Clinical trial NCT02509624: Study to Evaluate the Pharmacokinetics of Selonsertib in Participants With Normal and Impaired Hepatic Function
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diabetic Kidney Disease
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2015-07-28
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Pharmacokinetic (PK) Parameter: AUCinf of Selonsertib and Its Metabolite GS-607509
timeFrame: 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.
measure: PK Parameter: AUClast of Selonsertib and Its Metabolite GS-607509
timeFrame: 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.
measure: PK Parameter: Cmax of Selonsertib and Its Metabolite GS-607509
timeFrame: 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 outcomes:
measure: Percentage of Participants Experiencing Treatment-Emergent Study Drug-related Adverse Events (AEs)
timeFrame: Day 1 plus 30 days
measure: Percentage of Participants Experiencing Any Treatment-Emergent and Grade ≥ 3 Laboratory Abnormalities
timeFrame: Day 1 plus 30 days
Other outcomes:
Locations:
city: Denver
country: United States
state: Colorado
city: Miami
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Minneapolis
country: United States
state: Minnesota
city: San Antonio
country: United States
state: Texas
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References: