Tenofovir DF With or Without Peginterferon for Chronic Hepatitis B

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )
ClinicalTrials.gov Identifier:
NCT01821794
First received: March 15, 2013
Last updated: July 1, 2014
Last verified: June 2014
  Purpose

Background:

- There are two forms of chronic hepatitis B. The difference between the forms is whether or not a viral protein called hepatitis B e antigen is present in the blood. Standard approaches to treating both forms of chronic hepatitis B involve different drugs. One drug is called peginterferon, another is called tenofovir DF. These drugs are often given separately and used for different forms of the disease. However, researchers want to see if combining peginterferon and tenofovir DF will be a more effective treatment than tenofovir DF alone.

Objectives:

- To see whether combining tenofovir DF and peginterferon, or using tenofovir DF alone, is a more effective treatment of chronic hepatitis B.

Eligibility:

- Individuals at least 18 years of age who have chronic hepatitis B and are in the Hepatitis B Research Network Cohort study.

Design:

  • Participants will be screened with a physical exam and medical history. Blood, urine, and liver tissue samples will be collected. Bone and liver imaging studies will also be performed.
  • Participants will be divided into two groups. One group will have tenofovir DF alone for 192 weeks (about 4 years). The other group will have tenofovir DF and peginterferon for 24 weeks (about 6 months), and then tenofovir DF alone for 168 weeks (about 3.5 years).
  • Participants will take the study drugs on the schedule determined by their study doctors. They will keep a diary to record their doses and any side effects.
  • Participants will have three study visits 4 weeks apart after the starting the treatment. At these visits, they will have a physical exam and provide blood samples. They may also provide urine samples and have imaging studies.
  • After the first three study visits, participants will continue to have study visits every 12 weeks until the treatment ends at week 192. These visits will have many of the same tests as the first three visits. At some of these visits, they may fill out questionnaires about their quality of life.
  • Participants who do not respond to the study drugs may have their medications changed. They may also be asked to stop treatment.

Condition Intervention Phase
Chronic Hepatitis B e Antigen Negative
Chronic Hepatitis B e Antigen Positive
Drug: Peginterferon and Tenofovir
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Combination Therapy of Pegylated Interferon Alfa-2a and Tenofovir DF Versus Tenofovir DF Monotherapy in HBeAg-Positive and HBeAg-Negative Chronic Hepatitis B

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • HBsAg loss at the end of 48-weeks post-treatment follow-up (week 240) [ Time Frame: 48 weeks post treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • ALT normalization [ Time Frame: 192 weeks; 240 weeks ] [ Designated as safety issue: No ]
  • Cumulative HBsAg loss [ Time Frame: 192 weeks; 240 weeks ] [ Designated as safety issue: No ]
  • HBsAg seroconversion [ Time Frame: 192 weeks; 240 weeks ] [ Designated as safety issue: No ]
  • HBeAg loss [ Time Frame: 192 weels; 240 weeks ] [ Designated as safety issue: No ]
  • ALT corresponding to approx 1.25XULN [ Time Frame: 192, 228, 240 weeks ] [ Designated as safety issue: No ]
  • HBV DNA & lt; 1000 IU/mL [ Time Frame: 192, 228, 240 weeks ] [ Designated as safety issue: No ]
  • HBV DNA & lt; 20 IU/m [ Time Frame: 192, 228, 240 weeks ] [ Designated as safety issue: No ]
  • Absence antiviral drug-resistance HBV mu [ Time Frame: 192 weeks ] [ Designated as safety issue: No ]
  • Sustained HBV DNA less than 1000 IU/mL [ Time Frame: 192 weeks; 240 weeks ] [ Designated as safety issue: No ]
  • Rate treatment discontinuation due to AE [ Time Frame: 192 weeks ] [ Designated as safety issue: Yes ]
  • Rates of AE and SAE [ Time Frame: 240 weeks ] [ Designated as safety issue: Yes ]
  • HBV DNA & lt; 1000IU/mL & amp; ALT approx 1.25XULN [ Time Frame: 228 and 240 weeks ] [ Designated as safety issue: No ]
  • Rate of treatment failure [ Time Frame: 240 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 31
Study Start Date: March 2013
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: TDF only
Tenofovir monotherapy
Drug: Peginterferon and Tenofovir
N/A

Detailed Description:

This is a randomized (1:1) parallel group design trial comparing (i) tenofovir DF 300 mg daily for 192 weeks (4 years) and (ii) peginterferon alfa-2a 180 micrograms/g weekly for 24 weeks plus tenofovir DF 300 mg daily for 192 weeks (4 years). Enrolled participants will be stratified by HBeAg status (positive/negative), genotype (A vs. all others) and cirrhosis (present vs. absent). After 192 weeks of treatment, participants meeting criteria for treatment discontinuation will stop treatment and be followed for 48 weeks (total duration of treatment and follow up is 240 weeks). A liver biopsy will be obtained at the end-of treatment (week 180-192) to assess improvement in histology. Emtricitabine/tenofovir coformulated as Truvada, approved for treating HIV but not for treating HBV infection, will be offered to participants with primary nonresponse, partial virological response or confirmed virologic breakthrough.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. Enrolled in the Hepatitis B Research Network (HBRN) Cohort Study or completed the necessary components of the Cohort baseline evaluation by the end of the baseline visit for this study.
    2. At least 18 years of age at the time of randomization (day 0).
    3. Chronic HBV infection as evidenced by at least one of the following:

      1. HBsAg positive result within 8 weeks prior to randomization and another time at least 24 weeks prior to randomization with no HBsAg negative result in between.
      2. HBsAg positive plus absence of detectable anti-HBc IgM in serum within 8 weeks prior to randomization.
      3. HBsAg positive within 8 weeks prior to randomization and HBV DNA greater than or equal to 1,000 IU/mL on 2 occasions at least 24 weeks apart (can include result from screening visit within 8 weeks of randomization).
    4. HBeAg positive or negative.
    5. Serum HBV DNA greater than or equal to 1000 IU/mL on 2 occasions at least 4 weeks apart within the 32 weeks prior to randomization (can include result from screening visit within 8 weeks of randomization).
    6. At least two elevated serum ALT levels (> 45 U/L for males and > 30 U/L for females) at least 4 weeks, and no more than 32 weeks apart with the second being within 8 weeks of randomization.
    7. Compensated liver disease, with total bilirubin less than or equal to 2 mg/dL (except if Gilbert s syndrome), direct bilirubin less than or equal to 0.5 mg/dL, INR less than or equal to 1.5, and serum albumin greater than or equal to 3.5 g/dL
    8. No evidence of HCC based upon alpha-fetoprotein (AFP) less than or equal to 20ng/mL within 8 weeks prior to randomization:

      1. Participants who meet AASLD criteria for HCC surveillance must have negative liver imaging by ultrasound (US), computerized tomography (CT) or magnetic resonance imaging (MR) within 28 weeks of randomization as part of standard of care.
      2. Participants with AFP > 20 ng/mL must be evaluated clinically with additional imaging and shown not to have HCC on CT or MRI.
    9. Liver biopsy that shows findings consistent with chronic hepatitis B with histology activity index (HAI) greater than or equal to 3 (necroinflammatory component only) or Ishak fibrosis score greater than or equal to 1 or both, as assessed by the local consortium pathologist on review of a liver biopsy done within 144 weeks of randomization. Slides must be available for review by the local consortium pathologist and meet adequacy requirements. If the participant had received previous treatment for hepatitis B, the biopsy must have been done after discontinuation of treatment.
    10. Females of child bearing potential must agree to use an adequate method of contraception throughout the study and must have a negative pregnancy test immediately prior to the start of treatment.
    11. Provide informed consent and agree to adhere to the requirements of the study.

EXCLUSION CRITERIA:

  1. Serum ALT > 450 U/L for males and > 300 U/L for females (participants are eligible for re-screening if ALT levels fall to the range of eligibility).
  2. Treatment with interferon or nucleos(t)ide analogues for hepatitis B within 48 weeks of randomization.
  3. More than 48 weeks of therapy with nucleos(t)ide analogues for hepatitis B at any time in the past.
  4. History of hepatic decompensation including, but not limited to, ascites, variceal bleeding, or hepatic encephalopathy.
  5. Known allergy or intolerance to any of the study medications.
  6. Females who are pregnant or breastfeeding.
  7. Previous organ transplantation including engrafted bone marrow transplant.
  8. Any other concomitant liver disease, including hemochromatosis or hepatitis C or D. Non-alcoholic fatty liver disease (NAFLD) with steatosis and/or mild to moderate steatohepatitis is acceptable but NALFD with severe steatohepatitis is exclusionary.
  9. Positive anti-HIV (test to be completed within 8 weeks prior to randomization).
  10. Renal insufficiency with calculated (by MDRD method) creatinine clearance < 60 mL/min within 8 weeks prior to randomization.
  11. Platelet count < 90,000 /mm3, hemoglobin < 13 g/dL (males) or < 12 g/dL (females), absolute neutrophil count < 1500 /mm3 (< 1000/mm3 for African-Americans) within 8 weeks prior to randomization.
  12. History of alcohol or drug abuse within 48 weeks of randomization.
  13. Pre-existing psychiatric condition(s), including, but not limited to:

    1. Current moderate or severe depression as determined by the study physician.
    2. History of depression requiring hospitalization within past 10 years.
    3. History of suicidal or homicidal attempt within the past 10 years.
    4. History of severe psychiatric disorders including, but not limited to, schizophrenia, psychosis, bipolar disorder as determined by a study physician.
  14. History of immune-mediated disease, or cerebrovascular, chronic pulmonary or cardiac disease associated with functional limitation, retinopathy, uncontrolled thyroid disease, poorly controlled diabetes or uncontrolled seizure disorder, as determined by a study physician.
  15. Any medical condition that would, in the opinion of a study physician be predicted to be exacerbated by therapy or that would limit study participation.
  16. Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids or other immunosuppressive medications during the course of this study.
  17. Evidence of active or suspected malignancy, or a history of malignancy within the last 144 weeks prior to randomization (except adequately treated carcinoma in situ or basal cell carcinoma of the skin).
  18. Expected need for ongoing use of any antivirals with activity against HBV during the course of the study.
  19. Participation in any other clinical trial involving investigational drugs within 30 days of randomization or intention to participate in another clinical trial involving investigational drugs during participation in this study.
  20. Any other condition that in the opinion of a study physician would make the participant unsuitable for enrollment or could interfere with the participant participating in and completing the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01821794

Contacts
Contact: Elenita Rivera, R.N. (301) 496-3531 erivera@cc.nih.gov
Contact: Marc G Ghany, M.D. (301) 402-5115 mg228m@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
United States, Minnesota
Mayo Clinic, Rochester Recruiting
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Investigators
Principal Investigator: Marc G Ghany, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )
ClinicalTrials.gov Identifier: NCT01821794     History of Changes
Other Study ID Numbers: 130091, 13-DK-0091
Study First Received: March 15, 2013
Last Updated: July 1, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Hepatitis B
Anti-Viral Treatment
Pegylated Interferon
Tenofovir Disoproxil Fumarate
Hepatitis B Surface Antigen

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis B
Hepatitis, Chronic
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Interferons
Tenofovir
Tenofovir disoproxil
Peginterferon alfa-2a
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents

ClinicalTrials.gov processed this record on July 22, 2014