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

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

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).

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: Placebo Oral Tablet; Drug: Nitazoxanide

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore
    • National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 98 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age at least 21 years
2. 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))
3. Hepatitis B e Antigen (HBeAg) negative
4. 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
5. Quantitative HBsAg greater than 100 IU/mL
6. Alanine Aminotransferase (ALT) below 1.5 times the upper limit of normal
7. Able to comply with the study requirements

Exclusion Criteria:

1. Unable to take oral medications
2. 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.
3. Any investigational drug therapy within 30 days prior to enrollment
4. Other causes of liver disease
5. Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis D virus (HDV) based on an enzyme immunoassay (EIA)
6. History of alcoholism or with an alcohol consumption of greater than 40 g per day
7. Clinically unstable
8. 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
9. History of hypersensitivity or intolerance to NTZ or any of the excipients comprising the NTZ tablets
10. Hepatocellular carcinoma
11. Decompensated liver disease including history of ascites, bleeding esophageal varices, portal hypertension or hepatic encephalopathy
12. FibroScan® score greater than 11 or history of cirrhosis on liver biopsy
13. Creatinine clearance <65 ml/minute (by the Cockcroft-Gault equation using ideal body weight)
14. 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
15. Malignant disease within 3 years of trial entry
16. Rheumatological conditions, inflammatory bowel disease or psoriasis requiring or anticipated to require biological/immunosuppressive therapies
17. Subjects taking or anticipated to need medications considered to be major CYP2C8 substrates

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Group 1; Three placebo tablets administered orally twice daily with food in addition to continuing TDF, TAF or ETV therapy	Drug: Placebo Oral Tablet; Number of placebo tablets administered orally depends on the arm
Active Comparator: Group 2; 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; Number of placebo tablets administered orally depends on the arm; Drug: Nitazoxanide; Number of Nitazoxanide 300 mg extended release tablets administered orally depends on the arm; Other Names: NTZ, NT-300
Active Comparator: Group 3; 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; Number of placebo tablets administered orally depends on the arm; Drug: Nitazoxanide; Number of Nitazoxanide 300 mg extended release tablets administered orally depends on the arm; Other Names: NTZ, NT-300
Active Comparator: Group 4; Three 300 mg NTZ tablets administered orally twice daily with food in addition to continuing TDF, TAF or ETV therapy	Drug: Nitazoxanide; Number of Nitazoxanide 300 mg extended release tablets administered orally depends on the arm; Other Names: NTZ, NT-300

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Romark Laboratories L.C.

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2019
• Primary Completion (Actual): March 10, 2021
• Study Completion (Actual): October 11, 2021

Study Registration Dates

• First Submitted: April 4, 2019
• First Submitted That Met QC Criteria: April 4, 2019
• First Posted (Actual): April 5, 2019

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 3, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Disease Attributes; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Chronic Disease; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic; Anti-Infective Agents; Antiparasitic Agents; Nitazoxanide
• Other Study ID Numbers: RM08-2001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No