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Trial registered on ANZCTR


Registration number
ACTRN12616001646437
Ethics application status
Approved
Date submitted
11/11/2016
Date registered
29/11/2016
Date last updated
8/01/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics, and the Effect of Food on GS 9688
Scientific title
A Phase 1 Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics, and the Effect of Food on GS 9688
Secondary ID [1] 290340 0
GS-US-389-2021
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hepatitis B Virus 300612 0
Condition category
Condition code
Infection 300461 300461 0 0
Other infectious diseases
Oral and Gastrointestinal 300779 300779 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 296153 0
Treatment: Drugs
Comparator / control treatment
Placebo-to-match (PTM) GS-9688 tablets are identical in size, shape, color and appearance to the corresponding active strength GS-9688 tablets. The PTM GS-9688 tablet cores contain commonly used excipients including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
Control group
Placebo

Outcomes
Primary outcome [1] 299897 0
To evaluate the safety and tolerability of escalating single oral doses of GS-9688. The primary safety endpoints are the incidences of adverse events, vital signs and ECG measurements, laboratory abnormalities, and ophthalmic assessments.
Timepoint [1] 299897 0
Safety will be evaluated throughout the study. Incidences of adverse events will be monitored continuously from screening to end of study.
Part A (Cohorts 1-5):
Vital signs: Screening, Day-1, Day1, 7, follow-up, early termination
ECG: Screening, Day-1, Day2, 7, early termination
Lab assessments: Screening, Day-1, Day2, 5, 7, follow-up, early termination
Ophthalmic exam: Day -1, 2, 4, 7, early termination

Part B and C (Cohorts 6 and 7):
Vital signs: Screening, Day-1, Day1, 8, 14, follow-up, early termination
ECG: Screening, Day-1, Day1, 8, 14, early termination
Lab assessments: Screening, Day-1, Day2, 5, 7, 14, follow-up, early termination
Ophthalmic exam: Day -1, 2, 4, 7, 10, 14, early termination

Note:
Follow up visits will occur 14 days (+/- 2 days) following the last dose of study drug.
Early termination visits will occur with 72hrs of early termination from the study
Primary outcome [2] 299898 0
To characterize the single-dose PK of GS-9688.
The primary PK endpoints are single- and multiple- dose plasma PK parameters: AUClast, AUCinf (single dose), AUCtau (multiple dose), % AUCexp (single dose), Ctau (multiple dose), and Cmax
Timepoint [2] 299898 0
Part A (Cohorts 1-5): Intensive PK sampling will occur relative to dosing of GS-9688 or placebo at the following time points for each cohort:
Day 1: 0 (predose, = 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24 hours postdose.
Part B and C (Cohort 6 and 7):
Day 1 and Day 8: 0 (predose, = 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24 hours postdose.
Primary outcome [3] 299899 0
To perform a preliminary evaluation of the effect of food on GS-9688 PK.
The primary PK endpoints are single- and multiple- dose plasma PK parameters: AUClast, AUCinf (single dose), AUCtau (multiple dose), % AUCexp (single dose), Ctau (multiple dose), and Cmax
Timepoint [3] 299899 0
Part A (Cohorts 1-5): Intensive PK sampling will occur relative to dosing of GS-9688 or placebo at the following time points for each cohort:
Day 1: 0 (predose, = 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24 hours postdose.
Part B and C (Cohort 6 and 7):
Day 1 and Day 8: 0 (predose, = 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24 hours postdose.
Secondary outcome [1] 328441 0
To evaluate the effect of GS-9688 on pharmacodynamic (PD) markers and to characterize GS-9688 dose and/or exposure-response (PD) relationships.
Timepoint [1] 328441 0
PD collection will occur relative to the morning dosing of GS-9688 at the following timepoints:
Serum/Plasma PD biomarkers and exploratory biomarkers:
Day 1: 0 (predose <= 5 min), 1, 2, 4, 8, and 12, hours postdose, Day 2, and Day 7
Whole blood gene expression biomarkers:
Day 1: 0 (predose <= 5 min), 2, 4, 8, and 12 hours postdose, Day 2, and Day 7
TLR8 SNP: Day 1

Eligibility
Key inclusion criteria
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 nonsmoker. 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 body mass index (BMI) of >= 19.0 and <= 30.0 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, 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)
6. 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)
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 -1), throughout the study period, and continuing for at least 90 days following the last dose of study drug
9. 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.
10. Screening laboratory and 12-lead electrocardiogram (ECG) evaluations must be without clinically significant abnormalities as assessed by the investigator
11. 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
12. Must be willing and able to comply with all study requirements
13. Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs.



Minimum age
18 Years
Maximum age
45 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
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 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)
5. Have poor venous access that limits phlebotomy
6. 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
7. 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)
8. 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.
9. 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer

Part A: (Cohorts 1-5): 15 per cohort (12 GS-9688, 3 placebo-to-match)
Part B: (Cohort 6): 12 active receiving GS-9688
Part C: (Cohort 7): 15 per cohort (12 GS-9688, 3 placebo-to-match)

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.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation. Randomized 4:1 to receive either blinded GS-9688 (N=12) or matching placebo (N=3)
This applies to Part A and C.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Other
Other design features
Part A
Cohorts 1-3: Randomized, blind, placebo-controlled, single doses with pre-specified staggered dose escalations.
Cohorts 4-5: Randomized, blind, placebo-controlled, single doses with adaptive
dose selection of GS-9688.
Part B
Cohort 6: Randomized, two-treatment, fixed sequence, single-dose food effect
with adaptive dose selection of GS-9688. The subjects are randomised to either the fasted arm or fed state arm.
Part C
Cohort 7: Randomized, blind, placebo-controlled exploration of safety of 2 doses of GS-9688 administered one week apart.
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 8325 0
New Zealand
State/province [1] 8325 0

Funding & Sponsors
Funding source category [1] 294725 0
Commercial sector/Industry
Name [1] 294725 0
Gilead Sciences, Inc.
Address [1] 294725 0
Gilead Sciences, Inc.
333 Lakeside Drive,
Foster City, CA 94404
Country [1] 294725 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Gilead Sciences, Inc.
Address
Gilead Sciences, Inc.
333 Lakeside Drive,
Foster City, CA 94404
Country
United States of America
Secondary sponsor category [1] 293568 0
None
Name [1] 293568 0
Address [1] 293568 0
Country [1] 293568 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296143 0
Health and Disability Ethics Committee (HDEC), NZ
Ethics committee address [1] 296143 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street, Wellington 6011
Ethics committee country [1] 296143 0
New Zealand
Date submitted for ethics approval [1] 296143 0
26/10/2016
Approval date [1] 296143 0
22/11/2016
Ethics approval number [1] 296143 0

Summary
Brief 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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69718 0
Prof Edward Gane
Address 69718 0
Auckland Clinical Studies Limited
3 Ferncroft Street, Auckland 1042
Country 69718 0
New Zealand
Phone 69718 0
+64 9 373 3474
Fax 69718 0
Email 69718 0
edgane@adhb.govt.nz
Contact person for public queries
Name 69719 0
Ms Lorraine Ampaw
Address 69719 0
Gilead Sciences, Inc.
333 Lakeside Drive,
Foster City, CA 94404
Country 69719 0
United States of America
Phone 69719 0
+1 650 389 8793
Fax 69719 0
Email 69719 0
lorraine.ampaw@gilead.com
Contact person for scientific queries
Name 69720 0
Ms Lorraine Ampaw
Address 69720 0
Gilead Sciences, Inc.
333 Lakeside Drive,
Foster City, CA 94404
Country 69720 0
United States of America
Phone 69720 0
+1 650 389 8793
Fax 69720 0
Email 69720 0
lorraine.ampaw@gilead.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary