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

NCT02195518 | Completed Phase 4 Results

• 1 other identifier: 201215
• Study Type: interventional
• Target: 213
• Locations: 1 country
• Sites: 12

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.

Conditions

Hepatitis B, Chronic

Keywords

Chronic Hepatitis B; Tenofovir disoproxil fumarate; Failure of multiple NAs treatment

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Serum Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) <20 International Unit Per Milliliter (IU/mL) at Week 144

  HBV DNA level were analyzed using the sensitive HBV test in central laboratory using Roche cobas Taqman HBV test from the blood samples collected at Week 144. A 95 percent confidence interval (CI) was constructed by normal approximation and continuity correction method. Percentage of participants with serum HBV DNA \<20 IU/mL at Week 144 have been presented. The Modified Intent-to-treat (mITT) Population was defined as all recruited participants who received at least one dose of study medication.

  At Week 144

Secondary Outcomes (17)

• Percentage of Participants With Serum HBV DNA <20 IU/mL and Serum HBV DNA <69 IU/mL at Weeks 48 and 96

  At Weeks 48 and 96

• Percentage of Participants in the Subgroup With Confirmed Multi-drug Resistance Mutations at Baseline With Serum HBV DNA <20 IU/mL and Serum HBV DNA <69 IU/mL at Weeks 48, 96 and 144

  At Weeks 48, 96, and 144

• Change From Baseline in Logarithm to the Base 10 (Log 10) Reduction in Serum HBV DNA at Week 48, 96 and 144

  Baseline (Day 0) and at Weeks 48,96, and 144

• Percentage of Hepatitis B e Antigen (HBeAg) Positive Participants Achieving HBeAg Loss, HBeAg Seroconversion or Hepatitis B s Antigen (HBsAg) Loss and HBsAg Seroconversion at Weeks 48, 96, and 144

  At Weeks 48, 96 and 144

• Percentage of HBeAg Negative Participants Achieving HBsAg Loss and HBsAg Seroconversion at Weeks 48, 96, and 144

  At Weeks 48,96, and 144

Study Arms (1)

Tenofovir Disoproxil Fumarate

EXPERIMENTAL

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

Interventions

Tenofovir disoproxil fumarate DRUG

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.

Tenofovir Disoproxil Fumarate

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (12)

GSK Investigational Site

Guangzhou, Guangdong, 510060, China

Location

GSK Investigational Site

Guangzhou, Guangdong, 510150, China

Location

GSK Investigational Site

Changchun, Jilin, China

Location

GSK Investigational Site

Chengdu, Sichuan, 610041, China

Location

GSK Investigational Site

Hangzhou, Zhejiang, 310000, China

Location

GSK Investigational Site

Beijing, 100034, China

Location

GSK Investigational Site

Beijing, 100044, China

Location

GSK Investigational Site

Beijing, 100050, China

Location

GSK Investigational Site

Beijing, 100054, China

Location

GSK Investigational Site

Shanghai, 200025, China

Location

GSK Investigational Site

Shanghai, 200040, China

Location

GSK Investigational Site

Zhengzhou, China

Location

MeSH Terms

Conditions

Hepatitis B, Chronic

Interventions

Tenofovir

Condition Hierarchy (Ancestors)

Hepatitis B; Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2014
• First Posted: July 21, 2014
• Study Start: March 18, 2015
• Primary Completion: August 14, 2018
• Study Completion: August 14, 2018
• Last Updated: November 4, 2019
• Results First Posted: November 4, 2019

Record last verified: 2019-10

Locations

CN (12)