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

NCT02224456 | Completed Phase 4 Results

• 1 other identifier: 201213
• Study Type: interventional
• Target: 197
• Locations: 1 country
• Sites: 19

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.

Conditions

Hepatitis B, Chronic

Keywords

Tenofovir disoproxil fumarate; hepatocellular carcinoma; chronic hepatitis B; Cirrhosis

Outcome Measures

Primary Outcomes (2)

• Incidence Rate of Newly Diagnosed Hepatocellular Carcinoma (HCC) at Week 240

  The newly diagnosed HCC was defined as HCC cases from Week 24 to Week 240 and the participants were required to meet one of the following criteria: without HCC before Week 24; a histological diagnosis of HCC (i.e. by biopsy or at post-mortem); participants with nodules \>2 centimeter (cm), identification of typical HCC characteristics (hyper-vascular in the arterial phase with washout in the portal venous or delayed phases) by 4-phase multi-detector computed tomography (CT) scan or dynamic contrast-enhanced magnetic resonance imaging (MRI); participants with nodules \>1 cm, identification of typical HCC characteristics by both techniques (4-phase multi-detector CT and dynamic contrast-enhanced MRI).

  Week 240

• Percentage of Participants With Disease Progression at Week 240

  Disease progression was defined as the first occurrence of any one of the following criteria: 1) an increase in Childs-Pugh score of 2 or more points from Baseline; 2) 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; 3) spontaneous bacterial peritonitis (with proven sepsis); 4) renal insufficiency; 5) bleeding gastric/esophageal varices; 6) hepatocellular carcinoma; 7)liver-related death.

  Week 240

Secondary Outcomes (22)

• Number of Participants With Newly Diagnosed Hepatocellular Carcinoma (HCC) at Week 48, Week 96, Week 144 and Week 192

  Week 48, Week 96, Week 144 and Week 192

• Percentage of Participants With Newly Diagnosed Hepatocellular Carcinoma (HCC) at Week 48, Week 96, Week 144, Week 192 and Week 240

  Week 48, Week 96, Week 144, Week 192 and Week 240

• Percentage of Participants With Disease Progression at Week 48, Week 96, Week 144, Week 192 and Week 240

  Week 48, Week 96, Week 144, Week 192 and Week 240

• Mean Change From Baseline in Liver Stiffness Measure at Week 48, Week 96, Week 144, Week 192 and Week 240

  Baseline (Day 0), Week 48, Week 96, Week 144, Week 192 and Week 240

• Percentage of Participants With Serum Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) <20 International Units Per Milliliter (IU/mL) at Weeks 48, 96, 144, 192 and 240

  Week 48, Week 96, Week 144, Week 192 and Week 240

Study Arms (1)

Tenofovir

EXPERIMENTAL

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

Interventions

Tenofovir disoproxil fumarate DRUG

White, almond-shaped, film-coated tablet containing 300 mg of TDF, debossed with "GILEAD" and "4331" on one side of the tablet.

Tenofovir

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (19)

GSK Investigational Site

Guangzhou, Guangdong, 510060, China

Location

GSK Investigational Site

Wuhan, Hubei, 430022, China

Location

GSK Investigational Site

Nanjing, Jiangsu, 210002, China

Location

GSK Investigational Site

Nanjing, Jiangsu, 210003, China

Location

GSK Investigational Site

Changchun, Jilin, 130000, China

Location

GSK Investigational Site

Xian, Shanxi, 710038, China

Location

GSK Investigational Site

Chengdu, Sichuan, 610041, China

Location

GSK Investigational Site

Beijing, 100044, China

Location

GSK Investigational Site

Beijing, 100050, China

Location

GSK Investigational Site

Beijing, 100069, China

Location

GSK Investigational Site

Chongqing, 400038, China

Location

GSK Investigational Site

Hangzhou, 310000, China

Location

GSK Investigational Site

Jinan, 250021, China

Location

GSK Investigational Site

Shanghai, 200025, China

Location

GSK Investigational Site

Shanghai, 200040, China

Location

GSK Investigational Site

Shanghai, 201508, China

Location

GSK Investigational Site

Taiyuan, 030001, China

Location

GSK Investigational Site

Xi'an, 710061, China

Location

GSK Investigational Site

Zhengzhou, 450000, China

Location

MeSH Terms

Conditions

Hepatitis B, Chronic; Carcinoma, Hepatocellular; Fibrosis

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; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site

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 Reponse 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: August 21, 2014
• First Posted: August 25, 2014
• Study Start: March 25, 2015
• Primary Completion: December 4, 2020
• Study Completion: December 4, 2020
• Last Updated: February 14, 2022
• Results First Posted: February 14, 2022

Record last verified: 2021-11

Locations

CN (19)