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Efficacy and Safety Study of Tenofovir Disoproxil Fumarate (TDF) in Chinese Chronic Hepatitis B (CHB) Subjects With Advanced Fibrosis & Compensated Cirrhosis

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ClinicalTrials.gov Identifier: NCT02224456
Recruitment Status : Active, not recruiting
First Posted : August 25, 2014
Last Update Posted : June 25, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
Chronic Hepatitis B infection (CHB) is known as the most frequently identified cause of liver disease that predisposes patients to the development of hepatocellular carcinoma (HCC). Active hepatitis B virus (HBV) replication is the key driver of liver injury and disease progression. Majority of Chinese patients are infected with genotype B and C HBV, which is different from Caucasian counterparts. This prospective multi-center cohort open-label study is designed to investigate the long-term effect of TDF on prevention of HCC and disease progression as well as to evaluate the efficacy and safety of long-term TDF in Chinese CHB subjects with advanced liver diseases. The study will enrol 240 subjects.

Condition or disease Intervention/treatment Phase
Hepatitis B, Chronic Drug: Tenofovir disoproxil fumarate Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective, Multi-center, Cohort Study to Evaluate the Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) Therapy in Chinese Chronic Hepatitis B (CHB) Subjects With Advanced Fibrosis & Compensated Cirrhosis
Actual Study Start Date : March 25, 2015
Estimated Primary Completion Date : December 2, 2020
Estimated Study Completion Date : January 8, 2021


Arm Intervention/treatment
Experimental: Tenofovir
Subjects will receive TDF 300 milligrams (mg) tablet once daily for 240 weeks in the study. Subjects who receive add-on rescue treatment may take LAM 100 mg, ETV 0.5 mg or LdT 600 mg per day upon investigator's decision in addition to TDF tablet.
Drug: Tenofovir disoproxil fumarate
White, almond-shaped, film-coated tablet containing 300 mg of TDF, debossed with "GILEAD" and "4331" on one side of the tablet.




Primary Outcome Measures :
  1. Incidence of hepatocellular carcinoma at Week 240 [ Time Frame: Week 240 ]
    Subject must meet one of the following criteria for determining incidence: A histological diagnosis of HCC (i.e. by biopsy or at post-mortem). In patients with nodules >2 centimeter (cm), identification of typical HCC characteristics (hypervascular in the arterial phase with washout in the portal venous or delayed phases) by 4-phase multidetector computed tomography (CT) scan or dynamic contrast-enhanced magnetic resonance imaging (MRI). In patients with nodules >1 cm, identification of typical HCC characteristics by both techniques (4-phase multidetector CT and dynamic contrast-enhanced MRI)

  2. Incidence of disease progression at Week 240 [ Time Frame: Week 240 ]
    Incidence of disease progression is defined as the first occurrence of any one of the following criteria: An increase in Childs-Pugh score of 2 or more points from baseline. An increase in Childs-Pugh score of 2 or more points, solely based on laboratory parameters (i.e. bilirubin, prothrombin time and/or albumin), confirmed between two consecutive visits at least one month apart; spontaneous bacterial peritonitis (with proven sepsis); renal insufficiency; bleeding gastric/oesophageal varices; hepatocellular carcinoma; liver-related death.


Secondary Outcome Measures :
  1. Incidence of HCC at Week 48, Week 96 Week 144, and Week 192 [ Time Frame: Up to Week 192 ]
  2. Cumulative incidence of HCC at Week 48, Week 96, Week 144, Week 192 and Week 240 [ Time Frame: Up to Week 240 ]
  3. Cumulative incidence of disease progression at Week 48, Week 96, Week 144, Week 192 and Week 240 [ Time Frame: Up to Week 240 ]
  4. The mean changes of liver stiffness measurement (LSM) at Week 48, Week 96, Week 144, Week 192 and Week 240 [ Time Frame: Up to Week 240 ]
    LSM will be obtained for all subjects by transient elastography using FibroScan (EchoSens) to assess liver fibrosis changes non-invasively

  5. Proportion of subjects with serum HBV Deoxyribonucleic Acid (DNA) <20 International units per milliliter (IU/mL) at Week 48, Week 96, Week 144, Week 192 and Week 240 [ Time Frame: Up to Week 240 ]
    HBV DNA will be tested

  6. Mean log10 reduction in serum HBV DNA at Week 48, Week 96, Week 144, Week 192 and Week 240 compared with baseline [ Time Frame: Up to Week 240 ]
  7. Proportion of subjects with alanine aminotransferase (ALT) normalization at Week 48, Week 96, Week 144, Week 192 and Week 240 [ Time Frame: Up to Week 240 ]
    To evaluate the biochemical response, ALT will be measured. ALT normalization is defined as ALT outside the normal range at baseline and within the normal range at Week 48, Week 96, Week 144, Week 192 and Week 240

  8. Proportion of hepatitis B early antigen (HBeAg) positive subjects achieving HBeAg loss, HBeAg seroconversion or hepatitis B surface antigen (HBsAg) loss and HBsAg seroconversion at Week 24, Week 48, Week 96, Week 144, Week 192 and Week 240 [ Time Frame: Up to Week 240 ]
    To evaluate the serological response, HBeAg loss, HBeAg seroconversion or HBsAg loss and HBsAg seroconversion will be measured for HBeAg positive subjects. HBeAg loss is defined as a negative HBeAg result for those subjects who were HBeAg positive at Baseline. Seroconversion to anti-HBe is defined as HBeAg loss and a positive anti-HBe result. HBsAg loss is defined as negative HBsAg results for those subjects with who were HBsAg positive at Baseline. Seroconversion to anti-HBs is defined as HBsAg loss and a positive anti-HBs result

  9. Proportion of HBeAg negative subjects achieving HBsAg loss and HBsAg seroconversion at Week 48, Week 96, Week 144, Week 192 and Week 240 [ Time Frame: Up to Week 240 ]
    To evaluate the serological response, HBsAg loss and HBsAg seroconversion will be measured for HBeAg negative subjects. HBsAg loss is defined as negative HBsAg results for those subjects with who were HBsAg positive at Baseline. Seroconversion to anti-HBs is defined as HBsAg loss and a positive anti-HBs result

  10. Incidence of virological breakthrough up to Week 48, Week 96, Week 144, Week 192 and Week 240 [ Time Frame: Up to Week 240 ]
    Incidence of virological breakthrough as defined by >=1 log10 increase in HBV DNA from nadir (as determined by two sequential HBV DNA measurements at least 1 month apart, or the last on-treatment measurement)

  11. Proportion of subjects with histological improvement at Week 216 in the subset of subjects with paired baseline and Week 216 liver biopsies [ Time Frame: Week 216 ]
    Histological improvement is defined as a reduction of two or more points in the Knodell necroinflammatory score with no increase in fibrosis. Knodell necroinflammatory score consists of 4 categories: piecemeal necrosis (scores from 0 to 4), confluent necrosis (scores from 0 to 6), Focal (spotty) lytic necrosis, apoptosis and focal inflammation (scores from 0 to 4) and Portal inflammation (scores from 0 to 4). By combining scores for each of the four individual necroinflammatory categories, histological grading scores ranging from 0-18 can be achieved

  12. Proportion of subjects with cirrhosis reversal at Week 216 in the subset of subjects with paired baseline and Week 216 liver biopsies and with a baseline Ishak score higher than or equal to five [ Time Frame: Week 216 ]
    Reversal of cirrhosis is defined as a reduction of one or more points in the Ishak score and no evidence of cirrhosis. The Ishak fibrosis score is a scoring system (ranging from 0 to 6) that measures the degree of fibrosis (scarring) of the liver, which is caused by chronic necroinflammation (an inflammatory process in the liver including or leading to death of liver cells). A score of 0 represents no fibrosis, and a score of 6 represents definite cirrhosis

  13. Safety as determined by adverse events (AEs) and laboratory assessments [ Time Frame: Up to Week 240 ]
    The proportion of subjects who experienced AEs will be calculated by dividing the number of subjects who experienced the AE during the treatment period by the number of subjects evaluable for safety analysis. Adverse events will be summarised by treatment group, and by body system and event within each body system. Laboratory assessments include hematology, clinical chemistry, and urinalysis



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18-60 years(inclusive);
  • Presence of HBsAg in serum at screening and for at least 6 months before screening assessment;
  • Serum HBV DNA>=2000 IU/mL if HBeAg positive at screening (with or without ALT elevation); or serum HBV DNA>=200IU/mL if HBeAg negative at screening (with or without ALT elevation);
  • Clinically diagnosed as advanced fibrosis or compensated cirrhosis defined as both of following : liver stiffness measure (LSM) >12.4 kiloPascals (kpa) (ALT> Upper limit of normal [ULN]) or LSM>9.0 kpa (ALT<=ULN); One of following: Liver biopsy showing advanced fibrosis or cirrhosis (Ishak score >=4, within the previous 6 months before screening and provided that no treatment likely to improve liver histology has been taken since). The slides must be available for review by an independent histopathologist; Endoscopy-proven gastroesophageal or gastric varices, non-cirrhotic portal hypertension excluded; Abdominal ultrasound or CT found changes indicating cirrhosis, irregular liver surface or nodularity, with/without splenomegaly (depth of spleen>4.0cm or spleen length>13cm); Blood platelets <100 x10^9/L (and other causes of thrombocytopenia excluded);
  • Ability to give written informed consent;
  • A female is eligible to enter and participate in this study if she is of: non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal), or Child-bearing potential, has a negative urine pregnancy test at screening, and agrees to one of the following methods for avoidance of pregnancy during the period of the study and until 30 days after last dose of study medication: Oral contraceptive, either combined or progestogen alone; Injectable progestogen; Implants of levonorgestrel; Oestrogenic vaginal ring; Percutaneous contraceptive patches; Intrauterine device (IUD) or intrauterine system (IUS) showing that the expected failure rate is less than 1% per year as stated in the IUD or IUS product label; Has a male partner who is sterilised; Double barrier method: condom and an occlusive cap (diaphragm orcervical/vault caps) with a vaginal spermicidal agent (foam/gel/film /cream/suppository).
  • Agreement not to participate in any other investigational trials or to undertake other HBV systemic antiviral or interferon (IFN) regimens during participation in this study.

Exclusion Criteria:

  • Hepatocellular carcinoma as evidenced by one of the following: Suspicious foci on ultrasound or radiological examination; Normal ultrasound serum alpha-fetoprotein >50 nanograms (ng)/mL at screening.
  • Serum ALT >10 times ULN at screening or history of acute exacerbation leading to transient decompensation;
  • Documented co-infection with hepatitis A (HAV), hepatitis C (HCV), hepatitis delta virus (HDV), hepatitis E virus (HEV) or human immunodeficiency virus (HIV). For HCV co-infection, subjects who are anti-HCV positive and in whom HCV ribonucleic acid (RNA) is undetectable are considered to be not eligible for enrolment.
  • Evidence of active liver disease due to autoimmune hepatitis (antinuclear antibody (ANA) titre >1:160).
  • Decompensated liver disease as indicated by any of the following: serum bilirubin >1.5 xULN prothrombin time activity <60% or International normalized ratio (INR)>1.5; serum albumin <32 grams per liter (g/L); history of previous clinical hepatic decompensation (e.g., ascites, variceal bleeding, or encephalopathy);
  • Planned for liver transplantation or previous liver transplantation;
  • Creatinine clearance less than 70 mL/minute (min);
  • Haemoglobin <10 g/deciliter (dL), white blood cell (WBC) count <1.5 x 10^9/liter (L), platelets <=50 x 10^9/L;
  • Any serious or active medical or psychiatric illnesses other than hepatitis B which, in the opinion of the Investigator, would interfere with subject treatment, assessment or compliance with the protocol. This would include any uncontrolled clinically significant renal, cardiac, pulmonary, vascular, neurogenic, digestive, metabolic (diabetes, thyroid disorders, adrenal disease), immunodeficiency disorders, pathological fractures or cancer;
  • Active alcohol or drug abuse or history of alcohol or drug abuse considered by the Investigator to be sufficient to hinder compliance with treatment, participation in the study or interpretation of results;
  • A female who is breastfeeding or plan to breastfeed;
  • Use of immunosuppressive therapy, immunomodulatory therapy (including IFN or thymosin alpha), systemic cytotoxic agents, chronic antiviral agents including Chinese herbal medicines known to have activity against HBV (e.g., lamivudine (LAM), adefovir, entecavir (ETV), telbivudine (LdT) or hepatitis B immunoglobulin (HBIg)) within the previous 6 months prior to screening into this study;
  • Have ever received TDF or any medicinal products containing the above mentioned antiviral agents or any investigative anti-HBV treatments (e.g., emtricitabine (FTC), (2R,4R)-4-(2,6-Diaminopurin-9-yl)-1,3-dioxolan-2-yl]methanol (DAPD) and 1-(2-fluoro-5-methyl-beta, Larabinofuranosyl) uracil (L-FMAU));
  • History of hypersensitivity to nucleoside and/or nucleotide analogues and/or any component of study medication;
  • Therapy with nephrotoxic drugs (e.g., aminoglycosides, amphotercin B, vancomycin, cidofovir, foscarnet, cis-platinum, pentamidine etc.) or competitors of renal excretion (e.g., probenecid) within 2 months prior to study screening or the expectation that subject will receive any of these during the course of the study;
  • Inability to comply with study requirements as determined by the study Investigator

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02224456


Locations
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China, Guangdong
GSK Investigational Site
Guangzhou, Guangdong, China, 510060
China, Hubei
GSK Investigational Site
Wuhan, Hubei, China, 430022
China, Jiangsu
GSK Investigational Site
Nanjing, Jiangsu, China, 210002
GSK Investigational Site
Nanjing, Jiangsu, China, 210003
China, Jilin
GSK Investigational Site
Changchun, Jilin, China
China, Shanxi
GSK Investigational Site
Xian, Shanxi, China
China, Sichuan
GSK Investigational Site
Chengdu, Sichuan, China, 610041
China
GSK Investigational Site
Beijing, China, 100044
GSK Investigational Site
Beijing, China, 100050
GSK Investigational Site
Beijing, China, 100069
GSK Investigational Site
Chongqing, China, 400038
GSK Investigational Site
Hangzhou, China
GSK Investigational Site
Jinan, China, 250021
GSK Investigational Site
Shanghai, China, 200025
GSK Investigational Site
Shanghai, China, 200040
GSK Investigational Site
Shanghai, China, 201508
GSK Investigational Site
Taiyuan, China, 030001
GSK Investigational Site
Xi'an, China, 710061
GSK Investigational Site
Zhengzhou, China
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02224456     History of Changes
Other Study ID Numbers: 201213
First Posted: August 25, 2014    Key Record Dates
Last Update Posted: June 25, 2019
Last Verified: June 2019
Keywords provided by GlaxoSmithKline:
Tenofovir disoproxil fumarate
hepatocellular carcinoma
chronic hepatitis B
Cirrhosis
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis B
Hepatitis B, Chronic
Hepatitis
Hepatitis, Chronic
Liver Cirrhosis
Fibrosis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Pathologic Processes
Hepadnaviridae Infections
DNA Virus Infections
Tenofovir
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