Efficacy of Switching or Adding Pegylated Interferon in Chronic Hepatitis B Patients on Long Term Oral Antiviral Therapy
Condition: Chronic Hepatitis B
MeSH terms: Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic
Study type: Interventional
Phase: Phase 4

Summary: 
      Patients with Chronic Hepatitis B on long term oral antiviral therapy have to continue
      treatment indefinitely unless they achieve HBeAg seroconversion or HBsAg seroclearance, when
      therapy can be stopped. While HBeAg seroconversion is a more achievable endpoint, only 20-25%
      of patients develop this after one year of oral antiviral therapy. HBsAg seroclearance is
      universally infrequent. Strategies to improve these endpoints such as combination oral
      antiviral therapy have not been generally successful and recently studies have examined the
      possibility of switching or adding peginterferon therapy. However these have not been tested
      adequately in the group of patients that have been on long term oral antiviral therapy.
      Consequently this study was conceived to evaluate whether switching or adding peginterferon
      compared to continuing oral antiviral therapy are more efficacious strategies. HBeAg positive
      and HBeAg negative patients (n=310)will be randomised to continue oral antiviral therapy,
      switch or add pegylated interferon for 48 weeks in a ratio of 1:2:2 respectively. The study
      endpoints are HBsAg seroclearance, reduction of qHBsAg >1 log, qHBsAg<200 IU/ml, HBeAg loss
      and seroconversion, and HBV DNA suppression, all at week 72.
    

Detailed description: 
      1. HYPOTHESIS AND OBJECTIVES PEG-IFN as an immunomodulatory agent could potentiate the
           antiviral efficacy of patients on long term nucleos(t)ide analogue therapy and improve
           early indicators of efficacy, HBeAg loss and reduction in qHBsAg. This study will also
           test whether add-on compared to switch PEG-IFN is superior, if at all.

        2. STUDY DESIGN This is a randomized, open-label, active-controlled study to evaluate
           safety and the efficacy of HBeAg loss or reduction in qHBsAg >1 log in nucleos(t)ide
           analogue treated chronic hepatitis B subjects who will be treated with add on PEG (A),
           switch to PEG (B) or continued nucleos(t)ide analogue (C) for 48 weeks. Patients
           randomized to Arm B will have a one-month overlap period when switching from existing NA
           to PEG monotherapy. This is to prevent viral rebound during the switch. Patients will be
           randomized in a 2:2:1 ratio to one of the 3 treatment arms A, B, and C. Arms A and B are
           experimental arms. Arm C is the control arm.

        3. STUDY POPULATION Approximately 255 subjects will be enrolled into this study.

      3.1 Inclusion Criteria

      For entry into this study, the following inclusion criteria must be met:

        -  Age 21 - 70 years old (inclusive)

        -  Male or female subjects with chronic hepatitis B (ie. presence of positive HBsAg or HBV
           DNA for at least 6 months.

        -  On any NA (lamivudine, adefovir, entecavir or tenofovir) for ≥ 1 year

        -  HBV DNA undetected at screening

        -  Patient has agreed not to take any other investigational drug or systemic anti-viral,
           cytotoxic, corticosteroid, immunomodulatory agents or Chinese traditional remedies
           unless clinically indicated.

        -  Patient is able to give written consent prior to study start and to comply with the
           study requirements.

        -  Women of childbearing age must have a negative urine (ß-HCG) pregnancy test taken within
           14 days of starting therapy

      3.2 Exclusion Criteria

      For entry into this study, the following exclusion criteria must not be met:

        -  Patient who is on telbivudine.

        -  Evidence of decompensated liver disease defined as direct (conjugated) bilirubin
           >1.2xULN, prothrombin time (PT) >1.5x upper limit of normal (ULN), serum albumin <35
           g/L, or prior history of clinical hepatic decompensation (egs. ascites, encephalopathy,
           variceal hemorrhage).

        -  Evidence of hepatocellular carcinoma.

        -  Active co-infection with HIV antibody or HCV antibody or HDV antibody positivity.

        -  Presence of viral resistance defined as virological breakthrough (>1 log increase in HBV
           DNA from nadir) and presence of viral resistance mutations at the time of screening

        -  Absolute neutrophil count <1.5 X 109/L or platelets <90 x 109/L or hemoglobin <13 g/dL
           for men or <12g/dL for women

        -  Creatinine >1.5 times upper limit of normal or creatinine clearance <60mL/min (performed
           by central lab)

        -  Uncontrolled thyroid disease defined as thyroid-stimulating hormone (TSH) >1.2xULN or
           0.8xLLN or thyroid dysfunction.

        -  Any interferon, Immunomodulators, systemic cytotoxic agents, or systemic corticosteroids
           within 6 months before trial entry.

        -  Active substance abuse as defined by DSM-IV, Diagnostic Criteria for Drug and Alcohol
           abuse (appendix 1), which in the opinion of the investigator would make the candidate
           inappropriate for participation in this study.

        -  History of clinically relevant psychiatric disease, seizures, central nervous system
           dysfunction, severe pre-existing cardiac, renal, hematological disease or medical
           illness that in the investigator's opinion might interfere with therapy.

        -  History of autoimmune diseases.

        -  Ophthalmological disorders such as retinopathy, cotton wool spots, optic nerve disorder,
           retinal hemorrhage, or any other clinically significant abnormality.

        -  Chronic pulmonary diseases (e.g., chronic obstructive pulmonary disease, interstitial
           lung disease, pulmonary fibrosis, sarcoidsis).

        -  Malignant disease within 5 years of trial entry.

        -  Women who are pregnant and who are not practicing adequate birth control measures, or
           who are lactating

      4.1 Study Treatment

      Product, Dose, and Mode of Administration:

      Peginterferon α-2b (PEG), 1.5 μg/kg, will be administered weekly by subcutaneous injection
      for the specified period of time (see Study Design, Arms A and B). Pegintron® (MSD
      Pharmaceuticals). The dosage will be determined based on the recommended dosing regimen
      stated in the Pegintron product brochure provided by MSD Pharmaceuticals.

      Reference Therapy, Dose, and Mode of Administration:

      Patients will be on their existing nucleosid(t)e analogue therapy comprising lamivudine 100mg
      daily, adefovir 10mg daily, entecavir 0.5mg or 1.0mg daily or tenofovir 300mg daily, (or
      combinations thereof) all taken as oral medication. These will not be provided by the study
      protocol.

      4.2 Method of Assigning Subjects to a Treatment Randomisation will be performed by computer
      generated random codes (performed by Singapore Clinical Research Institute) with a masked
      allocation sequence. Randomization across treatment arms will be stratified by HBeAg status,
      type of nucleosid(t) analogue, and fibroscan score (<8.8 or ≥8.8) to ensure equal
      distribution across the 3 treatment groups.

      4.3 Blinding/Unblinding There will be no blinding of therapy and the study will be conducted
      as an open label study as is standard for interferon clinical trials.

      5. STUDY ASSESSMENTS AND PROCEDURES 5.1 Time and Event schedule 5.1.1. Screening Visit (Days
      - 45 to 1) 5.1.2. Baseline Assessments (day 1) 5.1.3. Treatment Assessments (day 2 to week
      48) 5.1.4. Pegylated-interferon-free Follow-up (FU) Visits: FU-Week 1 to 24

      5.2 Clinical Laboratory Tests Hematology: Full blood count (FBC), prothrombin time and
      international normalized ratio (PT INR) Chemistry: creatinine, albumin, alkaline phosphatase,
      aspartate transaminase, alanine transaminase, lactate dehydrogenase, total bilirubin,
      creatine phosphokinase, alphafetoprotein, (thyroid stimulating hormone and free T4 for
      patient on PEG-IFN) Urinalysis: Protein, Blood, Glucose Viral serology: HBeAg, anti-HBe,
      HBsAg, qHBsAg and anti-HBs

      6.0 Efficacy assessments HBeAg qualitative Anti-HBe qualitative HBsAg qualitative HBsAg
      quantitative HBV DNA (real time PCR)
    

Intervention name(s): peg-interferon alpha 2b, 1.5mcg/kg s/c given weekly; Nucleos(t)ide analogue therapy
Intervention type(s): Drug; Drug
Other intervention name(s): includes lamivudine, adefovir, entecavir, tenofovir or combinations thereof
Intervention MeSH terms: Interferons; Tenofovir; Interferon-alpha; Lamivudine; Interferon alpha-2; Entecavir; Adefovir; Peginterferon alfa-2b
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Three arm parallel study randomised 1:2:2
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hepatitis B virus; HBeAg positive; HBeAg negative; antiviral therapy; nucleoside analogues