Anemia Study in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-Blood Pressure (ASCEND-BP)
- Registration Number
- NCT03029247
- Lead Sponsor
- GlaxoSmithKline
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 105
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Participants receiving Epoetin alfa 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. Participants receiving Daprodustat 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.
- Primary Outcome Measures
Name Time Method Average of Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring (ABPM) Over 6-hour Post Dosing on Day 57 Up to 6 hours post dose 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.
- Secondary Outcome Measures
Name Time Method Plasma Concentrations of Metabolite GSK2391220 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 Blood samples were collected at indicated time points for the concentrations of metabolite GSK2391220.
Average of HR Measured by ABPM Over 6 Hour Post Dosing on Day 57 Up to 6 hours post dose on Day 57 The effect of daprodustat and epoetin alfa on HR was compared using ABPM over 6 hour post-dosing. Analysis was based on ANCOVA with terms for treatment, prior ESA dose (low/high), post-HD/pre-AC1 HR, difference between post-HD/pre-AC2 HR and post-HD/pre-AC1 HR and treatment by difference in post-HD HR between AC1 and 2 interaction. LS mean of 6 hour average HR post AC2 on Day 57 and its corresponding standard error has been presented.
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 The initial effect of daprodustat and epoetin alfa on HR was compared using ABPM over 6 hour post-dosing on Day 1. Analysis was based on ANCOVA with terms for treatment, prior ESA dose (low/high), post-HD/pre-AC1 HR. LS mean of 6 hour average HR post AC1 on Day 1 and its corresponding standard error has been presented.
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 The initial effect of daprodustat and epoetin alfa on blood pressure was compared using AUEC of SBP, DBP and MAP measured by ABPM over 24-hour post dosing on Day 1. Analysis was based on ANCOVA with terms for treatment and prior ESA dose (low/high). LS mean of AUEC up to 24 hours post dose on Day 1 and its corresponding standard error has been presented.
Plasma Concentrations of Daprodustat Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 Blood samples were collected at indicated time points for the concentrations of daprodustat.
Plasma Concentrations of Metabolite GSK2506104 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 Blood samples were collected at indicated time points for the concentrations of metabolite GSK2506104.
Plasma Concentrations of Metabolite GSK2487818 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 Blood samples were collected at indicated time points for the concentrations of metabolite GSK2487818.
Plasma Concentrations of Metabolite GSK2506102 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 Blood samples were collected at indicated time points for the concentrations of metabolite GSK25206102.
Plasma Concentrations of Metabolite GSK2531398 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 Blood samples were collected at indicated time points for the concentrations of metabolite GSK2531398.
Plasma Concentrations of Metabolite GSK2531401 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 Blood samples were collected at indicated time points for the concentrations of metabolite GSK2531401.
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 The initial effect of daprodustat and epoetin alfa on blood pressure was compared using ABPM over 6 hour post-dosing on Day 1. Analysis was based on ANCOVA with terms for treatment, prior ESA dose (low/high), post-HD/pre-AC1 SBP, DBP and MAP. LS mean of 6 hour average SBP, DBP and MAP post AC1 on Day 1 and its corresponding standard error has been presented.
AUEC of HR Measured by ABPM Over 24-hour Post Dosing on Day 1 Up to 24 hours post dose on Day 1 The initial effect of daprodustat and epoetin alfa on HR was compared using AUEC of HR measured by ABPM over 24-hour post dosing. Analysis was based on ANCOVA with terms for treatment and prior ESA dose (low/high). LS mean of AUEC up to 24 hours post dose on Day 1 and its corresponding standard error has been presented.
AUEC of HR Measured by ABPM Over 24-hour Post Dosing on Day 57 Up to 24 hours post dose on Day 57 The effect of daprodustat and epoetin alfa on HR was compared using AUEC of HR measured by ABPM over 24-hour post dosing on Day 57. Analysis was based on ANCOVA with terms for treatment and prior ESA dose (low/high). LS mean of AUEC up to 24 hour post dose on Day 57 and its corresponding standard error has been presented.
Change From Pre-dose in SBP, DBP and MAP at Day 1 Day 1: Pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 hours post-dose The change from pre-dose in SBP, DBP and MAP was measured using ABPM to compare the initial effect of daprodustat to epoetin alfa after AC1 on Day 1. Change from pre-dose at each timepoint is calculated as measurement at post-dose minus pre-acute challenge 1 measurement.
Change From Pre-dose in HR at Day 1 Day 1: Pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 hours post-dose The change from pre-dose in HR was measured using ABPM to compare the initial effect of daprodustat to epoetin alfa after AC1 on Day 1. Change from pre-dose at each timepoint is calculated as measurement at post-dose minus pre-acute challenge 1 measurement.
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 The effect of daprodustat and epoetin alfa on blood pressure was compared using ABPM over 6 hour post-dosing after AC2 on Day 57. Analysis was based on ANCOVA with terms for treatment, prior ESA dose (low/high), post-HD/pre-AC1 DBP and MAP, difference between post-HD/pre-AC2 DBP and MAP and post-HD/pre-AC1 DBP and MAP and treatment by difference in post-HD DBP and MAP between AC1 and 2 interaction. LS mean of 6 hour average DBP and MAP post AC2 on Day 57 and its corresponding standard error has been presented.
AUEC of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 57 Up to 24 hours post dose on Day 57 The effect of daprodustat and epoetin alfa on blood pressure was compared using AUEC of SBP, DBP and MAP measured by ABPM over 24-hour post dosing on Day 57. Analysis was based on ANCOVA with terms for treatment and prior ESA dose (low/high). LS mean of AUEC up to 24 hour post dose on Day 57 and its corresponding standard error has been presented.
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat and its metabolites GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401. PK parameters were analyzed using standard non-compartmental analysis.
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat and its metabolites GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401. PK parameters were analyzed using standard non-compartmental analysis.
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat and its metabolites GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401. PK parameters were analyzed using standard non-compartmental analysis.
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat and its metabolites GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401. PK parameters were analyzed using standard non-compartmental analysis.
Trial Locations
- Locations (1)
GSK Investigational Site
šŗšøSan Antonio, Texas, United States