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The Efficacy and Safety of Nucleos(t)Ide Analogues in the Treatment of HBV-related Acute-on-chronic Liver Failure

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03640728
Recruitment Status : Recruiting
First Posted : August 21, 2018
Last Update Posted : May 6, 2019
Sponsor:
Information provided by (Responsible Party):
He Yingli, First Affiliated Hospital Xi'an Jiaotong University

Brief Summary:
HBV-related acute-on-chronic liver failure (ACLF) is a clinical syndrome defined as acute hepatic insult with diagnosed or undiagnosed chronic liver disease. Current clinical guidelines advocate oral antiviral treatment in HBV-related ACLF. However, no conclusion on which nucleoside analogue is the most satisfactory drug for the treatment of HBV-related liver failure has not been reached yet. In this cohort study, the investigators will compare the efficacy, safety, and tolerability of tenofovir alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF) and entecavir (ETV) in HBV-related ACLF in China.

Condition or disease Intervention/treatment
Hepatitis B Virus Diseases Liver Failure Drug: Tenofovir Alafenamide Drug: Entecavir Drug: Tenofovir disoproxil fumarate

Detailed Description:

Potent antivirals like entecavir (ETV), Tenofovir Disoproxil Fumarate (TDF) and Tenofovir alafenamide (TAF) now are recommended as first-line therapy for patients with chronic HBV infection because of their significant suppression of viral replication and a high barrier to resistance. HBV-related acute-on-chronic liver failure (ACLF) is a clinical syndrome defined as acute hepatic insult with diagnosed or undiagnosed chronic liver disease. Only a limited number of medical treatments are available for ACLF. Although liver transplantation is a life-saving treatment for ACLF, the difficulty in finding a suitable donor and the high cost hinder its extensive clinical use.

The precise mechanism underlying the liver injury caused by HBV-related ACLF and the factors contributing to the progression of liver failure remain unknown. HBV DNA replication is one of the key factors causing the progression from liver damage to liver failure. Current clinical guidelines advocate oral antiviral treatment in HBV-related ACLF. However, the specific antiviral treatment for patients with liver failure remains unclear. In the past years, efficacy of nucleoside analogues, such as lamivudine, entecavir, telbivudine and tenofovir, for HBV-related liver failure has been reported. However, no conclusion on which nucleoside analogue is the most satisfactory drug for the treatment of HBV-related liver failure has not been reached yet.

In this cohort study, the investigators will compare the efficacy, safety, and tolerability of tenofovir alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF) and entecavir (ETV) in HBV-related ACLF in China.

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Study Type : Observational
Estimated Enrollment : 200 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: A Multicenter Controlled Open-label Trial of Evaluating Tenofovir Alafenamide, Tenofovir Disoproxil Fumarate and Entecavir in Acute-on-chronic Liver Failure of Chronic Hepatitis B Patients
Actual Study Start Date : January 25, 2019
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : July 2022


Group/Cohort Intervention/treatment
ETV
patients receive entecavir 0.5 mg/day orally.
Drug: Entecavir
Entecavir 0.5 mg/day orally

TDF
patients receive Tenofovir Disoproxil Fumarate 300 mg/day orally.
Drug: Tenofovir disoproxil fumarate
Tenofovir Disoproxil Fumarate 300 mg/day orally

TAF
patients receive Tenofovir alafenamide 25 mg/day orally.
Drug: Tenofovir Alafenamide
Tenofovir alafenamide 25 mg/day orally




Primary Outcome Measures :
  1. Overall survival of ACLF subjects [ Time Frame: study day 1 through week 48 ]
    Overall survival in subjects with acute-on-chronic liver failure will be summarized and compared with control subjects through study day 28 and week 48.


Secondary Outcome Measures :
  1. Changes in serum HBV DNA levels [ Time Frame: at week 4 and 48 of treatment ]
  2. Proportion of patients with hepatitis B e-Ag(HBe-Ag) loss or seroconversion [ Time Frame: at week 4 and 48 of treatment ]
  3. Proportion of patients with HBs-Ag loss or seroconversion [ Time Frame: at week 4 and 48 of treatment ]
  4. Proportion of patients with normal alanine aminotransferase(ALT) [ Time Frame: at week 4 and 48 of treatment ]
  5. Liver function evaluation through Model for End-Stage Liver Disease (MELD) scores [ Time Frame: at week 4 and 48 of treatment ]
    Model for End-Stage Liver Disease(MELD) Score is calculated according to the equation:3.78×ln[serum bilirubin (mg/dl)] + 11.2×ln(INR) + 9.57×ln[serum creatinine (mg/dL)] + 6.43. Liver function improvement defined as the decline of total MELD score, whereas liver function deterioration defined as the rise of total MELD score. The risk of death increased when total MELD score above 25.

  6. Proportion of patients with virologic breakthrough [ Time Frame: at week 4 and 48 of treatment ]
    Virologic breakthrough is defined as the increase in serum HBV DNA by >1 log10 (10-fold) above nadir after achieving virologic response as determined by at least 2 consecutive measurements of at least 2 weeks apart, during continued treatment

  7. Proportion of patients with complete virologic response [ Time Frame: at week 4 and 48 of treatment ]
    Virologic response is defined as the serum HBV DNA concentrations below 20 IU/mL



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
All the patients received antivirals will be followed for at least 48 weeks and follow-up assessments were performed at week 1, 2, 3, 4, 12, 24 and 48.All the patients were detected Serum HBV DNA,HBV markers, including HBsAg, HBsAb, HBeAg, HBeAb and HBcAb, routine biochemical tests mainly including ALT,AST,TB and ALB.
Criteria

Inclusion Criteria:All of below

  1. age 18-70 years, male or female.
  2. HBsAg positive at least 6 months or more, HBeAg positive or negative.
  3. Serum HBV DNA positive (Serum HBV DNA should be determined by the PCR assay at the local laboratory at screening for this study)
  4. Recent development of increasing jaundice (a total serum bilirubin concentration of above 85μmol/L) and coagulopathy (INR ≥1.5 or prothrombin activity<40%)
  5. Recent development of complications such as hepatic encephalopathy, or abrupt and obvious increase in ascites, or spontaneous bacterial peritonitis, or hepatorenal syndrome.
  6. Patient is willing and able to comply with the study drug regimen and all other study requirements.
  7. The patient is willing and able to provide written informed consent to participate in the study.

Exclusion Criteria: Any of below

  1. Patient has concomitant other chronic viral infection (HCV or HIV)
  2. Patient has evidence of renal insufficiency defined as serum creatinine > 1.5 mg/dL
  3. Patient has medical condition that requires concurrent use of systemic prednisolone or other immunosuppressive agent (including chemotherapeutic agent)
  4. Patient is pregnant or breastfeeding or willing to be pregnant
  5. Patient has one or more additional known primary or secondary causes of liver disease, other than hepatitis B (e.g., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's Disease, other congenital or metabolic conditions affecting the liver, congestive heart failure or other severe cardiopulmonary disease, etc.).
  6. A history of treated malignancy (other than hepatocellular carcinoma) is allowable if the patient's malignancy has been in complete remission, off chemotherapy and without additional surgical intervention, during the preceding three years.
  7. Active ethanol/drug abuse/psychiatric problems such as major depression, schizophrenia, bipolar illness, obsessive-compulsive disorder, severe anxiety, personality disorder that might interfere with participation in the study.
  8. Current alcohol or substance abuse judged by the investigator to potentially interfere with participant compliance.

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): NCT03640728


Contacts
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Contact: Juan Li, M.D. 18209272726 lijuan1996xx@163.com
Contact: Yingli He, M.D.,Ph.D 18991232863 heyingli2000@163.com

Locations
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China
Ankang Central Hospital Recruiting
Ankang, China
Hanzhong 3201 Hospital Not yet recruiting
Hanzhong, China
Hanzhong Infectious Hospital Not yet recruiting
Hanzhong, China
Weinan Central Hospital Not yet recruiting
Weinan, China
First Affiliated Hospital Xi'an Jiaotong University Recruiting
Xi'an, China
Shaanxi provincial people's hospital Not yet recruiting
Xi'an, China
Tangdu Hospital, The Fourth Military Medical University, Not yet recruiting
Xi'an, China
The Second Affiliated Hospital of Xi'an Jiaotong University Recruiting
Xi'an, China
Xi'an Central Hospital Active, not recruiting
Xi'an, China
Xijing Hospital, The Fourth Military Medical University Not yet recruiting
Xi'an, China
The Affiliated Hospital of Yan'an University Not yet recruiting
Yan'an, China
Sponsors and Collaborators
First Affiliated Hospital Xi'an Jiaotong University
Investigators
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Principal Investigator: Yingli He, M.D.,Ph.D First Affiliated Hospital Xi'an Jiaotong University
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Responsible Party: He Yingli, He Yingli, Research Associate, First Affiliated Hospital Xi'an Jiaotong University
ClinicalTrials.gov Identifier: NCT03640728    
Other Study ID Numbers: XJTU1AF2018LSL-002
First Posted: August 21, 2018    Key Record Dates
Last Update Posted: May 6, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by He Yingli, First Affiliated Hospital Xi'an Jiaotong University:
Hepatitis B, Acute-on-Chronic liver failure
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis B
Virus Diseases
Hepatitis
Liver Failure
Hepatic Insufficiency
End Stage Liver Disease
Acute-On-Chronic Liver Failure
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Liver Failure, Acute
Tenofovir
Entecavir
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