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Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Investigating the Efficacy and Safety of Roxadustat (FG-4592) for Treatment of Anemia in Patients with Lower Risk Myelodysplastic Syndrome (MDS) with Low Red Blood Cell (RBC) Transfusion Burden (LTB)

Summary
EudraCT number	2017-001773-17
Trial protocol	DE ES GB BE DK IT
Global end of trial date	20 Jun 2023

Results information
Results version number	v2(current)
This version publication date	24 Aug 2024
First version publication date	29 Jun 2024
Other versions	v1
Version creation reason

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

FGCL-4592-082

ISRCTN number

-

US NCT number

NCT03263091

WHO universal trial number (UTN)

-

Sponsor organisation name

FibroGen, Inc.

Sponsor organisation address

409 Illinois Street, San Francisco, United States, CA 94158

Public contact

Clinical Trial Information Desk, FibroGen, Inc., 082MDSstudy@fibrogen.com

Scientific contact

Clinical Trial Information Desk, FibroGen, Inc., 082MDSstudy@fibrogen.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

20 Jun 2023

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

20 Jun 2023

Was the trial ended prematurely?

Yes

Main objective of the trial

The purpose of this study is to determine whether FG-4592 is safe and effective in the treatment of anemia in participants with lower risk MDS and low red blood cell transfusion burden.

Protection of trial subjects

This study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP), the International Council for Harmonisation (ICH) E6 Guidance for GCP, any other applicable local health and regulatory requirements and Institutional Ethics Committee (IEC) requirements.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

29 Jan 2018

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 11

Country: Number of subjects enrolled

Belgium: 4

Country: Number of subjects enrolled

Canada: 1

Country: Number of subjects enrolled

Denmark: 2

Country: Number of subjects enrolled

France: 7

Country: Number of subjects enrolled

Germany: 14

Country: Number of subjects enrolled

India: 7

Country: Number of subjects enrolled

Israel: 17

Country: Number of subjects enrolled

Italy: 10

Country: Number of subjects enrolled

Korea, Democratic People's Republic of: 15

Country: Number of subjects enrolled

Poland: 15

Country: Number of subjects enrolled

Russian Federation: 13

Country: Number of subjects enrolled

Spain: 21

Country: Number of subjects enrolled

Türkiye: 16

Country: Number of subjects enrolled

United Kingdom: 8

Country: Number of subjects enrolled

United States: 23

Worldwide total number of subjects

184

EEA total number of subjects

73

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

45

From 65 to 84 years

126

85 years and over

13

Subject disposition

Top of page

Recruitment details

The study included 3 components: Open-label (OL) Lead-in, Double-blind (DB), and OL High-erythropoietin (High-EPO) component. Participants were enrolled in sequential dose level cohorts in OL lead-in component prior to the start of DB component.

Screening details

Concurrent with enrollment in DB component, participants with high serum EPO levels (>400 milli-international units [mIU]/milliliter [mL]), exclusionary for DB component, were enrolled in an OL high-EPO component. Participants with lower-risk myelodysplastic syndrome (MDS) with LTB were randomized 3:2 to roxadustat or placebo in DB component.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

OL Component (Cohort 1): Roxadustat 1.5 mg/kg

Arm description

Participants received roxadustat 1.5 milligrams (mg)/kilograms (kg), three times a week (TIW) for 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Roxadustat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Roxadustat was administered per schedule specified in the arm description.

OL Component (Cohort 2): Roxadustat 2.0 mg/kg

Arm description

Participants received roxadustat 2.0 mg/kg, TIW for 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Roxadustat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Roxadustat was administered per schedule specified in the arm description.

OL Component (Cohort 3): Roxadustat 2.5 mg/kg

Arm description

Participants received roxadustat 2.5 mg/kg, TIW for 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Roxadustat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Roxadustat was administered per schedule specified in the arm description.

OL High-EPO Component: Roxadustat 2.5 mg/kg

Arm description

Participants with high serum EPO levels (>400 mIU/mL) received roxadustat 2.5 mg/kg TIW for 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Roxadustat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Roxadustat was administered per schedule specified in the arm description.

DB Component: Roxadustat

Arm description

Participants received roxadustat 2.5 mg/kg TIW for 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Roxadustat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Roxadustat was administered per schedule specified in the arm description.

DB Component: Placebo

Arm description

Participants received placebo matched to roxadustat for 52 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo matched to roxadustat was administered per schedule specified in the arm description.

Number of subjects in period 1	OL Component (Cohort 1): Roxadustat 1.5 mg/kg	OL Component (Cohort 2): Roxadustat 2.0 mg/kg	OL Component (Cohort 3): Roxadustat 2.5 mg/kg	OL High-EPO Component: Roxadustat 2.5 mg/kg	DB Component: Roxadustat	DB Component: Placebo
Started	8	8	8	20	82	58
Received at least 1 dose of study drug	8	8	8	20	82	58
Completed	6	6	6	10	38	37
Not completed	2	2	2	10	44	21
Adverse event, serious fatal	1	-	-	3	7	4
Consent withdrawn by subject	1	1	-	6	22	8
Physician decision	-	1	2	1	3	1
Adverse event, non-fatal	-	-	-	-	2	1
Other than specified	-	-	-	-	8	6
Lost to follow-up	-	-	-	-	2	1

Baseline characteristics

Top of page

Reporting group title

OL Component (Cohort 1): Roxadustat 1.5 mg/kg

Reporting group description

Participants received roxadustat 1.5 milligrams (mg)/kilograms (kg), three times a week (TIW) for 52 weeks.

Reporting group title

OL Component (Cohort 2): Roxadustat 2.0 mg/kg

Reporting group description

Participants received roxadustat 2.0 mg/kg, TIW for 52 weeks.

Reporting group title

OL Component (Cohort 3): Roxadustat 2.5 mg/kg

Reporting group description

Participants received roxadustat 2.5 mg/kg, TIW for 52 weeks.

Reporting group title

OL High-EPO Component: Roxadustat 2.5 mg/kg

Reporting group description

Participants with high serum EPO levels (>400 mIU/mL) received roxadustat 2.5 mg/kg TIW for 52 weeks.

Reporting group title

DB Component: Roxadustat

Reporting group description

Participants received roxadustat 2.5 mg/kg TIW for 52 weeks.

Reporting group title

DB Component: Placebo

Reporting group description

Participants received placebo matched to roxadustat for 52 weeks.

Reporting group values	OL Component (Cohort 1): Roxadustat 1.5 mg/kg	OL Component (Cohort 2): Roxadustat 2.0 mg/kg	OL Component (Cohort 3): Roxadustat 2.5 mg/kg	OL High-EPO Component: Roxadustat 2.5 mg/kg	DB Component: Roxadustat	DB Component: Placebo	Total
Number of subjects	8	8	8	20	82	58	184
Age Categorical
Units: participants
<65 Years	3	0	2	8	18	14	45
≥65 Years	5	8	6	12	64	44	139
Sex: Female, Male
Units: participants
Female	3	3	6	6	36	21	75
Male	5	5	2	14	46	37	109
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	0	0	0	3	14	7	24
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0	0
White	7	8	8	17	63	49	152
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	1	0	0	0	5	2	8
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	1	0	1	1	2	6
Not Hispanic or Latino	7	7	6	19	78	55	172
Unknown or Not Reported	0	0	2	0	3	1	6

End points

Top of page

Reporting group title

OL Component (Cohort 1): Roxadustat 1.5 mg/kg

Reporting group description

Participants received roxadustat 1.5 milligrams (mg)/kilograms (kg), three times a week (TIW) for 52 weeks.

Reporting group title

OL Component (Cohort 2): Roxadustat 2.0 mg/kg

Reporting group description

Participants received roxadustat 2.0 mg/kg, TIW for 52 weeks.

Reporting group title

OL Component (Cohort 3): Roxadustat 2.5 mg/kg

Reporting group description

Participants received roxadustat 2.5 mg/kg, TIW for 52 weeks.

Reporting group title

OL High-EPO Component: Roxadustat 2.5 mg/kg

Reporting group description

Participants with high serum EPO levels (>400 mIU/mL) received roxadustat 2.5 mg/kg TIW for 52 weeks.

Reporting group title

DB Component: Roxadustat

Reporting group description

Participants received roxadustat 2.5 mg/kg TIW for 52 weeks.

Reporting group title

DB Component: Placebo

Reporting group description

Participants received placebo matched to roxadustat for 52 weeks.

Primary: OL and OL High-EPO Components: Number of Participants who Achieved Red Blood Cell (RBC) Transfusion Independence (TI) ≥8 Weeks (≥56 Consecutive Days) Since First Dose in the First 28 weeks of Treatment

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End point title

OL and OL High-EPO Components: Number of Participants who Achieved Red Blood Cell (RBC) Transfusion Independence (TI) ≥8 Weeks (≥56 Consecutive Days) Since First Dose in the First 28 weeks of Treatment ^[1] ^[2]

End point description

The RBC TI was defined as the absence of any intravenous (IV) RBC transfusion (packed cell or whole blood) during any consecutive 56 days during the treatment period. Data presented is for number of participants with RBC TI ≥8 weeks (≥56 consecutive days) since first dose in the first 28 weeks of treatment. The full analysis set (FAS) included all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment hemoglobin (Hb) assessment.

End point type

Primary

End point timeframe

28 weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The end point is reporting statistics for the specified arms only.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the specified arms only.

End point values	OL Component (Cohort 1): Roxadustat 1.5 mg/kg	OL Component (Cohort 2): Roxadustat 2.0 mg/kg	OL Component (Cohort 3): Roxadustat 2.5 mg/kg	OL High-EPO Component: Roxadustat 2.5 mg/kg
Number of subjects analysed	8	8	8	20
Units: participants	3	1	5	3

No statistical analyses for this end point

Primary: DB Component: Number of Participants who Achieved RBC TI ≥56 Consecutive Days Since First Dose in the First 28 Weeks of Treatment

Top of page

End point title

DB Component: Number of Participants who Achieved RBC TI ≥56 Consecutive Days Since First Dose in the First 28 Weeks of Treatment ^[3]

End point description

RBC TI was defined as the absence of any IV RBC transfusion (packed cell or whole blood) during any consecutive 56 days during the treatment period. Data presented is for number of participants with RBC TI ≥56 consecutive days since first dose in the first 28 weeks of treatment. FAS included all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment Hb assessment.

End point type

Primary

End point timeframe

28 weeks

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the specified arms only.

End point values	DB Component: Roxadustat	DB Component: Placebo
Number of subjects analysed	80	57
Units: participants	38	19

Statistical Analysis 1

Statistical analysis description

The odds ratio along with its 95% confidence interval (CI) were calculated based on the Cochran-Mantel-Haenszel (CMH) chi-square test adjusting for the stratification factors (EPO level, International Prognostic Scoring System – Revised [IPSS-R] risk category and RBC transfusion burden).

Comparison groups

DB Component: Roxadustat v DB Component: Placebo

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.217

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.582

Confidence interval

level

95%

sides

2-sided

lower limit

0.761

upper limit

3.29

Secondary: OL and OL High-EPO Components: Number of Participants who Achieved TI ≥50% Reduction From Baseline in Number of Packs of Red Blood Cells (pRBC) Transfusions over 8 Weeks

Top of page

End point title

OL and OL High-EPO Components: Number of Participants who Achieved TI ≥50% Reduction From Baseline in Number of Packs of Red Blood Cells (pRBC) Transfusions over 8 Weeks ^[4]

End point description

Number of pRBC transfusions at baseline was defined as pRBC transfusions requirement during 8-week period prior to the start of first study medication. Responders were defined as participants with at least a 50% reduction in the number of pRBC transfusions over any 8-week (56 consecutive days) period during the study as compared with the baseline. FAS included all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment Hb assessment.

End point type

Secondary

End point timeframe

Baseline up to Week 8

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the specified arms only.

End point values	OL Component (Cohort 1): Roxadustat 1.5 mg/kg	OL Component (Cohort 2): Roxadustat 2.0 mg/kg	OL Component (Cohort 3): Roxadustat 2.5 mg/kg	OL High-EPO Component: Roxadustat 2.5 mg/kg
Number of subjects analysed	8	8	8	20
Units: participants	5	3	7	8

No statistical analyses for this end point

Secondary: DB Component: Number of Participants who Achieved TI ≥56 Consecutive Days Since First Dose in 52 Weeks of Treatment

Top of page

End point title

DB Component: Number of Participants who Achieved TI ≥56 Consecutive Days Since First Dose in 52 Weeks of Treatment ^[5]

End point description

RBC TI was defined as the absence of any IV RBC transfusion (packed cell or whole blood) during any consecutive 56 days during the treatment period. Data presented is for number of participants with RBC TI ≥56 consecutive days since first dose in the 52 weeks of treatment. FAS included all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment Hb assessment.

End point type

Secondary

End point timeframe

52 weeks

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the specified arms only.

End point values	DB Component: Roxadustat	DB Component: Placebo
Number of subjects analysed	80	57
Units: participants	44	23

No statistical analyses for this end point

Secondary: DB Component: Number of Participants who Achieved TI ≥56 Consecutive Days Anytime During the Study

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End point title

DB Component: Number of Participants who Achieved TI ≥56 Consecutive Days Anytime During the Study ^[6]

End point description

RBC TI was defined as the absence of any IV RBC transfusion (packed cell or whole blood) during any consecutive 56 days anytime during the study (up to Week 56). FAS included all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment Hb assessment.

End point type

Secondary

End point timeframe

Baseline up to Week 56

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the specified arms only.

End point values	DB Component: Roxadustat	DB Component: Placebo
Number of subjects analysed	80	57
Units: participants	52	29

No statistical analyses for this end point

Secondary: DB Component: Number of Participants who Achieved ≥50% Reduction From Baseline in Number of pRBC Transfusions Over 8 Weeks

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End point title

DB Component: Number of Participants who Achieved ≥50% Reduction From Baseline in Number of pRBC Transfusions Over 8 Weeks ^[7]

End point description

Baseline number of transfusions (pRBC/8-weeks) = total number of packs of rRBCs within 16 weeks prior to first dose/2. A pRBC transfusion reduction responder was defined as a participant who achieved ≥50% reduction in number of pRBC transfusions over 8 weeks compared to their baseline for any 8 week period in the duration begining with the first dose date (Day 1) and ending with the end of study or treatment discontinuation due to adverse event (AE)/serious adverse event (SAE) or death, whichever came earlier. FAS included all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment Hb assessment.

End point type

Secondary

End point timeframe

Baseline up to Week 8

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the specified arms only.

End point values	DB Component: Roxadustat	DB Component: Placebo
Number of subjects analysed	80	57
Units: participants	59	37

No statistical analyses for this end point

Secondary: DB Component: Cumulative Number of Participant Exposure Weeks (PEW) of TI Over the First 28 Weeks of Treatment

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End point title

DB Component: Cumulative Number of Participant Exposure Weeks (PEW) of TI Over the First 28 Weeks of Treatment ^[8]

End point description

The PEW of TI periods over the first 28 weeks was added up to a cumulative number of weeks. For a participant with at least 1 TI response period over the first 28 weeks, the last TI response period was ended with the date of a subsequent RBC transfusion, visit date at Week 28, date of the end of study or treatment discontinuation due to AE/SAE or death, whichever came earlier. For a participant with no TI response period over the first 28 weeks, the cumulative number of PEW was set to zero. FAS included all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment Hb assessment.

End point type

Secondary

End point timeframe

28 weeks

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the specified arms only.

End point values	DB Component: Roxadustat	DB Component: Placebo
Number of subjects analysed	80	57
Units: weeks
arithmetic mean (standard deviation)	9.60 ( 11.537 )	7.60 ( 11.557 )

No statistical analyses for this end point

Secondary: DB Component: Change From Baseline in Number of pRBC Packs Transfused Over the First 28 Weeks of Treatment

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End point title

DB Component: Change From Baseline in Number of pRBC Packs Transfused Over the First 28 Weeks of Treatment ^[9]

End point description

Number of pRBC transfusions at baseline was defined as pRBC transfusions requirement during 8-week period prior to the start of first study medication. FAS included all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment Hb assessment.

End point type

Secondary

End point timeframe

Baseline, Week 28

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the specified arms only.

End point values	DB Component: Roxadustat	DB Component: Placebo
Number of subjects analysed	80	57
Units: pRBC packs
arithmetic mean (standard deviation)	-0.13 ( 2.314 )	0.44 ( 1.833 )

No statistical analyses for this end point

Secondary: DB Component: Number of Participants who Achieved TI ≥20 Consecutive Weeks During the Study

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End point title

DB Component: Number of Participants who Achieved TI ≥20 Consecutive Weeks During the Study ^[10]

End point description

≥20 consecutive weeks TI was defined as the absence of any IV RBC transfusion (packed cell or whole blood) during any consecutive 140 days anytime during the study (up to 56 weeks). TI was estimated between the first dose date (Day 1) and the end of study (Week 56) or treatment discontinuation due to AE/SAE or death, whichever came earlier. FAS included all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment Hb assessment.

End point type

Secondary

End point timeframe

Baseline up to Week 56

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the specified arms only.

End point values	DB Component: Roxadustat	DB Component: Placebo
Number of subjects analysed	80	57
Units: participants	23	15

No statistical analyses for this end point

Secondary: DB Component: Mean Change from Baseline in the Patient-Reported Outcomes Measurement Information System-Short Form (PROMIS-SF) v2.0 Physical Function (PF) 10b Score at Week 9

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End point title

DB Component: Mean Change from Baseline in the Patient-Reported Outcomes Measurement Information System-Short Form (PROMIS-SF) v2.0 Physical Function (PF) 10b Score at Week 9 ^[11]

End point description

The PROMIS PF 10-item short form which contains 10 questions was used in this study, and each item was scored on a 5-point rating scale (1 [unable to do] to 5 [without any difficulty]), with higher scores indicating better functioning. Total raw score was the sum of the response to each question, with the lowest possible raw score 10 (poor physical function) and the highest possible raw score 50 (better physical function). Raw scores converted to T-scores (as detailed in the T-score conversion table for PROMIS-SF v2.0 Physical Function 10b) with a mean of 50 and a standard deviation (SD) of 10. T-scores ranged from minimum 13.8 to maximum 61.3 possible scores with higher scores indicating better physical functioning. FAS = all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment Hb assessment. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 9

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the specified arms only.

End point values	DB Component: Roxadustat	DB Component: Placebo
Number of subjects analysed	71	52
Units: T-score
arithmetic mean (standard deviation)	-1.9 ( 7.29 )	-0.4 ( 6.77 )

No statistical analyses for this end point

Secondary: DB Component: Mean Change from Baseline in the PROMIS-SF v1.0 Fatigue 13a Score at Week 9

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End point title

DB Component: Mean Change from Baseline in the PROMIS-SF v1.0 Fatigue 13a Score at Week 9 ^[12]

End point description

Fatigue was measured using 13-item fatigue scale of the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System, each item was scored on a 5-point rating scale ranging from 1 “not at all” to 5 “very much”, with lower scores indicating better functioning. Total raw score was the sum of response to each question, with the lowest possible raw score 13 (lowest level of fatigue) and the highest possible raw score 65 (highest level of fatigue), with lower scores indicating better functioning. Raw scores converted to T-scores (as detailed in the T-score conversion table for PROMIS-SF v1.0 Fatigue 13a) with a mean of 50 and a SD of 10. T-scores ranged from minimum 30.3 to maximum 83.5 possible scores with lower scores indicating better functioning. FAS = all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment Hb assessment. 'Overall number of participants analyzed' = participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 9

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the specified arms only.

End point values	DB Component: Roxadustat	DB Component: Placebo
Number of subjects analysed	67	52
Units: T-score
arithmetic mean (standard deviation)	1.9 ( 7.61 )	-0.6 ( 7.36 )

No statistical analyses for this end point

Secondary: DB Component: Mean Change from Baseline in the European Quality of Life Five Dimensional Five Level Health Questionnaire (EQ-5D-5L) Visual Analogue Scale Score at Week 9

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End point title

DB Component: Mean Change from Baseline in the European Quality of Life Five Dimensional Five Level Health Questionnaire (EQ-5D-5L) Visual Analogue Scale Score at Week 9 ^[13]

End point description

The EQ-5D questionnaire is designed for self-completion by participants. The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problem, moderate problems, severe problems, and unable to/extreme problems. The questionnaire also included a visual analogue scale, where the participant was asked to rate current health status on a scale of 0-100, with 0 being the worst imaginable health state and 100 being the best imaginable health. FAS included all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment Hb assessment. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Baseline, Week 9

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the specified arms only.

End point values	DB Component: Roxadustat	DB Component: Placebo
Number of subjects analysed	71	55
Units: units on a scale
arithmetic mean (standard deviation)	-1.7 ( 20.31 )	1.6 ( 16.18 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Baseline up to Week 56

Adverse event reporting additional description

The safety analysis set included all participants who received at least 1 dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

OL Component (Cohort 1): Roxadustat 1.5 mg/kg

Reporting group description

Participants received roxadustat 1.5 mg/kg, TIW for 52 weeks.

Reporting group title

OL Component (Cohort 2): Roxadustat 2.0 mg/kg

Reporting group description

Participants received roxadustat 2.0 mg/kg, TIW for 52 weeks.

Reporting group title

OL Component (Cohort 3): Roxadustat 2.5 mg/kg

Reporting group description

Participants received roxadustat 2.5 mg/kg, TIW for 52 weeks.

Reporting group title

OL High-EPO Component: Roxadustat 2.5 mg/kg

Reporting group description

Participants with high serum EPO levels (>400 mIU/mL) received roxadustat 2.5 mg/kg TIW for 52 weeks.

Reporting group title

DB Component: Roxadustat

Reporting group description

Participants received roxadustat 2.5 mg/kg TIW for 52 weeks.

Reporting group title

DB Component: Placebo

Reporting group description

Participants received placebo matched to roxadustat for 52 weeks.

Serious adverse events	OL Component (Cohort 1): Roxadustat 1.5 mg/kg	OL Component (Cohort 2): Roxadustat 2.0 mg/kg	OL Component (Cohort 3): Roxadustat 2.5 mg/kg	OL High-EPO Component: Roxadustat 2.5 mg/kg	DB Component: Roxadustat	DB Component: Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 8 (50.00%)	3 / 8 (37.50%)	1 / 8 (12.50%)	6 / 20 (30.00%)	22 / 82 (26.83%)	10 / 58 (17.24%)
number of deaths (all causes)	1	0	0	3	7	4
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	2 / 82 (2.44%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	2 / 82 (2.44%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute left ventricular failure
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Transient ischaemic attack
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	2 / 82 (2.44%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	2 / 82 (2.44%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Splenomegaly
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Portal hypertension
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	3 / 58 (5.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureteric stenosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Cervical spinal stenosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	4 / 82 (4.88%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Campylobacter gastroenteritis
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	OL Component (Cohort 1): Roxadustat 1.5 mg/kg	OL Component (Cohort 2): Roxadustat 2.0 mg/kg	OL Component (Cohort 3): Roxadustat 2.5 mg/kg	OL High-EPO Component: Roxadustat 2.5 mg/kg	DB Component: Roxadustat	DB Component: Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 8 (87.50%)	8 / 8 (100.00%)	6 / 8 (75.00%)	15 / 20 (75.00%)	68 / 82 (82.93%)	46 / 58 (79.31%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 20 (10.00%)	2 / 82 (2.44%)	0 / 58 (0.00%)
occurrences all number	0	0	0	2	2	0
Basal cell carcinoma
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	1	0	0	0
Sweat gland tumour
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	1	0	0	0	0
Pituitary tumour benign
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	1	0	0	0	0
Malignant neoplasm progression
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Vascular disorders
Orthostatic hypotension
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	1 / 82 (1.22%)	1 / 58 (1.72%)
occurrences all number	0	0	1	0	1	2
Hypotension
subjects affected / exposed	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	4 / 82 (4.88%)	2 / 58 (3.45%)
occurrences all number	2	0	0	0	5	2
Pallor
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	1	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	4 / 20 (20.00%)	11 / 82 (13.41%)	7 / 58 (12.07%)
occurrences all number	0	0	2	5	11	10
Fatigue
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 20 (10.00%)	15 / 82 (18.29%)	6 / 58 (10.34%)
occurrences all number	0	0	0	2	18	9
General physical health deterioration
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	2 / 82 (2.44%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	2	0
Generalised oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Influenza like illness
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	1	0	0	0	0
Malaise
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	1	0	0	0
Non-cardiac chest pain
subjects affected / exposed	3 / 8 (37.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	3	1	0	2	0	0
Pyrexia
subjects affected / exposed	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	5 / 82 (6.10%)	1 / 58 (1.72%)
occurrences all number	0	2	0	0	5	1
Oedema peripheral
subjects affected / exposed	2 / 8 (25.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 20 (10.00%)	9 / 82 (10.98%)	4 / 58 (6.90%)
occurrences all number	3	2	0	2	13	4
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences all number	0	0	1	0	0	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	3 / 58 (5.17%)
occurrences all number	0	1	0	1	0	3
Dyspnoea
subjects affected / exposed	2 / 8 (25.00%)	2 / 8 (25.00%)	2 / 8 (25.00%)	1 / 20 (5.00%)	8 / 82 (9.76%)	1 / 58 (1.72%)
occurrences all number	2	2	2	1	9	1
Cough
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 20 (5.00%)	4 / 82 (4.88%)	1 / 58 (1.72%)
occurrences all number	0	0	1	1	4	1
Epistaxis
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences all number	2	1	0	0	0	1
Nasal congestion
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Hypoventilation
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Nasal inflammation
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	1	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Pleuritic pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	0	0
Productive cough
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	2 / 58 (3.45%)
occurrences all number	0	1	0	0	0	2
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	2 / 82 (2.44%)	0 / 58 (0.00%)
occurrences all number	1	0	1	0	2	0
Depression
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences all number	0	0	1	0	0	1
Insomnia
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 20 (0.00%)	9 / 82 (10.98%)	0 / 58 (0.00%)
occurrences all number	1	1	1	0	9	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	10 / 82 (12.20%)	7 / 58 (12.07%)
occurrences all number	1	0	0	4	18	9
Aspartate aminotransferase increased
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	3 / 20 (15.00%)	8 / 82 (9.76%)	4 / 58 (6.90%)
occurrences all number	1	1	0	8	19	5
Weight decreased
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 20 (10.00%)	7 / 82 (8.54%)	1 / 58 (1.72%)
occurrences all number	0	1	0	2	7	1
Lymphocyte count decreased
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	4	0	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	2 / 58 (3.45%)
occurrences all number	0	1	0	1	0	2
Blood bilirubin increased
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	6 / 82 (7.32%)	1 / 58 (1.72%)
occurrences all number	1	0	0	2	7	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences all number	0	1	1	0	0	1
Fall
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	2 / 58 (3.45%)
occurrences all number	1	0	0	0	1	2
Injury
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	0	0
Nasal injury
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	1	0	0	0	0
Post-traumatic pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	0	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	3 / 82 (3.66%)	0 / 58 (0.00%)
occurrences all number	0	0	1	0	3	0
Cardiac failure chronic
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	0	0
Cardiac failure congestive
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	2	0	0
Palpitations
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 20 (0.00%)	2 / 82 (2.44%)	2 / 58 (3.45%)
occurrences all number	1	0	4	0	3	2
Tachycardia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	2	0	0	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	2 / 8 (25.00%)	1 / 20 (5.00%)	7 / 82 (8.54%)	4 / 58 (6.90%)
occurrences all number	0	1	3	1	9	4
Dizziness
subjects affected / exposed	2 / 8 (25.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	1 / 20 (5.00%)	11 / 82 (13.41%)	10 / 58 (17.24%)
occurrences all number	2	0	3	1	14	12
Hypoaesthesia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	2 / 82 (2.44%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	3	0
Restless legs syndrome
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	2 / 82 (2.44%)	0 / 58 (0.00%)
occurrences all number	0	0	1	0	2	0
Presyncope
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	2 / 58 (3.45%)
occurrences all number	1	0	0	0	0	2
Neuralgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences all number	0	0	1	0	0	1
Sciatica
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	1	0	0	0	0
Blood and lymphatic system disorders
Haemorrhagic diathesis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	0	0
Neutropenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	2 / 82 (2.44%)	4 / 58 (6.90%)
occurrences all number	0	0	0	3	4	9
Thrombocytopenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	5 / 82 (6.10%)	2 / 58 (3.45%)
occurrences all number	0	0	0	1	7	2
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	2 / 58 (3.45%)
occurrences all number	0	0	0	2	0	2
Eye disorders
Dry eye
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences all number	0	0	1	0	1	0
Visual impairment
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	2 / 82 (2.44%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	2	0
Abdominal pain
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	2 / 82 (2.44%)	4 / 58 (6.90%)
occurrences all number	1	1	0	0	2	5
Abdominal distension
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	1	0	1	0	0
Constipation
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	3 / 20 (15.00%)	11 / 82 (13.41%)	1 / 58 (1.72%)
occurrences all number	1	1	0	3	20	1
Diarrhoea
subjects affected / exposed	2 / 8 (25.00%)	3 / 8 (37.50%)	1 / 8 (12.50%)	2 / 20 (10.00%)	6 / 82 (7.32%)	9 / 58 (15.52%)
occurrences all number	2	4	1	2	7	11
Dry mouth
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	1 / 82 (1.22%)	1 / 58 (1.72%)
occurrences all number	0	0	1	0	1	1
Dyspepsia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	4 / 82 (4.88%)	1 / 58 (1.72%)
occurrences all number	0	0	0	1	4	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences all number	0	1	0	0	1	0
Haemorrhoids
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	1	0	0	0
Mouth haemorrhage
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences all number	0	1	0	0	1	0
Vomiting
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 20 (5.00%)	6 / 82 (7.32%)	2 / 58 (3.45%)
occurrences all number	0	4	1	4	12	2
Nausea
subjects affected / exposed	2 / 8 (25.00%)	1 / 8 (12.50%)	2 / 8 (25.00%)	1 / 20 (5.00%)	19 / 82 (23.17%)	7 / 58 (12.07%)
occurrences all number	3	2	4	1	23	8
Hepatobiliary disorders
Gallbladder disorder
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Hepatic steatosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	1	0	0	0
Jaundice
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	1	0	0	0	0
Skin and subcutaneous tissue disorders
Lichen planus
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	1	0	0	0
Madarosis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	0	0
Pruritus
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	8 / 82 (9.76%)	2 / 58 (3.45%)
occurrences all number	1	1	0	0	8	2
Rash
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	2 / 58 (3.45%)
occurrences all number	1	0	0	0	0	2
Trichodynia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	1	0	0	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	3 / 58 (5.17%)
occurrences all number	0	0	0	0	1	4
Chronic kidney disease
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Proteinuria
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	0	0
Renal cyst
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	2 / 82 (2.44%)	0 / 58 (0.00%)
occurrences all number	1	2	0	0	2	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	1 / 20 (5.00%)	2 / 82 (2.44%)	2 / 58 (3.45%)
occurrences all number	0	0	2	2	3	2
Arthralgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 20 (0.00%)	5 / 82 (6.10%)	5 / 58 (8.62%)
occurrences all number	0	0	2	0	6	5
Myalgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	3 / 82 (3.66%)	3 / 58 (5.17%)
occurrences all number	0	0	0	0	3	4
Muscle spasms
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 20 (5.00%)	5 / 82 (6.10%)	2 / 58 (3.45%)
occurrences all number	0	2	0	1	8	3
Muscle contracture
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	1	0	0	0
Flank pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences all number	0	0	0	1	0	1
Osteoarthritis
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	1	0	0	0	0
Spinal osteoarthritis
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences all number	0	1	0	0	0	1
Oligoarthritis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	0	0
Infections and infestations
Anal abscess
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	1	0	0	0	0
Atypical pneumonia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	0	0
COVID-19
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	4 / 82 (4.88%)	6 / 58 (10.34%)
occurrences all number	0	0	0	0	4	6
Bronchitis
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	2 / 8 (25.00%)	0 / 20 (0.00%)	2 / 82 (2.44%)	0 / 58 (0.00%)
occurrences all number	1	4	3	0	2	0
Gingivitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	0	0
Kidney infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Nasopharyngitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	4 / 82 (4.88%)	5 / 58 (8.62%)
occurrences all number	2	0	1	0	4	5
Onychomycosis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Pharyngitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	0	1	0	0
Pneumonia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	3 / 58 (5.17%)
occurrences all number	0	0	0	0	1	3
Respiratory tract infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences all number	1	0	0	0	1	0
Tonsillitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 20 (0.00%)	0 / 82 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	0	1	0	0	0
Sinusitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	2 / 58 (3.45%)
occurrences all number	1	0	0	0	0	2
Upper respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 20 (0.00%)	2 / 82 (2.44%)	5 / 58 (8.62%)
occurrences all number	0	0	2	0	3	7
Urinary tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	2 / 20 (10.00%)	2 / 82 (2.44%)	2 / 58 (3.45%)
occurrences all number	0	0	1	4	2	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	6 / 82 (7.32%)	5 / 58 (8.62%)
occurrences all number	1	0	0	0	10	7
Folate deficiency
subjects affected / exposed	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 20 (0.00%)	4 / 82 (4.88%)	4 / 58 (6.90%)
occurrences all number	0	2	0	0	4	5
Hyperglycaemia
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 8 (12.50%)	2 / 20 (10.00%)	2 / 82 (2.44%)	1 / 58 (1.72%)
occurrences all number	1	1	1	3	2	1
Hyperkalaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 20 (5.00%)	1 / 82 (1.22%)	1 / 58 (1.72%)
occurrences all number	0	0	0	2	1	1
Hypoalbuminaemia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	0 / 82 (0.00%)	1 / 58 (1.72%)
occurrences all number	0	1	0	0	0	2
Hypocalcaemia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	2 / 82 (2.44%)	2 / 58 (3.45%)
occurrences all number	0	1	0	0	2	2
Hypomagnesaemia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	1 / 58 (1.72%)
occurrences all number	0	2	0	0	1	1
Type 2 diabetes mellitus
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 20 (0.00%)	1 / 82 (1.22%)	0 / 58 (0.00%)
occurrences all number	0	1	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

16 May 2018

It included following changes: - Added the following sections for additional clarity and details: Blinding; Maintenance of Blinding; Planned and Unplanned Unblinding of Treatment Assignment. - Change in enrollment criteria for greater flexibility in participant enrollment. - Added 4 Weeks Post-end of treatment (EOT). - Added If Early Termination, every 8 weeks assessment from 4 Weeks Post-EOT visit. Last visit at Week 52 from first dose. - Added Point-of-care Urine Pregnancy (for females of child-bearing capabilities).

30 Jan 2020

It included following changes: - Added a new open-label exploratory cohort: Open-label High-erythropoietin Component. - Exclusion criteria updated to: Participants with elevated serum erythropoietin levels (>400 mIU/mL) at Screening 1 are allowed to repeat after ≥ 7 days. If the serum erythropoietin remains elevated (>400 mIU/mL) the participant may then qualify for the OL High-erythropoietin cohort. - Exclusion criteria updated to: Participants with TBili up to 2.0 x upper limit of normal (ULN) may be allowed to participate if the sspartate aminotransferase (AST) and alanine aminotransferase (ALT) are within normal limits. - Following has been inserted as a secondary efficacy endpoint: Proportion of participants achieved TI ≥56 consecutive days at any time during the study. - Study centers planned has been revised to “Approximately 100”. -

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.

Study did not meet its primary efficacy endpoint; hence, the study was terminated early.

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