Clinical trial NCT03029247: Anemia Study in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-Blood Pressure (ASCEND-BP)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Anaemia
Keywords: Anemia
Daprodustat
Blood pressure
ESA
CKD
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: ERT: Clinical Trial Technology Solutions
name: Q2 Solutions
name: Quintiles, Inc.
name: HemoCue
First posted: 2017-01-24
Enrollment: 105
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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%.

Primary outcomes:
measure: Average of Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring (ABPM) Over 6-hour Post Dosing on Day 57
timeFrame: Up to 6 hours post dose on Day 57
Secondary outcomes:
measure: Average of SBP, Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) Measured by ABPM Over 6-hour Post Dosing on Day 1
timeFrame: Up to 6 hours post dose on Day 1
measure: Average of Heart Rate (HR) Measured by ABPM Over 6 Hour Post Dosing on Day 1
timeFrame: Up to 6 hours post dose on Day 1
measure: Area Under the Effect Curve (AUEC) of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 1
timeFrame: Up to 24 hours post dose on Day 1
measure: AUEC of HR Measured by ABPM Over 24-hour Post Dosing on Day 1
timeFrame: Up to 24 hours post dose on Day 1
measure: Average of DBP and MAP Measured by ABPM Over 6-hour Post Dosing on Day 57
timeFrame: Up to 6 hours post dose on Day 57
measure: Average of HR Measured by ABPM Over 6 Hour Post Dosing on Day 57
timeFrame: Up to 6 hours post dose on Day 57
measure: AUEC of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 57
timeFrame: Up to 24 hours post dose on Day 57
measure: AUEC of HR Measured by ABPM Over 24-hour Post Dosing on Day 57
timeFrame: Up to 24 hours post dose on Day 57
measure: Change From Pre-dose in SBP, DBP and MAP at Day 1
timeFrame: 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
measure: Change From Pre-dose in HR at Day 1
timeFrame: 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
measure: Plasma Concentrations of Daprodustat
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57
measure: Plasma Concentrations of Metabolite GSK2391220
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57
measure: Plasma Concentrations of Metabolite GSK2506104
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57
measure: Plasma Concentrations of Metabolite GSK2487818
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57
measure: Plasma Concentrations of Metabolite GSK2506102
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57
measure: Plasma Concentrations of Metabolite GSK2531398
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57
measure: Plasma Concentrations of Metabolite GSK2531401
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57
measure: Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57
measure: Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57
measure: Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57
measure: Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57
Other outcomes:
measure: Number of Participants With Any Serious Adverse Events (SAEs)
timeFrame: Up to Week 10
measure: Number of Participants With Treatment Emergent Common (>=2%) Non-serious Adverse Events (Non-SAEs)
timeFrame: Up to Week 8
measure: Number of Participants Who Discontinued the Study Treatment
timeFrame: Up to Week 10
measure: Absolute Values for Clinical Chemistry Parameters: Albumin and Protein
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Absolute Values for Clinical Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Absolute Values for Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Indirect (Indrt) Bilirubin
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Absolute Values for Clinical Chemistry Parameters: Calcium Corrected for Albumin (CCA), Glucose, Potassium, Phosphate and Sodium
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Change From Baseline Values for Clinical Chemistry Parameters: Albumin and Protein
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Change From Baseline Values for Clinical Chemistry Parameters: ALP, ALT and AST
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Change From Baseline Values for Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Indrt. Bilirubin
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Change From Baseline Values for Clinical Chemistry Parameters: CCA, Glucose, Potassium, Phosphate and Sodium
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Absolute Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Absolute Values for Hematology Parameter: Hematocrit
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Absolute Values for Hematology Parameters: Erythrocytes and Reticulocytes
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Absolute Values for Hematology Parameters: Hemoglobin and Erythrocyte Mean Corpusclar Hemoglobin Concentration ( Ery. MCHC)
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Absolute Values for Hematology Parameter: Ery. Mean Corpuscular Hemoglobin (MCH) and Reticulocyte Corpuscular Hemoglobin Content (CHr)
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Absolute Values for Hematology Parameter: Ery. Mean Corpuscular Volume (MCV)
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Absolute Values for Hematology Parameter: Erythrocyte Distribution Width
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Change From Baseline Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Change From Baseline Values for Hematology Parameter: Hematocrit
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Change From Baseline Values for Hematology Parameters: Erythrocytes and Reticulocytes
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Change From Baseline Values for Hematology Parameters: Hemoglobin and Ery. MCHC
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Change From Baseline Values for Hematology Parameters: Ery. MCH and CHr
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Change From Baseline Values for Hematology Parameter: Ery. MCV
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Change From Baseline Values for Hematology Parameter: Erythrocyte Distribution Width
timeFrame: Baseline (Day 1) and at Days 29, 57 and Week 10
measure: Absolute Values for Electrocardiogram (ECG) Mean Heart Rate
timeFrame: Baseline (Day 1-predose) and at Day 1: 24 hours; Day 57: pre-dose; Day 57: 24 hours and Week 10
measure: Absolute Values for ECG Parameters: PR Interval, QRS Duration, QT Interval Corrected for Heart Rate (QTc) and QT Interval Corrected for Heart Rate Using Bazett's Formula (QTcB)
timeFrame: Baseline (Day 1-predose) and at Day 1: 24 hours; Day 57: pre-dose; Day 57: 24 hours and Week 10
measure: Change From Baseline Values for ECG Mean Heart Rate
timeFrame: Baseline (Day 1-predose) and at Day 1: 24 hours; Day 57: pre-dose; Day 57: 24 hours and Week 10
measure: Change From Baseline Values for ECG Parameters: PR Interval, QRS Duration, QTc and QTcB
timeFrame: Baseline (Day 1-predose) and at Day 1: 24 hours; Day 57: pre-dose; Day 57: 24 hours and Week 10
measure: Absolute Values for Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis
measure: Absolute Values for Temperature
timeFrame: Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis
measure: Absolute Values for Pulse Rate
timeFrame: Baseline (Day 1, predose) and at Day 1:3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis
measure: Change From Baseline Values for Vital Signs: SBP and DBP
timeFrame: Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis
measure: Change From Baseline Values for Temperature
timeFrame: Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis
measure: Change From Baseline Values for Pulse Rate
timeFrame: Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis
Locations:
city: La Mesa
country: United States
facility: GSK Investigational Site
state: California
city: Lakewood
country: United States
facility: GSK Investigational Site
state: Colorado
city: Coral Gables
country: United States
facility: GSK Investigational Site
state: Florida
city: DeLand
country: United States
facility: GSK Investigational Site
state: Florida
city: Hollywood
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Spartanburg
country: United States
facility: GSK Investigational Site
state: South Carolina
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.