Lamivudine and Adefovir to Treat Chronic Hepatitis B

NCT00023309 | Completed Phase 2 Results

• 2 other identifiers: 01024601-DK-0246
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate the safety and effectiveness of lamivudine plus adefovir versus adefovir alone to treat chronic hepatitis B infection. The Food and Drug Administration has approved lamivudine for the treatment of hepatitis B. However, the drug is not effective in all patients, and many of those in whom it initially works develop resistance after 1 to 3 years. Adefovir is an experimental drug that inhibits replication of the hepatitis B virus (HBV). Adefovir used alone may be adequate to provide sustained suppression of the virus and improvement in liver disease. However combining two anti-viral agents may be superior to using one alone, similar to the strategy employed for the treatment of AIDS. This study will test whether the combination of lamivudine and adefovir is better than adefovir alone for the treatment of chronic hepatitis B. Patients 18 years of age and older, who have been infected with HBV for at least 6 months, may be eligible for this study. Candidates may not have received lamivudine treatment in the past 6 months or prior treatment with adefovir and must not be taking other anti-viral treatments for their hepatitis. They will have a blood test to confirm HBV infection. Participants will be admitted to the NIH Clinical Center for 2 to 3 days for a medical evaluation. One to 2 weeks after the evaluation, patients will be randomized to begin taking lamivudine and adefovir, or adefovir alone. Therapy will continue for at least 12 months. Follow-up clinic visits will be scheduled weekly for the first month, then every 4 to 8 weeks for the rest of the treatment period. Patients will be evaluated at the end of 1 year. Patients who have not improved with treatment will stop taking the treatment and will be evaluated in the clinic once every 4 weeks for another 6 months. Patients who show an improvement in their liver injury may continue taking lamivudine and adefovir or adefovir alone for 4 more years, as long as they continue to improve with the medication. Progress will be evaluated. If the test results show no continued improvement or are negative for hepatitis B antigens, therapy will be stopped. Patients who continue treatment for 5 years will be readmitted at year 4 for another medical evaluation to assess the effects of treatment at that time. After the 5 years all patients will stop therapy at and be followed with regular clinic visits for at least 6 months.

Conditions

HBV (Hepatitis B Virus); Hepatitis B; Hepatitis

Keywords

Adefovir Dipivoxil; Lamivudine; Nucleoside/Nucleotide Analogue; Chronic Hepatitis B; Hepatitis B Mutants; Liver Biopsy; Hepatitis B; Hepatitis; HBV; Liver

Outcome Measures

Primary Outcomes (1)

• Maintained Combined Response (Virological, Biochemical and Histological Response).

  A maintained combined response was defined as a combination of a virological, biochemical and histological responses at weeks 48 and 192. A virological response was defined as a decrease in HBV DNA levels to undetectable by the Amplicor assay (\<500 copies/mL). A biochemical response was defined as a decrease in serum ALT levels into the normal range (\<41 U/L). A histological response was defined as a decrease in the HAI score by at least three points with no worsening of the Ishak fibrosis score.

  196 weeks from randomization

Secondary Outcomes (4)

• HBeAg Loss at Week 196

  Week 196 from randomization

• Virological Response

  Week 196 from randomization

• Biological Response

  week 196 from randomization

• Histological Response

  week 196 from randomization

Study Arms (2)

Lamivudine and adefovir

EXPERIMENTAL

Drug: Lamivudine and adefovir

Adefovir

ACTIVE COMPARATOR

Drug: Adefovir alone

Interventions

Lamivudine and adefovir DRUG

Lamivudine (100 mg/day) and adefovir (10 mg/day)

Lamivudine and adefovir

Adefovir alone DRUG

Adefovir (10 mg/day)

Adefovir

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 above, male or female
• Known serum HBsAg positivity for at least 6 months
• Detectable HBV-DNA in serum above 1 million copies per ml, as detected by quantitative PCR (Roche Cobas Assay)
• Serum ALT (alanine aminotransferase) or AST (aspartate aminotransferase)levels above the upper limit of normal based on two determinations taken at least one month apart during the 6 months before entry
• Liver biopsy within 2 years consistent with chronic hepatitis and with a histology activity index score (HAI) of 6 or more (out of a total possible score of 22) and an "Ishak" fibrosis score of at least 1 (out of a total possible score of 6). For patients with lamivudine resistance the liver biopsy may be performed either on or off lamivudine.
• Written informed consent.

You may not qualify if:

• Previous or current treatment with adefovir or tenofovir.
• Co-infection with HDV (Hepatitis D Virus) as defined by the presence of both anti-HDV in serum and HDV antigen in liver
• Co-infection with HCV (Hepatitis C Virus) as defined by the presence of both anti-HCV and HCV RNA in serum.
• Co-infection with HIV (Human immunodeficiency virus) as defined by the presence of anti-HIV in serum.
• Decompensated liver disease as defined by serum bilirubin greater than 2.5 mg%, prothrombin time of greater than 2 seconds prolonged, a serum albumin of less than 3.0 gm%, or a history of ascites, variceal bleeding, or hepatic encephalopathy.
• Presence of other causes of liver disease (i.e., hemochromatosis, Wilson's disease, alcoholic liver disease, non-alcoholic steatohepatitis, alpha-1 antitrypsin deficiency)
• A history of organ transplantation or in the absence of organ transplantation, any immunosuppressive therapy requiring the use of more than 5 mg of prednisone (or its equivalent) daily.
• Significant systemic illnesses other than liver diseases including congestive heart failure, renal failure, chronic pancreatitis, diabetes mellitus with poor control that in the opinion of the investigators might interfere with therapy.
• Pregnancy or inability to practice contraception in patients capable of bearing or fathering children
• Pre-existing bone marrow suppression: White Blood Cells (WBC) less than 2,000 cells/mm(3), hematocrit less than 30%, or platelets less than 50,000 cells/mm(3).
• 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
• Prior interferon treatment within 6 months of entry
• Sensory or motor neuropathy apparent from medical history and physical examination
• Creatinine clearance less than 50 ml/min or serum creatinine greater than 1.5 mg/dl; creatinine clearance will be determined on a 24 hour urine specimen. Accuracy of collection will be ensured by documenting appropriate total creatinine excretion in the 24 hour urine specimen (15 mg/kg) and correcting for the patient's age and gender.
• 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

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 (4)

• Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, Haussinger D. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. 1996 May 30;334(22):1422-7. doi: 10.1056/NEJM199605303342202.

  PMID: 8618580 BACKGROUND

• Malik AH, Lee WM. Chronic hepatitis B virus infection: treatment strategies for the next millennium. Ann Intern Med. 2000 May 2;132(9):723-31. doi: 10.7326/0003-4819-132-9-200005020-00007.

  PMID: 10787366 BACKGROUND

• Hoofnagle JH, di Bisceglie AM. The treatment of chronic viral hepatitis. N Engl J Med. 1997 Jan 30;336(5):347-56. doi: 10.1056/NEJM199701303360507. No abstract available.

  PMID: 9011789 BACKGROUND

• Ghany MG, Feld JJ, Zhao X, Heller T, Doo E, Rotman Y, Nagabhyru P, Koh C, Kleiner DE, Wright EC, Liang TJ, Hoofnagle JH. Randomised clinical trial: the benefit of combination therapy with adefovir and lamivudine for chronic hepatitis B. Aliment Pharmacol Ther. 2012 May;35(9):1027-35. doi: 10.1111/j.1365-2036.2012.05059.x. Epub 2012 Mar 26.

  PMID: 22449251 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Hepatitis B; Hepatitis; Hepatitis B, Chronic

Interventions

Lamivudine; adefovir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Liver Diseases; Digestive System Diseases; Hepatitis, Chronic; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides

Results Point of Contact

• Title: Marc G. Ghany, M.D
• Organization: National Institute of Diabetes and Digestive and Kidney Diseases, NIH

marcg@mail.nih.gov

3014961721

Study Officials

• Ghany Mark, MD

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 3, 2001
• First Posted: September 3, 2001
• Study Start: August 1, 2001
• Primary Completion: April 1, 2010
• Study Completion: August 1, 2013
• Last Updated: September 23, 2016
• Results First Posted: April 4, 2013

Record last verified: 2014-07

Locations

US (1)