This is an international, multicenter trial, evaluating pharmacokinetics (PK) (4 weeks), safety (52 weeks), and hemoglobin (Hgb) response (52 weeks) to daprodustat in children and adolescent participants with anemia associated with chronic kidney disease (CKD) incorporating 2 independent sub-trials (Non dialysis \[ND\] and Dialysis \[D\]). This study will enroll participants with anemia associated with CKD, in 2 distinct sub-populations differing only by their CKD stage and dialysis requirement (ND: CKD stage 3 to 5 not yet receiving dialysis and D: CKD stage 5d undergoing peritoneal dialysis \[PD\] or hemodialysis \[HD\]). The maximum duration of the study will be approximately 60 weeks, including Screening period (up to 4 weeks), treatment period (52 weeks), and follow-up period (4 weeks). Outcome measures are identical for the ND and D sub-trials, but will be separately assessed in each sub- trials, overall and within each age subgroups (12 to less than \[\<\] 18 years, 6 to \<12 years, 2 to \<6 years, and 3 months to \<2 years). Except for PK and dose change, which is within each age group only.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
4
Daprodustat will be administered up to Week 52.
GSK Investigational Site
Aichi, Japan
GSK Investigational Site
Saitama, Japan
GSK Investigational Site
Tokyo, Japan
GSK Investigational Site
Yangsan, South Korea
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. SAEs are defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other situations as per medical and scientific judgement of the Investigator.
Time frame: Up to 56 weeks
Number of Participants With Adverse Event of Special Interests (AESIs)
AESIs are AEs of scientific interest specific to the drug class as per investigator assessment. AESI included: Death, Myocardial Infarction (MI), stroke, Heart Failure (HF), thromboembolic events, thrombosis of vascular access, Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis, New diagnosis of hypertension or worsening of existing hypertension, Cancer related mortality and tumor progression and recurrence, Esophageal and gastric erosions. Number of participants with any AESIs have been presented.
Time frame: Up to 56 weeks
Number of Participants With AEs Leading to Study Intervention Discontinuation
All AEs leading to study intervention discontinuation were collected. Number of participants with any AEs leading to study intervention discontinuation have been presented
Time frame: Up to 52 weeks
Change From Baseline in Hematology Parameter: Hematocrit
Blood samples were collected to analyze the hematology parameter: hematocrit. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Hematology Parameter: Reticulocytes/Erythrocytes
Blood samples were collected to analyze the hematology parameter: Reticulocytes/Erythrocytes. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Hematology Parameter: Erythrocytes
Blood samples were collected to analyze the hematology parameter: Erythrocytes. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Leukocytes and Platelet Count
Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Leukocytes and Platelet count. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume
Blood samples were collected to analyze the hematology parameter: Erythrocytes Mean Corpuscular Volume. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin
Blood samples were collected to analyze the hematology parameter: Erythrocytes Mean Corpuscular Hemoglobin. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Clinical Chemistry Parameters: Calcium, Potassium, Sodium, Blood Urea Nitrogen (BUN)
Blood samples were collected to analyze the clinical chemistry parameters: Calcium, Potassium, Sodium and BUN. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Clinical Chemistry Parameter: Creatinine
Blood samples were collected to analyze the clinical chemistry parameter: Creatinine. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Aspartate Aminotransferase (AST)
Blood samples were collected to analyze the clinical chemistry parameters: ALT, ALP and AST. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 24, 32, 36, 40, 48, and 52
Change From Baseline in Clinical Chemistry Parameters: Bilirubin and Direct Bilirubin
Blood samples were collected to analyze the clinical chemistry parameters: Bilirubin and Direct Bilirubin. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 24, 32, 36, 40, 48, and 52
Change From Baseline in Clinical Chemistry Parameter: Protein
Blood samples were collected to analyze the clinical chemistry parameter: Protein. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 24, 32, 36, 40, 48, and 52
Change From Baseline in Clinical Chemistry Parameter: Ferritin
Blood samples were collected to analyze the clinical chemistry parameter: Ferritin. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Clinical Chemistry Parameter: Transferrin Saturation
Blood samples were collected to analyze the clinical chemistry parameter: Transferrin saturation. Transferrin saturation is measured as a percentage, it is the ratio of serum iron and total iron-binding capacity, multiplied by 100. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Clinical Chemistry Parameter: Estimated Glomerular Filtration Rate
Blood samples were collected to analyze the clinical chemistry parameter: Estimated Glomerular Filtration Rate. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Hematology Parameter: Prothrombin International Normalized Ratio
Blood samples were collected to analyze the hematology parameter: Prothrombin International Normalized Ratio. It is used to assess the clotting ability of blood. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 4, 8, 12, 24, 32, 36, 40, 48, and 52
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Systolic and diastolic blood pressure (BP) were assessed using an appropriate size cuff preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, cell phones). Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Heart Rate (HR)
Heart rate (HR) were assessed using an appropriate size cuff preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, cell phones). Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Weight
Weight readings in kilogram (kg) were collected. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Height
Height readings in centimeters (cm) were collected. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline.
Time frame: Baseline (Day 1), at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Absolute Values of Hemoglobin (Hgb)
Blood samples were collected from all participants for measurement of Hgb values in grams per deciliter (g/dL). Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Hgb results of participants with intercurrent events were excluded from the summary.
Time frame: Baseline (Day 1), at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change From Baseline in Hemoglobin (Hgb)
Blood samples were collected from all participants for measurement of Hgb values in g/dL. Baseline value was defined as the last non-missing value prior to the start date and time of the study medication (Day 1). Change from Baseline was calculated as the value at indicated time point minus the value at Baseline. Hgb results of participants with intercurrent events were excluded from the summary.
Time frame: Baseline (Day 1), at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Number of Participants With Hgb Values Above, Below and Within the Target Range (10 to 12 g/dL)
Number of participants with Hgb values above, below, and within the target range (10 to 12 g/dL) were assessed. Baseline assessment was defined as the last non-missing value prior to the start date and time of the study drug (Day 1). Hgb results of participants with intercurrent events were excluded from the summary.
Time frame: Baseline (Day 1), at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
Change in Daprodustat Dose From Starting Dose at Each Study Time Point
Daprodustat dose was adjusted, if required, one step at a time in the range of 1 to 24 mg, to maintain the target range for Hgb between 10 to 12 g/dL. Dose change values of daprodustat from starting dose at each study time point were calculated as dose level at indicated time point minus starting dose at Day 1 (Baseline).
Time frame: Day 1 (Baseline), at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48
Number of Participants With 0 to 10, or Greater Than (>) 10 Dose Adjustments
Number of participants who required daprodustat dose adjustments form the starting dose were assessed. Data were categorized for number of participants who required no dose change (0 times) to 10 times and \>10 times dose adjustments during the study.
Time frame: Up to Week 52
Daprodustat Dose at Each Study Time Point
Mean and standard deviation of daprodustat dose received by participants at each study time point has been presented.
Time frame: Baseline (Day 1), at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48
Maximum Plasma Concentration (Cmax) of Daprodustat
Blood samples were collected for the plasma concentrations of daprodustat from which pharmacokinetic (PK) parameters were determined. Mean and standard deviation of daprodustat Cmax at steady state obtained via modeling in each sub-trial (requiring Dialysis and not yet requiring Dialysis).
Time frame: Day 1: 1, 2 and 6 hours Post-dose; Week 2: Pre-dose and 1, 2 and 6 hours Post-dose
Area Under the Curve (AUC) at Steady State of Daprodustat
Blood samples were collected for the plasma concentrations of daprodustat from which PK parameters were determined. Mean and standard deviation of daprodustat AUC at steady state obtained via modeling in each sub-trial (requiring Dialysis and not yet requiring Dialysis).
Time frame: Day 1: 1, 2 and 6 hours Post-dose; Week 2: Pre-dose and 1, 2 and 6 hours Post-dose
Plasma Concentrations of Daprodustat and Metabolites at Pre-dose (Ctrough)
Blood samples were collected for the plasma concentrations of daprodustat and metabolites from which PK parameters were determined. Mean and standard deviation of raw daprodustat and metabolites (GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401) at steady state at pre-dose obtained via modeling in each sub-trial (requiring Dialysis and not yet requiring Dialysis).
Time frame: Pre-dose on Week 2
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