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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: Tenofovir disoproxil fumarate; Biological: GS-4774

• Study Type: Interventional
• Enrollment (Actual): 195
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: TDF 48 weeks; Participants will receive TDF for 48 weeks. After Week 48, participants will have the option to continue receiving TDF for up to 144 weeks.	Drug: Tenofovir disoproxil fumarate; TDF 300 mg tablet administered orally once daily; Other Names: TDF; Viread®
Experimental: TDF plus GS-4774 2 YU; Participants will receive TDF plus GS-4774 2 yeast units (YU) for 20 weeks. After Week 20, GS-4774 will be discontinued and participants will continue on TDF for an additional 28 weeks. After Week 48, participants will have the option to continue receiving TDF for up to 144 weeks.	Drug: Tenofovir disoproxil fumarate; TDF 300 mg tablet administered orally once daily; Other Names: TDF; Viread®; Biological: GS-4774; GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses
Experimental: TDF plus GS-4774 10 YU; Participants will receive TDF plus GS-4774 10 YU for 20 weeks. After Week 20, GS-4774 will be discontinued and participants will continue on TDF for an additional 28 weeks. After Week 48, participants will have the option to continue receiving TDF for up to 144 weeks.	Drug: Tenofovir disoproxil fumarate; TDF 300 mg tablet administered orally once daily; Other Names: TDF; Viread®; Biological: GS-4774; GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses
Experimental: TDF plus GS-4774 40 YU; Participants will receive TDF plus GS-4774 40 YU for 20 weeks. After Week 20, GS-4774 will be discontinued and participants will continue on TDF for an additional 28 weeks. After Week 48, participants will have the option to continue receiving TDF for up to 144 weeks.	Drug: Tenofovir disoproxil fumarate; TDF 300 mg tablet administered orally once daily; Other Names: TDF; Viread®; Biological: GS-4774; GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
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
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
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
Percentage of Participants With HBV DNA < Lower Limit of Quantification (LLOQ) at Week 24	The LLOQ was defined as 20 IU/mL.	Week 24
Percentage of Participants With HBV DNA < LLOQ at Week 48	The LLOQ was defined as 20 IU/mL.	Week 48
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
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
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

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• 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):122A.
• Boni C, Janssen HLA, Rossi M, Yoon SK, Vecchi A, Barili V, Yoshida EM, Trinh H, Rodell TC, 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, Joshi A, Woo J, Lau AH, Gaggar A, Subramanian GM, Massetto B, Fung S, Ahn SH, Ma X, Mangia A, Ferrari C. Combined GS-4774 and Tenofovir Therapy Can Improve HBV-Specific T-Cell Responses in Patients With Chronic Hepatitis. Gastroenterology. 2019 Jul;157(1):227-241.e7. doi: 10.1053/j.gastro.2019.03.044. Epub 2019 Mar 28.

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2014
• Primary Completion (Actual): February 17, 2016
• Study Completion (Actual): May 30, 2018

Study Registration Dates

• First Submitted: June 23, 2014
• First Submitted That Met QC Criteria: June 23, 2014
• First Posted (Estimate): June 25, 2014

Study Record Updates

• Last Update Posted (Actual): June 4, 2019
• Last Update Submitted That Met QC Criteria: May 15, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir
• Other Study ID Numbers: GS-US-330-1401; 2014-001011-39 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No