None listed
Conditions
Brief summary
Part A of this Phase 1 study entails administration of GS-4224 to humans for the first time with the objective of evaluating in a step-wise fashion the safety, tolerability, PK, and PD, and thereby understand the clinical pharmacology profile of GS-4224 to determine if it is suitable for clinical development as a treatment for CHB. The results from this study will form the basis for further evaluation of GS-4224 and dose selection for Part B of this study in subjects with CHB. Part B of this Phase 1 study entails administration of GS-4224 in CHB subjects for the first time with the objective of evaluating its safety, tolerability, PK and PD, and thereby understand the clinical pharmacology profile of GS-4224 to determine if it is suitable for clinical development as a treatment for CHB. The results from this study will form the basis for further evaluation of GS-4224 and dose selection for a Phase 2 study in subjects with CHB. The main aims of the study is to evaluate the safety and tolerability of escalating single and multiple doses of GS-4224 as well as evaluating the PK of escalating single and multiple doses of GS-4224
Interventions
This is a Phase 1, placebo-controlled, randomized study evaluating the safety, PK, and PD of GS-4224. The study will consist of 2 parts (A and B).
Part A: Up to 149 subjects
Cohorts 1-7: Up to 105 subjects (12 active, 3 placebo per cohort)
Single and Multiple Ascending Doses (S/MAD):
Randomized, blinded, placebo-controlled, single- and multiple-doses with staggered GS-4224 dose escalations.
For cohorts 2-10, the dose of GS-4224 will be determined following the review of safety data from previo
This is a Phase 1, placebo-controlled, randomized study evaluating the safety, PK, and PD of GS-4224. The study will consist of 2 parts (A and B). Part A: Up to 149 subjects Cohorts 1-7: Up to 105 subjects (12 active, 3 placebo per cohort) Single and Multiple Ascending Doses (S/MAD): Randomized, blinded, placebo-controlled, single- and multiple-doses with staggered GS-4224 dose escalations. For cohorts 2-10, the dose of GS-4224 will be determined following the review of safety data from previous cohort. Cohort 1: GS-4224 20 mg (2 x 10 mg tablets) will be administered orally in a single dose and once daily for 10 days Cohort 2: GS-4224 up to 60 mg will be administered orally in a single dose and once daily for 10 days Cohort 3: GS-4224 up to 180 mg will be administered orally in a single dose and once daily for 10 days Cohort 4: GS-4224 up to 540 mg will be administered orally in a single dose and once daily for 10 days Cohorts 5-7: GS-4224 up to 1000 mg will be administered orally in a single dose and once daily for 10 days Cohort 8: Up to 20 subjects, for 17 evaluable GS-4224 and tenofovir alafenamide (TAF) Drug-Drug Interaction (DDI): Open label, two treatment, fixed sequence, DDI with single-dose TAF and multiple-doses GS-4224. Cohort 8: GS-4224 up to 1000 mg will be administered orally once daily for 10 days, with TAF (1 x 25 mg) administered orally as a single dose on the 10th day with GS-4224 administration Cohort 9: Up to 12 subjects, for 10 evaluable Food Effect (FE): Open label, two treatment, fixed sequence, single GS-4224 dose food effect evaluation. Cohort 9: GS-4224 up to 1000 mg will be administered orally as a single dose, with a high fat/high calorie breakfast. The meal will be initiated 30mins prior to the planned study drug administration. GS-4224 will be given at or within 5 minutes of subjects consuming the meal. Cohort 10: Up to 12 subjects, for 10 evaluable Acid Reducing Agent Effect (ARA): Open label, three treatment, fixed sequence, DDI with single dose GS 4224 and single doses of famotidine (FAM). Cohort 10: GS-4224 up to 1000 mg will be administered orally as a single dose, 2 hrs after FAM (1 x 40 mg) administered orally as a single dose, and 12 hrs after FAM (1 x 40 mg) administered orally as a single dose Part B: Approximately 60 subjects Multicenter, randomized, blinded, placebo-controlled study of GS 4224 in subjects with CHB. Cohorts 11-16: Approximately 10 subjects (GS-4224: n=8 and PTM: n= 2) in each cohort Cohort 11-16: GS-4224 up to the highest dose (mg) deemed safe from Part A will be administered orally for 28 daily doses Dosing is planned in up to 6 cohorts as described below: Adaptive Cohorts 11-13 in virally suppressed CHB subjects: Randomized, blinded, placebo-controlled, multiple (28) daily doses of a dose at or below the highest dose (mg) deemed safe from Part A, Cohorts 1-7 of GS-4224 or Placebo to Match (PTM) administered daily. Cohorts 11 through 13 may be conducted in parallel, staggered or sequential fashion. If conducted in a staggered manner, dose escalation between Cohorts 11-13 will take place after review of the safety data up to Day 14 and available PK and PD data. Adaptive Cohort 14 in viremic CHB subjects not on OAV treatment: Randomized, blinded, placebo-controlled, multiple (28) daily doses of a dose at or below the highest dose (mg) deemed safe from Part A, Cohorts 1-7 of GS-4224 or PTM administered daily. Dosing in Cohort 14 may occur after review of all available safety data up to Day 14 and available PK and PD data from Cohorts 11-13 and/or Cohorts 15-16 (if enrolled prior to commencement of Cohort 14). Randomized, blinded, placebo-controlled, multiple (28) daily doses of a dose at or below the highest dose (mg) deemed safe from Part A, Cohorts 1-7 of GS-4224 or PTM administered daily. Dosing in Cohorts 15 and/or 16 may be conducted in parallel, staggered, or sequential fashion, but will take place after review of the safety data and available PK and PD data up to Day 14 of the respective corresponding populations from Cohorts 11-14 (e.g. if Adaptive Cohort 15 is evaluated in virally suppressed CHB subjects then only safety data from Cohorts 11-13 are required to be reviewed prior to initiation). All doses being evaluated will be determined based on the safety and available PK and PD data from Part A, Cohorts 1-7 of this protocol and available data from the previous cohort(s) in Part B. Maximum doses evaluated in Part B will be a dose at or below the highest dose deemed to be safe in Part A, Cohorts 1-7. The Sponsor may elect to terminate enrollment of a cohort or not to enroll a particular cohort. The investigator will maintain an accurate inventory of all study drug(s). Each dose of the study drug(s) administered at the study centre will be administered by qualified study centre 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.
Sponsors
Gilead Sciences, Inc
Study design
Allocation
Randomised controlled trial
Intervention model
Other
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
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 able to comply with all study requirements Additionally, subjects in Cohorts 11–13 and IF virally suppressed subjects are selected for Cohorts 15 and/or 16 should meet the following criteria to be eligible to participate in this study: 10) Have been on prescribed OAV treatment(s) (TAF, TDF and approved generics of TDF, entecavir, adefovir, lamivudine, TBV, either as single agents or in combination) with no change in regimen for 3 months prior to screening. - TAF and TDF (or generics of TDF) are not permitted unless new data becomes available that would allow concomitant use of TAF or TDF (or generics of TDF) during the trial (Cohort 8) 11) HBV DNA < 69IU/mL measure at least once at local lab for 6 or more months prior to screening
Exclusion criteria
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 available) If liver biopsy is available, the liver biopsy result supersedes (b) and/or (c, if available) If an appropriate liver biopsy is not available, fibrosis will be evaluated by (b) and/or (c, if available). In the event of discordance between (b) and (c), the FibroScan results will take precedence 2) Subjects meeting any of the following laboratory parameters at screening: a) Hemoglobin < 12 g/dL (for males) or < 11 g/dL (for females) b) White Blood cell count < 2500 cells/uL c) Neutrophil count < 1500 cell/mm3 (or < 1000 cell/mm3 if considered a physiological variant in a subject of African descent). d) ALT > 3x ULN e) INR > ULN f) Albumin < 3.5 g/dL g) Direct bilirubin >1.5x ULN h) Platelet Count < 100,000 /ml i) ANA >= 1:80 j) anti-SMA >1:80 k) AMA >1:40 l) anti-TPO >1:40 3) Estimated creatinine clearance (CRCL) < 80 ml/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at the screening evaluation. 4) Co-infection with HIV, HCV or hepatitis D virus (HDV) a) Subjects who are HCV or HDV positive by serology, but have a documented screening negative HCV or HDV RNA, respectively, are eligible 5) Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging) 6) 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 7) Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (e.g. basal cell skin cancer). Subjects under evaluation for possible malignancy are not eligible. 8) Significant cardiovascular, pulmonary, or neurological disease. 9) Documented myocardial infarction or unstable/uncontrolled cardiac disease (e.g., unstable angina, congestive heart failure) within 6 months of randomization should be excluded 10) Diagnosis of autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune hepatitis, sarcoidosis, psoriasis of greater than mild severity, autoimmune uveitis, autoimmune thyroid disease), poorly controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive pulmonary disease (COPD), malignancy (with exception of certain skin cancers), hemoglobinopathy, or are immunosuppressed 11) Chronic liver disease of a non-HBV etiology (e.g. Wilson’s disease, hemochromatosis, alpha-1-antitrypsin deficiency, cholangitis), except for non-alcoholic fatty liver disease 12) History of hepatic decompensation (e.g. ascites, encephalopathy, or variceal hemorrhage) within 5 years prior to screening 13) Received solid organ or bone marrow transplant 14) Received prolonged therapy with immunomodulators (e.g. corticosteroids) or biologics (e.g. monoclonal antibody, interferon) within 3 months of screening 15) 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 16) Have donated blood within 28 days of screening or plasma within 7 days of screening and must refrain from blood donation from screening, throughout the study period, and continuing for at least 30 days following the last dose of study drug 17) Use of anticoagulant therapy 18) Use of another investigational agent within 30 days of screening, unless allowed by the Sponsor 19) Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance 20) Known hypersensitivity to study drug, metabolites or formulation excipients 21) Women who are breastfeeding or may wish to become pregnant during the course of the study 22) Female subjects unwilling to refrain from egg donation and in vitro fertilization during and until at least 30 days after the last study drug dose 23) Male subjects unwilling to refrain from sperm donation during and until at least 90 days after the last dose of study drug 24) Use of any prohibited concomitant medications 25) Believed by the Study Investigator to be inappropriate for study participation for any reason not otherwise listed. a) Additionally, subjects in Cohort 14 and IF subjects not on OAV therapy are selected for Cohorts 15 and/or 16 who meet the following criterion are not to be enrolled in this study: 26) Received OAV treatment for HBV within 3 months of screening
Outcome results
None listed