Phase 3 Study of GSK548470 in Patients With Compensated Chronic Hepatitis B With Poor Response to Other Drugs

Hepatitis B, Chronic Clinical Trial

Official title:

A Multi-center, Open-label Study of GSK548470 (Tenofovir Disoproxil Fumarate) in Patients With Compensated Chronic Hepatitis B With Poor Response to Other Drugs

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01475851
• Other study ID #: 115912
• Status: Completed
• Phase: Phase 3
• First received: November 17, 2011
• Last updated: June 18, 2015
• Start date: December 2011
• Est. completion date: October 2014

Study information

• Verified date: May 2015
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Japan: Pharmaceuticals and Medical Devices Agency
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy and safety of once-daily treatment with GSK548470 300 mg in Japanese patients with compensated chronic hepatitis B with poor response to other drugs.

Description:

This is a multicenter, open-label study in Japanese patients with compensated chronic hepatitis B with poor response to other drugs in order to evaluate the efficacy and safety of GSK548470 administered at a dose of 300 mg once daily. The target sample size is set at 32 subjects. The primary objective is to evaluate the efficacy and safety of once-daily treatment with GSK548470 300 mg in subjects with compensated chronic hepatitis B with poor response to other drugs. The secondary objective is to evaluate the long-term efficacy and safety of once-daily treatment with GSK548470 300 mg.To evaluate the efficacy and safety of GSK548470 in the study, subjects receiving a combination of lamivudine (LAM) and adefovir pivoxil (ADV) will be switched to a combination of LAM and GSK548470, while subjects on entecavir hydrate (ETV) with or without ADV will be switched to a combination of ETV and GSK548470.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: October 2014
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years to 69 Years

Eligibility

Inclusion Criteria:

• The ability to understand and sign a written informed consent form

• 16 to 69 years of age at the time of informed consent

• Females of childbearing potential must have a negative pregnancy test and agree to avoidance of pregnancy

• Subject must show QTc <450 millisecond (msec) or <480msec with Bundle Branch Block

• Chronic HBV infection, defined as positive serum HBsAg for at least 6 month

• Subjects currently treated with LAM/ADV, ETV or ETV/ADV for greater than 24 weeks

• Chronic hepatitis B ; HBV NDA >= 4 log10 copies/mL, Chronic hepatitis B with cirrhosis ; HBV NDA >= 3 log10 copies/mL

• Serum ALT <= 10 × ULN

• Creatinine clearance >= 70 mL/min

• Haemoglobin >= 8 g/dL

• WBC >= 1,000 /mm3

Exclusion Criteria:

• Decompensated liver disease

• Co-infection with HIV or HCV

• Autoimmune hepatitis rather than chronic hepatitis B

• Subject with serious complication

• Received or have a plan for solid organ or bone marrow transplantation

• Has proximal tubulopathy

• History of hypersensitivity to nucleoside and/or nucleotide analogues

• Evidence of hepatocellular carcinoma by diagnostic imaging at screening and/or serum a-fetoprotein > 50 ng/mL at screening

• History of HCC

• Received any interferon or HB vaccine therapy within 24 weeks prior to initiation

• Received overdose NSAIDs, excluding temporary or topical use, within 7 days prior to initiation

• Received drugs for injection containing glycyrrhizin as the main component within 4 weeks prior to initiation

• Received drugs causing renal impairment, competitors of renal excretion, immunosuppressants, chemotherapeutics and/or corticosteroids within 8 weeks prior to initiation

• Participation in another clinical study within 6 months of study entry or planned participation in another clinical study after entry to this study

• Woman who is pregnant, lactating, possibly pregnant or planning a pregnancy during the study period

• Psychiatry disorder or cognitive disorder that may affect the subject ability to give informed consent or to follow specified study procedures

• History of alcohol or drug abuse

• Any condition or situation that may interfere with the subject's participation in the study

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• GSK548470 300 mg tablet
Blue tablets containing 300 mg of tenofovir disoproxil fumarate

Locations

Country	Name	City	State
Japan	GSK Investigational Site	Aichi
Japan	GSK Investigational Site	Aichi
Japan	GSK Investigational Site	Chiba
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Hiroshima
Japan	GSK Investigational Site	Hokkaido
Japan	GSK Investigational Site	Kagoshima
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Miyagi
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With HBV DNA Level < 2.1 log10 Copies/mL at Week 24	The number of participants with serum hepatitis B virus deoxyribonucleic acid (HBV DNA) level < the lower limit of quantitation (2.1 log10 copies/millilitres[copies/mL]) (i.e., the rate of suppression) at Week 24 was summarized. Statistical analysis was not provided for the number of participants achieving HBV DNA <2.1 log10 copies/mL (at Week 24). Missing values observed during the treatment period was imputed by the last observation carried forward (LOCF) method.	Week 24	No
Secondary	Mean Change From Baseline in Serum HBV DNA Level at Week 24, Week 48 and Week 96	The mean change from Baseline in the hepatitis B virus deoxyribonucleic acid (HBV DNA) level at Week 24, Week 48 and Week 96 were assessed (HBV DNA values below the lower limit of quantitation [i.e. 2.1 log10 copies/mL] for the assay were set to the lower limit minus 0.1 [i.e. 2.0 log10 copies/mL]). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Last Observation Carried Forward (LOCF) method was applied for missing values.	Baseline and Week 24, Week 48 and Week 96	No
Secondary	Number of Participants With Serum HBV DNA < 2.1 log10 Copies/mL at Week 48 and Week 96	The number of participants with serum HBV DNA level < the lower limit of quantitation (2.1 log10 copies/mL) (i.e., the rate of suppression) at Week 48 and Week 96 were summarized. The LOCF method was applied for missing values.	Week 48 and Week 96	No
Secondary	Number of Participants With Alanine Aminotransferase (ALT) Normalization at Week 24, Week 48 and Week 96	The number of participants with alanine aminotransferase (ALT) normalization at Week 24, Week 48 and Week 96 were summarized. ALT normalization is defined as when an ALT value exceeds the upper limit of normal range (ULN) at Baseline and within the normal range at the end of treatment. The LOCF method was applied for missing values.	Week 24, Week 48 and Week 96	No
Secondary	Number of Participants With HBeAg Loss at Week 24, Week 48 and Week 96	The number of participants achieving hepatitis Be antigen (HBeAg) loss at Week 24, Week 48 and Week 96 in positive HBeAg participants at Baseline were summarized. Loss of HBeAg is defined as the change of detectable HBeAg from positive to negative. The LOCF method was applied for missing values.	Week 24, Week 48 and Week 96	No
Secondary	Number of Participants With HBeAg/HBeAb Seroconversion at Week 24, Week 48 and Week 96	The number of participants achieving hepatitis Be antigen (HBeAg)/hepatitis B e antibody (HBeAb) seroconversion at Week 24, Week 48 and Week 96 in positive HBeAg and negative HBeAb participants at Baseline were summarized. Seroconversion to HBeAg is defined as change of detectable antibody to HBeAg from negative to positive. The LOCF method was applied for missing values.	Week 24, Week 48 and Week 96	No
Secondary	Number of Participants Achieving HBsAg Loss at Week 24, Week 48 and Week 96	The number of participants with hepatitis B surface antigen (HBsAg) loss at Week 24, Week 48 and Week 96 in positive HBsAg participants at Baseline were summarized. Loss of HBsAg is defined as change of detectable HBsAg from positive to negative. The LOCF method was applied for missing values.	Week 24, Week 48 and Week 96	No
Secondary	Number of Participants Achieving HBsAg/HBsAb Seroconversion at Week 24, Week 48 and Week 96	The number of participants with hepatitis B surface antigen (HBsAg)/hepatitis B surface antibody (HBsAb) seroconversion at Week 24, Week 48 and Week 96 in positive HBsAg and negative HBsAb participants at Baseline were summarized. HBsAg seroconversion was defined as change of detectable antibody to HBsAg from negative to positive. The LOCF method was applied for missing values.	Week 24, Week 48 and Week 96	No
Secondary	Number of Participants With Virological Breakthrough and Resistance-related Mutations	The number of participants who harbored resistance-related mutations and developed virological breakthrough was summarized. Virological breakthrough defined as HBV DNA level increase >=1 log10 copies/mL above the treatment nadir were analyzed through end of treatment. Subjects who achieved the HBV-DNA values below lower limit of quantification (LLQ) (< 2.1 log10 copies/mL) in quantitative analysis at Week 96 were also considered "negative" in drug-resistance without implementation of genotypic analysis. Lamivudine (LAM), adefovir pivoxil (ADV), and entecavir hydrate (ETV) resistance-related mutations were analyzed at Screening (i.e. Baseline), Week 24, Week 48 and Week 96 in participants with HBV DNA level above the lower limit of detection. Virologic breakthrough was defined as 1.0 log10 or greater increases in serum HBV DNA levels from on-treatment nadir. The LOCF method was applied for missing values.	Screening, Week 24, Week 48, Week 96 and Virological Breakthrough	No
Secondary	Number of Participants Achieving Each Indicated HBsAg Category at Baseline, Week 24, Week 48 and Week 96	The number of participants achieving each indicated hepatitis B surface antigen (HBsAg) category (HBsAg <80, 80 to 800, 800 to 8000, 8000 to 80000, >=80000) (kilo international unit per liter [KIU/L]) by study visit was summarized.	Baseline, Week 24, Week 48 and Week 96	No
Secondary	Number of Participants Achieving Each Indicated HBcrAg Category at Baseline,Week 24, Week 48 and Week 96	The number of participants achieving each indicated hepatitis B core-related antigen (HBcrAg) category (HBcrAg <3.0 log10, 3.0 to 4.0 log10, 4.0 to 5.0 log10, 5.0 to 6.0 log10, >=6.0 log10) (kilo units per liter [KU/L]) by study visit was summarized. The LOCF method was applied for missing values.	Baseline, Week 24, Week 48 and Week 96	No