version publication date	16 Nov 2018
Other versions	v1 , v2
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

1517-CL-0608

ISRCTN number

US NCT number

NCT01887600

WHO universal trial number (UTN)

Sponsor organisation name

Astellas Pharma Europe B.V. (APEB)

Sponsor organisation address

Sylviusweg 62, Leiden, Netherlands, 2333 BE

Public contact

Clinical Trial Disclosure, Astellas Pharma Europe B.V. (APEB), 31 (0) 71 5455 050, astellas.resultsdisclosure@astellas.com

Scientific contact

Clinical Trial Disclosure, Astellas Pharma Europe B.V. (APEB), 31 (0) 71 5455 050, astellas.resultsdisclosure@astellas.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

01 Nov 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Nov 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to evaluate the efficacy of roxadustat in the treatment of anemia in non-dialysis chronic kidney disease (CKD) participants.

Protection of trial subjects

This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Sep 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belarus: 12

Country: Number of subjects enrolled

Belgium: 9

Country: Number of subjects enrolled

Bulgaria: 35

Country: Number of subjects enrolled

Colombia: 3

Country: Number of subjects enrolled

Dominican Republic: 12

Country: Number of subjects enrolled

Estonia: 1

Country: Number of subjects enrolled

Georgia: 17

Country: Number of subjects enrolled

Greece: 6

Country: Number of subjects enrolled

Guatemala: 27

Country: Number of subjects enrolled

Hungary: 12

Country: Number of subjects enrolled

Italy: 6

Country: Number of subjects enrolled

Panama: 12

Country: Number of subjects enrolled

Peru: 3

Country: Number of subjects enrolled

Poland: 48

Country: Number of subjects enrolled

Romania: 46

Country: Number of subjects enrolled

Russian Federation: 98

Country: Number of subjects enrolled

South Africa: 16

Country: Number of subjects enrolled

Spain: 17

Country: Number of subjects enrolled

Turkey: 19

Country: Number of subjects enrolled

United Kingdom: 12

Country: Number of subjects enrolled

Ukraine: 98

Country: Number of subjects enrolled

Serbia: 85

Worldwide total number of subjects

594

EEA total number of subjects

180

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

335

From 65 to 84 years

249

85 years and over

Subject disposition

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Recruitment details

Study population consisted of anemic participants with stages 3, 4 or 5 chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m^2) who are not on dialysis. Participants were recruited from 125 study centers located in 22 countries.

Screening details

A total of 594 participants with CKD were randomized to receive one of the 2 treatment arms in a 2:1 ratio receiving roxadustat or placebo. Anemia was defined as a mean Hb ≤ 10.0 g/dL upon repeated measurements during the screening period. Participants needed a ferritin ≥30 ng/mL (≥ 67.4 pm ol/L) and transferrin saturation (TSAT) ≥ 5%.

Period 1 title

Overall Treatment Period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject

Are arms mutually exclusive

Yes

Roxadustat

Arm description

Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for at least 52 weeks up to a maximum of 104 weeks.

Arm type

Experimental

Investigational medicinal product name

roxadustat

Investigational medicinal product code

ASP1517

Other name

FG-4592

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Roxadustat was administered initially according to the tiered weight-based dosing, where participants with weight from ≥ 45 to ≤ 70 kg received 70 mg and participants with > 70 to ≤ 160 kg received 100 mg of roxadustat. Dose-titration based upon regular measurement of Hb levels was performed until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL.

Placebo

Arm description

Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received matching placebo for at least 52 weeks up to a maximum of 104 weeks.

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo was administered initially according to the tiered weight-based dosing, where participants with weight from ≥ 45 to ≤ 70 kg received 70 mg and participants with > 70 to ≤ 160 kg received 100 mg of roxadustat. Dose-titration based upon regular measurement of Hb levels was performed until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL.

Number of subjects in period 1	Roxadustat	Placebo
Started	391	203
Treatment Received	391	203
Completed	245	89
Not completed	146	114
Physician decision	7	8
Consent withdrawn by subject	58	52
Adverse Event	21	9
Death	39	16
Miscellaneous	6	2
Non-compliance with study drug	3	-
Lost to follow-up	5	1
Progressive disease	1	-
Lack of efficacy	3	26
Protocol deviation	3	-

Baseline characteristics

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Reporting group title

Roxadustat

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	Roxadustat	Placebo	Total
Number of subjects	391	203
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	60.6 ( 13.5 )	61.7 ( 13.8 )	-
Gender categorical
Units:
Male	169	99	268
Female	222	104	326
Race
Units: Subjects
White	335	182	517
Black or African American	10	3	13
Asian	9	0	9
Other	37	18	55
History of Diabetes
Units: Subjects
1. Yes	146	89	235
2. No	245	114	359
Iron Repletion at Baseline
Units: Subjects
TSAT >= 20% and Ferritin >= 100 ng/mL	204	109	313
TSAT < 20% or Ferritin < 100 ng/mL	187	94	281
Baseline Hemoglobin (Baseline Hb) Value
Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose).
Units: g/dL
arithmetic mean (standard deviation)	9.08 ( 0.76 )	9.10 ( 0.72 )	-
Baseline Estimated Glomerular Filtration Rate (eGFR)
Units: ml/min/1.73 m^2
arithmetic mean (standard deviation)	16.5 ( 10.2 )	17.2 ( 11.7 )	-
Time From Chronic Kidney Disease (CKD) Diagnosis
Units: Years
arithmetic mean (standard deviation)	5.65 ( 7.02 )	4.91 ( 5.99 )	-

End points

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Reporting group title

Roxadustat

Reporting group description

Reporting group title

Placebo

Reporting group description

Primary: Percentage of Participants With a Hemoglobin (Hb) Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy Prior to Hb Response

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End point title

Percentage of Participants With a Hemoglobin (Hb) Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy Prior to Hb Response

End point description

Hemoglobin (Hb) response was measured as Yes or No. Response Yes (responders) 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 two 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, erythropoiesis-stimulating agent (ESA), or intravenous (IV) iron prior to Hb response. This was the primary efficacy endpoint for EU (EMA). The analysis population was the full analysis set (FAS), which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Primary

End point timeframe

Baseline to week 24

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of Participants
number (confidence interval 95%)
Responders	79.2 (74.8 to 83.1)	9.9 (6.1 to 14.8)

Hemoglobin (Hb) Response to Treatment (Yes/No)

Statistical analysis description

The Cochran-Mantel-Haenszel (CMH) test was adjusted by region, history of of cardiovascular, cerebrovascular or thromboembolic (CV) disease, baseline Hb and baseline estimated glomerular filtration rate (eGFR). Superiority of roxadustat versus placebo was to be declared if the lower bound of the two-sided 95% confidence interval of the CMH odds ratio was higher than 1.

Comparison groups

Placebo v Roxadustat

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

34.74

Confidence interval

level

95%

sides

2-sided

lower limit

20.48

upper limit

58.93

Primary: Hb Change From Baseline (BL) to the Average Hb in Weeks 28-52 Regardless of Rescue Therapy

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End point title

Hb Change From Baseline (BL) to the Average Hb in Weeks 28-52 Regardless of Rescue Therapy

End point description

The change from baseline to the average Hb values across weeks 28 to 52 without having received rescue therapy. The Hb values from visit windows at weeks 28, 32, 36, 40, 44, 48 and 52 were used for the calculation of the average of weeks 28 to 52. This was the primary efficacy endpoint for US (FDA). The analysis population was All Randomized, and it consisted of all randomized participants with available data at all time points.

End point type

Primary

End point timeframe

Baseline and weeks 28 to 52

End point values	Roxadustat	Placebo
Number of subjects analysed	312	146
Units: g/dL
least squares mean (confidence interval 95%)	1.992 (1.82 to 2.16)	0.300 (0.09 to 0.51)

Change From BL to the Average Hb in Weeks 28-52

Statistical analysis description

The Analysis of Covariance (ANCOVA) with Multiple Imputations (MI) model, adjusting for covariates was used for the analysis. The model included treatment as fixed factor, region and history of CV disease as class factors and baseline Hb, baseline eGFR as continuous covariates. Superiority of roxadustat versus placebo was considered successful if the lower bound of the two-sided 95% confidence interval of the difference between treatment arms (roxadustat minus placebo) was higher than 0.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

458

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Least squares mean difference

Point estimate

1.692

Confidence interval

level

95%

sides

2-sided

lower limit

1.52

upper limit

1.86

Secondary: Hb Change From BL to the Average Hb in Weeks 28-36 Without Having Received Rescue Therapy Within 6 Weeks Prior to and During 8-Week Evaluation Period

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End point title

Hb Change From BL to the Average Hb in Weeks 28-36 Without Having Received Rescue Therapy Within 6 Weeks Prior to and During 8-Week Evaluation Period

End point description

The Hb values from visit windows at weeks 28, 32 and 36 were used for the calculation of the average of weeks 28 to 36. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 28 to 36

End point values	Roxadustat	Placebo
Number of subjects analysed	311	139
Units: g/dL
least squares mean (confidence interval 95%)	2.069 (1.94 to 2.20)	0.470 (0.30 to 0.64)

Change from BL to the Average Hb in weeks 28-36

Statistical analysis description

A Mixed Model of Repeated Measures (MMRM) has been applied using the visits up to week 36. The results were based on the estimated difference between the two treatment arms overall mean effects throughout the evaluation period (weeks 28 to 36). The model included treatment arm, region, CV History, visits and visit by treatment as categorical variables and baseline Hb, baseline eGFR and baseline Hb by visit as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

450

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[1]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.599

Confidence interval

level

95%

sides

2-sided

lower limit

1.41

upper limit

1.78

Notes
[1] - LSM Difference p-value is for test of differences. Tested using a fixed sequence testing procedure to maintain the overall two-sided type I error rate at 0.05.

Secondary: Change From BL in Low-Density Lipoprotein (LDL) Cholesterol (Regardless of Fasting Status) to the Average LDL Cholesterol of Weeks 12 to 28

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End point title

Change From BL in Low-Density Lipoprotein (LDL) Cholesterol (Regardless of Fasting Status) to the Average LDL Cholesterol of Weeks 12 to 28

End point description

Analysis was completed on all values collected on day 1 and weeks 12, 20 and 28. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 12 to 28

End point values	Roxadustat	Placebo
Number of subjects analysed	342	185
Units: mmol/l
least squares mean (confidence interval 95%)	-0.650 (-0.76 to -0.54)	0.051 (-0.08 to 0.18)

LDL Change From BL

Statistical analysis description

A Mixed Model of Repeated Measures has been applied using the visits up to week 28. The results were based on the estimated difference between the two treatment arms and overall mean effects throughout the evaluation period (weeks 12 to 28). The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb, baseline eGFR and baseline LDL as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

527

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

< 0.001 ^[3]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

-0.701

Confidence interval

level

95%

sides

2-sided

lower limit

-0.83

upper limit

-0.57

Notes
[2] - Superiority of roxadustat versus placebo was considered successful if the upper bound of the two-sided 95% confidence interval of the difference between treatment arms (roxadustat minus placebo) is below 0.
[3] - LSM Difference p-value is for test of differences. Tested using a fixed sequence testing procedure to maintain the overall two-sided type I error rate at 0.05.

Secondary: Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis-stimulating Agent (ESA) Use, and Intravenous (IV) Iron)

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End point title

Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis-stimulating Agent (ESA) Use, and Intravenous (IV) Iron)

End point description

The time to first use of rescue therapy was calculated (in years) as: (First event date – Analysis date of first dose intake + 1) / 365.25. The First event date was defined as Date of first dose of rescue medication during the efficacy emergent period and Analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1. The Efficacy Emergent Period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or the end of treatment (EOT) visit, whichever occurred first. Data reported was analysed by Kaplan-Meier estimate for cumulative proportion. Medication onset date was the date of the first use of rescue medication. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline to week 104 (End of Treatment)

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5	6.1 (3.6 to 8.7)	33.3 (26.5 to 40.1)
Year 1	13.0 (9.3 to 16.7)	50.1 (42.4 to 57.7)
Year 1.5	22.0 (16.6 to 27.3)	52.5 (44.5 to 60.5)
Year 2	26.3 (20.2 to 32.4)	57.8 (48.7 to 66.9)

Time to First Use of Rescue Therapy

Statistical analysis description

Hazard ratio was calculated using stratified Cox Proportional Hazards Regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates. Superiority is declared if the upper bound of the 95% CI is below 1.0.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[4]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.238

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

0.33

Notes
[4] - Tested using a fixed sequence testing procedure to maintain the overall two-sided type I error rate at 0.05.

Secondary: Change From BL in Short Form (SF)-36 Vitality (VT) Sub-score to the Average VT Sub-score of Weeks 12 to 28

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End point title

Change From BL in Short Form (SF)-36 Vitality (VT) Sub-score to the Average VT Sub-score of Weeks 12 to 28

End point description

Change from BL in SF-36 VT sub-score to the average value in weeks 12-28 was calculated using the physical component scores (PCS) of SF-36. The multi-purpose, short-form health survey has 36 questions with an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. The survey measures eight dimensions or scales: (1) physical functioning (PF) (10 items); (2) role limitations due to physical health problems (RP) (3 items); (3) bodily pain (BP) (2 items); (4) social functioning (SF) (2 items); (5) general health perceptions (GH) (5 items); (6) role limitations due to emotional problems (RE) (3 items); (7) vitality, energy or fatigue (VT) (4 items); and (8) mental health (MH) (5 items). The SF-36 scores ranged from 0-100 with higher scores indicating better health status.The analysis population was the FAS.

End point type

Secondary

End point timeframe

Baseline and weeks 12 to 28

End point values	Roxadustat	Placebo
Number of subjects analysed	340	185
Units: Units on a Scale
least squares mean (confidence interval 95%)	2.788 (1.56 to 4.01)	1.661 (0.23 to 3.10)

Change from BL in Vitality SF-36

Statistical analysis description

A Mixed Model of Repeated Measures has been applied using the visits up to week 28. The results were based on the estimated difference between the two treatment arms and overall mean effects throughout the evaluation period (weeks 12 to 28). The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline SF-36 VT, baseline Hb and baseline eGFR as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

525

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.093 ^[5]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.127

Confidence interval

level

95%

sides

2-sided

lower limit

-0.19

upper limit

2.44

Notes
[5] - LSM Difference p-value is for test of differences. Tested using a fixed sequence testing procedure to maintain the overall two-sided type I error rate at 0.05.

Secondary: Change From BL in SF-36 Physical Functioning (PF) Sub-score to the Average PF Sub-score of Weeks 12 to 28

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End point title

Change From BL in SF-36 Physical Functioning (PF) Sub-score to the Average PF Sub-score of Weeks 12 to 28

End point description

Change from baseline in SF-36 PF normalized sub-score compared to the average PF sub-score of weeks 12 to 28. The multi-purpose, short-form health survey has 36 questions with an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. Change from baseline in PF subscore of SF-36 to the average of weeks 12–28 was compared by treatment arm for all participants (primary analysis) and in the subsets of participants with baseline PF subscore below 35 and equal or above 35. The SF-36 scores ranged from 0-100 with higher scores indicating better health status. All available SF-36 PF values were used i.e., both scheduled and unscheduled for the calculation of the average PF sub-score of weeks 12 to 28. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 12 to 28

End point values	Roxadustat	Placebo
Number of subjects analysed	340	185
Units: Units on a Scale
least squares mean (confidence interval 95%)	1.344 (0.15 to 2.54)	0.632 (-0.76 to 2.03)

Change from BL in Physical Functioning SF-36

Statistical analysis description

A Mixed Model of Repeated Measures has been applied using the visits up to week 28. The results were based on the estimated difference between the two treatment arms and overall mean effects throughout the evaluation period (weeks 12 to 28). The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline SF-36 PF, baseline Hb and baseline eGFR as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

525

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.27 ^[6]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

0.713

Confidence interval

level

95%

sides

2-sided

lower limit

-0.56

upper limit

1.98

Notes
[6] - LSM Difference p-value is for test of differences. Tested using a fixed sequence testing procedure to maintain the overall two-sided type I error rate at 0.05.

Secondary: Change From BL in Mean Arterial Pressure (MAP) to the Average MAP of Weeks 20 to 28

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End point title

Change From BL in Mean Arterial Pressure (MAP) to the Average MAP of Weeks 20 to 28

End point description

The MAP was derived for each visit from the average systolic (SBP) and diastolic blood pressure (DBP) calculated for each visit using the three readings and the following equation: MAP = (2/3) * DBP + (1/3) * SBP. Baseline assessment was the assessment on day 1 (average of the three readings). If the baseline assessment was missing, then the latest available value prior to first drug administration was used. The analysis population was the per protocol set (PPS), which consisted of all FAS participants who did not meet any reasons for exclusion from the PPS and had all available data at all time points.

End point type

Secondary

End point timeframe

Baseline and weeks 20 to 28

End point values	Roxadustat	Placebo
Number of subjects analysed	310	146
Units: mmHg
least squares mean (confidence interval 95%)	-0.814 (-1.83 to 0.20)	-1.656 (-2.91 to -0.41)

Change From BL MAP to Average MAP

Statistical analysis description

A Mixed Model of Repeated Measures was applied using the visits up to week 28. The results were based on the estimated difference between the two treatment arms with overall mean effects throughout the evaluation period (weeks 20 to 28). The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline MAP, baseline Hb, baseline eGFR as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

456

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

P-value

= 0.182 ^[8]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

0.842

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

2.08

Notes
[7] - Non-inferiority can be concluded if the upper bound of the two-sided 95% CI of the difference between roxadustat and placebo (roxadustat minus placebo) is below 2 mmHg.
[8] - LSM Difference p-value is for test of differences.

Secondary: Time to First Occurrence of Hypertension

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End point title

Time to First Occurrence of Hypertension

End point description

Occurrence of hypertension was defined as SBP increase from BL ≥20 mmHg and SBP >170 mmHg or DBP increase from BL ≥15 mmHg and DBP ≥110 mmHg. Time to first occurrence of hypertension was defined as first date where SBP criterion or DBP criterion is met, whichever occurred first. Data was analysed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the PPS, which consisted of all FAS participants who did not meet any reasons for exclusion from the PPS and had all available data at all time points.

End point type

Secondary

End point timeframe

Baseline and year 0.5, year 1, year 1.5 and year 2

End point values	Roxadustat	Placebo
Number of subjects analysed	359	183
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5	11.4 (7.9 to 14.8)	10.1 (5.5 to 14.7)
Year 1	14.8 (10.9 to 18.8)	12.5 (7.3 to 17.7)
Year 1.5	17.5 (13.0 to 21.9)	12.5 (7.3 to 17.7)
Year 2	18.5 (13.7 to 23.3)	12.5 (7.3 to 17.7)

Time to First Occurrence of Hypertension

Statistical analysis description

Hazard ratio was calculated using stratified Cox Proportional Hazards Regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

542

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[9]

P-value

= 0.334

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

2.16

Notes
[9] - Non-inferiority is declared if the upper bound of the 95% CI is below 1.3 (hazard ratio).

Secondary: Rate of Progression of CKD Measured by Annualized Estimated Glomerular Filtration Rate (eGFR) Slope Over Time

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End point title

Rate of Progression of CKD Measured by Annualized Estimated Glomerular Filtration Rate (eGFR) Slope Over Time

End point description

Annualized eGFR slope over time was estimated by a random slopes and intercepts model using all available eGFR values (one baseline and all post-treatment values up to EOT period or start of dialysis adjusted on baseline Hb, region, CV history at baseline and the interaction terms (baseline eGFR by timepoint and baseline Hb by timepoint). All assessments collected after initiation of chronic dialysis (acute or chronic) are excluded from the analysis. Baseline assessment was the assessment from day 1 visit. If this value was missing, the value from screening visit was used. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline up to week 108

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: ml/min per 1.73 m^2 per year
least squares mean (confidence interval 95%)	-2.65 (-3.29 to -2.02)	-3.24 (-4.21 to -2.28)

Annualized eGFR Slope

Statistical analysis description

Annualized eGFR slope over time was estimated by a random slopes and intercepts model using all available eGFR values adjusted on baseline Hb, region, CV history at Baseline and the interaction terms.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.316

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

0.59

Confidence interval

level

95%

sides

2-sided

lower limit

-0.57

upper limit

1.75

Secondary: Average Level of Hb Over Weeks 28 to 36 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

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End point title

Average Level of Hb Over Weeks 28 to 36 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

End point description

All scheduled and unscheduled hemoglobin values from weeks 28 to 36 were taken into account for calculating the average values. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Weeks 28 to 36

End point values	Roxadustat	Placebo
Number of subjects analysed	311	139
Units: g/dl
least squares mean (confidence interval 95%)	11.106 (10.97 to 11.24)	9.468 (9.29 to 9.65)

Average Level of Hb Over Weeks 28 to 36

Statistical analysis description

A Mixed Model of Repeated Measures was applied using the visits over weeks 28 to 36. The results were based on the estimated difference between the two treatment arms by visit based on this MMRM model. The model included treatment arm, region, CV History, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

450

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[10]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.638

Confidence interval

level

95%

sides

2-sided

lower limit

1.44

upper limit

1.84

Notes
[10] - LSM Difference p-value is for test of differences

Secondary: Average Level of Hb Over Weeks 44 to 52 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

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End point title

Average Level of Hb Over Weeks 44 to 52 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

End point description

All scheduled and unscheduled hemoglobin values from weeks 44 to 52 were taken into account for calculating the average values. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Weeks 44 to 52

End point values	Roxadustat	Placebo
Number of subjects analysed	287	118
Units: g/dl
least squares mean (confidence interval 95%)	10.984 (10.85 to 11.12)	9.381 (9.19 to 9.58)

Average Level of Hb Over Weeks 44 to 52

Statistical analysis description

A Mixed Model of Repeated Measures was applied using the visits over weeks 44 to 52. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

405

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[11]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.604

Confidence interval

level

95%

sides

2-sided

lower limit

1.39

upper limit

1.82

Notes
[11] - LSM difference p-value is for test of differences.

Secondary: Average Level of Hb Over Weeks 96 to 104 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

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End point title

Average Level of Hb Over Weeks 96 to 104 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

End point description

All scheduled and unscheduled hemoglobin values from weeks 96 to 104 were taken into account for calculating the average values. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Weeks 96 to 104

End point values	Roxadustat	Placebo
Number of subjects analysed	120	32
Units: g/dl
least squares mean (confidence interval 95%)	10.816 (10.63 to 11.00)	9.324 (9.01 to 9.64)

Average Level of Hb Over Weeks 96 to 104

Statistical analysis description

A Mixed Model of Repeated Measures was applied using the visits over weeks 96 to 104. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[12]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.492

Confidence interval

level

95%

sides

2-sided

lower limit

1.14

upper limit

1.85

Notes
[12] - LSM Difference p-value is for test of differences

Secondary: Time to Achieve the First Hb Response Without Rescue Therapy, as Defined by Primary Endpoint

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End point title

Time to Achieve the First Hb Response Without Rescue Therapy, as Defined by Primary Endpoint

End point description

For a participant without rescue therapy before Hb response (defined in 1 primary outcome), the time to achieve Hb response was calculated (in weeks) as: (First event date – Analysis date of first dose intake + 1) / 7 where First event date was defined as First date of both values that met the criteria for response. Participants who discontinued or received rescue therapy prior to the first Hb response or before the second consecutive Hb value defined as a response were classified as non- responders and were censored at week 24 or end of efficacy emergent period, whichever came first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline to week 24

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of participants
number (confidence interval 95%)
Week 4	26.0 (21.6 to 30.4)	3.5 (0.9 to 6.0)
Week 8	59.8 (54.7 to 64.9)	6.2 (2.8 to 9.7)
Week 16	83.4 (79.3 to 87.5)	9.4 (5.1 to 13.7)
Week 24	89.1 (85.5 to 92.6)	11.6 (6.8 to 16.5)

Time to Achieve the First Hb Response

Statistical analysis description

Hazard ratio was calculated using stratified Cox Proportional Hazards Regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

19.001

Confidence interval

level

95%

sides

2-sided

lower limit

11.98

upper limit

30.15

Secondary: Hb Change From BL to Each Post-Dosing Time Point

Top of page

End point title

Hb Change From BL to Each Post-Dosing Time Point

End point description

All scheduled and unscheduled hemoglobin values that belong to each visit window were taken into account using one value per analysis window. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose). N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline (day 1) and weeks 1,2,4,6,8,10,12,14,16,18,20,22,24,28,32,36,40,44,48,52,56,60,64, 68,72,76,80,84,88,92,96,100,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Number
least squares mean (confidence interval 95%)
Hb Change From BL to Week 1 [N=372,193]	0.390 (0.29 to 0.49)	-0.006 (-0.12 to 0.11)
Hb Change From BL to Week 2 [N=363,195]	0.977 (0.87 to 1.08)	0.039 (-0.09 to 0.17)
Hb Change From BL to Week 4 [N=360,189]	1.591 (1.47 to 1.71)	0.119 (-0.04 to 0.27)
Hb Change From BL to Week 6 [N=347,186]	1.927 (1.79 to 2.06)	0.100 (-0.07 to 0.27)
Hb Change From BL to Week 8 [N=346,188]	2.236 (2.10 to 2.37)	0.178 (0.01 to 0.35)
Hb Change From BL to Week 10 [N=335,184]	2.129 (1.99 to 2.26)	0.180 (0.01 to 0.35)
Hb Change From BL to Week 12 [N=337,179]	2.412 (2.28 to 2.55)	0.322 (0.15 to 0.49)
Hb Change From BL to Week 14 [N=332,174]	2.214 (2.08 to 2.35)	0.163 (0.00 to 0.33)
Hb Change From BL to Week 16 [N=321,173]	2.365 (2.23 to 2.50)	0.378 (0.20 to 0.56)
Hb Change From BL to Week 18 [N=317,161]	2.087 (1.95 to 2.23)	0.246 (0.06 to 0.43)
Hb Change From BL to Week 20 [N=310,151]	2.191 (2.04 to 2.34)	0.367 (0.18 to 0.56)
Hb Change From BL to Week 22 [N=312,149]	1.873 (1.73 to 2.02)	0.222 (0.03 to 0.41)
Hb Change From BL to Week 24 [N=307,142]	1.802 (1.66 to 1.95)	0.355 (0.16 to 0.55)
Hb Change From BL to Week 28 [N=301,145]	1.996 (1.85 to 2.14)	0.435 (0.24 to 0.63)
Hb Change From BL to Week 32 [N=300,137]	1.911 (1.77 to 2.05)	0.324 (0.13 to 0.52)
Hb Change From BL to Week 36 [N=290,131]	2.100 (1.95 to 2.25)	0.410 (0.21 to 0.61)
Hb Change From BL to Week 40 [N=290,125]	1.887 (1.74 to 2.03)	0.241 (0.04 to 0.45)
Hb Change From BL to Week 44 [N=275,122]	1.977 (1.82 to 2.13)	0.278 (0.06 to 0.49)
Hb Change From BL to Week 48 [N=282,114]	1.695 (1.54 to 1.85)	0.249 (0.03 to 0.46)
Hb Change From BL to Week 52 [N=267,111]	1.939 (1.78 to 2.10)	0.298 (0.07 to 0.52)
Hb Change From BL to Week 56 [N=217,74]	1.725 (1.56 to 1.88)	0.085 (-0.16 to 0.33)
Hb Change From BL to Week 60 [N=198,68]	1.988 (1.81 to 2.16)	0.354 (0.09 to 0.62)
Hb Change From BL to Week 64 [N=174,55]	1.637 (1.45 to 1.82)	0.233 (-0.06 to 0.52)
Hb Change From BL to Week 68 [N=173,49]	1.913 (1.74 to 2.09)	0.414 (0.13 to 0.70)
Hb Change From BL to Week 72 [N=158,50]	1.765 (1.58 to 1.95)	0.328 (0.03 to 0.63)
Hb Change From BL to Week 76 [N=156,47]	1.859 (1.67 to 2.05)	0.674 (0.36 to 0.99)
Hb Change From BL to Week 80 [N=145,43]	1.752 (1.57 to 1.93)	0.308 (0.01 to 0.61)
Hb Change From BL to Week 84 [N=143,37]	1.854 (1.66 to 2.05)	0.480 (0.14 to 0.82)
Hb Change From BL to Week 88 [N=132,31]	1.570 (1.38 to 1.76)	0.399 (0.06 to 0.74)
Hb Change From BL to Week 92 [N=125,32]	1.800 (1.60 to 2.00)	0.418 (0.06 to 0.78)
Hb Change From BL to Week 96 [N=122,32]	1.701 (1.49 to 1.91)	0.139 (-0.23 to 0.51)
Hb Change From BL to Week 100 [N=119,30]	1.763 (1.57 to 1.96)	0.315 (-0.03 to 0.66)
Hb Change From BL to Week 104 [N=102,26]	1.857 (1.64 to 2.08)	0.511 (0.11 to 0.91)

Hb Change From BL to Week 1

Statistical analysis description

A Mixed Model of Repeated Measures was applied using the visits up to Week 104. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[13]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

0.396

Confidence interval

level

95%

sides

2-sided

lower limit

0.29

upper limit

0.5

Notes
[13] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 2

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[14]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

0.938

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.07

Notes
[14] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 4

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[15]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.471

Confidence interval

level

95%

sides

2-sided

lower limit

1.3

upper limit

1.64

Notes
[15] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 6

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[16]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.827

Confidence interval

level

95%

sides

2-sided

lower limit

1.64

upper limit

2.02

Notes
[16] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 8

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[17]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

2.058

Confidence interval

level

95%

sides

2-sided

lower limit

1.87

upper limit

2.25

Notes
[17] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 10

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[18]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.949

Confidence interval

level

95%

sides

2-sided

lower limit

1.75

upper limit

2.14

Notes
[18] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 12

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[19]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

2.09

Confidence interval

level

95%

sides

2-sided

lower limit

1.9

upper limit

2.28

Notes
[19] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 14

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[20]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

2.051

Confidence interval

level

95%

sides

2-sided

lower limit

1.86

upper limit

2.24

Notes
[20] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 16

Statistical analysis description

A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[21]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.987

Confidence interval

level

95%

sides

2-sided

lower limit

1.79

upper limit

2.19

Notes
[21] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 18

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[22]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.841

Confidence interval

level

95%

sides

2-sided

lower limit

1.64

upper limit

2.05

Notes
[22] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 20

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[23]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.824

Confidence interval

level

95%

sides

2-sided

lower limit

1.61

upper limit

2.04

Notes
[23] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 22

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[24]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.651

Confidence interval

level

95%

sides

2-sided

lower limit

1.43

upper limit

1.87

Notes
[24] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 24

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[25]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.447

Confidence interval

level

95%

sides

2-sided

lower limit

1.23

upper limit

1.67

Notes
[25] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 28

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[26]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.561

Confidence interval

level

95%

sides

2-sided

lower limit

1.34

upper limit

1.78

Notes
[26] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 32

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[27]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.587

Confidence interval

level

95%

sides

2-sided

lower limit

1.37

upper limit

1.81

Notes
[27] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 36

Statistical analysis description

A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visitl. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[28]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.69

Confidence interval

level

95%

sides

2-sided

lower limit

1.46

upper limit

1.92

Notes
[28] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 40

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[29]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.645

Confidence interval

level

95%

sides

2-sided

lower limit

1.41

upper limit

1.88

Notes
[29] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 44

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[30]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.699

Confidence interval

level

95%

sides

2-sided

lower limit

1.45

upper limit

1.94

Notes
[30] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 48

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[31]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.446

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

1.69

Notes
[31] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 52

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[32]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.641

Confidence interval

level

95%

sides

2-sided

lower limit

1.39

upper limit

1.89

Notes
[32] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 56

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[33]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.64

Confidence interval

level

95%

sides

2-sided

lower limit

1.37

upper limit

1.91

Notes
[33] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 60

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[34]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.634

Confidence interval

level

95%

sides

2-sided

lower limit

1.33

upper limit

1.94

Notes
[34] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 64

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[35]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.404

Confidence interval

level

95%

sides

2-sided

lower limit

1.08

upper limit

1.73

Notes
[35] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 68

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[36]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.499

Confidence interval

level

95%

sides

2-sided

lower limit

1.18

upper limit

1.82

Notes
[36] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 72

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[37]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.438

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

1.78

Notes
[37] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 76

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[38]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.185

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.54

Notes
[38] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 80

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[39]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.443

Confidence interval

level

95%

sides

2-sided

lower limit

1.11

upper limit

1.78

Notes
[39] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 84

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[40]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.374

Confidence interval

level

95%

sides

2-sided

lower limit

0.99

upper limit

1.75

Notes
[40] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 88

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[41]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.171

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

1.55

Notes
[41] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 92

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[42]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.382

Confidence interval

level

95%

sides

2-sided

lower limit

0.98

upper limit

1.78

Notes
[42] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 96

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[43]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.563

Confidence interval

level

95%

sides

2-sided

lower limit

1.15

upper limit

1.97

Notes
[43] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 100

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[44]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.448

Confidence interval

level

95%

sides

2-sided

lower limit

1.06

upper limit

1.83

Notes
[44] - LSM Difference p-value is for test of differences.

Hb Change From BL to Week 104

Statistical analysis description

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[45]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.347

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.79

Notes
[45] - LSM Difference p-value is for test of differences.

Secondary: Hb Change From BL to the Average Hb Value of Weeks 28-36 Regardless of the Use of Rescue Therapy

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End point title

Hb Change From BL to the Average Hb Value of Weeks 28-36 Regardless of the Use of Rescue Therapy

End point description

The Hb values from visit windows from weeks 28 to 36 were used for the calculation of the average regardless of rescue therapy. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dosing). The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and week 28 to 36

End point values	Roxadustat	Placebo
Number of subjects analysed	312	146
Units: g/dl
least squares mean (confidence interval 95%)	2.013 (1.88 to 2.15)	0.399 (0.22 to 0.58)

Change From Baseline to Average Hb Weeks 28-36

Statistical analysis description

A Mixed Model of Repeated Measures was applied using the visits up to week 36. The results were based on the estimated difference between the two treatment arms overall mean effect during week 28 to 36 period based on this MMRM model. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

458

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[46]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.614

Confidence interval

level

95%

sides

2-sided

lower limit

1.42

upper limit

1.81

Notes
[46] - LSM difference p-value is for test of differences.

Secondary: Hb Change From BL to the Average Hb Value of Weeks 44-52 Regardless of the Use of Rescue Therapy

Top of page

End point title

Hb Change From BL to the Average Hb Value of Weeks 44-52 Regardless of the Use of Rescue Therapy

End point description

The Hb values from visit windows from weeks 44 to 52 were used for the calculation of the average regardless of rescue therapy. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dosing). The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and week 44 to 52

End point values	Roxadustat	Placebo
Number of subjects analysed	291	123
Units: g/dl
least squares mean (confidence interval 95%)	1.886 (1.75 to 2.03)	0.292 (0.10 to 0.48)

Change From Baseline to Average Hb Weeks 44-52

Statistical analysis description

A Mixed Model of Repeated Measures was applied using the visits up to week 52. The results were based on the estimated difference between the two treatment arms overall mean effect during week 44 to 52 period based on this MMRM model. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.594

Confidence interval

level

95%

sides

2-sided

lower limit

1.38

upper limit

1.81

Secondary: Hb Change From BL to the Average Hb Value of Weeks 96-104 Regardless of the Use of Rescue Therapy

Top of page

End point title

Hb Change From BL to the Average Hb Value of Weeks 96-104 Regardless of the Use of Rescue Therapy

End point description

The Hb values from visit windows from weeks 96 to 104 were used for the calculation of the average regardless of rescue therapy. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dosing). The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and week 96 to 104

End point values	Roxadustat	Placebo
Number of subjects analysed	124	32
Units: g/dl
least squares mean (confidence interval 95%)	1.779 (1.60 to 1.96)	0.327 (0.01 to 0.64)

Change From Baseline to Average Hb Weeks 96-104

Statistical analysis description

A Mixed Model of Repeated Measures was applied using the visits up to week 104. The results were based on the estimated difference between the two treatment arms overall mean effect during week 96 to 104 period based on this MMRM model. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[47]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.452

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

1.8

Notes
[47] - LSM difference p-value is for test of differences.

Secondary: Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 28-36 Without Use of Rescue Therapy

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End point title

Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 28-36 Without Use of Rescue Therapy

End point description

The percentage of Hb values measured during weeks 28-36 within 10.0 -12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and week 28 to 36

End point values	Roxadustat	Placebo
Number of subjects analysed	311	139
Units: Percentage
arithmetic mean (standard deviation)	64.18 ( 32.90 )	34.20 ( 39.47 )

No statistical analyses for this end point

Secondary: Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 44-52 Without Use of Rescue Therapy

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End point title

Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 44-52 Without Use of Rescue Therapy

End point description

The percentage of Hb values measured during weeks 44-52 with values within 10.0 - 12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and week 44 to 52

End point values	Roxadustat	Placebo
Number of subjects analysed	287	118
Units: Percentage
arithmetic mean (standard deviation)	69.39 ( 32.47 )	35.45 ( 41.75 )

No statistical analyses for this end point

Secondary: Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 96-104 Without Use of Rescue Therapy

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End point title

Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 96-104 Without Use of Rescue Therapy

End point description

The percentage of Hb values measured during weeks 96-104 within 10.0 -12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and week 96 to 104

End point values	Roxadustat	Placebo
Number of subjects analysed	120	32
Units: Percentage
arithmetic mean (standard deviation)	64.65 ( 37.16 )	40.63 ( 44.39 )

No statistical analyses for this end point

Secondary: Time to First Hospitalization

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End point title

Time to First Hospitalization

End point description

Time to first hospitalization was defined in years as the First event date during the Efficacy Emergent Period – (Analysis date of first dose intake +1)/365.25. The first event date was defined as the Date of first admission. The Efficacy Emergent Period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occured first. Analysis date of first dose intake was defined as the date of first study drug intake collected on day 1 visit. For participants who experienced more than one hospitalization, only their first event following study treatment was used. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. Data for Year 2 roxadustat could not be calculated and is denoted as "99999" as applicable. The analysis population was the FAS.

End point type

Secondary

End point timeframe

Baseline up to week 104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5	32.2 (27.3 to 37.0)	39.8 (32.7 to 46.9)
Year 1	49.9 (44.6 to 55.2)	49.3 (41.8 to 56.8)
Year 1.5	62.1 (56.3 to 67.9)	64.0 (54.5 to 73.4)
Year 2	99999 (99999 to 99999)	67.8 (57.9 to 77.7)

Time to First Hospitalization

Statistical analysis description

Hazard ratio was calculated using stratified Cox Proportional Hazards Regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.643

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.945

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

1.2

Secondary: Number of Days of Hospitalization Per Patient Exposure Year (PEY)

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End point title

Number of Days of Hospitalization Per Patient Exposure Year (PEY)

End point description

The sum of the durations of all hospitalizations in days was adjusted for the duration of exposure. Derived only for participants with at least one hospitalization. The number of days of hospitalization per PEY was calculated as the sum of the durations of all hospitalizations in days [Minimum (Date of discharge, End of Efficacy Emergent Period) - Date of admission + 1] / [Duration of Efficacy Emergent Period in days / 365.25]. The analysis population was the FAS, which consisted of participants with hospitalizations. Participants can have more than one hospitalization.

End point type

Secondary

End point timeframe

Baseline up to week 104

End point values	Roxadustat	Placebo
Number of subjects analysed	214	101
Units: Number of days per year
arithmetic mean (standard deviation)	26.479 ( 35.182 )	31.928 ( 36.441 )

No statistical analyses for this end point

Secondary: Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis Stimulating Agent (ESA) Use, and Intravenous (IV) Iron) in the First 24 Weeks of Treatment

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End point title

Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis Stimulating Agent (ESA) Use, and Intravenous (IV) Iron) in the First 24 Weeks of Treatment

End point description

Time to first use of rescue therapy in years. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline up to week 24

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of participants
number (confidence interval 95%)
Week 6	0.8 (0.0 to 1.7)	6.0 (2.7 to 9.3)
Week 12	2.5 (0.9 to 4.1)	15.8 (10.7 to 20.9)
Week 18	3.3 (1.5 to 5.2)	25.3 (19.2 to 31.5)
Week 24	5.5 (3.1 to 7.9)	32.1 (25.4 to 38.7)

Time to Start Rescue Therapy Within First 24 Weeks

Statistical analysis description

Hazard ratio was calculated using stratified Cox Proportional Hazards Regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.139

Confidence interval

level

95%

sides

2-sided

lower limit

0.08

upper limit

0.23

Secondary: Time to First Use of RBC Transfusions

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End point title

Time to First Use of RBC Transfusions

End point description

Time to First Use of RBC Transfusions during efficacy emergent period. For participants who have experienced more than one RBC transfusion, only their first event following study treatment was used. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occurred first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline to week 104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5	2.9 (1.1 to 4.7)	15.2 (10.1 to 20.4)
Year 1	5.6 (3.0 to 8.1)	20.2 (14.2 to 26.2)
Year 1.5	12.1 (7.7 to 16.5)	21.8 (15.1 to 28.5)
Year 2	15.0 (9.9 to 20.1)	27.0 (17.7 to 36.4)

Time To First Use of RBS Transfusions

Statistical analysis description

Hazard ratio was calculated using stratified Cox Proportional Hazards Regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.343

Confidence interval

level

95%

sides

2-sided

lower limit

0.21

upper limit

0.55

Secondary: Mean Monthly Number of RBC Packs

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End point title

Mean Monthly Number of RBC Packs

End point description

During efficacy emergent period, the mean monthly number of RBC packs was calculated as the sum of units transfused between the first dose and up to the last dose in the period divided by duration of efficacy emergent period (in days) divided by 28 days. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occured first. In case of missing number of packs, values were estimated based on 1 unit for packed cells = 250 mL or 1 unit for whole blood = 500 mL. Participants without RBC transfusion were included with a value of zero. No estimation if values were missing. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline to week 104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: RBC Packs per 28 days
arithmetic mean (standard deviation)	0.041 ( 0.397 )	0.089 ( 0.243 )

Mean Monthly Number of RBC Packs

Statistical analysis description

The Analysis of Covariance (ANCOVA) model was applied including treatment as fixed factor, region and history of CV disease as class factors and baseline Hb, baseline eGFR as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.128

Method

ANCOVA

Parameter type

Least squares mean difference

Point estimate

-0.045

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.01

Secondary: Mean Monthly Volume of Blood transfused

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End point title

Mean Monthly Volume of Blood transfused

End point description

During efficacy emergent period, the mean monthly volume of blood transfused was calculated as the sum of blood volume transfused between the first dose and up to the la st dose in the period divide d by duration of efficacy emergent period (in days) divide d by 28 days. The efficacy emergent period was define d a s the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, which ever occurred first. The mean monthly volume transfused was calculated as the sum of the volume transfused between the first dose and up to the last dose in the period divided by duration (in days) and multiplied by 28 days. Participants without RBC transfusion were included with a value of zero. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline to week 104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Milliliters (ml) per 28 days
arithmetic mean (standard deviation)	11.331 ( 106.624 )	22.596 ( 60.666 )

Mean Monthly Volume of Blood Transfused

Statistical analysis description

The Analysis of Covariance (ANCOVA) model was applied included treatment arm, region, CV history as categorical variables and baseline Hb and baseline eGFR as continuous variables.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.183

Method

ANCOVA

Parameter type

Least squares mean difference

Point estimate

-10.429

Confidence interval

level

95%

sides

2-sided

lower limit

-25.81

upper limit

4.95

Secondary: Time to First Use of ESA Rescue Therapy

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End point title

Time to First Use of ESA Rescue Therapy

End point description

Time to First Use of ESA Rescue Therapy during efficacy emergent period. For participants with use of ESA, the time to first use of ESA was calculated as (First event date – Analysis date of first dose intake + 1) / 365.25. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occurred first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. Participants without ESA rescue were censored at the end of treatment. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline to week 104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5	1.8 (0.4 to 3.2)	20.4 (14.5 to 26.3)
Year 1	4.8 (2.4 to 7.2)	36.4 (28.9 to 43.9)
Year 1.5	6.0 (3.1 to 8.9)	42.3 (33.9 to 50.8)
Year 2	6.7 (3.5 to 9.9)	42.3 (33.9 to 50.8)

Time to First Use of ESA Rescue Therapy

Statistical analysis description

Hazard ratio was calculated using stratified Cox Proportional Hazards Regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.101

Confidence interval

level

95%

sides

2-sided

lower limit

0.06

upper limit

0.17

Secondary: Time to First Use of IV Iron

Top of page

End point title

Time to First Use of IV Iron

End point description

Time to first use of IV iron during efficacy emergent period in years. For participants with use of IV iron, the time to first use of IV iron was calculated as (First event date – Analysis date of first dose intake + 1) / 365.25. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occurred first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline to week 104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5	2.3 (0.7 to 3.9)	6.2 (2.7 to 9.8)
Year 1	5.3 (2.8 to 7.8)	9.4 (4.8 to 14.0)
Year 1.5	7.5 (4.3 to 10.7)	10.7 (5.5 to 15.9)
Year 2	10.6 (6.3 to 14.8)	19.1 (8.8 to 29.5)

Time to First Use of IV Iron Supplementation

Statistical analysis description

Hazard Ratio was calculated using stratified Cox Proportional Hazards Regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.045

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.538

Confidence interval

level

95%

sides

2-sided

lower limit

0.29

upper limit

0.99

Secondary: Change From BL to Each Post-Dosing Visit in Total Cholesterol

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End point title

Change From BL to Each Post-Dosing Visit in Total Cholesterol

End point description

Change from baseline to each planned assessment for total cholesterol is reported. Baseline was defined as the value on day 1. If the value was missing, the latest value prior to first study drug administration was used. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 4,8,12,20,28,36,44,52,68,84,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: mmol/L
arithmetic mean (standard deviation)
Week 4 [N=368,194]	-1.151 ( 1.058 )	0.108 ( 0.842 )
Week 8 [N=348,191]	-1.066 ( 1.086 )	0.048 ( 0.932 )
Week 12 [N=342,185]	-0.836 ( 1.173 )	0.088 ( 1.116 )
Week 20 [N=323,167]	-0.747 ( 1.227 )	0.193 ( 1.129 )
Week 28 [N=310,149]	-0.816 ( 1.284 )	0.201 ( 1.271 )
Week 36 [N=295,133]	-0.803 ( 1.300 )	0.183 ( 1.174 )
Week 44 [N=285,126]	-0.854 ( 1.238 )	0.077 ( 1.346 )
Week 52 [N=278,120]	-0.815 ( 1.314 )	0.104 ( 1.304 )
Week 68 [N=197,67]	-0.971 ( 1.382 )	0.188 ( 1.222 )
Week 84 [N=154,43]	-1.055 ( 1.554 )	0.102 ( 1.284 )
Week 104 [N=123,32]	-0.944 ( 1.584 )	0.218 ( 1.067 )

No statistical analyses for this end point

Secondary: Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio

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End point title

Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio

End point description

Change from baseline to each planned assessment for LDL/HDL ratio is reported. Baseline was defined as the value on Day 1. If this value was missing, the latest value prior to first study drug administration was used. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 4,8,12,20,28,36,44,52,68,84,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Ratio
arithmetic mean (standard deviation)
Week 4 [N=367,193]	-0.331 ( 0.777 )	0.076 ( 0.635 )
Week 8 [N=347,190]	-0.374 ( 0.952 )	0.068 ( 0.685 )
Week 12 [N=341,185]	-0.268 ( 0.905 )	0.081 ( 0.915 )
Week 20 [N=322,166]	-0.250 ( 1.024 )	0.155 ( 0.788 )
Week 28 [N=309,149]	-0.313 ( 1.057 )	0.156 ( 0.861 )
Week 36 [N=293,133]	-0.349 ( 1.040 )	0.157 ( 1.053 )
Week 44 [N=283,126]	-0.368 ( 1.099 )	0.099 ( 1.198 )
Week 52 [N=277,120]	-0.429 ( 1.125 )	0.019 ( 1.076 )
Week 68 [N=196,67]	-0.466 ( 1.219 )	0.052 ( 0.955 )
Week 84 [N=154,43]	-0.509 ( 1.307 )	0.114 ( 1.113 )
Week 104 [N=122,32]	-0.414 ( 1.306 )	0.105 ( 0.873 )

No statistical analyses for this end point

Secondary: Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol

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End point title

Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol

End point description

Change from baseline to each planned assessment for non-HDL is reported. Baseline was defined as the value on day 1. If this value was missing, the latest value prior to first study drug administration was used. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 4,8,12,20,28,36,44,52,68,84,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: mmol/L
arithmetic mean (standard deviation)
Week 4 [N=367,193]	-0.969 ( 0.989 )	0.118 ( 0.789 )
Week 8 [N=347,190]	-0.909 ( 1.064 )	0.070 ( 0.864 )
Week 12 [N=341,185]	-0.709 ( 1.107 )	0.078 ( 1.050 )
Week 20 [N=322,166]	-0.638 ( 1.175 )	0.186 ( 1.072 )
Week 28 [N=309,149]	-0.710 ( 1.227 )	0.206 ( 1.227 )
Week 36 [N=293,133]	-0.711 ( 1.239 )	0.202 ( 1.133 )
Week 44 [N=283,125]	-0.751 ( 1.190 )	0.106 ( 1.342 )
Week 52 [N=277,120]	-0.751 ( 1.276 )	0.104 ( 1.299 )
Week 68 [N=196,67]	-0.882 ( 1.325 )	0.174 ( 1.187 )
Week 84 [N=154,43]	-0.939 ( 1.518 )	0.089 ( 1.343 )
Week 104 [N=123,32]	-0.839 ( 1.554 )	0.174 ( 1.014 )

No statistical analyses for this end point

Secondary: Change From BL to Each Post-Dosing Visit in Apolipoproteins A1

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End point title

Change From BL to Each Post-Dosing Visit in Apolipoproteins A1

End point description

Change from baseline to each planned assessment for apolipoproteins A1 is reported. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 4,8,12,20,28,36,44,52,68,84,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: g/L
arithmetic mean (standard deviation)
Apolipoprotein A1 Week 4 [N=183,102]	-0.168 ( 0.232 )	0.013 ( 0.190 )
Apolipoprotein A1 Week 8 [N=174,102]	-0.148 ( 0.229 )	0.008 ( 0.227 )
Apolipoprotein A1 Week 12 [N=170,97]	-0.072 ( 0.723 )	0.004 ( 0.203 )
Apolipoprotein A1 Week 20 [N=158,90]	-0.114 ( 0.245 )	0.036 ( 0.222 )
Apolipoprotein A1 Week 28 [N=134,67]	-0.104 ( 0.265 )	0.006 ( 0.233 )
Apolipoprotein A1 Week 36 [N=149,77]	-0.101 ( 0.252 )	0.002 ( 0.223 )
Apolipoprotein A1 Week 44 [N=140,72]	-0.135 ( 0.259 )	-0.013 ( 0.268 )
Apolipoprotein A1 Week 52 [N=139,71]	-0.090 ( 0.260 )	-0.028 ( 0.248 )
Apolipoprotein A1 Week 68 [N=63,28]	-0.157 ( 0.310 )	0.018 ( 0.204 )
Apolipoprotein A1 Week 84 [N=30,12]	-0.132 ( 0.282 )	0.060 ( 0.196 )
Apolipoprotein A1 Week 104 [N=12,4]	-0.098 ( 0.227 )	0.070 ( 0.136 )

No statistical analyses for this end point

Secondary: Change From BL to Each Post-Dosing Visit in Apolipoproteins B

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End point title

Change From BL to Each Post-Dosing Visit in Apolipoproteins B

End point description

Change from baseline to each planned assessment for apolipoproteins B is reported. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 4,8,12,20,28,36,44,52,68,84,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: mg/dL
arithmetic mean (standard deviation)
Apolipoproteins B Week 4 [N=183,102]	-19.891 ( 20.669 )	2.059 ( 22.220 )
Apolipoproteins B Week 8 [N=174,102]	-19.483 ( 21.009 )	2.059 ( 20.297 )
Apolipoproteins B Week 12 [N=170,97]	-14.935 ( 24.613 )	0.278 ( 21.707 )
Apolipoproteins B Week 20 [N=158,90]	-12.709 ( 24.424 )	5.711 ( 25.883 )
Apolipoproteins B Week 28 [N=133,67]	-13.782 ( 28.634 )	9.746 ( 26.864 )
Apolipoproteins B Week 36 [N=149,77]	-14.866 ( 25.469 )	6.623 ( 25.895 )
Apolipoproteins B Week 44 [N=140,72]	-15.593 ( 26.594 )	3.222 ( 30.771 )
Apolipoproteins B Week 52 [N=139,71]	-14.122 ( 27.503 )	4.676 ( 31.440 )
Apolipoproteins B Week 68 [N=63,28]	-18.746 ( 28.633 )	2.786 ( 28.900 )
Apolipoproteins B Week 84 [N=30,12]	-20.133 ( 28.134 )	12.500 ( 32.152 )
Apolipoproteins B Week 104 [N=12,4]	-10.917 ( 22.885 )	14.750 ( 20.271 )

No statistical analyses for this end point

Secondary: Change From BL to Each Post-Dosing Visit in Ratio Apolipoprotein ApoB/ApoA1

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End point title

Change From BL to Each Post-Dosing Visit in Ratio Apolipoprotein ApoB/ApoA1

End point description

Change from baseline to each planned assessment for ratio ApoB/ApoA1 is reported. Baseline was defined as the value on day 1. If this value was missing, the latest value prior to first study drug administration was used. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 4,8,12,20,28,36,44,52,68,84,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Ratio
arithmetic mean (standard deviation)
Week 4 [N=183,101]	-0.073 ( 0.165 )	0.010 ( 0.169 )
Week 8 [N=172,101]	-0.084 ( 0.202 )	0.000 ( 0.184 )
Week 12 [N=169,96]	-0.059 ( 0.164 )	-0.006 ( 0.201 )
Week 20 [N=158,89]	-0.043 ( 0.189 )	0.009 ( 0.198 )
Week 28 [N=133,66]	-0.066 ( 0.222 )	0.063 ( 0.205 )
Week 36 [N=149,76]	-0.070 ( 0.200 )	0.045 ( 0.213 )
Week 44 [N=140,71]	-0.053 ( 0.220 )	0.031 ( 0.265 )
Week 52 [N=137,70]	-0.065 ( 0.207 )	0.047 ( 0.266 )
Week 68 [N=63,28]	-0.086 ( 0.212 )	0.001 ( 0.184 )
Week 84 [N=29,12]	-0.066 ( 0.210 )	0.058 ( 0.295 )
Week 104 [N=12,4]	-0.024 ( 0.126 )	0.085 ( 0.132 )

No statistical analyses for this end point

Secondary: Percentage of Participants With Mean LDL Cholesterol <100 mg/dL Calculated Over Weeks 12 to 28

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End point title

Percentage of Participants With Mean LDL Cholesterol <100 mg/dL Calculated Over Weeks 12 to 28

End point description

Mean LDL cholesterol <100 mg/dL over weeks 12 to 28 was defined as a binary variable (Yes/No), where Yes was defined as mean LDL cholesterol <100 mg/dL over weeks 12 to 28. Participants without any LDL value within this duration were excluded. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Weeks 12-28

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of Participants
number (not applicable)
Yes (Regardless of fasting status)	62.9	41.1
No (Regardless of fasting status)	37.1	58.9

No statistical analyses for this end point

Secondary: Percentage of Participants Who Have Achieved Antihypertensive Treatment Goal in CKD Participants Over Weeks 12-28

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End point title

Percentage of Participants Who Have Achieved Antihypertensive Treatment Goal in CKD Participants Over Weeks 12-28

End point description

Occurrence of achieved antihypertensive treatment goal was defined as the average SBP < 130 mmHg and the average DBP < 80 mmHg over the period of weeks 12-28. Participants without any blood pressure measurement were excluded. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Weeks 12-28

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of Participants
number (not applicable)
Yes	25.6	28.0
No	74.4	72.0

No statistical analyses for this end point

Secondary: Change From BL to the Average Value of Weeks 12-28 in Quality of Life (QoL) SF-36 Physical Component Score (PCS)

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End point title

Change From BL to the Average Value of Weeks 12-28 in Quality of Life (QoL) SF-36 Physical Component Score (PCS)

End point description

The 36-Item short-form health survey (SF-36) is a multi-purpose survey with 36 questions. It provides an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. For each scale scores range from 0-100. The physical component score was calculated based on the results of the SF-36 scores. Higher scores indicate better health status. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 12-28

End point values	Roxadustat	Placebo
Number of subjects analysed	340	185
Units: Units on a Scale
least squares mean (confidence interval 95%)	1.842 (0.88 to 2.80)	1.468 (0.34 to 2.59)

Change from Baseline to Weeks 12-28 SF-36 PCS

Statistical analysis description

The Mixed Model of Repeated Measures included treatment, visit (week 8, week 12 and week 28), visit by treatment interaction, region and history of CV disease as fixed class factors and baseline SF-36 PCS, baseline Hb, baseline eGFR as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

525

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.475

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

0.374

Confidence interval

level

95%

sides

2-sided

lower limit

-0.65

upper limit

1.4

Secondary: Change From BL to the Average Value of Weeks 12-28 in Anemia Subscale (Ans) of Functional Assessment of Cancer Therapy (FACT-An) Score

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End point title

Change From BL to the Average Value of Weeks 12-28 in Anemia Subscale (Ans) of Functional Assessment of Cancer Therapy (FACT-An) Score

End point description

Baseline FACT-An AnS was defined as the FACT-An AnS value on Day 1. Together with the Functional Assessment of Cancer Therapy - General (FACT-G), the Anemia Subscale (AnS) is referred to as the FACT-An Total. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The Anemia AnS score range is 0 to 80. For the above score, a higher score indicates better QoL.

End point type

Secondary

End point timeframe

Baseline and weeks 12-28

End point values	Roxadustat	Placebo
Number of subjects analysed	339	185
Units: Units on a Scale
least squares mean (confidence interval 95%)	4.470 (2.86 to 6.08)	2.766 (0.91 to 4.62)

FACT-An Ans Change from Baseline to Weeks 12-28

Statistical analysis description

A Mixed Model of Repeated Measures was applied using the visits up to week 28. The model includes treatment, visit (week 8, week 12 and week 28), visit by treatment interaction, region and history of CV disease as fixed class factors and baseline FACT-An Ans, baseline Hb, baseline eGFR as continuous covariates. Baseline FACT-An Ans is defined as the FACT-An Ans value on day 1.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

524

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.047 ^[48]

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

1.704

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

3.38

Notes
[48] - LSM difference p-value is for test of differences

Secondary: Change From BL to the Average Value of Weeks 12-28 in Total FACT-An Score

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End point title

Change From BL to the Average Value of Weeks 12-28 in Total FACT-An Score

End point description

Baseline FACT-An Total Score was defined as the FACT-An Total score on Day 1. Total Fact-An score is composed of FACT-G and Ans scales. FACT-G contains 27 items that cover four dimensions of well-being: physical (PWB) - 7 items, functional (FWB) - 7 items, social/family (SWB) - 7 items, and emotional (EWB) - 6 items. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The total score is obtained by summation of the scores from PWB, SWB, EWB, FWB and AnS. The FACT-An Total Score scale range is 0-188. A higher score indicates better QoL.

End point type

Secondary

End point timeframe

Baseline and weeks 12-28

End point values	Roxadustat	Placebo
Number of subjects analysed	338	185
Units: Units on a Scale
least squares mean (confidence interval 95%)	5.777 (2.60 to 8.95)	3.691 (0.01 to 7.37)

Total FACT-An Score Change from BL to Average

Statistical analysis description

A Mixed Model of Repeated Measures was applied using the visits up to week 28. The results were based on the estimated difference between the two treatment arms overall mean effect during week 12 to 28 period based on this MMRM model.The model includes treatment, visit (week8, week12 and week28), visit by treatment interaction, region and history of CV disease as fixed class factors and baseline FACT-An Total Score, baseline Hb, baseline eGFR as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

523

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.225

Method

Mixed models analysis

Parameter type

Least squares mean difference

Point estimate

2.086

Confidence interval

level

95%

sides

2-sided

lower limit

-1.29

upper limit

5.46

Secondary: Change From BL to the Average Value of Weeks 12-28 The Euroqol Questionnaire – 5 Dimensions 5 Levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score

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End point title

Change From BL to the Average Value of Weeks 12-28 The Euroqol Questionnaire – 5 Dimensions 5 Levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score

End point description

The Euroqol Questionnaire – 5 Dimensions 5 Levels (EQ-5D 5L) is a self-reported questionnaire. The EQ-5D is used as a measure of respondents' Health Related Quality of Life (HRQoL). The EQ- 5D consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D descriptive system comprises of 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, extreme problems. The VAS records the respondent's self-rated health status on a graduated (0–100) scale, where the answers are labeled ‘Best imaginable health state’ and ‘Worst imaginable health state’ with higher scores for higher HRQoL. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 12-28

End point values	Roxadustat	Placebo
Number of subjects analysed	340	184
Units: Units on a Scale
arithmetic mean (standard deviation)
Average in week 12-28	5.390 ( 17.278 )	0.990 ( 15.859 )

No statistical analyses for this end point

Secondary: Change From BL to the Average Value of Weeks 12-28 in Overall Work Impairment Due to Anaemic Symptoms

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End point title

Change From BL to the Average Value of Weeks 12-28 in Overall Work Impairment Due to Anaemic Symptoms

End point description

Work productivity and activity impairment: anemic symptoms (WPAI:ANS) questionnaire version 2 was used to measure work and activity impairment during the last seven days due to anemia. It is self-assessed questionnaire which consists of 6 questions covering work and daily activities. Questions include asking if participant is working, how many hours the person missed work due to anemic symptoms, how many hours the person missed work due to other reasons, how many hours participant actually worked and how the anemic symptoms impacted their productivity and ability to do daily activities. For the last 2 questions, they were scored from 0-10 with 0 identifying no effect on work and 10 completely prevented from working. Overall work impairment due to ANS was calculated as 100 x Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)]. Scores were calculated with the formula to derive the overall work impairment on each timepoints in percentage, and then changes of the percentage from baseline are reported.

End point type

Secondary

End point timeframe

Baseline and weeks 12 and 28

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of work impairment
arithmetic mean (standard deviation)
Average in week 12-28	-5.965 ( 21.856 )	-4.230 ( 23.679 )

No statistical analyses for this end point

Secondary: Percentage of Participants in Each Category in Patients’ Global Impression of Change (PGIC)

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End point title

Percentage of Participants in Each Category in Patients’ Global Impression of Change (PGIC)

End point description

The Patients' Global Impression of Change (PGIC) is a participant rated instrument that measures change in participants overall status on a 7-point scale ranging from 1 (very much improved) t0 7 (very much worse).' The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Weeks 12 and 28

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of Participants
number (not applicable)
Week 12 [Very much improved + Much improved]	41.2	18.9
Week 28 [Very much improved + Much improved]	46.4	28.6

No statistical analyses for this end point

Secondary: Change From BL to Each Study Visit in Serum Hepcidin

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End point title

Change From BL to Each Study Visit in Serum Hepcidin

End point description

Baseline was assessed on Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 4,12,20,36,52,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: ug/L
arithmetic mean (standard deviation)
Week 4 [N=345,182]	-19.835 ( 29.765 )	1.748 ( 35.368 )
Week 12 [N=323,171]	-17.369 ( 31.572 )	0.971 ( 33.952 )
Week 20 [N=303,148]	-10.684 ( 35.858 )	-1.879 ( 30.661 )
Week 36 [N=218,98]	-12.981 ( 32.351 )	0.803 ( 39.816 )
Week 52 [N=268,114]	-12.274 ( 37.445 )	2.025 ( 40.678 )
Week 104 [N=108,28]	-10.051 ( 33.671 )	-7.436 ( 22.923 )

No statistical analyses for this end point

Secondary: Change From BL to Each Study Visit in Serum Ferritin

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End point title

Change From BL to Each Study Visit in Serum Ferritin

End point description

End point type

Secondary

End point timeframe

Baseline and weeks 4,8,12,20,28,36,44,52,60, 68,76, 84,92,100,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: pmol/L
arithmetic mean (standard deviation)
Week 4 [N=360,192]	-221.827 ( 248.902 )	11.564 ( 335.096 )
Week 8 [N=346,191]	-247.955 ( 295.920 )	-8.004 ( 252.615 )
Week 12 [N=337,179]	-265.818 ( 318.445 )	-31.548 ( 257.410 )
Week 20 [N=318,154]	-198.349 ( 284.015 )	-32.561 ( 320.382 )
Week 28 [N=308,146]	-184.501 ( 341.114 )	-5.123 ( 470.691 )
Week 36 [N=295,132]	-142.876 ( 608.677 )	36.005 ( 538.357 )
Week 44 [N=287,124]	-137.151 ( 352.715 )	57.373 ( 594.125 )
Week 52 [N=276,118]	-164.009 ( 564.396 )	93.245 ( 640.998 )
Week 60 [N=200,70]	-133.499 ( 467.931 )	-18.833 ( 441.131 )
Week 68 [N=177,50]	-159.906 ( 453.802 )	39.794 ( 581.616 )
Week 76 [N=160,47]	-149.226 ( 408.126 )	25.291 ( 627.834 )
Week 84 [N=149,38]	-103.284 ( 530.021 )	93.647 ( 753.265 )
Week 92 [N=132,32]	-106.070 ( 464.192 )	1.011 ( 474.434 )
Week 100 [N=127,30]	-119.647 ( 452.209 )	30.829 ( 514.823 )
Week 104 [N=112,30]	-107.814 ( 458.702 )	4.524 ( 475.524 )

No statistical analyses for this end point

Secondary: Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT)

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End point title

Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT)

End point description

End point type

Secondary

End point timeframe

Baseline and weeks 4,8,12,20,28,36,44,52,60, 68,76, 84,92,100,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage
arithmetic mean (standard deviation)
Week 4 [N=357,190]	-7.4 ( 11.7 )	0.7 ( 11.4 )
Week 8 [N=344,191]	-5.7 ( 11.7 )	-0.4 ( 13.0 )
Week 12 [N=334,181]	-4.6 ( 13.5 )	-0.7 ( 11.5 )
Week 20 [N=317,152]	-1.1 ( 13.4 )	-0.3 ( 11.5 )
Week 28 [N=306,145]	-1.8 ( 13.8 )	0.8 ( 13.2 )
Week 36 [N=292,127]	-1.6 ( 13.6 )	1.1 ( 14.6 )
Week 44 [N=281,123]	-0.2 ( 14.0 )	1.0 ( 16.0 )
Week 52 [N=275,115]	-0.7 ( 13.6 )	0.0 ( 16.3 )
Week 60 [N=198,68]	-0.6 ( 14.1 )	-2.7 ( 13.9 )
Week 68 [N=177,49]	-2.2 ( 13.1 )	-3.3 ( 12.3 )
Week 76 [N=158,44]	-2.6 ( 13.8 )	-1.7 ( 13.9 )
Week 84 [N=148,35]	-3.4 ( 13.3 )	-3.6 ( 13.8 )
Week 92 [N=131,31]	-1.9 ( 13.2 )	-1.8 ( 12.8 )
Week 100 [N=125,29]	0.0 ( 13.4 )	0.7 ( 12.0 )
Week 104 [N=112,29]	-0.4 ( 12.6 )	0.0 ( 12.3 )

No statistical analyses for this end point

Secondary: Change From BL to Each Study Visit in Serum HbA1c Level

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End point title

Change From BL to Each Study Visit in Serum HbA1c Level

End point description

HbA1c was measured at each timepoint and presented in ‘fraction of 1’ unit by dividing the values in percentage by 100, in order to fit for CDISC (Clinical Data Interchange Standards Consortium) standard terminology. Changes from baseline to each timepoint were reported in unit ‘fraction of 1’. Baseline was assessed on Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

End point type

Secondary

End point timeframe

Baseline and weeks 12,28,36,44,60,84,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Fraction of 1
arithmetic mean (standard deviation)
Week 12 [N=338,182]	0.0007 ( 0.0064 )	-0.0001 ( 0.0061 )
Week 28 [N=304,145]	0.0006 ( 0.0086 )	0.0008 ( 0.0091 )
Week 36 [N=225,108]	0.0011 ( 0.0098 )	0.0007 ( 0.0075 )
Week 44 [N=282,125]	0.0018 ( 0.0081 )	-0.0002 ( 0.0074 )
Week 60 [N=200,70]	0.0009 ( 0.0073 )	0.0012 ( 0.0080 )
Week 84 [N=147,38]	0.0028 ( 0.0085 )	0.0022 ( 0.0111 )
Week 104 [N=111,29]	0.0014 ( 0.0073 )	0.0004 ( 0.0059 )

No statistical analyses for this end point

Secondary: Change From BL to Each Study Visit in Fasting Blood Glucose

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End point title

Change From BL to Each Study Visit in Fasting Blood Glucose

End point description

End point type

Secondary

End point timeframe

Baseline and weeks 4,8,12,20,28,36,44,52,60, 68,76,84,92,100,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: mmol/L
arithmetic mean (standard deviation)
Week 4 [N=241,134]	0.107 ( 2.573 )	-0.076 ( 2.730 )
Week 8 [N=233,128]	-0.103 ( 3.179 )	-0.162 ( 3.118 )
Week 12 [N=223,118]	-0.100 ( 3.504 )	-0.153 ( 4.629 )
Week 20 [N=211,99]	-0.302 ( 4.052 )	0.523 ( 2.981 )
Week 28 [N=199,95]	0.160 ( 3.489 )	0.045 ( 3.281 )
Week 36 [N=185,83]	0.015 ( 2.991 )	-0.117 ( 2.812 )
Week 44 [N=167,76]	0.073 ( 2.683 )	0.801 ( 3.416 )
Week 52 [N=168,79]	0.048 ( 4.348 )	-0.086 ( 4.883 )
Week 60 [N=116,47]	0.130 ( 2.907 )	1.190 ( 3.946 )
Week 68 [N=91,33]	0.185 ( 2.831 )	0.698 ( 3.386 )
Week 76 [N=81,28]	-0.015 ( 2.031 )	-0.671 ( 5.148 )
Week 84 [N=75,20]	0.495 ( 3.117 )	0.435 ( 2.037 )
Week 92 [N=65,19]	0.612 ( 2.494 )	-0.861 ( 3.298 )
Week 100 [N=58,19]	0.405 ( 2.932 )	-0.699 ( 2.161 )
Week 104 [N=59,20]	0.125 ( 2.633 )	0.237 ( 3.938 )

No statistical analyses for this end point

Secondary: Change From BL to Each Study Visit in Albumin/Creatinine Ratio in Urine

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End point title

Change From BL to Each Study Visit in Albumin/Creatinine Ratio in Urine

End point description

Baseline assessment was the assessment from day 1 visit. If baseline value was missing, value from screening visit was used. In case of missing data, no imputation rules were applied. To compute the geometric mean of albumin/creatinine ratio in urine and associated 95% CI, the mean of log-transformed albumin/creatinine ratio in urine values (ratio) and associated 95% CI are back-transformed to the raw scale. All assessments collected after initiation of dialysis (acute or chronic) were excluded from the analysis. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 12,24,36,52,64,76,88,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Ratio
geometric mean (confidence interval 95%)
Week 12 [N=122,75]	1.08 (0.96 to 1.20)	1.06 (0.84 to 1.34)
Week 24 [N=103,53]	1.19 (1.04 to 1.36)	1.16 (0.89 to 1.53)
Week 36 [N=90,49]	1.21 (1.04 to 1.41)	1.04 (0.77 to 1.40)
Week 52 [N=74,38]	1.28 (1.02 to 1.59)	1.04 (0.72 to 1.51)
Week 64 [N=22,11]	1.25 (0.84 to 1.87)	0.96 (0.53 to 1.71)
Week 76 [N=14,10]	1.12 (0.51 to 2.44)	0.82 (0.41 to 1.65)
Week 88 [N=11,2]	1.10 (0.38 to 3.17)	0.51 (0.27 to 0.97)
Week 104 [N=4,2]	1.92 (0.75 to 4.89)	0.38 (0.08 to 1.88)

No statistical analyses for this end point

Secondary: Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio

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End point title

Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio

End point description

Baseline assessment was the assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied. To compute the geometric mean of serum Cr (ratio) and associated 95% CI, the mean of log-transformed serum Cr (ratio) values and associated 95% CI are back-transformed to the raw scale. All assessments collected after initiation of dialysis (acute or chronic) were excluded from the analysis. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.

End point type

Secondary

End point timeframe

Baseline and weeks 4,8,12,20,28,36,44,52,60, 68,76,84,92,100,104

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Ratio
geometric mean (confidence interval 95%)
Week 4 [N=355,188]	1.01 (1.00 to 1.03)	1.05 (1.03 to 1.07)
Week 8 [N=338,184]	1.03 (1.01 to 1.05)	1.07 (1.04 to 1.09)
Week 12 [N=323,169]	1.04 (1.02 to 1.06)	1.07 (1.04 to 1.11)
Week 20 [N=289,135]	1.08 (1.06 to 1.12)	1.09 (1.05 to 1.13)
Week 28 [N=267,124]	1.12 (1.08 to 1.16)	1.13 (1.08 to 1.17)
Week 36 [N=238,108]	1.12 (1.08 to 1.16)	1.12 (1.07 to 1.18)
Week 44 [N=216,99]	1.12 (1.07 to 1.16)	1.16 (1.10 to 1.22)
Week 52 [N=201,90]	1.12 (1.07 to 1.16)	1.15 (1.09 to 1.22)
Week 60 [N=135,52]	1.09 (1.05 to 1.14)	1.15 (1.07 to 1.23)
Week 68 [N=117,36]	1.11 (1.06 to 1.17)	1.24 (1.13 to 1.37)
Week 76 [N=102,33]	1.13 (1.07 to 1.20)	1.23 (1.12 to 1.36)
Week 84 [N=94,26]	1.13 (1.07 to 1.20)	1.19 (1.05 to 1.35)
Week 92 [N=83,24]	1.19 (1.12 to 1.27)	1.22 (1.05 to 1.41)
Week 100 [N=75,22]	1.16 (1.08 to 1.24)	1.26 (1.06 to 1.50)
Week 104 [N=66,23]	1.16 (1.05 to 1.27)	1.28 (1.09 to 1.51)

No statistical analyses for this end point

Secondary: Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline

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End point title

Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline

End point description

The endpoint was defined as time to doubling serum creatinine or chronic dialysis or renal transplant what ever came first. Time to event was defined as (First event date – Analysis date of first dose intake + 1) / 365.25. First event date was defined as date of dialysis or date of renal transplant (whichever occurred first) and analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1 visit. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment. The data evaluated until the safety emergent period, which was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose, and results were presented for every 6 months up to 2 years.

End point type

Secondary

End point timeframe

Baseline and year 0.5, year 1, year 1.5 and year 2

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of participants
number (confidence interval 95%)
Years 0.5	17.4 (13.4 to 21.4)	17.8 (12.3 to 23.4)
Years 1	36.8 (31.6 to 42.1)	35.4 (27.9 to 42.9)
Years 1.5	47.3 (41.4 to 53.1)	48.2 (38.6 to 57.8)
Years 2	55.0 (48.5 to 61.4)	54.7 (43.8 to 65.6)

Time to Doubling of Serum Creatinine

Statistical analysis description

Hazard ratio was calculated using stratified Cox Proportional Hazards Regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.973

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.995

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.32

Secondary: Time to Chronic Kidney Disease (CKD) Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death)

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End point title

Time to Chronic Kidney Disease (CKD) Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death)

End point description

CKD progression was defined as occurrence of chronic dialysis or renal transplant or doubled serum creatinine or death. The time to CKD progression was calculated (in years) as (First event date – Analysis date of first dose intake + 1) / 365.25. First event date was defined as first occurrence of any of the CKD progression, whichever occurred first. Analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1 visit. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment. The data evaluated until the safety emergent period, which was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose, and results were presented for every 6 months up to 2 years.

End point type

Secondary

End point timeframe

Baseline and year 0.5, year 1, year 1.5 and year 2

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of participants
number (confidence interval 95%)
Years 0.5	20.5 (16.3 to 24.7)	20.0 (14.2 to 25.8)
Years 1	40.3 (35.1 to 45.5)	38.3 (30.7 to 45.8)
Years 1.5	50.2 (44.5 to 55.9)	50.5 (41.1 to 59.9)
Years 2	58.9 (52.7 to 65.1)	61.1 (50.5 to 71.7)

Time to CKD Progression

Statistical analysis description

Hazard ratio was calculated using stratified Cox Proportional Hazards Regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.972

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.995

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.3

Secondary: Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant

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End point title

Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant

End point description

All eGFR values collected during the safety emergent period are considered, excluding those collected on or after initiation of dialysis (acute or chronic). The First event date was defined as First occurrence of 40% decrease in eGFR from baseline, first occurrence of chronic dialysis or renal transplant (whichever occurred first and Analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1 visit. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment. The data evaluated until the safety emergent period, which was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose, and results were presented for every 6 months up to 2 years.

End point type

Secondary

End point timeframe

Baseline and year 0.5, year 1, year 1.5 and year 2

End point values	Roxadustat	Placebo
Number of subjects analysed	389	203
Units: Percentage of participants
number (confidence interval 95%)
Years 0.5	20.7 (16.5 to 25.0)	22.3 (16.2 to 28.4)
Years 1	44.4 (39.0 to 49.8)	44.0 (36.2 to 51.7)
Years 1.5	54.6 (48.9 to 60.4)	62.8 (53.2 to 72.5)
Years 2	64.5 (64.5 to 70.7)	67.0 (56.8 to 77.1)

Time to at Least 40% Decrease in eGFR from BL

Statistical analysis description

Hazard ratio was calculated using stratified Cox Proportional Hazards Regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates.

Comparison groups

Roxadustat v Placebo

Number of subjects included in analysis

592

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.439

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.905

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.16

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks), and up to 2.836 years at maximum for all-cause mortality

Adverse event reporting additional description

The safety emergent period was defined as the period from date of first drug intake up to 28 days after the analysis last dose. All-cause mortality was monitored at any time after first administration of study drug to the end of the post-study follow-up, which includes deaths reported after the 28-day follow-up after the last dose.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Roxadustat

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Roxadustat	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	241 / 391 (61.64%)	115 / 203 (56.65%)
number of deaths (all causes)	45	20
number of deaths resulting from adverse events	40	19
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lipoma
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Metastases to the mediastinum
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Metastatic carcinoma of the bladder
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Myelodysplastic syndrome
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Aortic stenosis
subjects affected / exposed	2 / 391 (0.51%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Blood pressure inadequately controlled
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	4 / 391 (1.02%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic vascular disorder
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Extremity necrosis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	4 / 391 (1.02%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	1 / 4	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Hypertensive crisis
subjects affected / exposed	4 / 391 (1.02%)	5 / 203 (2.46%)
occurrences causally related to treatment / all	0 / 4	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Hospitalisation
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leg amputation
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 391 (0.26%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site haemorrhage
subjects affected / exposed	0 / 391 (0.00%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	4 / 391 (1.02%)	3 / 203 (1.48%)
occurrences causally related to treatment / all	1 / 4	0 / 3
deaths causally related to treatment / all	1 / 4	0 / 3
Gait disturbance
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 391 (0.26%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2
Non-cardiac chest pain
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	0 / 391 (0.00%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Sudden death
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Immune system disorders
Allergy to arthropod bite
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metrorrhagia
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian cyst torsion
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	2 / 391 (0.51%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Acute respiratory distress syndrome
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 391 (0.51%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hydrothorax
subjects affected / exposed	0 / 391 (0.00%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	3 / 391 (0.77%)	3 / 203 (1.48%)
occurrences causally related to treatment / all	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 391 (0.77%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	2 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Pulmonary hypertension
subjects affected / exposed	3 / 391 (0.77%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	3 / 391 (0.77%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	1 / 3	0 / 2
deaths causally related to treatment / all	1 / 1	0 / 0
Respiratory disorder
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory failure
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Disorientation
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device malfunction
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic mass
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Steatohepatitis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Blood bilirubin increased
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Blood urea increased
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerular filtration rate decreased
subjects affected / exposed	21 / 391 (5.37%)	11 / 203 (5.42%)
occurrences causally related to treatment / all	0 / 23	1 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Arterial injury
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site complication
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula thrombosis
subjects affected / exposed	14 / 391 (3.58%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	5 / 17	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	3 / 391 (0.77%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Facial bones fracture
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fat embolism
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	4 / 391 (1.02%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative wound complication
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pubis fracture
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Congenital cystic kidney disease
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute left ventricular failure
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Acute myocardial infarction
subjects affected / exposed	6 / 391 (1.53%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	1 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Atrial fibrillation
subjects affected / exposed	3 / 391 (0.77%)	3 / 203 (1.48%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	3 / 391 (0.77%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0
Cardiac failure
subjects affected / exposed	3 / 391 (0.77%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac failure chronic
subjects affected / exposed	3 / 391 (0.77%)	3 / 203 (1.48%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure congestive
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiogenic shock
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiopulmonary failure
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 391 (0.26%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	8 / 391 (2.05%)	3 / 203 (1.48%)
occurrences causally related to treatment / all	5 / 8	0 / 3
deaths causally related to treatment / all	1 / 1	0 / 2
Myocardial ischaemia
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	5 / 391 (1.28%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Dementia
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic neuropathy
subjects affected / exposed	0 / 391 (0.00%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	2 / 391 (0.51%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 1
Headache
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive encephalopathy
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemic coma
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	4 / 391 (1.02%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	1 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myasthenic syndrome
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	3 / 391 (0.77%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular encephalopathy
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	8 / 391 (2.05%)	7 / 203 (3.45%)
occurrences causally related to treatment / all	0 / 10	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic anaemia
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Heparin-induced thrombocytopenia
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenopathy mediastinal
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrogenic anaemia
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Macular hole
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ulcerative keratitis
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic gastroparesis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	3 / 391 (0.77%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gastric ulcer
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer perforation
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Gastritis
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis erosive
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic erosive gastritis
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Large intestinal ulcer
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	3 / 391 (0.77%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	3 / 391 (0.77%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis chronic
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	3 / 391 (0.77%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic foot
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eczema nummular
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Panniculitis
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pruritus
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Toxic skin eruption
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 391 (0.26%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Acute prerenal failure
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Azotaemia
subjects affected / exposed	10 / 391 (2.56%)	8 / 203 (3.94%)
occurrences causally related to treatment / all	0 / 11	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Calculus bladder
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
End stage renal disease
subjects affected / exposed	135 / 391 (34.53%)	62 / 203 (30.54%)
occurrences causally related to treatment / all	1 / 135	0 / 63
deaths causally related to treatment / all	0 / 8	0 / 4
Haematuria
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oliguria
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Renal colic
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperparathyroidism primary
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperparathyroidism secondary
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Gouty arthritis
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Joint contracture
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis bacterial
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bursitis infective
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	3 / 391 (0.77%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	2 / 391 (0.51%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	4 / 391 (1.02%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Diabetic foot infection
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterobacter bacteraemia
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	3 / 391 (0.77%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye infection
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gangrene
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic echinococciasis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningoencephalitis herpetic
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Orchitis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	5 / 391 (1.28%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	1 / 6	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0
Pneumonia
subjects affected / exposed	17 / 391 (4.35%)	12 / 203 (5.91%)
occurrences causally related to treatment / all	1 / 21	0 / 14
deaths causally related to treatment / all	0 / 4	0 / 3
Pneumonia staphylococcal
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis chronic
subjects affected / exposed	5 / 391 (1.28%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 0
Pyonephrosis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	6 / 391 (1.53%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Septic shock
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Sinusitis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vulvovaginitis
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 391 (0.26%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic metabolic decompensation
subjects affected / exposed	1 / 391 (0.26%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gout
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 391 (0.26%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	4 / 391 (1.02%)	2 / 203 (0.99%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypervolaemia
subjects affected / exposed	2 / 391 (0.51%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Hypoglycaemia
subjects affected / exposed	2 / 391 (0.51%)	0 / 203 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 391 (0.00%)	1 / 203 (0.49%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Roxadustat	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	204 / 391 (52.17%)	103 / 203 (50.74%)
Investigations
Glomerular filtration rate decreased
subjects affected / exposed	24 / 391 (6.14%)	13 / 203 (6.40%)
occurrences all number	25	13
Vascular disorders
Hypertension
subjects affected / exposed	85 / 391 (21.74%)	27 / 203 (13.30%)
occurrences all number	138	44
Nervous system disorders
Headache
subjects affected / exposed	20 / 391 (5.12%)	10 / 203 (4.93%)
occurrences all number	21	11
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	16 / 391 (4.09%)	31 / 203 (15.27%)
occurrences all number	17	45
General disorders and administration site conditions
Asthenia
subjects affected / exposed	18 / 391 (4.60%)	11 / 203 (5.42%)
occurrences all number	22	13
Oedema peripheral
subjects affected / exposed	44 / 391 (11.25%)	21 / 203 (10.34%)
occurrences all number	53	22
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	32 / 391 (8.18%)	6 / 203 (2.96%)
occurrences all number	38	9
Nausea
subjects affected / exposed	34 / 391 (8.70%)	6 / 203 (2.96%)
occurrences all number	44	6
Infections and infestations
Viral upper respiratory tract infection
subjects affected / exposed	38 / 391 (9.72%)	9 / 203 (4.43%)
occurrences all number	50	15
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	36 / 391 (9.21%)	13 / 203 (6.40%)
occurrences all number	48	19
Hyperuricaemia
subjects affected / exposed	9 / 391 (2.30%)	11 / 203 (5.42%)
occurrences all number	9	11
Iron deficiency
subjects affected / exposed	26 / 391 (6.65%)	8 / 203 (3.94%)
occurrences all number	26	10

More information

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Were there any global substantial amendments to the protocol? Yes

17 Dec 2014

The changes include: -Changes in the study dosing regimen as follows: Dosing frequency changed from thrice weekly (TIW), twice weekly (BIW) and once weekly (QW) to TIW only; Initial study drug dose changed from 70, 100 and 150 mg to 70 and 100 mg only; Maximum dose reduced from 3.5 mg/kg to 3.0 mg/kg and maximum absolute dose reduced from 400 mg to 300 mg. - Reduction in visit schedule by removal of 12 study visits, resulting in 39 visits. - Addition of a post-study follow-up period. - Addition of a primary efficacy endpoint to support submission of the data to the FDA

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 3, Randomized, Double-Blind, Placebo Controlled Study of the Efficacy and Safety of Roxadustat for the Treatment of Anemia in Chronic Kidney Disease Patients not on Dialysis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With a Hemoglobin (Hb) Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy Prior to Hb Response

Primary: Percentage of Participants With a Hemoglobin (Hb) Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy Prior to Hb Response

Primary: Hb Change From Baseline (BL) to the Average Hb in Weeks 28-52 Regardless of Rescue Therapy

Primary: Hb Change From Baseline (BL) to the Average Hb in Weeks 28-52 Regardless of Rescue Therapy

Secondary: Hb Change From BL to the Average Hb in Weeks 28-36 Without Having Received Rescue Therapy Within 6 Weeks Prior to and During 8-Week Evaluation Period

Secondary: Hb Change From BL to the Average Hb in Weeks 28-36 Without Having Received Rescue Therapy Within 6 Weeks Prior to and During 8-Week Evaluation Period

Secondary: Change From BL in Low-Density Lipoprotein (LDL) Cholesterol (Regardless of Fasting Status) to the Average LDL Cholesterol of Weeks 12 to 28

Secondary: Change From BL in Low-Density Lipoprotein (LDL) Cholesterol (Regardless of Fasting Status) to the Average LDL Cholesterol of Weeks 12 to 28

Secondary: Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis-stimulating Agent (ESA) Use, and Intravenous (IV) Iron)

Secondary: Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis-stimulating Agent (ESA) Use, and Intravenous (IV) Iron)

Secondary: Change From BL in Short Form (SF)-36 Vitality (VT) Sub-score to the Average VT Sub-score of Weeks 12 to 28

Secondary: Change From BL in Short Form (SF)-36 Vitality (VT) Sub-score to the Average VT Sub-score of Weeks 12 to 28

Secondary: Change From BL in SF-36 Physical Functioning (PF) Sub-score to the Average PF Sub-score of Weeks 12 to 28

Secondary: Change From BL in SF-36 Physical Functioning (PF) Sub-score to the Average PF Sub-score of Weeks 12 to 28

Secondary: Change From BL in Mean Arterial Pressure (MAP) to the Average MAP of Weeks 20 to 28

Secondary: Change From BL in Mean Arterial Pressure (MAP) to the Average MAP of Weeks 20 to 28

Secondary: Time to First Occurrence of Hypertension

Secondary: Time to First Occurrence of Hypertension

Secondary: Rate of Progression of CKD Measured by Annualized Estimated Glomerular Filtration Rate (eGFR) Slope Over Time

Secondary: Rate of Progression of CKD Measured by Annualized Estimated Glomerular Filtration Rate (eGFR) Slope Over Time

Secondary: Average Level of Hb Over Weeks 28 to 36 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

Secondary: Average Level of Hb Over Weeks 28 to 36 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

Secondary: Average Level of Hb Over Weeks 44 to 52 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

Secondary: Average Level of Hb Over Weeks 44 to 52 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

Secondary: Average Level of Hb Over Weeks 96 to 104 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

Secondary: Average Level of Hb Over Weeks 96 to 104 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

Secondary: Time to Achieve the First Hb Response Without Rescue Therapy, as Defined by Primary Endpoint

Secondary: Time to Achieve the First Hb Response Without Rescue Therapy, as Defined by Primary Endpoint

Secondary: Hb Change From BL to Each Post-Dosing Time Point

Secondary: Hb Change From BL to Each Post-Dosing Time Point

Secondary: Hb Change From BL to the Average Hb Value of Weeks 28-36 Regardless of the Use of Rescue Therapy

Secondary: Hb Change From BL to the Average Hb Value of Weeks 28-36 Regardless of the Use of Rescue Therapy

Secondary: Hb Change From BL to the Average Hb Value of Weeks 44-52 Regardless of the Use of Rescue Therapy

Secondary: Hb Change From BL to the Average Hb Value of Weeks 44-52 Regardless of the Use of Rescue Therapy

Secondary: Hb Change From BL to the Average Hb Value of Weeks 96-104 Regardless of the Use of Rescue Therapy

Secondary: Hb Change From BL to the Average Hb Value of Weeks 96-104 Regardless of the Use of Rescue Therapy

Secondary: Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 28-36 Without Use of Rescue Therapy

Secondary: Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 28-36 Without Use of Rescue Therapy

Secondary: Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 44-52 Without Use of Rescue Therapy

Secondary: Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 44-52 Without Use of Rescue Therapy

Secondary: Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 96-104 Without Use of Rescue Therapy

Secondary: Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 96-104 Without Use of Rescue Therapy

Secondary: Time to First Hospitalization

Secondary: Time to First Hospitalization

Secondary: Number of Days of Hospitalization Per Patient Exposure Year (PEY)

Secondary: Number of Days of Hospitalization Per Patient Exposure Year (PEY)

Secondary: Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis Stimulating Agent (ESA) Use, and Intravenous (IV) Iron) in the First 24 Weeks of Treatment

Secondary: Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis Stimulating Agent (ESA) Use, and Intravenous (IV) Iron) in the First 24 Weeks of Treatment

Secondary: Time to First Use of RBC Transfusions

Secondary: Time to First Use of RBC Transfusions

Secondary: Mean Monthly Number of RBC Packs

Secondary: Mean Monthly Number of RBC Packs

Secondary: Mean Monthly Volume of Blood transfused

Secondary: Mean Monthly Volume of Blood transfused

Secondary: Time to First Use of ESA Rescue Therapy

Secondary: Time to First Use of ESA Rescue Therapy

Secondary: Time to First Use of IV Iron

Secondary: Time to First Use of IV Iron

Secondary: Change From BL to Each Post-Dosing Visit in Total Cholesterol

Secondary: Change From BL to Each Post-Dosing Visit in Total Cholesterol

Secondary: Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio

Secondary: Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio

Secondary: Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol

Secondary: Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol

Secondary: Change From BL to Each Post-Dosing Visit in Apolipoproteins A1

Secondary: Change From BL to Each Post-Dosing Visit in Apolipoproteins A1

Secondary: Change From BL to Each Post-Dosing Visit in Apolipoproteins B

Secondary: Change From BL to Each Post-Dosing Visit in Apolipoproteins B

Secondary: Change From BL to Each Post-Dosing Visit in Ratio Apolipoprotein ApoB/ApoA1

Secondary: Change From BL to Each Post-Dosing Visit in Ratio Apolipoprotein ApoB/ApoA1

Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo Controlled Study of the Efficacy and Safety of Roxadustat for the Treatment of Anemia in Chronic Kidney Disease Patients not on Dialysis