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CompletedNCT03457701Updated Mar 27, 2024Results posted

Anemia Studies in CKD: Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat- Iron (ASCEND: Fe)

A Phase 2 interventional study of Daprodustat and rhEPO in Anaemia, sponsored by GlaxoSmithKline. Completed at 3 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-03-27.

Sponsored by GlaxoSmithKline · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
15
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

Daprodustat administration has the potential, by virtue of increasing hypoxia-inducible factor (HIF) levels, to increase oral iron absorption and incorporation into hemoglobin (Hgb). Therefore, the purpose of this study is to compare the effect of daprodustat to rhEPO (i.e., epoetin alfa or darbepoetin alfa) on non-heme oral iron absorption using stable isotopic iron (57Fe and 58Fe) by measuring incorporation of iron in erythrocytes. This study will be a randomized, repeat dose, open label, two period cross-over study in adult, male and female participants with anemia associated with chronic kidney disease who are not on dialysis currently treated with stable doses less than or equal to (\<=) 50 percent (%) 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). Sufficient participants will be enrolled such that at least 12 participants comprise the Evaluable Population. The study will compare the fractional iron absorption between treatment arms (daprodustat and rhEPO [i.e., epoetin alfa or darbepoetin alfa]) and will evaluate the difference is equal/not equal to zero.

02

Conditions studied

  • Anaemia

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Keywords

  • Recombinant human erythropoietin
  • Anemia
  • Daprodustat
  • Chronic kidney disease
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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.
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Crossover assignment
Masking
None (open label)
Enrollment
15 participants (actual)

Study arms

  • Experimental
    rhEPO+57Fe followed by Daprodustat+58Fe

    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)

  • Experimental
    rhEPO+58Fe followed by Daprodustat+57Fe

    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 · Drug: Ferrous sulfate containing the stable iron isotope (57Fe) · Drug: Ferrous sulfate containing the stable iron isotope (58Fe)

  • Experimental
    Daprodustat+57Fe followed by rhEPO+58Fe

    Participants will be randomly assigned to receive Daprodustat 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 rhEPO (either epoetin alfa or darbepoetin alfa) 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: 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)

  • Experimental
    Daprodustat+58Fe followed by rhEPO+57Fe

    Participants will be randomly assigned to receive Daprodustat 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 rhEPO (either epoetin alfa or darbepoetin alfa) 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 · Drug: Ferrous sulfate containing the stable iron isotope (57Fe) · Drug: Ferrous sulfate containing the stable iron isotope (58Fe)

Interventions

  • DrugDaprodustat

    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.

  • DrugrhEPO

    rhEPO (epoetin alfa OR darbepoetin alfa) is commercially available in various single dose vials and single-dose prefilled syringes. It will be given as subcutaneous injection.

  • DrugFerrous sulfate containing the stable iron isotope (57Fe)

    57Fe will be available in oral solution. An oral solution will be administered containing 10 mg of 57Fe as ferrous sulfate.

  • DrugFerrous sulfate containing the stable iron isotope (58Fe)

    58Fe will be available in oral solution. An oral solution will be administered containing 3 mg of 58Fe as ferrous sulfate with 7 mg of 56Fe as ferrous sulfate (natural abundance Fe).

05

What researchers measure

Primary outcomes

  1. 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.

    Time frame: Up to Day 57

Secondary outcomes

  1. 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.

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

  2. 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.

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

  3. 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.

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

  4. 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.

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

  5. 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.

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

  6. 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.

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

  7. 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.

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

  8. 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.

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

  9. 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.

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

  10. 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.

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

  11. 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.

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

  12. 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.

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

  13. 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.

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

06

Results

Posted Jul 25, 2023

Participant flow

This was a two-period cross over study to compare the effect of Daprodustat to recombinant, human erythropoietin (rhEPO) on oral iron absorption.

Treatment Period 1 (up to Day 28)
Participant flow — Treatment Period 1 (up to Day 28)
MilestoneDaprodustat Followed by rhEPOrhEPO Followed by Daprodustat
Started78
Safety population77
Completed67
Not completed11
Withdrew: Participant reached protocol-defined stopping criteria11
Treatment Period 2 (Up to Day 28)
Participant flow — Treatment Period 2 (Up to Day 28)
MilestoneDaprodustat Followed by rhEPOrhEPO Followed by Daprodustat
Started67
Completed66
Not completed01
Withdrew: Participant reached protocol-defined stopping criteria01

Outcome measures

PrimaryPercentage 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.

Time frame:
Up to Day 57
Reported as:
Mean · Percentage (%) of iron absorbed
Percentage of Fractional Oral Iron Absorption Following Treatment With Daprodustat and rhEPO
Percentage (%) of iron absorbedDaprodustatrhEPO
Percentage of Fractional Oral Iron Absorption Following Treatment With Daprodustat and rhEPO20.64 (10.96 to 30.32)20.62 (10.95 to 30.30)
Statistical analysis
  • Daprodustat vs rhEPO · Mixed Models Analysis · p = 0.9971 · Adjusted mean difference.: 0.02 · 95% CI -10.13 to 10.16Analysis was based on a mixed effects model fitted with fixed effect terms for treatment, period, and iron isotope type and a random participant effect.
SecondaryPeriods 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Mean · Micromoles per liter (umol/L)
Periods 1 and 2: Change From Baseline in Serum Iron Following Treatment With Daprodustat and rhEPO
Micromoles per liter (umol/L)DaprodustatrhEPO
Period 1, DAY 14-1.5 ± 6.721.7 ± 4.93
Period 1, DAY 282.5 ± 8.963.3 ± 5.47
Period 2, DAY 14-1.3 ± 4.93-3.5 ± 6.66
Period 2, DAY 28-2.2 ± 4.79-3.3 ± 5.01
SecondaryPeriod 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Mean · Gram per Liter (g/L)
Period 1 and 2: Change From Baseline in Transferrin Following Treatment With Daprodustat or rhEPO
Gram per Liter (g/L)DaprodustatrhEPO
Period 1, DAY 140.182 ± 0.29140.145 ± 0.2501
Period 1, DAY 280.283 ± 0.2824-0.040 ± 0.1756
Period 2, DAY 14-0.177 ± 0.4664-0.163 ± 0.2461
Period 2, DAY 280.138 ± 0.2381-0.352 ± 0.2531
SecondaryPeriods 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Mean · Percentage (%) of transferrin saturation
Periods 1 and 2: Change From Baseline in Transferrin Saturation Following Treatment With Daprodustat or rhEPO
Percentage (%) of transferrin saturationDaprodustatrhEPO
Period 1, DAY 14-5.2 ± 13.633.5 ± 12.05
Period 1, DAY 283.0 ± 18.138.2 ± 14.41
Period 2, DAY 14-5.5 ± 13.40-4.8 ± 10.98
Period 2, DAY 28-6.7 ± 14.57-4.7 ± 11.29
SecondaryPeriods 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Mean · Milligrams per liter (mg/L)
Periods 1 and 2: Change From Baseline in Soluble Transferrin Receptor Following Treatment of Daprodustat and rhEPO
Milligrams per liter (mg/L)DaprodustatrhEPO
Period 1, DAY 14-0.218 ± 0.17360.063 ± 0.1669
Period 1, DAY 28-0.340 ± 0.2665-0.015 ± 0.1598
Period 2, DAY 14-0.338 ± 0.29780.227 ± 0.1086
Period 2, DAY 28-0.308 ± 0.31800.195 ± 0.2239
SecondaryPeriods 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Geometric mean · Microgram per liter (ug/L)
Periods 1 and 2: Ratio to Baseline in Ferritin Following Treatment With Daprodustat and rhEPO
Microgram per liter (ug/L)DaprodustatrhEPO
Period 1, DAY 141.126 ± 20.18530.937 ± 16.2891
Period 1, DAY 281.109 ± 24.70521.004 ± 5.4818
Period 2, DAY 141.067 ± 32.76970.957 ± 20.2623
Period 2, DAY 281.278 ± 53.11280.911 ± 23.5414
SecondaryPeriods 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Geometric mean · Microgram per liter (ug/L)
Periods 1 and 2: Ratio to Baseline (Day 1) in Hepcidin Following Treatment With Daprodustat and rhEPO
Microgram per liter (ug/L)DaprodustatrhEPO
Period 1, DAY 140.860 ± 86.48440.904 ± 52.1384
Period 1, DAY 280.916 ± 61.28981.052 ± 27.7868
Period 2, DAY 140.703 ± 74.46941.201 ± 63.6067
Period 2, DAY 280.802 ± 73.55981.306 ± 47.6931
SecondaryPeriods 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Mean · Microgram per liter (ug/L)
Periods 1 and 2: Change From Baseline in Erythroferrone Following Treatment With Daprodustat and rhEPO
Microgram per liter (ug/L)DaprodustatrhEPO
Period 1, DAY 140.135 ± 0.3086-0.062 ± 0.1824
Period 1, DAY 280.075 ± 0.2544-0.090 ± 0.1380
Period 2, DAY 140.063 ± 0.2225-0.068 ± 0.2405
Period 2, DAY 280.032 ± 0.3578-0.110 ± 0.2278
SecondaryPeriods 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Mean · Grams per liter (g/L)
Periods 1 and 2: Change From Baseline in Hemoglobin Following Treatment With Daprodustat and rhEPO
Grams per liter (g/L)DaprodustatrhEPO
Period 1, DAY 140.7 ± 3.672.8 ± 2.99
Period 1, DAY 28-5.0 ± 5.873.5 ± 3.39
Period 2, DAY 14-5.3 ± 4.803.7 ± 3.01
Period 2, DAY 28-4.3 ± 10.192.3 ± 2.94
SecondaryPeriods 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Mean · Proportion of red blood cells in blood
Periods 1 and 2: Change From Baseline in Hematocrit Following Treatment With Daprodustat and rhEPO
Proportion of red blood cells in bloodDaprodustatrhEPO
Period 1, DAY 140.002 ± 0.00860.011 ± 0.0144
Period 1, DAY 28-0.017 ± 0.01830.009 ± 0.0139
Period 2, DAY 14-0.006 ± 0.02050.009 ± 0.0105
Period 2, DAY 28-0.010 ± 0.03430.002 ± 0.0114
SecondaryPeriods 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Mean · 10^12 cells/liter
Periods 1 and 2: Change From Baseline in Erythrocytes Following Treatment With Daprodustat and rhEPO
10^12 cells/literDaprodustatrhEPO
Period 1, DAY 140.05 ± 0.1380.13 ± 0.137
Period 1, DAY 28-0.13 ± 0.1630.13 ± 0.082
Period 2, DAY 14-0.17 ± 0.2250.13 ± 0.121
Period 2, DAY 28-0.13 ± 0.3670.07 ± 0.151
SecondaryPeriods 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Mean · Femtoliter (fL)
Periods 1 and 2: Change From Baseline in Erythrocyte Mean Corpuscular Volume Following Treatment With Daprodustat and rhEPO
Femtoliter (fL)DaprodustatrhEPO
Period 1, DAY 14-0.8 ± 3.25-0.5 ± 2.43
Period 1, DAY 28-1.5 ± 3.45-0.8 ± 2.71
Period 2, DAY 142.8 ± 4.17-0.3 ± 3.72
Period 2, DAY 280.3 ± 1.97-0.8 ± 3.31
SecondaryPeriods 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Mean · Picogram (pg)
Periods 1 and 2: Change From Baseline in Reticulocyte Hemoglobin Following Treatment of Daprodustat and rhEPO
Picogram (pg)DaprodustatrhEPO
Period 1, DAY 140.333 ± 1.4334-0.033 ± 0.5888
Period 1, DAY 280.250 ± 1.39250.717 ± 0.6882
Period 2, DAY 140.817 ± 1.5433-0.350 ± 0.7450
Period 2, DAY 281.083 ± 0.8819-0.117 ± 0.9948
SecondaryPeriods 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.

Time frame:
Baseline (Day 1), Day 14 and Day 28 in treatment periods 1 and 2 (each period is of 28 days)
Reported as:
Mean · 10^12 cells/liter
Periods 1 and 2: Change From Baseline in Reticulocytes Following Treatment With Daprodustat and rhEPO
10^12 cells/literDaprodustatrhEPO
Period 1, DAY 140.001 ± 0.01550.002 ± 0.0090
Period 1, DAY 280.004 ± 0.0169-0.004 ± 0.0135
Period 2, DAY 140.004 ± 0.0088-0.005 ± 0.0216
Period 2, DAY 280.020 ± 0.0099-0.010 ± 0.0213

Adverse events

Collected over All-cause mortality, SAEs and non-serious AEs were collected up to Day 73. Non-serious events are listed at a 2% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Daprodustat in Period 10/7 (0%)0/7 (0%)3/7 (42.9%)
rhEPO in Period 10/7 (0%)1/7 (14.3%)3/7 (42.9%)
rhEPO in Period 20/7 (0%)0/7 (0%)2/7 (28.6%)
Daprodustat in Period 20/7 (0%)1/7 (14.3%)3/7 (42.9%)
Most frequent serious events
Most frequent serious events
EventDaprodustat in Period 1rhEPO in Period 1rhEPO in Period 2Daprodustat in Period 2
Cholecystitis infectiveInfections and infestations0/71/70/70/7
HyperkalaemiaMetabolism and nutrition disorders0/70/70/71/7
Lumbar spinal stenosisMusculoskeletal and connective tissue disorders0/70/70/71/7
Most frequent other events
Showing 10 of 19
Most frequent other events
EventDaprodustat in Period 1rhEPO in Period 1rhEPO in Period 2Daprodustat in Period 2
HypertensionVascular disorders0/70/70/73/7
COVID-19Infections and infestations0/70/70/72/7
HypoacusisEar and labyrinth disorders0/71/70/70/7
VertigoEar and labyrinth disorders0/71/70/70/7
Retinal haemorrhageEye disorders1/70/70/70/7
NauseaGastrointestinal disorders0/70/70/71/7
BronchitisInfections and infestations0/71/70/70/7
Cholecystitis infectiveInfections and infestations0/71/70/70/7
SinusitisInfections and infestations1/70/70/70/7
Tooth infectionInfections and infestations0/70/71/70/7

Baseline characteristics

Safety population comprised of participants who received at least 1 dose of study treatment.

Age, Continuous
Age, Continuous(Years)Daprodustat Followed by rhEPOrhEPO Followed by DaprodustatTotal
Mean66.3 ± 5.3564.6 ± 13.8865.4 ± 10.14
Sex: Female, Male
Sex: Female, Male(Participants)Daprodustat Followed by rhEPOrhEPO Followed by DaprodustatTotal
Female6511
Male123
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Daprodustat Followed by rhEPOrhEPO Followed by DaprodustatTotal
White/Caucasian/European Heritage7714
07

Study locations

3 sites
  • GSK Investigational Site
    Fort Worth, Texas 76104, United States
  • GSK Investigational Site
    Lufkin, Texas 75904, United States
  • GSK Investigational Site
    San Antonio, Texas 78212, United States
08

References and documents

Publications

  • 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. PubMed 36005278 ↗

Study documents

  • Study protocol · Jul 14, 2021
  • Statistical analysis plan · Sep 14, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — IPD for this study will be made available via the Clinical Study Data Request site.

Supporting information: Study protocol, Sap, Icf, Csr

09

Registry details

Key details

Study ID
NCT03457701
Lead sponsor
GlaxoSmithKline
Responsible party
Sponsor
First posted
Mar 7, 2018
Start date
Jul 30, 2019
Primary completion
Jul 5, 2022
Completion
Jul 5, 2022
Results posted
Jul 25, 2023
Last update
Mar 27, 2024

Study contacts

GSK Clinical Trials
study director · GlaxoSmithKline

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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