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Clinical Trial Results:
A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis

Summary
EudraCT number	2013-000951-42
Trial protocol	GB DE ES NL CZ SK SI PT AT IE DK FI LV SE FR HR HU BG
Global end of trial date	15 Nov 2019

Results information
Results version number	v1(current)
This version publication date	04 Nov 2020
First version publication date	04 Nov 2020
Other versions

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-0610

ISRCTN number

US NCT number

NCT02021318

WHO universal trial number (UTN)

Sponsor organisation name

Astellas Pharma Europe B.V.

Sponsor organisation address

Sylviusweg 62, Leiden, Netherlands, 2333 BE

Public contact

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

Scientific contact

Clinical Trial Disclosure, Astellas Pharma Europe B.V., 31 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

15 Nov 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 Nov 2019

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study was to evaluate the efficacy of roxadustat compared to darbepoetin alfa in the treatment of anemia in nondialysis-dependent chronic kidney disease 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

12 Mar 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 3

Country: Number of subjects enrolled

Belarus: 17

Country: Number of subjects enrolled

Bulgaria: 19

Country: Number of subjects enrolled

Croatia: 73

Country: Number of subjects enrolled

Czech Republic: 33

Country: Number of subjects enrolled

Finland: 3

Country: Number of subjects enrolled

France: 18

Country: Number of subjects enrolled

Georgia: 19

Country: Number of subjects enrolled

Germany: 37

Country: Number of subjects enrolled

Hungary: 32

Country: Number of subjects enrolled

Ireland: 8

Country: Number of subjects enrolled

Israel: 3

Country: Number of subjects enrolled

Latvia: 4

Country: Number of subjects enrolled

Macedonia, the former Yugoslav Republic of: 12

Country: Number of subjects enrolled

Montenegro: 4

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Poland: 30

Country: Number of subjects enrolled

Portugal: 17

Country: Number of subjects enrolled

Romania: 16

Country: Number of subjects enrolled

Russian Federation: 48

Country: Number of subjects enrolled

Serbia: 48

Country: Number of subjects enrolled

Slovakia: 26

Country: Number of subjects enrolled

Slovenia: 15

Country: Number of subjects enrolled

Spain: 33

Country: Number of subjects enrolled

Ukraine: 36

Country: Number of subjects enrolled

United Kingdom: 61

Worldwide total number of subjects

616

EEA total number of subjects

429

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)

237

From 65 to 84 years

349

85 years and over

Subject disposition

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Recruitment details

Participants of ≥18 years of age with a diagnosis of chronic kidney disease, with kidney disease outcomes quality initiative stage 3, 4 or 5, anaemic and not receiving dialysis; with an estimated glomerular filtration rate (eGFR) < 60 milliliter per minute per 1.73 meter square (mL/min/1.73 m^2) were enrolled in this study.

Screening details

Participants were randomized in a 1:1 ratio to roxadustat or darbepoetin alfa. Randomization was stratified by 4 factors: region, screening hemoglobin (Hb) values (Hb ≤ 8.0 g/dL versus > 8.0 g/dL), history of cardiovascular, cerebrovascular or thromboembolic diseases and screening eGFR (<30 mL/min/1.73 m^2 versus ≥30 mL/min/1.73 m^2 ).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Darbepoetin alfa

Arm description

Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 microgram per kilogram [μg/kg] of body weight, as a single subcutaneous or intravenous [IV] injection once weekly or 0.75 μg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per European Summary of Product Characteristics (EU SmPC) along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 grams per deciliter (g/dL) and Hb increase from baseline 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 darbepoetin alfa 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 darbepoetin alfa for up to a maximum of 104 weeks.

Arm type

Active comparator

Investigational medicinal product name

Darbepoetin alfa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

Roxadustat

Arm description

Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 milligram (mg) given three times weekly (TIW) to participants weighing between 45 kilogram (kg) up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 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 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 up to a maximum of 104 weeks.

Arm type

Experimental

Investigational medicinal product name

Roxadustat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	Darbepoetin alfa	Roxadustat
Started	293	323
Completed	230	250
Not completed	63	73
Physician decision	3	3
Adverse Event	1	2
Death	34	33
Miscellaneous	3	2
Withdrawal by Subject	18	30
Lost to follow-up	3	3
Progressive disease	1	-

Baseline characteristics

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Reporting group title

Darbepoetin alfa

Reporting group description

Reporting group title

Roxadustat

Reporting group description

Reporting group values	Darbepoetin alfa	Roxadustat	Total
Number of subjects	293	323
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	65.7 ( 14.4 )	66.8 ( 13.6 )	-
Gender categorical
Units: Subjects
M	129	145	274
F	164	178	342
Analysis Race
Units: Subjects
White	281	306	587
Black or African American	2	8	10
Asian	10	9	19
Baseline Hb Value
Units: Subjects
<=8.0 g/dL	10	11	21
>8.0 g/dL	283	312	595

End points

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Reporting group title

Darbepoetin alfa

Reporting group description

Reporting group title

Roxadustat

Reporting group description

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

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End point title

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

End point description

Hb response was measured as Yes or No. Response Yes (responders) was defined as: Hb ≥11.0 g/dL and Hb change from baseline by ≥ 1.0 g/dL, for participants with baseline Hb > 8.0 g/dL; or Hb change from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at two consecutive visits with available data separated by at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell [RBC] transfusion for all participants or darbepoetin for roxadustat treated participant). The analysis population was the Per Protocol Set (PPS) which consisted of all Full Analysis Set (FAS) participants who did not meet any of exclusion criteria from the PPS. The FAS consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose valid Hb assessment.

End point type

Primary

End point timeframe

Baseline to week 24

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	273	286
Units: Percentage of participants
number (not applicable)	78.0	89.5

Statistical Analysis 1

Statistical analysis description

A generalized linear model as an approximation for the Miettinen and Nurminen method, adjusted for stratification factors (actual) was used to estimate the difference of proportions and 95% confidence interval (CI).

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

559

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

Method

Parameter type

Difference in percentage

Point estimate

11.51

Confidence interval

level

95%

sides

2-sided

lower limit

5.66

upper limit

17.36

Notes
[1] - Non-inferiority of roxadustat versus darbepoetin alfa, margin = -15% (non-inferiority is concluded if the lower limit of the 95% confidence interval of the difference was >-15%).

Secondary: Change from Baseline in Hb to the Average Hb of Weeks 28 to 36 Without Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period

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End point title

Change from Baseline in Hb to the Average Hb of Weeks 28 to 36 Without Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period

End point description

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose). The analysis population was the PPS, with participants who had available data.

End point type

Secondary

End point timeframe

Baseline and weeks 28 to 36

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	249	258
Units: g/dL
arithmetic mean (standard deviation)	1.839 ( 0.973 )	1.848 ( 1.079 )

Statistical Analysis 1

Statistical analysis description

The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular (CV) disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

507

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

P-value

= 0.839

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.015

Confidence interval

level

95%

sides

2-sided

lower limit

-0.131

upper limit

0.162

Notes
[2] - Non-Inferiority, margin = -0.75 (non-inferiority is concluded if the lower bound of the 95% confidence interval of the least square mean difference (LSM) is > -0.75 g/dL).

Secondary: Change from Baseline in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28

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End point title

Change from Baseline in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28

End point description

Baseline LDL was defined as the LDL value on day 1. If this value was missing, the latest value prior to first study drug administration was used. The analysis population was the FAS, with participants who had available data.

End point type

Secondary

End point timeframe

Baseline and weeks 12 to 28

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	277	307
Units: Millimoles per liter (mmol/L)
arithmetic mean (standard deviation)	0.049 ( 0.705 )	-0.352 ( 0.772 )

Statistical Analysis 1

Statistical analysis description

The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline LDL, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.

Comparison groups

Darbepoetin alfa v Roxadustat

Number of subjects included in analysis

584

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.403

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

-0.296

Secondary: Time to First Intavenous Iron use

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End point title

Time to First Intavenous Iron use

End point description

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to end of treatment (EOT) Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had received more than one intravenous iron, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N is the number of participants with available data at each time point.

End point type

Secondary

End point timeframe

Weeks 6, 12, 18, 24, 30 and 36

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (confidence interval 95%)
Week 6 (N=318, 280)	2.8 (0.9 to 4.6)	0 (0 to 0)
Week 12 (N=307, 259)	6.7 (3.8 to 9.6)	1.3 (0 to 2.5)
Week 18 (N=290, 247)	9.2 (5.8 to 12.6)	3.3 (1.3 to 5.2)
Week 24 (N=281, 243)	10.7 (7.1 to 14.3)	4.3 (2 to 6.5)
Week 30 (N=272, 231)	12.6 (8.7 to 16.5)	5.3 (2.8 to 7.8)
Week 36 (N=263, 226)	13.3 (9.3 to 17.3)	6.7 (3.9 to 9.6)

Statistical Analysis 1

Statistical analysis description

Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on cardiovascular history and Region and adjusting on Hb and eGFR at baseline as continuous covariate. Superiority was declared if the upper bound of the 95% CI was below 1.0.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.004

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.45

Confidence interval

level

95%

sides

2-sided

lower limit

0.26

upper limit

0.78

Secondary: Change from Baseline in Short Form-36 (SF-36) Physical Functioning (PF) Sub-Score to the Average PF Sub-Score in Weeks 12 to 28

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End point title

Change from Baseline in Short Form-36 (SF-36) Physical Functioning (PF) Sub-Score to the Average PF Sub-Score in Weeks 12 to 28

End point description

Baseline SF-36 PF was defined as the SF-36 PF value on day 1.The SF-36 is a Quality of Life (QoL) instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 contains 36 items that measured eight scales: (1) physical functioning; (2) role limitations due to physical health problems; (3) bodily pain; (4) social functioning; (5) general health perceptions; (6) role limitations due to emotional problems; (7) vitality, energy or fatigue; and (8) mental health. Each scale is transformed into 0-100 score, with higher scores indicating better health status. The SF-36 PF consisted of 11 questions that focused on health and ability to do usual activities, with higher scores indicating better health status. The analysis population was the PPS, with participants who had available data.

End point type

Secondary

End point timeframe

Baseline and weeks 12 to 28

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	256	274
Units: Units on a scale
arithmetic mean (standard deviation)	2.062 ( 7.838 )	0.913 ( 7.182 )

Statistical Analysis 1

Statistical analysis description

The model included treatment, visit (weeks 8, 12 and 28) visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline SF-36 PF, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

P-value

= 0.027

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-1.284

Confidence interval

level

95%

sides

2-sided

lower limit

-2.423

upper limit

-0.145

Notes
[3] - Non-Inferiority, margin = -3 (non-inferiority is concluded if the lower bound of the 95% confidence interval of the LSM difference is > - 3 points).

Secondary: Change from Baseline in SF-36 Vitality (VT) Sub-Score to the Average VT Sub-Score in Weeks 12 to 28

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End point title

Change from Baseline in SF-36 Vitality (VT) Sub-Score to the Average VT Sub-Score in Weeks 12 to 28

End point description

Baseline VT Subscore was defined as the VT value on day 1. The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 vitality has four questions with score range from 0-100 with higher scores indicating better vitality status. The analysis population was the PPS, with participants who had available data.

End point type

Secondary

End point timeframe

Baseline and weeks 12 to 28

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	256	274
Units: Units on a scale
arithmetic mean (standard deviation)	3.881 ( 8.76 )	4.077 ( 8.657 )

Statistical Analysis 1

Statistical analysis description

The model included treatment, visit (weeks 8, 12 and 28), visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline SF-36 VT, baseline Hb, baseline eGFR as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

P-value

= 0.454

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.457

Confidence interval

level

95%

sides

2-sided

lower limit

-1.656

upper limit

0.742

Notes
[4] - Non-Inferiority, margin = -3 (non-inferiority is concluded if the lower bound of the 95% confidence interval of the LSM difference is > - 3 points).

Secondary: Change from Baseline in Mean Arterial Pressure (MAP) to the Average MAP Value in Weeks 20 to 28: Per Protocol Set

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End point title

Change from Baseline in Mean Arterial Pressure (MAP) to the Average MAP Value in Weeks 20 to 28: Per Protocol Set

End point description

Baseline MAP was defined as the MAP value on day 1. If this value was missing, the latest value prior to first study drug administration was used. MAP was derived as: MAP = (2/3)*diastolic blood pressure (DBP) + (1/3)*systolic blood pressure (SBP). The analysis population was the PPS, with participants who had available data.

End point type

Secondary

End point timeframe

Baseline and weeks 20 to 28

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	252	265
Units: Millimeters of mercury (mmHg)
arithmetic mean (standard deviation)	0.588 ( 8.779 )	0.541 ( 8.549 )

Statistical Analysis 1

Statistical analysis description

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 Darbepoetin alfa

Number of subjects included in analysis

517

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

P-value

= 0.547

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.372

Confidence interval

level

95%

sides

2-sided

lower limit

-1.587

upper limit

0.842

Notes
[5] - Non-Inferiority, margin = 1 mmHg (non-inferiority is concluded if the upper bound of the 95% confidence interval of the LSM difference is < 1).

Secondary: Time to First Occurrence of Hypertension During Weeks 1 to 36: Per Protocol Set

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End point title

Time to First Occurrence of Hypertension During Weeks 1 to 36: Per Protocol Set

End point description

Hypertension was defined as either SBP ≥ 170 mmHg and an increase from baseline ≥ 20 mmHg or as DBP ≥ 110 mmHg and an increase from baseline ≥ 15 mmHg. For participants who had experienced more than one event, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure. The analysis population was the PPS.

End point type

Secondary

End point timeframe

Weeks 1 to 36

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	273	286
Units: Percentage of participants
number (not applicable)	19.4	17.5

Statistical Analysis 1

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 Darbepoetin alfa

Number of subjects included in analysis

559

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

P-value

= 0.336

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.22

Notes
[6] - Non-Inferiority, hazard ratio margin = 1.3 (non-inferiority is concluded if the upper bound of the 95% confidence interval of the hazard ratio is < 1.3).

Secondary: Change from Baseline in MAP to the Average MAP Value in Weeks 20 to 28: Full Analysis Set

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End point title

Change from Baseline in MAP to the Average MAP Value in Weeks 20 to 28: Full Analysis Set

End point description

Baseline MAP was defined as the MAP value on day 1. If this value was missing, the latest value prior to first study drug administration was used. MAP was derived as: MAP = (2/3)*DBP + (1/3)*SBP. The analysis population was the FAS, with participants who had available data.

End point type

Secondary

End point timeframe

Baseline and weeks 20 to 28

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	269	294
Units: mmHg
arithmetic mean (standard deviation)	0.457 ( 8.741 )	0.635 ( 8.529 )

Statistical Analysis 1

Statistical analysis description

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 Darbepoetin alfa

Number of subjects included in analysis

563

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.818

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.136

Confidence interval

level

95%

sides

2-sided

lower limit

-1.299

upper limit

1.026

Secondary: Time to First Occurrence of Hypertension During Weeks 1 to 36: Full Analysis Set

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End point title

Time to First Occurrence of Hypertension During Weeks 1 to 36: Full Analysis Set

End point description

End point type

Secondary

End point timeframe

Weeks 1 to 36

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of Participants
number (not applicable)	18.8	17.4

Statistical Analysis 1

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 was declared if the upper bound of the 95% CI is lower than 1.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.452

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

1.26

Secondary: Change From Baseline in Hb to the Average Hb Value of Weeks 28 to 52 Regardless Use of Rescue Therapy

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End point title

Change From Baseline in Hb to the Average Hb Value of Weeks 28 to 52 Regardless Use of Rescue Therapy

End point description

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (pre-dose). The analysis population was the FAS, with participants who had available data.

End point type

Secondary

End point timeframe

Baseline and weeks 28 to 52

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	266	287
Units: g/dL
arithmetic mean (standard deviation)	1.673 ( 0.923 )	1.718 ( 0.958 )

Statistical Analysis 1

Statistical analysis description

The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

553

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.529

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.038

Confidence interval

level

95%

sides

2-sided

lower limit

-0.081

upper limit

0.157

Secondary: Time to First Hb Response During First 24 Weeks of Treatment Regardless of Administration of Rescue Therapy

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End point title

Time to First Hb Response During First 24 Weeks of Treatment Regardless of Administration of Rescue Therapy

End point description

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure. The analysis population was the FAS.

End point type

Secondary

End point timeframe

Weeks 1 to 24

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (not applicable)	77.7	88.8

Statistical Analysis 1

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 Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.64

Confidence interval

level

95%

sides

2-sided

lower limit

1.38

upper limit

1.96

Secondary: Time to First Hb Response During First 24 Weeks of Treatment Without Rescue Therapy

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End point title

Time to First Hb Response During First 24 Weeks of Treatment Without Rescue Therapy

End point description

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure. The analysis population was the FAS.

End point type

Secondary

End point timeframe

Weeks 1 to 24

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (not applicable)	77.4	88.2

Statistical Analysis 1

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 Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.66

Confidence interval

level

95%

sides

2-sided

lower limit

1.39

upper limit

1.98

Secondary: Hb Level Averaged Over Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80 and Weeks 96 to 104 Without Rescue Therapy

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End point title

Hb Level Averaged Over Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80 and Weeks 96 to 104 Without Rescue Therapy

End point description

End point type

Secondary

End point timeframe

Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: g/dL
least squares mean (confidence interval 95%)
Weeks 28-36 (N=286, 266)	11.351 (11.247 to 11.455)	11.403 (11.302 to 11.503)
Weeks 44-52 (N=266, 251)	11.188 (11.082 to 11.294)	11.185 (11.082 to 11.289)
Weeks 72-80 (N=241, 233)	11.217 (11.110 to 11.324)	11.225 (11.120 to 11.331)
Weeks 96-104 (N=218, 215)	11.078 (10.960 to 11.196)	11.102 (10.986 to 11.219)

Statistical Analysis 1

Statistical analysis description

Weeks 28-36 - The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.478

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.051

Confidence interval

level

95%

sides

2-sided

lower limit

-0.091

upper limit

0.194

Statistical Analysis 2

Statistical analysis description

Weeks 44-52 - The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.969

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.003

Confidence interval

level

95%

sides

2-sided

lower limit

-0.149

upper limit

0.143

Statistical Analysis 3

Statistical analysis description

Weeks 72-80 - The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.91

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.009

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

0.157

Statistical Analysis 4

Statistical analysis description

Weeks 96-104 - The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.775

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.024

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

0.188

Secondary: Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of rescue Therapy

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End point title

Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of rescue Therapy

End point description

End point type

Secondary

End point timeframe

Baseline 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, and 104

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: g/dL
least squares mean (confidence interval 95%)
Hb Change From BL to Week 1(N=308, 273)	0.294 (0.221 to 0.368)	0.381 (0.311 to 0.450)
Hb Change From BL to Week 2 (N=314, 284)	0.584 (0.500 to 0.667)	0.862 (0.782 to 0.941)
Hb Change From BL to Week 4 (N=311, 283)	1.073 (0.962 to 1.183)	1.508 (1.403 to 1.613)
Hb Change From BL to Week 6 (N=306, 278)	1.423 (1.3 to 1.546)	1.845 (1.729 to 1.962)
Hb Change From BL to Week 8 (N=301, 277)	1.682 (1.554 to 1.810)	2.063 (1.940 to 2.185)
Hb Change From BL to Week 10 (N=301, 266)	1.611 (1.483 to 1.739)	1.941 (1.819 to 2.062)
Hb Change From BL to Week 12 (N=288, 263)	2.030 (1.897 to 2.162)	2.330 (2.204 to 2.456)
Hb Change From BL to Week 14 (N=293, 266)	1.745 (1.616 to 1.875)	1.904 (1.781 to 2.027)
Hb Change From BL to Week 16 (N= 289, 264)	1.994 (1.864 to 2.124)	2.177 (2.053 to 2.301)
Hb Change From BL to Week 18 (N=286, 260)	1.609 (1.490 to 1.729)	1.783 (1.699 to 1.896)
Hb Change From BL to Week 20 (N=282, 262)	1.900 (1.778 to 2.023)	1.986 (1.869 to 2.103)
Hb Change From BL to Week 22 (N=276, 260)	1.615 (1.499 to 1.731)	1.584 (1.473 to 1.696)
Hb Change From BL to Week 24 (N=283, 254)	1.554 (1.438 to 1.669)	1.493 (1.383 to 1.603)
Hb Change From BL to Week 28 (N=276, 252)	1.869 (1.748 to 1.989)	1.803 (1.688 to 1.919)
Hb Change From BL to Week 32 (N=269, 252)	1.673 (1.549 to 1.797)	1.687 (1.568 to 1.806)
Hb Change From BL to Week 36 (N=264, 247)	1.781 (1.657 to 1.905)	1.913 (1.793 to 2.032)
Hb Change From BL to Week 40 (N=266, 254)	1.438 (1.320 to 1.556)	1.625 (1.510 to 1.740)
Hb Change From BL to Week 44 (N=257, 248)	1.628 (1.502 to 1.754)	1.650 (1.527 to 1.773)
Hb Change From BL to Week 48 (N=259, 245)	1.447 (1.322 to 1.572)	1.459 (1.338 to 1.581)
Hb Change From BL to Week 52 (N=254, 242)	1.710 (1.585 to 1.835)	1.682 (1.560 to 1.803)
Hb Change From BL to Week 56 (N=251, 243)	1.444 (1.321 to 1.567)	1.412 (1.292 to 1.533)
Hb Change From BL to Week 60 (N=250, 242)	1.670 (1.543 to 1.796)	1.735 (1.611 to 1.859)
Hb Change From BL to Week 64 (N=247, 236)	1.547 (1.414 to 1.681)	1.546 (1.415 to 1.676)
Hb Change From BL to Week 68 (N=242, 229)	1.747 (1.620 to 1.875)	1.851 (1.726 to 1.976)
Hb Change From BL to Week 72 (N=236, 227)	1.548 (1.416 to 1.680)	1.615 (1.486 to 1.745)
Hb Change From BL to Week 76 (N=231, 225)	1.767 (1.636 to 1.898)	1.745 (1.616 to 1.873)
Hb Change From BL to Week 80 (N=220, 220)	1.579 (1.451 to 1.707)	1.534 (1.408 to 1.661)
Hb Change From BL to Week 84 (N=220, 219)	1.679 (1.548 to 1.809)	1.723 (1.594 to 1.853)
Hb Change From BL to Week 88 (N=219, 220)	1.370 (1.236 to 1.504)	1.424 (1.291 to 1.557)
Hb Change From BL to Week 92 (N=223, 215)	1.643 (1.505 to 1.780)	1.677 (1.541 to 1.812)
Hb Change From BL to Week 96 (N=217, 213)	1.404 (1.266 to 1.542)	1.429 (1.293 to 1.566)
Hb Change From BL to Week 100 (N=215, 204)	1.598 (1.454 to 1.742)	1.488 (1.346 to 1.629)
Hb Change From BL to Week 104 (N=207, 201)	1.452 (1.299 to 1.606)	1.489 (1.339 to 1.640)

Statistical Analysis 1

Statistical analysis description

Week 1- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.086

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.087

Confidence interval

level

95%

sides

2-sided

lower limit

-0.012

upper limit

0.185

Statistical Analysis 2

Statistical analysis description

Week 2- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.278

Confidence interval

level

95%

sides

2-sided

lower limit

0.165

upper limit

0.391

Statistical Analysis 3

Statistical analysis description

Week 4- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.435

Confidence interval

level

95%

sides

2-sided

lower limit

0.284

upper limit

0.586

Statistical Analysis 4

Statistical analysis description

Week 6- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.422

Confidence interval

level

95%

sides

2-sided

lower limit

0.254

upper limit

0.59

Statistical Analysis 5

Statistical analysis description

Week 8- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.38

Confidence interval

level

95%

sides

2-sided

lower limit

0.205

upper limit

0.556

Statistical Analysis 6

Statistical analysis description

Week 10- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.155

upper limit

0.505

Statistical Analysis 7

Statistical analysis description

Week 12- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.119

upper limit

0.482

Statistical Analysis 8

Statistical analysis description

Week 14- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.079

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.159

Confidence interval

level

95%

sides

2-sided

lower limit

-0.018

upper limit

0.336

Statistical Analysis 9

Statistical analysis description

Week 16- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.044

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.183

Confidence interval

level

95%

sides

2-sided

lower limit

0.005

upper limit

0.361

Statistical Analysis 10

Statistical analysis description

Week 18- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.037

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.173

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

0.336

Statistical Analysis 11

Statistical analysis description

Week 20- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.319

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.085

Confidence interval

level

95%

sides

2-sided

lower limit

-0.083

upper limit

0.253

Statistical Analysis 12

Statistical analysis description

Week 22- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.709

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.19

upper limit

0.129

Statistical Analysis 13

Statistical analysis description

Week 24- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.45

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.061

Confidence interval

level

95%

sides

2-sided

lower limit

-0.219

upper limit

0.097

Statistical Analysis 14

Statistical analysis description

Week 28- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.44

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.065

Confidence interval

level

95%

sides

2-sided

lower limit

-0.231

upper limit

0.101

Statistical Analysis 15

Statistical analysis description

Week 32- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.874

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.157

upper limit

0.184

Statistical Analysis 16

Statistical analysis description

Week 36- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.132

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.131

Confidence interval

level

95%

sides

2-sided

lower limit

-0.039

upper limit

0.302

Statistical Analysis 17

Statistical analysis description

Week 40- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.024

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.187

Confidence interval

level

95%

sides

2-sided

lower limit

0.024

upper limit

0.351

Statistical Analysis 18

Statistical analysis description

Week 44- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.807

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.022

Confidence interval

level

95%

sides

2-sided

lower limit

-0.153

upper limit

0.197

Statistical Analysis 19

Statistical analysis description

Week 48- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.89

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.012

Confidence interval

level

95%

sides

2-sided

lower limit

-0.16

upper limit

0.185

Statistical Analysis 20

Statistical analysis description

Week 52- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.746

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.029

Confidence interval

level

95%

sides

2-sided

lower limit

-0.201

upper limit

0.144

Statistical Analysis 21

Statistical analysis description

Week 56- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.715

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.032

Confidence interval

level

95%

sides

2-sided

lower limit

-0.202

upper limit

0.139

Statistical Analysis 22

Statistical analysis description

Week 60- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.463

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.066

Confidence interval

level

95%

sides

2-sided

lower limit

-0.11

upper limit

0.242

Statistical Analysis 23

Statistical analysis description

Week 64- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.987

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.002

Confidence interval

level

95%

sides

2-sided

lower limit

-0.187

upper limit

0.184

Statistical Analysis 24

Statistical analysis description

Week 68- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.251

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.104

Confidence interval

level

95%

sides

2-sided

lower limit

-0.074

upper limit

0.281

Statistical Analysis 25

Statistical analysis description

Week 72- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.473

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.067

Confidence interval

level

95%

sides

2-sided

lower limit

-0.117

upper limit

0.251

Statistical Analysis 26

Statistical analysis description

Week 76- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.813

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.022

Confidence interval

level

95%

sides

2-sided

lower limit

-0.204

upper limit

0.16

Statistical Analysis 27

Statistical analysis description

Week 80- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.622

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.045

Confidence interval

level

95%

sides

2-sided

lower limit

-0.223

upper limit

0.134

Statistical Analysis 28

Statistical analysis description

Week 84- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.632

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.045

Confidence interval

level

95%

sides

2-sided

lower limit

-0.138

upper limit

0.227

Statistical Analysis 29

Statistical analysis description

Week 88- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.568

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.055

Confidence interval

level

95%

sides

2-sided

lower limit

-0.133

upper limit

0.242

Statistical Analysis 30

Statistical analysis description

Week 92- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.729

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.034

Confidence interval

level

95%

sides

2-sided

lower limit

-0.158

upper limit

0.226

Statistical Analysis 31

Statistical analysis description

Week 96- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.797

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.025

Confidence interval

level

95%

sides

2-sided

lower limit

-0.168

upper limit

0.218

Statistical Analysis 32

Statistical analysis description

Week 100- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.28

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.31

upper limit

0.09

Statistical Analysis 33

Statistical analysis description

Week 104- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.733

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.037

Confidence interval

level

95%

sides

2-sided

lower limit

-0.177

upper limit

0.251

Secondary: Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80, Weeks 96 to 104 Regardless of Use of Rescue Therapy

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End point title

Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80, Weeks 96 to 104 Regardless of Use of Rescue Therapy

End point description

End point type

Secondary

End point timeframe

Baseline and weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: g/dL
least squares mean (confidence interval 95%)
Hb Change From BL to Weeks 28-36 (N=287, 266)	1.799 (1.694 to 1.905)	1.825 (1.723 to 1.926)
Hb Change From BL to Weeks 44-52 (N=267, 252)	1.620 (1.512 to 1.729)	1.619 (1.513 to 1.724)
Hb Change From BL to Weeks 72-80 (N=243, 233)	1.649 (1.540 to 1.758)	1.652 (1.545 to 1.759)
Hb Change From BL to Weeks 96-104 (N=223, 217)	1.502 (1.378 to 1.626)	1.486 (1.363 to 1.608)

Statistical Analysis 1

Statistical analysis description

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.727

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.026

Confidence interval

level

95%

sides

2-sided

lower limit

-0.119

upper limit

0.17

Statistical Analysis 2

Statistical analysis description

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.985

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.151

upper limit

0.148

Statistical Analysis 3

Statistical analysis description

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.965

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.003

Confidence interval

level

95%

sides

2-sided

lower limit

-0.148

upper limit

0.154

Statistical Analysis 4

Statistical analysis description

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.856

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.016

Confidence interval

level

95%

sides

2-sided

lower limit

-0.188

upper limit

0.157

Secondary: Percentage of Hb Values ≥ 10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80 and Weeks 96 to 104 Without Use of Rescue Therapy

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End point title

Percentage of Hb Values ≥ 10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80 and Weeks 96 to 104 Without Use of Rescue Therapy

End point description

Percentage for each participant was calculated from the number of Hb values within 10.0 to 12.0 g/dL / total number of Hb values*100 in weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104 without use of rescue therapy within 6 weeks prior to and during the 8 week evaluation period. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of Hb values
arithmetic mean (standard deviation)
Weeks 28-36, ≥ 10 (N=286, 266)	92.481 ( 19.876 )	93.078 ( 20.671 )
Weeks 28-36, Within 10-12 (N=286, 266)	69.217 ( 34.171 )	67.896 ( 33.499 )
Weeks 44-52, ≥ 10 (N=266, 251)	89.416 ( 24.833 )	90.921 ( 23.123 )
Weeks 44-52, Within 10-12 (N=266, 251)	68.931 ( 35.367 )	74.104 ( 32.119 )
Weeks 72-80, ≥ 10 (N=241, 233)	90.343 ( 24.364 )	91.494 ( 20.923 )
Weeks 72-80, Within 10-12 (N=241, 233)	67.861 ( 37.024 )	69.710 ( 32.444 )
Weeks 96-104, ≥10 (N=218, 215)	87.777 ( 27.03 )	90.436 ( 22.725 )
Weeks 96-104, Within 10-12 (N=218, 215)	68.629 ( 35.352 )	72.393 ( 33.277 )

No statistical analyses for this end point

Secondary: Time to First Hb Rate of Rise > 2 g/dL Within 4 weeks

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End point title

Time to First Hb Rate of Rise > 2 g/dL Within 4 weeks

End point description

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Year 0.5, 1, 1.5 and 2

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5 (N=155, 188)	28.9 (23.6 to 34.1)	45.5 (40.0 to 51.0)
Year 1 (N=131, 171)	30.9 (25.4 to 36.3)	48.8 (43.2 to 54.4)
Year 1.5 (N=104, 145)	35.0 (29.3 to 40.7)	53.4 (47.7 to 59.1)
Year 2 (N=10, 22)	37.8 (31.9 to 43.7)	55.3 (49.5 to 61.0)

Statistical Analysis 1

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 Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.74

Confidence interval

level

95%

sides

2-sided

lower limit

1.36

upper limit

2.22

Secondary: Number of Hospitalizations

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End point title

Number of Hospitalizations

End point description

The number of hospitalizations per participant were calculated during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). The analysis population was the FAS.

End point type

Secondary

End point timeframe

Baseline to EOT (Up to week 104)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Hospitalizations
arithmetic mean (standard deviation)	1.4 ( 2.3 )	1.5 ( 2.4 )

No statistical analyses for this end point

Secondary: Number of Days of Hospitalization per Year

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End point title

Number of Days of Hospitalization per Year

End point description

The number of days of hospitalization per year was calculated as the sum of the durations of all hospitalizations in days (minimum [date of discharge, end of efficacy of emergent period] - date of admission + 1) / (duration of efficacy emergent period in days / 365.25). The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). The analysis population was the FAS.

End point type

Secondary

End point timeframe

Baseline to EOT (Up to week 104)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Days per year
arithmetic mean (standard deviation)	11.3 ( 27.7 )	12.6 ( 22.0 )

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 in years was defined in years as: (first event date during the efficacy emergent period – analysis date of first dose intake +1)/365.25, and the ‘first event date’ was defined as ‘date of first admission and ‘analysis date of first dose intake. Date of end of efficacy emergent period was defined as as the treatment period up to the EOT visit. For participants who have experienced more than one hospitalization, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Year 0.5, 1, 1.5 and 2

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5 (N=207, 216)	21.8 (17 to 26.7)	31.7 (26.5 to 36.8)
Year 1 (N=162, 158)	40.4 (34.6 to 46.2)	43.7 (38.2 to 49.3)
Year 1.5 (N=122, 124)	50.2 (44.2 to 56.1)	55.2 (49.6 to 60.9)
Year 2 (N=15, 24)	56.7 (50.7 to 62.7)	62.3 (56.7 to 67.9)

Statistical Analysis 1

Statistical analysis description

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.079

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.98

upper limit

1.5

Secondary: Time to First Use of RBC Transfusion

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End point title

Time to First Use of RBC Transfusion

End point description

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one RBC transfusion, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Year 0.5, 1, 1.5 and 2

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5 (N=281, 263)	2.1 (0.4 to 3.8)	3 (1.1 to 4.9)
Year 1 (N=244, 233)	6.5 (3.5 to 9.5)	7.3 (4.3 to 10.3)
Year 1.5 (N=214, 207)	9.4 (5.8 to 13)	10.9 (7.2 to 14.6)
Year 2 (N=31, 34)	11.2 (7.3 to 15.1)	13.9 (9.7 to 18.2)

Statistical Analysis 1

Statistical analysis description

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

2.11

Secondary: Number of RBC Packs

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End point title

Number of RBC Packs

End point description

The number of RBC packs were calculated as the sum of units transfused during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). Participants with no medication records of RBC have their number of RBC packs set to 0. The analysis population was the FAS.

End point type

Secondary

End point timeframe

Baseline to EOT (Up to week 104)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: RBC packs
arithmetic mean (standard deviation)	0.4 ( 1.98 )	0.4 ( 1.20 )

No statistical analyses for this end point

Secondary: Volume of RBC Transfused

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End point title

Volume of RBC Transfused

End point description

The volume of blood transfused was calculated as the sum of blood volume transfused during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). Participants with no medication records of RBC have their volume set to 0. The analysis population was the FAS.

End point type

Secondary

End point timeframe

Baseline to EOT (Up to week 104)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: mL
arithmetic mean (standard deviation)	334.63 ( 508.40 )	97.0 ( 112.2 )

No statistical analyses for this end point

Secondary: Number of Particpants who Received RBC Transfusions

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End point title

Number of Particpants who Received RBC Transfusions

End point description

Participants who received RBC transfusions during the efficacy emergent period were reported. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). The analysis population was the FAS.

End point type

Secondary

End point timeframe

Baseline to EOT (Up to week 104)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Participants	28	38

No statistical analyses for this end point

Secondary: Time to First Use of Rescue Therapy

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End point title

Time to First Use of Rescue Therapy

End point description

Rescue therapy for partcipants in the roxadustat group included RBC transfusion or ESA therapy and for partcipants in the darbepoetin alfa group included RBC transfusion only. Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who have experienced more than one use of rescue therapy (i.e. RBC and ESA), only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Year 0.5, 1, 1.5 and 2

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5 (N=278, 263)	2.1 (0.4 to 3.8)	4 (1.8 to 6.2)
Year 1 (N=241, 233)	6.5 (3.5 to 9.5)	9.3 (6 to 12.7)
Year 1.5 (N=213, 207)	9.4 (5.8 to 13)	13.3 (9.3 to 17.3)
Year 2 (N=31, 34)	11.2 (7.3 to 15.1)	16.7 (12.2 to 21.2)

Statistical Analysis 1

Statistical analysis description

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.055

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.99

upper limit

2.54

Secondary: Number of Participants who Received Rescue Therapy (Composite of RBC Transfusions (all Participants) and Darbepoetin alfa use (Roxadustat Treated Participants only)

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End point title

Number of Participants who Received Rescue Therapy (Composite of RBC Transfusions (all Participants) and Darbepoetin alfa use (Roxadustat Treated Participants only)

End point description

Rescue therapy for participants in the roxadustat group included RBC transfusion or ESA therapy and for participants in the darbepoetin alfa group included RBC transfusion only. Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who have experienced more than one use of rescue therapy (i.e. RBC and ESA), only their first event was used. The analysis population was the FAS.

End point type

Secondary

End point timeframe

Baseline to EOT (Up to week 104)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Participants	28	46

No statistical analyses for this end point

Secondary: Mean Monthly Intravenous Iron per Participant During Weeks 37 to 52 and Weeks 53 to 104

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End point title

Mean Monthly Intravenous Iron per Participant During Weeks 37 to 52 and Weeks 53 to 104

End point description

Participants with no or missing medication records of IV Iron had their monthly IV Iron use set to 0 mg. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Weeks 37 to 52 and 53 to 104

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: mg per month
arithmetic mean (standard deviation)
Weeks 37 to 52 (N=275, 258)	13.208 ( 46.408 )	11.208 ( 64.282 )
Weeks 53 to 104 (N=259, 248)	31.315 ( 95.306 )	18.702 ( 68.074 )

No statistical analyses for this end point

Secondary: Time to First Use of IV Iron Supplementation

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End point title

Time to First Use of IV Iron Supplementation

End point description

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had received more than one IV iron, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Year 0.5, 1, 1.5 and 2

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5 (N=278, 238)	11.8 (8 to 15.6)	4.3 (2 to 6.5)
Year 1 (N=240, 201)	19.2 (14.5 to 23.9)	10 (6.5 to 13.5)
Year 1.5 (N=206, 176)	24.2 (19 to 29.4)	15.9 (11.5 to 20.2)
Year 2 (N=26, 30)	29.1 (23.1 to 35.1)	24.9 (18.8 to 31)

Statistical Analysis 1

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 covariate. Superiority was declared if the upper bound of the 95% CI is below 1.0.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.052

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

Secondary: Percentage of Participants with Oral Iron Use Only

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End point title

Percentage of Participants with Oral Iron Use Only

End point description

Percentage of participants with oral iron use only were calculated based on total number of participants within the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). The analysis population was the FAS.

End point type

Secondary

End point timeframe

Day 1 to week 36, weeks 37 to 52, weeks 53 to 104, efficacy emergent period (up to week 104)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (not applicable)
During efficacy emergent period	52.7	50.6
During day 1 to week 36	55.1	55.3
During week 37 to 52	55.4	55.6
During week 53 to 104	50.6	53.1

No statistical analyses for this end point

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol

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End point title

Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol

End point description

Baseline was defined as the value on day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Baseline and weeks 8, 28, 52, 104

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: mmol/L
arithmetic mean (standard deviation)
Change from BL to week 8 (N=311, 282)	-0.046 ( 0.836 )	-0.92 ( 0.98 )
Change from BL to week 28 (N=285, 264)	0.016 ( 0.953 )	-0.531 ( 1.153 )
Change from BL to week 52 (N=256, 245)	-0.111 ( 1.097 )	-0.524 ( 1.232 )
Change from BL to week 104 (N=215, 212)	-0.197 ( 1.171 )	-0.695 ( 1.284 )

No statistical analyses for this end point

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein cholesterol (HDL-C) Ratio

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End point title

Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein cholesterol (HDL-C) Ratio

End point description

End point type

Secondary

End point timeframe

Baseline and weeks 8, 28, 52, 104

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Ratio
arithmetic mean (standard deviation)
Change from BL to week 8 (N=310, 282)	-0.049 ( 0.629 )	-0.209 ( 0.665 )
Change from BL to week 28 (N=284, 262)	0.053 ( 0.747 )	0.016 ( 0.893 )
Change from BL to week 52 (N=256, 245)	-0.065 ( 0.871 )	0.014 ( 1.095 )
Change from BL to week 104 (N=215, 209)	0.012 ( 1.06 )	-0.069 ( 1.579 )

No statistical analyses for this end point

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol

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End point title

Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol

End point description

End point type

Secondary

End point timeframe

Baseline and weeks 8, 28, 52, 104

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: mmoL/L
arithmetic mean (standard deviation)
Change from BL to week 8 (N=310, 282)	-0.045 ( 0.787 )	-0.729 ( 0.9 )
Change from BL to week 28 (N=284, 262)	0.02 ( 0.911 )	-0.392 ( 1.098 )
Change from BL to week 52 (N=256, 245)	-0.114 ( 1.062 )	-0.383 ( 1.19 )
Change from BL to week 104 (N=215, 211)	-0.15 ( 1.151 )	-0.562 ( 1.162 )

No statistical analyses for this end point

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1)

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End point title

Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1)

End point description

End point type

Secondary

End point timeframe

Baseline and weeks 8, 28, 52, 104

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Grams per liter (g/L)
arithmetic mean (standard deviation)
Change from BL to week 8 (N=310, 283)	0.026 ( 0.204 )	-0.184 ( 0.222 )
Change from BL to week 28 (N=287, 264)	0.055 ( 0.217 )	-0.104 ( 0.258 )
Change from BL to week 52 (N=254, 243)	0.027 ( 0.229 )	-0.12 ( 0.254 )
Change from BL to week 104 (N=214, 212)	-0.018 ( 0.242 )	-0.116 ( 0.311 )

No statistical analyses for this end point

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB)

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End point title

Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB)

End point description

End point type

Secondary

End point timeframe

Baseline and weeks 8, 28, 52, 104

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Milligrams per deciliter (mg/dL)
arithmetic mean (standard deviation)
Change from BL to week 8 (N=310, 283)	-0.71 ( 17.791 )	-16.5 ( 19.581 )
Change from BL to week 28 (N=287, 264)	0.091 ( 19.672 )	-10.659 ( 23.644 )
Change from BL to week 52 (N=254, 243)	-3.539 ( 23.811 )	-10.74 ( 25.155 )
Change from BL to week 104 (N=214, 212)	-2.038 ( 25.857 )	-13.561 ( 25.461 )

No statistical analyses for this end point

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in ApoB/ApoA1 Ratio

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End point title

Change From Baseline to Weeks 8, 28, 52 and 104 in ApoB/ApoA1 Ratio

End point description

End point type

Secondary

End point timeframe

Baseline and weeks 8, 28, 52, 104

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Ratio
arithmetic mean (standard deviation)
Change from BL to week 8 (N=252, 252)	-0.019 ( 0.13 )	-0.031 ( 0.185 )
Change from BL to week 28 (N=231, 234)	-0.034 ( 0.159 )	-0.026 ( 0.208 )
Change from BL to week 52 (N=204, 217)	-0.038 ( 0.191 )	-0.025 ( 0.254 )
Change from BL to week 104 (N=170, 187)	-0.009 ( 0.218 )	-0.044 ( 0.238 )

No statistical analyses for this end point

Secondary: Number of Participants with Mean LDL Cholesterol < 100 mg/dL

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End point title

Number of Participants with Mean LDL Cholesterol < 100 mg/dL

End point description

Missing category for fasting only includes non-fasting participants and the participants with missing values. The analysis population was the FAS.

End point type

Secondary

End point timeframe

Weeks 12 to 28 and 36 to 52

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Participants
Weeks 12-28: Yes (Regardless Fasting Status)	111	147
Weeks 12-28: No (Regardless Fasting Status)	33	20
Weeks 12-28: Missing (Regardless Fasting Status)	8	10
Weeks 12-28: Yes (Fasting only)	69	90
Weeks 12-28: No (Fasting only)	18	11
Weeks 12-28: Missing (Fasting only)	65	76
Weeks 36-52: Yes (Regardless Fasting Status)	104	129
Weeks 36-52: No (Regardless Fasting Status)	31	26
Weeks 36-52: Missing (Regardless Fasting Status)	17	22
Weeks 36-52: Yes (Fasting only)	57	78
Weeks 36-52: No (Fasting only)	22	15
Weeks 36-52: Missing (Fasting only)	73	84

No statistical analyses for this end point

Secondary: Number of Participants who Had Achieved Antihypertensive Treatment Goal

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End point title

Number of Participants who Had Achieved Antihypertensive Treatment Goal

End point description

Achieved antihypertensive treatment goal was defined as SBP < 130 mmHg and DBP < 80 mmHg over an evaluation period defined as the average of available values in weeks 12 to 28 and 36 to 52. The analysis population was the FAS.

End point type

Secondary

End point timeframe

Weeks 12 to 28 and 36 to 52

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Participants
Weeks 12-28: Yes	64	76
Weeks 12-28: No	212	228
Week 12-28: Missing	16	18
Weeks 36-52: Yes	64	80
Weeks 36-52: No	193	196
Weeks 36-52: Missing	35	46

No statistical analyses for this end point

Secondary: Change from Baseline to the Average of Weeks 12 to 28 and Weeks 36 to 52 in SF-36 Physical Component Score (PCS)

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End point title

Change from Baseline to the Average of Weeks 12 to 28 and Weeks 36 to 52 in SF-36 Physical Component Score (PCS)

End point description

Baseline SF-36 PCS was defined as the SF-36 PCS value on day 1.The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 contains 36 items that measured eight scales: (1) physical functioning; (2) role limitations due to physical health problems; (3) bodily pain; (4) social functioning; (5) general health perceptions; (6) role limitations due to emotional problems; (7) vitality, energy or fatigue; and (8) mental health. Each scale is transformed into 0-100 score, with higher scores indicating better health status. The PCS was calculated based on all 8 scales and ranged from 5.02-79.78. For each of these above scales, higher scores always indicated better health status. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Baseline, weeks 12 to 28 and 36 to 52

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Units on a scale
least squares mean (confidence interval 95%)
Change from BL to weeks 12-28 (N=303, 272)	2.29 (1.576 to 3.004)	1.222 (0.54 to 1.904)
Change from BL to weeks 36-52 (N=271, 258)	1.686 (0.939 to 2.433)	1.083 (0.358 to 1.808)

Statistical Analysis 1

Statistical analysis description

Weeks 12-28 - The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline SF-36 PCS, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.027

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-1.068

Confidence interval

level

95%

sides

2-sided

lower limit

-2.012

upper limit

-0.124

Statistical Analysis 2

Statistical analysis description

Weeks 36-52 - The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline SF-36 PCS, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.239

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.603

Confidence interval

level

95%

sides

2-sided

lower limit

-1.606

upper limit

0.401

Secondary: Change From Baseline to the Average of Weeks 12 to 28 and Weeks 36 to 52 in Anemia Subscale (AnS) (Additional Concerns) of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score

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End point title

Change From Baseline to the Average of Weeks 12 to 28 and Weeks 36 to 52 in Anemia Subscale (AnS) (Additional Concerns) of Functional Assessment of Cancer Therapy-Anemia (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 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. Higher scores indicated better QoL. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Baseline, weeks 12 to 28 and 36 to 52

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Units on a scale
least squares mean (confidence interval 95%)
Change from BL to weeks 12-28 (N=303, 272)	5.238 (4.029 to 6.446)	4.71 (3.558 to 5.861)
Change from BL to weeks 36-52 (N=272, 257)	4.608 (3.252 to 5.964)	3.661 (2.355 to 4.967)

Statistical Analysis 1

Statistical analysis description

Weeks 12-28 - The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline FACT-An AnS, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.517

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.528

Confidence interval

level

95%

sides

2-sided

lower limit

-2.127

upper limit

1.072

Statistical Analysis 2

Statistical analysis description

Weeks 36-52 - The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline FACT-An AnS, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.308

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.947

Confidence interval

level

95%

sides

2-sided

lower limit

-2.771

upper limit

0.877

Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in FACT-An Total Score

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End point title

Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in FACT-An Total Score

End point description

Baseline FACT-An total Score was defined 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 well being (PWB) – 7 items, functional well being (FWB) - 7 items, social/family well being (SWB) - 7 items, and emotional well being (EWB) - 6 items. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The total score was obtained by summation of the scores from PWB, SWB, EWB, FWB and AnS. The FACT-An Total Score scale range was 0-188. A higher score indicated better QoL. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Baseline, weeks 12 to 28 and 36 to 52

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Units on a scale
least squares mean (confidence interval 95%)
Change from BL to weeks 12-28 (N=299, 270)	8.665 (6.299 to 11.031)	7.761 (5.501 to 10.02)
Change from BL to weeks 36-52 (N=268, 255)	7.259 (4.593 to 9.925)	5.492 (2.915 to 8.069)

Statistical Analysis 1

Statistical analysis description

Week 12-28 - The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline FACT-An total score, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.57

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.904

Confidence interval

level

95%

sides

2-sided

lower limit

-4.032

upper limit

2.224

Statistical Analysis 2

Statistical analysis description

Weeks 36-52 -The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline FACT-An total score, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.334

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-1.767

Confidence interval

level

95%

sides

2-sided

lower limit

-5.354

upper limit

1.82

Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in FACT-An Trial Outcome Index (TOI) Score

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End point title

Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in FACT-An Trial Outcome Index (TOI) Score

End point description

Baseline FACT-An total TOI Score was defined on day 1. Total FACT-An TOI score is a sum of PWB subscale score, FWB subscale score and Ans scale score. Fact-An TOI scale contains 14 items that cover four dimensions of well-being: PWB -7 items, FWB -7 items, where score range for each PWB subscale and FWB subscale is 0-28. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia, where score range for Ans scale is 0-80. The total score was obtained by summation of the scores from PWB, FWB and AnS. The FACT-An Total TOI score range was 0-136. A higher score indicated better QoL. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Baseline, weeks 12 to 28 and 36 to 52

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Units on a scale
arithmetic mean (standard deviation)
Weeks 12-28 (N=300, 270)	6.876 ( 16.960 )	6.798 ( 17.830 )
Weeks 36-52 (N=269, 255)	5.595 ( 19.922 )	5.602 ( 19.302 )

No statistical analyses for this end point

Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 in Euroqol Questionnaire-5 Dimensions 5 levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score

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End point title

Change from Baseline to the Average Value of Weeks 12 to 28 in Euroqol Questionnaire-5 Dimensions 5 levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score

End point description

Baseline assessment was defined as the value on day 1. The EuroQol Questionnaire -5 Dimensions -5 Levels (EQ-5D-5L) is a self-reported questionnaire, used as a measure of respondents' Health Related Quality of Life (HRQoL) and utility values. The EQ-5D consists of the descriptive system and the visual analogue scale (VAS). The EQ-5D descriptive system comprises 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 endpoints are labeled ‘Best imaginable health state’ and ‘Worst imaginable health state’ with higher scores for higher HRQoL. The analysis population was the FAS, with participants who had available data.

End point type

Secondary

End point timeframe

Baseline and weeks 12 to 28

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	271	300
Units: Units on a scale
least squares mean (confidence interval 95%)	4.353 (2.643 to 6.064)	5.137 (3.498 to 6.776)

Statistical Analysis 1

Statistical analysis description

The model includes treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline EQ-5D 5L VAS, baseline Hb, baseline eGFR as continuous covariates.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

571

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.497

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.784

Confidence interval

level

95%

sides

2-sided

lower limit

-1.481

upper limit

3.049

Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in Work Productivity and Activity Impairment-Anemic Symptoms (WPAI:ANS) Score: Percent Work Time Missed

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End point title

Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in Work Productivity and Activity Impairment-Anemic Symptoms (WPAI:ANS) Score: Percent Work Time Missed

End point description

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Multiply scores by 100 to express in percentages. Percent work time missed due to problem: Q2/(Q2+Q4). The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Baseline, weeks 12 to 28 and 36 to 52

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percent work time
arithmetic mean (standard deviation)
Change from BL to weeks 12-28 (N=35,49)	0.842 ( 21 )	-3.793 ( 32.987 )
Change from BL to weeks 36-52 (N=23,44)	0.216 ( 23.483 )	-0.078 ( 37.047 )

No statistical analyses for this end point

Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in WPAI:ANS Score: Percent Impairment While Working

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End point title

Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in WPAI:ANS Score: Percent Impairment While Working

End point description

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent impairment while working due to problem: Q5/10. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Baseline, weeks 12 to 28 and 36 to 52

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percent impairment
arithmetic mean (standard deviation)
Change from BL to weeks 12-28 (N=34,50)	-2.433 ( 28.598 )	-6.618 ( 22.419 )
Change from BL to weeks 36-52 (N=22,48)	1.083 ( 23.102 )	-7.879 ( 25.872 )

No statistical analyses for this end point

Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in WPAI:ANS Score: Percent Overall Work Impairment

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End point title

Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in WPAI:ANS Score: Percent Overall Work Impairment

End point description

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent overall work impairment due to problem: Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4))x(Q5/10)]. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Baseline, weeks 12 to 28 and 36 to 52

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percent impairment
arithmetic mean (standard deviation)
Change from BL to weeks 12-28 (N=32,49)	-1.217 ( 20.743 )	-6.112 ( 23.21 )
Change From BL to weeks 36-52 (N=21,44)	0.197 ( 23.431 )	2.817 ( 30.432 )

No statistical analyses for this end point

Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in WPAI:ANS Score: Percent Activity Impairment

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End point title

Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in WPAI:ANS Score: Percent Activity Impairment

End point description

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent activity impairment due to problem: Q6/10. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Baseline, weeks 12 to 28 and 36 to 52

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percent impairment
arithmetic mean (standard deviation)
Change from BL to weeks 12-28 (N=300, 269)	-9.34 ( 27.09 )	-9.581 ( 27.367 )
Change from BL to weeks 36-52 (N=270, 254)	-8.17 ( 27.486 )	-9.365 ( 28.956 )

No statistical analyses for this end point

Secondary: Percentage of Participants with Improvements Measured by Patients' Global Impression of Change (PGIC)

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End point title

Percentage of Participants with Improvements Measured by Patients' Global Impression of Change (PGIC)

End point description

The PGIC is a patient-rated instrument that measured change in participant's overall status on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), when compared to the start of treatment. The percentage of participants presented included very much improved, much improved and minimally improved. The analysis population was the FAS.

End point type

Secondary

End point timeframe

Weeks 8, 12, 28, 52, 76, 104, last assessment (week 108)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (not applicable)
Week 8	79.4	76.1
Week 12	83.6	83.7
Week 28	81	83
Week 52	79.8	79.3
Week 76	74.9	73
Week 104	76	71.8
Last Assessment (week 108)	71.4	70.6

No statistical analyses for this end point

Secondary: Change from Baseline to Each Scheduled Measurement Serum Ferritin

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End point title

Change from Baseline to Each Scheduled Measurement Serum Ferritin

End point description

Baseline assessment was 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. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

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 and end of study (EOS) (up to 108 weeks)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Picomoles per liter (pmol/L)
arithmetic mean (standard deviation)
Week 4 (N=316, 288)	-159.174 ( 218.981 )	-190.762 ( 241.695 )
Week 8 (N=307, 280)	-208.356 ( 309.893 )	-229.471 ( 255.677 )
Week 12 (N=300, 271)	-201.587 ( 346.59 )	-205.722 ( 271.752 )
Week 20 (N=286, 265)	-140.26 ( 338.512 )	-99.86 ( 334.486 )
Week 28 (N=286, 262)	-121.574 ( 348.136 )	-97.622 ( 366.153 )
Week 36 (N=271, 256)	-120.424 ( 362.08 )	-131.801 ( 355.463 )
Week 44 (N=261, 250)	-60.149 ( 425.455 )	-120.864 ( 368.902 )
Week 52 (N=254, 241)	-72.383 ( 459.342 )	-93.074 ( 521.433 )
Week 60 (N=252, 243)	-47.714 ( 459.319 )	-141.264 ( 355.419 )
Week 68 (N=245, 239)	-14.283 ( 464.714 )	-110.907 ( 422.28 )
Week 76 (N=235, 230)	3.424 ( 615.735 )	-99.697 ( 412.982 )
Week 84 (N=224, 221)	-1.351 ( 576.437 )	-126.615 ( 403.693 )
Week 92 (N=222, 219)	-26.73 ( 547.371 )	-98.025 ( 460.364 )
Week 100 (N=216, 206)	31.391 ( 750.432 )	-95.513 ( 486.758 )
Week 104 (N=212, 208)	26.454 ( 730.126 )	-89.276 ( 476.167 )
EOS (N=245, 225)	119.157 ( 697.39 )	78.577 ( 680.524 )

No statistical analyses for this end point

Secondary: Change from Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT)

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End point title

Change from Baseline to Each Scheduled Measurement in 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 and EOS (up to 108 weeks)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of saturation
arithmetic mean (standard deviation)
Week 4 (N=312, 287)	-2.1 ( 11.5 )	-6 ( 10.7 )
Week 8 (N=304, 278)	-2.4 ( 10.6 )	-5.9 ( 11.5 )
Week 12 (N=294, 268)	-0.5 ( 12.3 )	-2.4 ( 13.2 )
Week 20 (N=286, 263)	2.9 ( 11.6 )	1.6 ( 13.9 )
Week 28 (N=284, 263)	4 ( 12.5 )	1.1 ( 12.5 )
Week 36 (N=270, 256)	3.9 ( 11.5 )	1.6 ( 12 )
Week 44 (N=259, 247)	4.9 ( 12.9 )	0.6 ( 12 )
Week 52 (N=252, 242)	5.2 ( 13.2 )	1.3 ( 11.8 )
Week 60 (N=250, 238)	4.8 ( 12.7 )	0.4 ( 12.4 )
Week 68 (N=245, 237)	6.3 ( 13.1 )	1 ( 13.4 )
Week 76 (N=235, 228)	6 ( 13.7 )	0.1 ( 12.2 )
Week 84 (N=222, 220)	6.5 ( 13.9 )	1.1 ( 12.5 )
Week 92 (N=222, 216)	5.6 ( 13.8 )	-0.2 ( 11.7 )
Week 100 (N=214, 201)	5.8 ( 14 )	0.6 ( 12.4 )
Week 104 (N=210, 207)	5 ( 13.3 )	0.5 ( 11.9 )
EOS (N=242, 222)	4.7 ( 13.9 )	5.3 ( 12.3 )

No statistical analyses for this end point

Secondary: Change from Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c)

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End point title

Change from Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c)

End point description

Percentage of change from baseline to each study visit were calculated for HbA1c. Baseline assessment was 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. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Baseline and weeks 12, 28, 36, 44, 60, 84, 104 and EOS (up to 108 weeks)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of HbA1c
arithmetic mean (standard deviation)
Week 12 (N=296, 267)	0.001 ( 0.0073 )	0.0021 ( 0.0071 )
Week 28 (N=277, 256)	0.0015 ( 0.0067 )	0.0009 ( 0.0072 )
Week 36 (N=265, 252)	0.0021 ( 0.0073 )	0.0021 ( 0.0075 )
Week 44 (N=254, 249)	0.002 ( 0.0066 )	0.0026 ( 0.0077 )
Week 60 (N=250, 242)	0.0019 ( 0.0074 )	0.0025 ( 0.0083 )
Week 84 (N=223, 222)	0.0025 ( 0.0077 )	0.0024 ( 0.0093 )
Week 104 (N=212, 202)	0.002 ( 0.008 )	0.0018 ( 0.0086 )
EOS (N=244, 225)	0.0034 ( 0.0081 )	0.0031 ( 0.0087 )

No statistical analyses for this end point

Secondary: Change from Baseline to Each Scheduled Measurement in Fasting Blood Glucose

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End point title

Change from Baseline to Each Scheduled Measurement 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, 106 and EOS (up to 108 weeks)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: mg/dL
arithmetic mean (standard deviation)
Week 4 (N=169, 143)	10.3 ( 76.9 )	7 ( 62.8 )
Week 8 (N=168, 136)	1.3 ( 40.3 )	4.1 ( 60.1 )
Week 12 (N=156, 134)	7.1 ( 58.2 )	9.3 ( 64.5 )
Week 20 (N=147, 131)	4.3 ( 57.9 )	6.9 ( 69.4 )
Week 28 (N=137, 122)	2.8 ( 37.7 )	8.7 ( 66.9 )
Week 36 (N=133, 126)	3.6 ( 45.3 )	6.4 ( 52.5 )
Week 44 (N=129, 123)	0.4 ( 45.1 )	3.3 ( 44.7 )
Week 52 (N=129, 115)	1.1 ( 41.1 )	7.1 ( 69.7 )
Week 60 (N=121, 104)	6.3 ( 43.1 )	6.6 ( 65.6 )
Week 68 (N=119, 109)	5.5 ( 48.2 )	3.8 ( 66.1 )
Week 76 (N=113, 102)	5.8 ( 55.2 )	0.9 ( 41.9 )
Week 84 (N=115, 101)	12 ( 57.4 )	1.4 ( 49.1 )
Week 92 (N=107, 95)	2.1 ( 46.5 )	6 ( 69.5 )
Week 100 (N=101, 87)	4 ( 48.9 )	2.7 ( 45.3 )
Week 104 (N=104, 90)	1 ( 48.6 )	-2.6 ( 60.7 )
Week 106 (N=106, 92)	9.2 ( 53.3 )	-2.4 ( 31.2 )
EOS (N=116, 100)	9.8 ( 43.6 )	2.5 ( 58.2 )

No statistical analyses for this end point

Secondary: Change from Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR)

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End point title

Change from Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR)

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, 106 and EOS (up to 108 weeks)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Geometric mean ratio
geometric mean (confidence interval 95%)
Week 4 (N=311, 284)	0.97 (0.95 to 0.99)	1.01 (0.99 to 1.03)
Week 8 (N=300, 272)	0.96 (0.94 to 0.99)	1.01 (0.98 to 1.03)
Week 12 (N=286, 261)	0.95 (0.93 to 0.98)	1.02 (1.00 to 1.05)
Week 20 (N=267, 249)	0.93 (0.90 to 0.96)	0.98 (0.95 to 1.01)
Week 28 (N=252, 244)	0.89 (0.86 to 0.93)	0.93 (0.89 to 0.96)
Week 36 (N=227, 227)	0.89 (0.85 to 0.93)	0.93 (0.89 to 0.97)
Week 44 (N=211, 209)	0.89 (0.84 to 0.93)	0.90 (0.86 to 0.93)
Week 52 (N=200, 191)	0.88 (0.83 to 0.92)	0.90 (0.86 to 0.94)
Week 60 (N=189, 182)	0.86 (0.82 to 0.91)	0.90 (0.86 to 0.94)
Week 68 (N=177, 174)	0.84 (0.79 to 0.89)	0.87 (0.83 to 0.91)
Week 76 (N=167, 166)	0.84 (0.78 to 0.90)	0.83 (0.78 to 0.88)
Week 84 (N=155, 157)	0.83 (0.77 to 0.89)	0.83 (0.78 to 0.88)
Week 92 (N=152, 151)	0.85 (0.79 to 0.90)	0.84 (0.79 to 0.90)
Week 100 (N=145, 141)	0.86 (0.81 to 0.92)	0.84 (0.78 to 0.89)
Week 104 (N=142, 140)	0.84 (0.79 to 0.91)	0.84 (0.79 to 0.90)
Week 106 (N=154, 139)	0.86 (0.79 to 0.92)	0.84 (0.78 to 0.90)
EOS (N=159, 146)	0.85 (0.79 to 0.92)	0.86 (0.81 to 0.91)

No statistical analyses for this end point

Secondary: Rate of Progression of Chronic Kidney Disease Measured by eGFR Slope Over Time

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End point title

Rate of Progression of Chronic Kidney Disease Measured by 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 dialysis (acute or chronic) were 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.

End point type

Secondary

End point timeframe

Baseline up to EOS (Up to week 108)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: change/ year in ml/min per 1.73 m^2
least squares mean (confidence interval 95%)	-2.89 (-3.51 to -2.27)	-2.95 (-3.56 to -2.34)

Statistical Analysis 1

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.902

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.93

upper limit

0.82

Secondary: Change from Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR)

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End point title

Change from Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR)

End point description

End point type

Secondary

End point timeframe

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

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Geometric mean ratio
geometric mean (confidence interval 95%)
Week 12 (N=230, 214)	1.23 (1.1 to 1.38)	1.19 (1.07 to 1.34)
Week 24 (N=225, 200)	1.22 (1.08 to 1.39)	1.18 (1.06 to 1.33)
Week 36 (N=187, 181)	1.18 (1.03 to 1.36)	1.22 (1.07 to 1.4)
Week 52 (N=164, 147)	1.1 (0.92 to 1.32)	1.28 (1.1 to 1.49)
Week 64 (N=149, 141)	1.11 (0.9 to 1.38)	1.23 (1.03 to 1.46)
Week 76 (N=135, 133)	1.18 (0.94 to 1.48)	1.39 (1.14 to 1.7)
Week 88 (N=122, 119)	1.1 (0.86 to 1.39)	1.21 (0.97 to 1.5)
Week 104 (N=109, 101)	1.18 (0.92 to 1.51)	1.46 (1.17 to 1.82)

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

For participants who had doubled their serum creatinine or had chronic dialysis or renal transplant more than once, only their first occurrence during safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Year 0.5, 1, 1.5 and 2

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5 (N=255, 247)	8.6 (5.3 to 11.9)	12.9 (9.1 to 16.6)
Year 1 (N=196, 186)	27.2 (21.9 to 32.6)	27.4 (22.3 to 32.6)
Year 1.5 (N=155, 148)	38.8 (32.9 to 44.7)	38.2 (32.5 to 44)
Year 2 (N=122, 113)	45.4 (39.2 to 51.5)	46.5 (40.5 to 52.5)

Statistical Analysis 1

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 was declared if the upper bound of the 95% CI was below 1.0.

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.96

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

1.29

Secondary: Number of Participants With End Stage Renal Disease (ESRD)

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End point title

Number of Participants With End Stage Renal Disease (ESRD)

End point description

Occurrence of end stage renal disease during the study (i.e from day 1 up to the end of study) was defined as at least one of the following: underwent >30 days dialysis therapy, received kidney transplant, planned kidney transplant, physician recommended renal replacement therapy and participant refused therapy, began dialysis and died < 30 days later. The analysis population was the FAS.

End point type

Secondary

End point timeframe

Baseline up to EOS (Up to week 108)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Participants	107	110

No statistical analyses for this end point

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

End point description

Chronic kidney disease progression was defined as date of occurrence of chronic dialysis or date of renal transplant or doubled serum creatinine or date of death, whichever came first. For participants who had chronic dialysis or renal transplant or died, only their first occurrence during the safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Year 0.5, 1, 1.5 and 2

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5 (N=255, 247)	10.2 (6.7 to 13.8)	14 (10.1 to 17.9)
Year 1 (N=196, 186)	29.5 (24.1 to 34.9)	30.9 (25.6 to 36.2)
Year 1.5 (N=155, 148)	42.6 (36.6 to 48.5)	42.1 (36.4 to 47.8)
Year 2 (N=122, 113)	51 (44.9 to 57)	49.9 (44 to 55.8)

Statistical Analysis 1

Statistical analysis description

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.939

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

1.25

Secondary: Time to Chronic Dialysis or Renal Transplant or Death

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End point title

Time to Chronic Dialysis or Renal Transplant or Death

End point description

For participants who had chronic dialysis or renal transplant or died, only their first occurrence during the safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Year 0.5, 1, 1.5 and 2

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5 (N=259, 250)	9.2 (5.8 to 12.6)	12.7 (9 to 16.4)
Year 1 (N=207, 195)	26.2 (21 to 31.4)	27.1 (22 to 32.2)
Year 1.5 (N=169, 161)	37.7 (31.9 to 43.5)	37.1 (31.6 to 42.7)
Year 2 (N=139, 126)	45.6 (39.6 to 51.7)	42.9 (37.1 to 48.7)

Statistical Analysis 1

Statistical analysis description

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.948

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

1.27

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

For participants who had at least 40% decrease in eGFR from baseline, chronic dialysis or renal transplant during the safety emergent period, only their first occurrence was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. The analysis population was the FAS. Percentage of participants were reported in this outcome measure. Here, N signifies participants with available data at specified time points.

End point type

Secondary

End point timeframe

Year 0.5, 1, 1.5 and 2

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	292	322
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5 (N=248, 235)	13 (9 to 16.9)	15.4 (11.3 to 19.5)
Year 1 (N=178, 166)	35.5 (29.8 to 41.3)	34.5 (29 to 40)
Year 1.5 (N=133, 122)	50.2 (44.1 to 56.3)	47.2 (41.3 to 53.1)
Year 2 (N=104, 85)	59.3 (53.2 to 65.3)	55.7 (49.7 to 61.7)

Statistical Analysis 1

Statistical analysis description

Comparison groups

Roxadustat v Darbepoetin alfa

Number of subjects included in analysis

614

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.568

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.17

Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

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End point title

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

End point description

An AE was defined as any untoward medical occurrence in a participant who was given the study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. All AEs collected during the safety emergent period were counted as TEAE. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Based on national cancer institute common terminology criteria (NCI-CTCAE), AEs were graded as grade 1=mild, grade 2=moderate, grade 3 =severe or medically significant, grade 4 =life threatening, grade 5 =death related to AE. All reported deaths after the first study drug administration and up to 28 days after the analysis date of last dose were based on last dosing frequency. The Safety Analysis Set included all randomized participants who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline up to EOS (Up to week 108)

End point values	Darbepoetin alfa	Roxadustat
Number of subjects analysed	293	323
Units: Participants
TEAE	271	296
Drug-Related TEAE	66	78
Serious TEAE	181	209
Drug-Related Serious TEAE	9	18
TEAE Leading to Death	34	34
Drug-Related TEAE Leading to Death	0	2
TEAE Leading to Withdrawal of Treatment	11	25
Drug-Related TEAE Leading to Withdraw of Treatment	1	7
NCI CTCAE Grades 3 or Higher	164	181

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug up to end of study (up to week 108)

Adverse event reporting additional description

Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Darbepoetin alfa

Reporting group description

Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 μg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 μg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment 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 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 darbepoetin alfa 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 darbepoetin alfa for up to a maximum of 104 weeks.

Reporting group title

Roxadustat

Reporting group description

Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 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 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 up to a maximum of 104 weeks.

Serious adverse events	Darbepoetin alfa	Roxadustat
Total subjects affected by serious adverse events
subjects affected / exposed	181 / 293 (61.77%)	209 / 323 (64.71%)
number of deaths (all causes)	37	40
number of deaths resulting from adverse events	34	34
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma gastric
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 293 (0.00%)	4 / 323 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Benign neoplasm of thyroid gland
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Benign renal neoplasm
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Breast cancer stage I
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Carcinoma in situ of skin
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic myelomonocytic leukaemia
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatocellular carcinoma
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Malignant melanoma
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Meningioma
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastasis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Oesophageal adenocarcinoma
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Parathyroid tumour benign
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	2 / 293 (0.68%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Small cell lung cancer metastatic
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine neoplasm
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Aortic intramural haematoma
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood pressure fluctuation
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 293 (0.34%)	4 / 323 (1.24%)
occurrences causally related to treatment / all	0 / 1	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism arterial
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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	5 / 293 (1.71%)	8 / 323 (2.48%)
occurrences causally related to treatment / all	3 / 6	1 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	5 / 293 (1.71%)	5 / 323 (1.55%)
occurrences causally related to treatment / all	2 / 6	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	2 / 293 (0.68%)	4 / 323 (1.24%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1
Hypovolaemic shock
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Iliac artery occlusion
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
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	4 / 293 (1.37%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	2 / 293 (0.68%)	4 / 323 (1.24%)
occurrences causally related to treatment / all	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 293 (0.68%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac death
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Catheter site haemorrhage
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site pain
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 293 (0.34%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Complication associated with device
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	4 / 293 (1.37%)	5 / 323 (1.55%)
occurrences causally related to treatment / all	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 4	0 / 5
General physical health deterioration
subjects affected / exposed	4 / 293 (1.37%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	1 / 293 (0.34%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Inflammation
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Immune system disorders
Anti-neutrophil cytoplasmic antibody positive vasculitis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal transplant failure
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sarcoidosis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
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
Menometrorrhagia
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopulmonary disease
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	2 / 293 (0.68%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Dyspnoea
subjects affected / exposed	0 / 293 (0.00%)	6 / 323 (1.86%)
occurrences causally related to treatment / all	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Emphysema
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hydrothorax
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	4 / 293 (1.37%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 293 (0.68%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary fibrosis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	3 / 293 (1.02%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	2 / 293 (0.68%)	4 / 323 (1.24%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 2
Pulmonary vasculitis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	2 / 293 (0.68%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Psychiatric disorders
Alcoholism
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Confusional state
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium
subjects affected / exposed	2 / 293 (0.68%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Frustration tolerance decreased
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device leakage
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Blood glucose increased
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood potassium increased
subjects affected / exposed	2 / 293 (0.68%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Blood sodium increased
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
C-reactive protein increased
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerular filtration rate decreased
subjects affected / exposed	25 / 293 (8.53%)	26 / 323 (8.05%)
occurrences causally related to treatment / all	0 / 37	0 / 28
deaths causally related to treatment / all	0 / 2	0 / 0
Haemoglobin decreased
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Occult blood positive
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arterial bypass occlusion
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site complication
subjects affected / exposed	1 / 293 (0.34%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site haematoma
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula thrombosis
subjects affected / exposed	5 / 293 (1.71%)	9 / 323 (2.79%)
occurrences causally related to treatment / all	2 / 5	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Brain contusion
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest injury
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Complications of transplanted kidney
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Fall
subjects affected / exposed	2 / 293 (0.68%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
Femur fracture
subjects affected / exposed	0 / 293 (0.00%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple injuries
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritoneal dialysis complication
subjects affected / exposed	2 / 293 (0.68%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative wound complication
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt malfunction
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt occlusion
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin injury
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic rupture
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	2 / 293 (0.68%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Synovial rupture
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary anastomotic leak
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access malfunction
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access site bruising
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access site swelling
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access site thrombosis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular pseudoaneurysm
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 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	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lown-Ganong-Levine syndrome
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinocerebellar ataxia
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	2 / 293 (0.68%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	8 / 293 (2.73%)	5 / 323 (1.55%)
occurrences causally related to treatment / all	1 / 10	2 / 5
deaths causally related to treatment / all	0 / 2	1 / 3
Angina pectoris
subjects affected / exposed	5 / 293 (1.71%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 293 (0.34%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 293 (0.34%)	4 / 323 (1.24%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	3 / 293 (1.02%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 2
Cardiac failure
subjects affected / exposed	10 / 293 (3.41%)	12 / 323 (3.72%)
occurrences causally related to treatment / all	0 / 15	1 / 15
deaths causally related to treatment / all	0 / 3	0 / 2
Cardiac failure acute
subjects affected / exposed	6 / 293 (2.05%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 7	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 3
Cardiac failure chronic
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	10 / 293 (3.41%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 12	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiogenic shock
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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	3 / 293 (1.02%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Long QT syndrome
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial fibrosis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
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	0 / 293 (0.00%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 2
Myocardial ischaemia
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nodal arrhythmia
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus node dysfunction
subjects affected / exposed	1 / 293 (0.34%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Trifascicular block
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Carotid artery stenosis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Central nervous system lesion
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
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	2 / 293 (0.68%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cognitive disorder
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coma
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic neuropathy
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	2 / 293 (0.68%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 293 (0.34%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Headache
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemic coma
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemic unconsciousness
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxic-ischaemic encephalopathy
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
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	3 / 293 (1.02%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0
Lumbar radiculopathy
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Simple partial seizures
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Somnolence
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	3 / 293 (1.02%)	6 / 323 (1.86%)
occurrences causally related to treatment / all	0 / 3	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Thalamus haemorrhage
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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 / 293 (1.02%)	4 / 323 (1.24%)
occurrences causally related to treatment / all	1 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Uraemic encephalopathy
subjects affected / exposed	2 / 293 (0.68%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	6 / 293 (2.05%)	5 / 323 (1.55%)
occurrences causally related to treatment / all	0 / 7	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic anaemia
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocoagulable state
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
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 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Ear and labyrinth disorders
Deafness neurosensory
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Glaucoma
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Macular degeneration
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal artery occlusion
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal incarcerated hernia
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal haemorrhage
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bloody peritoneal effluent
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Colitis microscopic
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 293 (0.68%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum intestinal
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric antral vascular ectasia
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer perforation
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 293 (0.34%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis erosive
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis haemorrhagic
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 293 (0.34%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedematous pancreatitis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reactive gastropathy
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subileus
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tongue haemorrhage
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	0 / 293 (0.00%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary colic
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	3 / 293 (1.02%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic congestion
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis toxic
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Liver injury
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Portal vein thrombosis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Decubitus ulcer
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
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	1 / 293 (0.34%)	0 / 323 (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 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	0 / 293 (0.00%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Toxic epidermal necrolysis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	7 / 293 (2.39%)	7 / 323 (2.17%)
occurrences causally related to treatment / all	0 / 10	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 1
Acute prerenal failure
subjects affected / exposed	2 / 293 (0.68%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anuria
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Azotaemia
subjects affected / exposed	3 / 293 (1.02%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
End stage renal disease
subjects affected / exposed	106 / 293 (36.18%)	108 / 323 (33.44%)
occurrences causally related to treatment / all	0 / 106	3 / 108
deaths causally related to treatment / all	0 / 2	0 / 1
Haematuria
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nephropathy toxic
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Obstructive uropathy
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal artery stenosis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal colic
subjects affected / exposed	2 / 293 (0.68%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cyst haemorrhage
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cyst ruptured
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Urinary bladder rupture
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Thyroid mass
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gouty arthritis
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 293 (0.34%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Acute hepatitis B
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial pyelonephritis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Bronchitis
subjects affected / exposed	2 / 293 (0.68%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis viral
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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	2 / 293 (0.68%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium colitis
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	3 / 293 (1.02%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	4 / 293 (1.37%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal sepsis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis bacterial
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia pyelonephritis
subjects affected / exposed	2 / 293 (0.68%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	2 / 293 (0.68%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gangrene
subjects affected / exposed	0 / 293 (0.00%)	4 / 323 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
Gastritis viral
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	3 / 293 (1.02%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Groin abscess
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic cyst infection
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	4 / 293 (1.37%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Klebsiella sepsis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphangitis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nosocomial infection
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal candidiasis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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 / 293 (0.34%)	0 / 323 (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	3 / 293 (1.02%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Parotitis
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	3 / 293 (1.02%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	14 / 293 (4.78%)	21 / 323 (6.50%)
occurrences causally related to treatment / all	0 / 17	0 / 23
deaths causally related to treatment / all	0 / 4	0 / 1
Pneumonia bacterial
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pneumonia viral
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural sepsis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pyelonephritis acute
subjects affected / exposed	7 / 293 (2.39%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 10	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis chronic
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cyst infection
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Salpingo-oophoritis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (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	9 / 293 (3.07%)	7 / 323 (2.17%)
occurrences causally related to treatment / all	0 / 9	0 / 8
deaths causally related to treatment / all	0 / 1	0 / 3
Skin infection
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 293 (0.00%)	4 / 323 (1.24%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal skin infection
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal endocarditis
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tubo-ovarian abscess
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection bacterial
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	3 / 293 (1.02%)	7 / 323 (2.17%)
occurrences causally related to treatment / all	0 / 4	0 / 7
deaths causally related to treatment / all	0 / 1	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	1 / 293 (0.34%)	5 / 323 (1.55%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection enterococcal
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection pseudomonal
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	3 / 293 (1.02%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Viral infection
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Alkalosis
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Alkalosis hypochloraemic
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	7 / 293 (2.39%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 10	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic metabolic decompensation
subjects affected / exposed	0 / 293 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	1 / 293 (0.34%)	4 / 323 (1.24%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	6 / 293 (2.05%)	7 / 323 (2.17%)
occurrences causally related to treatment / all	0 / 6	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Hypervolaemia
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypochloraemia
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 293 (0.34%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	1 / 293 (0.34%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 293 (0.68%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Iron deficiency
subjects affected / exposed	1 / 293 (0.34%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	2 / 293 (0.68%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Mineral deficiency
subjects affected / exposed	0 / 293 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Darbepoetin alfa	Roxadustat
Total subjects affected by non serious adverse events
subjects affected / exposed	203 / 293 (69.28%)	223 / 323 (69.04%)
Investigations
Glomerular filtration rate decreased
subjects affected / exposed	28 / 293 (9.56%)	33 / 323 (10.22%)
occurrences all number	30	35
Vascular disorders
Hypertension
subjects affected / exposed	97 / 293 (33.11%)	93 / 323 (28.79%)
occurrences all number	149	129
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	11 / 293 (3.75%)	16 / 323 (4.95%)
occurrences all number	15	18
Nervous system disorders
Dizziness
subjects affected / exposed	13 / 293 (4.44%)	16 / 323 (4.95%)
occurrences all number	15	20
Headache
subjects affected / exposed	12 / 293 (4.10%)	20 / 323 (6.19%)
occurrences all number	12	23
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	36 / 293 (12.29%)	48 / 323 (14.86%)
occurrences all number	52	59
Gastrointestinal disorders
Constipation
subjects affected / exposed	15 / 293 (5.12%)	21 / 323 (6.50%)
occurrences all number	18	23
Diarrhoea
subjects affected / exposed	28 / 293 (9.56%)	27 / 323 (8.36%)
occurrences all number	36	38
Nausea
subjects affected / exposed	24 / 293 (8.19%)	35 / 323 (10.84%)
occurrences all number	26	40
Vomiting
subjects affected / exposed	19 / 293 (6.48%)	21 / 323 (6.50%)
occurrences all number	22	31
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	12 / 293 (4.10%)	19 / 323 (5.88%)
occurrences all number	13	20
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	13 / 293 (4.44%)	20 / 323 (6.19%)
occurrences all number	13	27
Psychiatric disorders
Insomnia
subjects affected / exposed	8 / 293 (2.73%)	19 / 323 (5.88%)
occurrences all number	9	19
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	14 / 293 (4.78%)	18 / 323 (5.57%)
occurrences all number	19	21
Back pain
subjects affected / exposed	16 / 293 (5.46%)	20 / 323 (6.19%)
occurrences all number	19	22
Muscle spasms
subjects affected / exposed	15 / 293 (5.12%)	25 / 323 (7.74%)
occurrences all number	20	33
Infections and infestations
Bronchitis
subjects affected / exposed	17 / 293 (5.80%)	21 / 323 (6.50%)
occurrences all number	21	27
Urinary tract infection
subjects affected / exposed	24 / 293 (8.19%)	17 / 323 (5.26%)
occurrences all number	29	24
Viral upper respiratory tract infection
subjects affected / exposed	25 / 293 (8.53%)	29 / 323 (8.98%)
occurrences all number	30	33
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	39 / 293 (13.31%)	34 / 323 (10.53%)
occurrences all number	44	38
Hyperphosphataemia
subjects affected / exposed	15 / 293 (5.12%)	28 / 323 (8.67%)
occurrences all number	18	29
Iron deficiency
subjects affected / exposed	24 / 293 (8.19%)	20 / 323 (6.19%)
occurrences all number	33	24

More information

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Were there any global substantial amendments to the protocol? Yes

18 May 2015

The changes included: a) Changes in the study dosing regimen as follows: 1. Dosing frequency changed from tiw, biw and qw to tiw only; 2. Initial study drug dose changed from 70, 100 and 150 mg to 70 and 100 mg only; 3. Maximum dose reduced from 3.5 mg/kg to 3.0 mg/kg and maximum absolute dose reduced from 400 mg to 300 mg. b) Reduction in the number of treatment groups changed the randomization ratio of roxadustat:darbepoetin from 2:1 to 1:1. c) Reduction in visit schedule by removal of 12 study visits, resulting in 39 visits.

31 Mar 2016

The changes included: 1.The number of Hb values assessed during the screening period was reduced from 3 to 2 and the mean Hb entry threshold was increased from ≤ 10.0 g/dL to ≤ 10.5 g/dL. 2.The iron criteria were updated to better reflect clinical practices, therefore inclusion criteria 6 (ferritin ≥ 100 ng/mL) and 7 (transferrin saturation level ≥ 20% at screening) were removed. 3. Exclusion criterion 21 was extended to exclude participants who were close to initiating renal replacement therapy including dialysis.

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, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of Roxadustat in 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 Hb Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy

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

Secondary: Change from Baseline in Hb to the Average Hb of Weeks 28 to 36 Without Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period

Secondary: Change from Baseline in Hb to the Average Hb of Weeks 28 to 36 Without Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period

Secondary: Change from Baseline in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28

Secondary: Change from Baseline in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28

Secondary: Time to First Intavenous Iron use

Secondary: Time to First Intavenous Iron use

Secondary: Change from Baseline in Short Form-36 (SF-36) Physical Functioning (PF) Sub-Score to the Average PF Sub-Score in Weeks 12 to 28

Secondary: Change from Baseline in Short Form-36 (SF-36) Physical Functioning (PF) Sub-Score to the Average PF Sub-Score in Weeks 12 to 28

Secondary: Change from Baseline in SF-36 Vitality (VT) Sub-Score to the Average VT Sub-Score in Weeks 12 to 28

Secondary: Change from Baseline in SF-36 Vitality (VT) Sub-Score to the Average VT Sub-Score in Weeks 12 to 28

Secondary: Change from Baseline in Mean Arterial Pressure (MAP) to the Average MAP Value in Weeks 20 to 28: Per Protocol Set

Secondary: Change from Baseline in Mean Arterial Pressure (MAP) to the Average MAP Value in Weeks 20 to 28: Per Protocol Set

Secondary: Time to First Occurrence of Hypertension During Weeks 1 to 36: Per Protocol Set

Secondary: Time to First Occurrence of Hypertension During Weeks 1 to 36: Per Protocol Set

Secondary: Change from Baseline in MAP to the Average MAP Value in Weeks 20 to 28: Full Analysis Set

Secondary: Change from Baseline in MAP to the Average MAP Value in Weeks 20 to 28: Full Analysis Set

Secondary: Time to First Occurrence of Hypertension During Weeks 1 to 36: Full Analysis Set

Secondary: Time to First Occurrence of Hypertension During Weeks 1 to 36: Full Analysis Set

Secondary: Change From Baseline in Hb to the Average Hb Value of Weeks 28 to 52 Regardless Use of Rescue Therapy

Secondary: Change From Baseline in Hb to the Average Hb Value of Weeks 28 to 52 Regardless Use of Rescue Therapy

Secondary: Time to First Hb Response During First 24 Weeks of Treatment Regardless of Administration of Rescue Therapy

Secondary: Time to First Hb Response During First 24 Weeks of Treatment Regardless of Administration of Rescue Therapy

Secondary: Time to First Hb Response During First 24 Weeks of Treatment Without Rescue Therapy

Secondary: Time to First Hb Response During First 24 Weeks of Treatment Without Rescue Therapy

Secondary: Hb Level Averaged Over Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80 and Weeks 96 to 104 Without Rescue Therapy

Secondary: Hb Level Averaged Over Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80 and Weeks 96 to 104 Without Rescue Therapy

Secondary: Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of rescue Therapy

Secondary: Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of rescue Therapy

Secondary: Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80, Weeks 96 to 104 Regardless of Use of Rescue Therapy

Secondary: Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80, Weeks 96 to 104 Regardless of Use of Rescue Therapy

Secondary: Percentage of Hb Values ≥ 10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80 and Weeks 96 to 104 Without Use of Rescue Therapy

Secondary: Percentage of Hb Values ≥ 10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80 and Weeks 96 to 104 Without Use of Rescue Therapy

Secondary: Time to First Hb Rate of Rise > 2 g/dL Within 4 weeks

Secondary: Time to First Hb Rate of Rise > 2 g/dL Within 4 weeks

Secondary: Number of Hospitalizations

Secondary: Number of Hospitalizations

Secondary: Number of Days of Hospitalization per Year

Secondary: Number of Days of Hospitalization per Year

Secondary: Time to First Hospitalization

Secondary: Time to First Hospitalization

Secondary: Time to First Use of RBC Transfusion

Secondary: Time to First Use of RBC Transfusion

Secondary: Number of RBC Packs

Secondary: Number of RBC Packs

Secondary: Volume of RBC Transfused

Secondary: Volume of RBC Transfused

Secondary: Number of Particpants who Received RBC Transfusions

Secondary: Number of Particpants who Received RBC Transfusions

Secondary: Time to First Use of Rescue Therapy

Secondary: Time to First Use of Rescue Therapy

Secondary: Number of Participants who Received Rescue Therapy (Composite of RBC Transfusions (all Participants) and Darbepoetin alfa use (Roxadustat Treated Participants only)

Secondary: Number of Participants who Received Rescue Therapy (Composite of RBC Transfusions (all Participants) and Darbepoetin alfa use (Roxadustat Treated Participants only)

Secondary: Mean Monthly Intravenous Iron per Participant During Weeks 37 to 52 and Weeks 53 to 104

Secondary: Mean Monthly Intravenous Iron per Participant During Weeks 37 to 52 and Weeks 53 to 104

Secondary: Time to First Use of IV Iron Supplementation

Secondary: Time to First Use of IV Iron Supplementation

Secondary: Percentage of Participants with Oral Iron Use Only

Secondary: Percentage of Participants with Oral Iron Use Only

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein cholesterol (HDL-C) Ratio

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein cholesterol (HDL-C) Ratio

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1)

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1)

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB)

Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB)

Clinical Trial Results:
A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis