Anemia Studies in CKD: Erythropoiesis Via a Novel Prolyl... | NCT03457701

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
rhEPO+57Fe followed by Daprodustat+58Fe	Experimental	Participants will be randomly assigned to remain on their current therapy (either epoetin alfa or darbepoetin alfa) in Treatment Period 1. For assessment of incorporation of iron into erythrocytes, participants will be administered ferrous sulfate containing a stable isotope of iron (57Fe) orally in a randomized fashion following 2 weeks of administration of randomized study treatment. At Day 29 participants will be crossed over to receive Daprodustat in Treatment Period 2. At 2 weeks following initiation of dosing in Treatment Period 2, participants will again be administered ferrous sulfate containing the stable iron isotope (58Fe) orally. Participants will be advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: Histamine [H2] receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency.	Drug: Daprodustat Drug: rhEPO Drug: Ferrous sulfate containing the stable iron isotope (57Fe) Drug: Ferrous sulfate containing the stable iron isotope (58Fe)
rhEPO+58Fe followed by Daprodustat+57Fe	Experimental	Participants will be randomly assigned to remain on their current therapy (either epoetin alfa or darbepoetin alfa) in Treatment Period 1. For assessment of incorporation of iron into erythrocytes, participants will be administered ferrous sulfate containing a stable isotope of iron (58Fe) orally in a randomized fashion following 2 weeks of administration of randomized study treatment. At Day 29 participants will be crossed over to receive Daprodustat in Treatment Period 2. At 2 weeks following initiation of dosing in Treatment Period 2, participants will again be administered ferrous sulfate containing the stable iron isotope (57Fe) orally. Participants will be advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: H2 receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency.	Drug: Daprodustat Drug: rhEPO

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Daprodustat	Drug	Daprodustat will be available as 1 milligram (mg), 2 mg and 4 mg tablets strengths. One tablet to be taken daily without regard for food.	Daprodustat+57Fe followed by rhEPO+58Fe

Measure	Description	Time Frame
Percentage of Fractional Oral Iron Absorption Following Treatment With Daprodustat and rhEPO	Blood samples were collected at indicated time points for analysis of fractional oral iron absorption following treatment with Daprodustat and rhEPO. Adjusted mean and 95 percent (%) confidence interval (CI) has been presented.	Up to Day 57

Measure	Description	Time Frame
Periods 1 and 2: Change From Baseline in Serum Iron Following Treatment With Daprodustat and rhEPO	Blood samples were collected for measurement of serum iron at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Participants must be at least 18 years of age inclusive, at the time of signing the informed consent.
Participants who are Stage 3, 4 or 5 Chronic kidney disease (CKD) (confirmed at Week-4 only) defined by estimated glomerular filtration rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula.
Participants who are currently treated with stable doses (<=50% change in 4-weekly dose) for at least 8 weeks prior to and including the screening period, of rhEPO (i.e., epoetin alfa or darbepoetin alfa).
Participants with Hgb levels between 9.0 and 11.5 g/dL, inclusive, who meet the Hgb stability criteria.
Participants may be on stable maintenance oral iron supplementation (less than [<] 50% change in overall dose and compliance of 80% of prescribed doses in the 4 weeks prior to and including the screening period). If participants have been on intravenous (IV) iron, then participants will not have received IV iron for 8 weeks prior to the Day 1 visit.
Male or Female participants may participate. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: not a woman of childbearing potential (WOCBP), or a WOCBP who agrees to follow the contraceptive guidance during the treatment period to the follow-up visit.
Capable of giving signed informed consent.

Exclusion Criteria:

On dialysis or clinical evidence of impending need to initiate dialysis within 90 days after study start (i.e., Day 1).
Planned kidney transplant within 3 months after study start.
A positive test for Human Immunodeficiency Virus (HIV) antibody.
History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational products
Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from screening until the end of Treatment Period 2.
Planned or current administration of methoxy polyethylene glycol (PEG)-epoetin beta.
The participant has participated in a clinical trial and has received an experimental investigational product within the prior 30 days or 5 half lives, whichever is longer, from screening through Day 1.
At or below the lower limit of the reference range at screening for Vitamin B12 (may rescreen in a minimum of 8 weeks).
Ferritin outside the range between 100 and 500 nanogram per milliliter (ng/mL), inclusive, at screening.
Transferrin saturation (TSAT) outside the range between 15% and 40%, inclusive, at Screening.
Folate < 2.0 ng/mL (4.5 nanomoles per liter [nmol/L]; may rescreen in a minimum of 8 weeks) at screening.
High sensitivity C-reactive protein (hsCRP) >=20 microgram per milliliter (μg/mL) at screening.
Myocardial infarction or acute coronary syndrome: <=8 weeks prior to screening through Day 1.
Hospitalization for greater than 24 hours: <=8 weeks prior to screening through Day 1
Stroke or transient ischemic attack <=8 weeks prior to screening through Day 1.
Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
Current uncontrolled hypertension as determined by the investigator.
QT interval corrected for heart rate using Bazett's formula (QTcB): QTcB >500 milliseconds (msec), or QTcB > 530 msec in participants with Bundle Branch Block. There is no corrected QT interval (QTc) exclusion for participants with a predominantly paced rhythm.
Active chronic inflammatory disease that could impact erythropoiesis.
History of bone marrow aplasia or pure red cell aplasia.
Conditions, other than anemia associated with chronic kidney disease, which can affect erythropoiesis.
Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease OR clinically significant gastrointestinal (GI) bleeding from <=4 weeks prior to screening through Day 1.
Liver disease (any of the following): Alanine transaminase (ALT) >2 times upper limit of normal (ULN; screening only); Bilirubin >1.5 times ULN (screening only). Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
Major surgery (excluding vascular access surgery) within the 8 weeks prior to screening through Day 1, or planned during the study.
Blood transfusion within 8 weeks prior to screening through Day 1, or an anticipated need for blood transfusion during the study.
Clinical evidence of an acute infection, or history of infection requiring IV antibiotic therapy from 4 weeks prior to screening through Day 1.
History of malignancy within the two years prior to screening through Day 1 or currently receiving treatment for cancer, with the exception of localized squamous cell or basal cell carcinoma of the skin definitively treated 12 weeks prior to Day 1.
Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the participant at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Fort Worth	Texas	76104	United States
GSK Investigational Site

PubMed Identifier	Type	Citation	Retractions
36005278	Derived	Natale P, Palmer SC, Jaure A, Hodson EM, Ruospo M, Cooper TE, Hahn D, Saglimbene VM, Craig JC, Strippoli GF. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Daprodustat Followed by rhEPO	Participants were randomly assigned to receive Daprodustat in Treatment Period 1. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. At Day 29 participants were crossed over to receive rhEPO (either epoetin alfa or darbepoetin alfa) in Treatment Period 2. At 2 weeks following initiation of dosing in Treatment Period 2, participants were again administered ferrous sulfate containing the stable iron isotope (58Fe or 57Fe). Participants were advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: H2 receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency. There was no washout period between Treatment Period 1 and Treatment Period 2.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jul 14, 2021	Jul 4, 2023

Arm/Group Information

ID	Title	Description
BG000	Daprodustat Followed by rhEPO	Participants were randomly assigned to receive Daprodustat in Treatment Period 1. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. At Day 29 participants were crossed over to receive rhEPO (either epoetin alfa or darbepoetin alfa) in Treatment Period 2. At 2 weeks following initiation of dosing in Treatment Period 2, participants were again administered ferrous sulfate containing the stable iron isotope (58Fe or 57Fe). Participants were advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: H2 receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency. There was no washout period between Treatment Period 1 and Treatment Period 2.
BG001	rhEPO Followed by Daprodustat	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. At Day 29 participants were crossed over to receive Daprodustat in Treatment Period 2. At 2 weeks following initiation of dosing in Treatment Period 2, participants were again administered ferrous sulfate containing the stable iron isotope (58Fe or 57Fe). Participants were advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: Histamine [H2] receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency. There was no washout period between Treatment Period 1 and Treatment Period 2.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG0007 BG0017 BG00214

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Percentage of Fractional Oral Iron Absorption Following Treatment With Daprodustat and rhEPO

Blood samples were collected at indicated time points for analysis of fractional oral iron absorption following treatment with Daprodustat and rhEPO. Adjusted mean and 95 percent (%) confidence interval (CI) has been presented.

Evaluable Population consisted of all randomized participants who received study medication and completed the iron absorption assessment for both treatment periods.

Posted

Mean

95% Confidence Interval

Percentage (%) of iron absorbed

Up to Day 57

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Units	Counts
Participants	OG00012 OG00112

Title

Denominators

Categories

Title	Measurements
	OG00020.64(10.96 to 30.32) OG00120.62(10.95 to 30.30)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	The null hypotheses is defined as the difference in fractional iron absorption between treatment arms (Daprodustat - rhEPO [i.e., epoetin alfa or darbepoetin alfa]) is equal to zero.	Mixed Models Analysis		0.9971		Adjusted mean difference.	0.02			2-Sided	95	-10.13	10.16			Analysis was based on a mixed effects model fitted with fixed effect terms for treatment, period, and iron isotope type and a random participant effect.		Superiority

Secondary

Periods 1 and 2: Change From Baseline in Serum Iron Following Treatment With Daprodustat and rhEPO

Blood samples were collected for measurement of serum iron at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Evaluable Population that included all randomized participants who received study medication and completed the iron absorption assessment for both treatment periods. Only those participants with data available at the specified data points were analyzed.

Posted

Mean

Standard Deviation

Micromoles per liter (umol/L)

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Secondary

Period 1 and 2: Change From Baseline in Transferrin Following Treatment With Daprodustat or rhEPO

Blood samples were collected from participants for measurement of transferrin at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Posted

Mean

Standard Deviation

Gram per Liter (g/L)

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Secondary

Periods 1 and 2: Change From Baseline in Transferrin Saturation Following Treatment With Daprodustat or rhEPO

Blood samples were collected from participants for measurement of transferrin saturation at indicated time points. Transferrin saturation was measured as a percentage and is the ratio of serum iron and total iron-binding capacity multiplied by 100. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Posted

Mean

Standard Deviation

Percentage (%) of transferrin saturation

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO

Secondary

Periods 1 and 2: Change From Baseline in Soluble Transferrin Receptor Following Treatment of Daprodustat and rhEPO

Blood samples were collected from participants for measurement of soluble transferrin receptor at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Posted

Mean

Standard Deviation

Milligrams per liter (mg/L)

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Secondary

Periods 1 and 2: Ratio to Baseline in Ferritin Following Treatment With Daprodustat and rhEPO

Blood samples were collected from participants for measurement of ferritin at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. The summary of log transformed ration to baseline on markers of iron status for Ferritin is presented here.

Posted

Geometric Mean

Geometric Coefficient of Variation

Microgram per liter (ug/L)

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Secondary

Periods 1 and 2: Ratio to Baseline (Day 1) in Hepcidin Following Treatment With Daprodustat and rhEPO

Blood samples were collected from participants for measurement of hepcidin at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. The summary of log transformed ration to baseline on markers of iron status for Hepcidin is presented here.

Posted

Geometric Mean

Geometric Coefficient of Variation

Microgram per liter (ug/L)

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Secondary

Periods 1 and 2: Change From Baseline in Erythroferrone Following Treatment With Daprodustat and rhEPO

Blood samples were collected from participants for measurement of erythroferrone at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Posted

Mean

Standard Deviation

Microgram per liter (ug/L)

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Secondary

Periods 1 and 2: Change From Baseline in Hemoglobin Following Treatment With Daprodustat and rhEPO

Blood samples were collected from participants for measurement of hemoglobin at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Posted

Mean

Standard Deviation

Grams per liter (g/L)

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Secondary

Periods 1 and 2: Change From Baseline in Hematocrit Following Treatment With Daprodustat and rhEPO

Blood samples were collected from participants for measurement of hematocrit at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Posted

Mean

Standard Deviation

Proportion of red blood cells in blood

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Secondary

Periods 1 and 2: Change From Baseline in Erythrocytes Following Treatment With Daprodustat and rhEPO

Blood samples were collected from participants for measurement of erythrocytes (red blood cells number) at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Posted

Mean

Standard Deviation

10^12 cells/liter

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Secondary

Periods 1 and 2: Change From Baseline in Erythrocyte Mean Corpuscular Volume Following Treatment With Daprodustat and rhEPO

Blood samples were collected from participants for measurement of erythrocyte mean corpuscular volume at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Posted

Mean

Standard Deviation

Femtoliter (fL)

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Secondary

Periods 1 and 2: Change From Baseline in Reticulocyte Hemoglobin Following Treatment of Daprodustat and rhEPO

Blood samples were collected from participants for measurement of reticulocyte hemoglobin at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Posted

Mean

Standard Deviation

Picogram (pg)

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Secondary

Periods 1 and 2: Change From Baseline in Reticulocytes Following Treatment With Daprodustat and rhEPO

Blood samples were collected from participants for measurement of reticulocytes number at indicated time points. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits in the associated treatment period. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Posted

Mean

Standard Deviation

10^12 cells/liter

Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)

ID	Title	Description
OG000	Daprodustat	Participants were randomly assigned to receive Daprodustat in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.
OG001	rhEPO	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1 or 2. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of study treatment. There was no washout period between treatment periods.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Daprodustat in Period 1	Participants were randomly assigned to receive Daprodustat in Treatment Period 1. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of randomized study treatment. Participants were advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: H2 receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency.	7	0	7	3	7
EG001	rhEPO in Period 1	Participants were randomly assigned to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 1. For assessment of incorporation of iron into erythrocytes, participants were administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) in a randomized fashion following 2 weeks of administration of randomized study treatment. Participants were advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: Histamine [H2] receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency.	7	1	7	3	7
EG002	rhEPO in Period 2	At Day 29 participants were crossed over to receive rhEPO (i.e., epoetin alfa or darbepoetin alfa) in Treatment Period 2. At 2 weeks following initiation of dosing in Treatment Period 2, participants were again administered ferrous sulfate containing the stable iron isotope (58Fe or 57Fe). Participants were advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: H2 receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency.	7	0	7	2	7
EG003	Daprodustat in Period 2	At Day 29 participants were crossed over to receive Daprodustat in Treatment Period 2. At 2 weeks following initiation of dosing in Treatment Period 2, participants were again administered ferrous sulfate containing the stable iron isotope (58Fe or 57Fe). Participants were advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: H2 receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency.	7	1	7	3	7

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Hypoacusis	Ear and labyrinth disorders	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0011 events1 affected7 at risk EG0020 events0 affected7 at risk EG0030 events0 affected7 at risk
Vertigo	Ear and labyrinth disorders	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0011 events1 affected7 at risk EG0020 events0 affected7 at risk EG003
Retinal haemorrhage	Eye disorders	v.25.1	Systematic Assessment	EG0001 events1 affected7 at risk EG0010 events0 affected7 at risk EG0020 events0 affected7 at risk EG003
Nausea	Gastrointestinal disorders	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0010 events0 affected7 at risk EG0020 events0 affected7 at risk EG003
Bronchitis	Infections and infestations	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0011 events1 affected7 at risk EG0020 events0 affected7 at risk EG003
COVID-19	Infections and infestations	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0010 events0 affected7 at risk EG0020 events0 affected7 at risk EG003
Cholecystitis infective	Infections and infestations	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0011 events1 affected7 at risk EG0020 events0 affected7 at risk EG003
Sinusitis	Infections and infestations	v.25.1	Systematic Assessment	EG0001 events1 affected7 at risk EG0010 events0 affected7 at risk EG0020 events0 affected7 at risk EG003
Tooth infection	Infections and infestations	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0010 events0 affected7 at risk EG0021 events1 affected7 at risk EG003
Urinary tract infection	Infections and infestations	v.25.1	Systematic Assessment	EG0001 events1 affected7 at risk EG0010 events0 affected7 at risk EG0020 events0 affected7 at risk EG003
Hyperkalaemia	Metabolism and nutrition disorders	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0010 events0 affected7 at risk EG0020 events0 affected7 at risk EG003
Hyperphosphataemia	Metabolism and nutrition disorders	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0010 events0 affected7 at risk EG0020 events0 affected7 at risk EG003
Hypervolaemia	Metabolism and nutrition disorders	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0010 events0 affected7 at risk EG0021 events1 affected7 at risk EG003
Hypocalcaemia	Metabolism and nutrition disorders	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0011 events1 affected7 at risk EG0020 events0 affected7 at risk EG003
Metabolic acidosis	Metabolism and nutrition disorders	v.25.1	Systematic Assessment	EG0001 events1 affected7 at risk EG0010 events0 affected7 at risk EG0020 events0 affected7 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0010 events0 affected7 at risk EG0020 events0 affected7 at risk EG003
Osteoarthritis	Musculoskeletal and connective tissue disorders	v.25.1	Systematic Assessment	EG0001 events1 affected7 at risk EG0010 events0 affected7 at risk EG0020 events0 affected7 at risk EG003
Depression	Psychiatric disorders	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0010 events0 affected7 at risk EG0020 events0 affected7 at risk EG003
Hypertension	Vascular disorders	v.25.1	Systematic Assessment	EG0000 events0 affected7 at risk EG0010 events0 affected7 at risk EG0020 events0 affected7 at risk EG003

ID	Term
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D051437	Renal Insufficiency
D007674	Kidney Diseases
D014570	Urologic Diseases
D052776	Female Urogenital Diseases
D005261	Female Urogenital Diseases and Pregnancy Complications
D000091642	Urogenital Diseases
D052801	Male Urogenital Diseases
D002908	Chronic Disease
D020969	Disease Attributes
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms