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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01300234
First received: February 3, 2011
Last updated: September 19, 2013
Last verified: September 2013
  Purpose

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 Intervention Phase
Hepatitis B
Drug: Tenofovir disoproxil fumarate (TDF) tablets
Drug: Adefovir dipivoxil (ADV) tablets
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, 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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Participants With Hepatitis B Virus (HBV) DNA <400 Copies/Milliliter (mL) at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Participants With HBV DNA <400 Copies/mL at Weeks 96, 144, 192, and 240 [ Time Frame: Weeks 96, 144, 192, and 240 ] [ Designated as safety issue: No ]
    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.

  • Log 10 Copies/mL Reduction From Baseline HBV DNA at Week 48 [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    The log 10 copies/mL reduction from Baseline HBV DNA at Week 48 in the HBeAg-positive and HBeAg-negative population was assessed. This report includes data up to and including Week 48. Long-term efficacy data (up to Week 240) will eventually be reported. 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.

  • Number of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48 in Participants Who Had Abnormal ALT at Baseline [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    Participants who had abnormal ALT at Baseline and had normalized ALT at Week 48 were assessed. This report includes data up to and including Week 48. Long-term efficacy data (up to Week 240) will eventually be reported. An increased level of ALT is referred to as abnormal ALT (the normal range is 0 to 48 units per liter [U/L]). Week 96, 144, 192, and 240 data are not yet available, as this report includes data up to and including Week 48.

  • Number of Participants With Histological Improvement at Week 48 Who Had a Baseline Knodell Necroinflammatory Score (KNS) >=2 [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    Histological improvement is defined as a reduction of >=2 points in the KNS with no increase in fibrosis at Week 48 in participants with a 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 as 0 [best], 1, 3, 4, 5, 6, or 10 [worst]); and intralobular degeneration/focal necrosis, portal inflammation, and fibrosis (all scored as 0-4). The necroinflammatory score (0 [best] to 14 [worst]) is the combined score for necrosis (0-10) plus inflammation (0-4; the participant is scored for only one inflammatory condition). Liver biopsy was done at selected sites. Liver biopsy slides within 6 months prior to randomization could be accepted as the Baseline evaluation.

  • Number of HBeAg-positive Participants Achieving HBeAg Loss and HBeAg Seroconversion at Weeks 24 and 48 [ Time Frame: Week 24 and 28 ] [ Designated as safety issue: No ]
    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 Week 48. Long-term efficacy data (up to Week 240) will eventually be reported.

  • Number of HBeAg-positive Participants Achieving HBsAg Loss and HBsAg Seroconversion at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ] [ Designated as safety issue: No ]
    Hepatitis B surface Antigen (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 48. Long-term efficacy data (up to Week 240) will eventually be reported.

  • Number of HBeAg-negative Participants Achieving HBsAg Loss and HBsAg Seroconversion at Weeks 24 and 48 [ Time Frame: Weeks 24 and 48 ] [ Designated as safety issue: No ]
    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 48. Long-term efficacy data (up to Week 240) will eventually be reported.

  • Number of Participants Achieving Durable HBsAg Loss From Weeks 24 to Week 48 [ Time Frame: Week 24 to Week 48 ] [ Designated as safety issue: No ]
    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. Long-term efficacy data (up to Week 240) will eventually be reported.

  • Number of Participants With Virological Breakthrough at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    The number of HBeAg-positive and HBeAg-negative participants who had virological breakthrough at Week 48 was assessed. Virological breakthrough is defined as an HBV DNA increase of >=1 log10 copies/mL above the treatment nadir, confirmed on two consecutive visits.

  • Number of Participants With Any Serious Adverse Event (SAE) and Any Adverse Event (AE) [ Time Frame: up to Week 48 ] [ Designated as safety issue: No ]
    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). Refer to the general AE/SAE module for a complete list of AEs and SAEs.

  • Number of Participants With the Indicated Grade 3 and Grade 4 Treatment-emergent (TE) Laboratory Abnormalities (LAs) [ Time Frame: Baseline; up to Week 48/Early Withdrawal ] [ Designated as safety issue: No ]
    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 used for grading. Sodium: hyponatremia, Grade (G) 3=121-125 millimoles per Liter (mmol/L), G4=<121 mmol/L; hypernatremia, G3=154-159 mmol/L, G4=>159 mmol/L. Phosphate: hypokalemia, G3=2.0-2.5 mmol/L, G4=<2,0 mmol/L; hyperkalemia, G3=>6.5-7 mmol/L, G4=>7.0 mmol/L. Alanine aminotransferase/aspartate aminotransferase: G3=5.00-10.00 × upper limit of normal (ULN), G4=>10.0 × ULN. Bilirubin: G3=2.5-5.0 × ULN, G4=>5.0 × ULN. Creatinine kinase: G3=10.0-20.0 × ULN, G4=>=2.0 × ULN. Hemoglobin: 70-90 grams per Liter (g/L), G4=<70 g/L. Platelets: G3=25-<50 GI (10^9)/L, G4=<25 GI/L. Neutrophils: G3, 0.50-0.75 GI/L, G4=<0.50 GI/L. Prothrombin time: G3=1.50-3.00 × ULN, G4=>3.00 × ULN.

  • Number of Participants With the Indicated Treatment-emergent Laboratory Abnormalities for Serum Creatinine and Serum Phosphorus [ Time Frame: up to Week 48/Early Withdrawal ] [ Designated as safety issue: No ]
    The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities, version 21, September 2011 was used 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 mmol/L; the upper limit for a Grade 2 abnormality is 0.80 mmol/L. Therefore, no Grade 1 abnormalities could be attributed, as values were contained within the normal range.

  • Number of Participants in the Indicated Category for Hepatic Laboratory Abnormalities [ Time Frame: Baseline; up to Week 48/Early Withdrawal ] [ Designated as safety issue: No ]
    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.


Enrollment: 512
Study Start Date: March 2011
Estimated Study Completion Date: December 2016
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 69 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01300234

Locations
China, Guangdong
GSK Investigational Site
Guangzhou, Guangdong, China, 510515
GSK Investigational Site
Guangzhou, Guangdong, China, 510060
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, 210029
GSK Investigational Site
Nanjing, Jiangsu, China, 210003
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, 100050
GSK Investigational Site
Beijing, China, 100044
GSK Investigational Site
Chongqing, China, 400038
GSK Investigational Site
Fuzhou, China, 350025
GSK Investigational Site
Jinan, China, 250021
GSK Investigational Site
Shanghai, China, 200040
GSK Investigational Site
Shanghai, China, 200025
GSK Investigational Site
Shanghai, China, 201508
GSK Investigational Site
Shanghai, China, 200001
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01300234     History of Changes
Other Study ID Numbers: 114648
Study First Received: February 3, 2011
Results First Received: June 13, 2013
Last Updated: September 19, 2013
Health Authority: China: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
tenofovir disoproxil fumarate
chronic hepatitis B
adefovir dipivoxil

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis B, Chronic
Hepatitis, Chronic
Hepatitis B
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Tenofovir disoproxil
Tenofovir
Adefovir
Adefovir dipivoxil
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents

ClinicalTrials.gov processed this record on September 22, 2014