A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GS-4224 in Healthy Volunteers and Subjects with the Chronic Hepatitis B (CHB) Virus
- Conditions
- Hepatitis BInfection - Other infectious diseasesOral and Gastrointestinal - Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
- Registration Number
- ACTRN12618001957280
- Lead Sponsor
- Gilead Sciences, Inc
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- All
- Target Recruitment
- 210
Part A:
1)Have the ability to understand and sign a written informed consent form (ICF), which must be obtained prior to initiation of study procedures
2)Be aged 18 through 45 years of age, inclusive at screening
3)Be a non-smoker. The use of nicotine or nicotine-containing products must be discontinued 90 days prior to the first dose of study drug
4)Have a calculated BMI of >=19 and =< 30 kg/m2 at screening
5)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
6)Females of childbearing potential must have a negative serum pregnancy test at screening and negative urine pregnancy test at clinic admission (unless permanently sterile or greater than 2 years postmenopausal)
7)Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception.
8)Male subjects must refrain from sperm donation from clinic admission (eg, Day -2 or Day -1), throughout the study period, and continuing for at least 90 days following the last dose of study drug
9)Female subjects must refrain from egg donation and in vitro fertilization during treatment and until at least 30 days after the end of relevant systemic exposure
10)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.
11)Screening laboratory and 12-lead electrocardiogram (ECG) evaluations must be without clinically significant abnormalities as assessed by the investigator
12)Have no 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
13)Must be willing and able to comply with all study requirements
14)Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs.
Part B:
1)Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
2)Adult male and non-pregnant, non-lactating female subjects, 18 - 65 years of age inclusive based on the date of the Screening visit
3)A negative serum pregnancy test is required for female subjects (unless permanently sterile or greater than two years postmenopausal)
4)Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception.
5)Documented evidence of chronic HBV infection (e.g. HBsAg positive for more than 6 months) with detectable HBsAg levels at Screening (no retest permitted if initial screening HBsAg is negative)
6)HBV DNA levels by central lab at Screening:
a) < 20 IU/mL (for subjects in Cohorts 11–13 and if virally suppressed subjects are enrolled into Cohorts 15 and/or 16)
b) >= 2000 IU/mL (for subjects in Cohort 14 and if subjects not on OAV therapy are enrolled into Cohorts 15 and/or 16)
7)Screening ECG without clinically significant abnormalities and with QTcF interval (QT corrected using Fridericia’s formula) =< 450 msec for males and =< 470 msec for females.
8)BMI 18-34 kg/m2 (inclusive)
9)Must be willing and
Part A:
1)Be a lactating female
2)Have received any study drug within 30 days prior to study dosing
3)Have current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance or subject safety
4)Have a positive test result for HIV, HBsAg, or HCV antibody
a)Subjects who are HCV Ab positive, but have a documented negative HCV RNA, are eligible
5)Have a positive test result for autoantibodies (ANA >1:80 and/or anti-SMA >1:80 and/or AMA>1:40 and/or anti-TPO >1:40)
6)Have poor venous access that limits phlebotomy
7)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.
8)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)
9)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.
10)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), autoimmune disorders, immunodeficiency disorders, active infection, or malignancy that are clinically significant or requiring treatment.
11)Have received inactivated vaccinations (e.g. injectable influenza or pneumococcal) within 4 weeks prior to randomization or received live vaccinations within 4 weeks prior to screening
Part B:
1)Extensive bridging fibrosis or cirrhosis as defined clinically, by imaging or by the following:
a)Metavir >= 3 or Ishak fibrosis score >= 4 by a liver biopsy within 5 years of screening, or, in the absence of an appropriate liver biopsy, either:
b)Screening FibroTest score of > 0.48 and APRI > 0.8, or
c)Historic FibroScan with a result > 8 kPa within = 6 months of screening (if ava
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method