Switch From Adefovir to Tenofovir in Chronic Hepatitis B for Suboptimal Response to Adefovir-based Combination Therapy

Chronic Hepatitis B Clinical Trial

Official title:

Randomized Study Comparing Nucleoside Analogues Plus Tenofovir and Nucleoside Analogues Plus Adefovir in Chronic Hepatitis B Patients With Suboptimal Response to Adefovir-based Combination Therapy Due to Nucleoside Analogues Resistance

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01595633
• Other study ID #: 4-2011-0937
• Status: Recruiting
• Phase: Phase 4
• First received: March 11, 2012
• Last updated: May 9, 2012
• Start date: March 2012
• Est. completion date: February 2014

Study information

• Verified date: May 2012
• Source: Yonsei University
• Contact: BeomKyung Kim, Dr.
• Phone: 82-2-2228-1930
• Email: beomkkim[@]yuhs.ac
• Is FDA regulated: No
• Health authority: Korea: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

In Korea, the number of suboptimal responders to rescue combination therapy is also increasing. As a matter of fact, according to the investigations in Korea, HBV DNA undetectability at 48 weeks of adefovir and lamivudine combination rescue therapy for patients with lamivudine resistance was reported to be only 32.4%, which suggested that the appropriate another rescue therapy might be urgently required. However, there is no promising oral antiviral agents to control these patients in Asia-Pacific region, where tenofovir is not widely available. Tenofovir has a higher potent antiviral efficacy and a negligible drug resistance rate. The switch from adefovir to tenofovir in patients who have insufficient hepatitis B virus (HBV) suppression (HBV DNA ≥ 60 IU/mL by PCR) may lead to increased viral suppression or more HBeAg loss/seroconversion.

Here, the investigators aimed to conduct a randomized study on evaluating the antiviral efficacy, safety, and tolerability of switching from adefovir to tenofovir in chronic hepatitis B patients who have suboptimal response to adefovir-based combination rescue therapy due to nucleoside analogues Resistance (SATIS study).

Description:

The major goal of antiviral therapy against chronic hepatitis B is to suppress viral replications successfully, ultimately preventing the chronic liver damage, development of liver cirrhosis and hepatocellular carcinoma. In Korea, the number of multi-drug resistant CHB has been rapidly increased last few years. It is because that the national health insurance coverage is very limited for the patients who experienced primary treatment failure. The only switch to adefovir has been allowed in lamivudine resistant patients and thus this sequential rescue therapy generated multi-drug resistance to both adefovir and another drugs. Thus, nowadays, add-on therapy rather than switch therapy might be preferred from major guidelines in this point.

However, the number of suboptimal responders to rescue combination therapy is also increasing. As a matter of fact, according to the investigations in Korea, HBV DNA undetectability at 48 weeks of adefovir and lamivudine combination rescue therapy for patients with lamivudine resistance was reported to be only 32.4%, which suggested that the appropriate another rescue therapy might be urgently required. However, there is no promising oral antiviral agents to control these patients in Asia-Pacific region, where tenofovir is not widely available. Tenofovir has a higher potent antiviral efficacy and a negligible drug resistance rate. It belongs to the different class compared to other oral nucleoside analogues (NAs) such as lamivudine, telbivudine, clevudine and entecavir. The switch from adefovir to tenofovir in patients who have insufficient hepatitis B virus (HBV) suppression (HBV DNA ≥ 60 IU/mL by PCR) may lead to increased viral suppression or more HBeAg loss/seroconversion. The results of this study will provide a rationale for switch from adefovir to tenofovir in combination to another drug continued (lamivudine, telbivudine, clevudine and entecavir).

Here, the investigators aimed to conduct a randomized study on evaluating the antiviral efficacy, safety, and tolerability of switching from adefovir to tenofovir in chronic hepatitis B patients who have suboptimal response to adefovir-based combination rescue therapy due to nucleoside analogues Resistance (SATIS study).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 124
• Est. completion date: February 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years and older

Eligibility

Inclusion Criteria:

• subjects with age >= 20 years

• subjects with chronic hepatitis B

• subjects treated with nucleoside analogues plus adefovir for at least 6 months due to resistance to nucleoside analogues (Lamivudine, Telbivudine, Entecavir, or Clevudine)

• subjects with partial virologic response to nucleoside analogues plus adefovir HBV DNA = 60 IU/mL)

• subjects with ALT less than 5 times of upper limit of normal

• subjects who agreed to participate in the clinical trials and signed the informed consents

Exclusion Criteria:

• subjects with decompensate liver cirrhosis Child-Pugh B, C)

• subjects with Adefovir mutation

• subjects with HCV, HDV, or HIV infection

• pregnant or lactating women

• women of childbearing age who do not use the appropriate contraception method

• subjects who have the abnormal lesion suspected of hepatocellular carcinoma on imaging modalities

• subjects with other liver diseases such as hemochromatosis, Wilson's disease, alcoholic liver disease, nonalcoholic liver disease, alpha-1 antitrypsin deficiency

• subjects with hypersensitivity for study drugs

• subjects who participated in other clinical trials 60 days before the current recruitment

• subjects who are judged as inappropriate by investigators

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis B
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Switching from adefovir (10mg/day) to tenofovir (300mg/day)
active comparator: Nucleoside analogues (Lamivudine 100mg, Telbivudine 600mg, Entecavir 1mg, or Clevudine 30mg/day) + Adefovir 10mg/day Experimental: Nucleoside analogues (Lamivudine 100mg, Telbivudine 600mg, Entecavir 1mg, or Clevudine 30mg/day) + Tenofovir 300mg/day

Locations

Country	Name	City	State
Korea, Republic of	Department of Internal Medicine, Yonsei University College of Medicine	Seoul

Sponsors (1)

Lead Sponsor	Collaborator
Yonsei University

Country where clinical trial is conducted

Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	number of patients with complete virologic response (HBV DNA < 60 IU/mL, approximately 300 copies/mL) at 48 weeks treatment	Complete virologic response (HBV DNA < 60 IU/mL, approximately 300 copies/mL) at 48 weeks treatment	48 weeks	No
Secondary	number of patients with antiviral response at 48 weeks therapy	number of patients with antiviral response (defined as decrement of HBV DNA level with 2 Log from baseline) at 48 weeks therapy	48 weeks	No
Secondary	number of patients with biochemical response at 48 weeks therapy	number of patients with biochemical response (defined as ALT normalization) at 48 weeks therapy	48 weeks	No
Secondary	number of patients with serologic response at 48 weeks therapy	number of patients with serologic response (defined as HBeAg seroconversion in case of HBeAg-positive hepatitis) at 48 weeks therapy	48 weeks	No
Secondary	number of patients with appearance of resistant mutant strain at 48 weeks	number of patients with appearance of resistant mutant strain at 48 weeks	48 weeks	No
Secondary	Number of Participants with Adverse Events	Number of Participants with Adverse Events during treatments (Adverse effects will be monitored every visit using physical examination and routine blood chemistry tests.)	48 weeks	Yes