Study of Nitazoxanide Compared to Placebo in Subjects With HBeAG-Negative Chronic Hepatitis B

Study Overview
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Brief Summary
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This randomized controlled trial is designed to evaluate safety, effectiveness and pharmacokinetic-pharmacodynamic (PK/PD) relationships associated with three different Nitazoxanide (NTZ) treatment regimens added to Tenofovir Disoproxil Fumarate (TDF), Tenofovir Alafenamide (TAF) or Entecavir (ETV) in treating Chronic Hepatitis B (CHB).

Official Title
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Randomized Double-Blind Study of Nitazoxanide Compared to Placebo in Subjects With HBeAG-Negative Chronic Hepatitis B Virologically Suppressed for at Least Twelve Months on Tenofovir Disoproxil Fumarate, Tenofovir Alafenamide or Entecavir

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Placebo Oral Tablet
* Drug: Nitazoxanide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age at least 21 years CHB virus infection (serum HBsAg-positive for at least 6 months or serum HBsAg-positive and negative immunoglobulin M (IgM) antibodies to Hepatitis B Virus (HBV) core antigen (IgM anti-HBc)) Hepatitis B e Antigen (HBeAg) negative Virologically suppressed (HBV DNA less than the lower limit of quantitation) for at least 12 months on Tenofovir Disoproxil Fumarate (TDF), Tenofovir Alafenamide (TAF) or Entecavir (ETV) therapy Quantitative HBsAg greater than 100 IU/mL Alanine Aminotransferase (ALT) below 1.5 times the upper limit of normal Able to comply with the study requirements Exclusion Criteria: Unable to take oral medications Females who are pregnant, breast-feeding or not using birth control. A double barrier method, oral birth control pills administered for at least 2 monthly cycles prior to study drug administration, an intrauterine device (IUD), or medroxyprogesterone acetate administered intramuscularly for a minimum of one month prior to study drug administration are acceptable methods of birth control for inclusion into the study. In addition, female subjects should have a baseline pregnancy test and should agree to continue an acceptable method of birth control for the duration of the study (including follow-up) if sexually active. Any investigational drug therapy within 30 days prior to enrollment Other causes of liver disease Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis D virus (HDV) based on an enzyme immunoassay (EIA) History of alcoholism or with an alcohol consumption of greater than 40 g per day Clinically unstable Any concomitant condition that, in the opinion of the investigator would preclude evaluation of response or make it unlikely that the contemplated course of therapy and follow-up could be completed History of hypersensitivity or intolerance to NTZ or any of the excipients comprising the NTZ tablets Hepatocellular carcinoma Decompensated liver disease including history of ascites, bleeding esophageal varices, portal hypertension or hepatic encephalopathy FibroScan® score greater than 11 or history of cirrhosis on liver biopsy Creatinine clearance <65 ml/minute (by the Cockcroft-Gault equation using ideal body weight) History of clinically relevant psychiatric disease, seizures, central nervous system dysfunction, severe pre-existing cardiac, renal, pathologic bone fracture or other risk factors for osteoporosis, hematological disease or medical illness that in the investigator's opinion might interfere with therapy Malignant disease within 3 years of trial entry Rheumatological conditions, inflammatory bowel disease or psoriasis requiring or anticipated to require biological/immunosuppressive therapies Subjects taking or anticipated to need medications considered to be major CYP2C8 substrates

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients are randomized 1:1:1:1 (12 subjects per group)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group 1<br>Three placebo tablets administered orally twice daily with food in addition to continuing TDF, TAF or ETV therapy | Drug: Placebo Oral Tablet<br>* Number of placebo tablets administered orally depends on the arm<br>|
| Active Comparator: Group 2<br>Two 300 mg NTZ tablets and one placebo tablet administered orally in the morning and three placebo tablets in the evening in addition to continuing TDF, TAF or ETV therapy | Drug: Placebo Oral Tablet<br>* Number of placebo tablets administered orally depends on the arm<br>Drug: Nitazoxanide<br>* Number of Nitazoxanide 300 mg extended release tablets administered orally depends on the arm<br>* Other names: NTZ, NT-300;|
| Active Comparator: Group 3<br>Two 300 mg NTZ tablets and one placebo tablet administered orally twice daily with food in addition to continuing TDF, TAF or ETV therapy | Drug: Placebo Oral Tablet<br>* Number of placebo tablets administered orally depends on the arm<br>Drug: Nitazoxanide<br>* Number of Nitazoxanide 300 mg extended release tablets administered orally depends on the arm<br>* Other names: NTZ, NT-300;|
| Active Comparator: Group 4<br>Three 300 mg NTZ tablets administered orally twice daily with food in addition to continuing TDF, TAF or ETV therapy | Drug: Nitazoxanide<br>* Number of Nitazoxanide 300 mg extended release tablets administered orally depends on the arm<br>* Other names: NTZ, NT-300;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Quantitative Hepatitis B Surface Antigen (qHBsAg) | Mean change in quantitative Hepatitis B Surface Antigen (qHBsAg) from Baseline | Baseline to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained HBsAg Loss With Suppression of HBV DNA for 24 Weeks After the End of Treatment | Proportion of participants with sustained HBsAg loss with suppression of HBV DNA for 24 weeks after the end of treatment | Baseline to 24 weeks after the end of treatment | 
| Change in Quantitative Hepatitis B Surface Antigen (qHBsAg) From Baseline to Different Time Points on Treatment | Change in mean Quantitative Hepatitis B Surface Antigen (qHBsAg) from Baseline to Day 3, Week 1, Week 2, Week 4, and Week 8 | 8 weeks | 
| Hepatitis B Surface Antigen (HBsAg) Loss | Proportion of participants with HBsAg loss defined as quantitative HBsAg below the lower limit of quantitation at Day 3, Week 1, Week 2, Week 4, Week 8, and Week 12 | 12 weeks | 
| Hepatitis B Surface Antigen (HBsAg) Seroconversion | Proportion of participants with hepatitis B surface antigen (HBsAg) seroconversion defined as HBsAg loss and gain of anti-hepatitis B antibodies at Day 3, Week 1, Week 2, Week 4, Week 8, and Week 12 | 12 weeks | 
| Hepatitis B Virus DNA Suppression | Proportion of participants with hepatitis B virus DNA suppression defined as hepatitis B virus DNA below the lower limit of quantitation (20 IU/mL) at Day 3, Week 1, Week 2, Week 4, Week 8, and Week 12 | 12 weeks | 
| Change in Fibrosis-4 (FIB-4) Score | Mean change in Fibrosis-4 (FIB-4) score from Baseline to Week 1, Week 2, Week 4, Week 8, and Week 12. FIB-4 score is calculated as (age in years * Aspartate aminotransferase (AST) in U/L)/(platelet count in 10^9 U/L * square root of alanine aminotransferase (ALT) in U/L). FIB-4 scores under 1.45 have a negative predictive value of 90% for advanced fibrosis (better outcome) and FIB-4 scores >3.25 have a positive predictive value of 65% for advanced fibrosis (worse outcome). See Sterling RK, Lissen E, Clumeck N, et. al. Development of a simple noninvasive index to predict significant fibrosis patients with HIV/HCV co-infection. Hepatology 2006;43:1317-1325. | 12 weeks | 
| Change in FibroScan Score | Mean change in FibroScan score from Baseline to end of treatment. Fibroscan is a kind of liver elastography measuring liver stiffness in kilopascals (kPa). Higher results are consistent with liver disease (worse outcome). | Baseline to end of treatment |