Anemia Study in Chronic Kidney Disease (CKD) : Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat -Forearm Blood Flow (ASCEND-FBF)

NCT ID: NCT03446612

Last Updated: 2024-03-27

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-10
• Study Completion Date: 2019-05-29

Brief Summary

Daprodustat has demonstrated an ability to effectively raise hemoglobin concentrations with lower erythropoietin (EPO) levels than those observed after administration of recombinant human erythropoietin (rhEPOs). Therefore, daprodustat has the potential to treat anemia of chronic kidney disease (CKD) with a lower cardiovascular (CV) risk than is observed with the rhEPOs. While the effect of rhEPOs on endothelial function has been assessed, to date the effect of daprodustat or other prolyl hydroxylase inhibitor (PHI) compounds on endothelial function has not. Therefore, the purpose of this study is to compare the effect of daprodustat to darbepoetin alfa on endothelial function by assessing FBF in participants with anemia of CKD by using venous occlusion plethysmography as a means to estimate the potential for daprodustat to have a lower risk of CV events as compared to rhEPO.

This study will use a randomized, repeat dose, open label, parallel group design, in adult, not on-dialysis, male and female participants with anemia of CKD that are currently not treated with rhEPOs.

The study will comprise of three study periods: a screening period starting up to 30 days prior to Day 1, a 42 day (6 week) treatment period, and a follow-up visit up to 14 days later. The total duration of participants involvement is up to 14 weeks (including screening and follow up visit). Approximately 50 participants will be randomized to either daprodustat or darbepoetin alfa.

Conditions

Anaemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Participants receiving Daprodustat

Participants will receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days.

Group Type: EXPERIMENTAL

Daprodustat

Intervention Type: DRUG

Daprodustat will be available as 1 mg, 2 mg and 4 mg oral tablets. Daprodustat will be administered once daily by oral route without regard for food.

Acetylcholine

Intervention Type: DRUG

Acetylcholine will be used as a challenge agent and will be infused at 7.5, 15 and 30 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.

Sodium nitroprusside

Intervention Type: DRUG

Sodium nitroprusside will be used as a challenge agent and will be infused at 3 and 10 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.

L-N-monomethyl arginine acetate (L-NMMA)

Intervention Type: DRUG

L-N-monomethyl arginine acetate will be used as a challenge agent and will be infused at a doses of 2 and 8 micromoles/minute for 6 minutes into the brachial artery of the test arm.

Participants receiving Darbepoetin alfa

Participants will receive Darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28).

Group Type: ACTIVE_COMPARATOR

Darbepoetin alfa

Intervention Type: DRUG

Darbepoetin alfa will be given as solution for injection for subcutaneous administration every 2 weeks.

Acetylcholine

Intervention Type: DRUG

Acetylcholine will be used as a challenge agent and will be infused at 7.5, 15 and 30 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.

Sodium nitroprusside

Intervention Type: DRUG

Sodium nitroprusside will be used as a challenge agent and will be infused at 3 and 10 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.

L-N-monomethyl arginine acetate (L-NMMA)

Intervention Type: DRUG

L-N-monomethyl arginine acetate will be used as a challenge agent and will be infused at a doses of 2 and 8 micromoles/minute for 6 minutes into the brachial artery of the test arm.

Interventions

Daprodustat

Daprodustat will be available as 1 mg, 2 mg and 4 mg oral tablets. Daprodustat will be administered once daily by oral route without regard for food.

Intervention Type: DRUG

Darbepoetin alfa

Darbepoetin alfa will be given as solution for injection for subcutaneous administration every 2 weeks.

Intervention Type: DRUG

Acetylcholine

Acetylcholine will be used as a challenge agent and will be infused at 7.5, 15 and 30 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.

Intervention Type: DRUG

Sodium nitroprusside

Sodium nitroprusside will be used as a challenge agent and will be infused at 3 and 10 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.

Intervention Type: DRUG

L-N-monomethyl arginine acetate (L-NMMA)

L-N-monomethyl arginine acetate will be used as a challenge agent and will be infused at a doses of 2 and 8 micromoles/minute for 6 minutes into the brachial artery of the test arm.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Participant 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 CKD defined by estimated Glomerular Filtration Rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula.
• Hemoglobin as measured by HemoCue at screening visit and Day 1 is <=11.0 grams/deciliter (g/dL) [<=110 gram/Litre (g/L)].
• Palpable brachial artery as assessed at screening.
• Participants, if necessary may be on stable maintenance oral iron supplementation (<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 4 weeks prior to the Day 1 visit.
• Male or female participants will be included.
• 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 has been on an approved form of contraceptive for the 4 weeks prior to Day 1 and agrees to follow the contraceptive guidance until the Follow-up visit.
• Capable of giving signed informed consent.

Exclusion Criteria

• On dialysis or clinical evidence of impending need to initiate dialysis within 12 weeks of Day 1.
• Planned kidney transplant within 12 weeks of Day 1.
• Presence of an arteriovenous (AV) fistula.
• Recombinant human erythropoietin use within the 12 weeks prior to the screening visit and through Day 1.
• History of severe allergic or anaphylactic reactions or hypersensitivity to the study treatment or challenge agents, or excipients in the study treatments or challenge agents.
• Planned use of any prescription or non-prescription drugs or dietary supplements that are prohibited from screening until all assessments on Day 42 have been successfully completed.
• The participant has participated in a clinical trial and has received an experimental investigational product within the prior 30 days or within 5 half-lives of the investigational product (whichever is longer) prior to screening and 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 <=50 nanograms/milliliter [<=50 microgram/liter (µg/L)] at screening.
• Transferrin saturation (TSAT) <=15% (0.15) at screening.
• Folate <2.0 nanogram/milliliter (4.5 nanomoles/liter; may rescreen in a minimum of 8 weeks) at screening.
• High sensitivity C-reactive protein (hs-CRP) >=50 micrograms/milliliter (>=50 mg/L) at screening.
• Myocardial infarction or acute coronary syndrome <=12 weeks prior to screening and through Day 1.
• Hospitalization for greater than 24 hours <=12 weeks prior to screening and through Day 1.
• Stroke or transient ischemic attack <=12 weeks prior to screening and through Day 1.
• Class 4 heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
• Resting SBP >180 millimeters of mercury (mmHg) or DBP >110 mmHg at screening visit or current uncontrolled hypertension as determined by the investigator.
• QT interval corrected for heart rate using Bazett's formula (QTcB) >500 milliseconds (msec), or QTcB >530 msec in participants with bundle branch block. There is no corrected QT (QTc) exclusion for participants with a predominantly ventricular paced rhythm.
• Active chronic inflammatory disease that could impact erythropoiesis.
• History of bone marrow aplasia or pure red cell aplasia.
• Conditions, other than anemia of CKD, which can affect erythropoiesis.
• Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant gastrointestinal bleeding from <=8 weeks prior to screening and through Day 1.
• ALT >2 times upper limit of normal (ULN; screening only).
• Bilirubin >1.5 times ULN (screening only); Isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%
• 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 within the 12 weeks prior to screening and through Day 1, or planned during the study.
• Anticipated or planned vascular access surgery (i.e., arteriovenous [AV] fistula) within the 12 weeks prior to screening and through the Day 42 assessments.
• Received a tissue heart valve replacement or repair within the 6 months prior to screening or has received a mechanical heart valve replacement.
• Blood transfusion within 6 weeks prior to screening and 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 8 weeks prior to screening and through Day 1. Prophylactic oral antibiotics are allowed.
• History of malignancy within the two years prior to screening and 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.
• Platelet count <50,000/µL (<50 Giga cells per liter).
• History of a bleeding disorder (e.g., hemophilia).
• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Cambridge, Cambridgeshire, United Kingdom

GSK Investigational Site

Edinburgh, , United Kingdom

GSK Investigational Site

London, , United Kingdom

Countries

United Kingdom

References

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.

Reference Type: DERIVED

PMID: 36005278 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2017-002268-42

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

205767

Identifier Type: -

Identifier Source: org_study_id