Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics, and the Effect of Food on GS 9688
A Phase 1 Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics, and the Effect of Food on GS 9688
Gilead Sciences, Inc.
102 participants
Dec 16, 2016
Interventional
Conditions
Summary
This Phase 1 study entails administration of GS-9688 to humans for the first time with the objective of evaluating in a step-wise fashion the safety, tolerability, PK, and pharmacodynamics (PD), and thereby understand the clinical pharmacology profile of GS-9688 to determine if it is suitable for further clinical development. The study will proceed in three parts. Part A will first evaluate the safety, tolerability, PK and PD of single doses of GS-9688 administered in the fasted state via a pre specified dose escalation through 3 cohorts. As guided by the safety and available PK and PD data from pre-specified cohorts, the adaptive Part A will commence to evaluate the safety, tolerability, PK, and PD of GS-9688 with dose selection (up to 30 mg) through the next 2 cohorts. The effect of food (moderate-fat calorie meal) will be explored in Part B in which the subjects will receive single doses of GS-9688 one week apart. The doses to be evaluated in Part B will be informed by the safety and available PK and PD data from Parts A (pre-specified and adaptive cohorts). The results from Parts A and B will subsequently inform the dose and the mode of administration (fed or fasted) of GS-9688 in Part C, designed to examine the safety and PK and PD of two single doses of GS-9688 administered one week apart.
Eligibility
Inclusion Criteria15
- 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 (unless permanently sterile or greater than 2 years postmenopausal)
- 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 electrocardiogram (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
- 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 Criteria18
- Be a 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 (confirmation of HBV vaccine status should be documented)
- 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 and/or acetaminophen 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)
- 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 uticaria
- 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.
- 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
Part A (Cohorts 1 - 5): Fasted Cohort 1a: 0.5 mg GS-9688 or placebo, oral tablet, single dose (sentinel group of 2 subjects) Cohort 1b: 0.5 mg GS-9688 or placebo, oral tablet, single dose Cohort 2: 1.5 mg GS-9688 or placebo, oral tablet, single dose Cohort 3: 5 mg GS-9688 or placebo, oral tablet, single dose Cohort 4: 0.5 mg to 15 mg GS-9688 or placebo, oral tablet, single dose Cohort 5: 0.5 mg to 30 mg GS-9688 or placebo, oral tablet, single dose Cohort 1 will be conducted in two separate groups with a Sentinel group (Cohort 1a) of 2 subjects (1 active: 1 placebo) and Cohort 1b for the remaining 13 subjects (11 active: 2 placebo). Cohort 1a safety data up to and including Day 5 will support commencement of dosing (Day 1) for Cohort 1b. Cohorts 4 and 5 dose will be decided based on available safety and PK and PD data from cohorts 1 - 3. Part B (Cohort 6): Food Effect Cohort 6 - Day 1: 0.5 mg to 30 mg GS-9688, oral tablet, single dose, fasted Cohort 6 - Day 8: 0.5 mg to 30 mg GS-9688, oral tablet, single dose, fed state (Part B dose will be determined based on safety and available PK and PD data from within Part A, Cohort 6 may be initiated in parallel with cohorts in Part A if the dose under evaluation is at or below a dose that has already been evaluated.) Part C (Cohort 7): Adaptive Cohort Cohort 7 - Day 1: 0.5 mg to 30 mg GS-9688 or placebo, oral tablet, single dose, fasted or fed state Cohort 7 - Day 8: 0.5 mg to 30 mg GS-9688 or placebo, oral tablet, single dose, fasted or fed state (Dose and mode of administration (fed or fasted) will be decided based on available safety and PK and PD data from Parts A and B) GS-9688 dose will be at or below the highest dose from which data are available from Parts A and B. Day 1 and day 8 dose will be the same and the same conditions will apply (fed or fasted). *Fasted: no food or liquids, except water, for at least 10 hours prior to dosing *Fed State: administered with a moderate fat meal (~ 600 kcal; 25-30% fat) and with 240 mL of water after an overnight fast (no food or liquids, except water for at least 10 hours). 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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ACTRN12616001646437