Evaluate the Pharmacokinetics of GS-9876 in Subjects with Impaired Renal Function
A Phase 1 Open-Label Study to Evaluate the Pharmacokinetics of GS-9876 in Subjects with Impaired Renal Function
Gilead Sciences, Inc
60 participants
Nov 21, 2016
Interventional
Conditions
Summary
This is a Phase 1, open-label, parallel-group, adaptive, single-dose, multi-center, pharmacokinetic study in subjects with renal impairment and matched healthy controls. A maximum of 60 subjects using an adaptive design that includes up to 3 enrolled cohorts. Adaptive Cohorts 2 and/or 3 will be enrolled as determined by safety and/or PK data in Cohort 1. Specifically, Cohort 2 (Severe Renal Impairment) will be evaluated if supported by safety and/or PK data from Cohort 1 (Moderate Renal Impairment). Cohort 3 (Mild Renal Impairment) will be evaluated if supported by safety and if substantial changes (>=2-fold mean difference from matched controls) in the exposure of GS-9876 is observed in subjects with moderate renal impairment in Cohort 1. Cohorts 2 and 3 may not be enrolled or may be enrolled sequentially or in parallel, as governed by safety and PK data in Cohort 1. Each control subject may be matched to multiple renal impaired subjects across different cohorts and can be matched to only 1 renal impaired subject within a cohort.
Eligibility
Inclusion Criteria39
- All Subjects:
- Have the ability to understand and sign a written informed consent form (ICF), which must be obtained prior to initiation of study procedures
- Be between 18 through 75 years of age, inclusive at screening
- Must be able to comply with the smoking restrictions at the study site.
- Have a calculated body mass index (BMI) of >=18 kg/m2 and <=36 kg/m2 at screening
- Females of childbearing potential must have a negative serum pregnancy test at screening and clinic admission (Day -1).
- Female subjects must refrain from egg donation and in vitro fertilization during treatment and until at least 36 days after the last dose of study drug.
- Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception.
- Male subjects must refrain from sperm donation from clinic admission (eg, Day -1),
- throughout the study period, and continuing for at least 90 days following the last dose of study drug
- Subjects have not donated blood within 56 days of study entry or plasma within 7 days of study entry and must refrain from blood donation from clinic admission, throughout the study period, and continuing for at least 30 days following the last dose of study drug.
- Have either a normal 12-lead ECG or one with abnormalities that are considered clinically insignificant by the investigator in consultation with the sponsor
- Must be willing and able to comply with all study requirements
- Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs
- Subjects must have the following laboratory parameters at screening:
- a) Hemoglobin >=8.0 g/dL (International System of Units [SI]: <80 g/L)
- b) White blood cells >=3.0 x 10^3 cells/mm3 (SI: <3.0 x 10^9 cells/L)
- c) Neutrophils >=1.5 x 10^3 cells/mm3 (SI: <1.5 x 10^9 cells/L)
- d) Lymphocytes >=0.5 x 10^3 cells/mm3 (SI: <0.5 x 10^9 cells/L)
- e) Platelets >=100 x 10^3 cells/mm3 (SI: <100 x 10^9 cells/L)
- f) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <1.5 x ULN
- g) Total bilirubin level <2 x ULN
- Subjects with Renal Impairment:
- Must have diagnosis of chronic (>6 months), stable renal impairment with no clinically
- significant change in renal function status within 90 days prior to study drug administration (Day 1).
- Have a creatinine clearance (CLcr) =<90 mL/min (using the Cockcroft-Gault method
- based on serum creatinine and actual body weight as measured at screening, ie,
- Male: (140 – Age [years]) x (Weight [kg]) / 72 x (Serum Creatinine [mg/dL]) = CLcr (mL/min)
- Female: (140 – Age [years]) x (Weight [kg]) / 72 x (Serum Creatinine [mg/dL]) x 0.85 = CLcr (mL/min)
- Mild: CLcr 60-89 mL/min
- Moderate: CLcr 30-59 mL/min
- Severe: CLcr 15-29 mL/min
- Healthy Matched Controlled Subjects (Normal Renal Function):
- Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs.
- Have a creatinine clearance (CLcr) >=90 mL/min (using the Cockcroft-Gault method
- based on serum creatinine and actual body weight as measured at screening, ie,
- Male: (140 – Age [years]) x (Weight [kg]) / 72 x (Serum Creatinine [mg/dL]) = CLcr (mL/min)
- Female: (140 – Age [years]) x (Weight [kg]) / 72 x (Serum Creatinine [mg/dL]) x 0.85 = CLcr (mL/min)
- Match in age (+/- 10 years), gender, and body mass index (+/- 20%, 18 kg/m2 =< BMI =<36 kg/m2).
Exclusion Criteria38
- All Subjects:
- Be a lactating female
- Have received any investigational compound within 30 days prior to study dosing
- Have current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance or subject safety as judged by the investigator
- Have a positive test result for human immunodeficiency virus type 1 (HIV-1) antibody,
- hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus
- (HCV) antibody
- Have poor venous access that limits phlebotomy
- Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to screening or is expected to receive these agents during the study (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies)
- Have a history of any of the following:
- a) Significant serious skin disease, such as but not limited to rash, food allergy, eczema,
- psoriasis, or urticaria
- b) Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
- c) Known hypersensitivity to the study drugs, their metabolites or to formulation excipients
- d) Significant cardiac disease (including history of myocardial infarction based on ECG
- and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or
- dilated cardiomyopathy with left ventricular ejection fraction <40%), a family history of
- long QT syndrome, or unexplained death in an otherwise healthy individual between the
- ages of 1 and 30 years
- e) Syncope, palpitations, or unexplained dizziness
- f) Implanted defibrillator or pacemaker
- g) Liver disease, including Gilbert disease
- h) Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid
- hypersecretory conditions requiring prolonged (>6 months) medical treatment.
- i) Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or intestinal surgery). A history of cholecystectomy is not exclusionary.
- j) History of any major bleeding event defined as Grade 3 severity and above (as defined by the modified CTCAE 4.03) within the last year or personal or family history of bleeding disorder
- k) Current use of chronic anticoagulant or anti-platelet agent, not including daily aspirin for cardiac prophylaxis.
- Have any serious or active medical or psychiatric illness (including depression) that, in the opinion of the investigator, would interfere with subject treatment, assessment, or compliance with the protocol. This would include cardiac, hematological, hepatic, pulmonary (including chronic asthma), endocrine (including diabetes), central nervous, gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), immunodeficiency disorders, active infection, or malignancy that are clinically significant or requiring treatment.
- Recent significant changes in the use of nicotine or nicotine containing products
- (ie, initiation, substantial increase or decrease or cessation of use) in the 90 days prior to
- study drug dosing, or anticipated significant changes in the use of nicotine or nicotine
- containing products during the course of the study through the follow-up visit.
- Subjects with Renal Impairment:
- Require or are anticipated to require dialysis within 90 days of study dosing
- Require during the study or have received moderate or strong inhibitors or inducers of
- CYP3A within 2 weeks prior to study drug administration.
- Healthy Matched Controlled Subjects (Normal Renal Function):
- Have taken any prescription medications or over-the-counter medications, including herbal products and antacids, within 28 days prior to start of study drug dosing, with the exception of vitamins and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive medications and/or stable hormone replacement therapy in peri- /post-menopausal females
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Interventions
Cohort 1 (Moderate Renal Impairment): single oral dose of GS-9876 20 mg (2 × 10 mg tablet) in a fasted state on Day 1. Adaptive Cohort 2 (Severe Renal Impairment): single oral dose of GS-9876 20 mg (2 × 10 mg tablet) in a fasted state on Day 1. Adaptive Cohort 3 (Mild Renal Impairment): single oral dose of GS-9876 20 mg (2 × 10 mg tablet) in a fasted state on Day 1. Based on safety and PK results from subjects with moderate renal impairment (Cohort 1), subjects with severe renal impairment (Cohort 2) and/or mild renal impairment (Cohort 3) will be enrolled. Cohorts 2 and 3 may not be enrolled or may be enrolled sequentially or in parallel, as governed by safety and PK data in Cohort 1. Dose administered following an overnight fast of at least 8 hours (no food or drink except water), study drug will be administered in the morning with 240 mL of water. Subjects will continue to fast until after collection of the 4-hour PK sample, relative to study drug dosing. Additionally, subjects will be restricted from water consumption 1 hour before until 2 hours after dosing, except for the 240 mL given with the study treatment. The investigator will maintain an accurate inventory of all study drug(s). Each dose of the study drug(s) administered at the study center will be administered by qualified study center staff. The dose of study drug(s) administered to subjects in the clinic under the supervision of staff will be accurately recorded, which indicates the date and quantity of each dosage formulation dispensed to individual subjects. Used and unused study drug supplies, including empty containers, are to be returned to the shipping facility from which it came for destruction following drug accountability and drug inventory reconciliation.
Locations(3)
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ACTRN12616001548426