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

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03457701

Collaborator

(none)

Enrollment

Locations

Arms

37.8

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Anaemia	Drug: Daprodustat Drug: rhEPO Drug: Ferrous sulfate containing the stable iron isotope (57Fe) Drug: Ferrous sulfate containing the stable iron isotope (58Fe)	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

12 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Participants will be randomly assigned either to remain on their current therapy (either epoetin alfa or darbepoetin alfa) or be switched to daprodustat in either of the treatment periods.Participants will be randomly assigned either to remain on their current therapy (either epoetin alfa or darbepoetin alfa) or be switched to daprodustat in either of the treatment periods.

Masking:

None (Open Label)

Masking Description:

This is an Open-label study.

Primary Purpose:

Treatment

Official Title:

A Repeat Dose, Open Label, Two Period, Randomized, Cross Over Study to Compare the Effect of Daprodustat to Recombinant, Human Erythropoietin (rhEPO) on Oral Iron Absorption in Adult Participants With Anemia Associated With Chronic Kidney Disease Who Are Not on Dialysis

Actual Study Start Date :

Jul 30, 2019

Anticipated Primary Completion Date :

Sep 23, 2022

Anticipated Study Completion Date :

Sep 23, 2022

Arms and Interventions

Arm	Intervention/Treatment
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 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. Drug: rhEPO 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. Drug: Ferrous 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. Drug: Ferrous 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).
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 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. Drug: rhEPO 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. Drug: Ferrous 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. Drug: Ferrous 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).
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 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. Drug: rhEPO 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. Drug: Ferrous 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. Drug: Ferrous 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).
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 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. Drug: rhEPO 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. Drug: Ferrous 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. Drug: Ferrous 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).

Outcome Measures

Primary Outcome Measures

Percentage of iron absorbed [Up to Day 57]
Venous blood samples will be collected for measurement of erythrocyte isotopic iron content to compare the efficacy of daprodustat to rhEPO (i.e., epoetin alfa or darbepoetin alfa) on iron absorption on Days 29 and 57.

Secondary Outcome Measures

Change from Baseline in serum iron at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on serum iron.
Change from Baseline in serum iron at Day 28 [Baseline (Day 1) and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on serum iron.
Change from Baseline in transferrin at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on transferrin.
Change from Baseline in transferrin at Day 28 [Baseline (Day 1) and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on transferrin.
Change from Baseline in transferrin saturation at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on transferrin saturation.
Change from Baseline in transferrin saturation at Day 28 [Baseline (Day 1) and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on transferrin saturation.
Change from Baseline in soluble transferrin receptor at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on soluble transferrin receptor.
Change from Baseline in soluble transferrin receptor at Day 28 [Baseline (Day 1) and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on soluble transferrin receptor.
Change from Baseline in ferritin at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on ferritin.
Change from Baseline in ferritin at Day 28 [Baseline (Day 1) and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on ferritin.
Change from Baseline in hepcidin at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on hepcidin.
Change from Baseline in hepcidin at Day 28 [Baseline (Day 1) and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on hepcidin.
Change from Baseline in erythroferrone at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on erythroferrone.
Change from Baseline in erythroferrone at Day 28 [Baseline (Day 1) and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on erythroferrone.
Change from Baseline in Hgb at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on Hgb.
Change from Baseline in Hgb at Day 28 [Baseline (Day 1) and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on Hgb.
Change from Baseline in hematocrit at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on hematocrit.
Change from Baseline in hematocrit at Day 28 [Baseline (Day 1) and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on hematocrit.
Change from Baseline in red blood cell number at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on red blood cell number.
Change from Baseline in red blood cell number at Day 28 [Baseline (Day 1 and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on red blood cell number.
Change from Baseline in mean corpuscular volume at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on mean corpuscular volume.
Change from Baseline in mean corpuscular volume at Day 28 [Baseline (Day 1) and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on mean corpuscular volume.
Change from Baseline in reticulocyte Hgb at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on reticulocyte Hgb.
Change from Baseline in reticulocyte Hgb at Day 28 [Baseline (Day 1) and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on reticulocyte Hgb.
Change from Baseline in reticulocyte number at Day 14 [Baseline (Day 1) and Day 14]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on reticulocyte number.
Change from Baseline in reticulocyte number at Day 28 [Baseline (Day 1) and Day 28]
Blood samples will be collected to characterize the effect of daprodustat or rhEPO on reticulocyte number.

Other Outcome Measures

Number of participants with any adverse event (AE) [Up to 73 days]
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention.
Number of participants with any AE by severity [Up to 73 days]
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention.
Number of participants with any serious AE (SAE) [Up to 73 days]
A SAE is defined as any untoward medical occurrence that, at any dose may result in death, is life-threatening, may require inpatient hospitalization or prolongation of existing hospitalization, result in persistent disability/incapacity, or may lead to any congenital anomaly or birth defect.
Number of participants with any SAE by severity [Up to 73 days]
A SAE is defined as any untoward medical occurrence that, at any dose may result in death, is life-threatening, may require inpatient hospitalization or prolongation of existing hospitalization, result in persistent disability/incapacity, or may lead to any congenital anomaly or birth defect.
Number of participants discontinued the study medication due to AE [Up to 73 days]
Number of participants discontinuing study medication due to adverse event will be analyzed
Number of participants with abnormal systolic blood pressure assessment (SBP) and diastolic blood pressure (DBP) [Up to 73 days]
Systolic and diastolic blood pressure will be measured in seated position with a completely automated device. Measurements will be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions
Number of participants with abnormal pulse rate [Up to 73 days]
Pulse rate will be measured in seated position with a completely automated device. Measurements will be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions.
Number of participants with abnormal oral temperature [Up to 73 days]
Number of participants with abnormal oral temperature will be evaluated.
Number of participants with abnormal respiratory rate [Up to 73 days]
Number of participants with abnormal respiratory rate will be evaluated.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Fort Worth	Texas	United States	76104
2	GSK Investigational Site	Lufkin	Texas	United States	75904
3	GSK Investigational Site	San Antonio	Texas	United States	78212
4	GSK Investigational Site	San Antonio	Texas	United States	78215