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

NCT03446612 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: 2057672017-002268-42
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 3

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

Keywords

darbepoetin alpha; challenge agents; daprodustat; FBF-CKD

Outcome Measures

Primary Outcomes (1)

• Change in FBF Ratio in Response to Acetylcholine (Day 1 to Day 42)

  Venous occlusion plethysmography was used for FBF assessment. Acetylcholine (ACH) was infused intra-arterially at 7.5, 15 and 30 micrograms/minute (ug/min) each for 6 minutes per infusion. FBF ratio was defined as the ratio of a participant's treatment (infused) arm value divided by the non-treatment (non-infused) arm value. The overall ratio was determined by taking the participant's Day 42 FBF ratio and dividing by the Day 1 FBF ratio.

  Day 1 to Day 42

Secondary Outcomes (22)

• Change in the Absolute FBF From Day 1 to Day 42 in Response to Acetylcholine

  Day 1 to Day 42

• Change in FBF Ratio in Response to Sodium Nitroprusside (Day 1 to Day 42)

  Day 1 to Day 42

• Change in the Absolute FBF From Day 1 to Day 42 in Response to Sodium Nitroprusside

  Day 1 to Day 42

• Change in FBF Ratio in Response to NG-monomethyl Arginine Acetate (L-NMMA) (Day 1 to Day 42)

  Day 1 to Day 42

• Change in the Absolute FBF From Day 1 to Day 42 in Response to L-NMMA

  Day 1 to Day 42

Other Outcomes (30)

• Absolute Values of Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

  Days 1, 14, 28, 42 and 59

• Change From Baseline in DBP and SBP

  Baseline (Day 1) and at Days 14, 28, 42 and 59

• Absolute Values of Electrocardiogram (ECG) Mean Heart Rate

  Days 1, 42 and 59

Study Arms (2)

Participants receiving Daprodustat

EXPERIMENTAL

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

Drug: Daprodustat; Drug: Acetylcholine; Drug: Sodium nitroprusside; Drug: L-N-monomethyl arginine acetate (L-NMMA)

Participants receiving Darbepoetin alfa

ACTIVE COMPARATOR

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

Drug: Darbepoetin alfa; Drug: Acetylcholine; Drug: Sodium nitroprusside; Drug: L-N-monomethyl arginine acetate (L-NMMA)

Interventions

Daprodustat 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.

Participants receiving Daprodustat

Darbepoetin alfa DRUG

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

Participants receiving Darbepoetin alfa

Acetylcholine 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.

Participants receiving Daprodustat; Participants receiving Darbepoetin alfa

Sodium nitroprusside 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.

Participants receiving Daprodustat; Participants receiving Darbepoetin alfa

L-N-monomethyl arginine acetate (L-NMMA) 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 Daprodustat; Participants receiving Darbepoetin alfa

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (3)

GSK Investigational Site

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

GSK Investigational Site

Edinburgh, EH16 4TJ, United Kingdom

Location

GSK Investigational Site

London, SE1 7EH, United Kingdom

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

Interventions

GSK1278863; Darbepoetin alfa; Acetylcholine; Nitroprusside; omega-N-Methylarginine

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Erythropoietin; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Proteins; Amino Acids, Peptides, and Proteins; Biogenic Amines; Amines; Organic Chemicals; Ferricyanides; Cyanides; Anions; Ions; Electrolytes; Inorganic Chemicals; Ferric Compounds; Iron Compounds; Hydrogen Cyanide; Nitrogen Compounds; Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Diamino; Amino Acids, Essential

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. However, a central FBF reader, who will read and evaluate the FBF data, will be blinded to the treatment assignment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Participants will be randomized to either daprodustat or darbepoetin alfa. A central randomization approach will be used with stratification by center.

Study Record Dates

• First Submitted: February 20, 2018
• First Posted: February 27, 2018
• Study Start: January 10, 2019
• Primary Completion: May 29, 2019
• Study Completion: May 29, 2019
• Last Updated: March 27, 2024
• Results First Posted: July 21, 2021

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

GB (3)