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Evaluating the Safety and Efficacy of Inarigivir in Non-cirrhotic, Hepatitis B e Antigen-negative Subjects Infected With HBV Virus and Receiving or Stopping Treatment With a NUC Inhibitor

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ClinicalTrials.gov Identifier: NCT04023721
Recruitment Status : Terminated (Safety)
First Posted : July 17, 2019
Last Update Posted : July 22, 2020
Sponsor:
Collaborator:
PRA Health Sciences
Information provided by (Responsible Party):
Spring Bank Pharmaceuticals, Inc.

Brief Summary:
An open-label, Phase 2, exploratory study to examine the safety and efficacy of inarigivir in non-cirrhotic, hepatitis B e antigen (HBeAg)-negative subjects with chronic HBV infection.

Condition or disease Intervention/treatment Phase
Hepatitis B HBV Hepatitis B, Chronic Drug: Inarigivir soproxil Drug: Nucleoside/nucleotide (NUC) analogue inhibitors Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Exploratory Study Evaluating the Safety and Antiviral Efficacy of Inarigivir Soproxil in Non-cirrhotic, Hepatitis B e Antigen-negative Subjects Infected With Chronic Hepatitis B Virus and Receiving or Stopping Treatment With a Nucleoside/Nucleotide Inhibitor
Actual Study Start Date : June 18, 2019
Actual Primary Completion Date : July 16, 2020
Actual Study Completion Date : July 16, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1 - Inarigivir Soproxil Alone
Cohort 1, 400 mg Inarigivir daily for 24 weeks and after treatment discontinuation will be followed for a further 18 months.
Drug: Inarigivir soproxil
Inarigivir soproxil 200 mg tablets

Experimental: Cohort 2 Arm A - Inarigivir Soproxil and NUC
Cohort 2, Arm A, 400 Inarigivir daily in addition to their prestudy nucleoside/nucleotide (NUC) analogue inhibitors for 48 weeks. At Week 48 subjects will stop both inarigivir and the NUC and be followed for a further 48 weeks off treatment.
Drug: Inarigivir soproxil
Inarigivir soproxil 200 mg tablets

Drug: Nucleoside/nucleotide (NUC) analogue inhibitors
Continuation of prestudy NUC therapy

Experimental: Cohort 2 Arm B - Inarigivir Soproxil and NUC
Cohort 2, Arm B, 400 mg Inarigivir daily plus prestudy nucleoside/nucleotide (NUC) analogue inhibitors for at least 24 weeks and up to 48 weeks. After treatment discontinuation of both inarigivir and the NUC, subjects will be followed off treatment up to Week 96.
Drug: Inarigivir soproxil
Inarigivir soproxil 200 mg tablets

Drug: Nucleoside/nucleotide (NUC) analogue inhibitors
Continuation of prestudy NUC therapy




Primary Outcome Measures :
  1. Proportion of subjects reporting an adverse event, clinically significant adverse event, or laboratory abnormality [ Time Frame: 28 to 52 weeks ]
    Proportion of subjects in Cohort 1 and 2 reporting an adverse event, clinically significant adverse event, or laboratory abnormality from start to end of treatment, and 30 days after stopping treatment

  2. Change in quantitative HBsAg (Cohort 1) [ Time Frame: Baseline to Week 24 ]
    Reduction in quantitative hepatitis B surface antigen (HBsAg) by >0.3 log10 from Baseline to Week 24 of subjects in Cohort 1

  3. Change in the percentage of subjects with loss of HBsAg (Cohort 1) [ Time Frame: Baseline to Weeks 24 and Week 48 ]
    Percentage of subjects in Cohort 1 with loss of hepatitis B surface antigen (HBsAg) from Baseline to Weeks 24 and 48

  4. Percentage of subjects with ALT flares (Cohort 1) [ Time Frame: 96 Weeks ]
    Percentage of subjects in Cohort 1 with alanine transaminase (ALT) flares, defined as ALT >200 IU or hepatitis B virus (HBV) DNA >20,000 IU

  5. Percentage of subjects with suppression of HBV DNA <2000 IU/L (Cohort 1) [ Time Frame: Weeks 24 ]
    Percentage of subjects in Cohort 1 with suppression of hepatitis B virus (HBV) DNA <2000 IU/L at Weeks 24 and 48

  6. Percentage of subjects with suppression of HBV DNA <2000 IU/L (Cohort 1) [ Time Frame: Weeks 48 ]
    Percentage of subjects in Cohort 1 with suppression of hepatitis B virus (HBV) DNA <2000 IU/L at Weeks 24 and 48

  7. Percentage of subjects with ALT <40 IU/L (Cohort 1) [ Time Frame: Weeks 24 ]
    Percentage of subjects in Cohort 1 with alanine transaminase (ALT) <40 IU/L at Weeks 24, 48, 72, and 96

  8. Percentage of subjects with ALT <40 IU/L (Cohort 1) [ Time Frame: Weeks 48 ]
    Percentage of subjects in Cohort 1 with alanine transaminase (ALT) <40 IU/L at Weeks 24, 48, 72, and 96

  9. Percentage of subjects with ALT <40 IU/L (Cohort 1) [ Time Frame: Weeks 72 ]
    Percentage of subjects in Cohort 1 with alanine transaminase (ALT) <40 IU/L at Weeks 24, 48, 72, and 96

  10. Percentage of subjects with ALT <40 IU/L (Cohort 1) [ Time Frame: Weeks 96 ]
    Percentage of subjects in Cohort 1 with alanine transaminase (ALT) <40 IU/L at Weeks 24, 48, 72, and 96

  11. Percentage of subjects who lose HBsAg (Cohort 1) [ Time Frame: Weeks 72 ]
    Percentage of subjects in Cohort 1 who lose hepatitis B surface antigen (HBsAg) at Weeks 72 and 96

  12. Percentage of subjects who lose HBsAg (Cohort 1) [ Time Frame: Weeks 96 ]
    Percentage of subjects in Cohort 1 who lose hepatitis B surface antigen (HBsAg) at Weeks 72 and 96

  13. Percentage of subjects with suppression of HBV DNA <2000 IU/L (Cohort 2) [ Time Frame: Weeks 72 ]
    Percentage of subjects in Cohort 2 with suppression of hepatitis B virus (HBV) DNA <2000 IU/L at Weeks 72 and 96 (off inarigivir treatment)

  14. Percentage of subjects with suppression of HBV DNA <2000 IU/L (Cohort 2) [ Time Frame: Weeks 96 ]
    Percentage of subjects in Cohort 2 with suppression of hepatitis B virus (HBV) DNA <2000 IU/L at Weeks 72 and 96 (off inarigivir treatment)

  15. Percentage of subjects with ALT <40 IU/L (Cohort 2 ) [ Time Frame: Weeks 72 ]
    Percentage of subjects in Cohort 2 with alanine transaminase (ALT) <40 IU/L at Weeks 72 and 96 (off inarigivir treatment)

  16. Percentage of subjects with ALT <40 IU/L (Cohort 2 ) [ Time Frame: Weeks 96 ]
    Percentage of subjects in Cohort 2 with alanine transaminase (ALT) <40 IU/L at Weeks 72 and 96 (off inarigivir treatment)

  17. Percentage of subjects with HBsAg <1000 IU (Cohort 2) [ Time Frame: Weeks 72 ]
    Percentage of subjects in Cohort 2 with alanine transaminase (ALT) <40 IU/L at Weeks 72 and 96 (off inarigivir treatment)

  18. Percentage of subjects with HBsAg <1000 IU (Cohort 2) [ Time Frame: Weeks 96 ]
    Percentage of subjects in Cohort 2 with alanine transaminase (ALT) <40 IU/L at Weeks 72 and 96 (off inarigivir treatment)


Secondary Outcome Measures :
  1. Change in serum levels of IFN-α, IFN-γ, TNF, IL-6, IL-10, and IP-10 [ Time Frame: Baseline to Week 96 (100 weeks) ]
    Fold change from Baseline in markers of innate immunity in serum of IFN-α, IFN-γ, TNF, IL-6, IL-10, and IP-10 in subjects in Cohort 1 and 2

  2. Percentage of subjects with HBsAg decline >0.3 log10 (Cohort 2) [ Time Frame: Weeks 12, 24, 48, 72, and 96 ]
    Percentage of subjects in Cohort 2 with hepatitis B surface antigen (HBsAg) decline >0.3 log10 at Weeks 12, 24, 48, 72, and 96

  3. Percentage of subjects with HBsAg decline >0.5 log10 (Cohort 2) [ Time Frame: Weeks 12, 24, 48, 72, and 96 ]
    Percentage of subjects in Cohort 2 with hepatitis B surface antigen (HBsAg) decline >0.5 log10 at Weeks 12, 24, 48, 72, and 96

  4. Percentage of subjects with HBsAg loss (Cohort 2) [ Time Frame: Weeks 24, 48, 72, and 96 ]
    Percentage of subjects in Cohort 2 with hepatitis B surface antigen (HBsAg) loss at Weeks 24, 48, 72, and 96

  5. Percentage of subjects with undetectable HBV DNA (Cohort 2) [ Time Frame: Weeks 24, 48, 72, and 96 ]
    Percentage of subjects in Cohort 2 with undetectable hepatitis B virus (HBV) DNA at Weeks 24, 48, 72, and 96

  6. Percentage of subjects who suppress HBsAg <100 IU (Cohort 2) [ Time Frame: Weeks 24, 48, 72, and 96 ]
    Percentage of subjects in Cohort 2 who suppress hepatitis B surface antigen (HBsAg) <100 IU at Weeks 24, 48, 72, and 96

  7. Change in serum HBV DNA, HBsAg, and HBV RNA in log10 IU/mL (Cohort 2) [ Time Frame: Baseline to Week 96 (100 weeks) ]
    Change in serum hepatitis B virus (HBV) DNA, hepatitis B surface antigen (HBsAg), and HBV RNA in log10 IU/mL from Baseline to Weeks 12, 24, 48, 72, and 96 for subjects in Cohort 2



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. HBV-infected male and female subjects aged 18 to 70 years, inclusive
  2. Ultrasound, computed tomography (CT) scan, or magnetic resonance imaging (MRI) within 6 months of enrollment (Cohort 1) or randomization (Cohort 2) date with no evidence of cirrhosis or hepatocellular carcinoma (HCC)
  3. Must be willing and able to comply with all study requirements
  4. Have HBV DNA <LLOQ at Screening
  5. ALT normal or, if elevated, <2× ULN with a documented etiology for elevation such as non-alcoholic fatty liver disease (NAFLD) confirmed by either ultrasound or controlled attenuation parameter (CAP) score >280 on elastography
  6. Negative urine or serum pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of IP. If the urine pregnancy test is positive, a follow-up serum test is required for confirmation
  7. Women of childbearing potential must agree to use a highly effective method of contraception throughout the study and for 3 months after discontinuing study treatment. Men with female partners who are of childbearing potential must agree that they or their partners will use a highly effective method of contraception throughout the study and for 3 months after discontinuing study treatment. Male subjects must not donate sperm throughout the study and for 3 months after discontinuing study treatment.

    • Women of childbearing potential are sexually mature women who have not undergone bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or who have not been postmenopausal (ie, who have not menstruated at all) for at least 1 year.
    • Highly effective methods of contraception are hormonal contraceptives (oral, injectable, patch, intrauterine devices), male partner sterilization, or total abstinence from heterosexual intercourse, when this is the preferred and usual lifestyle of the subject. Note: The double-barrier method (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), periodic abstinence (such as calendar, symptothermal, post-ovulation), withdrawal (coitus interruptus), lactational amenorrhea method, and spermicide only are not acceptable as highly effective methods of contraception.
  8. Must have the ability to understand and sign a written informed consent form (ICF); consent must be obtained prior to initiation of study procedures

In addition, subjects must meet the cohort-specific criteria listed below:

Cohort 1:

  1. HBeAg-negative subjects on documented NUCs for ≥3 years with undetectable HBV DNA by polymerase chain reaction (PCR) documented at least annually over the last 2 years. NUCs can include tenofovir, entecavir, telbivudine, lamivudine, adefovir, and tenofovir-5TC.
  2. HBsAg <1000 IU at Screening
  3. Planning to discontinue NUC therapy

Cohort 2:

  1. HBeAg-negative subjects on documented NUCs for ≥1 year with undetectable HBV DNA by PCR documented on at least 1 occasion in the last 6 months. NUCs can include tenofovir, entecavir, telbivudine, lamivudine, adefovir, and tenofovir-5TC.
  2. Planning to continue NUC therapy

Exclusion Criteria:

  1. Any prior liver biopsy evidence of metavir F3 or F4 disease
  2. Any history of decompensation of liver disease including history of ascites, encephalopathy, or varices
  3. Evidence of advanced fibrosis as defined by Fibroscan at the Screening Visit of

    ≥8 kPa. If Fibroscan is not available, subjects with both a Fibrotest ≥0.65 and aspartate transaminase (AST):platelet ratio index (APRI) ≥1.0 are excluded (subjects will not be excluded if only 1 of the Fibrotest or APRI results is higher than allowed)

  4. Laboratory parameters not within defined thresholds:

    4.1 White blood cells <4000 cells/μL (<4.0×109/L) 4.2 Hemoglobin <11 g/dL (<110 g/L) for females, <13 g/dL (<130 g/L) for males 4.3 Platelets <130,000 per μL (<130×109/L) 4.4 Albumin <3.5 g/dL (<35 g/L) 4.5 International normalized ratio (INR) >1.5 4.6 Total bilirubin >1.2 mg/dL (>20.52 μmol/L) or alpha-fetoprotein (AFP) >50 ng/mL (>180.25 nmol/L). Subjects with an elevated indirect bilirubin and known Gilbert's disease can be included if direct bilirubin is within normal limits. Subjects with an AFP >50 ng/mL but <500 ng/mL can be included if CT scan or MRI performed within 3 months shows no evidence of HCC 4.7 Creatinine >1.2 mg/dL (>106.08 μmol/L) and creatinine clearance <50 mL/min (<0.83 L/s/m2)

  5. Co-infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or hepatitis D virus
  6. Evidence or history of HCC
  7. Malignancy within 5 years prior to Screening, with the exception of specific cancers that are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for possible malignancy are not eligible
  8. Significant cardiovascular, pulmonary, or neurological disease
  9. Received solid organ or bone marrow transplant
  10. Received within 3 months of Screening or expected to receive prolonged therapy with immunomodulators (eg, corticosteroids) or biologics (eg, monoclonal antibody, IFN)
  11. Subjects currently taking medication(s) that are transported through organic anion transporting polypeptide 1 (OATP1) including, but not limited to, atazanavir, rifampin, cyclosporine, eltrombopag, gemfibrozil, lopinavir/ritonavir, and saquinavir
  12. Use of another investigational agent within 3 months of Screening
  13. Current alcohol or substance abuse judged by the Investigator to potentially interfere with compliance
  14. Females who are pregnant or may wish to become pregnant during the study
  15. If the Investigator believes the prospective subject will not be able to comply with the requirements of the protocol and complete the study
  16. Any medical condition that, in the opinion of the Investigator, could interfere with evaluation of the study objectives or safety of the subjects

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04023721


Locations
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Canada, Alberta
University of Calgary
Calgary, Alberta, Canada
Canada, British Columbia
GI Research Institute
Vancouver, British Columbia, Canada
LAIR Centre
Vancouver, British Columbia, Canada
Canada, Ontario
Toronto General Hospital
Toronto, Ontario, Canada
Toronto Liver Center
Toronto, Ontario, Canada
United Kingdom
Barts Health NHS Trust
London, England, United Kingdom
King's College Hospital NHS Foundation Trust
London, England, United Kingdom
Sponsors and Collaborators
Spring Bank Pharmaceuticals, Inc.
PRA Health Sciences
Investigators
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Study Director: Don Mitchell Spring Bank Pharmaceuticals
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Responsible Party: Spring Bank Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04023721    
Other Study ID Numbers: SBP-9200-HBV-206
First Posted: July 17, 2019    Key Record Dates
Last Update Posted: July 22, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis B
Hepatitis B, Chronic
Hepatitis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Hepatitis, Chronic