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

NCT03457701 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 201771
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 3

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.

Conditions

Anaemia

Keywords

Recombinant human erythropoietin; Anemia; Daprodustat; Chronic kidney disease

Outcome Measures

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.

  Up to Day 57

Secondary Outcomes (13)

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

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

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

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

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

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

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

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

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

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

Study Arms (4)

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

Daprodustat+57Fe followed by rhEPO+58Fe

EXPERIMENTAL

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)

Daprodustat+58Fe followed by rhEPO+57Fe

EXPERIMENTAL

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

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; Daprodustat+58Fe followed by rhEPO+57Fe; rhEPO+57Fe followed by Daprodustat+58Fe; rhEPO+58Fe followed by Daprodustat+57Fe

rhEPO DRUG

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.

Daprodustat+57Fe followed by rhEPO+58Fe; Daprodustat+58Fe followed by rhEPO+57Fe; rhEPO+57Fe followed by Daprodustat+58Fe; rhEPO+58Fe followed by Daprodustat+57Fe

Ferrous sulfate containing the stable iron isotope (57Fe) DRUG

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

Daprodustat+57Fe followed by rhEPO+58Fe; Daprodustat+58Fe followed by rhEPO+57Fe; rhEPO+57Fe followed by Daprodustat+58Fe; rhEPO+58Fe followed by Daprodustat+57Fe

Ferrous sulfate containing the stable iron isotope (58Fe) DRUG

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).

Daprodustat+57Fe followed by rhEPO+58Fe; Daprodustat+58Fe followed by rhEPO+57Fe; rhEPO+57Fe followed by Daprodustat+58Fe; rhEPO+58Fe followed by Daprodustat+57Fe

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (3)

GSK Investigational Site

Fort Worth, Texas, 76104, United States

Location

GSK Investigational Site

Lufkin, Texas, 75904, United States

Location

GSK Investigational Site

San Antonio, Texas, 78212, United States

Location

Related Publications (1)

• 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.

  PMID: 36005278 DERIVED

MeSH Terms

Conditions

Anemia; Renal Insufficiency, Chronic

Interventions

GSK1278863

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: This is an Open-label study.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 1, 2018
• First Posted: March 7, 2018
• Study Start: July 30, 2019
• Primary Completion: July 5, 2022
• Study Completion: July 5, 2022
• Last Updated: March 27, 2024
• Results First Posted: July 25, 2023

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months .

Locations

US (3)