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Study of Anti-Viral Prophylaxis for HBsAg(+) or HBcAb(+)/HBsAb(-) Patients Starting Anti-TNFα

Primary Purpose

Chronic Hepatitis B, Rheumatoid Arthritis, Ankylosing Spondylitis

Status
Terminated
Phase
Phase 3
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Entecavir
Placebo
Sponsored by
Seoul National University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Chronic Hepatitis B focused on measuring HBV surface antigen, Anti-HBc positive, Anti-TNFα Treatment, Reactivation

Eligibility Criteria

16 Years - 85 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Chronic hepatitis B, inactive HBsAg carriers or anti-HBc antibody positive patients with AST, ALT level equal or lower than 2x ULN
  • Patient who has systemic rheumatic disease for which anti-TNFα treatment indication has been approved by the KFDA; rheumatoid arthritis (RA, 1987 ACR criteria), ankylosing spondylitis (AS, modified New York criteria), psoriatic arthritis (PsA, modified ESSG criteria), and juvenile rheumatoid arthritis (JRA, 1977 ACR criteria).
  • Patient who is eligible to start anti-TNFα treatment (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol) due to treatment failure of other DMARDs against underlying RA, AS, PsA, or JRA. Patient who also fully understands that anti-TNFα agent expenses are not covered in this study.
  • Patient who is willing and able to comply with the study drug regimen and all other study requirements
  • Patient who is willing and able to provide a written informed consent to participate in the study

Exclusion Criteria:

  • Patient who has liver cirrhosis or a history of hepatocellular carcinoma (HCC) or findings suggestive of HCC, such as suspicious foci or elevated serum alpha fetoprotein (AFP)
  • Patient who received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study
  • Patient who has concomitant other chronic viral infection (HCV or HIV)
  • Patient who is pregnant or breastfeeding or willing to be pregnant
  • A history of chronic infection, recent serious or life-threatening infection. Especially,

    • Patient with current clinical or laboratory evidence of active tuberculosis (TB) or latent TB unless there is documentation of prior anti-TB treatment was appropriate in duration according to the Korea Food and Drug Administration (KFDA) guidelines for management of latent TB in patients being treated with biologic agents
    • Patient with a history of herpes zoster within 2 months before screening for this study
  • Active malignancy or a history of treated malignancy less than 5 years prior to screening
  • Patients who are not cooperative or unable to comply with the study procedures
  • Patients with any other condition which the investigator's judgment would make the patient unsuitable for inclusion in the study such as alcohol and drug abuse

Sites / Locations

  • Hallym University Sacred Heart Hospital
  • Dong-A University, College of Medicine
  • Daegu Catholic Medical Center
  • Kyungpook National University Hospital
  • Chungnam National University Hospital
  • Daejun Eulji University Hospital
  • Chonnam National University Hospital
  • Gachon University Gil Medical Center
  • Inha University Hospital
  • Chonbuk National University Hospital
  • Seoul National University Hospital
  • Ewha Womans University Mokdong Hospital
  • Hanyang University Hospital
  • Konkuk University Hospital
  • Korea University Guro Hospital
  • Kyung Hee University Gangdong Hospital
  • Kyunghee University Medical Center
  • Severance Hospital
  • SMG-SNU Boramae Medical Center
  • The Catholic University of Korea, Seoul St. Mary's
  • The Catholic University of Korea, Yeouido St. Mary's Hospital
  • Ajou University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Experimental Group

Control Group

Arm Description

Entecavir (Baraclude (Bristol-Myers Squibb) 0.5mg.) will be taken orally on an empty stomach (2 hours after a meal or at least 2 hours before the next meal), once daily from 1 week before starting anti-TNFα and continue 72 weeks after anti-TNFα is administered.

Placebo of Entecavir (prepared by Bristol-Myers Squibb) will be taken orally on an empty stomach (2 hours after a meal or at least 2 hours before the next meal), once daily from 1 week before starting anti-TNFα and continue 72 weeks after anti-TNFα is administered.

Outcomes

Primary Outcome Measures

The frequency (events) of HBV reactivation
Elevated HBV DNA titer: ≥1 log10 rise in HBV DNA level compared with baseline level (virologic breakthrough), along with Increase of AST or ALT above 32 x upper limit of normal (ULN) (biochemical breakthrough)

Secondary Outcome Measures

Incidence of HBV reactivation among different anti-TNFα treatment groups

Full Information

First Posted
September 24, 2012
Last Updated
March 2, 2017
Sponsor
Seoul National University Hospital
Collaborators
Konkuk University Medical Center, Kyungpook National University Hospital, Kyunghee University Medical Center, Kyung Hee University Hospital at Gangdong, Gachon University Gil Medical Center, Daegu Catholic University Medical Center, Eulji University Hospital, SMG-SNU Boramae Medical Center, The Catholic University of Korea, Severance Hospital, Ajou University School of Medicine, Ewha Womans University Mokdong Hospital, Inha University Hospital, Chonnam National University Hospital, Chonbuk National University Hospital, Chungnam National University Hospital, Hallym University Medical Center, Hanyang University, Dong-A University, Korea University Guro Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01694264
Brief Title
Study of Anti-Viral Prophylaxis for HBsAg(+) or HBcAb(+)/HBsAb(-) Patients Starting Anti-TNFα
Official Title
A Randomized, Double-blinded, Phase 3, Multicenter, Investigator-initiated Trial for Entecavir for Prophylaxis of Hepatitis B Virus (HBV) Reactivation in HBV Surface Antigen or Anti-HBc Positive Patients Undergoing Anti-TNFα Treatment
Study Type
Interventional

2. Study Status

Record Verification Date
March 2017
Overall Recruitment Status
Terminated
Why Stopped
Delayed recruitment, unable to meet calculated sample size
Study Start Date
September 1, 2012 (Actual)
Primary Completion Date
August 31, 2015 (Actual)
Study Completion Date
December 31, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Seoul National University Hospital
Collaborators
Konkuk University Medical Center, Kyungpook National University Hospital, Kyunghee University Medical Center, Kyung Hee University Hospital at Gangdong, Gachon University Gil Medical Center, Daegu Catholic University Medical Center, Eulji University Hospital, SMG-SNU Boramae Medical Center, The Catholic University of Korea, Severance Hospital, Ajou University School of Medicine, Ewha Womans University Mokdong Hospital, Inha University Hospital, Chonnam National University Hospital, Chonbuk National University Hospital, Chungnam National University Hospital, Hallym University Medical Center, Hanyang University, Dong-A University, Korea University Guro Hospital

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Analysis of effect of anti-TNFα treatment on HBV reactivation among patients with systemic rheumatic disease, especially rheumatoid arthritis
Detailed Description
Biologic agents, especially anti-TNFα treatments are widely used in inflammatory arthritis such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). More than 60% of RA or AS patients achieve good clinical response to anti-TNFα treatment. However, TNFα is also an important mediator participating in the normal immune response to infectious agents, in particular intracellular microorganisms in the human body. Therefore, opportunistic infections such as tuberculosis, viral and fungal infections have been of concern when using anti-TNFα agents. With accumulating experience, the treatment guideline for anti-TNFα therapy in latent tuberculosis is now well established. It is noteworthy that there are a number of case reports describing hepatitis B virus (HBV) reactivation in otherwise asymptomatic carriers who received anti-TNFα treatment. Anti-TNFα agents are now utilized as a promising treatment regimen for RA and AS treatment for even HBsAg carriers, yet there are still concerns of the risk of anti-TNFα therapy contributing to HBV reactivation. In our previous studies, we found that anti-viral therapy before starting anti-TNFα treatment may reduce the incidence of HBV reactivation, and that entecavir is likely more suitable in long-term prophylaxis for HBsAg carriers under anti-TNFα treatment. This justifies the need of a prospective trial that could demonstrate the long-term effects of prophylaxis in using anti-TNFα therapy in this subgroup of patients. It would help clinicians understand 1) whether anti-viral therapy is necessary in inactive HBsAg carriers initiating anti-TNFα treatment, and 2) at what time point would we most likely witness HBV reactivation after starting anti-TNFα therapy without anti-viral therapy coverage. In addition to established nationwide network of Rheumatologists working in major academic institutes in Korea, our division in Seoul National University Hospital has led many multi-center trials throughout the past years. In summary, the question of whether to combine anti-viral prophylaxis in HBsAg carriers starting anti-TNFα therapy is an important issue to Rheumatologists. There is no guideline for managing this subset of patients, and clinicians normally begin anti-viral therapy after the patient's liver function worsens. Therefore, our nationwide network of specialists proposes to launch a prospective study to investigate the benefit of anti-viral prophylaxis with entecavir in HBsAg carriers starting anti-TNFα treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Hepatitis B, Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriatic Arthritis, Juvenile Idiopathic Arthritis
Keywords
HBV surface antigen, Anti-HBc positive, Anti-TNFα Treatment, Reactivation

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
43 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Experimental Group
Arm Type
Experimental
Arm Description
Entecavir (Baraclude (Bristol-Myers Squibb) 0.5mg.) will be taken orally on an empty stomach (2 hours after a meal or at least 2 hours before the next meal), once daily from 1 week before starting anti-TNFα and continue 72 weeks after anti-TNFα is administered.
Arm Title
Control Group
Arm Type
Placebo Comparator
Arm Description
Placebo of Entecavir (prepared by Bristol-Myers Squibb) will be taken orally on an empty stomach (2 hours after a meal or at least 2 hours before the next meal), once daily from 1 week before starting anti-TNFα and continue 72 weeks after anti-TNFα is administered.
Intervention Type
Drug
Intervention Name(s)
Entecavir
Other Intervention Name(s)
Baraclude (Bristol-Myers Squibb) 0.5mg
Intervention Description
Entecavir (Baraclude (Bristol-Myers Squibb) 0.5mg.) will be taken orally on an empty stomach (2 hours after a meal or at least 2 hours before the next meal), once daily from 1 week before starting anti-TNFα and continue 72 weeks after anti-TNFα is administered.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
placebo, prepared by Bristol-Myers Squibb
Intervention Description
Placebo of Entecavir (prepared by Bristol-Myers Squibb) will be taken orally on an empty stomach (2 hours after a meal or at least 2 hours before the next meal), once daily from 1 week before starting anti-TNFα and continue 72 weeks after anti-TNFα is administered.
Primary Outcome Measure Information:
Title
The frequency (events) of HBV reactivation
Description
Elevated HBV DNA titer: ≥1 log10 rise in HBV DNA level compared with baseline level (virologic breakthrough), along with Increase of AST or ALT above 32 x upper limit of normal (ULN) (biochemical breakthrough)
Time Frame
48 weeks
Secondary Outcome Measure Information:
Title
Incidence of HBV reactivation among different anti-TNFα treatment groups
Time Frame
72 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Chronic hepatitis B, inactive HBsAg carriers or anti-HBc antibody positive patients with AST, ALT level equal or lower than 2x ULN Patient who has systemic rheumatic disease for which anti-TNFα treatment indication has been approved by the KFDA; rheumatoid arthritis (RA, 1987 ACR criteria), ankylosing spondylitis (AS, modified New York criteria), psoriatic arthritis (PsA, modified ESSG criteria), and juvenile rheumatoid arthritis (JRA, 1977 ACR criteria). Patient who is eligible to start anti-TNFα treatment (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol) due to treatment failure of other DMARDs against underlying RA, AS, PsA, or JRA. Patient who also fully understands that anti-TNFα agent expenses are not covered in this study. Patient who is willing and able to comply with the study drug regimen and all other study requirements Patient who is willing and able to provide a written informed consent to participate in the study Exclusion Criteria: Patient who has liver cirrhosis or a history of hepatocellular carcinoma (HCC) or findings suggestive of HCC, such as suspicious foci or elevated serum alpha fetoprotein (AFP) Patient who received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study Patient who has concomitant other chronic viral infection (HCV or HIV) Patient who is pregnant or breastfeeding or willing to be pregnant A history of chronic infection, recent serious or life-threatening infection. Especially, Patient with current clinical or laboratory evidence of active tuberculosis (TB) or latent TB unless there is documentation of prior anti-TB treatment was appropriate in duration according to the Korea Food and Drug Administration (KFDA) guidelines for management of latent TB in patients being treated with biologic agents Patient with a history of herpes zoster within 2 months before screening for this study Active malignancy or a history of treated malignancy less than 5 years prior to screening Patients who are not cooperative or unable to comply with the study procedures Patients with any other condition which the investigator's judgment would make the patient unsuitable for inclusion in the study such as alcohol and drug abuse
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yeong wook Song, MD, PhD
Organizational Affiliation
Division of Rheumatology, Seoul National University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hallym University Sacred Heart Hospital
City
Anyang
Country
Korea, Republic of
Facility Name
Dong-A University, College of Medicine
City
Busan
Country
Korea, Republic of
Facility Name
Daegu Catholic Medical Center
City
Daegu
Country
Korea, Republic of
Facility Name
Kyungpook National University Hospital
City
Daegu
Country
Korea, Republic of
Facility Name
Chungnam National University Hospital
City
Daejun
Country
Korea, Republic of
Facility Name
Daejun Eulji University Hospital
City
Daejun
Country
Korea, Republic of
Facility Name
Chonnam National University Hospital
City
Gwangju
Country
Korea, Republic of
Facility Name
Gachon University Gil Medical Center
City
Incheon
Country
Korea, Republic of
Facility Name
Inha University Hospital
City
Incheon
Country
Korea, Republic of
Facility Name
Chonbuk National University Hospital
City
Jeonju
Country
Korea, Republic of
Facility Name
Seoul National University Hospital
City
Seoul
ZIP/Postal Code
110-744
Country
Korea, Republic of
Facility Name
Ewha Womans University Mokdong Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
Hanyang University Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
Konkuk University Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
Korea University Guro Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
Kyung Hee University Gangdong Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
Kyunghee University Medical Center
City
Seoul
Country
Korea, Republic of
Facility Name
Severance Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
SMG-SNU Boramae Medical Center
City
Seoul
Country
Korea, Republic of
Facility Name
The Catholic University of Korea, Seoul St. Mary's
City
Seoul
Country
Korea, Republic of
Facility Name
The Catholic University of Korea, Yeouido St. Mary's Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
Ajou University Hospital
City
Suwon
Country
Korea, Republic of

12. IPD Sharing Statement

Learn more about this trial

Study of Anti-Viral Prophylaxis for HBsAg(+) or HBcAb(+)/HBsAb(-) Patients Starting Anti-TNFα

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