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

NCT03029247 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 205665
• Study Type: interventional
• Target: 105
• Locations: 1 country
• Sites: 11

Brief Summary

This will be an open-label, randomized, parallel-group study in hemodialysis-dependent (HD) participants with anemia associated with chronic kidney disease (CKD), designed to compare the effects of daprodustat to epoetin alfa on blood pressure (BP). Participants will be screened for eligibility within 7 and 30 days prior to erythropoesis-stimulating agent (ESA) washout. Following a 2-week ESA washout period, on Day 1 participants will be randomized 1:1 and stratified by prior ESA dose before they undergo Acute Challenge 1, a single dose challenge to compare the acute effects on BP of the highest planned once-daily maintenance dose of daprodustat (24 milligrams \[mg\]) to the highest starting dose of epoetin alfa (100 units/kilogram \[U/kg\]). This will be followed by an 8-week hemoglobin (Hgb)-maintenance period, where doses of either daprodustat or epoetin alfa will be administered and adjusted. At the end of Hgb maintenance period, on Day 57 an Acute Challenge 2 will be repeated utilizing the same treatment dose administered in Acute Challenge 1; there will be a follow-up visit within 14+/-3 days after completing treatment.

Conditions

Anaemia

Keywords

Anemia; Daprodustat; Blood pressure; ESA; CKD

Outcome Measures

Primary Outcomes (1)

• Average of Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring (ABPM) Over 6-hour Post Dosing on Day 57

  The effect of daprodustat and epoetin alfa on blood pressure was compared using ABPM after 8 weeks of Hgb maintenace therapy on Day 57. Analysis was based on "analysis of covariance (ANCOVA) with terms for treatment, prior erythropoiesis-stimulating agent (ESA) dose (low/high), post-Hemodialysis dependent (HD)/pre-AC 1 SBP, difference between post-HD/pre-AC 2 SBP and post-HD/pre-AC 1 SBP and treatment by difference in post-HD SBP between AC 1 and 2 interaction." Least square (LS) mean of 6 hour average SBP post AC2 on Day 57 and its corresponding standard error has been presented.

  Up to 6 hours post dose on Day 57

Secondary Outcomes (21)

• Average of SBP, Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) Measured by ABPM Over 6-hour Post Dosing on Day 1

  Up to 6 hours post dose on Day 1

• Average of Heart Rate (HR) Measured by ABPM Over 6 Hour Post Dosing on Day 1

  Up to 6 hours post dose on Day 1

• Area Under the Effect Curve (AUEC) of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 1

  Up to 24 hours post dose on Day 1

• AUEC of HR Measured by ABPM Over 24-hour Post Dosing on Day 1

  Up to 24 hours post dose on Day 1

• Average of DBP and MAP Measured by ABPM Over 6-hour Post Dosing on Day 57

  Up to 6 hours post dose on Day 57

Other Outcomes (35)

• Number of Participants With Any Serious Adverse Events (SAEs)

  Up to Week 10

• Number of Participants With Treatment Emergent Common (>=2%) Non-serious Adverse Events (Non-SAEs)

  Up to Week 8

• Number of Participants Who Discontinued the Study Treatment

  Up to Week 10

Study Arms (2)

Participants receiving Epoetin alfa

ACTIVE COMPARATOR

On Day 1, participants will undergo 24-hour Acute Challenge 1, in which participants will receive a single dose of 100 U/kg epoetin alfa IV. After completing Acute Challenge 1, participants will enter in an 8-week Hgb maintenance period. At the end of Hgb maintenance period, on Day 57, Acute Challenge 2 will be performed utilizing the same treatment dose administered in Acute Challenge 1.

Drug: Epoetin alfa

Participants receiving Daprodustat

EXPERIMENTAL

On Day 1, participants will undergo 24-hour Acute Challenge 1, in which participants will receive 24 mg daprodustat. After completing Acute Challenge 1, participants will enter an 8-week Hgb maintenance period. At the end of Hgb maintenance period, on Day 57, Acute Challenge 2 will be performed utilizing the same treatment dose administered in Acute Challenge 1.

Drug: Daprodustat

Interventions

Daprodustat DRUG

Daprodustat will be available as oral tablets at unit dose strength of 1, 2, 4, 6, 8 and 10 mg.

Participants receiving Daprodustat

Epoetin alfa DRUG

Epoetin alfa will be administered according to local labelling and clinical practice guidelines to keep Hgb in the target range (10.0-11.0 g/dL)

Participants receiving Epoetin alfa

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• More than or equal to 40 years of age, at the time of signing the informed consent
• Stable Hgb 8.5 to 11.5 grams per deciliter (g/dL) inclusive.
• Dialysis frequency: On hemodialysis (HD, hemofiltration or hemodiafiltration) three-to five-times weekly for at least 4 weeks prior to screening.
• A single pool Kt/Vurea \>=1.2 based on a historical value obtained within 3 months prior to screening in order to ensure the adequacy of dialysis. If Kt/Vurea is not available, then an average of the last 2 values of urea reduction ratio should be at least 65 percent (%).
• Treated with an ESA (epoetins or their biosimilars, darbepoetin, or methoxy polyethylene glycol \[PEG\]-epoetin beta) for at least 4 weeks prior to screening.
• Participants may be on stable (\<=50% change in overall dose and compliance of 80% of prescribed doses in the 4 weeks prior to and including the screening period) maintenance oral or intravenous (IV; \<=100 mg/week) iron supplementation. If participants are on oral or IV iron, then doses must be stable for the 4 weeks prior to Washout.
• Weight: Mid-week weight change between dialysis treatments \<5% as assessed post-dialysis at the Screening and Washout visits.
• On at least 1 antihypertensive medication (excluding diuretics) and on that same medication and the same dose for at least 1 week prior to Washout.
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and the protocol.
• Willing and able to wear ABPM device for at least 25 hours on two separate sessions.

You may not qualify if:

• Planned change from HD to peritoneal dialysis within the study time period, or on home dialysis.
• Planned for kidney transplant within the 16 weeks following the Screening visit.
• An epoetin alfa dose of \>=360 U/kg/week IV or \>=250 U/kg/week subcutaneous (SC), or darbepoetin dose of \>=1.8 micrograms (μg)/kg/week IV or SC, or methoxy PEG-epoetin beta dose of \>=2.2 μg/kg/week within the 8 weeks prior to screening through Week -4.
• Planned or recorded administration of Mircera (methoxy PEG-epoetin beta) within the 4 weeks prior to the Washout.
• Occurrence of myocardial infarction or acute coronary syndrome within 3 months prior to Washout.
• Stroke or transient ischemic attack within 3 months prior to Washout.
• Chronic Class 4 heart failure, as defined by the New York Heart Association functional classification system diagnosed prior to Washout.
• Resting post dialysis SBP \>160 millimeters of mercury (mmHg); or DBP \>100 mmHg at screening or uncontrolled hypertension as determined by the investigator.
• Presence of atrial fibrillation.
• Active chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosus, rheumatoid arthritis, celiac disease) diagnosed prior to Washout.
• History of bone marrow aplasia or pure red cell aplasia.
• Other causes of anemia including Pernicious anemia, thalassemia major, sickle cell disease or myelodysplastic syndrome.
• Alanine transaminase (ALT) \>2 times upper limit of normal (ULN) (screening only) or Bilirubin \>1.5 times ULN (screening only) or Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
• Major surgery (excluding vascular access surgery) within the 3 months prior to Washout or planned during the study.
• Blood transfusion within the 8 weeks prior to Washout or an anticipated need for blood transfusion during the study.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• ERT: Clinical Trial Technology Solutions: collaborator
• Q2 Solutions: collaborator
• Quintiles, Inc.: collaborator
• HemoCue: collaborator

Study Sites (11)

GSK Investigational Site

La Mesa, California, 91942, United States

Location

GSK Investigational Site

Lakewood, Colorado, 80228, United States

Location

GSK Investigational Site

Coral Gables, Florida, 33134, United States

Location

GSK Investigational Site

DeLand, Florida, 32720, United States

Location

GSK Investigational Site

Hollywood, Florida, 33024, United States

Location

GSK Investigational Site

Miami, Florida, 33133, United States

Location

GSK Investigational Site

Orlando, Florida, 32809, United States

Location

GSK Investigational Site

Chicago, Illinois, 60643, United States

Location

GSK Investigational Site

Minneapolis, Minnesota, 55404, United States

Location

GSK Investigational Site

Spartanburg, South Carolina, 29301, United States

Location

GSK Investigational Site

San Antonio, Texas, 78215, 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

Interventions

GSK1278863; Epoetin Alfa

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Erythropoietin; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

8664357343

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
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 20, 2017
• First Posted: January 24, 2017
• Study Start: July 27, 2017
• Primary Completion: July 9, 2020
• Study Completion: July 9, 2020
• Last Updated: June 3, 2021
• Results First Posted: June 3, 2021

Record last verified: 2021-06

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 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 (11)