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Trial registered on ANZCTR


Registration number
ACTRN12618001843246p
Ethics application status
Submitted, not yet approved
Date submitted
7/11/2018
Date registered
13/11/2018
Date last updated
13/11/2018
Date data sharing statement initially provided
13/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1b Open-Label, Proof of Concept Study to Evaluate the Safety and Efficacy of Novel Hepatitis B Virus (HBV) Combination Therapies in Chronic Hepatitis B (CHB) Subjects
Scientific title
A Phase 1b Open-Label, Proof of Concept Study to Evaluate the Safety and Efficacy of Novel Hepatitis B Virus (HBV) Combination Therapies in Chronic Hepatitis B (CHB) Subjects
Secondary ID [1] 296545 0
GS-US-493-5342
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hepatitis B 310326 0
Condition category
Condition code
Infection 309058 309058 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Approximately 36 virally-suppressed, chronic hepatitis B (CHB) infected subjects, currently being treated with a commercially available nucleos(t)ide (NUC), may be enrolled and assigned into a cohort. Subjects will remain on their current commercially available NUC(s) therapy for the entire duration of the study.

Cohorts 1-3 will be enrolled sequentially and receive:
Cohort 1 (n = 12): Nivolumab 0.3 mg/kg IV once every 4 weeks for 12 weeks (total 3 doses)

Cohort 2 (n=12): Ledipasvir/sofosbuvir (90 mg/400 mg) tablet orally administered once daily for 12 weeks, followed by Ledipasvir/sofosbuvir tablet orally administered once daily plus nivolumab 0.3 mg/kg IV once every 4 weeks for 12 weeks (total 3 doses)

Cohort 2 will be enrolled after Cohort 1 has completed enrollment. Prior to administration of nivolumab in Cohort 2, safety of 12 Weeks of nivolumab in at least 10 subjects will have been demonstrated in Cohort 1. Safety data review of 12 weeks of nivolumab will be completed by the Medical Monitor.

Cohort 3 (n=12): GS-9688 3 mg (2 x 1.5 mg tablets) orally administered on the same day once a week for 12 weeks (total 12 doses), plus Nivolumab 0.3 mg/kg IV once every 4 weeks for 12 weeks (total 3 doses). On the days when nivolumab is to be administered, the scheduled weekly dose of GS-9688 is to be administered on the same day.

Cohort 3 will be enrolled after Cohorts 1 and 2 have completed enrollment. Safety in Cohort 1 of nivolumab alone will have been demonstrated prior to enrollment of Cohort 3. Cohort 3 will initially enroll a sentinel group of 3 subjects that will complete at least 4 weeks of combination treatment. After demonstration of safety of 4 weeks of combination treatment in the first 3 subjects, enrollment of the remaining 9 subjects will commence. Safety data review of 4 weeks of GS-9688 plus nivolumab will be completed by the Medical Monitor.

For Cohorts 1-3, all subjects will complete 24 weeks of follow up after completion of study treatment(s).

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] 312850 0
Treatment: Drugs
Comparator / control treatment
NA
Control group
Uncontrolled

Outcomes
Primary outcome [1] 308022 0
To evaluate the efficacy of study treatment(s) as measured by the proportion of subjects with >=0.5 log10 IU/mL decline from Baseline in circulating serum HBV surface antigen (HBsAg) at 8 weeks post-completion of study treatment(s)
Timepoint [1] 308022 0
The primary efficacy endpoint is the proportion of subjects with >=0.5 log10 IU/mL decline from Baseline at 8 weeks post-completion of study treatment(s).
Primary outcome [2] 308068 0
To evaluate the safety and tolerability of study treatment(s) in virally-suppressed subjects with chronic hepatitis B (CHB) infection on oral nucleos(t)ide (NUC).

Examples of Adverse Events that may occur:
Nivolumab: fatigue and ALT flare
Ledipasvir/sofosbuvir: fatigue, headache, and upper respiratory infection
GS-9688: nausea and dizziness
Timepoint [2] 308068 0
Safety will be evaluated by assessment of clinical laboratory tests and adverse events. Primary safety analysis will be evaluated through 30 days post-completion of study treatment(s). The analysis through 24 weeks post-completion of study treatment(s) for nivolumab containing regimens will also be provided.

The investigator or qualified subinvestigator is responsible for assessing adverse events and serious adverse events for causality and severity, and for final review and confirmation of accuracy of event information and assessments.
Secondary outcome [1] 353666 0
To evaluate the change from Baseline (BL) in serum HBsAg (log10 IU/mL) levels during and after study treatment(s) discontinuation
Timepoint [1] 353666 0
The mean change in log10 IU/mL serum HBsAg at on-treatment Weeks 12 and 24 (if applicable), and post-treatment Week 4, 8, 12, and 24

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, 18-65 years of age inclusive based on the date of the Screening visit
3) Documented evidence of chronic HBV infection (e.g. HBsAg positive for more than 6 months) with detectable HBsAg levels at Screening
4) Have been on a commercially available HBV nucleos(t)ide treatment(s) (tenofovir
alafenamide, tenofovir disoproxil fumurate, entecavir, adefovir, lamivudine, telbivudine,
either as single agents or in combination) with no change in regimen for 3 months prior to
screening.
5) Have a historic HBV DNA <69 IU/mL, measured at least once at local laboratory, 3 or more months prior to screening
6) HBV DNA < 20 IU/mL by central laboratory at Screening
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) Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline prior to enrollment
9) Male and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
10) Must be willing and able to comply with all study requirements
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Extensive bridging fibrosis or cirrhosis as defined clinically by any one of the following:
a) Metavir >= 3 or Ishak fibrosis score >= 4 by a liver biopsy within 3 years of screening, or,
in the absence of an appropriate liver biopsy, either:
b) Screening FibroTest score of > 0.48 and APRI > 1 by central laboratory, or
c) Historic FibroScan with a result > 9 kPa within =< 1 year of screening
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/mm3
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 unless the subject is stable on an anticoagulant regimen affecting INR
f) Albumin < 3.5 g/dL
g) Direct bilirubin >1.5x ULN
h) Platelet Count < 100,000/uL
i) Positive autoantibodies, defined as any one or more of the following:
i) Antinuclear antibodies (ANA) >1:80
ii) Smooth muscle antibodies (anti-SMA) >1:80
iii) Antimitochondrial antibodies (AMA) >1:40
iv) Anti-thyroid peroxidase (anti-TPO) >1:40
j) Estimated creatinine clearance (CrCl) < 60 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 human immunodeficiency virus (HIV), hepatitis C virus (HCV) or
hepatitis D virus (HDV). Subjects who are HCV Ab or HDV Ab positive, but have a
documented negative HCV RNA or HDV RNA, respectively, are eligible.
4) Current or prior history of hepatocellular carcinoma (HCC) (e.g. as evidenced by prior
imaging) or screening alpha-fetoprotein (AFP) >= 50 ng/mL without imaging to rule out HCC
5) Current or prior history of clinical hepatic decompensation (e.g. ascites, encephalopathy, or variceal hemorrhage).
6) 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
7) Significant cardiovascular, ophthalmological, pulmonary, or neurological disease in the
opinion of the investigator
8) Diagnosis of any autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid
arthritis, inflammatory bowel disease, ulcerative colitis, pneumonitis, autoimmune hepatitis, sarcoidosis, psoriasis of greater than mild severity, autoimmune uveitis, autoimmune nephritis, thyroiditis), poorly controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive pulmonary disease (COPD), hemoglobinopathy, retinal disease, or are immunosuppressed
9) 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
10) Received solid organ or bone marrow transplant
11) Received prolonged therapy with immunomodulators (e.g. corticosteroids) or biologics
(e.g. monoclonal antibody, interferon, nivolumab) within 3 months of screening
12) 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 pneumococcal] are allowed)
13) Use of another investigational agent within 90 days of screening, unless allowed by the
Sponsor
14) Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance
15) Known hypersensitivity to study drug or formulation excipients
16) Women who are breastfeeding, pregnant or who wish to become pregnant during the course of the study
17) 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 or 5 months after last dose of nivolumab, if administered.
18) Male subjects unwilling to refrain from sperm donation during and until at least 90 days after the last study drug dose
19) Use of any prohibited concomitant medications
20) Believed by the Study Investigator to be inappropriate for study participation for any reason not otherwise listed.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Safety Analysis:
Safety will be evaluated by assessment of clinical laboratory tests and adverse events. Primary safety analysis will be evaluated through 30 days post-completion of study treatment(s). The analysis through 24 weeks post-completion of study treatment(s) for nivolumab containing regimens will also be provided.

Efficacy Analysis:
The proportion of subjects with >=0.5 log10 IU/mL decline from Baseline at 8 weeks post completion of study treatment(s) (e.g., 12 weeks from last dose of nivolumab) will be analyzed within each treatment group (cohort 1, 2, and 3). A point estimate with a two-sided 95% exact confidence interval will be constructed for the proportions using the binomial distribution (Clopper-Pearson method).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
31/01/2019
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
36
Accrual to date
Final
Recruitment outside Australia
Country [1] 21005 0
New Zealand
State/province [1] 21005 0
Country [2] 21006 0
Hong Kong
State/province [2] 21006 0

Funding & Sponsors
Funding source category [1] 301125 0
Commercial sector/Industry
Name [1] 301125 0
Gilead Sciences, Inc
Country [1] 301125 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Gilead Sciences, Inc
Address
333 Lakeside Drive
Foster City, CA 94404
Country
United States of America
Secondary sponsor category [1] 300744 0
None
Name [1] 300744 0
Address [1] 300744 0
Country [1] 300744 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 301877 0
Health and Disability Ethics Committee (HDEC), NZ
Ethics committee address [1] 301877 0
Ministry of Health Ethics Department
Freyberg Building Reception
Ground Floor 20 Aitken Street,
Wellington 6011
Ethics committee country [1] 301877 0
New Zealand
Date submitted for ethics approval [1] 301877 0
08/11/2018
Approval date [1] 301877 0
Ethics approval number [1] 301877 0

Summary
Brief summary
Given the low rate of HBsAg loss with currently available therapies and the treatment burden associated with life-long treatment to maintain viral suppression, there is a need to identify new therapies that may provide durable HBsAg loss with a finite treatment duration. The primary objective of this study is to evaluate the safety, tolerability and efficacy of novel HBV combination regimens in association with an oral nucleotide (NUC) HBV polymerase inhibitor for the treatment of CHB subjects. In addition, this study will evaluate changes in HBV specific immune responses following administration of study treatment (nivolumab±ledipasvir/sofosbuvir or nivolumab±GS-9688).

This Phase 1b study will be conducted in virally-suppressed CHB subjects to minimize safety risks and maximize efficacy benefits associated with study treatment(s). Because they have stable viral suppression on treatment with an oral antiviral medication, these subjects generally have lower levels of HBV virions and proteins, including HBsAg, within the serum as well as lower expression of HBV antigens within infected hepatocytes. This lower antigen burden enhances the safety profile of immune stimulating approaches to CHB treatment (e.g. nivolumab and/or GS-9688). In addition, a virally suppressed population may have a higher chance of response to immune modulatory therapies (e.g. nivolumab and/or GS-9688) as suggested by the observation that immune responsiveness of chronic HBV patients is improved in patients who are on chronic suppressive antiviral therapy. To further maximize safety in this study, all subjects will be closely monitored during the study and only subjects with sufficient hepatic reserve will be included.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88406 0
Prof Edward Gane
Address 88406 0
Auckland Clinical Studies Limited
3 Ferncroft Street, Auckland 1042
Country 88406 0
New Zealand
Phone 88406 0
+64 9 373 3474
Fax 88406 0
Email 88406 0
[email protected]
Contact person for public queries
Name 88407 0
Mr Wayne Paul
Address 88407 0
Gilead Sciences Pty Ltd
Level 6, 417 St Kilda Road
Melbourne VIC 3004
Country 88407 0
Australia
Phone 88407 0
+61 392724451
Fax 88407 0
Email 88407 0
[email protected]
Contact person for scientific queries
Name 88408 0
Dr Audrey Lau
Address 88408 0
Gilead Sciences, Inc
333 Lakeside Drive
Foster City CA 94404
Country 88408 0
United States of America
Phone 88408 0
+1 (650) 425-5065
Fax 88408 0
+1 (650) 524-9964
Email 88408 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.