Tenofovir Alone Versus Tenofovir With Emtricitabine to Treat Chronic Hepatitis B

NCT00524173 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: 07020707-DK-0207
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

This study will test whether the combination of two medications, tenofovir and emtricitabine, are safer and more effective for treating chronic hepatitis B than tenofovir alone. Chronic hepatitis B is a liver disease caused by infection with the hepatitis B virus. Several medications, including standard and pegylated interferon and the anti-viral drugs lamivudine, adefovir, entecavir and telbivudine, are currently used to treat the disease. Problems are associated with all of these agents, however, including development of viral resistance with long-term therapy of the anti-virals. Since many patients require long-term therapy to prevent their disease from worsening, a major goal of new approaches to treatment is to prevent the development of viral resistance. Combination treatment has been shown to be an effective strategy in preventing this resistance. Tenofovir is an anti-viral drug approved for use in patients with HIV infection. In small studies in patients infected with both HIV and hepatitis B, tenofovir lowered the level of hepatitis B virus in the blood, with no viral resistance reported when used for up to 5 years. Emtricitabine is an anti-viral drug similar to lamivudine and is effective at lowering viral load and improving liver damage. Patients 18 years of age and older with chronic hepatitis B may be eligible for this study. Participants are admitted to the NIH Clinical Center for a complete medical history and examination, including blood and urine tests, chest X-ray, electrocardiogram, abdominal ultrasound, Fibroscan (ultrasound exam of the liver that measures the amount of scarring), bone mineral density scan and liver biopsy. They are then randomly assigned to take combination treatment with tenofovir plus emtricitabine or tenofovir alone for at least 48 weeks. During the treatment period, patients visit the Clinical Center for blood tests and a physical examination every 2 weeks for the first month and then every 4 to 12 weeks. After 48 weeks, patients are readmitted to the Clinical Center for a complete evaluation that includes all the tests done at the start of therapy, including a liver biopsy. Patients who seem to have improved with treatment may continue therapy for up to 192 weeks, when they are again admitted to the Clinical Center for a complete medical evaluation and liver biopsy. Patients whose condition has not improved after 48 weeks of treatment have their treatment changed or stopped and continue to have regular outpatient clinic visits for 24 more weeks.

Conditions

Hepatitis B

Keywords

Emtricitabine; Tenofovir; Antiviral Therapy; Hepatitis B; HBV

Outcome Measures

Primary Outcomes (2)

• Number of Subjects With Hepatitis b Virus (HBV) DNA <1000 IU/ml at Week 48

  Number of subjects whose serum HBV DNA level was \<1000 IU/ml at Week 48

  At Week 48

• Number of Participants With HBV DNA <1000 IU/ml at Week 192

  Number of participants whose serum HBV DNA level was \<1000 IU/ml at Week 192

  At Week 192

Secondary Outcomes (2)

• Number of Participants With Normalized Alanine Aminotransferase (ALT)

  192 weeks

• Number of Participants With Loss of HBsAg

  192 weeks

Study Arms (2)

Tenofovir only

ACTIVE COMPARATOR

Tenofovir 300mg by mouth daily for 192 weeks

Drug: Tenofovir

Tenofovir & emtricitabine

EXPERIMENTAL

Tenofovir 300mg in combination with emtricitabine 200mg by mouth daily for 192 weeks

Drug: Tenofovir & Emtricitabine

Interventions

Tenofovir & Emtricitabine DRUG

Tenofovir & emtricitabine

Tenofovir DRUG

Tenofovir only

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age greater than 18 years and older, male or female.
• Known serum HBsAg positivity for 24 weeks.
• Detectable HBV DNA greater than 10(4) IU/ml. For patients with cirrhosis HBV DNA greater than 10(3) IU/ml
• Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels 1.5 times the upper limit of normal (for ALT: greater than or equal to 62 U/L and for AST greater than or equal to 46 U/L) based on at least two determinations taken at least one month apart during the 24 weeks before study entry; no ALT requirement for patients with cirrhosis.
• Liver biopsy within 2 years of entry that is consistent with chronic hepatitis and with a histology activity index (HAI) score of 4 or more (scores range from 0-18) and an Ishak fibrosis score of at least 1 (scores range from 0-6). For patients who have had a liver biopsy at another institution, slides must be obtained for reading and scoring at the NIH.
• Written informed consent.
• Age \>18 years and older, male or female
• Known serum HBsAg positivity for 6 months
• Detectable HBV DNA \>10(2) IU/ml.
• Liver biopsy within 5 years of entry that is consistent with chronic hepatitis
• Written informed consent
• Age greater than 18 years and older, male or female.
• Known serum HBsAg positivity for 6 months.
• Detectable HBV DNA greater than 10(3) IU per milliliter.
• Liver biopsy within 5 years of entry that is consistent with chronic hepatitis.

You may not qualify if:

• Previous or current treatment with tenofovir or emtricitabine.
• Co-infection with hepatitis delta virus (HDV) as defined by the presence of anti-HDV in serum and/or HDV antigen in the liver.
• Co-infection with hepatitis c virus (HCV) as defined by the presence of HCV RNA in serum.
• Co-infection with HIV as defined by the presence of anti-HIV in serum.
• Decompensated liver disease as defined by serum bilirubin greater than 2.5 milligram per deciliter (with direct bilirubin greater than 0.5 milligram per deciliter), prothrombin time of greater than 2 seconds prolonged, a serum albumin of less than 3 grams per deciliter, or a history of ascites, variceal bleeding or hepatic encephalopathy.
• Presence of other causes of liver disease (i.e. hemochromatosis, Wilson disease, alcoholic liver disease, nonalcoholic steatohepatitis, alpha-1anti-trypsin deficiency).
• A history of organ transplantation or in the absence of organ transplantation, any immunosuppressive therapy requiring the use of more than 5 milligrams of prednisone (or its equivalent) daily.
• Significant systemic illness other than liver diseases including congestive heart failure, renal failure, chronic pancreatitis, diabetes mellitus with poor control that in the opinion of the investigator may interfere with therapy.
• Pregnancy or inability to practice contraception in patients capable of bearing or fathering children and lactating women.
• Hepatocellular carcinoma (HCC), or the presence of a mass on imaging studies of the liver that is suggest of HCc, or an alpha-fetoprotein level of greater than 500ng/mL.
• History of clinically apparent pancreatitis or evidence of subclinical pancreatitis as shown by serum amylase values twice the upper limits of the normal range and abnormalities of the pancreas on CT or other imaging studies of the abdomen.
• Sensory or motor neuropathy apparent from medical history and physical examination.
• Creatinine clearance less than 50 ml/min, serum creatinine greater than 1.3 mg/dl or urine protein greater than 1 gram/24 hours; creatinine clearance will be determined on the average of two 24 hour urine specimens. Accuracy of collection will be ensured by documenting appropriate total creatinine excretion in the 24 hour urine specimen (15mg/kg) and correcting for the patient's age, gender and body surface area.
• Concurrent use of nephrotoxic agents (e.g. aminoglycosides, amphotericin B, vancomycin, foscarnet, cis-platinum, pentamidine, nonsteroidal anti-inflammatory agents) or competitors of renal tubular excretion (e.g. probenecid) within 2 months prior to study screening or the expectation that the subject will receive these during the course of the study.
• History of hypersensitivity to nucleoside analogues.

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L; BEHoLD AI463027 Study Group. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006 Mar 9;354(10):1011-20. doi: 10.1056/NEJMoa051287.

  PMID: 16525138 BACKGROUND

• Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL; Adefovir Dipivoxil 438 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003 Feb 27;348(9):800-7. doi: 10.1056/NEJMoa021812.

  PMID: 12606734 BACKGROUND

• Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, Crowther L, Condreay LD, Woessner M, Rubin M, Brown NA. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999 Oct 21;341(17):1256-63. doi: 10.1056/NEJM199910213411702.

  PMID: 10528035 BACKGROUND

MeSH Terms

Conditions

Hepatitis B

Interventions

Tenofovir; Emtricitabine

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Marc Ghany, MD
• Organization: NIDDK

marcg@intra.niddk.nih.gov

301-402-5115

Study Officials

• Marc G Ghany, M.D.

  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 31, 2007
• First Posted: September 3, 2007
• Study Start: August 29, 2007
• Primary Completion: February 16, 2017
• Study Completion: February 16, 2017
• Last Updated: June 5, 2019
• Results First Posted: April 18, 2018

Record last verified: 2018-03-16

Locations

US (1)