Safety and Efficacy of GS-4774 in Combination With Tenofovir Disoproxil Fumarate (TDF) for the Treatment of Participants With Chronic Hepatitis B (CHB) and Who Are Currently Not on Treatment

Chronic Hepatitis B Clinical Trial

Official title:

A Phase 2, Randomized, Open-Label Study to Evaluate the Safety and Efficacy of GS-4774 in Combination With Tenofovir Disoproxil Fumarate (TDF) for the Treatment of Subjects With Chronic Hepatitis B and Who Are Currently Not on Treatment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02174276
• Other study ID #: GS-US-330-1401
• Secondary ID: 2014-001011-39
• Status: Completed
• Phase: Phase 2
• Start date: July 24, 2014
• Est. completion date: May 30, 2018

Study information

• Verified date: May 2019
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objectives of this study are to evaluate the safety, tolerability, and efficacy of GS-4774 in adults with CHB and who are currently not on treatment. Participants will be randomized to receive TDF alone or GS-4774 plus TDF for 20 weeks. After Week 20, GS-4774 will be discontinued. All participants will continue on TDF and will be followed for an additional 28 weeks. Following completion of the 48 week study period, all participants will be eligible for a treatment extension for 96 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 195
• Est. completion date: May 30, 2018
• Est. primary completion date: February 17, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study

• Documented evidence of chronic hepatitis B virus (HBV) infection, for example, hepatitis B surface antigen (HBsAg) positive for more than 6 months

• Screening HBV DNA = 2000 IU/mL

• A negative serum pregnancy test is required for females (unless surgically sterile or > 2 years post-menopausal)

Key Exclusion Criteria:

• Cirrhosis

• Inadequate liver function

• Co-infection with hepatitis C virus (HCV), HIV or hepatitis D virus (HDV)

• Received antiviral treatment for HBV within 3 months of screening

• Evidence of hepatocellular carcinoma (eg, as evidenced by recent imaging)

• Significant cardiovascular, pulmonary, or neurological disease

• Women who are pregnant or may wish to become pregnant during the course of the study

• Received solid organ or bone marrow transplant

• Received prolonged therapy with immunomodulators (eg, corticosteroids) or biologics (eg, monoclonal antibody, interferon) within 3 months of screening

• Use of investigational agents within 3 months of screening

• Current alcohol or substance abuse judged by the investigator to potentially interfere with individual's compliance

• Receipt of immunoglobulin or other blood products within 3 months prior to enrollment

• History of demyelinating disease (Guillain-Barre), Bell's Palsy, Crohn's disease, Ulcerative colitis, or autoimmune disease

• Documented history of yeast allergy

• Known hypersensitivity to study drugs, metabolites or formulation excipients

• Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (basal cell skin cancer, etc). Individuals under evaluation for possible malignancy are not eligible

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Related Conditions & MeSH terms

• Chronic Hepatitis B
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Tenofovir disoproxil fumarate
TDF 300 mg tablet administered orally once daily

Biological:
• GS-4774
GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses

Locations

Country	Name	City	State
Canada	Toronto General Hospital-The University Health Network	Toronto	Ontario
Canada	Toronto Liver Centre	Toronto	Ontario
Canada	Toronto Western Hospital-The University Health Network	Toronto	Ontario
Canada	Gordon & Leslie Diamond Health Care Centre	Vancouver	British Columbia
Canada	Liver and Intestinal Research Center	Vancouver	British Columbia
Canada	University of Manitoba	Winnipeg	Manitoba
Italy	Aou-S.Orsola-Malpighi - Universita Degli Studi Di	Bologna
Italy	Azienda Ospedaliero-Universitaria di Parma	Parma
Italy	Azienda Ospedaliero-Universitaria Pisana	Pisa
Italy	IRCCS Casa Sollievo della Sofferenza	San Giovanni Rotondo
Korea, Republic of	Kyungpook National University Hospital	Daegu
Korea, Republic of	The Catholic University of Korea	Seocho
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University College of Medicine	Seoul
Korea, Republic of	Yonsei Universiity	Seoul
Korea, Republic of	Pusan National University Yangsan Hospital	Yangsan
Korea, Republic of	The Catholic University of Korea	Yangsan
New Zealand	Auckland Clinical Studies	Auckland
Romania	Dr. Victor Babes Hospital for Infectious Diseases	Bucharest
Romania	Institutul National de Boli Infectioase Prof.Dr. Matei Bals	Bucharest
United States	Digestive Disease Associates, PA	Baltimore	Maryland
United States	Tufts Medical Center	Boston	Massachusetts
United States	The Queen's Medical Center	Honolulu	Hawaii
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Stanford University Medical Center	Palo Alto	California
United States	Xiaoli Ma, PC	Philadelphia	Pennsylvania
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Kaiser Permanente	Sacramento	California
United States	Research and Education, Inc.	San Diego	California
United States	Kaiser Permanente San Francisco	San Francisco	California
United States	Silicon Valley Research Institute	San Jose	California
United States	Kaiser Permanente	Springfield	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Canada,  Italy,  Korea, Republic of,  New Zealand,  Romania, 

References & Publications (2)

Boni C, Janssen H, Rossi M, Yoon SK, Vecchi A, Barili V, Yoshida EM, Trinh H, Rodell T, Laccabue D, Alfieri A, Brillo F, Fisicaro P, Acerbi G, Pedrazzi G, Andreone P, Cursaro C, Margotti M, Santoro R, Piazzolla V, Brunetto MR, Coco B, Cavallone D, Zhao Y, — View Citation

Janssen HL, Yoon SK, Yoshida EM, Trinh HN, Rodell TC, Nguyen AH, et al. Safety and Efficacy of GS-4774 in combination with TDF in Patients with Chronic Hepatitis B not on Antiviral Medication [Abstract 231]. Hepatology AASLD Abstracts 2016;64 (Suppl S1):1

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Change in Serum HBsAg From Baseline to Week 24	The change from baseline to Week 24 in HBsAg was analyzed using a mixed effect model for repeated measures (MMRM). The model included treatment groups, ALT levels (> ULN or = ULN) at baseline, HBeAg status (positive or negative) at baseline, HBsAg level at baseline, visit and treatment-by-visit interaction as fixed effects and visit as a repeated measurement. Estimated least square means of treatment effects are presented with the 95% confidence intervals (CIs).	Baseline to Week 24
Secondary	Mean Change in HBsAg From Baseline to Week 12	The change from baseline to Week 12 in HBsAg was analyzed using a MMRM. The model included treatment groups, ALT levels (> ULN or = ULN) at baseline, HBeAg status (positive or negative) at baseline, HBsAg level at baseline, visit and treatment-by-visit interaction as fixed effects and visit as a repeated measurement. Estimated least square means of treatment effects are presented with the 95% CIs.	Baseline to Week 12
Secondary	Mean Change in HBsAg From Baseline to Week 48	The change from baseline to Week 48 in HBsAg was analyzed using a MMRM. The model included treatment groups, ALT levels (> ULN or = ULN) at baseline, HBeAg status (positive or negative) at baseline, HBsAg level at baseline, visit and treatment-by-visit interaction as fixed effects and visit as a repeated measurement. Estimated least square means of treatment effects are presented with the 95% CIs.	Baseline to Week 48
Secondary	Percentage of Participants With HBsAg Loss at Week 24	HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window.	Baseline to Week 24
Secondary	Percentage of Participants With HBsAg Loss at Week 48	HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window.	Baseline to Week 48
Secondary	Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 24	HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBsAg loss and seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBsAg loss within the targeted time window.	Baseline to Week 24
Secondary	Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 48	HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBsAg loss and seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBsAg loss within the targeted time window.	Baseline to Week 48
Secondary	Percentage of Participants With a = 0.5 Log10 IU/mL or a = 1.0 Log10 IU/mL Decline in HBsAg at Week 12	HBsAg with a = 0.5 or = 1.0 log10 IU/mL decline was defined as = 0.5 or = 1.0 decline from baseline in log10 IU/mL serum HBsAg at any postbaseline visit within the targeted time window.	Baseline to Week 12
Secondary	Percentage of Participants With a = 0.5 Log10 IU/mL or a = 1.0 Log10 IU/mL Decline in HBsAg at Week 24	HBsAg with a = 0.5 or = 1.0 log10 IU/mL decline was defined as = 0.5 or = 1.0 decline from baseline in log10 IU/mL serum HBsAg at any postbaseline visit within the targeted time window.	Baseline to Week 24
Secondary	Percentage of Participants With a = 0.5 Log10 IU/mL or a = 1.0 Log10 IU/mL Decline in HBsAg at Week 48	HBsAg with a = 0.5 or = 1.0 log10 IU/mL decline was defined as = 0.5 or = 1.0 decline from baseline in log10 IU/mL serum HBsAg at any postbaseline visit within the targeted time window.	Baseline to Week 48
Secondary	Percentage of Participants With HBeAg Loss at Week 24	HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window.	Baseline to Week 24
Secondary	Percentage of Participants With HBeAg Loss at Week 48	HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window.	Baseline to Week 48
Secondary	Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 24	HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBeAg loss and seroconversion was defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBeAg loss within the targeted time window.	Baseline to Week 24
Secondary	Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 48	HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBeAg loss and seroconversion was defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBeAg loss within the targeted time window.	Baseline to Week 48
Secondary	Percentage of Participants With HBV DNA < Lower Limit of Quantification (LLOQ) at Week 24	The LLOQ was defined as 20 IU/mL.	Week 24
Secondary	Percentage of Participants With HBV DNA < LLOQ at Week 48	The LLOQ was defined as 20 IU/mL.	Week 48
Secondary	Percentage of Participants Experiencing Virologic Breakthrough at Week 24	Virologic breakthrough was defined as HBV DNA = 69 IU/mL after having been < 69 IU/mL, or having had = 1.0 log10 increase in HBV DNA from nadir. Two consecutive visits that met the definition were required for a participant to be classified as having had virologic breakthrough.	Baseline to Week 24
Secondary	Percentage of Participants Experiencing Virologic Breakthrough at Week 48	Virologic breakthrough was defined as HBV DNA = 69 IU/mL after having been < 69 IU/mL, or a = 1.0 log10 increase in HBV DNA from nadir. Two consecutive visits that met the definition were required for a participant to be classified as having had virologic breakthrough.	Baseline to Week 48
Secondary	Number of Participants With Drug-Resistance Mutations at Week 48 or at the Last Visit Available	Resistance surveillance analysis was conducted at Week 48 or Early Discontinuation (with at least 24 weeks of exposure to TDF) for any participants who met inclusion criteria (HBV DNA = 69 IU/mL). Drug-resistant mutation status was assessed using HBV polymerase/ reverse transcriptase (pol/RT) population sequencing.	Baseline to Week 48