Please be advised that due to the high volume of submissions, the ANZCTR is currently experiencing delays in processing submissions from those outside of Australia and New Zealand. As the ANZCTR is funded by Australia and New Zealand, we must prioritise submissions from these countries first. International submissions should allow additional time for registration. Apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12616001375448
Ethics application status
Approved
Date submitted
3/10/2016
Date registered
5/10/2016
Date last updated
20/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1b Study Evaluating the Safety and Tolerability of GS-5801 in Patients with Chronic Hepatitis B
Scientific title
A Phase 1b Study Evaluating the Safety and Tolerability of GS-5801 in Patients with Chronic Hepatitis B
Secondary ID [1] 290230 0
GS-US-405-2065
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Hepatitis B 300418 0
Condition category
Condition code
Infection 300279 300279 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part A (Dose-escalation, pre-specified cohorts 1 and 2):
Cohort 1: 2 mg GS-5801 (1 x 2 mg tablet) or placebo once daily (Days 1 to 7) - fasted
Cohort 2: 6 mg GS-5801 (3 x 2 mg tablet) or placebo once daily (Days 1 to 7) - fasted

Part B (Adaptive cohorts 3 - 6):
Cohort 3 - 6: 2 mg to 100 mg GS-5801 or placebo once daily (Days 1 to 7) - fasted
Dose selection will be based on safety, tolerability, PK and PD data from previously completed cohorts.

Fasted - no food or drinks 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] 296007 0
Treatment: Drugs
Comparator / control treatment
Placebo to match (PTM) GS 5801 tablets are identical in size, shape, color and appearance to the corresponding active strength GS 5801 tablets. The PTM GS-5801 tablet cores contain commonly used excipients including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
Control group
Placebo

Outcomes
Primary outcome [1] 299758 0
To evaluate the safety and tolerability of multiple oral doses of GS-5801 in subjects with chronic hepatitis B (CHB) infection currently being treated with oral antivirals (OAV).
Timepoint [1] 299758 0
Safety will be evaluated throughout the study.
Incidences of adverse events will be monitored continuously from screening to end of study.
Vital signs: Screening, Day1, 2, 5, 7, 8, 14, 21, 35 and early termination
ECG: Screening, Day1, 2, 5 14, and early termination
Lab assessments: Screening, Day1, 2, 5, 7, 8, 14, 21, 35 and early termination
Secondary outcome [1] 328039 0
To evaluate the antiviral activity of GS-5801 measured by the change from Baseline (BL) in serum hepatitis B surface antigen (HBsAg log10 IU/mL) levels
Timepoint [1] 328039 0
HBsAg will be done at Screening, Day 1, 14, 35 and early termination.
Secondary outcome [2] 328040 0
To characterize the pharmacokinetics (PK) of GS-5801 and its metabolites.

Plasma PK concentrations and parameters assessed: AUClast, AUCinf, AUCtau, % AUCexp, Ctau, Tmax, Tlast, CL/F, t1/2 and Cmax, of GS-5801 and its metabolite GS-698080.
Timepoint [2] 328040 0
Part A and B (Cohorts 1-6): Intensive PK sampling will occur relative to dosing of GS-5801 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, 5, 6, 8, 10, 12, 24 hours postdose.
Days 7: 0 (predose, =< 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours postdose.

Eligibility
Key inclusion criteria
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, (lactating females must agree to discontinue nursing before the study drug is administered and through the follow up period), 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 surgically 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
6. Have been on approved HBV OAV treatment for =>1 year prior to Screening, with HBV DNA below LLOQ (measured at least once) 6 or more months prior to Screening, and HBV DNA < 20 IU/mL at Screening
7. Subjects currently taking Tenofovir DF, Tenofovir alafenamide, entecavir, adefovir, lamivudine, or telbivudine, either as single agent or in combination with no change in regimen for 3 months prior to screening.
8. 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
9. Body mass index (BMI) 18-34 kg/m2, inclusive
10. Must be willing and able to comply with all study requirements
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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 > 1, or
c. Historic FibroScan with a result > 9 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), <11 g/dL (for females)
b. White Blood cell count < 2500 IU/mL
c. ALT > 3x ULN
d. Direct bilirubin > 1.5x ULN
e. INR > ULN unless the subject is stable on an anticoagulant regimen affecting INR
f. Albumin < 3.9 g/dL
g. Platelet Count < 125,000 /mL
h. Estimate creatinine clearance (CLcr) < 80 mL/min (using the Cockcroft-Gault method based on serum creatinine and actual body weight as measured at the Screening evaluation)
3. Co-infection with HIV, hepatitis C virus (HCV) or hepatitis D virus (HDV)
4. Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging)
5. 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
6. Significant cardiovascular, pulmonary, or neurological disease
7. Diagnosis of autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, sarcoidosis, psoriasis of greater than mild severity), poorly controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive pulmonary disease (COPD), malignancy (with exception of certain skin cancers) hemoglobinopathy, retinal disease, or are immunosuppressed
8. Chronic liver disease of a non-HBV etiology (e.g. hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, cholangitis)
9. Received solid organ or bone marrow transplant
10. Received prolonged therapy with immunomodulators (e.g. corticosteroids) or biologics (e.g. monoclonal antibody, interferon) within 3 months of Screening
11. Use of another investigational agents within 30 days of Screening, unless allowed by the Sponsor
12. Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance
13. Known hypersensitivity to study drug, metabolites or formulation excipients
14. Women who may wish to become pregnant during the course of the study
15. Male subjects unwilling to refrain from sperm donation for at least 90 days after the last dose of study drug
16. Use of any prohibited concomitant -medications
17. Believed by the Study Investigator to be inappropriate for study

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)
Part A: (Cohorts 1-2): 10 per cohort (8 GS-5801, 2 placebo-to-match)
Part B: (Cohorts 3-6): 10 per cohort (8 GS-5801, 2 placebo-to-match)
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-5801 (N=8) or matching placebo (N=2)
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 1-2): Randomized, blinded, placebo-controlled, multiple-doses with two pre-specified doses.
Part B (Cohorts 3-6): Randomized, blinded, placebo-controlled, multiple-doses with adaptive dose selection.
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Study terminated early due to lack of efficacy
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 in Australia
Recruitment state(s)
VIC
Recruitment outside Australia
Country [1] 8268 0
New Zealand
State/province [1] 8268 0
Country [2] 8291 0
United States of America
State/province [2] 8291 0

Funding & Sponsors
Funding source category [1] 294592 0
Commercial sector/Industry
Name [1] 294592 0
Gilead Sciences, Inc.
Address [1] 294592 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City CA 94404
Country [1] 294592 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] 293460 0
None
Name [1] 293460 0
NA
Address [1] 293460 0
NA
Country [1] 293460 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296040 0
Health and Disability Ethics Committee (HDEC), NZ
Ethics committee address [1] 296040 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street, Wellington 6011
Ethics committee country [1] 296040 0
New Zealand
Date submitted for ethics approval [1] 296040 0
10/10/2016
Approval date [1] 296040 0
21/11/2016
Ethics approval number [1] 296040 0

Summary
Brief summary
This Phase 1 study entails administration of GS-5801 to subjects with chronic hepatitis B (CHB) for the first time with the objective of evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GS 5801, and thereby determining the clinical pharmacology profile and antiviral activity of GS 5801 to evaluate if it is suitable for further clinical development as a treatment for CHB. The results from this study will form the basis for further evaluation of GS 5801 and dose selection for upcoming studies in subjects with CHB.

The study will proceed in two parts, with the first part (Part A) evaluating the safety, tolerability, PK and PD of GS-5801 administered once daily for 7 days in the fasted state via a pre specified dose escalation through 2 cohorts. The second part (Part B) is designed to evaluate the safety, tolerability, PK, and PD of GS-5801 with adaptive dose selection (up to 100 mg administered once daily for 7 days). The doses evaluated in the adaptive cohorts (Part B) will be selected based on safety and available PK and PD data (up to day 14) from Part A (Cohorts 1-2) and available safety, PK and PD data from previously conducted cohorts from Study GS US 405 2064
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69314 0
Prof Edward Gane
Address 69314 0
Auckland Clinical Studies Limited
3 Ferncroft Street, Auckland 1042
Country 69314 0
New Zealand
Phone 69314 0
+64 9 373 3474
Fax 69314 0
Email 69314 0
edgane@adhb.govt.nz
Contact person for public queries
Name 69315 0
Ms Ansy Mathews
Address 69315 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City CA 94404
Country 69315 0
United States of America
Phone 69315 0
+1 650 524 3912
Fax 69315 0
Email 69315 0
ansy.mathews@gilead.com
Contact person for scientific queries
Name 69316 0
Ms Ansy Mathews
Address 69316 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City CA 94404
Country 69316 0
United States of America
Phone 69316 0
+1 650 524 3912
Fax 69316 0
Email 69316 0
ansy.mathews@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