Study to Evaluate the Pharmacokinetics of Selonsertib in Participants With Normal and Impaired Hepatic Function

A Phase 1, Open-Label, Parallel-Group, Single Dose Study to Evaluate the Pharmacokinetics of GS-4997 in Subjects With Normal and Impaired Hepatic Function

The primary objective of this study is to evaluate the pharmacokinetics (PK) of selonsertib in participants with impaired hepatic function relative to matched, healthy controls.

Study Overview

• Status: Completed
• Conditions: Diabetic Kidney Disease
• Intervention / Treatment: Drug: Selonsertib

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States
  • Florida
    • Miami, Florida, United States
    • Orlando, Florida, United States
  • Minnesota
    • Minneapolis, Minnesota, United States
  • Texas
    • San Antonio, Texas, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

All participants:

• Body mass index (BMI) from 18 to 40 kg/m^2, inclusive at study screening
• Creatinine clearance (CrCl) ≥ 60 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening

Participants with impaired hepatic function:

• Aside from hepatic insufficiency, participants must be sufficiently healthy for study participation based upon screening evaluations.
• Must have diagnosis of chronic (> 6 months), stable hepatic impairment with no clinically significant change in hepatic status within the 3 months (90 days) prior to study drug administration (Day 1).
• Participants with severe hepatic impairment must have a score on the Child-Pugh-Turcotte scale of 10-15 at screening.
• Participants with moderate hepatic impairment must have a score on the Child-Pugh-Turcotte scale of 7-9 at screening.
• Participants with mild hepatic impairment must have a score on the Child-Pugh-Turcotte scale of 5-6 at screening.

Healthy participants (matched control):

• Must be in good health based upon screening evaluations.

Key Exclusion Criteria:

All participants:

• Pregnant or lactating females
• Have received any investigational compound or device within 30 days prior to study dosing
• Current alcohol or substance abuse
• A positive test result for human immunodeficiency virus (HIV-1/2) antibody
• Have poor venous access that limits phlebotomy
• Have been treated with systemic steroids, anti-HIV agents, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to screening or expected to receive these agents during the study (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies) that would be contraindicated for other exclusion criteria.
• Significant serious skin disease, such as but not limited to rash, food allergy, eczema, psoriasis, or urticaria
• Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
• Unstable cardiac disease, including history of myocardial infarction within 1 year of screening, recurrent episodes of ventricular tachycardia despite appropriate medical therapy, decompensated congestive heart failure, or dilated cardiomyopathy with left ventricular ejection fraction < 40%, or a family history of Long QT Syndrome, or unexplained death in an otherwise healthy participants between the ages of 1 and 30 years.
• Syncope, palpitations, or unexplained dizziness
• Implanted defibrillator or pacemaker
• Severe peptic ulcer disease, severe gastroesophageal reflux disease, or other severe gastric acid hypersecretory conditions
• Medical or surgical treatment that permanently alters gastric absorption (eg, gastric or intestinal surgery). A history of cholecystectomy is not exclusionary.
• History of prior allogeneic bone marrow progenitor cell or solid organ transplantation.
• Currently registered on an organ transplantation list.
• History of bleeding from esophageal varices within 90 days prior to Admission (Day -1).
• Use of strong cytochrome P3A4 (CYP3A4) inhibitors (eg, indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, suboxone, telithromycin, atazanavir) and strong CYP3A4 inducers (eg, carbamazepine, rifampin, phenytoin and St. John's wort), within 28 days prior to study drug administration (Day 1).
• Consumption of grapefruit juice, grapefruits, and Seville orange juice within 2 weeks prior to study drug administration (Day 1).
• Recent significant changes in the use of nicotine or nicotine containing products

Participants with impaired hepatic function:

• Aside from hepatic insufficiency, serious or active medical or psychiatric illness that, in the opinion of the investigator, would interfere with treatment, assessment, or compliance with the protocol.
• Chronic hepatitis B virus (HBV) infection, defined as a positive test for hepatitis B surface antigen (HBsAg), unless the participant has been treated with a nucleos(t)ide analog (eg, tenofovir or entecavir) for at least 6 months and the HBV deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR) assay has been persistently undetectable for at least 6 months.
• Positive test for drugs of abuse, including alcohol at screening or on Day -1/check-in, with the exception of opioids and tetrahydrocannabinol (THC, marijuana) under prescription and investigator verification for pain management. Participants who screen positive for benzodiazepines may be allowed if prescribed under the care of a physician and after review by investigator and Sponsor.
• Requires paracentesis > 1 time per month.
• Participants with hepatic impairment with co-morbid diseases not associated with hepatic impairment requiring medication(s) must be taking the medication(s) without a change in dose for > 3 months prior to screening.
• Changes in concomitant medications or dosage used to treat symptoms of hepatic impairment or associated co-morbid conditions that could lead to clinically significant changes in medical conditions during the course of the study that would affect the ability to interpret potential drug-drug interactions within 28 days prior to dosing.

Healthy participants (matched control):

• A positive test result for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (anti-HBc)
• Positive test for drugs of abuse, including alcohol at screening or on Day -1/check-in.
• Have any serious or active medical or psychiatric illness (including depression) which, in the opinion of the investigator, would interfere with treatment, assessment, or compliance with the protocol.
• History of liver disease.
• Have taken any prescription medications or over-the-counter medications including herbal products within 28 days of commencing study drug dosing with the exception of vitamins, acetaminophen, ibuprofen, and hormonal contraceptive medications.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Moderate hepatic impairment (Cohort 1); Participants with moderate hepatic impairment and matched healthy controls will receive a single dose of selonsertib on Day 1.	Drug: Selonsertib; 6 mg tablets administered orally in fed state; Other Names: GS-4997
Experimental: Severe hepatic impairment (Cohort 2); Participants with severe hepatic impairment and matched healthy controls will receive a single dose of selonsertib on Day 1.	Drug: Selonsertib; 6 mg tablets administered orally in fed state; Other Names: GS-4997
Experimental: Mild hepatic impairment (Cohort 3); Participants with mild hepatic impairment and matched healthy controls will receive a single dose of selonsertib on Day 1.	Drug: Selonsertib; 6 mg tablets administered orally in fed state; Other Names: GS-4997

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) Parameter: AUCinf of Selonsertib and Its Metabolite GS-607509	AUCinf is defined as the concentration of drug extrapolated to infinite time.	0 (predose), 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1. Additional PK samples were collected at the Day 10 and 14 follow-up visits approximately the same time as the Day 1 predose sample.
PK Parameter: AUClast of Selonsertib and Its Metabolite GS-607509	AUClast is defined as the concentration of drug from time zero to the last observable concentration.	0 (predose), 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1. Additional PK samples were collected at the Day 10 and 14 follow-up visits approximately the same time as the Day 1 predose sample.
PK Parameter: Cmax of Selonsertib and Its Metabolite GS-607509	Cmax is defined as the maximum concentration of drug.	0 (predose), 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1. Additional PK samples were collected at the Day 10 and 14 follow-up visits approximately the same time as the Day 1 predose sample.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Experiencing Treatment-Emergent Study Drug-related Adverse Events (AEs)	An AE was any untoward medical occurrence in a clinical study participant which did not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Treatment-emergent AEs were defined as events that met one of the following criteria: 1) Any AEs with an onset date of on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug; or 2) Any AEs leading to premature discontinuation of study drug.	Day 1 plus 30 days
Percentage of Participants Experiencing Any Treatment-Emergent and Grade ≥ 3 Laboratory Abnormalities	Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from predose at any postdose visit, up to and including the date of last dose of study drug plus 30 days for participants who permanently discontinued study drug. If the relevant baseline laboratory value was missing, then any abnormality of at least Grade 1 observed within the time frame specified above was considered treatment-emergent. Severity grades were defined based on modified Common Terminology Criteria for Adverse Events (CTCAE) Laboratory Abnormality and Adverse Event Severity Grading, where 1=Mild, 2=Moderate, 3=Severe, 4=Potentially Life Threatening. The most severe graded abnormality from all tests was counted for each participant.	Day 1 plus 30 days

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2015
• Primary Completion (Actual): December 15, 2015
• Study Completion (Actual): December 15, 2015

Study Registration Dates

• First Submitted: July 16, 2015
• First Submitted That Met QC Criteria: July 24, 2015
• First Posted (Estimate): July 28, 2015

Study Record Updates

• Last Update Posted (Actual): January 27, 2021
• Last Update Submitted That Met QC Criteria: January 7, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Kidney Diseases; Diabetic Nephropathies; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Selonsertib
• Other Study ID Numbers: GS-US-223-1018; 2015-002444-14 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No