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

NCT ID: NCT03029247

Last Updated: 2021-06-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 105 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-07-27
• Study Completion Date: 2020-07-09

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

Study Design

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

Study Groups

Participants receiving Epoetin alfa

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.

Group Type: ACTIVE_COMPARATOR

Epoetin alfa

Intervention Type: 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 Daprodustat

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.

Group Type: EXPERIMENTAL

Daprodustat

Intervention Type: DRUG

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

Interventions

Daprodustat

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

Intervention Type: DRUG

Epoetin alfa

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)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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.
• 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 QTc exclusion for participants with a predominantly paced rhythm.
• 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.
• Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant gastrointestinal bleeding within the 8 weeks prior to Washout.
• Clinical evidence of acute infection or history of infection requiring IV antibiotic therapy within the 8 weeks prior to Washout.
• History of malignancy within the two years prior to screening through Day 1 or currently receiving treatment for cancer, or has a known complex kidney cyst (e.g., Bosniak Category IIF, III or IV) >=3 centimeters.
• Participants with an upper arm diameter which cannot be measured by oscillometer/ sphygmomanometer cuff or for whom BP cannot be measured in the opposite arm of current vascular access.
• History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.
• Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from screening until Washout.
• The participant has participated in a clinical trial and has received an experimental investigational product within the 30 days prior to Day 1 or within 5 half lives of the investigational product prior to screening, whichever is longer.
• 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.
• A female participant is pregnant (as confirmed by a positive serum human chorionic gonadotrophin test for females of reproductive potential only), participant is breastfeeding, or participant is of reproductive potential and does not agree to follow one of the pre-specified contraceptive options
• Vitamin B12 at or below the lower limit of the reference range (may rescreen in a minimum of 8 weeks, following treatment).
• Folate at <2.0 nanograms/milliliter (ng/mL) (4.5 Nanomoles per Liter) (may rescreen in a minimum of 4 weeks, following treatment).
• Ferritin at <100 ng/mL
• Transferrin saturation at <20%.

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ERT: Clinical Trial Technology Solutions

OTHER

Sponsor Role: collaborator

Q2 Solutions

INDUSTRY

Sponsor Role: collaborator

Quintiles, Inc.

INDUSTRY

Sponsor Role: collaborator

HemoCue

INDUSTRY

Sponsor Role: collaborator

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

La Mesa, California, United States

GSK Investigational Site

Lakewood, Colorado, United States

GSK Investigational Site

Coral Gables, Florida, United States

GSK Investigational Site

DeLand, Florida, United States

GSK Investigational Site

Hollywood, Florida, United States

GSK Investigational Site

Miami, Florida, United States

GSK Investigational Site

Orlando, Florida, United States

GSK Investigational Site

Chicago, Illinois, United States

GSK Investigational Site

Minneapolis, Minnesota, United States

GSK Investigational Site

Spartanburg, South Carolina, United States

GSK Investigational Site

San Antonio, Texas, United States

Countries

United States

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

205665

Identifier Type: -

Identifier Source: org_study_id