Clinical trial NCT04023721: 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
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hepatitis B
HBV
Hepatitis B, Chronic
Lead sponsor: F-star Therapeutics, Inc.
Sponsor class: INDUSTRY
Collaborators: name: PRA Health Sciences
First posted: 2019-07-17
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Proportion of subjects reporting an adverse event, clinically significant adverse event, or laboratory abnormality
timeFrame: 28 to 52 weeks
measure: Change in quantitative HBsAg (Cohort 1)
timeFrame: Baseline to Week 24
measure: Change in the percentage of subjects with loss of HBsAg (Cohort 1)
timeFrame: Baseline to Weeks 24 and Week 48
measure: Percentage of subjects with ALT flares (Cohort 1)
timeFrame: 96 Weeks
measure: Percentage of subjects with suppression of HBV DNA <2000 IU/L (Cohort 1)
timeFrame: Weeks 24
measure: Percentage of subjects with suppression of HBV DNA <2000 IU/L (Cohort 1)
timeFrame: Weeks 48
measure: Percentage of subjects with ALT <40 IU/L (Cohort 1)
timeFrame: Weeks 24
measure: Percentage of subjects with ALT <40 IU/L (Cohort 1)
timeFrame: Weeks 48
measure: Percentage of subjects with ALT <40 IU/L (Cohort 1)
timeFrame: Weeks 72
measure: Percentage of subjects with ALT <40 IU/L (Cohort 1)
timeFrame: Weeks 96
measure: Percentage of subjects who lose HBsAg (Cohort 1)
timeFrame: Weeks 72
measure: Percentage of subjects who lose HBsAg (Cohort 1)
timeFrame: Weeks 96
measure: Percentage of subjects with suppression of HBV DNA <2000 IU/L (Cohort 2)
timeFrame: Weeks 72
measure: Percentage of subjects with suppression of HBV DNA <2000 IU/L (Cohort 2)
timeFrame: Weeks 96
measure: Percentage of subjects with ALT <40 IU/L (Cohort 2 )
timeFrame: Weeks 72
measure: Percentage of subjects with ALT <40 IU/L (Cohort 2 )
timeFrame: Weeks 96
measure: Percentage of subjects with HBsAg <1000 IU (Cohort 2)
timeFrame: Weeks 72
measure: Percentage of subjects with HBsAg <1000 IU (Cohort 2)
timeFrame: Weeks 96
Secondary outcomes:
measure: Change in serum levels of IFN-α, IFN-γ, TNF, IL-6, IL-10, and IP-10
timeFrame: Baseline to Week 96 (100 weeks)
measure: Percentage of subjects with HBsAg decline >0.3 log10 (Cohort 2)
timeFrame: Weeks 12, 24, 48, 72, and 96
measure: Percentage of subjects with HBsAg decline >0.5 log10 (Cohort 2)
timeFrame: Weeks 12, 24, 48, 72, and 96
measure: Percentage of subjects with HBsAg loss (Cohort 2)
timeFrame: Weeks 24, 48, 72, and 96
measure: Percentage of subjects with undetectable HBV DNA (Cohort 2)
timeFrame: Weeks 24, 48, 72, and 96
measure: Percentage of subjects who suppress HBsAg <100 IU (Cohort 2)
timeFrame: Weeks 24, 48, 72, and 96
measure: Change in serum HBV DNA, HBsAg, and HBV RNA in log10 IU/mL (Cohort 2)
timeFrame: Baseline to Week 96 (100 weeks)
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Vancouver
country: Canada
facility: GI Research Institute
state: British Columbia
city: Vancouver
country: Canada
facility: LAIR Centre
state: British Columbia
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto Liver Center
state: Ontario
city: London
country: United Kingdom
facility: Barts Health NHS Trust
state: England
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
state: England
Study officials:
affiliation: Spring Bank Pharmaceuticals
name: Don Mitchell
role: STUDY_DIRECTOR
References: