A study to evaluate safety and tolerability of GS -5801 in healthy subjects
A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-5801, and the Effect of Food on GS-5801 Pharmacokinetics in Healthy Subjects
Gilead Sciences, Inc.
70 participants
Sep 26, 2016
Interventional
Conditions
Summary
This study will proceed in three parts, governed within and between parts by reviews of safety data and application of stopping rules. Based on safety and available pharmacokinetic (PK) and pharmacodynamic (PD) data, and at the discretion of the sponsor in consultation with the investigator, the adaptive cohorts may be repeated at the same dose level, be held until further data are available, or not be initiated at all. Part A will proceed in 3 staggered pre-specified cohorts. Within each cohort, 10 unique subjects will be randomized 4:1 to receive either blinded GS-5801 (N=8) or matching placebo (N=2). All study drugs in Part A will be administered in a fasted state. Part B: Based on available safety, PK, and PD data from cohorts in Part A, doses for Part B (Cohorts 4 - 6) will be selected between 2 and 100 mg. Within each cohort, 10 unique subjects will be randomized 4:1 to receive either active GS-5801 (N=8) or matching placebo (N=2). Within each cohort, subjects may be administered up to 100 mg GS-5801 once daily in either the fed or fasted state. Part C: The dose of GS-5801 selected for evaluation in Cohort 7 will be determined based on review of available safety, PK, and PD data from Cohorts in Part A and/or B and will not exceed a dose previously evaluated in Parts A or B. 10 unique subjects will receive a single dose of GS-5801 (up to 100 mg) administered in the fasted state on Day 1, followed by a 6-day washout, and a second single dose of GS-5801 (up to 100 mg) administered with a moderate-fat-calorie breakfast.
Eligibility
Inclusion Criteria17
- Have the ability to understand and sign a written informed consent form (ICF), which must be obtained prior to initiation of study procedures.
- Be aged 18 through 45 years of age, inclusive at screening
- Be a nonsmoker. The use of nicotine or nicotine-containing products must be discontinued 90 days prior to the first dose of study drug
- Have a calculated body mass index (BMI) of >=19.0 and =<30.0 kg/m2 at screening
- 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)
- Females of childbearing potential must have a negative serum pregnancy test at screening and clinic admission
- 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.
- Screening laboratory and 12-lead ECG evaluations must be without clinically significant abnormalities as assessed by the investigator
- Have liver disease or liver function tests such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin below the upper limit of normal at screening
- 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.
Exclusion Criteria21
- Be a pregnant or lactating female
- Have received any study drug 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
- Have a positive test result for human immunodeficiency virus type 1 (HIV-1) antibody,
- hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody
- Have poor venous access that limits phlebotomy
- Have taken any prescription medications or over-the-counter medications, including herbal products, within 28 days prior to start of study drug dosing, with the exception of vitamins, fish oil, protein powder, and/or paracetamol and/or ibuprofen and/or hormonal contraceptive medications
- 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)
- Significant serious skin disease, such as but not limited to rash, food allergy, eczema,
- psoriasis, or uticaria
- Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
- Known hypersensitivity to the study drugs their metabolites or to formulation excipients
- 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
- Syncope, palpitations, or unexplained dizziness
- Implanted defibrillator or pacemaker
- Liver disease, including Gilbert disease
- Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid
- hypersecretory conditions requiring prolonged (> 6 months) medical treatment.
- Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or intestinal surgery). A history of cholecystectomy is not exclusionary.
- 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 renal, 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.
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Interventions
Cohort 1: 2 mg GS-5801 (1x 2 mg tablet) or placebo tablet. Fasted. Dosing Day 1, Day 2-7 Washout, Dosing Days 8 - 14. Cohort 2: 6 mg GS-5801 (3x 2 mg tablets) or placebo tablets. Fasted. Dosing Day 1, Day 2-7 Washout, Dosing Days 8 - 14. Cohort 3: 20 mg GS-5801 (1x 20 mg tablet) or placebo tablet. Fasted. Dosing Day 1, Day 2-7 Washout, Dosing Days 8 - 14. Cohort 4-6: between 2mg and 100 mg GS-5801 or placebo tablet(s). Fed or fasted. Dosing Day 1, Day 2-7 Washout, Dosing Days 8 - 14. Dose will be determined based on available safety, PK, and PD data from cohorts 1-3 which informs on the effect of food on the PK and PD of GS-5801. Cohort 7: Day 1: 2mg to 100 mg GS-5801, single dose. Fasted. Day 2-7 Washout. Day 8: up to 100 mg GS-5801, single dose. Fed Fasted state: no food or drinks except water, for at least 10 hours. Fed state: study drug(s) will be administered at approximately the same time each day and within 5 minutes of completing a specified moderate-fat-calorie breakfast (~600 calories, 25% to 30% fat). 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(1)
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ACTRN12616001260415