Clinical trial NCT03223337: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Anaemia
Keywords: GSK1278863
Daprodustat
Healthy control
Single dose
Hepatic Impairment
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-07-21
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: All subjects will receive 6 mg of daprodustat as a single oral dose in parallel way throughout the study period.
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: 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
timeFrame: 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
measure: Part 2: AUC (0-infinity) of GSK1278863 and Its Metabolites
timeFrame: 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
measure: Part 1: Percentage of AUC (0-infinity) Obtained by Extrapolation (Percentage AUCex) of GSK1278863 and Its Metabolites
timeFrame: 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
measure: Part 2: Percentage AUCex of GSK1278863 and Its Metabolites
timeFrame: 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
measure: 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
timeFrame: 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
measure: Part 2: AUC (0-t) of GSK1278863 and Its Metabolites
timeFrame: 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
measure: Part 1: Maximum Observed Concentration (Cmax) of GSK1278863 and Its Metabolites
timeFrame: 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
measure: Part 2: Cmax of GSK1278863 and Its Metabolites.
timeFrame: 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
measure: Part 1: Apparent Terminal Phase Half-life (t1/2) of GSK1278863 and Its Metabolites
timeFrame: 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
measure: Part 2: T1/2 of GSK1278863 and Its Metabolites
timeFrame: 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
measure: Part 1: Time of Occurrence of Cmax (Tmax) of GSK1278863 and Its Metabolites
timeFrame: 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
measure: Part 2: Tmax of GSK1278863 and Its Metabolites
timeFrame: 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
measure: Part 1: Unbound Concentration in Plasma of GSK1278863 and Its Metabolites
timeFrame: 3 hours, 12 hours and 24 hours post-dose
measure: Part 2: Unbound Concentration in Plasma of GSK1278863 and Its Metabolites
timeFrame: 3 hours, 12 hours and 24 hours post-dose
measure: Part 1: Unbound Fraction in Plasma of GSK1278863 and Its Metabolites
timeFrame: 3 hours, 12 hours and 24 hours post-dose
measure: Part 2: Unbound Fraction in Plasma of GSK1278863 and Its Metabolites
timeFrame: 3 hours, 12 hours and 24 hours post-dose
Secondary outcomes:
measure: Part 1: Maximum Observed Erythropoietin Concentration (Cmax, EPO) Following Administration of GSK1278863
timeFrame: 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
measure: Part 2: Cmax, EPO Following Administration of GSK1278863
timeFrame: 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
measure: Part 1: Time of the Maximum Observed Erythropoietin Concentration (Tmax, EPO) Following Administration of GSK1278863
timeFrame: 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
measure: Part 2: Tmax, EPO Following Administration of GSK1278863
timeFrame: 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
measure: 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
timeFrame: 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
measure: Part 2: AUC (0-t, EPO) Following Administration of GSK1278863
timeFrame: 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
measure: Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 16 days
measure: Part 2: Number of Participants With AEs and SAEs
timeFrame: Up to 16 days
measure: Part 1: Number of Participants With Worst Case Hematology Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline
timeFrame: Baseline (Screening) and up to Day 16
measure: Part 2: Number of Participants With Worst Case Hematology Results Relative to PCI Criteria Post-Baseline Relative to Baseline
timeFrame: Baseline (Screening) and up to Day 16
measure: Part 1: Number of Participants With Worst Case Chemistry Results Relative to PCI Criteria Post-Baseline Relative to Baseline
timeFrame: Baseline (Screening) and up to Day 16
measure: Part 2: Number of Participants With Worst Case Chemistry Results Relative to PCI Criteria Post-Baseline Relative to Baseline
timeFrame: Baseline (Screening) and up to Day 16
measure: Part 1: Number of Participants With Abnormal Urinalysis Findings
timeFrame: Up to Day 16
measure: Part 2: Number of Participants With Abnormal Urinalysis Findings
timeFrame: Up to Day 16
Other outcomes:
Locations:
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.