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Hepatitis BPhase 2NCT00524173

Tenofovir Alone Versus Tenofovir With Emtricitabine to Treat Chronic Hepatitis B

A Phase 2 study testing Tenofovir & Emtricitabine and Tenofovir in people with Hepatitis B, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Hepatitis B
What is being tested?
Tenofovir & Emtricitabine and Tenofovir
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
35 participants
Where
1 siteUnited States
Study dates
29 Aug 2007to 16 Feb 2017
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • INCLUSION CRITERIA SALVAGE STUDY (nucleoside analogue experienced subjects):
  • 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.
  • Written informed consent.
  • Serum ALT or AST levels 1.5 times the upper limit of norma (ULN) (for ALT: greater than 62 U/L and for AST: greater than 46 U/L) based on at least two determinations taken at least 2 weeks apart.

Who cannot join

  • 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).
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  • 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.
  • Active ethanol/drug abuse/psychiatric problems such as major depression, schizophrenia, bipolar illness, obsessive-compulsive disorder, severe anxiety, personality disorder that, in the investigator's opinion, might interfere with participation in the study.
  • History of renal tubular acidosis.
  • History of malignancy or treatment for a malignancy within the past 5 years.
  • Presence of conditions that, in the opinion of the investigators, would not allow the patient to be followed in the current study for at least 5 years.

Trial locations and contacts

1 site in 1 country.

United States1 site
  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: Tenofovir Disoproxil Fumarate Alone Versus Its Combination With Emtricitabine for Treatment of Chronic Hepatitis B

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.

Read the detailed description

Chronic hepatitis B is a major cause of cirrhosis, end-stage liver disease and hepatocellular carcinoma and affects approximately 1.25 million Americans. Six medications have been licensed for use in chronic hepatitis B in the United States, but their relative benefit and long-term efficacy remain unclear. In previous studies, we have shown that maintained suppression of hepatitis b virus DNA (HBV DNA) can be achieved with nucleoside analogues and that suppression is associated with marked improvements in disease. In this randomized study, we propose to evaluate long-term therapy with tenofovir alone or in combination with emtricitabine (FTC). Forty treatment-naive patients with chronic hepatitis B will be enrolled in the primary study. After medical evaluation and liver biopsy, patients will be stratified by hepatitis B e antigen (HBeAg) status and randomized to receive either tenofovir alone or in combination with FTC. Treatment will be continued long-term (at least four years) and patients will be carefully monitored for side effects, serum aminotransferase and HBV DNA levels. Patients will undergo repeat liver biopsy and assessment of antiviral resistance at 1 and 4 years. The primary endpoint of therapy will be the maintained suppression of HBV DNA to below 10(2) copies/ml (lower limit of detection of current assays). The study will assess the relative efficacy and safety of combination versus mono-therapy. A separate group of 60 previously treated patients will also be enrolled and randomized to mono- or combination-therapy to assess the safety profile of these agents. The primary analysis will be conducted on the entire study cohort.

Conditions
Hepatitis B
Being tested
Tenofovir & Emtricitabine, Tenofovir
Keywords
Emtricitabine, Tenofovir, Antiviral Therapy, Hepatitis B, HBV
Medical subject headings
Hepatitis B

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Tenofovir & EmtricitabineDrug

  • TenofovirDrug

Study groups in NCT00524173
Study groupRoleWhat they receive
Tenofovir onlyActive comparatorTenofovir 300mg by mouth daily for 192 weeks
Receives: Drug: Tenofovir
Tenofovir & emtricitabineExperimentalTenofovir 300mg in combination with emtricitabine 200mg by mouth daily for 192 weeks
Receives: Drug: Tenofovir & Emtricitabine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: At Week 48

  2. 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

    Measured: At Week 192

Secondary outcomes (2)
  1. Number of Participants With Normalized Alanine Aminotransferase (ALT)

    Number of participants whose serum ALT levels were measured within normal limits.

    Measured: 192 weeks

  2. Number of Participants With Loss of HBsAg

    The number of participants whose serum hepatitis B surface antigen was no longer detectable.

    Measured: 192 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Sep 2007 (estimated)
  2. Study start29 Aug 2007
  3. Primary completion16 Feb 2017
  4. Study completion16 Feb 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
35 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00524173
Sponsor's protocol ID
070207
Other IDs
07-DK-0207
Status last verified
16 Mar 2018
First submitted
31 Aug 2007
Last updated
5 Jun 2019
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 16525138
  • 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.

    PubMed 12606734
  • 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.

    PubMed 10528035

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Tenofovir & Emtricitabine and Tenofovir in people with Hepatitis B, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 5 Jun 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 18 Apr 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Subjects With Hepatitis b Virus (HBV) DNA <1000 IU/ml at Week 48 (time frame: At Week 48). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00524173, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jun 2019.

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