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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 Maintenance Treatment of Anemia in End Stage Renal Disease Patients on Stable Dialysis

Summary
EudraCT number	2013-001497-16
Trial protocol	GB DE IT BE PT HU ES BG HR SK CZ
Global end of trial date	06 Jul 2018

Results information
Results version number	v2(current)
This version publication date	13 Jun 2021
First version publication date	18 Jul 2019
Other versions	v1
Version creation reason

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

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Trial information

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Sponsor protocol code

1517-CL-0613

ISRCTN number

US NCT number

NCT02278341

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

06 Jul 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 Jul 2018

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 epoetin alfa and darbepoetin alfa in the maintenance treatment of anemia in end stage renal disease (ESRD) participants on stable dialysis.

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

Oral iron treatment was recommended for supplementation to support erythropoiesis and as first-line treatment for iron deficiency, unless participant was intolerant to this treatment. For participants receiving roxadustat the recommended daily dose was 200 mg of elemental iron. Participants were advised to take roxadustat at least 1 hour before or 1 hour after oral iron. Intravenous iron supplementation for participants receiving roxadustat was allowed if all of the following criteria were met: The participant’s Hb level had not responded adequately to roxadustat following two consecutive dose increases or reached the maximum dose limit, and participant’s ferritin was < 100 ng/mL (< 220 pmol/L) or TSAT < 20%, or the participant was intolerant of oral iron therapy. For participants treated with epoetin alfa or darbepoetin alfa, IV iron supplementation was given according to standard of care.

Evidence for comparator

Actual start date of recruitment

21 Nov 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 31

Country: Number of subjects enrolled

Bulgaria: 156

Country: Number of subjects enrolled

Croatia: 59

Country: Number of subjects enrolled

Czechia: 16

Country: Number of subjects enrolled

France: 12

Country: Number of subjects enrolled

Georgia: 6

Country: Number of subjects enrolled

Germany: 35

Country: Number of subjects enrolled

Hungary: 136

Country: Number of subjects enrolled

Italy: 40

Country: Number of subjects enrolled

Poland: 29

Country: Number of subjects enrolled

Portugal: 17

Country: Number of subjects enrolled

Romania: 40

Country: Number of subjects enrolled

Russian Federation: 98

Country: Number of subjects enrolled

Serbia: 86

Country: Number of subjects enrolled

Slovakia: 32

Country: Number of subjects enrolled

Spain: 29

Country: Number of subjects enrolled

United Kingdom: 14

Worldwide total number of subjects

836

EEA total number of subjects

632

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)

452

From 65 to 84 years

361

85 years and over

Subject disposition

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Recruitment details

Study population consisted of participants with end-stage renal disease (ESRD) who were on stable hemodialysis (HD) or peritoneal dialysis (PD, and were also on stable treatment with epoetin (i.e. epoetin alfa, beta, theta, zeta, delta or omega) or darbepoetin alfa for anemia.

Screening details

Participants were randomized in a 1:1 ratio, receiving roxadustat or ESA (epoetin alfa or darbepoetin alfa). Randomization was stratified by 5 factors: previous ESA treatment, region, history of cardiovascular, cerebrovascular or thromboembolic diseases, average weekly ESA dose 4 weeks prior to randomization and the screening hemaglobin (Hb) value.

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

Roxadustat

Arm description

Participants received roxadustat three times a week (TIW) for at least 52 weeks up to a maximum of 104 weeks. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant’s Hb levels between 10.0 to 12.0 g/dL. Dose adjustment steps were as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. Oral iron treatment of 200 mg was allowed for supplementation to support erythropoiesis. Treatment with intravenous iron was allowed only if certain protocol criteria were met.

Arm type

Experimental

Investigational medicinal product name

Roxadustat

Investigational medicinal product code

ASP1517, FG-4592

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received initial dose of roxadustat in doses of 100 mg, 150 mg or 200 mg, according to the average weekly dose of epoetin or darbepoetin alfa prior to randomization. Participants' roxadustat dosage was adjusted every 4 weeks to maintain Hb level within the target range 10.0 to 12.0 g/dL. Dose adjustment steps were as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. Oral iron treatment of 200 mg was allowed for supplementation to support erythropoiesis. Treatment with intravenous iron was allowed only if certain protocol criteria were met.

ESA (Erythropoiesis-Stimulating Agent)

Arm description

Participants received epoetin alfa once weekly, twice weekly or TIW and darbepoetin alfa once a week or once every other week. Participants were treated for at least 52 weeks up to a maximum of 104 weeks. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant’s Hb levels between 10.0 to 12.0 g/dL. Participants were not allowed to switch from epoetin alfa to darbepoetin alfa or vice versa.

Arm type

Active comparator

Investigational medicinal product name

Epoetin alfa

Investigational medicinal product code

Other name

Eprex®

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

Participants received epoetin alfa once a week, twice a week, or three times a week (TIW). Epoetin alfa dosage was adjusted to maintain Hb level within the target range. Dosing of epoetin alfa was per UK SmPC of Eprex®. Participants received IV iron supplementation according to the standard of care.

Investigational medicinal product name

Darbepoetin alfa

Investigational medicinal product code

Other name

Aranesp®

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

Participants received darbepoetin alfa once a week or once every other week. Darbepoetin alfa dosage was adjusted to maintain Hb level within the target range. Dosing of darbepoetin alfa was per EU SmPC of Aranesp®. Participants received IV iron supplementation according to the standard of care.

Number of subjects in period 1	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Started	415	421
Received Treatment	414	420
Completed	297	329
Not completed	118	92
Randomized but never received study drug	1	1
Physician decision	1	1
Adverse event, non-fatal	3	-
Death	68	56
Micellaneous	15	14
Withdrawal by Subject	30	19
Lost to follow-up	-	1

Baseline characteristics

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Reporting group title

Roxadustat

Reporting group description

Reporting group title

ESA (Erythropoiesis-Stimulating Agent)

Reporting group description

Reporting group values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)	Total
Number of subjects	415	421
Age categorical
Units: Subjects
Age continuous
The analysis population was the All randomized population, which consisted of participants who were randomized into the study.
Units: years
arithmetic mean (standard deviation)	61 ( 13.8 )	61.8 ( 13.4 )	-
Gender categorical
The analysis population was the All randomized population, which consisted of participants who were randomized into the study.
Units: Subjects
Male	246	236	482
Female	169	185	354
Race
The analysis population was the All randomized, which consisted of participants who were randomized into the study.
Units: Subjects
WHITE	405	408	813
BLACK OR AFRICAN AMERICAN	6	6	12
ASIAN	2	3	5
OTHER	2	4	6
Baseline Hemoglobin (Hb) Value
The analysis population was the All randomized, which consisted of participants who were randomized into the study.
Units: Subjects
<=11.0 g/dL	267	266	533
>11.0 g/dL	148	155	303
Baseline Mean Hb
Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose). The analysis population was the All randomized, which consisted of participants who were randomized into the study.
Units: g/dL
arithmetic mean (standard deviation)	10.75 ( 0.62 )	10.77 ( 0.62 )	-

End points

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Reporting group title

Roxadustat

Reporting group description

Reporting group title

ESA (Erythropoiesis-Stimulating Agent)

Reporting group description

Primary: Change From Baseline (BL) to the Average Hemoglobin (Hb) in Weeks 28-36 Without Rescue Therapy [EU (EMA)]

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End point title

Change From Baseline (BL) to the Average Hemoglobin (Hb) in Weeks 28-36 Without Rescue Therapy [EU (EMA)]

End point description

Baseline Hb was defined as the mean of four central laboratory Hb values: four latest Hb values prior or on the same date as the first study drug intake. For participants who did not have an available Hb value during the week 28-36 period, imputation rules were applied. For analyses without rescue therapy, participants who used rescue therapy after the initiation of rescue therapy were set to missing for 6 weeks from the start date of rescue therapy. If no Hb value was available, an imputation technique was used, with the mean of all available values from Day 1 to minimum (End of Efficacy Emergent Period ) carried forward. 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 and weeks 28 to 36

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	354	381
Units: g/dL
least squares mean (confidence interval 95%)	0.428 (0.350 to 0.506)	0.193 (0.117 to 0.268)

Statistical analysis 1

Statistical analysis description

The model includes treatment arm, region, CV History, previous ESA treatment, visits and visit by treatment as categorical variables and baseline Hb and baseline Hb by visit as continuous variable.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

735

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

P-value

< 0.001 ^[2]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.235

Confidence interval

level

95%

sides

2-sided

lower limit

0.132

upper limit

0.339

Notes
[1] - Non Inferiority, Margin = -0.75
[2] - p-value for non-inferiority test based on 1-sided significance level.

Primary: Change From BL to the Average Hb in Weeks 28 to 52 Regardless of Rescue Therapy [US (FDA)]

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End point title

Change From BL to the Average Hb in Weeks 28 to 52 Regardless of Rescue Therapy [US (FDA)]

End point description

Baseline Hb was defined as the mean of four central laboratory Hb values: four latest Hb values prior or on the same date as first study drug intake. Change from baseline to the average Hb are observed values. Missing hemoglobin data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model with treatment, baseline hemoglobin, randomization stratification factors and the available non missing hemoglobin for each scheduled week. The analysis population was the All Randomized, which consisted of participants who received at least one dose of study drug, and who had available data.

End point type

Primary

End point timeframe

Baseline and weeks 28 to 52

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: g/dL
least squares mean (confidence interval 95%)	0.363 (0.288 to 0.438)	0.192 (0.121 to 0.262)

Statistical analysis 1

Statistical analysis description

The model includes treatment arm, region, CV History, previous ESA treatment as categorical variables and baseline Hb as continuous variable. Statistical analysis used was ANCOVA model with multiple imputations (MI). Missing hemoglobin data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the MCMC imputation model.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

P-value

< 0.001 ^[4]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

0.171

Confidence interval

level

95%

sides

2-sided

lower limit

0.082

upper limit

0.261

Notes
[3] - Non-Inferiority, Margin = -0.75
[4] - p-value for non-inferiority test based on 1-sided significance level.

Secondary: Percentage of Participants with Hb Response During Weeks 28 to 36

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End point title

Percentage of Participants with Hb Response During Weeks 28 to 36

End point description

Hb response during weeks 28–36, was defined as mean Hb from 10–12 g/dL without receiving rescue therapy in the 6 weeks prior to, or during, the evaluation period. The percentages and 95% CI were unadjusted, the exact method of Clopper-Pearson was used for 95% CI. 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). The analysis population was the PPS.

End point type

Secondary

End point timeframe

Weeks 28 to 36

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	386	397
Units: Percentage of participants
number (confidence interval 95%)	84.2 (80.2 to 87.7)	82.4 (78.3 to 86.0)

Statistical analysis 1

Statistical analysis description

A generalized linear model was used to estimate the difference in response rates between the arms, as an approximation for the Miettinen and Nurminen method, adjusting for following covariates: region, previous ESA treatment, cardiovascular history and baseline Hb as categorical variables.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

783

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

P-value

< 0.05 ^[6]

Method

Miettinen and Nurminen

Parameter type

Difference of Percentages

Point estimate

2.3

Confidence interval

level

95%

sides

2-sided

lower limit

-2.9

upper limit

7.6

Notes
[5] - Non-inferiority of roxadustat versus ESA (the non-inferiority margin for the difference between groups is -15%).
[6] - p-value for non-inferiority test based on 1-sided significance level

Secondary: Change From BL 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 BL 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	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	394	412
Units: mmol/L
least squares mean (confidence interval 95%)	-0.459 (-0.517 to -0.401)	-0.082 (-0.138 to -0.026)

Statistical analysis 1

Statistical analysis description

The model includes treatment arm, region, CV History, previous ESA treatment, visits and visit by treatment as categorical variables and baseline LDL, baseline Hb as continuous variables.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

806

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[7]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.377

Confidence interval

level

95%

sides

2-sided

lower limit

-0.451

upper limit

-0.304

Notes
[7] - p-value for superiority test based on 2-sided significance level

Secondary: Mean Monthly Intravenous (IV) Iron Use

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End point title

Mean Monthly Intravenous (IV) Iron Use

End point description

Participants with no or missing medication records of IV Iron have their monthly IV Iron use set to 0 mg. For participants who took IV Iron, but without a dosing frequency, the average values were set to missing. The analysis population was the FAS, with participants who had available data.

End point type

Secondary

End point timeframe

Day 1 to week 36

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	419
Units: mg per month
least squares mean (confidence interval 95%)	21.6 (14.0 to 29.3)	53.5 (46.0 to 61.1)

Statistical analysis 1

Statistical analysis description

The model includes treatment arm, region, CV History, previous ESA treatment as categorical variables and baseline Hb as continuous variable.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

832

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[8]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-31.9

Confidence interval

level

95%

sides

2-sided

lower limit

-41.4

upper limit

-22.4

Notes
[8] - p-value for superiority test based on 2-sided significance level

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

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End point title

Change From BL in Short Form-36 (SF-36) Health Survey Physical Functioning (PF) Sub-score to the Average of 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 measure eight scales: (1) physical functioning (PF); (2) role limitations due to physical health problems (RP); (3) bodily pain (BP); (4) social functioning (SF); (5) general health perceptions (GH); (6) role limitations due to emotional problems (RE); (7) vitality, energy or fatigue (VT); and (8) mental health(MH). Each scale is transformed into 0-100 score, with higher scores indicating better health status. The SF-36 PF consists of 11 questions 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	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	376	391
Units: Units on a scale
least squares mean (confidence interval 95%)	0.050 (-0.640 to 0.740)	-0.155 (-0.825 to 0.514)

Statistical analysis 1

Statistical analysis description

The model includes treatment arm, region, CV History, previous ESA treatment, visits (week 8, week 12, week 28) and visit by treatment as categorical variables, and baseline SF-36 PF, baseline Hb as continuous variables.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

767

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[9]

P-value

< 0.05 ^[10]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.205

Confidence interval

level

95%

sides

2-sided

lower limit

-0.649

upper limit

1.059

Notes
[9] - The margin for non-inferiority was -3.
[10] - p-value for non-inferiority test based on 1-sided significance level

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

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End point title

Change From BL in SF-36 Vitality (VT) Sub-score to the Average of 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	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	377	391
Units: Units on a scale
least squares mean (confidence interval 95%)	0.460 (-0.329 to 1.249)	-0.396 (-1.165 to 0.373)

Statistical analysis 1

Statistical analysis description

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

768

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[11]

P-value

< 0.05

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.856

Confidence interval

level

95%

sides

2-sided

lower limit

-0.115

upper limit

1.828

Notes
[11] - The margin for non-inferiority was -3.

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

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End point title

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

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. Mean Arterial Pressure (MAP) is derived as: MAP = (2/3)*DBP + (1/3)*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	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	373	388
Units: mmHg
least squares mean (confidence interval 95%)	-0.969 (-1.838 to -0.099)	-0.120 (-0.972 to 0.732)

Statistical analysis 1

Statistical analysis description

The model includes treatment arm, region, CV History, previous ESA treatment, visits and visit by treatment as categorical variables, and baseline MAP, baseline Hb as continuous variables.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

761

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.05 ^[12]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.849

Confidence interval

level

95%

sides

2-sided

lower limit

-1.971

upper limit

0.273

Notes
[12] - p-value for non-inferiority test based on 1-sided significance level

Secondary: Time to First Occurrence of an Increase in Blood Pressure in PPS

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End point title

Time to First Occurrence of an Increase in Blood Pressure in PPS

End point description

Increase in Blood Pressure was defined as either: Systolic Blood Pressure (SBP) ≥ 170 mmHg and an increase from BL ≥ 20 mmHg, or as: Diastolic Blood Pressure (DBP) ≥ 100 mmHg and an increase from BL ≥ 15 mmHg. For participants who have 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 and the 95% confidence interval was calculated with Greenwood's formula. The analysis population was the PPS, with participants who had available data.

End point type

Secondary

End point timeframe

Weeks 1 to 36

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	386	397
Units: Percentage of participants
number (confidence interval 95%)
Week 12	11.7 (8.5 to 14.9)	11.1 (8.0 to 14.2)
Week 24	15.9 (12.2 to 19.6)	15.4 (11.9 to 19.0)
Week 36	21.1 (14.0 to 28.2)	23.5 (16 to 30.9)

Statistical analysis 1

Statistical analysis description

Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on region, CV history, previous ESA treatment, and adjusting on Hb at baseline as continuous covariate. Non-inferiority was declared if the upper bound of the 95% CI is below 1.3.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

783

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[13]

P-value

< 0.05 ^[14]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.924

Confidence interval

level

95%

sides

2-sided

lower limit

0.669

upper limit

1.276

Notes
[13] - Non-inferiority (hazard ratio margin of 1.3).
[14] - p-value for non-inferiority test based on 1-sided significance level

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

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End point title

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

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. Mean Arterial Pressure (MAP) is 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	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	381	401
Units: mmHg
least squares mean (confidence interval 95%)	-0.739 (-1.600 to 0.123)	-0.160 (-0.997 to 0.678)

Statistical analysis 1

Statistical analysis description

The model includes treatment arm, region, CV History, previous ESA treatment, visits and visit by treatment as categorical variables, and baseline MAP, baseline Hb as continuous variables.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

782

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.308 ^[15]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.579

Confidence interval

level

95%

sides

2-sided

lower limit

-1.694

upper limit

0.536

Notes
[15] - p-value for superiority test based on 2-sided significance level

Secondary: Time to First Occurrence of an Increase in Blood Pressure in FAS

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End point title

Time to First Occurrence of an Increase in Blood Pressure in FAS

End point description

Increase in Blood Pressure was defined as either: SBP ≥ 170 mmHg and an increase from BL ≥ 20 mmHg, or as: DBP ≥ 100 mmHg and an increase from BL ≥ 15 mmHg. 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, with participants who had available data.

End point type

Secondary

End point timeframe

Weeks 1 to 36

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Percentage of participants
number (confidence interval 95%)
Week 12	11.6 (8.5 to 14.8)	12.0 (8.9 to 15.1)
Week 24	16.1 (12.5 to 19.7)	16.2 (12.6 to 19.7)
Week 36	21.2 (14.1 to 28.3)	24.1 (16.7 to 31.4)

Statistical analysis 1

Statistical analysis description

Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on region, CV history, previous ESA treatment, and adjusting on Hb at baseline as continuous covariate. Superiority was declared if the upper bound of the 95% CI is lower than 1.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.582 ^[16]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.915

Confidence interval

level

95%

sides

2-sided

lower limit

0.668

upper limit

1.254

Notes
[16] - p-value for superiority test based on 2-sided significance level

Secondary: Percentage of Participants with a Hb Response During Weeks 28 and 36 Regardless of Use of Rescue Therapy

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End point title

Percentage of Participants with a Hb Response During Weeks 28 and 36 Regardless of Use of Rescue Therapy

End point description

Hb response was defined as mean Hb during weeks 28 to 36 within the target range of 10.0 to 12.0 g/dL. The percentages and 95% CI are unadjusted, the exact method of Clopper-Pearson was used for 95% CI. The analysis population was the FAS, with participants who had available data.

End point type

Secondary

End point timeframe

Weeks 28 to 36

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Percentage of participants
number (confidence interval 95%)	83.1 (79.1 to 86.5)	82.1 (78.1 to 85.7)

Statistical analysis 1

Statistical analysis description

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.609 ^[17]

Method

Miettinen and Nurminen method

Parameter type

Difference of Percentages

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-3.8

upper limit

6.5

Notes
[17] - p-value for superiority test based on 2-sided significance level

Secondary: Change From BL in Hb to Each Postdosing Time Point

Top of page

End point title

Change From BL in Hb to Each Postdosing Time Point

End point description

Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose). The analysis population was the FAS, with participants who had available data. N is the number of participants with available data at each time point.

End point type

Secondary

End point timeframe

Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18,20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72,76, 80, 84, 88, 92, 96, 100, and 104

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: g/dL
least squares mean (confidence interval 95%)
Hb Change From BL to Week 1 [N=407,411]	0.232 (0.164 to 0.300)	0.068 (0.000 to 0.135)
Hb Change From BL to Week 2 [N=401,411]	0.496 (0.420 to 0.572)	0.054 (-0.022 to 0.129)
Hb Change From BL to Week 3 [N=394,408]	0.633 (0.552 to 0.714)	0.071 (-0.008 to 0.151)
Hb Change From BL to Week 4 [N=399,413]	0.803 (0.715 to 0.891)	0.095 (0.009 to 0.181)
Hb Change From BL to Week 5 [N=399,407]	0.723 (0.633 to 0.812)	-0.045 (-0.133 to 0.043)
Hb Change From BL to Week 6 [N=391,405]	0.868 (0.776 to 0.959)	0.138 (0.048 to 0.228)
Hb Change From BL to Week 7 [N=389,404]	0.698 (0.606 to 0.791)	-0.031 (-0.122 to 0.060)
Hb Change From BL to Week 8 [N=393,402]	0.816 (0.724 to 0.907)	0.116 (0.026 to 0.206)
Hb Change From BL to Week 10 [N=396,409]	0.640 (0.546 to 0.734)	-0.019 (-0.111 to 0.073)
Hb Change From BL to Week 12 [N=384,399]	0.732 (0.634 to 0.830)	0.139 (0.043 to 0.235)
Hb Change From BL to Week 14 [N=383,400]	0.508 (0.409 to 0.608)	0.005 (-0.093 to 0.103)
Hb Change From BL to Week 16 [N=381,401]	0.613 (0.511 to 0.716)	0.244 (0.144 to 0.344)
Hb Change From BL to Week 18 [N=378,395]	0.380 (0.283 to 0.477)	0.017 (-0.078 to 0.112)
Hb Change From BL to Week 20 [N=376,394]	0.501 (0.405 to 0.596)	0.217 (0.124 to 0.309)
Hb Change From BL to Week 22 [N=370,395]	0.266 (0.170 to 0.363)	0.069 (-0.025 to 0.163)
Hb Change From BL to Week 24 [N=362,387]	0.262 (0.168 to 0.356)	0.075 (-0.017 to 0.166)
Hb Change From BL to Week 26 [N=359,387]	0.316 (0.220 to 0.412)	0.073 (-0.020 to 0.165)
Hb Change From BL to Week 28 [N=360,388]	0.549 (0.452 to 0.647)	0.342 (0.248 to 0.437)
Hb Change From BL to Week 30 [N=351,380]	0.333 (0.236 to 0.429)	0.106 (0.013 to 0.198)
Hb Change From BL to Week 32 [N=345,376]	0.310 (0.211 to 0.409)	0.111 (0.016 to 0.207)
Hb Change From BL to Week 34 [N=342,374]	0.364 (0.268 to 0.460)	0.084 (-0.007 to 0.176)
Hb Change From BL to Week 36 [N=339,373]	0.482 (0.382 to 0.581)	0.225 (0.130 to 0.321)
Hb Change From BL to Week 40 [N=336,373]	0.199 (0.095 to 0.304)	0.064 (-0.036 to 0.163)
Hb Change From BL to Week 44 [N=328,367]	0.335 (0.221 to 0.448)	0.252 (0.145 to 0.360)
Hb Change From BL to Week 48 [N=323,365]	0.158 (0.047 to 0.270)	0.131 (0.027 to 0.236)
Hb Change From BL to Week 52 [N=308,363]	0.385 (0.273 to 0.496)	0.186 (0.082 to 0.290)
Hb Change From BL to Week 56 [N=311,360]	0.217 (0.104 to 0.329)	0.069 (-0.035 to 0.174)
Hb Change From BL to Week 60 [N=299,353]	0.368 (0.256 to 0.479)	0.171 (0.067 to 0.275)
Hb Change From BL to Week 64 [N=289,344]	0.181 (0.067 to 0.295)	-0.093 (-0.198 to 0.012)
Hb Change From BL to Week 68 [N=290,349]	0.306 (0.195 to 0.416)	0.100 (-0.002 to 0.202)
Hb Change From BL to Week 72 [N=284,339]	0.109 (-0.005 to 0.222)	-0.009 (-0.113 to 0.095)
Hb Change From BL to Week 76 [N=278,338]	0.401 (0.280 to 0.521)	0.189 (0.079 to 0.299)
Hb Change From BL to Week 80 [N=274,327]	0.087 (-0.028 to 0.203)	-0.015 (-0.120 to 0.091)
Hb Change From BL to Week 84 [N=270,328]	0.318 (0.199 to 0.438)	0.126 (0.017 to 0.235)
Hb Change From BL to Week 88 [N=258,326]	0.026 (-0.091 to 0.144)	-0.018 (-0.124 to 0.088)
Hb Change From BL to Week 92 [N=255,313]	0.357 (0.232 to 0.483)	0.154 (0.041 to 0.267)
Hb Change From BL to Week 96 [N=253,312]	0.126 (0.010 to 0.242)	-0.058 (-0.163 to 0.046)
Hb Change From BL to Week 100 [N=248,311]	0.302 (0.175 to 0.430)	0.138 (0.024 to 0.253)
Hb Change From BL to Week 104 [N=240,299]	0.232 (0.100 to 0.363)	0.133 (0.014 to 0.251)

Statistical analysis 1

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[18]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.164

Confidence interval

level

95%

sides

2-sided

lower limit

0.072

upper limit

0.256

Notes
[18] - p-value for superiority test based on 2-sided significance level

Statistical analysis 2

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[19]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.443

Confidence interval

level

95%

sides

2-sided

lower limit

0.339

upper limit

0.546

Notes
[19] - p-value for superiority test based on 2-sided significance level

Statistical analysis 3

Statistical analysis description

Week 3 - The model included treatment, visit, visit by treatment interaction, Previous ESA Treatment, region and history of CV disease as fixed class factors and baseline Hb as continuous covariates.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[20]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.561

Confidence interval

level

95%

sides

2-sided

lower limit

0.451

upper limit

0.672

Notes
[20] - p-value for superiority test based on 2-sided significance level

Statistical analysis 4

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[21]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.708

Confidence interval

level

95%

sides

2-sided

lower limit

0.588

upper limit

0.828

Notes
[21] - p-value for superiority test based on 2-sided significance level

Statistical analysis 5

Statistical analysis description

Week 5 - The model included treatment, visit, visit by treatment interaction, Previous ESA Treatment, region and history of CV disease as fixed class factors and baseline Hb as continuous covariates.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[22]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.768

Confidence interval

level

95%

sides

2-sided

lower limit

0.645

upper limit

0.89

Notes
[22] - p-value for superiority test based on 2-sided significance level

Statistical analysis 6

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[23]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.729

Confidence interval

level

95%

sides

2-sided

lower limit

0.604

upper limit

0.855

Notes
[23] - p-value for superiority test based on 2-sided significance level

Statistical analysis 7

Statistical analysis description

Week 7 - The model included treatment, visit, visit by treatment interaction, Previous ESA Treatment, region and history of CV disease as fixed class factors and baseline Hb as continuous covariates.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[24]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.729

Confidence interval

level

95%

sides

2-sided

lower limit

0.603

upper limit

0.856

Notes
[24] - p-value for superiority test based on 2-sided significance level

Statistical analysis 8

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[25]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.574

upper limit

0.826

Notes
[25] - p-value for superiority test based on 2-sided significance level

Statistical analysis 9

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[26]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.659

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

0.788

Notes
[26] - p-value for superiority test based on 2-sided significance level

Statistical analysis 10

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[27]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.593

Confidence interval

level

95%

sides

2-sided

lower limit

0.459

upper limit

0.727

Notes
[27] - p-value for superiority test based on 2-sided significance level

Statistical analysis 11

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[28]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.503

Confidence interval

level

95%

sides

2-sided

lower limit

0.366

upper limit

0.64

Notes
[28] - p-value for superiority test based on 2-sided significance level

Statistical analysis 12

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[29]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.369

Confidence interval

level

95%

sides

2-sided

lower limit

0.229

upper limit

0.51

Notes
[29] - p-value for superiority test based on 2-sided significance level

Statistical analysis 13

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[30]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.363

Confidence interval

level

95%

sides

2-sided

lower limit

0.23

upper limit

0.496

Notes
[30] - p-value for superiority test based on 2-sided significance level

Statistical analysis 14

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[31]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.284

Confidence interval

level

95%

sides

2-sided

lower limit

0.154

upper limit

0.414

Notes
[31] - p-value for superiority test based on 2-sided significance level

Statistical analysis 15

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[32]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.197

Confidence interval

level

95%

sides

2-sided

lower limit

0.065

upper limit

0.329

Notes
[32] - p-value for superiority test based on 2-sided significance level

Statistical analysis 16

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[33]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.187

Confidence interval

level

95%

sides

2-sided

lower limit

0.059

upper limit

0.316

Notes
[33] - p-value for superiority test based on 2-sided significance level

Statistical analysis 17

Statistical analysis description

Week 26 - The model included treatment, visit, visit by treatment interaction, Previous ESA Treatment, region and history of CV disease as fixed class factors and baseline Hb as continuous covariates.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[34]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.243

Confidence interval

level

95%

sides

2-sided

lower limit

0.113

upper limit

0.373

Notes
[34] - p-value for superiority test based on 2-sided significance level

Statistical analysis 18

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002 ^[35]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.207

Confidence interval

level

95%

sides

2-sided

lower limit

0.074

upper limit

0.34

Notes
[35] - p-value for superiority test based on 2-sided significance level

Statistical analysis 19

Statistical analysis description

Week 30 - The model included treatment, visit, visit by treatment interaction, Previous ESA Treatment, region and history of CV disease as fixed class factors and baseline Hb as continuous covariates.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[36]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.227

Confidence interval

level

95%

sides

2-sided

lower limit

0.096

upper limit

0.358

Notes
[36] - p-value for superiority test based on 2-sided significance level

Statistical analysis 20

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[37]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.199

Confidence interval

level

95%

sides

2-sided

lower limit

0.064

upper limit

0.334

Notes
[37] - p-value for superiority test based on 2-sided significance level

Statistical analysis 21

Statistical analysis description

Week 34 - The model included treatment, visit, visit by treatment interaction, Previous ESA Treatment, region and history of CV disease as fixed class factors and baseline Hb as continuous covariates.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[38]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.279

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

0.409

Notes
[38] - p-value for superiority test based on 2-sided significance level

Statistical analysis 22

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[39]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.256

Confidence interval

level

95%

sides

2-sided

lower limit

0.121

upper limit

0.391

Notes
[39] - p-value for superiority test based on 2-sided significance level

Statistical analysis 23

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.06 ^[40]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.136

Confidence interval

level

95%

sides

2-sided

lower limit

-0.006

upper limit

0.277

Notes
[40] - p-value for superiority test based on 2-sided significance level

Statistical analysis 24

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.293 ^[41]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.082

Confidence interval

level

95%

sides

2-sided

lower limit

-0.071

upper limit

0.236

Notes
[41] - p-value for superiority test based on 2-sided significance level

Statistical analysis 25

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.723 ^[42]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.027

Confidence interval

level

95%

sides

2-sided

lower limit

-0.123

upper limit

0.177

Notes
[42] - p-value for superiority test based on 2-sided significance level

Statistical analysis 26

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.009 ^[43]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.199

Confidence interval

level

95%

sides

2-sided

lower limit

0.049

upper limit

0.348

Notes
[43] - p-value for superiority test based on 2-sided significance level

Statistical analysis 27

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.056 ^[44]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.147

Confidence interval

level

95%

sides

2-sided

lower limit

-0.004

upper limit

0.298

Notes
[44] - p-value for superiority test based on 2-sided significance level

Statistical analysis 28

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01 ^[45]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.196

Confidence interval

level

95%

sides

2-sided

lower limit

0.047

upper limit

0.346

Notes
[45] - p-value for superiority test based on 2-sided significance level

Statistical analysis 29

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[46]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.275

Confidence interval

level

95%

sides

2-sided

lower limit

0.122

upper limit

0.427

Notes
[46] - p-value for superiority test based on 2-sided significance level

Statistical analysis 30

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006 ^[47]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.206

Confidence interval

level

95%

sides

2-sided

lower limit

0.059

upper limit

0.353

Notes
[47] - p-value for superiority test based on 2-sided significance level

Statistical analysis 31

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.127 ^[48]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.118

Confidence interval

level

95%

sides

2-sided

lower limit

-0.033

upper limit

0.269

Notes
[48] - p-value for superiority test based on 2-sided significance level

Statistical analysis 32

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01 ^[49]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.211

Confidence interval

level

95%

sides

2-sided

lower limit

0.051

upper limit

0.371

Notes
[49] - p-value for superiority test based on 2-sided significance level

Statistical analysis 33

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.191 ^[50]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.102

Confidence interval

level

95%

sides

2-sided

lower limit

-0.051

upper limit

0.255

Notes
[50] - p-value for superiority test based on 2-sided significance level

Statistical analysis 34

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.018 ^[51]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.192

Confidence interval

level

95%

sides

2-sided

lower limit

0.033

upper limit

0.351

Notes
[51] - p-value for superiority test based on 2-sided significance level

Statistical analysis 35

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.576 ^[52]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.044

Confidence interval

level

95%

sides

2-sided

lower limit

-0.111

upper limit

0.2

Notes
[52] - p-value for superiority test based on 2-sided significance level

Statistical analysis 36

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.017 ^[53]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.203

Confidence interval

level

95%

sides

2-sided

lower limit

0.037

upper limit

0.369

Notes
[53] - p-value for superiority test based on 2-sided significance level

Statistical analysis 37

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.019 ^[54]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.184

Confidence interval

level

95%

sides

2-sided

lower limit

0.031

upper limit

0.338

Notes
[54] - p-value for superiority test based on 2-sided significance level

Statistical analysis 38

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.056 ^[55]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.164

Confidence interval

level

95%

sides

2-sided

lower limit

-0.004

upper limit

0.333

Notes
[55] - p-value for superiority test based on 2-sided significance level

Statistical analysis 39

Statistical analysis description

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

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.267 ^[56]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.099

Confidence interval

level

95%

sides

2-sided

lower limit

-0.076

upper limit

0.273

Notes
[56] - p-value for superiority test based on 2-sided significance level

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

Top of page

End point title

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

End point description

Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose). Averaged Hb values over weeks 28-36, weeks 44-52 and weeks 96-104 are observed values. The analysis population was the FAS, with participants who had available data. N is the number of participants with available data at each time point.

End point type

Secondary

End point timeframe

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

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: g/dL
least squares mean (confidence interval 95%)
Average Hb Over Weeks 28-36 N=[362,393]	11.183 (11.100 to 11.265)	10.946 (10.867 to 11.025)
Average Hb Over Weeks 44-52 N=[330,370]	11.099 (11.009 to 11.189)	10.994 (10.909 to 11.079)
Average Hb Over Weeks 96-104 N=[252,317]	11.007 (10.904 to 11.110)	10.858 (10.766 to 10.950)

Statistical analysis 1

Statistical analysis description

Weeks 28-36 - The model includes treatment arm, region, CV History, previous ESA treatment, visits and visit by treatment as categorical variables and baseline Hb as continuous variable.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[57]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.237

Confidence interval

level

95%

sides

2-sided

lower limit

0.127

upper limit

0.347

Notes
[57] - p-value for superiority test based on 2-sided significance level

Statistical analysis 2

Statistical analysis description

Weeks 44-52 - The model includes treatment arm, region, CV History, previous ESA treatment, visits and visit by treatment as categorical variables and baseline Hb as continuous variable.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.086 ^[58]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.105

Confidence interval

level

95%

sides

2-sided

lower limit

-0.015

upper limit

0.225

Notes
[58] - p-value for superiority test based on 2-sided significance level

Statistical analysis 3

Statistical analysis description

Weeks 96-104 - The model includes treatment arm, region, CV History, previous ESA treatment, visits and visit by treatment as categorical variables and baseline Hb as continuous variable.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.031 ^[59]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.149

Confidence interval

level

95%

sides

2-sided

lower limit

0.014

upper limit

0.284

Notes
[59] - p-value for superiority test based on 2-sided significance level

Secondary: Change From BL in Hb to the Average of Weeks 28 to 36, 44 to 52, and 96 to 104 Regardless of the Use of Rescue Therapy

Top of page

End point title

Change From BL in Hb to the Average of Weeks 28 to 36, 44 to 52, and 96 to 104 Regardless of the Use of Rescue Therapy

End point description

Change from baseline to the average Hb are observed values. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose). The analysis population was the FAS, with participants who had available data. N is the number of participants with available data at each time point.

End point type

Secondary

End point timeframe

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

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: g/dL
least squares mean (confidence interval 95%)
Hb Change From BL to Weeks 28-36 [N=364,393]	0.408 (0.325 to 0.491)	0.173 (0.093 to 0.252)
Hb Change From BL to Weeks 44-52 [N=331,371]	0.298 (0.203 to 0.394)	0.194 (0.104 to 0.284)
Hb Change From BL to Weeks 96-104 [N=254,318]	0.225 (0.119 to 0.331)	0.076 (-0.020 to 0.171)

Statistical analysis 1

Statistical analysis description

Weeks 28-36 - The model includes treatment arm, region, CV History, previous ESA treatment, visits and visit by treatment as categorical variables and baseline Hb as continuous variable.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.235

Confidence interval

level

95%

sides

2-sided

lower limit

0.125

upper limit

0.346

Statistical analysis 2

Statistical analysis description

Weeks 44-52 - The model includes treatment arm, region, CV History, previous ESA treatment, visits and visit by treatment as categorical variables and baseline Hb as continuous variable.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.11

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.104

Confidence interval

level

95%

sides

2-sided

lower limit

-0.024

upper limit

0.232

Statistical analysis 3

Statistical analysis description

Weeks 96-104 - The model includes treatment arm, region, CV History, previous ESA treatment, visits and visit by treatment as categorical variables and baseline Hb as continuous variable.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.036

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.149

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

0.288

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

Top of page

End point title

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

End point description

Percentage for each participant was calculated as Number of Hb values >= 10.0 g/dL / Total number of Hb values*100 in weeks 28 to 36, 44 to 52 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, with participants who had available data. N is the number of participants with available data at each time point.

End point type

Secondary

End point timeframe

Weeks 28-36, 44-52 and 96-104

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: percentage of Hb values
arithmetic mean (standard deviation)
Weeks 28-36 [N=364,393]	93.002 ( 18.320 )	87.286 ( 25.114 )
Weeks 44-52[N=331,371]	89.421 ( 24.267 )	86.914 ( 25.366 )
Weeks 96-104[N=254,318]	88.858 ( 24.708 )	83.543 ( 30.296 )

No statistical analyses for this end point

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

Top of page

End point title

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

End point description

Percentage for each participant was calculated as Number of Hb values within 10.0-12.0 g/dL / Total number of Hb values*100 in weeks 28 to 36, 44 to 52 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. N is the number of participants with available data at each time point.

End point type

Secondary

End point timeframe

Weeks 28-36, 44-52 and 96-104

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: percentage of Hb values
arithmetic mean (standard deviation)
Weeks 28-36 [N=364, 393]	76.326 ( 28.175 )	76.098 ( 28.991 )
Weeks 44-52 [N=331, 371]	75.891 ( 31.047 )	74.634 ( 30.589 )
Weeks 96-104 [N=254, 318]	76.522 ( 30.378 )	73.690 ( 33.040 )

No statistical analyses for this end point

Secondary: Number of Hospitalizations

Top of page

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). It included all Non-Hemodialysis (HD) hospitalizations. The HD days were not counted as hospitalizations, even when performed overnight. The analysis population was the FAS, with participants who had available data.

End point type

Secondary

End point timeframe

Baseline to End of Treatment (EOT) (Up to week 104)

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Hospitalizations
arithmetic mean (standard deviation)	0.9 ( 1.3 )	0.9 ( 1.5 )

No statistical analyses for this end point

Secondary: Number of Days of Hospitalization per Year

Top of page

End point title

Number of Days of Hospitalization per Year

End point description

The number of days of hospitalizations per year was calculated as the sum of the durations of all non-HD hospitalizations in days (Date of discharge – Date of admission + 1)] / (duration of efficacy emergent period in days / 365.25). In case of missing dates, the hospitalization duration was imputed by the average duration per stay derived from the participants with non-missing duration within the same treatment group. The analysis population was the FAS, with participants who had available data.

End point type

Secondary

End point timeframe

Baseline to EOT (Up to week 104)

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Days per year
arithmetic mean (standard deviation)	12.186 ( 34.121 )	7.868 ( 22.948 )

No statistical analyses for this end point

Secondary: Time to First Hospitalization

Top of page

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. For participants without hospitalization, the time to censoring was calculated as: (Date of End of Efficacy Emergent Period – Analysis Date of first dose intake + 1) / 365.25. 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. The analysis population was the FAS

End point type

Secondary

End point timeframe

Baseline to EOT (Up to week 104)

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5	19.4 (15.5 to 23.3)	18.3 (14.6 to 22.0)
Year 1	32.0 (27.3 to 36.6)	32.7 (28.2 to 37.3)
Year 1.5	43.5 (38.5 to 48.6)	41.9 (37.0 to 46.7)
Year 2	52.6 (47.5 to 57.8)	48.3 (43.3 to 53.3)

Statistical analysis 1

Statistical analysis description

Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on region, CV history, previous ESA treatment and adjusting on Hb at baseline as continuous covariate. Superiority was declared if the upper bound of the 95% CI was below 1.0.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.164 ^[60]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.154

Confidence interval

level

95%

sides

2-sided

lower limit

0.943

upper limit

1.411

Notes
[60] - p-value for superiority test based on 2-sided significance level

Secondary: Time to First Use of Rescue Therapy

Top of page

End point title

Time to First Use of Rescue Therapy

End point description

Rescue therapy was defined as red blood cell (RBC) transfusion for both treatment groups and ESA for roxadustat participants. Only rescue medication that was started during the study treatment and up to end of efficacy emergent period was taken into account and considered as use of rescue medication. For participants who have experienced more than one use of rescue therapy, 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. The analysis population was the FAS.

End point type

Secondary

End point timeframe

Baseline to EOT (Up to week 104)

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5	3.9 (2.0 to 5.8)	3.2 (1.5 to 4.8)
Year 1	8.2 (5.4 to 11.1)	8.4 (5.6 to 11.1)
Year 1.5	11.4 (8.1 to 14.8)	10.9 (7.8 to 14.0)
Year 2	12.8 (9.3 to 16.4)	14.4 (10.8 to 18.0)

Statistical analysis 1

Statistical analysis description

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.917

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.979

Confidence interval

level

95%

sides

2-sided

lower limit

0.656

upper limit

1.462

Secondary: Time to First RBC Transfusion

Top of page

End point title

Time to First RBC Transfusion

End point description

For participants who have experienced more than one RBC transfusion, only their first event following study treatment was used. For RBC transfusions, when the number of units was not given but the volume transfused was, the number of units were estimated by volume transfused/250 mL (for transfusion of packed cell units) or volume transfused/500 mL (for transfusion of full blood). 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.

End point type

Secondary

End point timeframe

Baseline to EOT (Up to week 104)

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5	3.6 (1.8 to 5.5)	3.2 (1.5 to 4.8)
Year 1	7.4 (4.7 to 10.1)	8.4 (5.6 to 11.1)
Year 1.5	10.0 (6.9 to 13.2)	10.9 (7.8 to 14.0)
Year 2	11.4 (8.0 to 14.9)	14.4 (10.8 to 18.0)

Statistical analysis 1

Statistical analysis description

Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on region, CV history, previous ESA treatment, and adjusting on Hb at baseline as continuous covariate. Superiority was declared if the upper bound of the 95% CI was below 1.0.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.501 ^[61]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.867

Confidence interval

level

95%

sides

2-sided

lower limit

0.573

upper limit

1.313

Notes
[61] - p-value for superiority test based on 2-sided significance level

Secondary: Mean Monthly Number of RBC Packs Per Participant

Top of page

End point title

Mean Monthly Number of RBC Packs Per Participant

End point description

During efficacy emergent period, the mean monthly number of RBC packs were calculated as the sum of blood volume and units transfused between the first dose and up to the last dose in the period divided by duration of efficacy emergent period (in days) divided by 28 days. Participants without medication records of RBC have their number of RBC packs and 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	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: RBC packs per month
least squares mean (confidence interval 95%)	0.026 (0.01 to 0.04)	0.032 (0.02 to 0.05)

Statistical analysis 1

Statistical analysis description

The model included treatment arm, region, CV History, previous ESA treatment as categorical variables and baseline Hb as continuous variable.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.507 ^[62]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.006

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.01

Notes
[62] - p-value for superiority test based on 2-sided significance level

Secondary: Mean Monthly Volume of RBC Transfusion Per Participant

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End point title

Mean Monthly Volume of RBC Transfusion Per Participant

End point description

During Efficacy Emergent Period, the mean monthly volume of blood transfused are calculated as the sum of blood volume and units transfused between the first dose and up to the last dose in the period divided by duration of efficacy emergent period (in days) divided by 28 days. The Efficacy Emergent Period was defined as the evaluation period from the Analysis date of first dose intake up to 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	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: mL per month
least squares mean (confidence interval 95%)	6.061 (2.82 to 9.30)	5.929 (2.74 to 9.12)

Statistical analysis 1

Statistical analysis description

The model included treatment arm, region, CV History, previous ESA treatment as categorical variables and baseline Hb as continuous variable.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.949

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

0.132

Confidence interval

level

95%

sides

2-sided

lower limit

-3.9

upper limit

4.16

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

For participants who have 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. The analysis population was the FAS.

End point type

Secondary

End point timeframe

Baseline to EOT (Up to week 104)

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Percentage of participants
number (confidence interval 95%)
Year 0.5	11.2 (8.1 to 14.3)	33.5 (29.0 to 38.1)
Year 1	17.4 (13.5 to 21.2)	44.1 (39.3 to 49.0)
Year 1.5	23.6 (19.1 to 28.1)	55.0 (50.1 to 59.9)
Year 2	33.3 (26.0 to 40.7)	59.3 (54.4 to 64.3)

Statistical analysis 1

Statistical analysis description

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.368

Confidence interval

level

95%

sides

2-sided

lower limit

0.291

upper limit

0.465

Secondary: Mean Monthly Intravenous (IV) Iron per Participant During Weeks 37-52 and Weeks 53-104

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End point title

Mean Monthly Intravenous (IV) Iron per Participant During Weeks 37-52 and Weeks 53-104

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.

End point type

Secondary

End point timeframe

Weeks 37-52 and weeks 53-104

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: mg per month
least squares mean (confidence interval 95%)
Weeks 37-52	34.9 (20.9 to 48.9)	70.0 (56.9 to 83.2)
Weeks 53-104	49.5 (31.0 to 67.9)	98.1 (81.1 to 115.2)

Statistical analysis 1

Statistical analysis description

Weeks 37-52 - Participants with no or missing medication records of IV Iron had their monthly IV Iron use set to 0 mg. The model includes treatment arm, region, CV History, previous ESA treatment as categorical variables and baseline Hb as continuous variable.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-35.1

Confidence interval

level

95%

sides

2-sided

lower limit

-51.8

upper limit

-18.4

Statistical analysis 2

Statistical analysis description

Weeks 53-104 - Participants with no or missing medication records of IV Iron had their monthly IV Iron use set to 0 mg. The model includes treatment arm, region, CV History, previous ESA treatment as categorical variables and baseline Hb as continuous variable.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

833

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-48.7

Confidence interval

level

95%

sides

2-sided

lower limit

-70.3

upper limit

-27

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/without IV iron was calculated based on total number of participants within the efficacy emergent period. The Efficacy Emergent Period is 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	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Percentage of participants
number (not applicable)	31.0	11.7

No statistical analyses for this end point

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

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End point title

Change From BL to Each Post-dosing Study Visit in Total Cholesterol

End point description

Baseline assessment was the assessment from Day 1 visit. If baseline value was missing, then the latest screening period value was used as the baseline regardless of fasting status. The analysis population was the FAS, with participants who had available data at all time points. N is the number of participants with available data at each time point.

End point type

Secondary

End point timeframe

Baseline and week 8, 28, 52, 104

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: mmol/L
arithmetic mean (standard deviation)
Change from BL to Week 8 [N=392,411]	-0.608 ( 0.889 )	-0.105 ( 0.712 )
Change from BL to Week 28 [N=364,393]	-0.641 ( 0.960 )	-0.135 ( 0.805 )
Change from BL to Week 52 [N=318,362]	-0.803 ( 1.027 )	-0.241 ( 0.906 )
Change from BL to Week 104 [N=247,307]	-0.904 ( 1.053 )	-0.277 ( 1.002 )

No statistical analyses for this end point

Secondary: Change From BL to Each Post-dosing Study Visit in LDL-C/High-density Lipoprotein cholesterol (HDL-C) Ratio

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End point title

Change From BL to Each Post-dosing Study Visit in LDL-C/High-density Lipoprotein cholesterol (HDL-C) Ratio

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, with participants who had available data at all time points. N is the number of participants with available data at each time point.

End point type

Secondary

End point timeframe

Baseline and week 8, 28, 52, 104

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Ratio
arithmetic mean (standard deviation)
Change from BL to Week 8 [N=390,411]	-0.245 ( 0.818 )	-0.060 ( 0.726 )
Change from BL to Week 28 [N=362,393]	-0.155 ( 1.046 )	-0.057 ( 0.922 )
Change from BL to Week 52 [N=317,361]	-0.345 ( 0.904 )	-0.078 ( 0.886 )
Change from BL to Week 104 [N=246,307]	-0.261 ( 1.167 )	-0.013 ( 1.048 )

No statistical analyses for this end point

Secondary: Change From BL to Each Postdosing Study Visit in Non-HDL Cholesterol

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End point title

Change From BL to Each Postdosing Study Visit in Non-HDL Cholesterol

End point description

End point type

Secondary

End point timeframe

Baseline and week 8, 28, 52, 104

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: mmol/L
arithmetic mean (standard deviation)
Change from BL to Week 8 [N=388,404]	-0.518 ( 0.823 )	-0.107 ( 0.701 )
Change from BL to Week 28 [N=360,391]	-0.540 ( 0.907 )	-0.127 ( 0.789 )
Change from BL to Week 52 [N=314,360]	-0.700 ( 0.965 )	-0.229 ( 0.886 )
Change from BL to Week 104 [N=245,304]	-0.788 ( 1.024 )	-0.240 ( 1.010 )

No statistical analyses for this end point

Secondary: Change From BL to Each Postdosing Study Visit in Apolipoproteins A1 (ApoA1)

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End point title

Change From BL to Each Postdosing Study Visit in Apolipoproteins A1 (ApoA1)

End point description

End point type

Secondary

End point timeframe

Baseline and week 8, 28, 52, 104

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: g/L
arithmetic mean (standard deviation)
Change from BL to Week 8 [N=394,415]	-0.114 ( 0.197 )	-0.006 ( 0.172 )
Change from BL to Week 28 [N=367,393]	-0.113 ( 0.217 )	-0.012 ( 0.193 )
Change from BL to Week 52 [N=320,366]	-0.097 ( 0.230 )	-0.013 ( 0.195 )
Change from BL to Week 104 [N=246,309]	-0.097 ( 0.220 )	-0.012 ( 0.196 )

No statistical analyses for this end point

Secondary: Change From BL to Each Postdosing Study Visit in Apolipoproteins B (ApoB)

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End point title

Change From BL to Each Postdosing Study Visit in Apolipoproteins B (ApoB)

End point description

End point type

Secondary

End point timeframe

Baseline and week 8, 28, 52, 104

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: mg/dL
arithmetic mean (standard deviation)
Change from BL to Week 8 [N=394,415]	-11.03 ( 18.49 )	1.00 ( 14.34 )
Change from BL to Week 28 [N=366,393]	-11.18 ( 20.39 )	-0.12 ( 16.91 )
Change from BL to Week 52 [N=320,366]	-13.18 ( 20.67 )	-0.01 ( 18.88 )
Change from BL to Week 104 [N=246,309]	-13.50 ( 24.94 )	-0.01 ( 20.00 )

No statistical analyses for this end point

Secondary: Change From BL to Each Postdosing Study Visit in ApoB/ApoA1 Ratio

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End point title

Change From BL to Each Postdosing Study Visit in ApoB/ApoA1 Ratio

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. The analysis population was the FAS, with participants who had available data at all time points. N is the number of participants with available data at each time point.

End point type

Secondary

End point timeframe

Baseline and week 8, 28, 52, 104

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Ratio
arithmetic mean (standard deviation)
Change from BL to Week 8 [N=393,415]	-0.037 ( 0.147 )	0.013 ( 0.141 )
Change from BL to Week 28 [N=365,392]	-0.034 ( 0.177 )	0.002 ( 0.148 )
Change from BL to Week 52 [N=318,365]	-0.051 ( 0.191 )	0.007 ( 0.164 )
Change from BL to Week 104 [N=246,309]	-0.062 ( 0.210 )	0.007 ( 0.201 )

No statistical analyses for this end point

Secondary: Number of Participants with Mean LDL Cholesterol < 100 mg/dL Over Weeks 12 to 28

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End point title

Number of Participants with Mean LDL Cholesterol < 100 mg/dL Over Weeks 12 to 28

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

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Percentage of participants
number (not applicable)
Yes [Regardless of Fasting Status]	275	231
No [Regardless of Fasting Status]	119	181
Missing [Regardless of Fasting Status]	19	8
Yes [Fasting Only]	111	85
No [Fasting Only]	61	80
Missing [Fasting Only]	241	255

No statistical analyses for this end point

Secondary: Number of Participants with CKD Who Achieved Antihypertensive Treatment Goal

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End point title

Number of Participants with CKD Who Achieved Antihypertensive Treatment Goal

End point description

Achieved antihypertensive treatment goal was defined as SBP < 140 mmHg and DBP < 90 mmHg over an evaluation period based on the average of available values in weeks 12-28 (pre-dialysis). The analysis population was the FAS.

End point type

Secondary

End point timeframe

Weeks 12 to 28

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Percentage of participants
number (not applicable)
Antihypertensive Treatment Goal - Yes	264	261
Antihypertensive Treatment Goal - No	130	149
Antihypertensive Treatment Goal - Missing	19	10

No statistical analyses for this end point

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

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End point title

Change From BL to the Average of Weeks 12 to 28 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. SF-36 contains 36-item that measures 8 scales with scores ranging from 0-100: physical functioning (PF); role limitations due to physical health problems (RP); bodily pain (BP); social functioning (SF); general health perceptions (GH); role limitations due to emotional problems (RE); vitality, energy or fatigue (VT); and mental health (MH). These scores are normed to the US population (norm-based scoring had very little impact on results when data was collected in Western European countries) to have a mean of 50 and standard deviation of 10. The PCS was calculated based on all 8 scales and ranges from 5.02-79.78. For each of these above scales, higher scores always indicating better health status. The analysis population was the FAS, with participants who had available data at all time point.

End point type

Secondary

End point timeframe

Baseline and weeks 12 to 28

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	384	404
Units: Units on a scale
least squares mean (confidence interval 95%)	0.560 (-0.029 to 1.148)	0.039 (-0.528 to 0.605)

Statistical analysis 1

Statistical analysis description

The model includes treatment, visit, visit by treatment interaction, Previous ESA Treatment, region and history of CV disease as fixed class factors and baseline SF-36 PCS, baseline Hb, as continuous covariates.

Comparison groups

ESA (Erythropoiesis-Stimulating Agent) v Roxadustat

Number of subjects included in analysis

788

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.161 ^[63]

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.521

Confidence interval

level

95%

sides

2-sided

lower limit

-0.208

upper limit

1.25

Notes
[63] - p-value for superiority test based on 2-sided significance level

Secondary: Change From BL to the Average of Weeks 12 to 28 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 BL to the Average of Weeks 12 to 28 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 Anemia Subscale (AnS) is referred to as the FACT-An Total. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The Anemia score range is 0 to 80. For the above score, a higher score indicates better QoL. The analysis population was the FAS, with participants who had available data at all time point.

End point type

Secondary

End point timeframe

Baseline and weeks 12 to 28

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	384	403
Units: Units on a scale
least squares mean (confidence interval 95%)	0.400 (-0.624 to 1.424)	0.274 (-0.709 to 1.257)

Statistical analysis 1

Statistical analysis description

The model includes treatment, visit, visit by treatment interaction, Previous ESA Treatment, region and history of CV disease as fixed class factors and baseline FACT-An Ans, baseline Hb, as continuous covariates.

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

787

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.845

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.126

Confidence interval

level

95%

sides

2-sided

lower limit

-1.135

upper limit

1.387

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

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End point title

Change From BL to the Average Value of Weeks 12 to 28 in Total FACT-An 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 (PWB) - 7 items, functional (FWB) - 7 items, social/family (SWB) - 7 items, and emotional (EWB) - 6 items. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The total score is obtained by summation of the scores from PWB, SWB, EWB, FWB and AnS. The FACT-An Total Score scale range is 0-188. A higher score indicates better QoL. The analysis population was the FAS, with participants who had available data at all time points.

End point type

Secondary

End point timeframe

Baseline and weeks 12 to 28

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	383	403
Units: Units on a scale
least squares mean (confidence interval 95%)	-0.501 (-2.581 to 1.580)	-0.373 (-2.367 to 1.622)

Statistical analysis 1

Statistical analysis description

Comparison groups

Roxadustat v ESA (Erythropoiesis-Stimulating Agent)

Number of subjects included in analysis

786

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.922

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.128

Confidence interval

level

95%

sides

2-sided

lower limit

-2.703

upper limit

2.447

Secondary: Change From BL to the Average 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 BL to the Average 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 at all time points.

End point type

Secondary

End point timeframe

Baseline and weeks 12 to 28

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	385	401
Units: Units on a scale
arithmetic mean (standard deviation)	3.041 ( 14.910 )	2.735 ( 14.477 )

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 measures 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 includes very much improved, much improved and minimally improved. The analysis population was the FAS, with participants who had available data at all time points.

End point type

Secondary

End point timeframe

Baseline and weeks 8, 12, 28, 36, 52, 76, 104

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: Percentage of participants
number (not applicable)
Week 8	59.6	49.5
Week 12	65.5	49.5
Week 28	62.3	57.1
Week 36	60.4	56.3
Week 52	57.1	55.3
Week 76	61.2	51.9
Week 104	61.6	51.3

No statistical analyses for this end point

Secondary: Change From BL in Serum Hepcidin

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End point title

Change From BL in Serum Hepcidin

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, with participants who had available data at baseline. N is the number of participants with available data at each time point.

End point type

Secondary

End point timeframe

Baseline and weeks 4, 12, 20, 36, 52, 104, and End of Study (EOS - up to 108 weeks)

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: µg/L
arithmetic mean (standard deviation)
Week 4 [N=387,400]	-14.265 ( 42.393 )	-4.265 ( 33.518 )
Week 12 [N=375,391]	-12.298 ( 41.335 )	-6.741 ( 38.507 )
Week 20 [N=361,382]	-15.149 ( 43.152 )	-11.818 ( 41.596 )
Week 36 [N=332,366]	-23.405 ( 43.033 )	-14.530 ( 43.449 )
Week 52 [N=310,357]	-32.709 ( 42.342 )	-17.522 ( 47.307 )
Week 104 [N=242,298]	-40.101 ( 48.611 )	-18.735 ( 51.632 )
EOS (up to 108 weeks) [N=280,320]	-27.192 ( 52.169 )	-17.664 ( 51.688 )

No statistical analyses for this end point

Secondary: Change From BL in Serum Ferritin

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End point title

Change From BL in Serum Ferritin

End point description

End point type

Secondary

End point timeframe

Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76,84, 92, 100, 104, and EOS (up to 108 weeks)

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	420
Units: pmol/L
arithmetic mean (standard deviation)
Week 4 [N=400,408]	-214.64 ( 824.96 )	-141.78 ( 456.15 )
Week 8 [N=394,405]	-245.37 ( 668.51 )	-160.75 ( 607.39 )
Week 12 [N=389,404]	-269.76 ( 761.24 )	-179.47 ( 586.95 )
Week 20 [N=379,396]	-337.94 ( 645.73 )	-246.89 ( 727.64 )
Week 28 [N=363,392]	-427.46 ( 699.95 )	-265.21 ( 816.64 )
Week 36 [N=343,379]	-507.34 ( 726.61 )	-269.26 ( 855.01 )
Week 44 [N=328,371]	-545.14 ( 668.02 )	-323.30 ( 986.38 )
Week 52 [N=318,365]	-615.19 ( 677.97 )	-347.58 ( 1058.87 )
Week 60 [N=304,359]	-622.55 ( 675.22 )	-394.40 ( 837.81 )
Week 68 [N=293,349]	-604.47 ( 773.19 )	-456.16 ( 1039.18 )
Week 76 [N=283,339]	-646.76 ( 838.76 )	-447.70 ( 967.63 )
Week 84 [N=274,333]	-629.31 ( 1060.24 )	-454.44 ( 1193.43 )
Week 92 [N=258,326]	-749.58 ( 828.32 )	-371.64 ( 1157.18 )
Week 100 [N=250,313]	-746.86 ( 796.74 )	-364.78 ( 1802.37 )
Week 104 [N=248,308]	-753.82 ( 791.12 )	-348.70 ( 1292.49 )
EOS (up to 108 weeks) [N=290,323]	-554.53 ( 910.01 )	-166.94 ( 2035.26 )

No statistical analyses for this end point

Secondary: Change From BL in Transferrin Saturation (TSAT)

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End point title

Change From BL 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	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	412	420
Units: Percentage of saturation
arithmetic mean (standard deviation)
Week 4 [N=392,402]	-4.151 ( 16.147 )	-2.331 ( 13.178 )
Week 8 [N=383,399]	-3.681 ( 17.062 )	-3.128 ( 14.461 )
Week 12 [N=381,397]	-2.643 ( 17.551 )	-3.189 ( 13.912 )
Week 20 [N=363,387]	-3.782 ( 16.634 )	-4.398 ( 14.444 )
Week 28 [N=356,385]	-5.463 ( 17.798 )	-3.829 ( 15.216 )
Week 36 [N=336,372]	-5.351 ( 17.803 )	-4.022 ( 15.471 )
Week 44 [N=320,358]	-6.069 ( 16.349 )	-5.254 ( 15.144 )
Week 52 [N=313,353]	-7.278 ( 17.244 )	-5.788 ( 14.666 )
Week 60 [N=295,348]	-6.997 ( 16.774 )	-5.187 ( 16.097 )
Week 68 [N=287,338]	-7.279 ( 17.809 )	-6.237 ( 15.934 )
Week 76 [N=275,332]	-7.156 ( 17.682 )	-6.623 ( 16.395 )
Week 84 [N=270,331]	-7.867 ( 17.654 )	-5.378 ( 17.771 )
Week 92 [N=251,320]	-6.996 ( 19.850 )	-6.259 ( 16.605 )
Week 100 [N=248,308]	-8.379 ( 17.809 )	-6.354 ( 17.147 )
Week 104 [N=243,299]	-7.650 ( 17.842 )	-5.054 ( 17.195 )
EOS (up to 108 weeks) [N=283,321]	-5.466 ( 16.626 )	-3.763 ( 17.813 )

No statistical analyses for this end point

Secondary: Change From BL in Glycated Hemoglobin (HbA1c) Level to Weeks 12, 28, 36, 44, 52, 60, 84, 104 and EOS (up to Week 108)

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End point title

Change From BL in Glycated Hemoglobin (HbA1c) Level to Weeks 12, 28, 36, 44, 52, 60, 84, 104 and EOS (up to Week 108)

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, with participants who had available data at baseline. N is the number of participants with available data at each time point.

End point type

Secondary

End point timeframe

Baseline and weeks 12, 28, 36, 44, 52, 60, 84, 104 and EOS (up to 108 weeks)

End point values	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	413	419
Units: percentage of Glycated Hemoglobin
arithmetic mean (standard deviation)
Week 12 [N=385,401]	0.0009 ( 0.0071 )	-0.0005 ( 0.0057 )
Week 28 [N=360,389]	-0.0004 ( 0.0067 )	-0.0006 ( 0.0064 )
Week 36 [N=342,378]	-0.0001 ( 0.0065 )	-0.0004 ( 0.0067 )
Week 44 [N=327,370]	-0.0001 ( 0.0069 )	-0.0006 ( 0.0067 )
Week 52 [N=317,363]	-0.0001 ( 0.0070 )	-0.0007 ( 0.0068 )
Week 60 [N=303,355]	0.0000 ( 0.0080 )	-0.0004 ( 0.0070 )
Week 84 [N=269,331]	0.0003 ( 0.0072 )	0.0001 ( 0.0078 )
Week 104 [N=242,305]	0.0000 ( 0.0075 )	-0.0003 ( 0.0082 )
EOS (up to 108 weeks) [N=286,319]	0.0011 ( 0.0076 )	0.0001 ( 0.0080 )

No statistical analyses for this end point

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

Safety was assessed by evaluation of the following variables: (TEAEs; frequency, severity, seriousness, and relationship to study drug), Vital signs (systolic and diastolic blood pressure, pulse, respiratory rate and weight), Clinical laboratory variables (hematology, biochemistry including liver enzymes and total bilirubin, and urinalysis), Physical examination, 12-lead electrocardiogram (ECG) and Vascular Access Thrombosis. All AEs collected during the Safety Emergent Period were counted as TEAE. The TEAE was defined as an adverse event (AE) if it was observed after starting administration of the roxadustat or ESA. Any clinically significant abnormalities were reported as an AE. All reported deaths after the first study drug administration and up to 28 days after the Analysis Date of Last Dose and considering last dosing frequency. The analysis population was the Safety Analysis Set (SAF) which consisted of 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	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Number of subjects analysed	414	420
Units: Participants
TEAE	359	361
Drug-Related TEAE	77	35
Serious TEAE	210	189
Drug-Related Serious TEAE	33	10
TEAE Leading to Death	67	55
Drug-Related TEAE Leading to Death	5	2
TEAE Leading to Withdrawal of Treatment	35	16
Drug-Related TEAE Leading to Withdraw of Treatment	9	1
TEAE NCI CTC Grades 3 or Higher	181	149
Death During the Safety Emergent Period	64	51
Death	78	59

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 (EOS) (Up to week 108)

Adverse event reporting additional description

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

Reporting group title

Roxadustat

Reporting group description

Participants received roxadustat three times a week (TIW) for at least 40 weeks up to a maximum of 104 weeks. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant’s Hb levels between 10.0 to 12.0 g/dL.

Reporting group title

ESA (Erythropoiesis-Stimulating Agent)

Reporting group description

Participants received epoetin alfa once weekly, twice weekly or TIW and darbepoetin alfa once a week or once every other week. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant’s Hb levels between 10.0 to 12.0 g/dL.

Serious adverse events	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Total subjects affected by serious adverse events
subjects affected / exposed	210 / 414 (50.72%)	189 / 420 (45.00%)
number of deaths (all causes)	78	59
number of deaths resulting from adverse events	67	55
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma gastric
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	2 / 414 (0.48%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Benign lung neoplasm
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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 / 414 (0.00%)	1 / 420 (0.24%)
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 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bowen's disease
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Carcinoid tumour pulmonary
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colon adenoma
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colorectal adenocarcinoma
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colorectal cancer metastatic
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endometrial adenocarcinoma
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemangioma of bone
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypopharyngeal neoplasm
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Kidney angiomyolipoma
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	3 / 414 (0.72%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
Malignant neoplasm of choroid
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastatic neoplasm
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian neoplasm
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Papillary thyroid cancer
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parathyroid tumour benign
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Penile cancer
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Refractory anaemia with an excess of blasts
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin cancer
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small cell lung cancer
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Squamous cell carcinoma of skin
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Aortic dissection
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arterial disorder
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Deep vein thrombosis
subjects affected / exposed	4 / 414 (0.97%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic vascular disorder
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dry gangrene
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 414 (0.00%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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	10 / 414 (2.42%)	5 / 420 (1.19%)
occurrences causally related to treatment / all	3 / 10	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	3 / 414 (0.72%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 4	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	4 / 414 (0.97%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1
Intermittent claudication
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant hypertension
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Orthostatic hypotension
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	2 / 414 (0.48%)	4 / 420 (0.95%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
Peripheral artery occlusion
subjects affected / exposed	0 / 414 (0.00%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery thrombosis
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	2 / 414 (0.48%)	4 / 420 (0.95%)
occurrences causally related to treatment / all	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Steal syndrome
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subclavian artery thrombosis
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subclavian vein thrombosis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vasculitis necrotising
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Venous stenosis
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Catheter placement
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Therapy cessation
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 414 (0.72%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site haematoma
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site inflammation
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Chills
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Complication associated with device
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	6 / 414 (1.45%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	1 / 6	0 / 3
deaths causally related to treatment / all	1 / 6	0 / 3
Device related thrombosis
subjects affected / exposed	3 / 414 (0.72%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	1 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Medical device site phlebitis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	4 / 414 (0.97%)	4 / 420 (0.95%)
occurrences causally related to treatment / all	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Sudden death
subjects affected / exposed	7 / 414 (1.69%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	1 / 7	0 / 3
deaths causally related to treatment / all	1 / 7	0 / 3
Vascular stent stenosis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Anti-neutrophil cytoplasmic antibody positive vasculitis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian disorder
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Acute respiratory failure
subjects affected / exposed	2 / 414 (0.48%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Atelectasis
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Bronchitis chronic
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	2 / 414 (0.48%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic respiratory failure
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	4 / 414 (0.97%)	4 / 420 (0.95%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0
Eosinophilic pneumonia
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	6 / 414 (1.45%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 7	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural thickening
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary alveolar haemorrhage
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	4 / 414 (0.97%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	1 / 4	0 / 1
deaths causally related to treatment / all	1 / 3	0 / 1
Pulmonary hypertension
subjects affected / exposed	2 / 414 (0.48%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pulmonary infarction
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary oedema
subjects affected / exposed	6 / 414 (1.45%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	1 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory arrest
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory failure
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Disorientation
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fear of falling
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mental disorder due to a general medical condition
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Organic brain syndrome
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device failure
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device malfunction
subjects affected / exposed	4 / 414 (0.97%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Blood potassium increased
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Electrocardiogram abnormal
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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
Ankle fracture
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula aneurysm
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula occlusion
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site complication
subjects affected / exposed	6 / 414 (1.45%)	5 / 420 (1.19%)
occurrences causally related to treatment / all	0 / 7	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site haemorrhage
subjects affected / exposed	2 / 414 (0.48%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula thrombosis
subjects affected / exposed	29 / 414 (7.00%)	15 / 420 (3.57%)
occurrences causally related to treatment / all	6 / 37	4 / 18
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous graft site haemorrhage
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous graft site stenosis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous graft thrombosis
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	1 / 1	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Back injury
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Comminuted fracture
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 414 (0.00%)	6 / 420 (1.43%)
occurrences causally related to treatment / all	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	2 / 414 (0.48%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Femur fracture
subjects affected / exposed	2 / 414 (0.48%)	5 / 420 (1.19%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Graft thrombosis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lip injury
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Poisoning
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Post procedural haematoma
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural inflammation
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural complication
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pubis fracture
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt aneurysm
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt occlusion
subjects affected / exposed	2 / 414 (0.48%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	1 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt stenosis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt thrombosis
subjects affected / exposed	1 / 414 (0.24%)	4 / 420 (0.95%)
occurrences causally related to treatment / all	1 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Skin injury
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin wound
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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	2 / 414 (0.48%)	0 / 420 (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 haemorrhage
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular pseudoaneurysm
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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	3 / 414 (0.72%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 3	0 / 1
Acute left ventricular failure
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	9 / 414 (2.17%)	11 / 420 (2.62%)
occurrences causally related to treatment / all	0 / 9	1 / 13
deaths causally related to treatment / all	0 / 4	1 / 6
Angina pectoris
subjects affected / exposed	5 / 414 (1.21%)	6 / 420 (1.43%)
occurrences causally related to treatment / all	1 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	2 / 414 (0.48%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Arteriosclerosis coronary artery
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	12 / 414 (2.90%)	8 / 420 (1.90%)
occurrences causally related to treatment / all	1 / 14	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial tachycardia
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	4 / 414 (0.97%)	8 / 420 (1.90%)
occurrences causally related to treatment / all	0 / 4	0 / 9
deaths causally related to treatment / all	0 / 2	0 / 6
Cardiac failure
subjects affected / exposed	8 / 414 (1.93%)	9 / 420 (2.14%)
occurrences causally related to treatment / all	0 / 8	0 / 9
deaths causally related to treatment / all	0 / 5	0 / 3
Cardiac failure acute
subjects affected / exposed	3 / 414 (0.72%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0
Cardiac failure chronic
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
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	5 / 414 (1.21%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac fibrillation
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardio-respiratory arrest
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	1 / 1	0 / 3
deaths causally related to treatment / all	1 / 1	0 / 1
Cardiogenic shock
subjects affected / exposed	2 / 414 (0.48%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Cardiopulmonary failure
subjects affected / exposed	3 / 414 (0.72%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 1
Cardiovascular insufficiency
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Coronary artery disease
subjects affected / exposed	2 / 414 (0.48%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diastolic dysfunction
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive heart disease
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mitral valve stenosis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 414 (0.24%)	6 / 420 (1.43%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 2
Myocardial ischaemia
subjects affected / exposed	4 / 414 (0.97%)	4 / 420 (0.95%)
occurrences causally related to treatment / all	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
Pericarditis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	1 / 414 (0.24%)	5 / 420 (1.19%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Tachyarrhythmia
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tricuspid valve incompetence
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
Nervous system disorders
Carotid artery stenosis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebellar infarction
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral arteriosclerosis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral artery occlusion
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 414 (0.00%)	4 / 420 (0.95%)
occurrences causally related to treatment / all	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	3 / 414 (0.72%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Cerebrovascular disorder
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cognitive disorder
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coma
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Disturbance in attention
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Embolic cerebral infarction
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epileptic encephalopathy
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hypoxic-ischaemic encephalopathy
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Idiopathic partial epilepsy
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lethargy
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular dementia
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vertigo CNS origin
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 414 (1.21%)	7 / 420 (1.67%)
occurrences causally related to treatment / all	1 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 1
Hypocoagulable state
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Hypoacusis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vertigo
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Angle closure glaucoma
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cataract
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye haemorrhage
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal adhesions
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal wall haematoma
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute abdomen
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal fissure
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal incontinence
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic gastritis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Constipation
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 414 (0.48%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum intestinal
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	4 / 414 (0.97%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erosive duodenitis
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis erosive
subjects affected / exposed	2 / 414 (0.48%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 414 (0.00%)	6 / 420 (1.43%)
occurrences causally related to treatment / all	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal ischaemia
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gastrointestinal necrosis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2
Intestinal obstruction
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal ulcer perforation
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intra-abdominal haematoma
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestinal haemorrhage
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mechanical ileus
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal ulcer
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 414 (0.00%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Ulcerative gastritis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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	2 / 414 (0.48%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 414 (0.24%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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
Cutaneous vasculitis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ingrowing nail
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neurodermatitis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash vesicular
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin lesion
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Skin necrosis
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Toxic epidermal necrolysis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Urticaria
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Calculus urinary
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
End stage renal disease
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Haematuria
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cyst ruptured
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urethral perforation
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinoma
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hyperparathyroidism secondary
subjects affected / exposed	3 / 414 (0.72%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperthyroidism
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Toxic goitre
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fistula discharge
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint contracture
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mobility decreased
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteitis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	2 / 414 (0.48%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sarcopenia
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Abdominal infection
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess neck
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute hepatitis B
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	2 / 414 (0.48%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site infection
subjects affected / exposed	3 / 414 (0.72%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	5 / 414 (1.21%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 414 (0.48%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	2 / 414 (0.48%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	3 / 414 (0.72%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Diabetic gangrene
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalomyelitis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Enterobacter bacteraemia
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal sepsis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 414 (0.24%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal oesophagitis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gangrene
subjects affected / exposed	5 / 414 (1.21%)	4 / 420 (0.95%)
occurrences causally related to treatment / all	0 / 6	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer helicobacter
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 414 (0.00%)	6 / 420 (1.43%)
occurrences causally related to treatment / all	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal candidiasis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma infection
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Incision site infection
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infectious colitis
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	2 / 414 (0.48%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral discitis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Medical device site joint infection
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis bacterial
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis bacterial
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Penile abscess
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Periodontitis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	10 / 414 (2.42%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	0 / 15	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
Peritonitis bacterial
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	15 / 414 (3.62%)	21 / 420 (5.00%)
occurrences causally related to treatment / all	0 / 15	0 / 22
deaths causally related to treatment / all	0 / 2	0 / 6
Pneumonia pneumococcal
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudomonal sepsis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Pyelonephritis chronic
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyonephrosis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal abscess
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cyst infection
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 414 (0.00%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection bacterial
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	8 / 414 (1.93%)	9 / 420 (2.14%)
occurrences causally related to treatment / all	0 / 8	0 / 9
deaths causally related to treatment / all	0 / 4	0 / 3
Sepsis syndrome
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Sinusitis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin infection
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
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	3 / 414 (0.72%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Streptococcal sepsis
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Subcutaneous abscess
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic infection
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Tracheobronchitis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (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
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	4 / 414 (0.97%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection enterococcal
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection pseudomonal
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection staphylococcal
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Viral upper respiratory tract infection
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Dehydration
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	1 / 414 (0.24%)	2 / 420 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid retention
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 414 (0.24%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	2 / 414 (0.48%)	0 / 420 (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	4 / 414 (0.97%)	3 / 420 (0.71%)
occurrences causally related to treatment / all	1 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Hypervolaemia
subjects affected / exposed	0 / 414 (0.00%)	1 / 420 (0.24%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Metabolic acidosis
subjects affected / exposed	1 / 414 (0.24%)	0 / 420 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Roxadustat	ESA (Erythropoiesis-Stimulating Agent)
Total subjects affected by non serious adverse events
subjects affected / exposed	210 / 414 (50.72%)	209 / 420 (49.76%)
Injury, poisoning and procedural complications
Arteriovenous fistula thrombosis
subjects affected / exposed	27 / 414 (6.52%)	18 / 420 (4.29%)
occurrences all number	34	21
Vascular disorders
Hypertension
subjects affected / exposed	66 / 414 (15.94%)	75 / 420 (17.86%)
occurrences all number	101	116
Hypotension
subjects affected / exposed	30 / 414 (7.25%)	26 / 420 (6.19%)
occurrences all number	40	40
Nervous system disorders
Headache
subjects affected / exposed	36 / 414 (8.70%)	29 / 420 (6.90%)
occurrences all number	41	39
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	33 / 414 (7.97%)	32 / 420 (7.62%)
occurrences all number	51	60
Nausea
subjects affected / exposed	27 / 414 (6.52%)	8 / 420 (1.90%)
occurrences all number	29	10
Endocrine disorders
Hyperparathyroidism secondary
subjects affected / exposed	21 / 414 (5.07%)	16 / 420 (3.81%)
occurrences all number	21	17
Musculoskeletal and connective tissue disorders
Muscle spasms
subjects affected / exposed	15 / 414 (3.62%)	33 / 420 (7.86%)
occurrences all number	21	48
Infections and infestations
Bronchitis
subjects affected / exposed	29 / 414 (7.00%)	27 / 420 (6.43%)
occurrences all number	38	34
Upper respiratory tract infection
subjects affected / exposed	14 / 414 (3.38%)	21 / 420 (5.00%)
occurrences all number	19	29
Viral upper respiratory tract infection
subjects affected / exposed	28 / 414 (6.76%)	39 / 420 (9.29%)
occurrences all number	61	68
Metabolism and nutrition disorders
Iron deficiency
subjects affected / exposed	30 / 414 (7.25%)	51 / 420 (12.14%)
occurrences all number	39	64

More information

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Were there any global substantial amendments to the protocol? Yes

13 May 2015

The changes include: -For patients randomized to roxadustat, maximum dose was reduced from 3.5 mg/kg to 3.0 mg/kg. -For patients randomized to receive ESA, (i.e., epoetin alfa or darbepoetin alfa), dosing frequencies were converted to the protocol pre-specified frequencies irrespective of their frequency of administration prior to randomization. -Another primary efficacy endpoint added to support submission of the data to the US health authority (FDA). Existing primary efficacy endpoint was made specific for the EU submission. An additional secondary endpoint (Patients’ Global Impression of Change) was added. None of these changes were driven by safety concerns.

13 May 2015

The changes include: -Substantial changes included collection of serious adverse events (SAEs) and cardiovascular and thromboembolic adverse events (AEs) instead of hospitalizations during the follow-up period; requirement for female and male patients that, if required by local law, two highly effective methods of birth control be used, one of which must be a barrier method; the change in Hb over the past 4 weeks which was used for decisions on dose adjustments, was increased from ± 0.8 g/dL to ± 1.0 g/dL; the roxadustat dosing rules for excessive hematopoiesis were consolidated into one rule: “If Hb increased by > 2.0 g/dL within 4 weeks, the dose was to be reduced by one dose step.”; the text of ESA rescue therapy was updated; the text on the use of supplemental iron was updated and clarified; the statistical section was updated: a sensitivity analysis was added to check for homogeneity of the treatment difference before and after the protocol amendment; optional additional assessments at unscheduled visits were added; guidance text on the concomitant use of statins and other drugs that are substrates for Organic anion transporting polypeptide 1B1 was updated; information was added regarding the potential interaction between roxadustat and phosphate binders; lower strengths were added to the ESA study treatments and relevant medical conditions was clarified.

13 May 2015

The changes include: -The treatment period was 104 weeks and is being changed to a variable treatment period with a minimum of 52 weeks and maximum of 104 weeks. -A planned interim analysis was to be performed when all patients had completed 52 weeks of treatment; this interim analysis was removed.

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.

Overall 838 were randomized to receive treatment. Two participants randomized to the pooled ESA treatment group were excluded due to GCP violations and their data was excluded. Total of 836 were considered randomized.

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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 Maintenance Treatment of Anemia in End Stage Renal Disease Patients on Stable Dialysis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline (BL) to the Average Hemoglobin (Hb) in Weeks 28-36 Without Rescue Therapy [EU (EMA)]

Primary: Change From Baseline (BL) to the Average Hemoglobin (Hb) in Weeks 28-36 Without Rescue Therapy [EU (EMA)]

Primary: Change From BL to the Average Hb in Weeks 28 to 52 Regardless of Rescue Therapy [US (FDA)]

Primary: Change From BL to the Average Hb in Weeks 28 to 52 Regardless of Rescue Therapy [US (FDA)]

Secondary: Percentage of Participants with Hb Response During Weeks 28 to 36

Secondary: Percentage of Participants with Hb Response During Weeks 28 to 36

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

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

Secondary: Mean Monthly Intravenous (IV) Iron Use

Secondary: Mean Monthly Intravenous (IV) Iron Use

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

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

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

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

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

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

Secondary: Time to First Occurrence of an Increase in Blood Pressure in PPS

Secondary: Time to First Occurrence of an Increase in Blood Pressure in PPS

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

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

Secondary: Time to First Occurrence of an Increase in Blood Pressure in FAS

Secondary: Time to First Occurrence of an Increase in Blood Pressure in FAS

Secondary: Percentage of Participants with a Hb Response During Weeks 28 and 36 Regardless of Use of Rescue Therapy

Secondary: Percentage of Participants with a Hb Response During Weeks 28 and 36 Regardless of Use of Rescue Therapy

Secondary: Change From BL in Hb to Each Postdosing Time Point

Secondary: Change From BL in Hb to Each Postdosing Time Point

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

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

Secondary: Change From BL in Hb to the Average of Weeks 28 to 36, 44 to 52, and 96 to 104 Regardless of the Use of Rescue Therapy

Secondary: Change From BL in Hb to the Average of Weeks 28 to 36, 44 to 52, and 96 to 104 Regardless of the Use of Rescue Therapy

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

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

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

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

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 Rescue Therapy

Secondary: Time to First Use of Rescue Therapy

Secondary: Time to First RBC Transfusion

Secondary: Time to First RBC Transfusion

Secondary: Mean Monthly Number of RBC Packs Per Participant

Secondary: Mean Monthly Number of RBC Packs Per Participant

Secondary: Mean Monthly Volume of RBC Transfusion Per Participant

Secondary: Mean Monthly Volume of RBC Transfusion Per Participant

Secondary: Time to First Use of IV Iron Supplementation

Secondary: Time to First Use of IV Iron Supplementation

Secondary: Mean Monthly Intravenous (IV) Iron per Participant During Weeks 37-52 and Weeks 53-104

Secondary: Mean Monthly Intravenous (IV) Iron per Participant During Weeks 37-52 and Weeks 53-104

Secondary: Percentage of Participants with Oral Iron Use Only

Secondary: Percentage of Participants with Oral Iron Use Only

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

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

Secondary: Change From BL to Each Post-dosing Study Visit in LDL-C/High-density Lipoprotein cholesterol (HDL-C) Ratio

Secondary: Change From BL to Each Post-dosing Study Visit in LDL-C/High-density Lipoprotein cholesterol (HDL-C) Ratio

Secondary: Change From BL to Each Postdosing Study Visit in Non-HDL Cholesterol

Secondary: Change From BL to Each Postdosing Study Visit in Non-HDL Cholesterol

Secondary: Change From BL to Each Postdosing Study Visit in Apolipoproteins A1 (ApoA1)

Secondary: Change From BL to Each Postdosing Study Visit in Apolipoproteins A1 (ApoA1)

Secondary: Change From BL to Each Postdosing Study Visit in Apolipoproteins B (ApoB)

Secondary: Change From BL to Each Postdosing Study Visit in Apolipoproteins B (ApoB)

Secondary: Change From BL to Each Postdosing Study Visit in ApoB/ApoA1 Ratio

Secondary: Change From BL to Each Postdosing Study Visit in ApoB/ApoA1 Ratio

Secondary: Number of Participants with Mean LDL Cholesterol < 100 mg/dL Over Weeks 12 to 28

Secondary: Number of Participants with Mean LDL Cholesterol < 100 mg/dL Over Weeks 12 to 28

Secondary: Number of Participants with CKD Who Achieved Antihypertensive Treatment Goal

Secondary: Number of Participants with CKD Who Achieved Antihypertensive Treatment Goal

Clinical Trial Results:
A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of Roxadustat in the Maintenance Treatment of Anemia in End Stage Renal Disease Patients on Stable Dialysis