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Daprodustat Hepatic Impairment Study

Primary Purpose

Anaemia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Daprodustat (GSK1278863)

About this trial

This is an interventional treatment trial for Anaemia focused on measuring GSK1278863, Daprodustat, Healthy control, Single dose, Hepatic Impairment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

For all subjects:

Subject must be at least 18 years of age inclusive, at the time of signing the informed consent.
Hemoglobin values at screening <=16.0 gram per deciliter (g/dL) for males and <=14.0 g/dL for females.
Body weight >=45 kilograms (kg) and body mass index (BMI) within the range 18-40 kg per meter square (kg/m^2) (inclusive).
Male or female subjects will be included. A female subject is eligible to participate if she is not breastfeeding, and at least one of the following applies: Not pregnant as confirmed by two pregnancy tests; Not a woman of childbearing potential (WOCBP); For WOCBP that are currently utilizing a highly-effective contraceptive method prior to enrolment, agrees to follow the contraceptive guidance during the treatment period to the follow-up visit.
Capable of giving signed informed consent form.

Additional inclusion criteria for Hepatically-Impaired subjects:

Subjects in Part 1 with Moderate Hepatic Impairment Only (Cohort 1): Is considered to have moderate hepatic impairment (of any etiology) and has been clinically stable for at least 1 month prior to screening. To be classified as having moderate hepatic impairment, subjects must have a Child-Pugh (Class B) score of 7-9 AND previous confirmation of liver cirrhosis by liver biopsy or other medical imaging technique (including laparoscopy, computerized tomography (CT) scan, magnetic resonance imaging (MRI) or ultrasonography) associated with an unambiguous medical history (such as evidence of portal hypertension).
Subjects in Part 2 with Mild OR Severe Hepatic Impairment Only (Cohort 3; if conducted): Is considered to have mild or severe hepatic impairment (of any etiology) and has been clinically stable for at least 1 month prior to screening. To be classified as having mild OR severe hepatic impairment, subjects must have: classified as having mild hepatic impairment, subjects must have a Child- Pugh (Class A) score of 5-6 AND previous confirmation of chronic liver disease by liver biopsy or other medical imaging technique (including laparoscopy, CT scan, MRI or ultrasonography) associated with an unambiguous medical history (such as evidence of portal hypertension); classified as having severe hepatic impairment, subjects must have Child- Pugh (Class C) score of 10-13 AND previous confirmation of chronic liver disease by liver biopsy or other medical imaging technique (including laparoscopy, CT scan, MRI or ultrasonography) associated with an unambiguous medical history (such as evidence of portal hypertension).
Supplemental inclusion criteria for ALL hepatically-impaired subjects: Chronic (>6 months), stable (no acute episodes of illness due to deterioration in hepatic function within the previous 1 month prior to screening) hepatic impairment due to any etiology. Subjects must also remain stable throughout the Screening period. Assessment of the stability of the subjects hepatic function will be determined by the investigator.

Additional inclusion criteria for healthy control subjects:

Healthy control subjects will be matched for age +/-10 years to subjects in the respective hepatic impairment cohort but must also be at least 18 years of age inclusive, at the time of signing the informed consent.
Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator and/or the Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
Healthy control subjects will be matched for BMI +/-15% to subjects in the respective hepatic impairment cohort but must also remain in the range of body weight >=45 kg and BMI within the range 18-38 kg/m^2 (inclusive).

Exclusion Criteria:

For all subjects:

QT interval corrected for heart rate according to Fridericia's formula (QTcF) >500 milliseconds (msec).
Recent history of deep vein thrombosis, pulmonary embolism or other thrombosis related condition. Any prior medical history in these areas will be reviewed and approved by the PI and the sponsor's Medical Monitor on a case by case basis as needed.
Myocardial infarction or acute coronary syndrome, stroke or transient ischemic attack within the 12 weeks prior to enrollment.
Subjects with a pre-existing condition (other than liver disease) interfering with normal gastrointestinal anatomy or motility that could interfere with the absorption, metabolism, and/or excretion of daprodustat.
Subjects that have undergone cholecystectomy within the past 3 months.
Subjects with chronic inflammatory joint disease (example, scleroderma, systemic lupus erythematosis, rheumatoid arthritis).
History of malignancy within the prior 2 years or known kidney mass >3 centimeter (cm) (end stage renal disease subjects with impairment only) OR currently receiving treatment for cancer. ONLY exception is localized squamous cell or basal cell carcinoma of the skin definitively treated 12 weeks prior to enrollment.
Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
Current enrolment or past participation (i.e., administration of last dose of investigational study treatment) within the last 30 days (or 5 half-lives, whichever is longer) before Day 1 in this or any other clinical study involving an investigational study treatment or any other type of medical research.

Exclusion criteria for Hepatically-Impaired subjects:

Present of 8 times Upper limit of normal (ULN) elevations in Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), or bilirubin.
Subjects with any other medical condition which, in the judgment of the investigator and Medical Monitor, could jeopardize the integrity of the data derived from that subject or the safety of the subject.
Subjects with advanced ascites (Grade 3).
Subjects with refractory encephalopathy as judged by the investigator or significant Central Nervous System (CNS) disease (example dementia, or seizures) which the investigator considers will interfere with the informed consent, conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject.
Subjects with functional Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement.
Presence of hepatopulmonary or hepatorenal syndrome.
Presence of primarily cholestatic liver diseases.
History of liver transplantation.
Subjects with signs of active infection, including active spontaneous bacterial peritonitis.
Subjects with unstable cardiac function or subjects with hypertension whose blood pressure is not controlled (based on the investigator's discretion).
Diabetic subjects whose diabetes is not controlled (based on the investigator's discretion).

Exclusion criteria for healthy control subjects:

Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
Presence of Hepatitis B surface antigen (HBsAg) at screening or Positive Hepatitis C antibody test result at screening or within 3 months before the first dose of study treatment.
Positive pre-study drug/alcohol screen.
Positive human immunodeficiency virus (HIV) antibody test.
Regular use of known drugs of abuse.
Regular alcohol consumption within 6 months prior to the study defined as an average weekly intake of >14 drinks. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. One unit is equivalent to 8 g of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

Sites / Locations

GSK Investigational Site
GSK Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Experimental

Active Comparator

Arm Label

Subjects with moderate hepatic impairment: Part 1

Matched Healthy controls: Part 1

Subjects with either mild or severe hepatic impairment: Part 2

Matched healthy controls: Part 2

Arm Description

Approximately 8 subjects with moderate hepatic impairment will receive 6 mg of daprodustat as a single oral dose in the fasted state. This group will include at least one subject with a Child-Pugh score of 7, one with a score of 8 and one with a score of 9. The group will also include at least one female and at least one male subject.

Approximately 8 healthy controls, matched in gender, age and BMI to subjects with moderate hepatic impairment, will receive 6 mg of daprodustat as a single oral dose in the fasted state. The group will include at least one female and at least one male subject.

Approximately 8 subjects with mild or severe hepatic impairment will receive 6 mg of daprodustat as a single oral dose in the fasted state. This group will include at least one subject with a Child-Pugh score of 5 and one with a score of 6 for mild hepatic impairment and at least one subject with a Child-Pugh score of 10 or 11 and one with a score of 12 or 13 for severe hepatic impairment. The group will also include at least one female and at least one male subject.

Approximately 8 healthy controls, matched in gender, age and BMI to subjects with mild or severe hepatic impairment, will receive 6 mg of daprodustat as a single oral dose in the fasted state. The group will include at least one female and at least one male subject.

Outcomes

Primary Outcome Measures

Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-infinity]) of GSK1278863 and Its Metabolites

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK1278863 and its metabolites; GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), GSK2531398 (M6), and GSK2531401 (M13). Pharmacokinetic parameters were determined using standard non-compartmental methods. Pharmacokinetic Population comprised of all participants in the Safety Population for whom a pharmacokinetic sample was obtained and analyzed.

Part 2: AUC (0-infinity) of GSK1278863 and Its Metabolites

Part 1: Percentage of AUC (0-infinity) Obtained by Extrapolation (Percentage AUCex) of GSK1278863 and Its Metabolites

Part 2: Percentage AUCex of GSK1278863 and Its Metabolites

Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0-t]) of GSK1278863 and Its Metabolites

Part 2: AUC (0-t) of GSK1278863 and Its Metabolites

Part 1: Maximum Observed Concentration (Cmax) of GSK1278863 and Its Metabolites

Part 2: Cmax of GSK1278863 and Its Metabolites.

Part 1: Apparent Terminal Phase Half-life (t1/2) of GSK1278863 and Its Metabolites

Part 2: T1/2 of GSK1278863 and Its Metabolites

Part 1: Time of Occurrence of Cmax (Tmax) of GSK1278863 and Its Metabolites

Part 2: Tmax of GSK1278863 and Its Metabolites

Part 1: Unbound Concentration in Plasma of GSK1278863 and Its Metabolites

Part 2: Unbound Concentration in Plasma of GSK1278863 and Its Metabolites

Part 1: Unbound Fraction in Plasma of GSK1278863 and Its Metabolites

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK1278863 and its metabolites; GSK2391220 (M2), GSK2506104 (M3), GSK2487818, GSK2506102, GSK2531398 (M6), GSK2531401 (M13). Pharmacokinetic parameters were determined using standard non-compartmental methods. Unbound fraction is the percentage of unbound drug in plasma calculated as unbound concentration divided by total concentration.

Part 2: Unbound Fraction in Plasma of GSK1278863 and Its Metabolites

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK1278863 and its metabolites (GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), GSK2531398 (M6), GSK2531401 (M13)). Pharmacokinetic parameters were determined using standard non-compartmental methods. Unbound fraction is the percentage of unbound drug in plasma calculated as unbound concentration divided by total concentration.

Secondary Outcome Measures

Part 1: Maximum Observed Erythropoietin Concentration (Cmax, EPO) Following Administration of GSK1278863

Venous blood samples were collected for measurement of plasma EPO at the indicated time points. Pharmacodynamic Population comprised of all participants in the Safety Population who had at least one pharmacodynamic assessment.

Part 2: Cmax, EPO Following Administration of GSK1278863

Venous blood samples were collected for measurement of plasma EPO at the indicated time points following administration of GSK1278863.

Part 1: Time of the Maximum Observed Erythropoietin Concentration (Tmax, EPO) Following Administration of GSK1278863

Venous blood samples were collected for measurement of plasma EPO at the indicated time points following administration of GSK1278863.

Part 2: Tmax, EPO Following Administration of GSK1278863

Venous blood samples were collected for measurement of plasma EPO at the indicated time points following administration of GSK1278863.

Part 1: Erythropoietin Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the Last Time of Quantifiable Concentration (AUC [0-t, EPO]) Following Administration of GSK1278863

Venous blood samples were collected for measurement of plasma EPO at the indicated time points following administration of GSK1278863.

Part 2: AUC (0-t, EPO) Following Administration of GSK1278863

Venous blood samples were collected for measurement of plasma EPO at the indicated time points following administration of GSK1278863.

Part 1: Number of Participants With 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 treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation as per Medical or scientific judgment. Safety Population comprised of all participants who received at least one dose of study medication.

Part 2: Number of Participants With AEs and SAEs

Part 1: Number of Participants With Worst Case Hematology Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline

Blood samples were collected for analysis of hematocrit, hemoglobin, leukocytes, lymphocytes, neutrophils and platelets. PCI ranges were <0.075 or >0.54 proportion of red blood cells in blood for hematocrit, <25 or >180 grams per liter (g/L) for hemoglobin, <3 or >20 x10^9 cells per liter (cells/L) for leukocytes, <0.8 x10^9 cells/L for lymphocytes, <1.5 x10^9 cells/L for neutrophils, and <100 or >550 x10^9 cells/L for platelet. Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (example given [e.g.], High to High), or whose value became within range, were recorded in "To within Range or No Change" category. Participants were counted twice if the participant has values that changed 'To Low' and 'To High', so the percentages may not add to 100%. Baseline is defined as latest non-missing scheduled pre-dose assessment.

Part 2: Number of Participants With Worst Case Hematology Results Relative to PCI Criteria Post-Baseline Relative to Baseline

Blood samples were collected for analysis of hematocrit, hemoglobin, leukocytes, lymphocytes, neutrophils and platelets. PCI ranges were <0.075 or >0.54 proportion of red blood cells in blood for hematocrit, <25 or >180 g/L for hemoglobin, <3 or >20 x10^9 cells/L for leukocytes, <0.8 x10^9 cells/L for lymphocytes, <1.5 x10^9 cells/L for neutrophils, and <100 or >550 x10^9 cells/L for platelet. Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in "To within Range or No Change" category. Participants were counted twice if the participant has values that changed 'To Low' and 'To High', so the percentages may not add to 100%. Baseline is defined as latest non-missing scheduled pre-dose assessment.

Part 1: Number of Participants With Worst Case Chemistry Results Relative to PCI Criteria Post-Baseline Relative to Baseline

Blood samples were collected for analysis of following parameters. PCI ranges were <30g/L (albumin), <2 or >2.75 millimoles/L(mmol/L) (calcium), <3 or >9mmol/L(glucose), >=2 times Upper limit of Normal(ULN) units/L(U/L) (alanine aminotransferase [ALT]), >=2 times ULN U/L (alkaline phosphatase), >=2 times ULN U/L(aspartate aminotransferase [AST]), >=1.5 times ULN micromoles/L (µmol/L)(bilirubin), <3 or >5.5mmol/L(potassium), and <130 or >150mmol/L(sodium). Participants were counted in worst case category that their value changes to (low,within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in To within Range or No Change category. Participants were counted twice if participant has values that changed To Low and To High, so the percentages may not add to 100%. Baseline is defined as latest non-missing scheduled pre-dose assessment.

Part 2: Number of Participants With Worst Case Chemistry Results Relative to PCI Criteria Post-Baseline Relative to Baseline

Blood samples were collected for analysis of following parameters. PCI ranges were <30g/L (albumin), <2 or >2.75 mmol/L (calcium), <3 or >9mmol/L (glucose), >=2 times ULN U/L (ALT), >=2 times ULN U/L (alkaline phosphatase), >=2 times ULN U/L (AST), >=1.5 times ULN µmol/L (bilirubin), <3 or >5.5 mmol/L (potassium), and <130 or >150 mmol/L (sodium). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High), or whose value became within range, were recorded in To within Range or No Change category. Participants were counted twice if the participant has values that changed To Low and To High, so the percentages may not add to 100%. Baseline is defined as latest non-missing scheduled pre-dose assessment.

Part 1: Number of Participants With Abnormal Urinalysis Findings

Urine samples were collected at indicated time points for the analysis of urine parameters including specific gravity and Potential of hydrogen (pH) of urine, presence of glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte esterase in urine.

Part 2: Number of Participants With Abnormal Urinalysis Findings

Full Information

NCT ID

NCT03223337

First Posted

July 18, 2017

Last Updated

August 30, 2019

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT03223337

Brief Title

Daprodustat Hepatic Impairment Study

Official Title

A Phase 1, Open-label, Non-randomized, Parallel Group, Single-dose Adaptive Study in Adults With Hepatic Impairment and Matched, Healthy Control Participants With Normal Hepatic Function

Study Type

Interventional

2. Study Status

Record Verification Date

August 2019

Overall Recruitment Status

Completed

Study Start Date

July 24, 2017 (Actual)

Primary Completion Date

August 20, 2018 (Actual)

Study Completion Date

August 20, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Daprodustat (GSK1278863), is a small molecule currently in development for the treatment of anemia of chronic kidney disease (CKD). Results of the earlier studies shows that liver is involved in the clearance of Daprodustat and hence, hepatic impairment can affect Daprodustat levels in the body. This single dose study will assess the effect of liver impairment on the pharmacokinetics (PK) and pharmacodynamics (PD) of daprodustat. The study will be conducted in two parts, Part 1 will include subjects with moderate hepatic impairment and matched healthy control subjects whereas Part 2 will include subjects will either mild or severe hepatic impairment and matched healthy control subjects. Approximately 8 subjects will be included in each of the group and all subjects will receive 6 milligram (mg) of daprodustat as a single oral dose in the fasted state. Total duration of participation in the study for a subject will be up to 7 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Anaemia

Keywords

GSK1278863, Daprodustat, Healthy control, Single dose, Hepatic Impairment

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Model Description

All subjects will receive 6 mg of daprodustat as a single oral dose in parallel way throughout the study period.

Masking

None (Open Label)

Masking Description

This will be an open-label study and no blinding will be performed.

Allocation

Non-Randomized

Enrollment

37 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Subjects with moderate hepatic impairment: Part 1

Arm Type

Experimental

Arm Description

Arm Title

Matched Healthy controls: Part 1

Arm Type

Active Comparator

Arm Description

Arm Title

Subjects with either mild or severe hepatic impairment: Part 2

Arm Type

Experimental

Arm Description

Arm Title

Matched healthy controls: Part 2

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Daprodustat (GSK1278863)

Intervention Description

Daprodustat (GSK1278863) 6 mg tablet will be given to all subjects as a single dose via oral route. Daprodustat (GSK1278863) is a 9.0 millimeter (mm) round, compound radius, white film coated tablet.

Primary Outcome Measure Information:

Title

Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-infinity]) of GSK1278863 and Its Metabolites

Description

Time Frame