A Study Evaluating the Safety, Pharmacokinetics, and Antiviral Efficacy of SB 9200 in Subjects Infected With Chronic HBV
Condition: Hepatitis B; Hepatitis, Viral
MeSH terms: Hepatitis A; Hepatitis B; Hepatitis
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a Phase 2, open-label,randomized, multiple dose, varied administration regimen study
      with 2 parts (Parts A and B) in Subjects Infected with Chronic Hepatitis B Virus
    

Detailed description: 
      This is a Phase 2, open-label, randomized, multiple dose, varied administration regimen study
      with 2 parts (Parts A and B).

      Part A will utilize an ascending dose cohort design with sequential cohorts. Each cohort will
      be evaluated by the DSMB for safety. Additional cohorts may be added by the DSMB to determine
      doses of SB 9200 that exhibit significant antiviral response and safety.

      Approximately 80 subjects will be assigned sequentially to 1 of the following dosing cohorts
      (20 subjects per cohort) and randomized in a 4:1 ratio (active:placebo) within each cohort.
      Randomization will be stratified so that no more than 2 HBeAg positive subjects will be
      assigned to receive placebo.

        -  SB 9200 25 mg or matching placebo administered qd

        -  SB 9200 50 mg or matching placebo administered qd

        -  SB 9200 100 mg or matching placebo administered qd

        -  SB 9200 200 mg or matching placebo administered qd

      After informed consent is obtained, subjects will enter a Screening period, which will last
      up to 28 days. Once all eligibility criteria are confirmed and the subject is randomized,
      subjects will receive the IP or placebo as a 2-week supply of capsules/tablets. All
      randomized subjects will receive the IP or matching placebo for a total of 12 weeks. All
      subjects will then receive tenofovir 300 mg qd for an additional 12 weeks of treatment.

      Subjects will start the treatment period on Day 1. The PK samples will be collected on Day 1
      at predose, 30 minutes, 1, 2, 4, 6, and 24 hours (predose the following day). At Week 6, the
      same sampling times will be used to collect PK samples from the subjects to collect steady
      state PK data. Subjects will return biweekly for the entire 12-week IP treatment period,
      except when beginning IP administration when subjects will be seen weekly, for safety
      assessments including physical examination and laboratory sample analysis of chemistry,
      hematology, and urine. Sample collection for efficacy (HBV DNA, HBsAg, HBeAg, hepatitis B
      envelope antibody [HBeAb], HBV RNA, and HBV resistance) will be collected as indicated in the
      Schedule of Events. A sample for genotyping will be collected at Day 1. Samples for Locarnini
      biomarkers and other biomarkers will also occur at Day 1; Weeks 2, 4, 8, 12, and 14; and at
      the End of Study Visit. Samples for cytokine levels will be collected at Day 1, Week 6, and
      Week 12. At Week 12, the end of IP administration, all subjects will return to the clinic and
      be administered IP and 300 mg tenofovir. Samples will be collected to explore the potential
      of a drug-drug interaction between SB 9200 and tenofovir. All subjects will have a predose PK
      sample then take the last dose of IP/placebo together with their first dose of tenofovir. The
      PK samples will then be collected for SB 9200 and tenofovir at 30 minutes,and 1, 2, 4, 6, and
      24 hours. Thereafter, the subjects will receive only tenofovir 300 mg qd for an additional 12
      weeks as 4-week supplies. All subjects will return to the clinic at Weeks 13, 14, 16, 20, and
      24. Subjects will have safety assessments including symptom-directed physical examinations
      and safety hematology, biochemistry, and virological studies performed at these visits.

      At Week 24, all subjects will have completed the study Part A (or Part B, as applicable).

      Part B will be an open-label, randomized, combination therapy design consisting of multiple
      cohorts. The study is designed to evaluate the safety, tolerability, and antiviral response
      in subjects treated for 12 weeks with a dose of SB 9200 selected from Part A that exhibits
      significant antiviral response and safety when administered in combination with tenofovir 300
      mg qd (Cohort 1) or with tenofovir 300 mg qd monotherapy alone (Cohort 2). All subjects will
      then continue in the study for an additional 12 weeks with tenofovir alone. Randomization
      between the 2 initial cohorts will be conducted using a 3:1 ratio resulting in 30 subjects
      being allocated to SB 9200 in combination with tenofovir (Cohort 1) and 10 subjects being
      allocated to tenofovir monotherapy (Cohort 2). No cohort can enroll more than 60% of either
      hepatitis e antigen negative or hepatitis e antigen positive subjects.

      Part B will utilize an adaptive design. The first 2 cohorts of Part B may start concurrently
      to Part A at any time after a dose has been selected from Part A. SB 9200 doses for which all
      subjects have not completed the initial 12 weeks monotherapy of SB 9200 from Part A and
      demonstrated safety of IP will not be selected to be administered in combination with
      tenofovir during Part B.

      The first 2 cohorts will randomize concurrently using a 3:1 ratio.

        -  Cohort 1: 30 subjects will receive SB 9200 selected dose #1 from Part A administered in
           combination with tenofovir 300 mg qd.

        -  Cohort 2: 10 subjects will receive tenofovir 300 mg qd monotherapy.

      Based on the results of Part A completed and ongoing cohorts and Part B first cohort, up to 2
      additional cohorts for which the dose of SB 9200 will be either escalated or de-escalated may
      be opened to enrollment:

        -  Cohort 3: 30 subjects will receive SB 9200 selected dose #2 from Part A administered in
           combination with tenofovir 300 mg qd.

        -  Cohort 4: 30 subjects will receive SB 9200 selected dose #3 from Part A administered in
           combination with tenofovir 300 mg qd.

      Subjects will be enrolled into the Screening period, which will last up to 28 days. Once all
      eligibility criteria are confirmed, subjects will receive the IP as a 2-week supply of
      capsules/tablets and tenofovir as a 4-week supply. Subjects will be required to take the IP
      per protocol for 12 weeks. Subjects will return biweekly for the entire 12-week IP treatment
      period, except when beginning IP administration when subjects will be seen weekly, for safety
      assessments including physical examination and laboratory sample analysis of chemistry,
      hematology, and urine. Samples for Locarnini biomarkers will also occur at Day 1; Weeks 2, 4,
      6, 12, and 14; and at the End of Study Visit. Sample collection for cytokine levels and other
      biomarkers of immune response and plasma samples will also occur at predose on Day 1 and at
      Weeks 6,12 and 24. The PK samples will be collected on Day 1 at predose, 30 minutes, and 1,
      2, 4, 6, and 24 hours (predose the following day). At Week 12, the same sampling times will
      be used to collect PK samples from the subjects to collect steady state PK data. Sample
      collection for population PK analysis will also be collected before IP administration at
      Weeks 4 and 8. Urinary PK will be collected on Day 1 and Week 12 predose, 6 hours, and 24
      hours (predose the following day).

      At Week 12, all subjects will be administered tenofovir 300 mg qd for an additional 12 weeks
      as 4-week supplies. All subjects will return to the clinic at Weeks 13, 14, 16, 20, and 24.
      Subjects will have safety assessments including symptom-directed physical examinations and
      safety hematology, biochemistry, and virological studies performed at these visits.

      Safety reporting for each subject in each cohort will continue after the subject first
      consents to participate in the study through the 24 week duration of the study or through the
      Extension Period until 30 days after the last dose is administered.

      At Week 24, all subjects will have completed the study Part A (or Part B, as applicable).

      Extension Period:

      Any subject who completes Part A or Part B may be eligible to take part in a 12-month
      Extension Period. Before any study-related procedures are performed, the subjects will have
      all study procedures explained to them, including information regarding the nature of the
      study, and subjects must sign an informed consent/assent form. During the Extension Period,
      subjects will receive tenofovir and return for visits every 3 months with laboratory tests of
      liver function and virological efficacy including HBsAg, HBeAg, HBeAb, and HBV DNA. No
      further study-related testing will be performed. Subjects who undergo full termination from
      the study during Part A or Part B will not be eligible to enroll into the extension study.

      Safety reporting for each subject in each cohort will continue after the subject first
      consents to participate in the study through the 24-week duration of the study or through the
      Extension Period until 30 days after the last dose is administered.
    

Intervention name(s): SB 9200; Placebo; Tenofovir
Intervention type(s): Drug; Drug; Drug
Intervention description(s): SB 9200
Other intervention name(s): SB9200
Intervention MeSH terms: Tenofovir
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Chronic Hepatitis; HBV; Double blind