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Tenofovir Disoproxil Fumarate (TDF) 300mg 3 Years RD Therapy Chinese Chronic Hepatitis B (CHN) CHB Multiple Nucleos(t)Ide Analogues (NAs) Failure Points Pts PH4 PMS Study

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ClinicalTrials.gov Identifier: NCT02195518
Recruitment Status : Completed
First Posted : July 21, 2014
Last Update Posted : September 18, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
This is a phase IV, single-arm, open-label, multi-centre study to assess the efficacy of TDF in Chronic hepatitis B (CHB) subjects following failure of multiple Nucleos(t)ide analogues (NAs). The study will enrol 200 CHB subjects following failure of multiple NAs. Subjects will be assessed for eligibility at a screening visit, with eligible subjects returning for a baseline assessment after approximately 4 weeks (Screening phase). In the treatment phase all enrolled subjects will receive open label TDF at a dose of 300 milligrams (mg) orally once daily. All the eligible study subjects will undergo safety and efficacy assessments every 12 weeks for a total of 14 visits. Tenofovir disoproxil fumarate, the oral pro-drug of tenofovir (TFV), is a nucleotide analogue that inhibits viral polymerases by direct binding and after incorporation into deoxyribonucleic acid (DNA), by termination of the DNA) chain. TDF is a highly potent treatment in treatment-naïve and lamivudine (LAM) resistant CHB patients. The purpose of our study is to evaluate the efficacy of TDF treatment in Chinese CHB patients following failure of multiple NAs. In addition, the study will also explore the relationship of baseline factors and early HBV DNA suppression to long-term virological response. The efficacy of TDF in multi-drug resistant patients will be analysed separately. The data generated by this study could then be used to optimize the clinical application of TDF and provide new evidence for management of the HBV infections following failure of multiple NAs. The result of this study will help Chinese physicians better manage the CHB patients following failure of multiple NAs.

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 213 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multi-centre, Single-arm, Open-label Study to Evaluate the Efficacy and Safety of Tenofovir Disoproxil Fumarate(TDF) Treatment in Chinese Chronic Hepatitis B (CHB) Subjects Following Failure of Multiple Nucleos(t)Ide Analogues(NAs)
Actual Study Start Date : March 18, 2015
Actual Primary Completion Date : August 14, 2018
Actual Study Completion Date : August 14, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Tenofovir Disoproxil Fumarate
All enrolled subjects will receive open label TDF at a dose of 300 milligram (mg) orally once daily during the study period.
Drug: Tenofovir disoproxil fumarate
Tenofovir disoproxil fumarate tablets supplied will be white, almond-shaped, film-coated tablets containing 300 mg of TDF. Each tablet contains the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinised starch, croscarmellose sodium, and magnesium stearate.




Primary Outcome Measures :
  1. Proportion of subjects with serum HBV DNA <20 IU/mL at Week 144 [ Time Frame: Week 144 ]
    The proportion of multiple NAs treatment failure chronic hepatitis B patients who achieves HBV DNA<20 International Units (IU) per milliliter (mL) at Week 144 of TDF treatment will be assessed.


Secondary Outcome Measures :
  1. Proportion of subjects with serum HBV DNA <20 IU/mL at Week 48 and 96 [ Time Frame: Week 48 and Week 96 ]
    The proportion of multiple NAs treatment failure chronic hepatitis B patients who achieves HBV DNA<20 IU/mL at Week 48 and 96 of TDF treatment will be assessed.

  2. Log 10 reduction in serum HBV DNA at Week 48, 96 and144 [ Time Frame: Week 48, Week 96, Week 144 ]
    The efficacy of TDF will be assessed by evaluating the proportion of subjects with Log 10 reduction in serum HBV DNA.

  3. Proportion of HBeAg positive subjects achieving HBeAg loss, HBeAg seroconversion or HBsAg loss and HBsAg seroconversion at Week 48, 96, and 144. [ Time Frame: Week 48, Week 96, Week 144 ]
    The efficacy of TDF for Hepatitis B e antigen (HBeAg) positive subjects will be assessed by evaluating the proportion of subjects achieving HBeAg loss, HBeAg seroconversion or HBsAg loss and HBsAg seroconversion.

  4. Proportion of HBeAg negative subjects achieving HBsAg loss and HBsAg seroconversion at Week 48, 96, and 144 [ Time Frame: Week 48, Week 96, Week 144 ]
    The efficacy of TDF for HBeAg negative subjects will be assessed by evaluating the proportion of subjects achieving Hepatitis B s antigen (HBsAg) loss and HBsAg seroconversion.

  5. Proportion of subjects achieving with ALT normalization at Week 48, 96, and 144 in subjects who have abnormal ALT at baseline [ Time Frame: Week 48,Week 96,Week 144 ]
    The efficacy of TDF for subjects who have abnormal ALT at baseline will be assessed by evaluating the ALT normalization.

  6. Incidences of subjects who experience viral breakthrough up to week 144 [ Time Frame: Up to week 144 ]
    The efficacy of TDF will be assessed by evaluating the incidence of subjects who experience viral breakthrough which is defined as >=1 log increase in HBV DNA from nadir determined by two sequential HBV DNA measurements.

  7. Proportion of subjects in the subgroup with confirmed multi-drug resistance mutations at baseline with serum HBV DNA <20 IU/ml at week 48, 96 and 144 [ Time Frame: Week 48,Week 96,Week 144 ]
    The efficacy of TDF in a subgroup with confirmed multi-drug resistance will be assessed by the proportion of subjects with multi-drug resistance mutations at baseline who achieve serum HBV DNA <20 IU/mL.

  8. Safety as assessed by adverse events [ Time Frame: Up to week 144 ]
    The safety of TDF for subjects following failure of multiple NAs will be evaluated by assessments of adverse events. An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

  9. Safety as assessed by clinical laboratory tests [ Time Frame: Up to week 144 ]
    The safety of TDF for subjects following failure of multiple NAs will be evaluated by assessments of laboratory assessments. Clinical laboratory parameters include: Hematology, clinical chemistry and additional parameters.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Aged between 18-65years (inclusive). Male or female; 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 serum pregnancy test at baseline, 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 or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film /cream/suppository).
  • The ability to understand and sign a written informed consent prior to any study-related procedure and comply with the requirements of the study.
  • Positive HBsAg for more than 6 months, and anti-HBs negative.
  • Serum HBV DNA level >=200 IU/mL at study screening (Use central lab results).
  • Experienced multiple NAs treatment failure which is defined as HBV DNA greater than 200 IU/mL after at least two NAs treatment (at least 6 months continuous treatment for each NA(s), total duration is no less than 12 months). In addition, subjects judged by the treating physician to have adhered to previous NA therapy.
  • 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 but a history of rising serum alpha-fetoprotein and serum alpha-fetoprotein >20 nanogram (ng) per mL at screening.
  • Clinical signs of decompensated liver disease at baseline. These may include but are not limited to:Total serum bilirubin >1.5 x Upper limit of the normal range (ULN), International Normalized Ratio >1.3, Serum albumin <32grams per Liter (g/L), History of clinical hepatic decompensation (e.g., ascites, variceal bleeding, or encephalopathy).
  • Creatinine clearance less than 70 milliliter per minutes (mL/min).
  • Alanine aminotransferase >10 times ULN at screening or history of acute exacerbation leading to transient decompensation.
  • Haemoglobin <8 grams per deciliter (g/dL), absolute neutrophil count <1.0 x 10^9 per Liter, platelets <75 x 10^9 per Liter.
  • 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 RNA is undetectable are considered to be not eligible for enrolment.
  • Evidence of active liver disease due to autoimmune hepatitis (antinuclear antibody titre >1:160)
  • 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 breast.
  • Use of immunosuppressive therapy, immunomodulatory therapy [including Pegylated interferon (PEG-IFN) and short-acting interferon or thymosin alpha], systemic cytotoxic agents within the previous 6 months prior to screening.
  • Planned for liver transplantation or previous liver transplantation.
  • Receipt of TDF within 6 months prior to screening.
  • 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.
  • History of hypersensitivity to nucleoside and/or nucleotide analogues and/or any component of study medication.
  • 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): NCT02195518


Locations
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China, Guangdong
GSK Investigational Site
Guangzhou, Guangdong, China, 510060
GSK Investigational Site
Guangzhou, Guangdong, China, 510150
China, Jilin
GSK Investigational Site
Changchun, Jilin, China
China, Sichuan
GSK Investigational Site
Chengdu, Sichuan, China, 610041
China, Zhejiang
GSK Investigational Site
Hangzhou, Zhejiang, China, 310000
China
GSK Investigational Site
Beijing, China, 100034
GSK Investigational Site
Beijing, China, 100044
GSK Investigational Site
Beijing, China, 100050
GSK Investigational Site
Beijing, China, 100054
GSK Investigational Site
Shanghai, China, 200025
GSK Investigational Site
Shanghai, China, 200040
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: NCT02195518     History of Changes
Other Study ID Numbers: 201215
First Posted: July 21, 2014    Key Record Dates
Last Update Posted: September 18, 2018
Last Verified: September 2018

Keywords provided by GlaxoSmithKline:
Chronic Hepatitis B
Tenofovir disoproxil fumarate
Failure of multiple NAs treatment

Additional relevant MeSH terms:
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Hepatitis
Hepatitis A
Hepatitis, Chronic
Hepatitis B
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
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