Daprodustat Hepatic Impairment Study | NCT03223337

NCT03223337

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Subjects with moderate hepatic impairment: Part 1	Experimental	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.	Drug: Daprodustat (GSK1278863)
Matched Healthy controls: Part 1	Active Comparator	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.	Drug: Daprodustat (GSK1278863)
Subjects with either mild or severe hepatic impairment: Part 2	Experimental	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.	Drug: Daprodustat (GSK1278863)
Matched healthy controls: Part 2	Active Comparator	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.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Daprodustat (GSK1278863)	Drug	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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	Pre-dose, 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours post-dose
Part 2: 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.	Pre-dose, 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours post-dose
Part 1: Percentage of AUC (0-infinity) Obtained by Extrapolation (Percentage AUCex) 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.	Pre-dose, 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours post-dose
Part 2: Percentage AUCex 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.

Secondary Outcomes

Measure	Description	Time Frame
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.	Pre-dose, 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, and 48 hours post-dose

Eligibility Module

Eligibility Criteria

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.

Contacts/Locations Module

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Miami	Florida	33136	United States
GSK Investigational Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
35355447	Derived	Mahar KM, Shaddinger BC, Ramanjineyulu B, Andrews S, Caltabiano S, Lindsay AC, Cobitz AR. Pharmacokinetics of Daprodustat and Metabolites in Individuals with Normal and Impaired Hepatic Function. Clin Pharmacol Drug Dev. 2022 May;11(5):562-575. doi: 10.1002/cpdd.1090. Epub 2022 Mar 30.

IPD Sharing Statement Module

No data available

No data is available for this block.

All participants received 6 milligrams (mg) of daprodustat (GSK1278863) as a single oral dose in the fasted state. A total number of 16 participants were enrolled in Part 1 and 21 participants were enrolled in Part 2 of the study. In total 37 participants were enrolled in the study.

Arm/Group Information

ID	Title	Description
FG000	Part 1: Moderate Hepatic Impairment Participants	Participants with moderate hepatic impairment received 6 mg of GSK1278863 as a single oral dose tablet in the fasted state during Part 1 of the study. This group included at least one participant with a Child-Pugh score of 7, 8 and 9 for moderate hepatic impairment.
FG001	Part 1: Healthy Participants	Healthy control participants, matched to moderate hepatic impairment participants in gender, age and Body mass index (BMI) received 6 mg of GSK1278863 as a single oral dose tablet in the fasted state.
FG002	Part 2: Mild Hepatic Impairment Participants	Participants with mild hepatic impairment received 6 mg of GSK1278863 as a single oral dose tablet in the fasted state during part 2 of the study. This group included at least one participant with a Child-Pugh score of 5 and 6 for mild hepatic impairment.
FG003	Part 2: Healthy Participants	Healthy control participants, matched to mild hepatic impairment participants in gender, age and BMI received 6 mg of GSK1278863 as a single oral dose tablet in the fasted state in part 2 of the study.

Periods

Title

Milestones

Reasons Not Completed

Part 1 (Up to 16 Days)

Type	Comment	Milestone Data
STARTED		FG0008 subjects FG0018 subjects FG0020 subjects FG0030 subjects
COMPLETED		FG0008 subjects FG0018 subjects FG0020 subjects FG0030 subjects
NOT COMPLETED		FG0000 subjects FG0010 subjects FG0020 subjects FG0030 subjects

Part 2 (Up to 16 Days)

Type	Comment	Milestone Data
STARTED		FG0000 subjects FG0010 subjects FG00212 subjects FG003

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Part 1: Moderate Hepatic Impairment Participants	Participants with moderate hepatic impairment received 6 mg of GSK1278863 as a single oral dose tablet in the fasted state during Part 1 of the study. This group included at least one participant with a Child-Pugh score of 7, 8 and 9 for moderate hepatic impairment.
BG001

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

Pharmacokinetic Population

Posted

Geometric Mean

Geometric Coefficient of Variation

Hour*nanogram per milliliter

Pre-dose, 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours post-dose

ID	Title	Description
OG000	Part 1: Moderate Hepatic Impairment Participants

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Part 1: Moderate Hepatic Impairment Participants	Participants with moderate hepatic impairment received 6 mg of GSK1278863 as a single oral dose tablet in the fasted state during Part 1 of the study. This group included at least one participant with a Child-Pugh score of 7, 8 and 9 for moderate hepatic impairment.

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Toothache	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
GSK Response Center	GlaxoSmithKline	866-435-7343		GSKClinicalSupportHD@gsk.com

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
SAP	No	Yes	No	Statistical Analysis Plan	Nov 22, 2017	Mar 4, 2019	SAP_000.pdf
Prot	Yes	No	No	Study Protocol	May 23, 2017	Mar 5, 2019	Prot_001.pdf

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

ID	Term
D000740	Anemia

ID	Term
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases

Intervention Browse Module

ID	Term
C000599718	GSK1278863

Masking Info

Matched Healthy controls: Part 1
Matched healthy controls: Part 2
Subjects with either mild or severe hepatic impairment: Part 2
Subjects with moderate hepatic impairment: Part 1

EG0000 affected8 at risk

EG0011 affected8 at risk

EG0020 affected12 at risk

EG0030 affected9 at risk

OG0010.4176± 0.38893

OG0010.8105± 1.60084

OG0013.50(2.0 to 4.0)

OG0013.00(2.0 to 4.0)

Mean and Standard Deviation were not calculable because concentration values were below detectable levels, but were imputed in the analysis.

OG001NA± NAMean and Standard Deviation were not calculable because concentration values were below detectable levels, but were imputed in the analysis.

OG0010.15692± 0.138726

OG0010.0028± 0.00019

OG0010.0032± 0.00090