Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) 300mg in Chinese Subjects With Chronic Hepatitis B (CHB) (TDF in CHB)

• ClinicalTrials.gov Identifier: NCT01300234
• Recruitment Status: Completed
• First Posted: February 21, 2011
• Results First Posted: August 16, 2013
• Last Update Posted: July 13, 2018
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

This is a multi-centre, double blind, double dummy, randomised, controlled study to evaluate the efficacy and safety of TDF 300mg QD versus ADV 10mg QD in Chinese subjects with CHB. This study is designed to demonstrate the superiority of TDF 300mg QD over ADV 10mg QD in treating Chinese subjects with CHB (hepatitis B e antigen [HBeAg] positive subjects and HBeAg negative subjects). It will also provide long-term efficacy and safety data (up to 240 weeks) for TDF 300 mg administered once daily.

Condition or disease	Intervention/treatment	Phase
Hepatitis B	Drug: Tenofovir disoproxil fumarate (TDF) tablets; Drug: Adefovir dipivoxil (ADV) tablets	Phase 3

Detailed Description:

This is a multi-centre, double-blind, double-dummy, randomised, controlled study to evaluate the efficacy and safety of TDF 300mg QD versus ADV 10mg QD in Chinese subjects with CHB. Four hundred and ninety-four subjects with CHB (200 HBeAg positive subjects and 294 HBeAg negative subjects) will be randomised (1:1ratio) to either TDF 300mg QD or ADV 10mg QD treatment arms. The primary endpoint is the proportion of subjects with blood hepatitis B virus (HBV) deoxyribonucleic acid (DNA) <400copies/mL (Roche COBAS Taqman HBV test) at Week 48 in HBeAg positive subjects with CHB and HBeAg negative subjects with CHB. This is a two-part study. The first treatment period (baseline to Week 48) will investigate the effects of TDF and ADV on safety and efficacy endpoints; dosing will be double-blind. This period will be followed by 192 weeks in which all subjects will receive open-label TDF (Week 49 to Week 240). Subjects will undergo regular safety and efficacy assessments every 4 weeks for the first 12 weeks followed by every 12 weeks for a total of up to 5 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 512 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multi-centre, Double Blind, Double Dummy, Randomised, Controlled Study to Evaluate the Efficacy and Safety of TDF 300mg Once Daily (QD) Versus Adefovir Dipivoxil (ADV) 10mg QD in Chinese Subjects With CHB
• Actual Study Start Date: March 30, 2011
• Actual Primary Completion Date: October 17, 2012
• Actual Study Completion Date: December 6, 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: A (TDF tablets); Tenofovir disoproxil fumarate (TDF) tablets	Drug: Tenofovir disoproxil fumarate (TDF) tablets; white, almond-shaped, film-coated tablets containing 300mg of TDF; Other Name: TDF tablet
Active Comparator: B (ADV tablets); Adefovir dipivoxil (ADV) tablets	Drug: Adefovir dipivoxil (ADV) tablets; white to off-white, round, biconvex tablets containing 10mg of ADV; Other Name: ADV tablet

Outcome Measures

Primary Outcome Measures :

1. Participants With Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) <400 Copies/Milliliter (mL) at Week 48 [ Time Frame: Week 48 ]
   The number of participants with Hepatitis B Virus (HBV) deoxyribonucleic acid (DNA) <400 copies/milliliter (mL) at Week 48 in the hepatitis B e antigen (HBeAg)-positive and HBeAg-negative population was assessed. HBeAg is a viral protein that is secreted by hepatitis B-infected cells. It is associated with chronic hepatitis B infections and is used as a marker of active viral disease and a participant's degree of infectiousness. A positive result indicates that the participant has high levels of virus in the blood and greater infectiousness. Usually, a negative result indicates that the participant has lower levels of virus in the blood and is less infectious. A "non-completers equal failures" approach is used for the analysis in ITT population. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.

Secondary Outcome Measures :

1. Participants With HBV DNA <400 Copies/mL at Weeks 96, 144, 192, and 240 [ Time Frame: Weeks 96, 144, 192, and 240 ]
   The number of participants with HBV DNA <400 copies/mL in the hepatitis B e antigen (HBeAg)-positive and HBeAg-negative population was assessed. HBeAg is a viral protein that is secreted by hepatitis B-infected cells. It is associated with chronic hepatitis B infections and is used as a marker of active viral disease and a participant's degree of infectiousness. A positive result indicates that the participant has high levels of virus in the blood and greater infectiousness. Usually, a negative result indicates that the participant has lower levels of virus in the blood and is less infectious. Week 96, 144, 192, and 240 data are not yet available, as this report includes data up to and including Week 48. A "non-completers equal failures" approach is used for the analysis in ITT population. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.
2. Change From Baseline of Log 10 Copies/mL HBV DNA at Weeks 48, 96, 144, 192 and 240 [ Time Frame: Baseline, Weeks 48, 96, 144, 192 and 240 ]
   Change from Baseline of log 10 copies/mL HBV DNA at Weeks 48, 96, 144, 192 and 240 in the HBeAg-positive and HBeAg-negative population was assessed. HBeAg is a viral protein that is secreted by hepatitis B-infected cells. It is associated with chronic hepatitis B infections and is used as a marker of active viral disease and a participant's degree of infectiousness. A positive result indicates that the participant has high levels of virus in the blood and greater infectiousness. Usually a negative result indicates that the participant has lower levels of virus in the blood and less infectious. Values at Day 0 were considered as Baseline values. Change from Baseline was calculated as post Baseline values minus Baseline values. A "non-completers equal failures" approach is used for the analysis in ITT population. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.
3. Number of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48, 96, 144, 192 and 240 in Participants Who Had Abnormal ALT at Baseline [ Time Frame: Baseline; Weeks 48, 96, 144, 192 and 240 ]
   Participants who had abnormal ALT at Baseline and had normalized ALT at Weeks 48, 96, 144, 192 and 240 were assessed. This report includes data up to and including Weeks 48, 96, 144, 192 and 240. An increased level of ALT is referred to as abnormal ALT (the normal range is 0 to 48 units per liter [U/L]). Values at Day 0 were considered as Baseline values. A "non-completers equal failures" approach is used for the analysis in ITT population. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.
4. Number of Participants With Histological Improvement at Weeks 48 and 240 Who Had a Baseline Knodell Necroinflammatory Score (KNS) >=2. [ Time Frame: Baseline; Week 48 and Week 240 ]
   Histological improvement is defined as a reduction of >=2 points in the KNS with no increase in fibrosis at Week 48 and Week 240 in participants with Baseline KNS >=2 which was derived from the American Association for the Study of Liver Diseases Practice Guidelines for Management of Chronic Hepatitis B (2009) and the European Association for the Study of the Liver Clinical Practice Guidelines Management of chronic hepatitis B virus infection (2012). The Knodell scale consists of 5 domains: periportal +/- bridging necrosis (scored from best to worst: 0, 1, 3, 4, 5, 6, or 10); intralobular degeneration and focal necrosis (0 to 4); portal inflammation (0 to 4); and fibrosis (0 to 4). The necroinflammatory score (ranging from 0 [best] to 14 [worst]) is the combined score for necrosis (0 to 10) plus inflammation (0 to 4; the participant is scored for only one inflammatory condition). Liver biopsy slides within 6 months prior to randomization could be accepted as Baseline evaluation.
5. Number of HBeAg-positive Participants Achieving HBeAg Loss and HBeAg Seroconversion at Weeks 24, 48, 96, 144, 192 and 240. [ Time Frame: Weeks 24, 48, 96, 144, 192 and 240 ]
   HBeAg loss is defined as a negative HBeAg result for those participants who were HBeAg positive at Baseline. Seroconversion to anti-HBe is defined as HBeAg loss and a positive anti-HBe result. This report includes data up to and including Weeks 24, 48, 96, 144, 192 and 240.
6. Number of HBeAg-positive Participants Achieving Hepatitis B Surface Antigen (HBsAg) Loss and HBsAg Seroconversion at Weeks 24, 48, 96, 144, 192 and 240 [ Time Frame: Weeks 24, 48, 96, 144, 192 and 240 ]
   HBsAg loss is defined as negative HBsAg results for those participants with who were HBsAg positive at Baseline. Seroconversion to anti-HBs is defined as HBsAg loss and a positive anti-HBs result. This report includes data up to and including Week 240.
7. Number of HBeAg-negative Participants Achieving HBsAg Loss and HBsAg Seroconversion at Weeks 24, 48, 96, 144, 192, 240 [ Time Frame: Weeks 24, 48, 96, 144, 192 and 240 ]
   HBsAg loss is defined as a negative HBsAg result for those participants with who were HBsAg positive at Baseline. Seroconversion to anti-HBs is defined as HBsAg loss and a positive anti-HBs result. This report includes data up to and including Week 240.
8. Number of Participants Achieving Durable HBsAg Loss From Weeks 24 to Week 48 [ Time Frame: Week 24 to Week 48 ]
   Durable HBsAg loss is defined as the loss of HBsAg and no detectable HBV DNA and ALT normalization at any three consecutive visits at least 12 Weeks apart. This report includes data up to and including Week 48. A "non-completers equal failures" approach was used for the analysis in ITT population.
9. Number of Participants Achieving Durable HBsAg Loss From Weeks 96 to Week 240 [ Time Frame: Week 96 to Week 240 ]
   Durable HBsAg loss is defined as the loss of HBsAg and no detectable HBV DNA and ALT normalization at any three consecutive visits at least 12 Weeks apart from Week 96 to 240. This report includes data up to and including Week 240. A "non-completers equal failures" approach was used for the analysis in ITT population.
10. Number of Participants With Virological Breakthrough at Weeks 48, 96, 144, 192 and 240 [ Time Frame: Weeks 48, 96, 144, 192 and 240 ]
    The number of HBeAg-positive and HBeAg-negative participants who had virological breakthrough at Weeks 48, 96, 144, 192 and 240 were assessed. Virological breakthrough is defined by >= one log increase in HBV DNA from NADIR (as determined by two sequential HBV DNA measurements at least one month apart or last on treatment measurement). A "non-completers equal failures" approach was used for the analysis in ITT population.
11. Number of Participants With Any Serious Adverse Event (SAE) and Any Non-serious Adverse Event (AE) [ Time Frame: Up to Week 240 treatment period and 24 weeks follow-up visit off treatment ]
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is Grade 4 (life threatening or disabling). Participants with any non-serious AEs and SAEs has been reported.
12. Number of Participants With the Indicated Grade 3 and Grade 4 Treatment-emergent (TE) Laboratory Abnormalities (LAs) [ Time Frame: Up to Week 240 ]
    TE grade 3 or grade 4 LAs are defined as values that increase by >=1 grade from Baseline (Day 0) to Grade 3 (severe) or 4 (potentially life threatening) at any post-Baseline value. The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities, version 21, September 2011 was referred for grading. Laboratory parameters assessed included Sodium for hyponatremia and hypernatremia; Potassium for hypokalemia and hyperkalemia; glucose for hypoglycemia and hyperglycemia non-fasting; Phosphate for hypophosphatemia; alanine aminotransferase/aspartate aminotransferase, bilirubin, creatinine kinase, hemoglobin, platelets, neutrophils, lymphocytes, prothrombin time and amylase.
13. Number of Participants With the Indicated Treatment-emergent Laboratory Abnormalities for Serum Creatinine and Serum Phosphorus [ Time Frame: Up to Week 240 ]
    The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities, version 21, September 2011 was referred for grading. Serum creatinine: Grade 1, > 133 to 177 micromoles per Liter (µmoles/Liter), Grade 2, >177 to 265 µmoles/Liter, Grade 3, >265 to 530 µmoles/Liter, Grade 4, >530 µmoles/Liter. Serum phosphorus: Grade 2, 0.63 to <0.80 millimoles per Liter (mmoles/L), Grade 3, 0.31 to <0.63 mmoles/L, Grade 4, <0.31 mmoles/L. The normal range for serum phosphorus was 0.8 to 1.45 mmoles/L; the upper limit for a Grade 2 abnormality is 0.80 mmoles/L. Therefore, no Grade 1 abnormalities could be attributed, as values were contained within the normal range. NA indicates the value was not available for the indicated time point.
14. Number of Participants in the Indicated Category for Renal Laboratory Abnormalities [ Time Frame: Up to Week 240 ]
    The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities, version 21, September 2011 was used for grading. "Confirmed" is defined as two consecutive visits. mg=milligrams. dL=deciliter, G= Grade.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 69 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• HBeAg positive/negative CHB with blood HBVDNA≥10^5 copies/mL and elevated ALT
• Nucleoside and nucleotide naïve CHB subjects. Previous lamivudine treatment is allowed in less than 10% of the total study population

Exclusion Criteria:

• subjects with hepatocellular carcinoma (HCC) potential or decompensated liver disease
• subjects with acute liver disease due to other causes
• subjects with medication history of immunosuppressive therapy, immunomodulatory therapy, systemic cytotoxic agents, chronic antiviral agents including Chinese herbal medicines known to have activity against HBV (e.g., lamivudine, hepatitis B immunoglobulin (HBIg)) within the previous 6 months prior to randomisation into this study

Contacts and Locations

Locations

China, Guangdong

GSK Investigational Site

Guangzhou, Guangdong, China, 510060

GSK Investigational Site

Guangzhou, Guangdong, China, 510515

GSK Investigational Site

Guangzhou, Guangdong, China, 510630

China, Hubei

GSK Investigational Site

Wuhan, Hubei, China, 430030

China, Hunan

GSK Investigational Site

Changsha, Hunan, China, 410008

China, Jiangsu

GSK Investigational Site

Nanjing, Jiangsu, China, 210003

GSK Investigational Site

Nanjing, Jiangsu, China, 210029

China, Jilin

GSK Investigational Site

Changchun, Jilin, China, 130021

China, Sichuan

GSK Investigational Site

Chengdu, Sichuan, China, 610041

China, Zhejiang

GSK Investigational Site

Hangzhou, Zhejiang, China, 310003

China

GSK Investigational Site

Beijing, China, 100015

GSK Investigational Site

Beijing, China, 100044

GSK Investigational Site

Beijing, China, 100050

GSK Investigational Site

Chongqing, China, 400038

GSK Investigational Site

Fuzhou, China, 350025

GSK Investigational Site

Jinan, China, 250021

GSK Investigational Site

Shanghai, China, 200001

GSK Investigational Site

Shanghai, China, 200025

GSK Investigational Site

Shanghai, China, 200040

GSK Investigational Site

Shanghai, China, 201508

Sponsors and Collaborators

GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Liang X, Gao Z, Xie Q, Zhang J, Sheng J, Cheng J, Chen C, Mao Q, Zhao W, Ren H, Tan D, Niu J, Chen S, Pan C, Tang H, Wang H, Mao Y, Jia J, Ning Q, Xu M, Wu S, Li J, Zhang X, Zhang W, Xiong C, Hou J. Long-term efficacy and safety of tenofovir disoproxil fumarate in Chinese patients with chronic hepatitis B: 5-year results. Hepatol Int. 2019 May;13(3):260-269. doi: 10.1007/s12072-019-09943-6. Epub 2019 Apr 11.

Hou JL, Gao ZL, Xie Q, Zhang JM, Sheng JF, Cheng J, Chen CW, Mao Q, Zhao W, Ren H, Tan DM, Niu JQ, Chen SJ, Pan C, Tang H, Wang H, Mao YM, Jia JD, Ning Q, Xu M, Wu SM, Li J, Zhang XX, Ji Y, Dong J, Li J. Tenofovir disoproxil fumarate vs adefovir dipivoxil in Chinese patients with chronic hepatitis B after 48 weeks: a randomized controlled trial. J Viral Hepat. 2015 Feb;22(2):85-93. doi: 10.1111/jvh.12313. Epub 2014 Sep 22.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01300234
• Other Study ID Numbers: 114648
• First Posted: February 21, 2011
• Results First Posted: August 16, 2013
• Last Update Posted: July 13, 2018
• Last Verified: January 2018

Keywords provided by GlaxoSmithKline:

tenofovir disoproxil fumarate; chronic hepatitis B; adefovir dipivoxil

Additional relevant MeSH terms:

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