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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Chronic Hepatitis B	Drug: Telbivudine; Drug: Tenofovir; Drug: Entecavir	Phase 4

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	104 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	April 2012
Estimated Primary Completion Date :	December 2013
Estimated Study Completion Date :	December 2014

Arms and Interventions

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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 Name: 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 Name: Viread
Active Comparator: Entecavir	Drug: Entecavir; Maintain the entecavir through the study period; Other Name: Baraclude

Outcome Measures

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Primary Outcome Measures :

1. HBV DNA non-detectability [ Time Frame: Week 48 ]
   Low detection limit of HBV DNA is 50 IU/mL

Secondary Outcome Measures :

1. HBV DNA non-detectability [ Time Frame: Week 96 ]
   Low detection limit of HBV DNA is 50 IU/mL
2. Reduction of HBV DNA from baseline [ Time Frame: Week 12, 24, 36, 48, 60, 72, 84 & 96 ]
3. HBeAg loss or HBeAg seroconversion [ Time Frame: Week 48 & 96 ]
4. HBsAg loss or HBsAg seroconversion [ Time Frame: Week 48 & 96 ]
5. ALT normalization [ Time Frame: Week 48 & 96 ]
6. Accumulate rate of Viral breakthrough [ Time Frame: Week 48 & 96 ]
7. Accumulate rate of Biochemical Breakthrough [ Time Frame: Week 48 & 96 ]
8. Accumulate rate of genotypic mutation in HBV [ Time Frame: Week 48 & 96 ]
9. Change of eGFR from baseline [ Time Frame: Week 12, 24, 36, 48, 60, 72, 84 & 96 ]
10. Accumulate rate of CK abnormal elevation [ Time Frame: Week 48 & 96 ]
11. Accumulate rate of symptom related muscular disease [ Time Frame: Week 48 & 96 ]
12. Accumulate rate of Adverse event or serious adverse event [ Time Frame: Week 48 & 96 ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Ki Tae Yoon, M.D.	82-55-360-2362	ktyoon@pusan.ac.kr
Contact: Surin Tak	82-55-360-1738	surintak@hanmail.net

Locations

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

Sponsors and Collaborators

Pusan National University Yangsan Hospital

Investigators

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

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Ki Tae Yoon, Assistant Professor, Pusan National University Yangsan Hospital
ClinicalTrials.gov Identifier:	NCT01588912 History of Changes
Other Study ID Numbers:	CLDT600AKR07T
First Posted:	May 1, 2012
Last Update Posted:	May 2, 2012
Last Verified:	April 2012

Keywords provided by Ki Tae Yoon, Pusan National University Yangsan Hospital:

chronic hepatitis B; HBeAg positive; telbivudine	tenofovir; entecavir; roadmap

Additional relevant MeSH terms:

Hepatitis; Hepatitis A; Hepatitis, Chronic; Hepatitis B; Hepatitis B, Chronic; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Hepadnaviridae Infections	DNA Virus Infections; Tenofovir; Entecavir; Telbivudine; Antiviral Agents; Anti-Infective Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Retroviral Agents; Anti-HIV Agents