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

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Open-label Study to Evaluate the Effect of Daprodustat on Blood Pressure in Subjects With Anemia Associated With Chronic Kidney Disease on Hemodialysis Switched From a Stable Dose of an Erythropoiesis-stimulating Agent

Conditions
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Anaemia

Intervention / Treatment
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* Drug: Daprodustat
* Drug: Epoetin alfa


Participation Criteria
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Eligibility Criteria
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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%.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Participants receiving Epoetin alfa<br>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<br>* 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)<br>|
| Experimental: Participants receiving Daprodustat<br>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<br>* Daprodustat will be available as oral tablets at unit dose strength of 1, 2, 4, 6, 8 and 10 mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average of SBP, Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) Measured by ABPM Over 6-hour Post Dosing 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. | 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 | 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. | 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 | 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. | Up to 24 hours post dose on Day 1 | 
| AUEC of HR Measured by ABPM Over 24-hour Post Dosing 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. | 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 | 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. | Up to 6 hours post dose on Day 57 | 
| Average of HR Measured by ABPM Over 6 Hour Post Dosing 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. | Up to 6 hours post dose on Day 57 | 
| AUEC of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing 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. | Up to 24 hours post dose on Day 57 | 
| AUEC of HR Measured by ABPM Over 24-hour Post Dosing 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. | Up to 24 hours post dose on Day 57 | 
| Change From Pre-dose in SBP, DBP and MAP at Day 1 | 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. | 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 | 
| Change From Pre-dose in HR at Day 1 | 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. | 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 | 
| Plasma Concentrations of Daprodustat | Blood samples were collected at indicated time points for the concentrations of daprodustat. | Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 | 
| Plasma Concentrations of Metabolite GSK2391220 | Blood samples were collected at indicated time points for the 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 | 
| Plasma Concentrations of Metabolite GSK2506104 | Blood samples were collected at indicated time points for the 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 | 
| Plasma Concentrations of Metabolite GSK2487818 | Blood samples were collected at indicated time points for the 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 | 
| Plasma Concentrations of Metabolite GSK2506102 | Blood samples were collected at indicated time points for the concentrations of metabolite GSK25206102. | Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 | 
| Plasma Concentrations of Metabolite GSK2531398 | Blood samples were collected at indicated time points for the 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 | 
| Plasma Concentrations of Metabolite GSK2531401 | Blood samples were collected at indicated time points for the 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 | 
| Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 | 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. | Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 | 
| Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 | 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. | Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 | 
| Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 | 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. | Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 | 
| Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 | 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. | Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ESA, CKD, Anemia, Daprodustat, Blood pressure