Efficacy of Telbivudine With or Without add-on Tenofovir According to Roadmap Strategy Compare With Entecavir (TETRA)

A Randomized, Prospective, Multicenter, Open-label Study to Evaluate the Efficacy of Telbivudine With or Without add-on Tenofovir According to Roadmap Strategy Compare With Entecavir in HBeAg-positive Chronic Hepatitis B Patients

Oral antiviral drugs which can be given to patients with HBeAg-positive chronic hepatitis B include Lamivudine, Clevudine, Adefovir, Telbivudine, Entecavir and Tenofovir. 2009 American Association for the Study of Liver Disease (AASLD) Treatment Guidelines and 2009 European association for the Study of the Liver (EASL) Treatment Guidelines recommend the administration of Entecavir or Tenofovir with high potency and low resistance. Lamivudine has low antiviral potency and high incidence of mutation in long-term administration compared to Entecavir or Tenofovir. Clevudine causes the elevated creatinine kinase (CK), side effects including myositis/myopathy and much mutation in the long-term administration. Globe study demonstrated Telbivudine had more excellent antiviral potency than Lamivudine, which was also comparable to or higher than Entecavir or Tenofovir. Nevertheless, the choice of treatment drugs can be limited due to the mutation rate of 25% for 2 years. However, the analysis of Globe study results showed that 2-year treatment progress was very good in patient who showed virologic response at 24 weeks after the initiation of treatment and that high antiviral potency and low mutation rate were observed when the Telbivudine roadmap strategy (in the event that virologic response is shown at 24 weeks, telbivudine monotherapy is maintained and in the event that virologic response is not shown, tenofovir add-on therapy is done) recently implemented and announced in 2011 Asian Pacific Association for the Study of the Liver (APASL) was applied. However, the study was single arm study, which restricted the comparison between Entecavir and Tenofovir monotherapy groups. Therefore, this study intends to compare the anti-viral effect and mutation rate between Entecavir 0.5mg monotherapy group and Telbivudine roadmap strategy group in patients with HBeAg-positive chronic hepatitis B through a randomized study.

Study Overview

• Status: Unknown
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: Telbivudine; Drug: Tenofovir; Drug: Entecavir

Detailed Description

104 treatment-naïve patients with HBeAg-positive chronic hepatitis B who fulfill the inclusion criteria will be randomized in a 1:1 ratio to receive either Telbivudine 600mg monotherapy or Entecavir monotherapy with stratification before randomization according to presence of cirrhosis. For Telbivudine group, Telbivudine monotherapy or Tenofovir combined therapy will be done according to virologic response at 24 weeks and the primary study will be completed at Week 48 and treatment response will be analyzed. The treatment will be extended to Week 96 and the secondary analysis will be performed then.

• Study Type: Interventional
• Enrollment (Anticipated): 104
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Busan, Korea, Republic of
    • Not yet recruiting
    • Byung Chul Yoon
    • Contact: Byung Chul Yoon
    • Principal Investigator: Byung Chul Yoon
  • Busan, Korea, Republic of
    • Not yet recruiting
    • Eun Uk Jung
    • Contact: Eun Uk Jung
    • Principal Investigator: Eun Uk Jung
  • Busan, Korea, Republic of
    • Not yet recruiting
    • Hyun Young Woo
    • Contact: Hyun Young Woo
    • Principal Investigator: Hyun Young Woo
  • Busan, Korea, Republic of
    • Not yet recruiting
    • Nae-Yun Heo
    • Contact: Nae-Yun Heo
    • Principal Investigator: Nae-Yun Heo
  • Busan, Korea, Republic of
    • Not yet recruiting
    • Yang Hyun Baek
    • Contact: Yang Hyun Baek
    • Principal Investigator: Yang Hyun Baek
  • Changwon, Korea, Republic of
    • Not yet recruiting
    • Hyun Jin Jo
    • Contact: Hyun Jin Jo
    • Principal Investigator: Hyun Jin Jo
  • Daegu, Korea, Republic of
    • Not yet recruiting
    • Byung Seok Kim
    • Contact: Byung Seok Kim
    • Principal Investigator: Byung Seok Kim
  • Daegu, Korea, Republic of
    • Not yet recruiting
    • Soo Young Park
    • Principal Investigator: Soo Young Park
  • Jinju, Korea, Republic of
    • Not yet recruiting
    • Hyun Ju Min
    • Contact: Hyun Ju Min
    • Principal Investigator: Hyun Ju Min
  • Yangsan, Korea, Republic of
    • Recruiting
    • Ki Tae Yoon
    • Contact: Ki Tae Yoon, M.D.; Phone Number: 82-55-360-2362; Email: ktyoon@pusan.ac.kr
    • Contact: Surin Tak; Phone Number: 82-55-360-1738; Email: surintak@hanmail.net
    • Principal Investigator: Ki Tae Yoon, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female, at least 18 years of age
• Documented CHB defined by HBsAg or HBeAg positive at least 6 month prior
• HBsAg positive at screening visit
• HBeAg positive and Anti-HBe negative at screening visit
• Serum HBV DNA 20,000~200,000,000 IU/mL as determined by Realtime PCR at screening visit
• Serum ALT 80~400 IU/mL at screening visit
• Patient is willing and able to comply with the study drug regimen and all other study requirements
• Patient is willing and able to provide written informed consent to participate in the study

Exclusion Criteria:

• Patient has received interferon, pegylated interferon, nucleoside or nucleotide drugs at any time
• Patient is co-infected with HCV, HDV, or HIV
• Patient with Child Pugh B or C (Child Pugh score ≥ 7)
• Patient has a history of or clinical signs/symptoms of hepatic decompensation such as ascites, esophageal variceal bleeding, hepatic encephalopathy
• Patient has any of the following laboratory values at screening visit:
• Hemoglobin <10 g/dL
• Absolute neutrophil count (ANC) <1,500/mm3
• Platelet count <70,000/mm3
• Patient has a history of clinical and laboratory evidence of chronic renal insufficiency defined as an estimated serum creatinine clearance < 50 mL/min using the MDRD formula at screening visit
• Patient is pregnant or breastfeeding
• Patient with currently abusing illegal drugs or alcohol sufficient
• Patient has organ transplantation
• History of any other acute or chronic medical condition that in the opinion of the investigator would make the patient unsuitable for inclusion into the study
• Patient has one or more additional known primary or secondary causes of liver disease, other than CHB, including steatohepatitis and autoimmune hepatitis
• Patient, if AFP is >50ng/mL at screening visit, has image findings suggestive of HCC at Liver CT or Liver MRI
• Patient with hypersensitivity for study drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Telbivudine-Tenofovir roadmap	Drug: Telbivudine; If virologic response, which means HBV DNA < 50 IU/mL, is shown at 24 weeks, telbivudine monotherapy is maintained and in the event that virologic response is not shown, tenofovir add-on therapy is done; Other Names: Sebivo; Drug: Tenofovir; If virologic response, which means HBV DNA < 50 IU/mL, is shown at 24 weeks, telbivudine monotherapy is maintained and in the event that virologic response is not shown, tenofovir add-on therapy is done; Other Names: Viread
Active Comparator: Entecavir	Drug: Entecavir; Maintain the entecavir through the study period; Other Names: Baraclude

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HBV DNA non-detectability	Low detection limit of HBV DNA is 50 IU/mL	Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HBV DNA non-detectability	Low detection limit of HBV DNA is 50 IU/mL	Week 96
Reduction of HBV DNA from baseline		Week 12, 24, 36, 48, 60, 72, 84 & 96
HBeAg loss or HBeAg seroconversion		Week 48 & 96
HBsAg loss or HBsAg seroconversion		Week 48 & 96
ALT normalization		Week 48 & 96
Accumulate rate of Viral breakthrough		Week 48 & 96
Accumulate rate of Biochemical Breakthrough		Week 48 & 96
Accumulate rate of genotypic mutation in HBV		Week 48 & 96
Change of eGFR from baseline		Week 12, 24, 36, 48, 60, 72, 84 & 96
Accumulate rate of CK abnormal elevation		Week 48 & 96
Accumulate rate of symptom related muscular disease		Week 48 & 96
Accumulate rate of Adverse event or serious adverse event		Week 48 & 96

Collaborators and Investigators

• Sponsor: Pusan National University Yangsan Hospital
• Investigators: Principal Investigator: Ki Tae Yoon, M.D., Pusan National University Yangsan Hospital

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Anticipated): December 1, 2013
• Study Completion (Anticipated): December 1, 2014

Study Registration Dates

• First Submitted: April 27, 2012
• First Submitted That Met QC Criteria: April 27, 2012
• First Posted (Estimate): May 1, 2012

Study Record Updates

• Last Update Posted (Estimate): May 2, 2012
• Last Update Submitted That Met QC Criteria: April 30, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: tenofovir; entecavir; chronic hepatitis B; HBeAg positive; telbivudine; roadmap
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir; Entecavir; Telbivudine
• Other Study ID Numbers: CLDT600AKR07T