Chronic Hepatitis B e Antigen Negative Clinical Trial
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
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.
| Status | Active, not recruiting |
| Enrollment | 26 |
| Est. completion date | December 2017 |
| Est. primary completion date | March 2013 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years and older |
| Eligibility |
- 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. HBsAg positive within 8 weeks prior to randomization plus evidence of chronic hepatitis B infection as indicated by a liver biopsy within 144 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 the Modified Ishak 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. |
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| United States | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland |
| United States | Mayo Clinic, Rochester | Rochester | Minnesota |
| Lead Sponsor | Collaborator |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) |
United States,
Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. Hepatology. 2007 Apr;45(4):1056-75. Review. — View Citation
Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007 Feb;45(2):507-39. Erratum in: Hepatology. 2007 Jun;45(6):1347. — View Citation
Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B virus infection: epidemiology and vaccination. Epidemiol Rev. 2006;28:112-25. Epub 2006 Jun 5. Review. — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | HBsAg loss at the end of 48-weeks post-treatment follow-up (week 240) | 48 weeks post treatment | No | |
| Secondary | ALT normalization | 192 weeks; 240 weeks | No | |
| Secondary | Cumulative HBsAg loss | 192 weeks; 240 weeks | No | |
| Secondary | HBsAg seroconversion | 192 weeks; 240 weeks | No | |
| Secondary | HBeAg loss | 192 weels; 240 weeks | No | |
| Secondary | ALT corresponding to approx 1.25XULN | 192, 228, 240 weeks | No | |
| Secondary | HBV DNA & lt; 1000 IU/mL | 192, 228, 240 weeks | No | |
| Secondary | HBV DNA & lt; 20 IU/m | 192, 228, 240 weeks | No | |
| Secondary | Absence antiviral drug-resistance HBV mu | 192 weeks | No | |
| Secondary | Sustained HBV DNA less than 1000 IU/mL | 192 weeks; 240 weeks | No | |
| Secondary | Rate treatment discontinuation due to AE | 192 weeks | Yes | |
| Secondary | Rates of AE and SAE | 240 weeks | Yes | |
| Secondary | HBV DNA & lt; 1000IU/mL & amp; ALT approx 1.25XULN | 228 and 240 weeks | No | |
| Secondary | Rate of treatment failure | 240 weeks | No |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT01581554 -
Withdrawal of Therapy After Long-Term Antiviral Treatment for Chronic Hepatitis B
|
||
| Recruiting |
NCT01306071 -
Observational Study of Persons With Hepatitis B Virus Infection in North America
|
N/A |